编辑丨王多鱼 排版丨水成文 干细胞 来源 的 类胚胎模型 为 探索 哺乳动物早期胚胎发育提供了 强有力的体外研究平台 。 目前， 通过 多能干细胞等早期干细胞的自组装或共组装， 研究者已能 在体外 建立类似 囊胚、原肠胚甚至器官发生期 的类胚胎结构。 然而， 现有 模型 多 聚焦于特定发育阶段 的模拟 。 如何 构建在体外 连续重现 小鼠胚胎 从 着床前至着床后 完整 发育 轨迹 的类胚胎模型，仍然是类胚胎研究亟待 突破 的 关键 问题 之一 。 然而，小鼠 T PS 细胞 存在 增殖缓慢 、 需持续传代才能进入稳定全能状态 等问题 。 因此， 如果能够建 立快速诱导具备强增殖能力 的类全能干 细胞，将为构建 覆盖 自 合子基因组激活 （ Zy gotic genome activation ） 至 着床后发育 全过程 的类胚胎模型带来新的可能。 2 025 年 10 月 1 5 日，北京大学 徐君 、 邓宏魁 、 李程 和 关景洋 团队在 N ature C ell B iology 期刊 发表了题为： A c ontinuous t otipotent- l ike c ell- b ased e mbr ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 T 细胞耗竭 （ T cell exhaustion ） 是一种适应性且独特的细胞命运，主要在慢性感染和癌症中因持续的抗原刺激而出现。其特征在于效应功能的逐渐丧失以及 多种抑制性受体的持续表达。 T 细胞耗竭的进展是由通过 T 细胞受体 （TCR） 的持续抗原刺激驱动的，并受到共刺激和抑制分子的信号以及细胞因子、代谢物和神经因子等微环境因素的调 控。这些外在细胞因素通过关键的内在细胞调控因子重塑 T 细胞的转录组、表观基因组和代谢，使其进入耗竭状态。 2025 年 10 月 1 日，西湖大学医学院 董晨 院士团队 （ 孙勤利 为第一作者） 在 Nature 旗下综述期刊 Nature Reviews Immunology 上发表了题为： Regulators of CD8⁺ T cell exhaustion 的综述论文。 T 细胞耗竭 （ T cell exhaustion ） 是一种独特的 T 细胞功能障碍状态，通常在慢性抗原刺激期间出现，例如在持续感染、癌症或自身免疫疾病中。 与效应 T 细胞相比， 耗竭 T 细胞 （Tex） 表现出效应功能受损、增殖减少以及抑制 ...

Core Viewpoint - The article discusses a groundbreaking research on AI-designed insulin receptor agonists that offer improved efficacy and safety for diabetes treatment compared to traditional insulin therapies [3][10]. Group 1: Research Background - Insulin has been a cornerstone in diabetes treatment since its discovery, but it has limitations such as complex production, strict storage conditions, and potential cancer risks [2]. - The insulin receptor acts as a "lock" that insulin "unlocks," initiating two main signaling pathways: one for metabolic regulation (AKT pathway) and another for cell growth (MAPK pathway) [2]. Group 2: Research Findings - Researchers from Washington University and Texas Southwestern Medical Center developed AI-designed insulin receptor agonists that outperform traditional insulin in lowering blood sugar and can precisely regulate signaling pathways, avoiding cancer cell proliferation [3][5]. - The new insulin receptor agonists exhibit remarkable properties, including enhanced thermal stability, remaining stable at 95°C, and precise signal regulation through adjustable linkers [7]. Group 3: Experimental Results - In mouse models, the AI-designed agonist RF-409 demonstrated superior blood sugar-lowering effects, requiring only half the dosage of insulin for the same effect and maintaining low blood sugar levels for up to 6 hours [7][8]. - These agonists can activate mutated insulin receptors in insulin-resistant patients, providing new treatment hope for rare genetic diabetes [8]. Group 4: Implications and Future Directions - The specificity of these agonists allows them to activate normal and mutated insulin receptors while avoiding activation of cancer cell receptors, significantly reducing potential cancer risks associated with traditional insulin therapy [8][10]. - The research lays the groundwork for developing safer and more effective next-generation diabetes treatments, with the founding of Lila Biologics aimed at utilizing AI protein design for breakthrough therapies [10][11].

Core Viewpoint - The research indicates that oral administration of clinical safe doses of Vitamin C can significantly delay ovarian aging in primates, revealing its protective mechanism through the activation of the NRF2 signaling pathway [2][4][5]. Group 1: Research Background - Ovarian aging plays a critical role in women's reproductive health, impacting treatment strategies and quality of life [3]. - Previous studies by Liu Guanghui's team have established that Vitamin C can delay cellular aging and has been linked to a significant decline in antioxidant capacity during ovarian aging in primates [3]. Group 2: Key Findings - A 3.3-year intervention study on middle-aged crab-eating macaques demonstrated that oral Vitamin C can reduce key aging biomarkers, including oxidative stress and follicle depletion [4]. - The study constructed a primate ovarian single-cell transcriptome aging clock, showing that Vitamin C can make oocyte biological age younger by an average of 1.35 years and somatic cell biological age younger by 5.66 years, particularly in granulosa, endothelial, and stromal cells [4]. - Vitamin C effectively reverses aging and inflammation-related phenotypes in endothelial cells, making their biological age nearly 7 years younger [4]. Group 3: Mechanism of Action - The effect of Vitamin C in delaying ovarian aging is partially mediated through the NRF2 pathway, which plays multiple protective roles in human ovarian cells, including delaying aging, inhibiting inflammation, maintaining chromatin stability, and enhancing mitochondrial function [5]. Group 4: Implications - This research validates the concept of using a single compound to delay ovarian aging in primate models and highlights the potential of Vitamin C in developing interventions for human ovarian aging [8].

Core Viewpoint - The research published by a team from China Pharmaceutical University reveals a novel brain-liver neurocircuit involving VMH Galnt2 neurons that counterregulate hypoglycemia by increasing hepatic glucose production, providing new insights into the mechanisms of hypoglycemia resistance and potential innovative treatment strategies for metabolic diseases related to glucose regulation [3][7]. Summary by Sections Research Findings - The study identifies a biphasic pattern of glucose dynamics in the blood and hypothalamus during prolonged fasting, highlighting an additional threshold-dependent counterregulatory mechanism [4]. - This mechanism is mediated by a neural pathway from the ventromedial hypothalamus (VMH) to the paraventricular nucleus (PVH), then to the lateral paragigantocellular nucleus (LPGi), and finally to the liver, which detects neuroglycopenic states and activates sympathetic signals to drive hepatic glucose production [4]. Key Highlights - The biphasic model explains the counterregulatory response to hypoglycemia [5]. - VMH glucose-inhibitory neurons play a critical functional role in sensing neuroglycopenia [5]. - The brain-liver neural circuit emphasizes the counterregulatory response to hypoglycemia [5]. - Galnt2 serves as both a genetic marker and a molecular brake for VMH glucose-inhibitory neurons, regulating the glucose sensing threshold and metabolic homeostasis [5]. Implications - The study underscores a brain-liver neural pathway originating from VMH Galnt2 neurons that can sense and counterregulate hypoglycemia, potentially guiding the development of innovative treatment strategies for metabolic diseases characterized by abnormal glucose regulation [7].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 植物进化出了一套具有强化管壁和创新壁结构的导管系统，以确保水分和养分的高效运输。 导管纹孔 （ Vessel pits ） ——精细的三维空腔结构——是决定植物水力系统和生长可塑性的关键因素。然而，其超微 结构及形成机制一直未知。 2025 年 10 月 14 日，中国科学院遗传与发育生物学研究所 张保才 、 周奕华 研究团队 （ 张兰军 、 高 易宏 为共同第一作者 ） 在国际顶尖学术期刊 Cell 上发表了题为： Shaping pit structure in vessel walls sustains xylem hydraulics and grain yield 的研究论文。 该研究利用新兴体电子显微镜技术， 首次揭示了水稻木质部导管纹孔的完整精细三维结构 ，通过克服多项 技术瓶颈，功能鉴定了塑造纹孔三维结构的关键分子模块，发现纹孔三维结构天然突变受 MYB61-PS1 分 子模块调控，并在维持木质部稳健性、促进氮素运输与水稻高产中发挥关键作用。 由此，研究团队发现了一条可提升木质部输水能力及作物产量的分子通路，为可持续农业发展提供了富有 前景的新策略。 论 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 冷冻电镜 （cryo-EM） 技术 带来了分辨率革命，让我们能够以原子级的高分辨率观察并描绘蛋白质结构。而基于 人工智能 （AI） 的 AlphaFold 等工具实现了 对蛋白质结构的快速且精准的预测。 2024 年 10 月， 颜宁 院士团队提出了一种名为 CryoSeek （酷寻） 的新策略， 将 冷冻电镜 （cryo-EM） 作为一种观察工具，结合 人工智能 （AI） 辅助的 自动建模和生物信息学分析，来发现自然界中完全未知的新型生物实体。 2025 年 10 月， 颜宁 院士团队连续发表两篇论文，解析了 CryoSeek 策略发现的全新糖纤维结构，并开发了 测定糖纤维绝对手性的新算法—— Ahaha 。 2025 年 10 月 1 日，深圳医学科学院/深圳湾实验室/清华大学 颜宁 院士、清华大学 李张强 、 王彤彤 等人在预印本平台 bioRxiv 发表了题为 ： CryoSeek identification of glycofibrils with diverse compositions and structural assemblies 的研究论文。 从 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 长期以来，我们都知道， 运动学习 涉及神经网络中突触强度的动态调整。突触在反复激活后会增强的活动 依赖性 突触强化 （ Synaptic Potentiation ） 是记忆和技能形成的基本过程。但同样重要的是，大脑必须 要有能力防止这些突触在强化后出现不适当的 突触去强化 （ Synaptic Depotentiation ） ，以确保新获得 的技能得以保留而非丧失。 在 运动学习 （ Motor Learning，指通过 反复练习和经验积累 ，个体逐渐掌握、优化和巩固运动技能的过 程） 期间，控制这种突触强化与突触去强化之间微妙平衡的分子和细胞机制，在很大程度上仍然是个谜。 2025 年 10 月 13 日，深圳湾实验室 甘文标 团队在 Nature 子刊 Nature Neuroscience 上发表了题为 ： Astrocytic Ca 2+ prevents synaptic depotentiation by limiting repetitive activity in dendrites during motor learning 的研究论文。 这项开创 ...

Core Viewpoint - Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons, leading to dopamine depletion and motor symptoms. Current treatments alleviate symptoms but do not halt neuronal loss [2][5]. Group 1: Research and Development - PD has long been considered a suitable candidate for cell replacement therapy due to its clear pathological features, specifically the loss of certain dopaminergic neuron populations [5]. - A recent study published in the journal Cell reported a Phase 1/2a clinical trial of human embryonic stem cell (hESC)-derived dopamine progenitors (A9-DPC) showing good safety and effective improvement in motor symptoms for PD patients [3][12]. - The development of hPSC, including hESC and induced pluripotent stem cells (iPSC), has provided scalable sources for generating dopamine progenitor cells, enabling large-scale production of high-purity dopamine progenitor cells [5][6]. Group 2: Clinical Trial Findings - The Phase 1/2a trial involved 12 patients with severe PD, where A9-DPC was transplanted into the bilateral shell nucleus under an immunosuppressive regimen. The low-dose group received 3.15 million cells, while the high-dose group received 6.3 million cells [8][9]. - Results indicated excellent safety with no dose-limiting toxicities or transplant-related adverse events. Motor function improved significantly, with the high-dose group showing greater improvement [8][9]. - PET imaging confirmed increased dopamine uptake in the bilateral posterior shell nucleus, particularly in the high-dose group, indicating cell survival post-transplant [9][12]. Group 3: Conclusion and Implications - The study concluded that hESC-derived dopamine progenitor cells (A9-DPC) transplantation into the bilateral shell nucleus demonstrates good safety and effectively improves motor symptoms in PD patients, exhibiting dose-dependent efficacy [12].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 T 细胞恶性肿瘤 是一组异质性疾病，复发率和死亡率都很高，其总体预后通常不佳 （尤其是与 B 细胞恶性肿瘤相比） 。尽管目前诸如化疗之类的策略对某些疾 病亚型有益，但对于复发或难治性疾病患者，其疗效仍然有限。因此，开发针对 T 细胞恶性肿瘤的创新疗法势在必行。 CD5 是恶性 T 细胞的特征性标志物，几乎在所有正常 T 细胞上均有表达。因此，在治疗 T 细胞恶性肿瘤时，不表达 CD5 的 自然杀伤 （NK） 细胞 ，可能比基 于 T 细胞的疗法具有更好的安全性。 2025 年 10 月 8 日，四川大学华西医院 仝爱平 教授、 牛挺 教授等在 Cell 子刊 Cell Reports Medicine 上发表了题为： A nanobody-based tri-specific NK cell engager targeting CD5 triggers antitumor immunity 的研究论文。 该研究开发了一种基于 纳米抗体 的 三特异性 NK 细胞接合器 （ tri-NKCE ） ，通过靶向 CD5， 对 CD5 + 恶性肿瘤细胞表现出更强的抗肿瘤效果， 与 ...