撰文丨王聪 编辑丨王多鱼 排版丨水成文 整合应激反应 （ Integrated Stress Response， ISR） 是一种保守的应激反应，可维持真核细胞的内环境稳定。调节整合刺激反应 （ISR） 对包括病毒感染、癌 症和神经退行性疾病在内的多种疾病具有治疗潜力，但目前鲜有已知化合物能够在无毒副作用的情况下实现这一调节。 2025 年 7 月 11 日，Broad 研究所 James Collins 教授 、 Integrated Biosciences 公司 的 Felix Wong 、 Maxwell Wilson 等人在国际顶尖学术期刊 Cell 上 发表了题为： Optogenetics-enabled discovery of integrated stress response modulators 的研究论文 【1】 。 该研究将 光遗传学 技术用于 药物发现 ，开发了一个用于发现能够选择性调节 整合刺激反应 （ISR） 的化合物的光遗传学平台，筛选出了能够选择性消除在各种 应激压力条件下具有高 ISR 的细胞的化合物，这些化合物在体外和小鼠体内均表现出 广谱抗病毒活性 。 Felix W ...

Core Viewpoint - Spinocerebellar ataxia type 3 (SCA3) is a common hereditary disorder with no effective treatment, leading to significant burdens on patients and healthcare systems [1][2]. Recent research indicates that transcranial alternating current stimulation (tACS) may provide a safe and effective intervention for improving symptoms in SCA3 patients [3][11]. Summary by Sections Disease Overview - SCA3 is caused by the expansion of CAG repeats in the ATXN3 gene, leading to progressive cerebellar ataxia, which manifests as unsteady gait, speech difficulties, swallowing problems, and poor motor accuracy [1]. - Most SCA3 patients lose mobility within 10-20 years of onset, with a survival period of 20-25 years from onset to death [2]. Recent Research Findings - A randomized controlled trial published in Cell Reports Medicine demonstrated that tACS is safe, effective, and well-tolerated, improving the severity of ataxia by modulating brain functional connectivity in SCA3 patients [3][11]. - The study involved 82 SCA3 patients, randomly assigned to receive either active tACS or sham stimulation for 2 weeks, with significant improvements observed in the active group [8]. Clinical Trial Details - The trial was a triple-blind, parallel-group, sham-controlled study assessing the effects of tACS on ataxia severity and quality of life, using functional MRI to evaluate changes in brain connectivity [7]. - Results showed that 80% of participants in the active tACS group met the primary outcome measure, compared to only 10% in the sham group, with significant reductions in SARA scores [8]. Implications for Future Treatment - The findings suggest that tACS could be a promising intervention for SCA3 and potentially other cerebellar disorders, highlighting the need for further research into its long-term effects [11].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 自然界中存在着多种生殖方式，除了 有性生殖 ，还有些动植物能够进行 孤雌生殖、 孤雄生殖 。但是对于高等的哺乳动物来说，只能进行 有性生殖 ，每一个 哺 乳动物生命都始于卵子与精子融合形成的受精卵，其中包含两套基因组，一套来自母亲，一套来自父亲。然而，有些基因只有来自父亲的等位基因表达，有些则 只有来自母亲的等位基因表达，也就是所谓的 基因组印记 ，这种基因组印记是通过表观遗传学的甲基化实现的，基因组印记的存在，阻碍了孤雌生殖或 孤雄生 殖 的实现。 近日，上海交通大学医学院附属仁济医院生殖医学中心 魏延昌 等人在《 美国国家科学院院刊 》 （PNAS） 上发表了题为： Fertile androgenetic mice generated by targeted epigenetic editing of imprinting control regions 的研究论文。 在这项新研究中，研究团队报告了由两个精子细胞的遗传物质培育出的成年哺乳动物后代。研究团队将这些小鼠称之为孤雄生殖小鼠，是通过基于 CRISPR 的表 观基因组工程对 7 个印记控制区域 （ICR） ...

Core Viewpoint - The article discusses the transformative potential of artificial intelligence (AI) in the biomedical field, emphasizing advancements in large language models (LLMs) and multimodal AI that can enhance diagnostics, patient interactions, and medical predictions [2][6][11]. Group 1: Technological Innovations - Recent advancements in AI, particularly in LLMs and multimodal AI, are set to revolutionize the medical field by improving diagnostics and patient interactions [6]. - Key architectural innovations such as Transformer architecture, generative adversarial networks, and diffusion models have contributed to the development of complex generative AI systems [2][4]. Group 2: Medical Practice Transformation - AI-enabled medical practices are shifting clinical care from sporadic interactions to continuous monitoring and regular follow-ups, allowing for proactive healthcare in familiar environments [8]. - New medical knowledge can be more easily integrated into care models, and AI technologies are facilitating the development of new drugs [8]. Group 3: Multiscale Medical Predictions - AI algorithms can predict future medical events based on various dynamic inputs, applicable at multiple levels from molecular to population [10]. - The future of medicine will involve tools capable of processing vast amounts of information, significantly improving diagnostic accuracy and patient outcomes [11]. Group 4: Challenges and Implementation - Despite the promising advancements, the widespread clinical adoption of AI tools faces significant challenges, including bias, privacy concerns, regulatory hurdles, and integration with existing healthcare systems [6][11]. - Most AI tools are still in development, with few demonstrating clear benefits across all users or situations, which remains a major barrier to broader usage by healthcare professionals [11]. Group 5: Roadmap for AI Implementation - The roadmap for implementing medical AI involves transitioning from basic scientific research to concept validation models, leading to larger models and early clinical applications that pave the way for final clinical deployment and optimization [14].

Core Viewpoint - The article discusses a groundbreaking study on tau protein disassembly in Alzheimer's disease, highlighting the potential of D-type peptides as a novel therapeutic strategy to combat neurodegenerative diseases [3][15]. Group 1: Alzheimer's Disease and Tau Protein - Alzheimer's disease (AD) is characterized by cognitive decline and is closely associated with the abnormal aggregation of tau protein and β-amyloid protein [2]. - Tau protein aggregation is more strongly correlated with the cognitive symptoms and severity of Alzheimer's disease compared to β-amyloid [2]. Group 2: Research Findings - A study published in Nature by Dr. Ke Hou from UCLA reveals that D-type peptides can disassemble tau fibrils without the need for enzymatic activity or external energy sources [3][15]. - The research introduces a new paradigm in amyloid protein studies, enhancing understanding of protein aggregation dynamics and inspiring innovative treatment strategies for Alzheimer's and other amyloid-related diseases [3][15]. Group 3: D-type Peptides Advantages - D-type peptides exhibit higher specificity and binding affinity compared to small molecules, with lower immunogenicity and resistance to proteolytic degradation [8]. - Previous studies indicated that D-type peptides could decompose tau protein fibers extracted from Alzheimer's patients and improve behavioral deficits in mouse models [8]. Group 4: Mechanism of Action - The study identified that D-type peptides assemble into amyloid-like fibers, which are essential for disassembling tau protein fibers [12]. - The tension released during the transition from left-handed to right-handed helical structures of these peptides is sufficient to disrupt local hydrogen bonds in tau fibers, leading to their disintegration [13][15]. Group 5: Implications for Treatment - The findings suggest that D-type peptides could revolutionize treatment methods for Alzheimer's disease and provide new tools for tackling other neurodegenerative diseases like Parkinson's and Huntington's disease [15]. - The stability, protease resistance, and good biocompatibility of D-type peptides allow them to cross the blood-brain barrier without eliciting harmful immune responses [15].

VI 型分泌系统 （T6SS） 在弧菌属中分布广泛，但其在产毒菌株和非产毒菌株共存中的作用，目前仍不清 楚。 2025 年 7 月 9 日，南方科技大学 傅暘 研究员团队 在 Cell 子刊 Cell Host & Microbe 上发表了题为： A Vibrio-specific T6SS effector reshapes microbial competition by disrupting Vibrio bioenergetics 的 研究论文，该论文被选为当期封面论文。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 非产毒型霍乱弧菌可通过体内/体外的 Ⅵ 型分泌系统 （T6SS） 在竞争中占据优势地位，战胜产毒 型对手； TseV 通过膜去极化和 ATP 耗竭使弧菌生物能量学崩溃； TseV 主要武装非产毒弧菌，维持遗传多样性； TseV 的杀弧菌特异性使精准抗菌药物得以保留微生物群。 总的来说，这些研究结果表明，TseV 代表了一种很有前景的精准抗菌策略模型，能将对共生微生物群的附 带损害降至最低。 论文链接 ： https://www.cell.com/cell-host-microbe/abstra ...

Core Viewpoint - The article discusses the development of a new type of laser called "metalaser," which enhances the understanding and performance of lasers in various optical and photonic applications [2][5]. Group 1: Introduction to Metalasers - The research team from Harbin Institute of Technology (Shenzhen) has proposed and realized the metalaser, utilizing the interaction between local and non-local responses of dielectric resonant metasurfaces [3][4]. - Traditional lasers require additional optical components to modify laser characteristics, leading to larger systems and limitations due to speckle noise [2]. Group 2: Features and Advantages of Metalasers - The non-local interactions between meta-atoms in planar structures limit laser modes, while local variations in dipole moments precisely shape the beam wavefront [4]. - Metalasers can emit with any desired profile, including focal points, focal lines, vector beams, vortex beams, and even holograms [4]. - The scattering waves from metalasers do not experience resonant amplification like traditional laser modes, resulting in significantly weaker intensity, which minimizes speckle noise issues found in conventional laser holography [4].

Core Insights - The article highlights significant advancements in various fields of research published in the journal Cell, with a notable contribution from Chinese scholars, indicating a strong presence in cutting-edge scientific research [1]. Group 1: Measles Virus Research - A study by Zhang Heqiao and Roger Kornberg's team elucidated the structure of the measles virus polymerase complex and its interaction with non-nucleoside inhibitors, laying the groundwork for rational antiviral drug design [3][4]. Group 2: AI in Protein Engineering - The research team led by Gao Caixia developed a novel AI protein engineering simulation method called AiCE, which integrates structural and evolutionary constraints, enabling efficient protein evolution simulation and functional design without the need for specialized AI model training [7]. Group 3: Vertebrate Genomics - The team from Zhejiang University introduced a high-throughput, sensitive single-nucleus ATAC sequencing technology (UUATAC-seq) to create chromatin accessibility maps, and developed the Nvwa model for predicting cis-regulatory elements, revealing the conserved syntax of vertebrate regulatory sequences [10][11]. Group 4: Primate Brain Research - A study identified cell type-specific enhancers in the macaque brain, establishing tools for understanding primate brain structure and diseases, which could enhance insights into cognitive functions [15]. Group 5: Peripheral Nerve Imaging - Researchers from the University of Science and Technology of China pioneered a high-speed, subcellular resolution imaging technique for whole-mouse peripheral nerves, providing a detailed peripheral nerve atlas and new tools for studying nerve regulation and disease mechanisms [19]. Group 6: Primate Prefrontal Cortex Connectivity - A study reconstructed the whole-brain connectivity network of the macaque prefrontal cortex at the single-neuron level, revealing refined axon targeting and arborization, which is crucial for understanding complex cognitive functions in primates [23]. Group 7: Optogenetics in Drug Discovery - The research led by Felix Wong developed an optogenetics platform for discovering selective modulators of the integrated stress response, identifying compounds that enhance cell death without toxicity, and demonstrating antiviral activity in a herpes simplex virus mouse model [27][28]. Group 8: Engineering Yeast Behavior - A study from Imperial College London established engineering principles for yeast, enabling programmable multicellular behaviors, transforming yeast from a "single-cell factory" to a "multicellular system chassis" [33][34].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 个性化新抗原疫苗已展现出巨大潜力，然而，其免疫原性仍有待提高。 2025 年 7 月 10 日，丹纳·法伯癌症研究所的研究人员在国际顶尖学术期刊 Cell 上发表了题为 ： A multi-adjuvant personal neoantigen vaccine generates potent immunity in melanoma 的研究论文。 该研究开发的 多佐剂个性化 新抗原疫苗 ，在 黑色素瘤 患者中激发了强效免疫。 由于抗原的可获得性以及有效的 T 细胞启动对于实现最大免疫原性至关重要，研究团队在 10 名 黑色素瘤 患者中测试了一种合成长肽疫苗 ，该疫苗采用两种佐 剂 Montanide、聚肌 胞 （poly-ICLC） 配制，并联合局部注射伊匹木单抗 （ Ipilimumab，抗 CTLA4单抗 ） 以及全身使用纳武单抗 （ Nivolumab，抗 PD-1 单抗 ） 。 在所有 9 名完成疫苗接种的黑色素瘤患者中，这些 个性化疫苗诱导了针对大多数免疫新 表位的新生 ex vivo T 细胞响应，并且在 9 名患者中有 6 名产生了 ex vivo C ...

Core Viewpoint - The study presents a novel microglia replacement therapy that effectively halts the progression of the lethal brain disease ALSP in both mice and humans, demonstrating clinical feasibility and long-term efficacy [3][9]. Group 1: Disease Background - Microglia are crucial immune cells in the central nervous system, and their dysfunction can lead to various CNS diseases. CSF1R mutations are linked to congenital microglial deficiency and ALSP, a severe condition with an average survival of only 3 years post-onset in China [2][5]. Group 2: Research Development - The research team developed a microglia replacement strategy, termed MISTER, which replaces pathogenic microglia with wild-type cells to potentially treat ALSP. This strategy was inspired by earlier findings and aimed to address the limitations of previous mouse models [6][7]. Group 3: Experimental Findings - The study utilized two newly generated mouse models that accurately replicate key features of human ALSP, including reduced microglial numbers and cognitive decline. The replacement of mutant microglia with wild-type cells significantly improved neurological function and halted disease progression [7][9]. Group 4: Clinical Application - In a clinical trial involving 8 ALSP patients, the microglia replacement therapy showed promising results, with increased brain glucose metabolism and stable cognitive function over a 24-month follow-up period. This marks the first systematic validation of microglia replacement in human patients [8][9]. Group 5: Implications for Future Research - The findings support the potential of microglia replacement strategies not only for ALSP but also for other CNS diseases associated with microglial dysfunction, indicating a broader therapeutic application [9].