Core Viewpoint - The article discusses the role of SARM1 in axonal degeneration and its activation mechanism, highlighting its significance in neurodegenerative diseases and potential therapeutic strategies [2][7]. Group 1: Mechanism of SARM1 Activation - SARM1 is a key executor of axonal degeneration, activated through its TIR domain's NADase activity, leading to NAD⁺ depletion [2]. - The activation process involves NMN initiating SARM1's base exchange activity, forming covalent adducts with ADP-ribose, which promotes the assembly of superhelical SARM1 filaments [5]. - These filaments eventually coalesce into stable phase-separated assemblies with full enzymatic activity upon reaching a solubility limit [5]. Group 2: Implications for Therapeutic Strategies - The findings reveal a molecular mechanism that confines SARM1 activation to damaged axons, providing new insights for developing neuroprotective strategies targeting SARM1 [7]. - Interestingly, several clinical-stage inhibitors targeting the SARM1 TIR domain paradoxically promote its activation by forming similar adducts [6].

以下文章来源于赛业生物订阅号 ，作者小赛 赛业生物订阅号 . 分享生命科学领域的前沿资讯、解读行业动态、讲解实用的学科知识、实验方法和技巧。 近日， Nature 期刊 发表了一项关于阿尔茨海默病的研究论文，哈佛医学院的研究团队通过阿尔茨海默病小 鼠模型和人类脑组织分析等， 首次揭示了锂在大脑正常功能中扮演关键角色，并可能抵抗脑衰老与阿尔茨海 默病 [1] 。这一突破性研究再次凸显了 可靠的疾病模型 于神经疾病研究中的重要价值。 包括阿尔茨海默病在内的神经退行性疾病机制复杂，想要深入理解疾病发生过程仍是一场漫长攻坚战。如何 使不同层次的模型——从细胞模型到动物实验——有效衔接、相互验证，从而更可靠地揭示疾病机制？ 在这一过程中研究人员仍面临着严峻挑战： 模型代表性有限： 传统细胞系难以模拟神经元特异性通路和慢性退行过程； 动物模型表型不稳定： 遗传背景、环境因素导致表型异质性，增加体内验证变数； 体外-体内相关性不足： 病理指标不匹配，阻碍研究成果向临床转化； 模型构建与验证周期长： 基因编辑、表型鉴定等技术流程复杂，延缓研发进程。 新一期线上课程 「神经退行性疾病的机制研究与模型应用——从体外筛选到体内验证 ...

Core Viewpoint - The article discusses the significance of synonymous mutations, traditionally considered "silent," in influencing phenotypic traits through epitranscriptomic regulation, particularly in cucumber domestication [4][11][13]. Group 1: Research Findings - A study published in the journal Cell demonstrates that synonymous mutations can regulate important traits in cucumber by altering m6A modifications and mRNA structural conformations [4][11]. - The specific synonymous mutation identified is 1287C>T in the ACS2 gene, which affects m6A modification and RNA structure, leading to changes in cucumber fruit length [9][11]. - The research provides a complete molecular evidence chain showing how synonymous mutations can influence complex traits, challenging the traditional view of these mutations as harmless [11][13]. Group 2: Mechanisms and Implications - The study reveals a dual mechanism by which synonymous mutations affect gene expression and protein synthesis efficiency: by disrupting m6A modifications and altering RNA structure [13]. - This research enhances the understanding of the molecular basis of crop domestication and suggests new strategies for crop improvement through precise editing, such as designing synonymous mutations [13][14]. - The findings have broader implications for understanding the relationship between synonymous mutations and diseases or phenotypes in other organisms, including humans [14].

Core Viewpoint - Artificial Intelligence (AI) has significantly transformed the field of precise organic synthesis, showcasing immense potential in predicting reaction performance and synthesis planning through data-driven methods, including machine learning and deep learning [2][3]. Group 1: Research Overview - A recent study published in Nature Machine Intelligence introduces a unified pre-trained deep learning framework called RXNGraphormer, which integrates Graph Neural Networks (GNN) and Transformer models to address the methodological discrepancies between reaction performance prediction and synthesis planning [3][5]. - The RXNGraphormer framework is designed to collaboratively handle both reaction performance prediction and synthesis planning tasks through a unified pre-training approach [5][7]. Group 2: Performance and Training - The RXNGraphormer model was trained on 13 million chemical reactions and achieved state-of-the-art (SOTA) performance across eight benchmark datasets in reaction activity/selectivity prediction and forward/reverse synthesis planning, as well as on three external real-world datasets [5][7]. - Notably, the chemical feature embeddings generated by the model can autonomously cluster by reaction type in an unsupervised manner [5].

Core Viewpoint - The article discusses a new artificial intelligence drug design technology called ED2Mol, which enhances the discovery of bioactive molecules by utilizing electron density information, overcoming limitations of traditional drug design methods [3][4][7]. Group 1: Research Development - The research team from Shanghai Jiao Tong University developed ED2Mol, which creates a unified intelligent framework for generating and optimizing lead molecules, achieving optimal reliability in both inter- and intra-molecular contexts [4][9]. - ED2Mol has shown a success rate exceeding 97% in generating reliable molecules, significantly outperforming existing methods in various benchmarks [7]. Group 2: Application and Validation - The ED2Mol framework has been applied to key real-world targets, successfully identifying bioactive compounds validated in wet laboratories, including FGFR3 inhibitors and CDC42 modulators [9]. - The generated binding modes of these compounds closely match predictions from molecular docking and have been further validated through X-ray co-crystal structures, highlighting the practical utility of ED2Mol in drug design [9].

Core Viewpoint - Chronic kidney disease (CKD) poses a significant threat to human life and health, with 130 million patients in China and a prevalence rate of 10.8%, the highest globally [3][4] Group 1: Research Findings - The study published in Cell Stem Cell introduces a CAR-T cell therapy targeting extracellular matrix (ECM) producing cells, successfully alleviating fibrosis in CKD and providing a new treatment paradigm for other fibrotic diseases [4][10] - Key ECM-producing cells identified in the kidneys include fibroblasts, pericytes, and myofibroblasts, which play a major role in kidney fibrosis [6][8] - PDGFRβ has been identified as a potential surface antigen for anti-fibrotic CAR-T cell therapy in CKD, with the engineered CAR-T cells showing significant improvement in kidney function and reduction of fibrosis in hypertensive mouse models [6][7] Group 2: Therapeutic Implications - The study demonstrates that PDGFRβ-targeted CAR-T cells can improve pathological conditions related to fibrosis in various CKD models, indicating a promising therapeutic strategy [10] - The research also explores in vivo CAR-T cell therapy using CD5 antibody-modified lipid nanoparticles to deliver PDGFRβ mRNA, effectively generating PDGFRβ-targeted CAR-T cells in vivo, showing good therapeutic effects in mouse models of multi-organ fibrosis [6][7]

Core Viewpoint - The study highlights the role of lactic acid in creating an immunosuppressive tumor microenvironment by activating the MondoA-TXNIP pathway, which inhibits CD8⁺ T cell responses and enhances T reg cell function, thereby promoting tumor growth and immune evasion [2][3][6]. Group 1 - Lactic acid accumulation in the tumor microenvironment damages CD8⁺ T cell cytotoxicity and promotes the immunosuppressive function of T reg cells, establishing a dual immune suppression barrier [2]. - The research team discovered that targeting the MondoA-TXNIP signaling axis can restore anti-tumor immunity in lactic acid-induced immunosuppressive environments and enhance the efficacy of anti-PD-1 therapy [3][7]. Group 2 - The study reveals that the transcription factor MondoA induces TXNIP, which is a common feature in the response of T reg and CD8⁺ T cells to lactic acid [6]. - MondoA deficiency in T reg cells reduces their immunosuppressive capacity, while its absence in lactic acid-induced environments enhances CD8⁺ T cell cytotoxicity by restoring glucose uptake and glycolysis [6]. Group 3 - Targeting the MondoA-TXNIP signaling axis can enhance anti-tumor immunity across various cancer types and synergize with anti-PD-1 therapies, particularly promoting effective T cell responses in colorectal cancer [7][10]. - The combination of MondoA inhibitor SBI-477 with anti-PD-1 monoclonal antibodies produces a synergistic anti-tumor effect, and SBI-477 alone is effective against microsatellite stable (MSS) tumors, which typically show poor T cell infiltration and resistance to immune checkpoint inhibitors [7][10].

Core Viewpoint - The interaction between the brain and tumors is a critical yet underexplored aspect of cancer biology, with evidence suggesting that psychological stress significantly influences tumor development and treatment response [2][4]. Group 1 - A large meta-analysis involving 2,611,907 participants found a strong correlation between depression and anxiety with increased cancer incidence, cancer-specific mortality, and all-cause mortality [2]. - The brain regulates tumor occurrence and development through various neuroendocrine and neural pathways, including the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system, although the exact mechanisms remain largely unclear [2][4]. Group 2 - A recent study published in Nature Cancer revealed that colorectal cancer cells hijack a brain-gut polysynaptic circuit from the lateral septum to enteric neurons to sustain tumor growth [3][4]. - The study identified that GABAergic neurons in the lateral septum connect with cholinergic neurons in the gut, which extend to the tumor microenvironment (TME), and these neurons are exploited by colorectal cancer cells to promote tumor growth [7]. - Chronic stress in a mouse model enhances the activity of this circuit, exacerbating tumor progression, and clinical observations indicate that increased neuronal activity in the lateral septum correlates with larger primary tumors in colorectal cancer patients [7][9].

Core Viewpoint - The research reveals the molecular mechanism of the plant anti-inflammatory factor AntiSYS in regulating the immune system of tomatoes, providing a theoretical basis for designing disease-resistant crops [3][5][6]. Group 1: Research Findings - AntiSYS is identified as a natural inhibitor of the tomato cytokine systemin, preventing excessive inflammation and growth abnormalities in plants [3][5][6]. - The study confirms that AntiSYS acts as a competitive receptor antagonist for the systemin receptor SYR1, highlighting its role in maintaining immune homeostasis in tomatoes [5][6]. - The absence of AntiSYS leads to significant growth and reproductive adaptability issues in tomato mutants, indicating its critical function in counteracting pro-inflammatory systemins [5][6]. Group 2: Research Context - The research was conducted by Dr. Wang Lei from the Yazhou Bay Science and Technology City and a team from the University of Tübingen, published in the journal Cell [3][5]. - The study contributes to understanding how plants can utilize anti-inflammatory factors to maintain immune stability, a previously unresolved question in plant immunology [3][5]. Group 3: Institutional Background - Yazhou Bay National Laboratory, established in September 2022, focuses on major scientific and technological issues related to national food security and seed industry innovation [8].

Core Insights - The article highlights nine research papers published in the prestigious journal Cell, with six authored by Chinese scholars, covering various advancements in molecular biology and plant science [3]. Group 1: RNA Editing and Gene Regulation - A study from Yale University transformed IscB and Cas9 into RNA-guided RNA editors, demonstrating potential applications in variable splicing interference and RNA base editing, with performance surpassing Cas13 and enhanced safety [5][7]. - The research on modified adenosines from Tohoku University revealed a detoxification mechanism involving adenosine kinase and ADAL, linking modified RNA metabolism to human diseases [14][17]. Group 2: Plant Science and Immunity - A unified cell atlas of vascular plants was created by researchers from the Chinese Academy of Sciences, identifying foundational genes and facilitating gene discovery, thus providing a new paradigm for plant developmental biology [9][12]. - A study on systemin antagonists in tomatoes uncovered a molecular mechanism regulating the plant immune system, which could inform the design of disease-resistant crops [19][22]. Group 3: CAR-T Cell Therapy - Researchers from Peking University developed a novel allogeneic CAR-T cell therapy by targeting the SPPL3 gene, which enhances the therapy's safety and efficacy, potentially revolutionizing CAR-T treatments [24][27]. Group 4: Neuroscience and Synaptic Plasticity - A study from Southern University of Science and Technology explored the material properties of postsynaptic density condensates, revealing how Shank3 oligomerization affects synaptic plasticity and could relate to autism spectrum disorders [29][32].