编辑丨王多鱼 排版丨水成文 蛋白质工程 领域在生物技术、医学和基础研究方面具有巨大潜力，但其发展往往受限于序列-功能关系理 解不足、AI 设计复杂性质的困难以及劳动密集型的定向进化过程。定向进化技术模仿自然选择，通过人为 引入基因突变并根据目标功能进行筛选，可以建立序列-功能的直接映射关系，是目前蛋白质工程领域最核 心的设计改造策略。但是定向进化技术本身需拆解成多步包括突变文库建立和筛选的繁琐流程，并需要经 过多轮迭代，极大的限制了技术的应用发展和提供高质量序列-功能数据用于训练 AI 算法。 因此，将定向进化技术进行多模块整合，实现一体化、标准化的工业标准蛋白质智能进化，并集成机器 人、软件、机械控制系统降低人为干预，提高通量水平，获取标准化蛋白质序列-功能数据，将成为未来的 发展趋势。 2025 年 11 月 19 日，清华大学药学院 张数一 团队联合 镁伽科技 和 智源深澜 的研究人员，在 Nature Chemical Engineering 期刊发表了题为： An industrial automated laboratory for programmable protein evolution 的 ...

编辑丨王多鱼 排版丨水成文 慢性脑生理信号监测器件有助于及时诊断和治疗发作性或复发性神经系统疾病。与传统无源金属电极相比，有源薄膜晶体管可提供微弱脑电信号的提取放大降噪 优势、提高采集信噪比。单晶硅纳米薄膜是一种超薄二维材料，由于其具备完美晶格对称性与高电子迁移率 （ 10 cm /V·s） ，具有广泛应用前景。基于 硅基- 碳基界面 的高密度集成晶体管阵列有望带来新一轮变革性突破，可实现高密度、高保真度、高信噪比的脑信号长效记录。 尽管有源器件在脑电监测方面取得了重大进展，诊断/治疗神经系统疾病通常需要多模态参数的综合监测，特别是像癫痫、肿瘤这些慢性神经疾病经常涉及脑皮层 温度异常等现象，甚至需要光遗传学等手段进行干预。然而，目前对植入式神经电、热和光模态的综合监测仍然较少报道，大多局限于单模态的脑信号传感，无 法满足当前神经动力学研究日益增长的需求。 近日，复旦大学 宋恩名 、 张荣君 课题组联合 提出了一种 硅基 -碳基组织界面 的 多模态脑机 接口系统 ，该系统支持 实时连续监测 脑 电、热和光动力信号 。 系统的 材料和结构设计基于 单晶硅 有源器 件 和用于 微弱脑信号的 电容耦合机制 （信噪比 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 肿瘤组织和肿瘤旁组织中的 代谢失调 都可能导致免疫抑制，这可能是癌症发展的潜在原因。然而，代谢干预作为一种潜在的癌症治疗策略，却始终未获成功。 早在 2022 年， 林圣彩 团队筛选出了一种醛缩酶 （Aldolase） 小分子抑制剂—— Aldometanib （辟谷精） ，它通过特异性靶向 溶酶体相关醛缩酶，模拟 葡萄 糖饥饿，从而激活 AMPK 通路。 小鼠模型研究显示，Aldometanib 不仅能够促进代谢健康、减轻肥胖和脂肪肝，还能延长寿命和健康寿命，延缓衰老。 2025 年 11 月 25 日，厦门大学 林圣彩 院士、 福建省肿瘤医院 刘景丰 教授 、 厦门大学 张宸崧 教授等，在 Cell Research 期刊发表了题为 ： Glucose starvation mimetic aldometanib removes immune barriers permitting mice with hepatocellular carcinoma to live to normal ages 的研究论文。 该研究表明，模拟葡萄糖饥饿的 AMPK 激活剂—— Al ...

Core Insights - The article discusses a recent study revealing the neuroimmune mechanisms behind social withdrawal during illness, suggesting that this behavior is an active choice driven by specific neurons in the brain rather than a passive response to physical discomfort [2][20]. Group 1: Research Background - Traditional views suggest that social withdrawal during illness is a passive reaction due to discomfort, but evolutionary biologists propose it may serve adaptive purposes, such as preventing disease spread and conserving energy [6]. - The research team from MIT and Harvard Medical School conducted experiments to explore the neural mechanisms underlying this behavior, focusing on cytokines as messengers between the immune and nervous systems [6]. Group 2: Key Molecule - IL-1β - In a large-scale behavioral screening, the study found that among 21 cytokines tested, only IL-1β uniquely induced social withdrawal in mice [8]. - The experimental design allowed mice to explore a runway, showing that those treated with IL-1β exhibited significant social withdrawal compared to normal mice [8]. Group 3: Identifying the "Loneliness Switch" - The study identified that IL-1β's main receptor, IL-1R1, is highly expressed in the dorsal raphe nucleus (DRN), a key source of serotonin neurons that regulate social behavior [12]. - Over 90% of IL-1R1-expressing neurons in the DRN are serotonin neurons, challenging the traditional view that serotonin primarily promotes social behavior [12]. Group 4: Causal Relationship Verification - The research confirmed that activating IL-1R1 neurons led to social withdrawal even without immune challenges, while inhibiting these neurons prevented social withdrawal induced by IL-1β [14][15]. - Gene knockout experiments showed that specifically knocking out IL-1R1 in DRN neurons completely blocked IL-1β-induced social withdrawal without affecting motor suppression [16]. Group 5: Real-World Implications - The study's findings were validated in a natural social environment, where IL-1β-treated mice actively isolated themselves from companions, demonstrating that social withdrawal is a conscious choice during illness [18]. - Both peripheral and central IL-1β contribute to this process, creating a self-reinforcing cycle that prolongs social withdrawal, with microglia playing a crucial role [18]. Group 6: Broader Implications - This research provides insights into the neuroimmune interactions that may help understand social withdrawal in certain mental disorders, such as depression, which often accompanies inflammatory states [20]. - The findings highlight the complexity of the dialogue between the brain and immune system, suggesting that the desire for solitude during illness is a biologically sophisticated self-protection strategy shaped by natural selection [20].

Core Viewpoint - The article discusses a novel non-absorptive carrier-drug conjugate (CaDC) strategy targeting TGR5, which shows promise in improving glycemic control while minimizing liver toxicity associated with traditional TGR5 agonists [2][3][4]. Group 1: Research Findings - TGR5 is an important GPCR expressed in the gastrointestinal tract that, when activated, promotes GLP-1 secretion and plays a role in glucose utilization [2]. - The newly developed TGR5-targeted CaDC demonstrates superior glycemic control compared to the GLP-1 receptor agonist liraglutide, addressing the challenge of liver toxicity in TGR5 agonist development [3][7]. - The CaDC is designed to remain localized in the intestinal lumen, ensuring sustained activation of TGR5 without entering systemic circulation, thus enhancing safety [4][6]. Group 2: Mechanism and Efficacy - The TGR5-CaDC utilizes a biomimetic receptor agonist with a mesoporous silica particle framework, modified with deoxycholic acid as the TGR5 agonist, allowing for prolonged retention in the gut [4][6]. - In studies with diabetic mice and miniature pigs, TGR5-CaDC exhibited sustained blood sugar-lowering effects and lower toxicity compared to deoxycholic acid or liraglutide alone [7]. Group 3: Broader Implications - The design concept of CaDC, which targets the extracellular binding domain and mimics natural ligand-receptor interactions, has potential applications in various gastrointestinal diseases mediated by GPCRs [9].

Core Insights - The article discusses a significant study on bipolar disorder, highlighting its genetic underpinnings and the importance of cross-ethnic research in understanding this complex mental health condition [2][7]. Group 1: Research Findings - The study published in Nature Neuroscience integrates the largest genetic resource for bipolar disorder in East Asian populations, including 5,164 patients and 13,460 controls from Han Chinese [3]. - A high correlation (0.86) in genetic effects of bipolar disorder was found between East Asian and European populations, indicating a conserved core genetic mechanism across different ethnicities [6]. - The research identified 93 significant genetic risk loci, with 23 being novel discoveries, enhancing the understanding of the genetic architecture of bipolar disorder [6]. Group 2: Developmental and Cellular Insights - The genetic risk for bipolar disorder shows developmental timing and cell-type specificity, with fetal risks primarily associated with GABAergic interneurons in the cerebral cortex, while postnatal risks are more concentrated in excitatory neurons [6]. - Key subcortical brain regions, such as the amygdala and hippocampus, also showed significant enrichment of genetic signals, suggesting the critical role of various interneurons at different developmental stages in the disease [6]. Group 3: Implications for Drug Development - A multidimensional gene prioritization framework identified 39 high-confidence risk genes, with 15 showing abnormal expression in patient brain tissues [6]. - Drug target analysis revealed that proteins encoded by 22 of these genes are targets for existing psychiatric medications and have potential for new drug development, providing crucial insights for drug repositioning and novel therapies [6][7].

2025 年 11 月 24 日，西奈山伊坎医学院、 巴黎西岱大学的研究人员在 Cell 子刊 Cell Stem Cell 上发表 了题为： Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells 的研究论文。 该研究表明 ， 溶酶体功能障碍 是 造血干细胞衰老 的关键驱动因素，使用 v-ATP 酶抑制剂 抑制过度活跃 的溶酶体，能够逆转溶酶体功能障碍，并使衰老的造血干细胞恢复年轻状态。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 衰老 （Aging） 会损害 造血干细胞 （HSC） ，导致克隆性造血、髓系恶性肿瘤以及免疫功能下降。 溶酶 体 （ Lysosome ） 在造血干细胞衰老中的作用 （除了其对细胞自噬的被动调节之外） ，目前 尚不明 确。 论文链接 ： 在这项最新研究中，研究团队发现，衰老的造血干细胞中的 溶酶体 呈过度酸性、含量减少、受损且异常激 活。 https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)0040 ...

Core Viewpoint - The article discusses the relationship between aging and the immune system, emphasizing how immune responses change with age and the potential for manipulating immune function to extend healthy lifespan [2][24]. Group 1: Aging and Immune Response - Aging leads to significant changes in immune cell function, including a bias towards myeloid output from bone marrow, accumulation of senescent T cells, and increased levels of systemic inflammatory cytokines [6][24]. - The immune system is increasingly recognized as a key regulator of systemic aging, potentially driving the aging process rather than merely responding to it [24]. Group 2: Mitochondrial Function and Immune Aging - Mitochondrial dysfunction is central to immune aging, as age-related decline in mitochondrial function weakens immune responses and promotes chronic inflammation [7][8]. - Mitochondria also play a role in systemic signaling, influencing immune responses across different tissues, which is often overlooked in current models of immune aging [7][8]. Group 3: Spaceflight as a Model for Aging - Research using spaceflight environments reveals that many immune changes observed in aging, such as increased inflammatory mediators and impaired adaptive immune responses, can also occur in microgravity [9][12]. - This suggests that spaceflight can serve as a valuable model for studying the mechanisms of immune aging [9][12]. Group 4: Vaccine Response in the Elderly - Elderly individuals typically exhibit lower antibody titers and fewer memory B cells post-vaccination, leading to impaired protective immune responses [14]. - Recent findings indicate that the germinal center response in older adults can be enhanced, paving the way for improved vaccine strategies tailored to aging populations [14]. Group 5: T Cell Changes with Age - Aging is associated with various changes in T cells, including reduced diversity in T cell receptor repertoires and a shift towards inflammatory phenotypes [15][16]. - Understanding whether these changes are adaptive or degenerative is crucial for developing therapeutic strategies targeting age-related immune dysfunction [15][16]. Group 6: Personalized Immunotherapy - The potential of immune modulation in treating diseases is significant, with a focus on how aging affects the efficacy of immunotherapies like CAR-T cell therapy [19]. - Tailoring immunotherapy strategies based on age-related changes in immune cell function could enhance treatment outcomes across different age groups [19]. Group 7: Future Directions in Aging Research - The field must transition from defining aging processes to developing interventions, including identifying biomarkers and strategies to selectively target pathological aging cells [21]. - Integrating artificial intelligence with systems immunology could provide new insights into the regulatory nodes of immune aging, potentially allowing for interventions that recalibrate immune responses to slow aging [24][21].

Core Insights - The article discusses a recent study published by South China Normal University, highlighting the relationship between environmental exposure and the abundance and transferability of antibiotic resistance genes (ARGs) in the respiratory tract [2][4]. Group 1: Study Findings - Exposure to environmental pollutants is linked to an increase in respiratory antibiotic resistance genes (ARGs) [5]. - The abundance and mobility of antibiotic resistance genes are negatively correlated with lung function [5]. - Enhanced mobility of antibiotic resistance genes is observed in early chronic obstructive pulmonary disease (COPD) [5]. - Environmental pollutant exposure is associated with increased antibiotic-resistant phenotypes in mouse lungs [5]. Group 2: Implications - The study elucidates a pathway through which environmental pollutants contribute to the increase of the respiratory resistance gene pool, indicating the need for action to mitigate the burden of antibiotic resistance by addressing environmental pollution [6].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 烟酰胺腺嘌呤二核苷酸 （NAD + ） 是所有活细胞中还原-氧化反应的基本辅助因子。 在包括代谢、衰老、细胞死亡、DNA 修复和基因表达在内的各种生物学过 程中起着至关重要的作用。随着年龄的增长，NAD + 的稳态平衡被破坏，导致其含量显著下降，这与年龄相关的缺陷有关。 在啮齿类动物和人类中补充 NAD + ，都是 系统性的，而 NAD + 或其代谢物在每种细胞类型内参与数百种反应，所以在大多数情况下很难确定治疗效果的作用机 制。此外，即使同一个细胞，其不同区室的 NAD + 水平及作用也有所不同，这让情况变得更加复杂。 最近有研究显示， 细胞的线粒体中的 NAD + 库是通过转运蛋白 SLC25A51 从细胞质中转运而来的。这为在特定细胞类型内操控和研究线粒体 NAD + 池提供了机 会。 在人体临床试验中，补充外源 NAD + 前体的效果喜忧参半，常常无法重现在小鼠实验中的抗衰老效果。但对于线粒体肌病、共济失调毛细血管扩张症以及外周动 脉疾病在内的几种病症中， 补充外源 NAD + 显示前体显示出了积极的效果。然而， NAD + 在每个细胞以及亚细胞区室中涉及的广泛 ...