万众博新

1.

Longitudinal dynamics of gene expression and metabolomics in an aging population cohort

El-Sayed Moustafa JS, Ramisch A, Raza YN, ... , Richardson S, Spector TD, Small KS.; science; (393, 6815)

『Abstract』Multiomic profiling provides a comprehensive physiological overview at the molecular level, but understanding of its spatiotemporal dynamics remains limited in human populations. We profiled longitudinal whole-blood gene expression and metabolite levels in 335 females over 8 years. Levels of 5061 genes and 181 metabolites changed over time, with individual trajectories often diverging from population-level trends. Longitudinally variable genes showed cell type specificity and enrichment for aging-relevant pathways, including cardiometabolic and neurodegenerative disorders. Longitudinal trajectories were further shaped by genetics, circadian rhythm, seasonality, and environmental pollutant exposures. Integrative analyses revealed extensive static and time-variable cross-omic connectivity. Longitudinal profiling offers insight into the temporal evolution of age-related conditions at the molecular level, and understanding individual variation within these longitudinal patterns will be essential for future precision medicine approaches.

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2. 生命早期艰难梭菌定植重塑发育中的肠道

Early-life colonization with Clostridioides difficile remodels the developing gut

Semon A, Manzer HS, Keenan O, ... , Conrad MA, Hamilton KE, Zackular JP.; science; (393, 6815)

『Abstract』Clostridioides difficile causes severe disease in adults but commonly colonizes infants asymptomatically. The consequences of early-life colonization on host development remain unknown. In a neonatal mouse model, C. difficile colonization drove proinflammatory and tissue repair responses in the intestinal epithelium, enriching injury-associated intestinal stem cell populations and skewing differentiation toward secretory lineages. Despite transient colonization, exposure to C. difficile early in life led to persistent changes into adulthood. Epithelial responses were toxin dependent, as colonization with nontoxigenic strains or maternal vaccination with a C. difficile-targeted messenger RNA-lipid nanoparticle vaccine protected neonates. Human infant intestinal epithelial cells were sensitive to C. difficile toxins, and biopsies from colonized infants exhibited altered intestinal stem cell behavior. This study redefines C. difficile as an underappreciated early-life pathogen with lasting effects on host development.

『摘要』 艰难梭菌在成人中可引发严重疾病，但常无症状地定植于婴儿体内，而早期定植对宿主发育的影响尚不明确。在小鼠模型中，艰难梭菌定植驱动肠道上皮的促炎和组织修复反应，富集损伤相关肠干细胞群体并促使分化向分泌细胞谱系倾斜；尽管定植为暂时性，但生命早期暴露会导致成年后持续改变；上皮反应依赖毒素，非产毒株定植或母体接种靶向艰难梭菌的mRNA-脂质纳米颗粒疫苗可保护新生小鼠；人类婴儿肠道上皮细胞对艰难梭菌毒素敏感，且定植婴儿活检显示肠干细胞行为异常。该研究重新定义了艰难梭菌为一种被低估的、对宿主发育具有长期影响的早期病原体。

『总结』 艰难梭菌早期定植通过毒素诱导肠道上皮促炎和修复反应，导致干细胞分化偏移及成年期持续影响，非产毒株或母体免疫可阻断其危害。

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3. 自热甲烷裂解：用于氢气和石墨生产的可扩展热集成

Autothermal methane pyrolysis: Scalable heat integration for hydrogen and graphite production

Moise H, Moll S, Pathak S, ... , McFarland E, Majumdar A, Cargnello M.; science; (393, 6815)

『Abstract』Methane pyrolysis (MP) offers a compelling opportunity to meet low-carbon hydrogen demand using existing energy infrastructure. A key limitation in scaling MP is the efficient delivery of high-temperature heat into the reactor. We show that hydrogen-fueled autothermal operation overcomes this limitation, enabling an increase of several orders of magnitude in the reactor throughput for commercially relevant bed diameters. It also yields a carbon coproduct of 96.0% degrees of graphitization, meeting graphite precursor specifications and enabling domestic graphite production from natural gas using low-cost iron oxide catalysts. We further demonstrate a strategy to suppress the direct emissions inherent to autothermal operation, reducing them to near zero. A process-level life cycle assessment estimates that carbon intensities for autothermal methane pyrolysis can be as low as 1.9 to 4.5 kilograms (kg) of CO_2,eq per kg H₂.

『摘要』 甲烷热解（MP）为利用现有能源基础设施满足低碳氢需求提供了有力途径，但将高温热有效输入反应器是规模化应用的关键限制因素；本研究表明氢燃料自热操作可突破这一瓶颈，使商用相关床层直径下的反应器通量提升数个数量级，同时生成的石墨化程度达96.0%的碳副产物符合石墨前驱体标准，并可通过低成本氧化铁催化剂实现天然气制石墨的国产化生产；此外研究提出抑制自热操作固有直接排放的策略使其接近零排放，生命周期评估显示自热甲烷热解的碳强度可低至每千克氢气1.9-4.5千克二氧化碳当量。

『总结』 氢燃料自热操作突破了甲烷热解规模化应用的热量传递瓶颈，显著提升反应效率并产出高附加值碳产品，同时通过排放控制策略和生命周期评估验证其低碳可行性。

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4. 肿瘤来源的抗氧化剂通过剥夺T细胞活性氧来抑制免疫

Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species

Wesolowski AJ, Pillay AM, Vardaka P, ... , Ho PC, Eil RL, Roychoudhuri R.; science; (393, 6815)

『Abstract』Reactive oxygen species (ROS) promote genomic instability and fuel oncogenic signaling in cancer, but antioxidant therapies have so far failed to improve, or worsen, cancer outcomes. Emerging data suggest that T cells depend on ROS for signal transduction. In this study, we show that tumors exploit this dependency, releasing antioxidant enzymes into the tumor environment to suppress T cell-mediated antitumor immunity. The interstitial fluid of tumors possesses potent antioxidant activity, associated with enrichment of the antioxidant enzyme peroxiredoxin 1 (PRDX1). Extracellular PRDX1 deprives T cells of ROS, preventing oxidative inactivation of phosphatases required for T cell receptor-driven kinase signaling and effector function. Prdx1 is up-regulated upon cancer immunoediting, and loss of PRDX1 within tumors enhances antitumor immunity and immunotherapy responses. These findings define a redox-dependent mechanism of tumor immunosuppression that is potentially amenable to therapeutic intervention.

『摘要』 活性氧（ROS）可促进癌症中的基因组不稳定并推动致癌信号传导，但抗氧化疗法迄今未能改善甚至恶化癌症预后。新兴数据表明T细胞依赖ROS进行信号转导，本研究发现肿瘤利用这一特性释放抗氧化酶至微环境以抑制T细胞介导的抗肿瘤免疫；肿瘤间质液具有强抗氧化活性且富含过氧化物还原酶1（PRDX1），胞外PRDX1通过剥夺T细胞的ROS阻止磷酸酶氧化失活，进而阻断T细胞受体驱动的激酶信号和效应功能；PRDX1在癌症免疫编辑过程中上调，而肿瘤内PRDX1缺失可增强抗肿瘤免疫及免疫治疗响应，该研究揭示了基于氧化还原机制的肿瘤免疫抑制途径及其潜在干预靶点。

『总结』 肿瘤通过分泌抗氧化酶PRDX1清除T细胞所需ROS，阻断其信号通路与抗肿瘤功能，靶向PRDX1可恢复免疫应答。

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5. 宜居带内附近岩石系外行星大气层中氦逃逸

Helium escaping from the atmosphere of a nearby rocky exoplanet orbiting in a habitable zone

Cherubim C, Vissapragada S, Cunningham T, ... , Zhang M, Dittmann JA, Lopez-Morales M.; science; (393, 6815)

『Abstract』Observations of highly irradiated gas giant exoplanets have shown helium escaping from their atmospheres. There is limited evidence for atmospheres on rocky exoplanets, perhaps because they have already escaped. We report near-infrared spectroscopic observations of LHS 1140b, a rocky exoplanet that orbits in the habitable zone of a nearby low-mass star. The transit spectra show absorption by helium escaping from the planet's atmosphere. Helium absorption is detected in 2024 but not in 2025, indicating time-variable atmospheric escape. We interpret these results as indicating an upper atmosphere dominated by helium and depleted in hydrogen, with other volatile species trapped at lower altitudes, which is consistent with atmospheric fractionation models. No helium absorption is detected for LHS 1140c, a smaller and more strongly irradiated exoplanet in the same system.

『摘要』 对高辐射气态巨行星系外行星的观测显示，其大气层中有氦逃逸现象，而岩石系外行星的大气证据有限，可能因其已完全逃逸。本研究报告了对LHS 1140b（一颗围绕邻近低质量恒星运行、位于宜居带的岩石系外行星）的近红外光谱观测结果，发现其凌日光谱中存在来自该行星大气逃逸的氦吸收信号；2024年检测到氦吸收但2025年未检测到，表明其大气逃逸具有时间变异性；研究认为这些结果表明LHS 1140b的高层大气以氦为主且氢贫乏，其他挥发性物质被困在较低高度，这与大气分馏模型一致；同一星系中更小且受辐射更强的LHS 1140c未检测到氦吸收。

『总结』 LHS 1140b大气存在时间可变的氦逃逸，高层大气为氦主导且氢贫乏，符合分馏模型，同系统另一行星无此现象。

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6. 成年果蝇完整味觉连接组揭示味觉如何指导进食觅食和社会行为

The complete gustatory connectome of adult Drosophila reveals how taste guides feeding, foraging, and social behavior

Tastekin I, de Haan Vicente I, Beresford RJ, ... , Costa M, Jefferis GSXE, Ribeiro C.; cell; (189, 18)

『Abstract』Gustatory systems drive critical survival behaviors such as feeding, foraging, and social interactions. However, gustation remains one of the least mapped sensory modalities at the connectome level. Here, we present the first complete wiring diagram of the male Drosophila adult gustatory system, comprehensively reconstructing gustatory receptor neurons (GRNs) from peripheral organs in a contiguous electron microscopy volume spanning brain, cervical connective, and ventral nerve cord. Integrating this with existing datasets, we generated a pan-central nervous system (CNS), cross-sex connectome that reveals GRN diversity through connectivity-based clustering, molecular identity mapping, and sexual dimorphism analysis. We mapped all feeding motor neurons and traced complete sensory-to-motor pathways to feeding, foraging, endocrine, and social behavior circuits. The emerging circuit architectures reveal distinct circuits for nutrient assessment, motor control, neuroendocrine regulation, and courtship. This work defines the gustatory system's organization at synaptic resolution and provides a framework for understanding how internal states modulate sensory-driven decisions across behavioral contexts.

『摘要』 味觉系统驱动进食、觅食和社交互动等关键生存行为，但其在连接组层面的研究仍属最不充分的感官模式之一。本研究首次构建了雄性果蝇成虫味觉系统的完整神经环路图谱，通过连续电子显微镜成像全面重建了跨越脑部、颈部连合及腹侧神经索的外周器官味觉受体神经元（GRNs），并结合现有数据集生成跨性别全中枢神经系统（CNS）连接组，通过基于连接的聚类、分子身份映射和性二态分析揭示GRN多样性，同时定位所有摄食运动神经元并追踪从感觉到运动的完整通路至摄食、觅食、内分泌及求偶行为相关神经环路，最终发现营养评估、运动控制、神经内分泌调节和求偶行为的独立回路架构。

『总结』 该研究首次绘制出雄性果蝇完整的味觉系统神经环路图谱，揭示其调控多种生存行为的独立回路机制。

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7. 果蝇雄性完整中枢神经系统连接组中的性别二态性

Sexual dimorphism in the complete Drosophila male central nervous system connectome

Berg S, Beckett IR, Costa M, ... , Hess HF, Rubin GM, Jefferis GSXE.; cell; (189, 18)

『Abstract』Sex differences in behavior exist across all animals, typically under strong genetic regulation. In Drosophila, fruitless/doublesex transcription factors identify dimorphic neurons, but their organization into functional circuits remains unclear. We present the connectome of the entire Drosophila male central nervous system. This contains 166,700 neurons spanning the brain and nerve cord, fully proofread and annotated, including fruitless/doublesex expression and 11,710 neuron types. We provide the first comprehensive comparison between male and female brain connectomes to synaptic resolution, finding 8,069 isomorphic, 138 dimorphic, 289 male-specific, and 71 female-specific types. This resource enables analysis of full sensory-to-motor circuits underlying complex behaviors and the impact of dimorphic elements. Sex-specific/dimorphic neurons are concentrated in higher brain centers, while the sensory and motor periphery is largely isomorphic. Within higher centers, male-specific connections are organized into hotspots defined by male-specific neurons or arbors. Dimorphic neurons reroute information across sexes.

『摘要』 动物行为存在性别差异，通常受强遗传调控。在果蝇中，fruitless/doublesex转录因子可识别二型性神经元，但其如何组织成功能性回路尚不清楚。本研究展示了整个雄性果蝇中枢神经系统的连接组图谱，包含166,700个跨越脑和神经索的神经元，经过全面校对和注释，包括fruitless/doublesex的表达情况和11,710种神经元类型；首次以突触分辨率对雄性和雌性脑连接组进行了全面比较，发现8,069种同构型、138种二型性、289种雄性特异型和71种雌性特异型的神经元类型；该资源有助于分析复杂行为背后完整的感觉-运动回路以及二型性元素的影响；性别特异性/二型性神经元主要集中在高级脑中心，而感觉和运动外周则主要是同构型；在高级中心内，雄性特有的连接被组织为由雄性特有神经元或树突定义的热点区域；二型性神经元在不同性别间重新路由信息。

『总结』 完整雄性果蝇中枢神经系统连接组揭示了性别特异性及二型性神经元的分布与功能特征，为解析复杂行为的性别差异机制提供了关键数据。

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8. 果蝇大脑中视觉通路的组织

The organization of visual pathways in the Drosophila brain

Hoeller J, Zhao A, Nern A, Rogers EM, Romani S, Reiser MB.; cell; (189, 18)

『Abstract』Visual systems transform photoreceptor inputs into rich perceptual representations through hierarchical networks that extract features along parallel pathways. Although this architecture is conserved across species, how visual information is routed throughout an entire brain remains elusive in any animal. Using the male Drosophila connectome, we trace signals from photoreceptors through the optic lobes-layered, retinotopic regions containing two-thirds of the brain's neurons-and onward into the central brain. Network-based analyses reveal a multilayered architecture of pathway classes with distinct input mixtures. Signals from visual-input channels spread broadly yet converge in focal regions apparently specialized for particular features and fine spatial sampling. Predictions of receptive-field structure and feature-related input biases are consistent with physiological data and extend to thousands of uncharacterized neuron types. These analyses provide a neuron-by-neuron account of how a visual system organizes and integrates information across an entire brain.

『摘要』 视觉系统通过分层网络将光感受器输入转化为丰富的感知表征，这些网络沿平行通路提取特征。尽管这种结构在物种间高度保守，但视觉信息在整个大脑中的传递路径在任何动物中仍不明确。本研究利用雄性果蝇连接组数据，追踪了从光感受器到视叶（包含大脑三分之二神经元的层状视网膜区域）再到中央脑的信号传递过程；基于网络分析揭示了具有不同输入组合的多层次通路架构，发现视觉输入通道的信号虽广泛传播但在特定功能区收敛，且预测的感受野结构和特征相关输入偏向与生理数据一致并可推广至数千种未被表征的神经元类型。

『总结』 果蝇全脑连接组解析揭示了视觉系统通过多层次并行通路整合信息的神经机制。

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9. 史前跨欧亚交流期间磨沟及甘肃其他遗址的基因组学与社会实践

Genomics and social practices at Mogou and other Gansu sites during prehistoric trans-Eurasian exchange

Shi H, Bennett EA, Chen G, ... , Hou H, Liu X, Fu Q.; cell; (189, 18)

『Abstract』Beginning approximately 4,000 years ago, southwest-Asian-originating domesticated crops and livestock began appearing in Gansu, a key crossroads in northwestern China, yet the population dynamics and social practices underlying these historically transformative events in the region have not been fully explored. Despite the adoption of western domesticates, genome sequences of 149 individuals from the large Mogou cemetery and ten other sites in Gansu, dating between 4,700 and 3,000 years ago, revealed migrations within East Asian regions but no detectable evidence of genetic influence from western or central Eurasia, suggesting that early agricultural dispersals may have followed a model distinct from that documented in Europe and Central Asia. The Mogou cemetery represents a continuous community that interacted with surrounding regions but does not exhibit clear matrilocal or patrilocal residential patterns. We found no strong evidence that co-buried individuals represented biological relatives. Non-local ancestry appears to be linked to lower-status burial practices.

『摘要』 大约4000年前，源自西南亚的家养作物和牲畜开始出现在中国西北的关键枢纽甘肃地区，但该地区这些具有历史变革意义事件背后的人口动态和社会实践尚未得到充分研究；尽管当地采用了西方家养物种，但对来自甘肃磨沟墓地（4700-3000年前）及其他10个遗址的149例个体基因组测序显示，存在东亚内部迁徙却未检测到欧亚西部或中部的遗传影响，表明早期农业传播模式可能与欧洲和中亚不同，且磨沟墓地代表了一个与周边互动但无明确母系/父系居住模式的连续社群，共葬个体间无明显生物学亲缘关系，非本地血统则与较低地位埋葬方式相关。

『总结』 约4000年前甘肃出现西亚家养物种但基因组显示仅存东亚内部迁徙，农业传播模式异于欧亚且共葬者多无亲缘、非本地血统关联低地位埋葬。

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10. 多胺缓冲不稳定铁以抑制铁死亡

Polyamines buffer labile iron to suppress ferroptosis

Sharma P, Keys HR, Mansell RP, ... , Pandelia ME, Henry WS, Jain A.; cell; (189, 18)

『Abstract』Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines contribute to endogenous buffering of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using a genome-wide CRISPR screen, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, glutathione peroxidase 4 (GPX4). Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.

『摘要』 多胺是哺乳动物细胞中以毫摩尔浓度存在的必需且进化保守的代谢物，细胞通过复杂的反馈机制严格调控多胺稳态，但其精确作用尚不明确；本研究表明多胺参与内源性氧化还原活性铁缓冲，揭示了多胺代谢与铁死亡之间的分子联系，并通过全基因组CRISPR筛选发现多胺耗竭与关键铁死亡抑制因子谷胱甘肽过氧化物酶4（GPX4）存在合成致死依赖性，进一步证实多胺缺乏会触发细胞铁重新分布、增加不稳定铁池并上调铁蛋白表达，最终开发遗传编码荧光探针直接可视化活细胞中的铁缓冲过程，单细胞分辨率分析显示胞内多胺水平与氧化还原活性铁呈显著负相关。

『总结』 多胺是铁稳态的关键调节因子，其缺失通过改变铁分布诱导铁死亡，为铁死亡相关疾病治疗提供新靶点。

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11. 靶向外周5-羟色胺2A受体增强结直肠癌抗肿瘤免疫

Targeting peripheral 5-HT<sub>2A</sub>R enhances antitumor immunity in colorectal cancer

Wen Y, Tang L, Duan W, ... , Cheng J, Wang S, Chen J.; cell; (189, 18)

『Abstract』Cancer remains a leading cause of morbidity and mortality worldwide. While classical psychedelics have been used clinically to treat cancer-associated psychiatric disorders, their impact on tumor progression is unclear. Here, we show that by targeting the serotonin receptor 5-HT_2AR, lysergic acid diethylamide (LSD) enhances CD8⁺ T cell-mediated antitumor immunity and suppresses colorectal cancer (CRC) growth. To harness this activity while avoiding psychedelic effects, we developed IHCH-8110, a non-brain-penetrant 5-HT_2AR agonist that selectively targets peripheral 5-HT_2AR. We show that IHCH-8110 inhibits CRC progression by activating 5-HT_2AR on enteric glial cells, thereby inducing CXCL10 and interleukin (IL)-18 expression to promote CD8⁺ T cell recruitment and effector polarization within the tumor microenvironment. By converting immune-cold CRC into a more immunologically responsive state, IHCH-8110 enhances the efficacy of PD-1 blockade. Together, our findings identify enteric 5-HT_2AR signaling as a regulator of antitumor immunity and support peripheral 5-HT_2AR agonists as a therapeutic strategy for CRC immunotherapy.

『摘要』 癌症仍是全球发病率和死亡率的主要原因之一。尽管经典致幻剂已在临床上用于治疗癌症相关精神疾病，但其对肿瘤进展的影响尚不明确。本研究发现，通过靶向5-羟色胺受体5-HT_2AR，麦角酸二乙酰胺（LSD）可增强CD8⁺T细胞介导的抗肿瘤免疫并抑制结直肠癌（CRC）生长；为利用这一作用同时避免致幻效应，研究开发了非脑渗透性5-HT_2AR激动剂IHCH-8110，其选择性作用于外周5-HT_2AR；结果显示，IHCH-8110通过激活肠神经胶质细胞上的5-HT_2AR抑制CRC进展，诱导CXCL10和白细胞介素（IL）-18表达以促进肿瘤微环境中CD8⁺T细胞的招募和效应极化；通过将免疫“冷”型CRC转化为更具免疫响应性的状态，IHCH-8110增强了PD-1阻断剂的疗效；这些发现表明，肠道5-HT_2AR信号是抗肿瘤免疫的调节因子，支持外周5-HT_2AR激动剂作为CRC免疫治疗的策略。

『总结』 靶向外周5-HT_2AR的非脑渗透性激动剂IHCH-8110可通过激活肠神经胶质细胞增强CD8⁺T细胞抗肿瘤免疫，抑制结直肠癌生长并提升PD-1抑制剂疗效。

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12. 基底膜更新控制细胞形态

Basement membrane turnover controls cell shape

Barrientos R, Meadowcroft B, Sanchez-Sanchez BJ, ... , Banerjee S, Saric A, Mao Y.; cell; (189, 18)

『Abstract』The regulation of 3D cell shape is a fundamental problem of life. In multicellular tissues, cell shape emerges through the balance of forces inside and outside the cell. In epithelia, the basement membrane (BM) is the first extracellular barrier that cells sense biochemically and mechanically. Despite this, little is known about how BM mechanical properties are regulated and how they impact cell shape. Through mathematical modeling, we show that the stress relaxation time of the BM can regulate cell shape. Using molecular dynamics simulations, we show that the stress relaxation time of a collagen IV network can be inferred from the lifetime of collagen IV molecules. To measure collagen IV lifetime in vivo, we develop a fluorescent timer reporter for collagen IV and show that perlecan modifies collagen IV lifetime. This cross-disciplinary approach establishes a multiscale framework to probe matrix turnover, and its regulation and function in cell shape control.

『摘要』 3D细胞形状的调控是生命科学的基本问题，在多细胞组织中，细胞形状通过细胞内外力的平衡来形成；上皮细胞的基底膜（BM）是细胞首先感知到的生化及机械性胞外屏障，但目前对BM力学特性如何被调控及其如何影响细胞形状知之甚少；本研究通过数学建模表明BM应力松弛时间可调控细胞形状，利用分子动力学模拟发现IV型胶原网络的应力松弛时间可从IV型胶原蛋白分子的寿命推断得出，为测量体内IV型胶原蛋白寿命开发了荧光定时报告器并证实Perlecan可改变其寿命，该跨学科方法建立了用于探究基质周转及其调控和细胞形状控制功能的多尺度框架。

『总结』 跨学科研究揭示基底膜应力松弛时间可通过IV型胶原蛋白寿命调控细胞形状，并建立多尺度分析框架。

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13. 通过蛛网膜裂孔清除脑脊液至嗅觉脑膜淋巴管

CSF clearance through arachnoid fenestrations to olfactory meningeal lymphatics

Hong SP, Jin C, Yang MJ, ... , Alitalo K, McDonald DM, Koh GY.; cell; (189, 18)

『Abstract』Meningeal (dural) lymphatics are essential for cerebrospinal fluid (CSF) clearance to cervical lymph nodes, yet the precise pathway is incompletely understood. Using a multifaceted approach in mice, we examined tracer dynamics and the CSF outflow pathway from the subarachnoid space (SAS) to the nasal mucosa and identified a discrete arachnoid region surrounding the olfactory bulbs with abundant fenestrations. Similar arachnoid fenestrations were found in cynomolgus monkeys. Fluorescent tracers in the SAS passed through arachnoid fenestrations into dural lymphatics, which traversed the cribriform plate foramina, joined the nasal lymphatics, and drained to the cervical lymph nodes. In aged mice, the known reduction in CSF outflow was accompanied by lymphatic atrophy in the olfactory dura and nasal mucosa and by fewer arachnoid fenestrations and smaller cribriform plate foramina. Importantly, the lymphatics and CSF clearance were restored to normal by intranasal delivery of vascular endothelial growth factor-C (VEGF-C), thereby documenting the reversibility of the aging-related impairment in CSF clearance.

『摘要』 脑膜（硬脑膜）淋巴管对脑脊液（CSF）向颈淋巴结的清除至关重要，但其确切通路尚未完全明确。本研究通过小鼠多模态方法研究示踪剂从蛛网膜下腔（SAS）到鼻黏膜的动力学及脑脊液流出路径，发现嗅球周围存在含丰富窗孔的离散蛛网膜区域；类似结构也存在于食蟹猴中；蛛网膜下腔中的荧光示踪剂可通过这些窗孔进入硬脑膜淋巴管，穿过筛板孔与鼻腔淋巴管汇合后引流至颈淋巴结；老年小鼠脑脊液外流减少的同时伴随嗅觉硬脑膜和鼻黏膜淋巴管萎缩、蛛网膜窗孔数量减少及筛板孔缩小；值得注意的是，经鼻递送血管内皮生长因子C（VEGF-C）可恢复淋巴管功能及脑脊液清除能力，证实衰老相关脑脊液清除障碍具有可逆性。

『总结』 嗅球周围蛛网膜窗孔是脑脊液经硬脑膜淋巴管流向鼻腔的关键通道，且衰老导致的清除障碍可通过VEGF-C治疗逆转。

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14. 局部PD-1嵌合抗原受体T细胞疗法可重编程神经炎症

Localized PD-1 CAR T therapy reprograms neuroinflammation

Shalita R, Ben Yehuda M, Gur C, ... , Yarkoni AW, Ingelfinger F, Amit I.; cell; (189, 18)

『Abstract』B cell-depleting therapies are effective in multiple sclerosis (MS), yet some patients relapse, underscoring the need for more precise interventions. To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched immunoglobulin G⁺ (IgG⁺) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1⁺ T follicular helper-like cells with B cell-recruiting features. To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1⁺ CD4 T cells and locally released IL-10. This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.

『摘要』 B细胞耗竭疗法对多发性硬化症（MS）有效，但部分患者仍会复发，凸显了更精准干预措施的必要性。为确定新的治疗靶点，本研究生成了非炎症对照者及MS或其他神经炎症疾病患者的脑脊液、大脑和血液的单细胞RNA测序图谱，发现MS脑脊液中存在与疾病相关的类别转换免疫球蛋白G⁺（IgG⁺）B细胞和浆细胞的富集；无偏倚分析鉴定出一类罕见的、在疾病中富集的激活型、T细胞受体限制性、PD-1⁺ T滤泡辅助样细胞亚群，具有招募B细胞的特性；为此开发了靶向PD-1的嵌合抗原受体（CAR）T细胞，可选择性耗竭致病性PD-1⁺ CD4 T细胞并在局部释放IL-10，该策略减轻了中枢神经系统炎症，重编程了局部免疫环境，并改善了小鼠神经炎症模型的临床结局。这些发现定义了MS中的中枢神经系统局部适应性免疫回路，并提出可编程PD-1 CAR T细胞作为破坏这一回路的策略。

『总结』 单细胞测序揭示MS脑脊液中特定B细胞和T细胞亚群的富集，开发的靶向PD-1的CAR T细胞可减轻CNS炎症并改善临床结局。

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15. 连接赖氨酸乙酰转移酶与癌基因诱导细胞死亡的二价分子胶

A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death

Nix MN, Gourisankar S, Bowman KJ, ... , Hinshaw SM, Gray NS, Crabtree GR.; cell; (189, 18)

『Abstract』Developing cancer therapies that induce specific death of malignant cells is critical for preventing relapse. Highly effective strategies, such as immunotherapy, exemplify this principle. Here, we provide the mechanistic basis for a small-molecule approach that leverages chemically induced proximity (CIP) to kill diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma. We developed lysine acetyltransferase (KAT)-based TCIPs (transcriptional/epigenetic chemical inducers of proximity), or KAT-TCIPs, which redirect p300/CREB-binding protein (CBP) to activate cell-death networks repressed by the oncogenic driver BCL6. Our lead KAT-TCIP reprograms the epigenome to initiate apoptosis. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance protein-protein interactions may be exploited to confer the potency and selectivity of KAT-TCIPs. Thus, oncogenic drivers can be co-opted to activate robust cell death. Consistent with their gain-of-function mechanism, TCIPs recruiting different transcriptional activators-p300, BRD4, or CDK9-produce distinct genomic responses, suggesting specialized therapeutic uses.

『摘要』 开发能诱导恶性细胞特异性死亡的癌症疗法对预防复发至关重要，免疫治疗等高效策略即为范例；本研究提出了一种基于小分子的方法，利用化学诱导接近（CIP）机制靶向杀灭最常见的非霍奇金淋巴瘤——弥漫性大B细胞淋巴瘤（DLBCL），开发了基于赖氨酸乙酰转移酶（KAT）的转录/表观遗传化学诱导接近剂（TCIPs，即KAT-TCIPs），其可重定向p300/CREB结合蛋白（CBP）以激活被致癌驱动因子BCL6抑制的细胞死亡网络，其中先导化合物KAT-TCIP通过重编程表观基因组启动细胞凋亡，且化学诱导的p300-BCL6复合物晶体结构揭示了如何利用偶然的蛋白质相互作用赋予KAT-TCIPs效力与选择性，表明致癌驱动因子可被利用来激活强大的细胞死亡途径，此外由于功能获得机制，招募不同转录激活因子（p300、BRD4或CDK9）的TCIP会产生不同的基因组反应，提示其在治疗中具有特殊用途。

『总结』 基于KAT的TCIPs通过重定向p300/CBP激活细胞死亡网络，有效诱导弥漫性大B细胞淋巴瘤凋亡并揭示其作用机制及潜在应用。

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16. 皮肤谷氨酸能神经元调节衰老

Skin-innervating glutamatergic neurons modulate aging

Wang Z, Jin X, Wu Y, ... , Wu Y, Zhang X, Wang H.; cell; (189, 18)

『Abstract』Peripheral nerves regulate skin homeostasis by secreting neurotransmitters, but their role during skin aging remains incompletely understood. Here, we report that cutaneous denervation accelerates skin aging, as evidenced by collagen reduction. Neurofilament heavy chain (Nefh) is decreased in aged skin and is predominantly expressed in vesicular glutamate transporter 2-positive (Vglut2⁺) skin-innervating glutamatergic neurons. Notably, dermal fibroblasts, the primary producers of collagen, frequently contact Nefh⁺ nerve fibers. Moreover, Nefh deletion in Vglut2⁺ glutamatergic neurons drives skin fibroblast senescence and collagen loss, whereas additional glutamate improves skin aging phenotypes. Mechanistically, cyclin-dependent kinase 5 (Cdk5) interacts with both Nefh and Vglut2 and maintains glutamate release and collagen homeostasis. Additionally, in skin fibroblasts, solute carrier family 1 member 3 (Slc1a3) governs the collagen-promoting and anti-senescence functions of glutamate. Together, these findings reveal Nefh-mediated glutamatergic neuromodulation of skin aging and provide therapeutic targets for aging-related skin disorders.

『摘要』 外周神经通过分泌神经递质调节皮肤稳态，但其在皮肤衰老过程中的作用尚不完全清楚。本研究发现皮肤去神经支配会加速皮肤衰老（表现为胶原蛋白减少）；老年皮肤中神经丝重链（Nefh）表达降低且主要分布于囊泡谷氨酸转运体2阳性（Vglut2⁺）的谷氨酸能感觉神经元；真皮成纤维细胞作为胶原蛋白的主要产生者常与Nefh⁺神经纤维接触；Vglut2⁺谷氨酸能神经元中Nefh缺失可诱导成纤维细胞衰老和胶原蛋白流失，而补充谷氨酸则改善皮肤衰老表型；机制上周期蛋白依赖性激酶5（Cdk5）通过调控Nefh-Vglut2相互作用维持谷氨酸释放和胶原蛋白稳态，同时皮肤成纤维细胞中溶质载体家族1成员3（Slc1a3）介导谷氨酸的促胶原生成和抗衰老功能。

『总结』 外周神经通过Nefh介导的谷氨酸能神经调节维持皮肤稳态，其异常导致胶原蛋白流失和成纤维细胞衰老。

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17. 主要神经退行性疾病共有的TOP1介导的神经元基因组损伤的重复模式

Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders

Zhou Z, Luquette LJ, Dong G, ... , Lagier-Tourenne C, Lee EA, Walsh CA.; cell; (189, 18)

『Abstract』Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) represent two major categories of neurodegenerative disorders-TAR DNA-binding protein 43 (TDP-43) and tau proteinopathies-for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 469 neurons from C9ORF72 ALS, C9ORF72 FTD, AD, and control brains revealed increased somatic single-nucleotide variants (sSNVs) and insertions/deletions (sIndels) in all three diseases. Mutational signature analysis identified a disease-associated sSNV signature consistent with oxidative damage and an sIndel process affecting 22% of ALS, 76% of FTD, and 61% of AD neurons-but only 2% of control neurons-resembling signature ID4, previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions. TOP1-associated sIndel mutagenesis and genome instability thus represent a mechanism shared by both TDP-43 and tau neurodegeneration.

『摘要』 肌萎缩侧索硬化症（ALS）、额颞叶痴呆（FTD）和阿尔茨海默病（AD）是两类主要的神经退行性疾病，分别涉及TAR DNA结合蛋白43（TDP-43）和tau蛋白病变，但其驱动神经元死亡的机制尚不明确。对来自C9ORF72 ALS、C9ORF72 FTD、AD及对照大脑的469个神经元进行单细胞全基因组测序发现，这三种疾病中体细胞单核苷酸变异（sSNVs）和插入/缺失（sIndels）均增加；突变特征分析揭示了一种与氧化损伤一致的疾病相关sSNV特征，以及影响22%的ALS、76%的FTD和61%的AD神经元（但仅2%的对照神经元）的sIndel过程，其类似于先前与拓扑异构酶1（TOP1）介导的诱变相关的ID4特征；DNA加合物快速回收法（RADAR）检测证实了TOP1-DNA共价复合物的增加，双链测序确认了sIndels的增加并识别出单链事件可能是前驱性损伤；因此，TOP1相关的sIndel诱变和基因组不稳定性是TDP-43和tau神经退行性变的共同作用机制。

『总结』 TOP1相关的sIndel诱变和基因组不稳定性是TDP-43和tau蛋白相关神经退行性疾病的共同致病机制。

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18. 从空间快照中进行四维分子图谱绘制揭示毛囊器官发生的动态变化

Four-dimensional molecular mapping from a spatial snapshot reveals the dynamics of hair follicle organogenesis

Asami S, Yin C, Fan J, Garza LA, Kalhor R.; cell; (189, 18)

『Abstract』Understanding organ formation requires capturing molecular information simultaneously in three-dimensional (3D) space and across developmental time. To this end, we developed 3D DNase-Enhanced Expression Profiling (3DEEP), a tissue-clearing approach that removes genomic DNA to extend spatial transcriptomic profiling hundreds of microns into intact tissues. We applied 3DEEP to neonatal mouse skin, capturing hundreds of developing hair follicles across their organogenesis trajectory. Ordering follicles by molecularly inferred developmental age transformed this single spatial snapshot into a four-dimensional (3D + time) molecular map of organogenesis. This map revealed developmental dynamics spanning stem cell compartment stratification, emergence of new cell subtypes within the follicle, and cascading structural transformations leading to hair canal formation. Comparative analysis of Foxn1-deficient nude mice, a hairlessness model, revealed organ-wide changes in developmental dynamics, including delayed molecular progression, reduced coordination, and increased developmental instability, preceding overt structural defects. This work demonstrates how deep-tissue spatial transcriptomics can uncover hidden dynamics of organ formation.

『摘要』 理解器官形成需要同时获取三维（3D）空间和发育时间上的分子信息。为此，我们开发了三维脱氧核糖核酸酶增强表达谱分析技术（3DEEP），这是一种组织透明化方法，通过去除基因组DNA将空间转录组分析扩展至完整组织的数百微米深度。我们将3DEEP应用于新生小鼠皮肤，捕捉到数百个毛囊在其器官发生轨迹中的发育过程；通过基于分子推断的发育年龄对毛囊进行排序，将单一的空间快照转化为器官发生的四维（3D+时间）分子图谱。该图谱揭示了干细胞区室分层、毛囊内新细胞亚型出现以及导致毛通道形成的级联结构转变等发育动态。通过对无毛模型Foxn1缺陷裸鼠的比较分析发现，其器官整体发育动态发生变化，包括分子进程延迟、协调性降低及发育不稳定性增加，这些变化先于明显的结构性缺陷出现。本研究展示了深层组织空间转录组学如何揭示器官形成中隐藏的动态过程。

『总结』 3DEEP技术通过整合空间与时间维度分子数据构建了毛囊发育的四维图谱，揭示了干细胞分层、细胞亚型分化及结构重塑等关键动态，并发现Foxn1缺失会导致发育进程延迟与不稳定性增加。

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19. 溶酶体机制协同作用塑造支持珊瑚礁的细胞内光共生进化

Co-option of lysosomal machinery shapes the evolution of the intracellular photosymbiosis supporting coral reefs

Maruyama S, Henderson CF, Swinhoe N, ... , Meier EK, Engelke TR, Cleves PA.; cell; (189, 18)

『Abstract』Endosymbiosis has spurred the evolution of new organelles across life. Corals and other cnidarians have repeatedly evolved an organelle, called the symbiosome, which houses intracellular algal symbionts. However, the molecular mechanisms enabling this repeated evolution remain unclear. Using the sea anemone Aiptasia, we generated a high-quality proteome of the symbiosome, revealing protein trafficking mechanisms and the types of biomolecules exchanged during symbiosis. Symbiosomal enrichment of lysosomal proteins, visualization of lysosomal fusion, and reduced symbiosis following knockdown of lysosomal genes indicate that the symbiosome functions through extensive co-option of lysosomal proteins. We identified a symbiosomal bicarbonate/sulfate transporter, SLC26A11, and showed through CRISPR/Cas9 mutagenesis that this lysosomal transporter is required for symbiosis in Aiptasia and a reef-building coral. Together, these findings reveal that corals and anemones have repeatedly co-opted lysosomal proteins to concentrate carbon and shuttle metabolites to support photosymbiosis, providing a relatively simple path for the repeated evolution of new photosymbioses.

『摘要』 内共生现象推动了生命中新细胞器的进化，珊瑚和其他刺胞动物多次进化出一种称为共生体的细胞器来容纳细胞内藻类共生体，但促成这种重复进化的分子机制尚不清楚。本研究利用海葵Aiptasia生成了高质量的共生体蛋白质组，揭示了蛋白质运输机制以及共生过程中交换的生物分子类型；通过共生体内溶酶体蛋白富集、溶酶体融合可视化及溶酶体基因敲低后共生关系减弱等实验，表明共生体通过广泛利用溶酶体蛋白发挥作用；研究还鉴定出共生体碳酸氢盐/硫酸盐转运蛋白SLC26A11，并通过CRISPR/Cas9突变证实该溶酶体转运蛋白对Aiptasia和造礁珊瑚的共生至关重要。这些发现共同揭示了珊瑚和海葵通过反复利用溶酶体蛋白集中碳元素并转运代谢物以支持光合共生，为新型光合共生关系的重复演化提供了相对简单的路径。

『总结』 珊瑚和海葵通过反复利用溶酶体蛋白实现碳集中与代谢物转运，从而支持光合共生并促进其重复演化。

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20. 疟原虫入侵宿主膜的结合与重塑的结构基础

Structural basis for host membrane binding and remodeling by invading malaria parasites

Haile MT, Kaxiras DA, Zhen J, ... , Jiang B, Small-Saunders JL, Ho CM.; cell; (189, 18)

『Abstract』The Plasmodium moving junction is central to malarial host-cell invasion, and yet its function remains unclear. Here, we determine the endogenous structure of the basic repeating unit of the moving junction, purified directly from invasion-stalled Plasmodium falciparum parasites, revealing a sailboat-shaped 1:1:1:1 assembly of apical membrane antigen 1 (PfAMA1) and rhoptry neck proteins 2, 4, and 5 (PfRON2, PfRON4, and PfRON5). We observe two PfRON2 transmembrane helices that anchor the complex in the red blood cell (RBC) membrane and display an extracellular handle for PfAMA1 binding. PfAMA1 directly contacts the RBC membrane, strengthening the connection. PfRON2/4/5 form a large, basic platform inside the RBC that electrostatically engages the RBC membrane and wedges seven amphipathic helices deep into the bilayer, suggesting an active role in host-membrane remodeling. We then leverage the native membrane context revealed by our structure, along with recent advances in computational protein design, to enable the rational design of a small protein binder that inhibits invasion.

『摘要』 疟原虫运动连接结构是疟原虫入侵宿主细胞的核心环节，但其功能机制尚不明确。本研究通过直接从入侵停滞的恶性疟原虫中纯化运动连接的基本重复单元，解析其天然结构为1:1:1:1比例组成的帆船状复合体，包含顶膜抗原1（PfAMA1）及棒状体颈部蛋白2、4、5（PfRON2/4/5），发现PfRON2的两个跨膜螺旋锚定于红细胞膜并形成胞外结合位点供PfAMA1识别，同时PfAMA1直接接触红细胞膜增强连接稳定性；PfRON2/4/5在红细胞内形成带正电平台，通过静电作用与膜相互作用并将七个两亲性螺旋插入脂双层，提示其在宿主膜重塑中的主动作用；基于该天然膜环境结构信息并结合计算蛋白质设计技术，成功理性设计了可抑制疟原虫入侵的小分子蛋白结合剂。

『总结』 疟原虫运动连接核心复合体的天然结构揭示了其入侵宿主细胞的分子机制，并为开发抗疟药物提供了新靶点。

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21. 通过胚外细胞协同作用重建人类原条形成

Reconstituting human primitive streak formation through extra-embryonic cell coordination

Shen Q, Zhang X, Chen N, ... , Jia X, Yu L, Wei Y.; cell; (189, 18)

『Abstract』Gastrulation is the fundamental stage of human development, governed by the faithful interaction between embryonic and extra-embryonic tissues. Despite its significance, the role of extra-embryonic lineages in directing embryonic diversification and organization remains elusive. Here, we developed a defined co-culture system where embryonic stem cells (ESCs) are cultured with various extra-embryonic cell types, mimicking in vivo amniotic ectoderm, trophoblast, and extra-embryonic mesoderm, and uncovered the previously unrecognized role of different extra-embryonic cells in regulating embryonic cells. Furthermore, leveraging the advantages of microengineering techniques, we spatially and molecularly reconstructed the interactions among distinct extra-embryonic and embryonic cells, demonstrating that the coordinated regulation of extra-embryonic cells alone can recapitulate the human primitive streak (PS) formation, while also exhibiting extended developmental potential. This advancement may allow for experimental exploration and manipulation of previously inaccessible stages of human early gastrulation, providing an opportunity to glimpse the onset of this crucial developmental process.

『摘要』 原肠胚形成是人类发育的基础阶段，受胚胎组织与胚外组织间可靠相互作用的调控；尽管其意义重大，但胚外谱系在指导胚胎多样化和组织化中的作用仍不明确；本研究开发了明确定义的共培养系统，将胚胎干细胞（ESCs）与各种胚外细胞类型共同培养以模拟体内羊膜外胚层、滋养层和胚外中胚层，揭示了不同胚外细胞在调节胚胎细胞中的先前未被认识的作用；此外，利用微工程技术的优势，从空间和分子层面重建了不同胚外细胞与胚胎细胞间的相互作用，证明仅通过胚外细胞的协调调控即可重现人类原始条纹（PS）的形成并展现出扩展的发育潜力；这一进展可能允许对以往难以触及的人类早期原肠胚形成阶段进行实验探索和操作，为洞察这一关键发育过程的起始提供机会。

『总结』 开发的共培养系统和微工程技术揭示了胚外细胞在调控胚胎细胞及重构人类原始条纹形成中的关键作用，为研究人类早期原肠胚形成提供了新途径。

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22. 抗癌药物三尖杉宁碱和同型红豆杉碱的完全生物合成

Complete biosynthesis of the anticancer cephalotaxinone and homoerythratine

Tian R, Lin F, Guo N, ... , Li Q, Yan J, Lei X.; cell; (189, 18)

『Abstract』Cephalotaxine-type and homoerythrina-type alkaloids are structurally unique and biologically important natural products isolated from endangered species that belong to the genus Cephalotaxus. Among them, homoharringtonine (HHT [1]) is a marketed drug used to treat leukemia. However, the scalable production of HHT is significantly hindered by limited natural resources. Despite intensive investigation over half a century, the complete biosynthetic pathways of these alkaloids remain unknown. Here, we applied a comprehensive multi-omics analysis and used a set of chemically synthesized standard compounds to identify the missing enzymes required for the biosynthesis of cephalotaxinone and homoerythratine. We also uncovered a rare case of divergent oxidation catalyzed by two highly homologous cytochrome P450 enzymes, CfCYP2 and CfCYP3, in the biosynthesis of two structurally distinct alkaloids. We further identified the key residues that significantly affect the divergent oxidation outcomes and ultimately reconstituted the complete biosynthetic pathways for producing these two alkaloids in N. benthamiana.

『摘要』 三尖杉宁碱型和荷包牡丹碱型生物碱是从属于三尖杉属的濒危物种中分离出的结构独特且具有重要生物学意义的天然产物，其中同型半夏碱（HHT [1]）是用于治疗白血病的上市药物，但受限于自然资源其规模化生产严重受阻，尽管经过半个多世纪的深入研究，这些生物碱的完整生物合成途径仍未知；本研究通过综合多组学分析并利用一组化学合成的标准化合物，确定了三尖杉酮和荷包牡丹碱生物合成所需的缺失酶，还揭示了两种高度同源的细胞色素P450酶CfCYP2和CfCYP3催化不同氧化反应的罕见案例，进一步鉴定出显著影响氧化结果的关键残基，最终在本氏烟草中重建了这两种生物碱的完整生物合成途径。

『总结』 多组学分析和化学合成标准物助力确定三尖杉酮和荷包牡丹碱生物合成所需酶及关键残基，实现本氏烟草中的完整生物合成途径重建。

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23. 通过极化和纠缠探索重子半轻子衰变

Exploring baryon semileptonic decays through polarization and entanglement

BESIII Collaboration.; nature; (657, 8130)

『Abstract』The unitarity of the Cabibbo-Kobayashi-Maskawa (CKM) matrix is a cornerstone of the standard model (SM). Precise tests of this unitarity require independent determinations of its elements, such as |V_us|, which governs the transition between strange and up quarks. Current measurements from kaon and tau decays show tensions that may hint at physics beyond the SM. Hyperon semileptonic decays provide alternative probes but have remained largely untapped because previous experiments lacked sufficient kinematic information, making the measurements insensitive to the relevant form factors. Here we report measurements of the axial-vector and weak-magnetism couplings, as well as the first determinations of the absolute branching fraction and weak-electricity coupling in Λ→pe-ν¯e , achieved by exploiting the polarization and quantum entanglement of ΛΛ¯ pairs produced at the J/ψ resonance. Combining our results with recent lattice quantum chromodynamics (QCD) calculations gives |V_us|_LQCD = 0.2339 ± 0.0041, a model-independent determination consistent with CKM unitarity. By pioneering the exploitation of polarization and quantum entanglement in baryon semileptonic decays, our method enhances single-event sensitivity and is broadly applicable to other baryon semileptonic decays, establishing the foundation for a systematic research programme that can achieve precision comparable with that of kaon decays and provide a stringent independent test of the SM.

『摘要』 卡比波-小林-益川（CKM）矩阵的幺正性是标准模型（SM）的基石，精确检验其幺正性需独立测定各元素如|V_us|（控制奇异夸克与上夸克间的跃迁），当前来自K介子和τ轻子衰变的测量结果存在张力，可能暗示超出标准模型的新物理；重子半轻子衰变虽可提供替代探测手段，但此前实验因缺乏足够运动学信息导致对相关形状因子不敏感，本研究通过利用J/ψ共振态产生的ΛΛ̄对的极化与量子纠缠特性，首次测定了Λ→pe⁻ν̄_e衰变的轴矢量耦合、弱磁耦合、绝对分支比及弱电耦合，结合近期格点量子色动力学（QCD）计算得到|V_us|_LQCD=0.2339±0.0041，该模型无关结果与CKM矩阵幺正性一致。

『总结』 基于ΛΛ̄对极化与量子纠缠的首次测量显著提升了重子半轻子衰变灵敏度，结合格点QCD给出与标准模型一致的|V_us|值并奠定系统研究基础。

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24. 可解释深度学习改进人类对自动驾驶汽车的思维模式

Explainable deep learning improves human mental models of self-driving cars

Kenny EM, Dharmavaram A, Lee SU, ... , Major L, Tomov MS, Shah JA.; nature; (657, 8130)

『Abstract』Self-driving cars increasingly rely on deep neural networks to achieve human-like driving. The opacity of these black-box planners makes it challenging to accurately anticipate when they will fail, with potentially catastrophic consequences. Although research into interpreting these systems has surged, most of it is confined to simulations or toy setups because of the difficulty of real-world deployment, leaving the practical utility of these techniques unknown. Here, we introduce the Concept-Wrapper Network (CW-Net), a method for faithfully explaining the behaviour of machine-learning-based planners that causally grounds their reasoning in human-interpretable concepts without sacrificing performance. We deploy CW-Net on a real self-driving car and show that the resulting explanations improve the human driver's mental model of the vehicle, allowing them to better predict its behaviour, particularly in surprising situations. This demonstrates that explainable deep learning integrated into self-driving cars can be both understandable and useful in a realistic deployment setting. We anticipate our method could be applied to other safety-critical systems, such as autonomous drones and robotic surgeons, as well as to other architectures, such as end-to-end learning systems and vision-language-action models. Overall, our study establishes a deployment-validated pathway to interpretability for autonomous agents, which could help make them more transparent and safe.

『摘要』 自动驾驶汽车日益依赖深度神经网络实现类人驾驶，但这些黑箱规划器的不透明性使其故障预测极具挑战且可能引发灾难性后果。尽管相关解释性研究激增，但受限于真实场景部署难度，多数仍局限于模拟或简化环境，导致其实际效用未知。本文提出概念包装网络（CW-Net），该方法通过将机器学习规划器的推理过程因果关联至人类可理解的概念，在保持性能的同时忠实解释其行为。我们将CW-Net部署于真实自动驾驶汽车，发现其生成的解释能优化人类驾驶员对车辆行为的心理模型，尤其在意外情境下提升行为预测能力，证明集成可解释深度学习的自动驾驶系统在现实部署中兼具可理解性与实用性。该方法有望扩展至无人机、手术机器人等安全关键系统及端到端学习、视觉语言动作模型等其他架构，为自主智能体建立了一条经部署验证的可解释性路径，助力提升其透明度与安全性。

『总结』 概念包装网络通过关联人类可理解概念解释自动驾驶决策，显著提升人类预测能力并验证了现实场景中的实用价值。

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25. 临界带过程限制了天然玄武岩系统的碱度输出

Critical zone processes limit alkalinity export from natural basaltic systems

Derry LA, Maher K, Chadwick OA.; nature; (657, 8130)

『Abstract』Enhanced weathering (EW) of rocks is a proposed strategy for carbon dioxide removal (CDR) that relies on the dissolution of silicate minerals, typically basalt, applied to soils. Globally, large-scale CDR by means of EW requires the generation of alkalinity during mineral dissolution in soils and preservation and transport of that alkalinity through groundwater and rivers to reach the ocean. Although field trials and models have focused on near-surface alkalinity generation after addition of crushed rock, the transmission of this alkalinity is modulated by hydrological and geochemical processes that unfold across watersheds. Here we synthesize observations from natural volcanic watersheds to evaluate alkalinity export along the complete reactive pathways from soil to river. Data from basaltic catchments demonstrate attenuation of alkalinity fluxes, leading to reductions in exported alkalinity. This attenuation is probably the result of precipitation of secondary clay and carbonate minerals along subsurface flow paths and during river transport. Although natural weathering systems differ from engineered EW deployments, these observations provide an empirical baseline on watershed-scale alkalinity export. Our results indicate that critical zone processes influence the efficiency with which weathering-derived alkalinity is exported, implying the need to incorporate watershed processes into future assessments of EW CDR.

『摘要』 岩石的增强风化（EW）是一种被提出的二氧化碳移除策略，依赖于应用于土壤的硅酸盐矿物（通常是玄武岩）的溶解；全球范围内通过增强风化实现大规模二氧化碳移除需要在土壤中矿物溶解期间产生碱度，并通过地下水和河流保存和运输这种碱度以到达海洋；尽管现场试验和模型重点关注了添加碎岩后近地表碱度的生成，但这种碱度的传输受到整个流域水文和地球化学过程的调节；本文综合了自然火山流域的观察结果，评估从土壤到河流完整反应路径上的碱度输出；来自玄武岩流域的数据表明碱度通量衰减，导致输出的碱度减少；这种衰减可能是沿地下水流动路径和河流输运过程中次生粘土和碳酸盐矿物的沉淀所致；虽然自然风化系统与人工增强的风化部署不同，但这些观察结果为流域尺度碱度输出提供了经验基准；研究结果表明关键带过程影响风化产生的碱度的输出效率，意味着未来对增强风化的二氧化碳移除评估需要将流域过程纳入考虑。

『总结』 自然火山流域观测显示风化产碱在向河流传输过程中因次生矿物沉淀而衰减，提示需将流域水文地质过程纳入增强风化固碳技术的效率评估。

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26. 通过氧到碳骨架编辑由异噁唑合成吡咯

Synthesis of pyrroles from isoxazoles by an O-to-C skeletal edit

Bracken AJ, Lawrie AP, Romita IF, Levin MD.; nature; (657, 8130)

『Abstract』Isoxazoles and pyrroles feature prominently in pharmaceutical and bioactive compounds of interest. Although their core structures differ by only a single atom (O versus C), their respective de novo ring assemblies require vastly different syntheses, as the electronically consonant isoxazole core is amenable to a range of disconnections that are inaccessible for the corresponding pyrroles. Given the structural similarity between these two heterocyclic classes, skeletal editing offers an opportunity to meet this need, as it empowers non-traditional retrosynthetic disconnections. Here we achieve an O-to-C atom replacement of isoxazoles, affording pyrroles in a one-pot sequence. We identify the N-propargylic enaminone as a key intermediate connecting the two heterocycle classes, providing a retrosynthetic disconnection orthogonal to traditional syntheses for otherwise challenging pyrrole scaffolds. During our investigations, we encountered unexpected enaminone reactivity and developed a predictive computational model capturing the conformational features controlling reaction outcomes. Regioselective syntheses of elusive pyrroles can be achieved by linking these two heterocycles with an O-to-C replacement reaction.

『摘要』 异噌唑和吡咯在药物及生物活性化合物中占据重要地位，尽管二者核心结构仅相差一个原子（氧与碳），但其从头环合成方法截然不同，因电子特性匹配的异噌唑可通过多种传统切断方式构建，而对应吡咯则无法适用；鉴于两类杂环的结构相似性，骨架编辑策略通过非传统逆合成切断为解决这一问题提供了可能——本研究实现了异噌唑向吡咯的一锅法O-to-C原子替换反应，发现N-炔丙基烯胺酮是连接二者的关键中间体，并建立了与传统合成路径正交的逆合成切断模式以构建具有挑战性的吡咯骨架；研究过程中观察到烯胺酮的非预期反应活性，开发了预测构象特征控制反应结果的计算模型，最终通过该原子替换反应实现了高区域选择性合成难获取的吡咯衍生物。

『总结』 通过O-to-C原子替换实现异噌唑到吡咯的高效转化，建立新合成路径并开发预测模型提升目标产物选择性。

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27. 聚焦电子探针的原子级双缝干涉测量法

Atomic-scale double-slit interferometry with a focused electron probe

Tabata K, Seki T, Susi T, Ishikawa R, Shibata N.; nature; (657, 8130)

『Abstract』Since Young's original work with light, double-slit interference experiments have been paradigmatic demonstrations of wave-particle duality. They now underpin modern electron, neutron, atom and molecule interferometers, whose fringe visibility and phase encode quantitative information about both the wave and the diffracting object. Extending this to atomic length scales would offer direct, local access to microscopic structure and dynamics, but has remained unexplored. Here we show that double-slit interferometry can be realized at atomic scales inside a crystal. Using scanning transmission electron microscopy (STEM), we demonstrate the generation of interference fringes with a focused electron beam that is delocalized over two adjacent Si [110] atomic columns separated by 1.36 Å. At finite temperature, these two atomic 'slits' vibrate strongly, imprinting their motion on the fringes. The fringes persist from 300 K to 900 K, indicating that only a subset of phonon modes degrades visibility; correlated thermal vibrations between neighbouring atoms preserve coherence that independent motion would otherwise destroy. Quantitative analysis of this preserved visibility provides direct experimental access to vibrational correlations between a pair of atomic columns. These correlations map to the anisotropic stiffness of the specific atomic bond, giving access to the low-energy phonon dynamics that affect thermal transport. By recasting crystals as atomic-scale interferometers, this platform enables direct visualization of local atomic arrangements and their correlated dynamics, opening routes to examine lattice dynamics at the single-bond level.

『摘要』 Double-slit interference, a foundational demonstration of wave-particle duality since Young’s experiments with light, has inspired modern interferometers for electrons, neutrons, atoms, and molecules, where fringe visibility and phase encode quantitative information about waves and diffracting objects; extending this to atomic length scales could provide direct access to microscopic structure and dynamics but remains unexplored until now, when researchers demonstrate double-slit interferometry at the atomic scale within a crystal using scanning transmission electron microscopy (STEM), generating interference fringes from an electron beam delocalized over two adjacent Si [110] columns separated by 1.36 Å, observing that while finite temperature causes strong vibrations in these atomic "slits"—imprinting motion onto the fringes—the fringes persist from 300 K to 900 K because only certain phonon modes reduce visibility, with correlated thermal vibrations between neighboring atoms preserving coherence otherwise destroyed by independent motion, enabling quantitative analysis of preserved visibility to directly measure vibrational correlations between atomic columns, which reflect anisotropic bond stiffness and low-energy phonon dynamics affecting thermal transport, thereby transforming crystals into atomic-scale interferometers for visualizing local atomic arrangements and their correlated dynamics at single-bond resolution.

『总结』 晶体中的双缝干涉实验实现了原子尺度上的波粒二象性演示，揭示了相邻原子间振动关联对维持相干性的关键作用，为研究晶格动力学和热输运提供了新方法。

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28. 物种内变异驱动热带森林抗旱性

Species intraspecific variation drives tropical forest drought resistance

Smith-Martin CM, Muscarella R, Brodribb TJ, Uriarte M.; nature; (657, 8130)

『Abstract』Severe droughts are increasingly driving tree mortality, yet predicting forest resilience remains limited by a lack of understanding of within-species variation in drought resistance. Although hydraulic traits such as embolism resistance are central to drought survival, studies conducted primarily in temperate regions have reported little intraspecific variation, implying that there are evolutionary constraints in the adaptive potential of tree species. Here we test this assumption using a dataset comprising 11 hydraulic traits for 290 trees representing 18 species collected along Puerto Rico's fourfold rainfall gradient (1,000 to 4,000 mm per year). We find that substantial intraspecific variation, together with species turnover, drives coordinated shifts in drought resistance across the gradient. Most species exhibit substantially more embolism resistance and wider stomatal safety margins in drier forests, demonstrating a considerable level of intraspecific variation in tropical trees and a mechanism for adaptation to increasingly dry conditions. Species lacking such trait variability may be highly vulnerable under a future drier climate. Incorporating both interspecific and intraspecific trait variation into predictive models will advance our ability to forecast forest resilience to intensifying droughts.

『摘要』 尽管严重干旱正日益导致树木死亡，但由于对树种内抗旱性变异的理解不足，预测森林恢复力仍受到限制。尽管栓塞抗性等水分生理特性是干旱生存的关键，但主要在温带地区开展的研究表明树种内的变异很小，这意味着树种的适应潜力存在进化上的限制。本研究利用波多黎各四倍降雨梯度（每年1000至4000毫米）下采集的290棵代表18个物种的树木的11项水分生理特性数据集检验了这一假设，发现树种内变异与物种更替共同驱动了整个梯度上抗旱性的协同变化；大多数物种在较干旱森林中表现出更高的栓塞抗性和更大的气孔安全边际，揭示了热带树木具有显著的种内变异及适应日益干燥环境的机制，缺乏这种性状变异的物种在未来气候更干燥的情况下可能高度脆弱，将种间和种内性状变异纳入预测模型将提高我们对森林应对干旱加剧能力的预测能力。

『总结』 热带树木在抗旱性方面存在显著种内变异，这有助于其适应干旱环境，而缺乏此类变异的物种则面临更高风险。

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29. 发光反应实现超分辨率成像

Luminescent-reaction-enabled super-resolution imaging

Zhu W, Zhang C, Gui J, ... , Han Z, Zhao W, Feng J.; nature; (657, 8130)

『Abstract』By breaking the optical diffraction limit, super-resolution fluorescence microscopy has advanced our understanding of biological complexity under the framework of light-excited luminescence. The use of external light excitation remains a key factor that shapes the imaging capabilities and live-cell compatibility of fluorescence-based approaches. An alternative is the reaction-excited luminescence, such as electrochemiluminescence (ECL), chemiluminescence (CL) and bioluminescence (BL), providing a chemically defined toolbox for enabling different imaging merits, from ultrasensitive analysis to biocompatible imaging. Despite its light-free excitation and high sensitivity, conventional luminescent-reaction-enabled imaging is fundamentally limited in spatiotemporal resolution owing to low photon budget. Here we develop a chemistry-based super-resolution imaging framework, luminescent-reaction-enabled super-resolution imaging via entropy-weighted correlation combined with deconvolution (RIED). As an experimental-computational concept, RIED introduces a spatiotemporal recording strategy to uncover specific luminescent-reaction-enabled imaging information content, which is efficiently collected and computed to achieve super resolution using a reconstruction strategy adapted to reaction-driven photon statistics. We achieve super-resolution ECL, CL and BL imaging of intracellular organelles, attaining approximately 100 nm resolution. This approach is used for highly sensitive imaging of surface proteins and 41-h ultralong-term continuous super-resolution live-cell imaging of mitochondrial transfer dynamics. Our work establishes an emerging class of chemistry-enabled, laser-free super-resolution microscopy with expanded biological imaging versatilities.

『摘要』 通过突破光学衍射极限，超分辨率荧光显微镜在光激发发光框架下增进了对生物复杂性的理解。使用外部光激发仍是影响基于荧光的成像方法的成像能力和活细胞兼容性的关键因素；反应激发发光（如电化学发光、化学发光和生物发光）提供了一种化学定义的工具箱，可实现从超灵敏分析到生物相容性成像的不同成像优势。尽管无光激发和高灵敏度，传统发光反应成像由于光子预算低，在时空分辨率上存在根本限制。本文开发了一种基于化学的超分辨率成像框架——通过熵加权相关结合反卷积的发光反应超分辨率成像（RIED）；作为一种实验计算概念，RIED引入了时空记录策略以揭示特定发光反应成像信息内容，并通过适应于反应驱动光子统计学的重建策略高效收集和计算这些信息以实现超分辨率。实现了细胞内细胞器的电化学发光、化学发光和生物发光的超分辨率成像，分辨率约为100 nm；该方法用于表面蛋白的高灵敏度成像以及线粒体转移动力学的41小时超长连续超分辨率活细胞成像。本研究建立了一类新兴的无激光、化学赋能的超分辨率显微镜，扩展了生物成像的多功能性。

『总结』 开发的RIED方法突破了传统发光反应成像的时空分辨率限制，实现了高灵敏度和超长时程的无激光超分辨生物成像。

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30. 量子模拟器中保形场理论光谱的观测

Observation of conformal field theory spectra in a quantum simulator

Sun X, Le Y, Naus S, ... , Knap M, Alicea J, Endres M.; nature; (657, 8130)

『Abstract』Conformal field theories (CFTs) feature prominently in high-energy physics, statistical mechanics and condensed matter. For example, CFTs govern emergent universal properties of systems tuned to quantum phase transitions, including their entanglement, correlations and low-energy excitation spectra. Much of the rich structure predicted by CFTs nevertheless remains unobserved in experiment. Here we directly observe the energy excitation spectra of emergent CFTs at quantum phase transitions-recovering universal energy ratios characteristic of the underlying field theories. Specifically, we develop and implement a modulation technique to resolve the finite-size spectra of a Rydberg chain, variably tuned to quantum phase transitions described by either Ising or tricritical Ising CFTs. We also use local control to distinguish parities of excitations under reflection and, in the tricritical Ising chain, to induce transitions between distinct CFT spectra associated with changing boundary conditions. By using a variant of the modulation technique, we furthermore study the dynamical structure factor of the critical system, which is closely related to the correlation of an underlying Ising conformal field. Our work not only probes the emergence of CFT features in a quantum simulator but also provides a technique for diagnosing a priori unknown universality classes in future experiments.

『摘要』 共形场论（CFTs）在高能物理、统计力学和凝聚态物理中占据重要地位，例如其支配了量子相变系统中的普适性特征，包括纠缠特性、关联性质及低能激发谱等；然而，实验上对CFT预测的丰富结构仍鲜有直接观测。本研究通过开发并应用调制技术解析了可调至伊辛或三临界伊辛共形场论描述的量子相变的里德堡链的有限尺寸激发谱，成功恢复了基础场理论所特有的普适能量比值；同时利用局部控制区分反射对称下的激发宇称，并在三临界伊辛链中通过改变边界条件诱导不同CFT谱间的跃迁；进一步采用调制技术的变体研究了临界系统的动力学结构因子，该因子与底层伊辛共形场的关联密切相关。研究不仅在量子模拟器中验证了CFT特征的涌现现象，还为未来实验诊断未知普适类提供了有效方法。

『总结』 通过调制技术和局部控制首次直接观测到量子相变中涌现的共形场论激发谱，揭示其普适能量比并实现不同普适类的动态调控。

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31. 人类转录因子DNA结合特异性的扩展代码本

An expanded codebook of human transcription factor DNA-binding specificity

Jolma A, Laverty KU, Fathi A, ... , Deplancke B, Kulakovskiy IV, Hughes TR.; nature; (657, 8130)

『Abstract』Gene expression is regulated by transcription factors (TFs), which recognize specific DNA sequence motifs. Several hundred putative human TFs, identified mainly by an apparent DNA-binding domain, lack known binding motifs. Furthermore, even for well-characterized TFs, it remains controversial the degree to which motifs accurately reflect binding sites in living cells. Here we describe a systematic effort ('Codebook') to determine the sequence specificity of 332 putative and poorly characterized human TFs. More than 4,000 independent experiments, encompassing multiple in vitro and in vivo assays, produced motifs for just over half (177; 53%) of the TFs, of which most are associated with only a single protein. These results extend the vocabulary of sequence recognition encoded by human TFs by around 130 distinct motifs. Moreover, binding motifs identified in vitro are strongly enriched in cellular binding sites. Collectively, the data reveal tens of thousands of previously unknown, conserved and direct TF-binding sites across the human genome. These sites are concentrated in promoter regions and are predictive of gene expression. In summary, this new codebook provides an important step forward in decoding the human genome.

『摘要』 基因表达受转录因子（TFs）调控，后者可识别特定DNA序列基序；目前数百种主要通过DNA结合结构域鉴定的人类假定转录因子缺乏已知结合基序，且即使是已充分研究的转录因子，其基序能否准确反映活细胞中的结合位点仍存在争议。本研究通过系统性“Codebook”计划对332个假定或研究不足的人类转录因子进行序列特异性分析，开展超过4000次独立实验（涵盖体内外多种检测方法），成功为其中177个（53%）转录因子确定基序（多数仅关联单一蛋白），新增约130种人类转录因子编码的序列识别模式；体外鉴定的结合基序在细胞结合位点中高度富集，全基因组范围内揭示数万个此前未知的保守型直接转录因子结合位点，这些位点集中分布于启动子区域并可预测基因表达。

『总结』 系统解析332个人类转录因子的序列特异性，新增130种结合基序并发现数万新结合位点，为解码基因组提供关键依据。

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32. 酶促糖基化和酰胺化重塑多烯生物活性

Enzymatic glycosylation and amidation reshapes polyene bioactivity

Mirza SN, Carella A, Thompson JW, ... , Thom A, Bromley M, Micklefield J.; nature; (657, 8130)

『Abstract』Fungal diseases are an escalating threat to human health, driven by rising antimicrobial resistance and a lack of new antifungal treatments. Polyenes, a class of complex natural products, have been widely used as antifungal agents due to their broad-spectrum activity. However, their clinical use is limited by severe toxicity and poor solubility, making safer and more effective alternatives urgently needed. Previous efforts to generate improved polyenes have relied on costly, step-inefficient and atom-inefficient chemical syntheses. Here we describe the discovery and characterization of pathways to previously undescribed polyenes, including unusual glycosyltransferase enzymes that introduce sugars onto polyene scaffolds. We also show how the reaction scope of an amidotransferase enzyme can be expanded to transform the detrimental carboxylate substituent of polyenes to alternative functionality. Introduction of a second sugar combined with carboxylate modifications leads to more potent polyene antifungals, with reduced toxicity, that are accessible by clean and efficient fermentation or enzymatic routes.

『摘要』 真菌疾病因抗菌药物耐药性增加和新抗真菌治疗手段缺乏，正日益威胁人类健康。多烯类化合物作为广谱抗真菌剂虽被广泛应用，但其临床应用受限于严重毒性和低溶解度，亟需开发更安全有效的替代品；此前改进多烯的研究依赖成本高、步骤和原子利用率低的化学合成方法，而本研究发现并表征了生成新型多烯的途径，包括将糖引入多烯骨架的不寻常糖基转移酶，还展示了如何扩大酰胺转移酶的反应范围以将多烯的有害羧酸取代基转化为其他功能基团，通过引入第二种糖并结合羧酸修饰可得到毒性更低且效力更强的多烯类抗真菌药物，这些药物可通过清洁高效的发酵或酶促途径获得。

『总结』 研究发现了新多烯生成途径及关键酶，经糖引入和羧酸修饰可得高效低毒多烯类抗真菌药，且生产路线清洁高效。

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33. 用于不对称自由基交叉偶联的吡哆醛光酶

Pyridoxal photoenzymes for asymmetric radical-radical cross-couplings

Sorensen CC, Wang S, Ouyang Y, ... , Mann G, Allmendinger S, Hyster TK.; nature; (657, 8130)

『Abstract』Non-native photoenzymes have enabled myriad asymmetric bond-forming events that are otherwise challenging or at present impossible with small-molecule catalysis. These reactions require enzymes with cofactors that are strong absorbers in the visible region with reasonably long-lived excited states, such as flavin and nicotinamide. However, there exists a substantial chromophoric cofactor 'dark space' in which no known photoenzymatic activity has been characterized. Increased knowledge of the photophysics of the cofactors in the 'dark space' would increase the types of bonds that photoenzymes can form by accessing new excited-state intermediates in enzyme classes with divergent reactivities and selectivities. Here, we establish pyridoxal 5'-phosphate (PLP) as a photoenzymatic cofactor by leveraging the excited-state quinonoid intermediate as a potent single-electron reductant. We overcome the poor photophysical properties of the native quinonoid intermediate by using non-native benzylamine substrates and exploiting Forster resonance energy transfer mechanism from an exogenous photosensitizer to access the quinonoid excited state. This redox neutral approach enables an asymmetric radical-radical cross-coupling between benzylamines and reductive radical precursors through concomitant generation and localization of a radical pair in an enzyme active site-overcoming the typical challenges associated with this reaction by removing the necessity for radical sorting and the persistent radical effect. The emergent photoexcited intermediates of PLP identified in this work greatly expand the potential avenues for valuable bond-forming events by PLP-dependent enzymes.

『摘要』 非天然光酶已实现众多不对称成键反应，这些反应在小分子催化下颇具挑战或目前无法完成；此类反应需含可见光强吸收且激发态寿命合理的辅因子（如黄素、烟酰胺）的酶参与，但大量色团辅因子“暗区”中尚无已知光酶活性被表征，深入了解“暗区”辅因子的光物理特性可拓展光酶成键类型，通过获取具有不同反应性和选择性的酶类中的新激发态中间体来实现。本文利用激发态醌式中间体作为强单电子还原剂，将磷酸吡哆醛(PLP)确立为光酶辅因子；针对天然醌式中间体光物理性质不佳的问题，采用非天然苄胺底物并借助外源光敏剂的福斯特共振能量转移机制激活其激发态；该氧化还原中性策略通过在酶活性位点同时生成并定位自由基对，实现了苄胺与还原性自由基前体的不对称自由基-自由基交叉偶联，克服了传统方法中自由基分选和持久自由基效应等难题。本研究发现的PLP新型光激发中间体显著拓宽了依赖PLP的酶实现高价值成键反应的可能性。

『总结』 通过利用PLP激发态醌式中间体及福斯特共振能量转移机制，首次实现苄胺与还原性自由基前体的不对称自由基交叉偶联，拓展了PLP依赖酶的光驱动成键能力。

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34. 最早的蛇类具有非凡的大脑和生态多样性

Exceptional brain and ecological diversity in the earliest snakes

Simoes TR, Sobral G, Macri S, ... , Chiappe LM, Di-Poi N, Hsiou AS.; nature; (657, 8130)

『Abstract』Understanding the ecological origin of snakes has remained a century-old challenge, hindered by an extremely sparse early fossil record and conflicting interpretations of fossil ecologies. Here we describe an exceptionally preserved Cretaceous fossil snake, Tametara mirim gen. et sp. nov., from Brazil, representing one of the earliest-diverging stem snakes. High-resolution micro-CT scans reveal unprecedented details of cranial nerves, inner ear and brain anatomy, enabling the most integrated reconstruction of stem snake neuroanatomy to date. Quantitative and qualitative endocast analyses demonstrate that Tametara had a brain morphology distinct from both other stem and extant snakes, revealing substantial early neuroanatomical disparity-and probably sensory functions-in snake evolution. Independent evidence from telencephalon shape and bone microstructure converges on a fossorial lifestyle for Tametara and non-fossorial for another stem snake: Dinilysia. These results indicate that major ecological transitions occurred early in snake evolution, and that known stem species do not represent the ancestral condition of crown snakes. Early snake evolution thus involved complex shifts in habitat use and sensory ecology, revealing greater ecological and neuroanatomical diversity than previously thought.

『摘要』 理解蛇的生态起源一直是一个百年难题，受限于早期化石记录的极度匮乏以及对化石生态的不同解释。本文描述了来自巴西的一具保存完好的白垩纪蛇类化石Tametara mirim gen. et sp. nov.，代表了最早分化的基干蛇之一；高分辨率显微CT扫描揭示了其颅神经、内耳和脑解剖结构的空前细节，实现了迄今最全面的基干蛇神经解剖重建；定量与定性内模分析表明，Tametara的脑形态既不同于其他基干蛇也不同于现生蛇类，揭示了蛇类演化早期存在显著的神经解剖差异——可能伴随感觉功能的分化；端脑形状和骨微结构独立证据共同支持Tametara为穴居生活，而另一基干蛇Dinilysia则为非穴居生活。这些结果表明蛇类演化早期已发生重大生态转变，已知基干物种并不代表冠群蛇类的祖先状态，早期蛇类演化涉及栖息地利用和感觉生态学的复杂转变，其生态和神经解剖多样性远超此前认知。

『总结』 新发现的白垩纪基干蛇化石通过神经解剖和骨骼特征揭示了蛇类早期演化中存在穴居与非穴居生态分化及显著的感觉系统多样性。

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35. 无双链断裂的高效精确可编程DNA敲入

Efficient and precise programmable DNA knock-in without double-strand breaks

Gao Y, Ma Y, Yu K, ... , Li Q, Liu M, Wang H.; nature; (657, 8130)

『Abstract』Programmable gene knock-in holds substantial promise for treating genetic diseases and advancing cell therapies. However, achieving precise and efficient kilobase-scale DNA fragment integration remains challenging. Here we report CRISPR kilobase-scale nickase-targeting (KNIT) editing for efficient, precise and programmable kilobase-scale DNA insertion without double-strand DNA cleavage, which is enabled through the coupling of a Cas9 nickase with a DNA donor recruiting system. KNIT editing facilitates programmable integration of DNA fragments from 0.7 kb to more than 10 kb and is effective across genomic loci and cell types. It achieves up to 89% efficiency and markedly reduces unintended insertion-deletion mutation (indels) rates, translocations and off-target editing. The system supports repeated insertion editing and multiloci gene knock-in with minimal translocations. Its enhanced version, KNIT editor 2, further improves efficiency via a single transfection. Moreover, in mutant cells with a pathological mutation, KNIT editing restores normal gene expression by inserting a therapeutic gene into a safe harbour locus or its native locus. Notably, KNIT editing enables non-viral and programmable chimeric antigen receptor T cell (CAR-T cell) engineering without double-strand breaks and with clinically relevant efficiencies. Moreover, the engineered CAR-T cells exhibit effective antitumour activity in vitro and in mouse models. Therefore, by achieving programmable and site-specific kilobase-scale DNA insertions without double-strand breaks while reducing unintended outcomes, KNIT editing provides a versatile platform for advancing personalized medicine.

『摘要』 可编程基因敲入在治疗遗传疾病和推进细胞疗法方面具有巨大潜力，但实现精确高效的千碱基规模DNA片段整合仍具挑战。本文报道了一种基于CRISPR的千碱基级切口酶靶向（KNIT）编辑技术，通过将Cas9切口酶与DNA供体招募系统偶联，可在无需双链DNA断裂的情况下实现高效、精准且可编程的千碱基规模DNA插入；该技术支持0.7 kb至超过10 kb DNA片段的可编程整合，适用于多种基因组位点和细胞类型，最高效率达89%，并显著降低非预期插入缺失突变、染色体易位及脱靶编辑的发生率；其增强版KNIT editor 2通过单次转染进一步提升效率，且在病理突变细胞中可通过将治疗基因插入安全位点或原始位点恢复正常基因表达；值得注意的是，KNIT编辑实现了无病毒、无双链断裂且临床相关效率的嵌合抗原受体T细胞（CAR-T细胞）工程化改造，体外和小鼠模型实验均证实了工程化CAR-T细胞的有效抗肿瘤活性。

『总结』 KNIT编辑技术通过无双链断裂的千碱基级DNA精准插入，为个性化医疗提供了多功能平台。

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36. 用于稳定叠层光伏的相均匀混合卤化物钙钛矿

Phase-homogeneous mixed-halide perovskites for stable tandem photovoltaics

Shi P, Zhuang J, Zhang D, ... , Liu C, Chen B, Sargent EH.; nature; (657, 8130)

『Abstract』Mixed-halide wide-bandgap (WBG) perovskites needed in tandem photovoltaics suffer from phase segregation, even at the time of initial film formation: the result of asymmetric nucleation of I-rich and Br-rich phases. Known homogenization strategies tune Pb²⁺ coordination strength; however, Pb²⁺-based modulation applies across all Pb²⁺ centres and does not preferentially address the problem that PbBr_x nucleates faster than does PbI_x. Here we introduce a selective coordination principle: we tune local Lewis-base hardness at the donor atom through a molecular dipole, an approach that constrains the polarizability of the oxygen donor's outermost electrons. The harder oxygen donor preferentially coordinates the harder Pb²⁺ of PbBr_x, selectively retarding Br-rich nucleation and synchronizing it with PbI_x. This leads to compositionally homogeneous WBG films, enabling solar cells with bandgaps of 1.62 eV, 1.68 eV and 1.88 eV, each achieving enhanced power conversion efficiency and extended stability (1,500 hours, ≥T₉₀, 1 sun and 65 °C). Perovskite-organic tandem cells fabricated with these WBG films and an infrared-active organic cell deliver certified 27.0% (steady-state 26.4%) efficiency, with T₉₁ (ISOS-L2 at 65 °C) of 1,000 hours.

『摘要』 混合卤化物宽禁带（WBG）钙钛矿在串联光伏器件中至关重要，但即使在初始成膜阶段也会因碘富集相和溴富集相的不对称形核而发生相分离；现有均质化策略通过调节Pb²⁺配位强度实现调控，但基于Pb²⁺的调制作用于所有铅中心且无法优先解决PbBrₓ比PbIₓ形核更快的问题。本研究提出选择性配位原理：通过分子偶极子调节供体原子处的局部路易斯碱硬度，约束氧供体外层电子的极化率，使较硬的氧供体优先与PbBrₓ中较硬的Pb²⁺配位，从而选择性地减缓富溴相形核并使其与PbIₓ同步，最终形成成分均匀的WBG薄膜，基于此制备出禁带宽度为1.62 eV、1.68 eV和1.88 eV的太阳能电池，其功率转换效率显著提升且稳定性延长至1500小时（≥T90，1个太阳光照及65 ℃条件下）；将这些WBG薄膜与红外活性有机电池结合制成的钙钛矿-有机叠层电池认证效率达27.0%（稳态效率26.4%），并在65 ℃下保持T91（ISOS-L2标准）达1000小时。

『总结』 选择性配位原理通过调控氧供体硬度抑制富溴相快速形核，实现了混合卤化物钙钛矿薄膜的成分均匀性，提升了单结和叠层太阳能电池的效率与稳定性。

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37. CRISPR-Cas调控嵌入式抗噬菌体防御系统的表达

CRISPR-Cas regulates expression of embedded anti-phage defence systems

Shu X, Wang R, Zhou X, ... , Zhang S, Zhang Y, Li M.; nature; (657, 8130)

『Abstract』Bacteria utilize diverse defence systems to protect against harmful foreign DNA such as bacteriophages, but how these systems coordinate with each other remains poorly understood. Here we uncover CRISIS (CRISPR-supervised immune system), a widespread regulatory paradigm whereby type I CRISPR-Cas loci embed and transcriptionally modulate diverse innate defences. Small non-canonical CRISPR RNA (crRNA)-like RNAs guide the I-C CRISPR-associated complex for antiviral defence (Cascade) effector complex to inhibit promoters of diverse immune cassettes-including composite multi-system clusters-enabling their basal expression for antiviral activity while mitigating fitness costs associated with hyperactivation, such as host growth impairment or exclusion of beneficial plasmids. When CRISPR-Cas is compromised by mutation or anti-CRISPR proteins, there is a burst in transcription of these embedded defence systems, leading to higher-level innate immunity at the expense of host fitness. Together, adaptive CRISPR-Cas systems orchestrate diverse innate immune systems into a layered defence network, comprising a prokaryotic 'immunity guard' strategy.

『摘要』 细菌利用多种防御系统抵御噬菌体等有害外源DNA，但这些系统如何协同作用仍知之甚少。本研究揭示了CRISIS（CRISPR监督的免疫系统）这一广泛存在的调控机制，即I型CRISPR-Cas位点嵌入并转录调控多种先天防御系统，通过小非经典CRISPR RNA样分子引导I-C型Cascade效应复合物抑制多种免疫模块（包括多系统复合簇）的启动子，在维持基础抗病毒活性的同时减轻过度激活带来的宿主生长受损或有益质粒排斥等适应性代价；当CRISPR-Cas因突变或抗CRISPR蛋白失活时，这些内嵌防御系统的转录爆发会引发更高水平的先天免疫反应，但以牺牲宿主适应性为代价。该发现表明适应性CRISPR-Cas系统将多种先天免疫机制整合为分层防御网络，构成原核生物"免疫守卫"策略。

『总结』 细菌通过CRISIS机制协调CRISPR-Cas与先天免疫系统形成分层防御网络，平衡抗病毒活性与宿主适应性。

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38. 粮食体系转型将重塑全球农业

Food systems transformation would reshape global agriculture

Gibson M, Sundiang M, Mason-D'Croz D, ... , Wiebe K, Zhao X, Herrero M.; nature; (657, 8130)

『Abstract』Food systems are a major contributor to exceeding planetary boundaries and poor quality diets are a key mortality risk globally. Projected population and income growth could exacerbate these challenges. In response, there are calls for transformation towards healthy and sustainable food systems. However, the scale and distribution of the impacts of this transformation on agriculture are underexplored. Here we show that, by 2050, the transformation of food systems towards healthy diets (adoption of the EAT-Lancet reference diet), improved productivity and halving of food waste results in a fundamental restructuring of global agriculture, aspects of which break with historical trends. Scenario simulations using a multimodel ensemble of ten global economic models show a 6% median decrease in agricultural land (+1% to -26%) compared with 2020 levels. By 2050, agricultural production would be 17% lower than business-as-usual projections (-2% to -32%) and, economically, the value of this production is US$1.6 trillion (26%) lower (+8% to -58%). Within this, the value of livestock production would be substantially lower than current 2050 projections (-49% to -83%), while vegetable, fruit, nut and legume production value would increase by 23% (-33% to +106%). Results are dependent on the assumed policies to achieve the transformation scenario. We highlight a more active role for food policy to consider the benefits of such a transformation (improved population health and reduced environmental pressures) and navigate the political economy of its impacts.

『摘要』 食物系统是突破地球边界的主要因素，而低质量饮食是全球死亡的关键风险因素。预计的人口和收入增长可能加剧这些挑战，因此人们呼吁向健康可持续的食物系统转型，但这种转型对农业的影响规模和分布尚未得到充分探索；本文表明，到2050年，食物系统向健康饮食（采用EAT-Lancet参考饮食）、提高生产力和减少一半食物浪费的转变将导致全球农业的根本性重组，其中一些方面将打破历史趋势；利用十个全球经济模型的多模型集合进行的情景模拟显示，与2020年相比，农业用地中位数下降6%（+1%至-26%），到2050年，农业生产将比常规预测低17%（-2%至-32%），经济上，该产值将减少1.6万亿美元（26%，+8%至-58%）；其中，畜牧业产值将大幅低于当前2050年的预测（-49%至-83%），而蔬菜、水果、坚果和豆类产值将增加23%（-33%至+106%）；结果取决于实现转型情景的假设政策；本文强调了食品政策在考虑此类转型的好处（改善人口健康和减轻环境压力）以及应对其影响的政治经济学方面应发挥更积极的作用。

『总结』 到2050年，向健康饮食、提高生产力及减少食物浪费转型将根本性重组全球农业，降低农业用地和生产值，改变不同农产品产值结构。

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39. 体内模块化抗体ADC点击逆转肿瘤耐药性

Modular in vivo antibody-ADC click to reverse drug resistance in tumours

Simo C, Vanover AC, D'Oliveira Albanus R, ... , Liu J, Dehdashti F, Pereira PMR.; nature; (657, 8130)

『Abstract』Antibody-drug conjugates (ADCs) have significantly advanced cancer therapy by enabling the selective delivery of cytotoxic agents to tumour cells. However, ADC efficacy remains constrained by its dependence on a single target antigen, which limits tumour targeting and promotes resistance in heterogeneous tumours with variable and low antigen expression. Here we introduce an in vivo bioorthogonal ligation strategy that generates functional antibody-ADC click constructs following systemic administration. This platform provides a modular and translatable approach for enhanced targeted drug delivery in heterogeneous tumours. We conjugate therapeutic antibodies and ADCs with trans-cyclooctene and tetrazine moieties for sequential administration to enable in vivo ligation of an antibody with an ADC after systemic delivery. The antibody-ADC click approach demonstrated improved antitumour activity relative to standard ADC monotherapy or antibody plus ADC combinations in preclinical models of HER2 and EGFR co-expression. These included tumours with low, ultralow, negative or heterogeneous HER2 expression and resistant or ineligible for conventional HER2-directed ADCs. This modular strategy leverages receptor biology and bioorthogonal chemistry for optimal therapeutic efficacy and does not require extensive antibody re-engineering. Moreover, the antibody-ADC click approach can be extended to other receptor pairs, which makes it a flexible modular platform to address heterogeneity and resistance to targeted therapies across different tumour types.

『摘要』 抗体药物偶联物（ADC）虽能选择性递送细胞毒性药物至肿瘤细胞，显著推进癌症治疗，但其疗效受限于对单一靶抗原的依赖，导致在异质性肿瘤中靶向性不足且易产生耐药性。本研究提出一种体内生物正交连接策略，通过全身给药后生成功能性抗体-ADC点击复合物，为增强异质性肿瘤的靶向药物递送提供模块化、可转化方案；研究将治疗性抗体与ADC分别修饰反式环辛烯和四嗪基团并序贯给药，实现抗体与ADC的体内连接，在HER2和EGFR共表达的临床前模型中，该策略较标准ADC单药或抗体+ADC联合疗法展现出更强的抗肿瘤活性，尤其适用于低/超低/阴性或异质性HER2表达及对传统HER2靶向ADC耐药或不适用的肿瘤，此模块化方法利用受体生物学与生物正交化学优化疗效，无需大规模抗体改造，且可扩展至其他受体组合，成为应对不同肿瘤类型异质性和靶向治疗耐药的灵活平台。

『总结』 基于体内生物正交连接的模块化抗体-ADC点击策略可突破单一靶点限制，有效克服肿瘤异质性与耐药性，提升靶向治疗效果。

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40. 褐鲶鱼黑色素瘤代表一种新型可传播癌症

Brown bullhead catfish melanoma represents a novel transmissible cancer

Curd EE, Hart SFM, Lubkowitz J, ... , Henderson MJ, Emerson P, Dragon JA.; nature; (657, 8130)

『Abstract』Since 2012, brown bullhead catfish (Ameiurus nebulosus) in a lake that spans Vermont, USA, and Quebec, Canada, have shown a high rate of melanomas, suggesting a causal contaminant or contagion. We tested the hypothesis that this affliction represents a clonally transmissible cancer, a rare phenomenon in which cancer cells themselves spread between individuals, behaving more like parasites than conventional tumours. Whole-genome sequencing of tumour and matched non-tumour host tissues revealed that tumour mitochondrial and nuclear genomes are more closely related to each other than to their hosts or unaffected fish. Hundreds of thousands of genetic variants are shared among tumour samples but are absent from host fish, vastly exceeding levels seen in conventional cancers. These findings indicate that melanoma in these brown bullheads represents the fourth documented type of naturally occurring transmissible cancer in animals, after dogs, Tasmanian devils and several bivalve species. This raises important questions about the cancer's origin, the mode of transmission and the long-term impact on fish populations.

『摘要』 自2012年起，美国佛蒙特州与加拿大魁北克省交界处某湖泊中的褐鲇鱼（Ameiurus nebulosus）出现高发黑色素瘤现象，研究通过假设该病症为克隆可传播癌症（即癌细胞本身在个体间传播的罕见机制），对肿瘤组织及宿主正常组织进行全基因组测序分析，发现肿瘤线粒体和核基因组间的亲缘关系远高于其与宿主或未患病鱼类的关联性，且数百个遗传变异在所有肿瘤样本中共享而未见于宿主鱼类，显著超出传统癌症的变异水平。这些证据表明褐鲇鱼的黑色素瘤是继犬类、袋獾和双壳贝类后第四种被证实的自然发生可传播癌症类型，引发对其起源、传播方式及对鱼类种群长期影响的关注。

『总结』 褐鲇鱼黑色素瘤被证实为第四种自然发生的可传播癌症，其癌细胞可在个体间直接传播。

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41. 果蝇出生顺序和神经元身份的全球分子编码

A global molecular code for birth order and neuronal identity in Drosophila

Cachero S, Mitletton M, Beckett IR, ... , Lacin H, Jefferis GSXE, Dona E.; nature; (657, 8130)

『Abstract』The assembly of functional neural circuits relies on the generation of diverse neural types with precise molecular identity and connectivity. Unlocking general principles of neuronal specification and wiring across the nervous system requires a systematic and high-resolution characterization of its diversity, recently enabled by advances in single-cell transcriptomics and connectomics. However, linking the molecular identity of neurons to circuit architecture remains a key challenge. Here we present a high-resolution developmental transcriptional atlas for the Drosophila melanogaster nerve cord, the central hub for sensory-motor circuits. With a considerable 38× aggregate coverage relative to its reference connectome, our atlas captures extensive molecular diversity and enables robust alignment to the adult connectome. We identified three developmental principles underlying neuronal diversity in the nerve cord. First, the timing of neurogenesis shapes diversification of molecular identity: embryonic-born neurons diverge faster than larval-born neurons, as also observed in the adult connectome. Second, 17 transcription factors common to neurons from all lineages provide a global molecular identity code for birth order. Lastly, by mapping sex-specific transcriptional profiles to the connectome, we identified female-specific apoptosis and transcriptional divergence as key global drivers of sex specification. By revealing key organizational axes of molecular identity, this atlas opens avenues to dissect the molecular mechanisms underpinning the development and evolution of neural circuits.

『摘要』 功能性神经回路的组装依赖于具有精确分子特征和连接性的多样化神经元类型的产生。要揭示整个神经系统神经元特化和布线的一般原则，需要对其多样性进行系统且高分辨率的表征，而单细胞转录组学和连接组学的最新进展为此提供了可能。然而，将神经元的分子特征与回路架构联系起来仍是一个关键挑战。本研究构建了黑腹果蝇神经索（感觉运动回路的中心枢纽）的高分辨率发育转录图谱，其综合覆盖度是参考连接组的38倍，该图谱捕捉到了广泛的分子多样性，并能与成年连接组实现可靠对齐。研究确定了神经索中神经元多样性的三个发育原则：首先，神经发生的时间影响分子特征的分化，胚胎期产生的神经元比幼虫期产生的神经元分化更快，这一现象在成年连接组中也存在；其次，所有谱系神经元共有的17个转录因子为出生顺序提供了一个全局分子身份编码；最后，通过将性别特异性转录谱映射到连接组上，发现雌性特有的细胞凋亡和转录差异是性别特化的主要驱动因素。该图谱揭示了分子身份的关键组织轴，为剖析神经回路发育和进化的分子机制开辟了新途径。

『总结』 黑腹果蝇神经索发育转录图谱揭示了神经元多样性形成的三大发育原则及分子机制。

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42. 阿尔茨海默病在不同人群中的细胞类型特征

Cell-type signatures of Alzheimer's disease shared across population groups

Luquez T, Algoo J, Chiu R, ... , Bennett DA, Zhang Y, Menon V.; nature; (657, 8130)

『Abstract』Genomic studies at single-cell resolution have identified several cell types associated with clinical and pathological traits in Alzheimer's disease, but have not examined associations that are shared across populations. To bridge this gap, here we use single-nucleus RNA sequencing and assay for transposase-accessible chromatin with sequencing to profile cortical and subcortical regions in post-mortem brain-tissue samples from Latin, white (excluding Latin) and African American (excluding Latin) individuals. Using discrete and continuous dissections of molecular programs, we identify cell-type-specific clusters associated with Alzheimer's disease in a region-specific manner across all three population groups, including microglial (GPNMB⁺ and CD74⁺ subgroups), astrocytic (SERPINH1⁺, CD44⁺ and WIF1⁺ subgroups) and neuronal (SST⁺ GABAergic and superficial-layer glutamatergic) signatures. We also report continuous gene-expression factors in astrocytes and oligodendrocytes that are not captured by discrete cluster assignments, but which show strong associations with disease phenotypes; these factors are enriched for genes associated with annotated functions such as lipid processing and neurotransmitter reuptake. Finally, we find that molecular programs reveal six distinct subgroups of individuals with cognitive impairment that span all three populations, are not captured by neuropathology, and are instead distinguished by molecular signatures that are not universally present but are nonetheless associated with ante-mortem impairment. Overall, our study identifies key cell types and gene programs implicated in Alzheimer's disease that are shared across population groups, and underscores how representative sampling can capture both shared signatures and disease heterogeneity, thereby enabling better prioritization of key cell types for further investigation.

『摘要』 单细胞分辨率的基因组研究已识别出与阿尔茨海默病临床和病理特征相关的多种细胞类型，但尚未探讨跨人群的共有关联。本研究通过单核RNA测序及转座酶可及染色质测序技术，对拉丁裔、非拉丁裔白人及非拉丁裔非洲裔个体的死后脑组织样本（皮质与皮层下区域）进行分子程序分析，发现所有三组人群中均存在区域特异性阿尔茨海默病相关细胞类型簇，包括小胶质细胞（GPNMB⁺和CD74⁺亚群）、星形胶质细胞（SERPINH1⁺、CD44⁺和WIF1⁺亚群）以及神经元（SST⁺ GABA能神经元和浅层谷氨酸能神经元）标志物；同时揭示了星形胶质细胞和少突胶质细胞中未被离散聚类捕获的连续基因表达因子，这些因子与疾病表型强相关且富集于脂质代谢和神经递质再摄取等通路功能；最终通过分子程序鉴定出横跨三组人群的六个认知障碍亚群，其特征为独立于神经病理学的非普遍性分子标志物，却与生前认知损害显著相关。

『总结』 跨种族单细胞分析揭示阿尔茨海默病共有关键细胞类型及基因程序，并发现独立于神经病理学的认知障碍分子亚群。

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43. 通过表位编辑实现非基因毒性移植和体内选择

Non-genotoxic transplantation and in vivo selection through epitope editing

Casirati G, Cosentino A, Freschi M, ... , Pellin D, Bauer D, Genovese P.; nature; (657, 8130)

『Abstract』The short-term and long-term effects of genotoxic pre-transplant conditioning remain barriers to the broader application of haematopoietic stem/progenitor cell (HSPC) transplantation and gene therapies. Although monoclonal antibodies targeting KIT have been proposed as alternatives to chemotherapy or radiotherapy, their pharmacokinetics hinder clinical applications owing to the risk of depleting transplanted HSPCs. Here, to address this issue, we identified amino acid changes in the extracellular domain of KIT that disrupt the binding of two therapeutic monoclonal antibodies, which impair stem cell factor (SCF)-mediated signalling without affecting KIT expression or functionality. We exploited adenine base editing or prime editing to efficiently introduce these mutations in HSPCs and combined them with the disruption of the BCL11A erythroid enhancer to promote expression of fetal haemoglobin (HbF), a therapeutic approach for several haemoglobinopathies. This strategy enables in vivo co-selection of gene-engineered cells to reach the threshold required to provide therapeutic benefit in patients affected by sickle cell disease and β-thalassaemia. We show progressive enrichment of KIT plus BCL11A multiplex-edited haematopoiesis under selective pressure with KIT monoclonal antibody, in vitro and in vivo. We report that extended treatment with anti-KIT regimens leads to superior in vivo enrichment while avoiding clonal selection, as assessed by a lentiviral barcoded library. Finally, by overcoming the limitations of monoclonal antibody pharmacokinetics, epitope editing enables novel haematopoietic replacement regimens that are not limited by on-target graft elimination, allowing prolonged immune-based conditioning that maximizes haematopoietic niche clearance without chemo-radiotherapy or monoclonal antibody wash-out.

『摘要』 基因毒性预处理方案的短期和长期影响仍是阻碍造血干细胞/祖细胞（HSPC）移植及基因治疗广泛应用的关键问题，尽管靶向KIT的单克隆抗体被提出作为化疗或放疗的替代方案，但其药代动力学特性导致移植后HSPCs耗竭风险，限制了临床应用。本研究通过鉴定KIT胞外域氨基酸突变位点，成功阻断两种治疗性单克隆抗体的结合而不影响KIT表达或功能，并利用腺嘌呤碱基编辑或先导编辑技术将突变引入HSPCs，同时敲除BCL11A红系增强子以促进胎儿血红蛋白（HbF）表达；该策略通过体内共选择实现基因工程细胞的富集，使镰状细胞病和β-地中海贫血患者达到治疗阈值，体外及体内实验均证实KIT与BCL11A双编辑造血系统在抗KIT单抗选择性压力下呈渐进性富集，慢病毒条形码文库分析表明延长抗KIT治疗可优化体内富集效果且避免克隆选择，最终通过表位编辑克服单抗药代动力学限制，建立无需化放疗或单抗清除的长效免疫调节预处理方案，实现造血微环境最大化清除。

『总结』 表位编辑联合基因编辑技术通过阻断单抗结合并维持KIT功能，实现了安全长效的体内细胞富集，为血液疾病基因治疗提供无化放疗预处理新策略。

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44. 手术中类人机器人的体内可行性研究

In vivo feasibility study of humanoid robots in surgery

Liang Z, Thareja N, Zhang P, ... , Liu S, Broderick R, Yip M.; nature; (657, 8130)

『Abstract』Recent advances in actuation, control and learning have rapidly pushed humanoid robots from a distant vision towards near-term real-world deployment. Healthcare is a particularly pressing domain, in which staffing shortages and increasing care demand are widening the gap between clinical workload and available skilled labour. Although current automation has largely focused on digital and logistical tasks, much hospital work remains embodied, requiring mobility, manipulation and safe interaction in human-designed environments. Humanoid form factors offer unique potential, particularly for assisting with surgical tasks. Traditionally, robotic systems for surgery are purpose-built platforms such as Intuitive Surgical's da Vinci Surgical System, and it remains unclear how close current humanoid systems are to meeting the precision, control and safety requirements of minimally invasive surgery. Here we present a systematic evaluation of contemporary humanoid technology for laparoscopic surgical tasks. We develop a humanoid-based laparoscopic teleoperation framework using general-purpose instruments and assess its abilities through benchtop characterization, dry-laboratory user studies spanning diverse surgical experience levels and in vivo porcine studies. Across these evaluations, we quantify technical feasibility, task performance and clinical readiness relative to established surgical platforms. Together, our study provides an evidence-based assessment of current humanoid abilities and limitations for surgical applications, highlighting both their promise and key technical challenges that must be addressed before clinical deployment.

『摘要』 在驱动、控制和学习领域的最新进展正迅速推动人形机器人从远景设想迈向近期现实应用，医疗领域因人员短缺和护理需求激增导致临床工作量与可用技术劳动力差距扩大，尽管当前自动化主要集中于数字和物流任务，但医院中大量工作仍需在人工设计环境中进行移动、操作和安全交互，而人形机器人在辅助外科手术方面具有独特潜力；传统手术机器人系统（如直觉外科公司的达芬奇手术系统）为专用平台，目前尚不清楚现有人形系统能否满足微创手术的精度、控制和安全性要求，为此本文系统性评估了当代人形技术在腹腔镜手术任务中的表现，开发了基于通用器械的人形机器人腹腔镜遥操作框架，并通过台架测试、涵盖不同外科经验水平的干实验室用户研究以及猪体内实验对其能力进行了评估，量化分析了其相对于现有手术平台的技术可行性、任务完成度和临床适用性。

『总结』 研究表明人形机器人具备辅助外科手术的潜力，但仍面临精度、控制和安全性等关键技术挑战。

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45. 人类增强子基因调控相互作用百科全书

An encyclopedia of human enhancer-gene regulatory interactions

Gschwind AR, Mualim KS, Karbalayghareh A, ... , Steinmetz LM, Kundaje A, Engreitz JM.; nature; (657, 8130)

『Abstract』Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the effect of human genetic variation on disease. Here we create and evaluate a resource of more than 92 million enhancer-gene regulatory interactions across 1,458 biosamples covering 369 cell types and tissues, by integrating predictive models, chromatin states, three-dimensional contacts and large-scale genetic perturbations generated by the ENCODE Consortium. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,356 element-gene pairs measured in CRISPR perturbation experiments, more than 30,000 fine-mapped expression quantitative trait loci and 569 fine-mapped genome-wide association study (GWAS) variants linked to a probable causal gene. Using this framework, we develop ENCODE-rE2G, a predictive model achieving state-of-the-art performance across several prediction tasks, demonstrating that iterative perturbations and supervised machine learning can build increasingly accurate predictive models of enhancer regulation. Using ENCODE-rE2G, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, revealing global properties of enhancer networks, identifying differences in regulatory complexity across genes and improving analyses linking noncoding variants to target genes and cell types for common complex diseases. By interpreting the model, we find that beyond enhancer activity and three-dimensional enhancer-promoter contacts, additional features that guide enhancer-promoter communication include promoter class and enhancer-enhancer synergy. These genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.

『摘要』 识别转录增强子及其靶基因对于理解基因调控以及人类遗传变异对疾病的影响至关重要。本研究通过整合预测模型、染色质状态、三维接触信息及ENCODE联盟生成的大规模遗传扰动数据，构建并评估了一个包含超过9200万条增强子-基因调控相互作用关系的资源库，覆盖1458个生物样本、369种细胞类型和组织；同时开发了系统化基准测试流程，利用CRISPR扰动实验测定的10,356个元件-基因对、超3万个精细定位的表达数量性状位点（eQTL）和569个与候选因果基因关联的全基因组关联研究（GWAS）变异进行模型比较，最终建立了高性能预测模型ENCODE-rE2G，并通过该模型绘制了人类基因组增强子-基因调控互作图谱，揭示了增强子网络的全局特性、基因间调控复杂性的差异，改进了非编码变异与靶基因及细胞类型的关联分析，还发现除增强子活性和三维增强子-启动子接触外，启动子类别和增强子协同作用也是指导增强子-启动子通信的关键特征。

『总结』 整合多维度数据构建的ENCODE-rE2G模型可精准预测增强子-基因调控关系，为解析非编码变异致病机制提供新工具。

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46. 内在细胞骨架振荡器建立神经元极性

An intrinsic cytoskeletal oscillator establishes neuronal polarity

Lin TC, Coles CH, Alfadil E, ... , Arnold HH, Schur FKM, Bradke F.; nature; (657, 8130)

『Abstract』Neurons acquire polarity by specifying one neurite as the axon, whereas the others become dendrites. But how this fundamental asymmetry is established remains unclear. Neuronal polarization has been thought to rely primarily on growth cones that sense external cues. Here we show that growth cones alone do not direct this process and that the soma acts as a central organizer of neuronal polarization. Using live imaging and genetic loss-of-function approaches in vivo, combined with optogenetic control and local cytoskeletal perturbations in cultured neurons, we uncover a soma-initiated oscillatory program that primes axon selection. Periodic actin branching that depends on the actin-related protein 2/3 (ARP2/3) complex at the soma remodels a global actomyosin network, thereby generating an actin wave that retracts neurites before propagating into a single neurite tip. Exposure to this wave relaxes local actomyosin contractility, which drives a transient microtubule-based protrusion and biases this neurite towards axon fate. As the cell exits this oscillatory stage, this neurite can overcome global inhibition and extend independently of ARP2/3, whereas actomyosin activity suppresses axon formation in the remaining neurites so that they subsequently become dendrites. This soma-driven mechanism ensures the emergence of a single axon independent of environmental cues and underpins the unidirectional information flow in neuronal circuits.

『摘要』 神经元通过指定一个神经突为轴突，其余为树突来获得极性，但这种基本不对称性的建立机制尚不明确；传统观点认为神经元极化主要依赖感受外界信号的生长锥，而本研究通过体内活体成像、遗传功能缺失方法及体外光遗传学调控和局部细胞骨架干扰实验发现，生长锥并非唯一决定因素，胞体作为神经元极化的核心组织者，启动了一个由胞体发起的振荡程序以促进轴突选择：胞体中依赖肌动蛋白相关蛋白2/3（ARP2/3）复合体的周期性肌动蛋白分支重塑了全局肌动球蛋白网络，产生沿单个神经突尖端传播的肌动蛋白波，该波暴露后松弛局部肌动球蛋白收缩力，驱动微管介导的瞬时突起并促使该神经突向轴突分化；当细胞退出振荡阶段后，此神经突可克服全局抑制独立延伸且不再依赖ARP2/3，而剩余神经突因持续受肌动球蛋白活性抑制最终形成树突，这一胞体驱动机制确保了单轴突的形成不依赖于环境线索，并为神经回路中的单向信息流奠定基础。

『总结』 神经元胞体通过启动振荡程序驱动轴突选择，确保单轴突形成不依赖环境线索。

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47. 利用纠缠重子反重子系统测量Λ电偶极矩

Measurement of the Λ electric dipole moment with an entangled baryon-antibaryon system

BESIII Collaboration†, Ablikim M, Achasov MN, ... , Zhuang XY, Zou JH, Zu J.; science; (393, 6815)

『Abstract』The dominance of matter over antimatter in the Universe has consistently driven the pursuit of new physics beyond the Standard Model that violates charge-parity symmetry. Strange baryons (hyperons) remain a largely unexplored territory in which interactions between hyperons and particles from new physics could induce a nontrivial electric dipole moment (EDM). However, direct measurements of hyperon EDMs through spin precession are highly challenging owing to their short lifetimes. In this work, we introduce a method to extract the EDM of the lightest hyperon, Λ, using the entangled [Formula: see text] system. Our result is consistent with zero, achieving a three-orders-of-magnitude improvement over the previous upper limit established in the 1980s with comparable statistics, providing stringent constraints on potential new physics.

『摘要』 宇宙中物质占主导而非反物质的现象持续推动着超越标准模型的新物理研究，这类新物理可能违反电荷宇称对称性。奇异重子（超子）领域尚未充分探索，其中超子与新物理粒子的相互作用可能引发显著的电偶极矩（EDM），但受限于超子短寿命特性，直接通过自旋进动测量其EDM极具挑战性。本研究提出利用纠缠态[公式]系统提取最轻超子Λ的电偶极矩，实验结果与零值一致，在统计量相当的情况下将20世纪80年代设定的上限提升了三个数量级，为潜在新物理提供了严格约束。

『总结』 基于纠缠态系统首次实现Λ超子电偶极矩的高精度测量，将现有理论限制提升三个数量级。

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48. 欧洲山峰上植物灭绝率不断上升

Rising plant extinction rates on European mountain summits

Wessely J, Chytry K, Gattringer A, ... , Wipf S, Pauli H, Dullinger S.; science; (393, 6815)

『Abstract』Climate change increases plant species richness in alpine ecosystems. However, to what extent this diversity enrichment masks extinction dynamics of resident species remains elusive. In this study, we used floristic resurvey data from 896 permanent vegetation plots across 62 European mountain summits to show that local extinctions have increased over the past 21 years. Extinction rates rose with the magnitude of warming, and species were more likely to go extinct toward their low-elevation range margins and in communities undergoing stronger thermophilization. Moreover, local extinctions were significantly related to preceding abundance declines, which can serve as an early warning signal. These findings suggest that despite increasing plant species richness, plant assemblages above the treeline face an accelerating but so far neglected loss of their most characteristic species.

『摘要』 气候变化虽增加了高山生态系统的植物物种丰富度，但其对本地物种灭绝动态的掩盖程度尚不明确。本研究利用欧洲62个山峰896个永久植被样地的植物学复查数据表明，过去21年里本地灭绝现象有所增加；灭绝率随升温幅度上升而升高，且物种更易在其海拔下限边缘及热化程度更高的群落中灭绝；此外，本地灭绝与前期丰度下降显著相关，后者可作为早期预警信号。这些发现表明尽管植物物种丰富度在增加，但树线以上植物群落正加速丧失其最具特征的物种，这一问题迄今尚未得到足够重视。

『总结』 气候变化导致高山植物群落虽物种丰富度上升，但特征性物种正加速灭绝且未受关注。

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49. 复制的人类染色体的构象不对称性

Conformational asymmetry of replicated human chromosomes

Corsi F, Steinacker TL, Kolesnikova S, ... , Mitter M, Gerlich DW, Goloborodko A.; science; (393, 6815)

『Abstract』DNA replication generates sister chromatids with identical sequence, yet its mechanism is fundamentally asymmetric: Chromatids inherit strands of opposite orientation, whereas forks synthesize new strands by distinct leading- and lagging-strand mechanisms. How this replication asymmetry affects chromosome organization is unknown. Using sister chromatid-sensitive conformation analysis, we found that human sister chromatids are consistently misaligned in the 5'→3' direction of inherited DNA strands. This shift persisted without cohesin-mediated loop extrusion but was lost upon disruption of cohesion. Polymer modeling showed that modest directional misalignment of cohesive cohesins can explain the observed shift, and we propose two models for how such misalignment could originate from replication fork asymmetry. This register shift between sister chromatids has implications for homology search during DNA repair.

『摘要』 DNA复制产生序列相同的姐妹染色单体，但其机制具有根本不对称性：染色单体继承方向相反的链，而复制叉通过不同的前导链和滞后链机制合成新链；目前尚不清楚这种复制不对称性如何影响染色体组织。利用对姐妹染色单体敏感的空间构象分析，研究发现人类姐妹染色单体会在遗传DNA链的5'→3'方向上持续错位，这种偏移在没有黏连蛋白介导的环挤压时仍然存在，但在破坏凝聚作用后消失；聚合物建模表明，黏附黏连蛋白的适度定向错位可以解释观察到的偏移现象，并提出了两种模型来解释这种错位可能源于复制叉的不对称性；姐妹染色单体间的这种位置偏移对DNA修复过程中的同源搜索具有重要意义。

『总结』 人类姐妹染色单体因复制叉不对称性在遗传DNA链5'→3'方向持续错位，该偏移依赖凝聚作用且影响DNA修复中的同源搜索。

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50. 工业级胶体光子薄膜的单体偏向制造

Monomer-biased manufacture of industrial-scale colloidal photonic films

Li H, Yang J, Zhao G, ... , McCune JA, Scherman OA, Wang C.; science; (393, 6815)

『Abstract』Complex functions in nature arise from the ordered assembly of simple building blocks. Transformation of colloidal aggregates into industrial-scale photonic crystals under rapid ambient conditions remains challenging owing to high energy barriers and limited assembly control. In this study, common monomers act as mediators that lower these barriers and bias ambient shear-induced ordering within seconds. This enables in situ processing compatible with roll-to-roll manufacturing of colloidal photonic crystal films with tunable mechanical properties. Robust 15-micrometer-thick films, incorporating a supramolecular matrix, can be produced up to 4000 meters long and 1.3 meters wide at a rate of 25 meters per minute. These combine vivid structural color and high transparency (>90%) with mechanical robustness and rapid self-healing, demonstrating a scalable route to high-quality colloidal photonic materials.

『摘要』 自然界中的复杂功能源于简单结构单元的有序组装，然而将胶体聚集体在快速环境条件下转化为工业级光子晶体仍面临高能垒和组装控制受限的挑战；本研究利用常见单体作为介导剂降低能垒并引导环境剪切力诱导有序化过程（耗时仅数秒），实现了与卷对卷制造工艺兼容的胶体光子晶体薄膜原位加工，其机械性能可调且可制备出含超分子基质的15微米厚稳健薄膜，生产速度达25米/分钟、长度可达4000米、宽度达1.3米，兼具鲜艳结构色、高透明度（>90%）、机械强韧性和快速自修复特性。

『总结』 通过引入单体介导环境剪切诱导有序化技术，实现高性能胶体光子晶体薄膜的大规模连续化生产。

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51. 空间分辨单细胞图谱揭示动物心脏宏观进化轨迹

Spatially resolved single-cell atlas reveals the macroevolutionary trajectory of animal hearts

Lian S, Wang W, Liu Y, ... , Fei JF, Pan S, Zhao L.; science; (393, 6815)

『Abstract』Animal hearts display diverse anatomical structures during adaptive evolution. Here, we present a multiomics atlas of adult hearts from 27 species across chordates, arthropods, and mollusks. Joint analysis indicates that Bilateria hearts share a core gene repertoire, taking a stepwise "add-on" approach as a universal evolutionary strategy. The "proto-heart" is populated by key cell types, including cardiomyocytes, fibroblasts, endothelial cells, and neural cells, which maintained core signatures while evolving with shifts in living environments and corresponding adaptations in the cardiovascular system. Additionally, we reveal an evolutionarily conserved cardiomyocyte state dynamic potentially linked to cardiac development and stress responses. Finally, we identify a common molecular program underpinning chamber evolution from a ventricular foundation. This work establishes a resource for understanding the intrinsic mechanisms of heart evolution.

『摘要』 动物心脏在适应性进化过程中展现出多样的解剖结构。本研究构建了涵盖脊索动物、节肢动物和软体动物27个物种的成年心脏多组学图谱，联合分析表明两侧对称动物心脏共享核心基因库，采用逐步“附加”策略作为普遍进化模式；“原初心脏”由心肌细胞、成纤维细胞、内皮细胞和神经细胞等关键细胞类型构成，这些细胞在维持核心特征的同时随生存环境变化发生心血管系统适应性演化；此外发现进化保守的心肌细胞状态动态可能与心脏发育及应激反应相关，并鉴定出以心室为基础的腔室进化的共同分子机制，为理解心脏进化的内在机制提供了资源。

『总结』 多组学分析揭示两侧对称动物心脏共享核心基因库，其进化依赖逐步附加策略及保守细胞状态动态机制。

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52. 丘脑NRXN1介导的对人类皮质祖细胞的输入驱动兴奋性神经发生

Thalamic NRXN1-mediated input to human cortical progenitors drives excitatory neurogenesis

Nguyen CV, Martija A, Jaklic DC, ... , Mostajo-Radji MA, Geschwind DH, Bhaduri A.; science; (393, 6815)

『Abstract』The human cerebral cortex develops through coordinated signals from within the cortex and from other brain regions, including the thalamus. However, how thalamic neuronal projections influence early human cortical development remains less well-understood. In this study, we fused cortical and thalamic organoids to investigate how thalamic input shapes the maturation of human cortical cells. Using single-nuclei RNA-sequencing and cellular imaging, we found that thalamic input increases the production of cortical excitatory neurons. We identify neurexin-1 (NRXN1) as a mediator of physical contact between thalamic axons and cortical outer radial glia. Genetic knockout of thalamic NRXN1 reduced these contacts and attenuated the production of upper-layer excitatory neurons. These findings reveal a mechanism by which thalamic input regulates human cortical progenitors and shapes excitatory neuron production during development.

『摘要』 人类大脑皮层通过皮层内部和其他脑区（包括丘脑）的协调信号发育，但丘脑神经元投射如何影响早期人类皮层发育尚不完全清楚。本研究融合皮层和丘脑类器官，利用单核RNA测序和细胞成像技术发现丘脑输入可增加皮层兴奋性神经元的生成，并鉴定出neurexin-1（NRXN1）是介导丘脑轴突与皮层外放射状胶质细胞物理接触的关键分子，敲除丘脑NRXN1会减少这种接触并削弱上层兴奋性神经元的产生，揭示了丘脑输入调控人类皮层祖细胞及兴奋性神经元生成的机制。

『总结』 丘脑输入通过NRXN1介导的物理接触促进人类皮层兴奋性神经元生成并调控其分层发育。

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53. 病原蛋白识别的合成植物免疫受体的可编程设计

Programmable design of synthetic plant immune receptors for pathogen protein recognition

Zhu H, Jiang D, Zhang Q, ... , Zhao KT, Qiu JL, Gao C.; science; (393, 6815)

『Abstract』The limited diversity and recognition scope of natural plant immune receptors impede resistance breeding against rapidly evolving pathogens. Here, we report the programmable design of synthetic plant immune receptors (SPIRs). De novo-designed binding modules targeting pathogen proteins were grafted into the integrated decoy domain of a plant immune receptor. SPIRs recognized proteins derived from viral, bacterial, fungal, and oomycete pathogens. Their performance was improved by combining artificial intelligence-guided protein design with in planta-directed evolution, enhancing immune activation while reducing autoactivation. The SPIRs exhibited high target specificity and could be stacked for multiplexed recognition of pathogen proteins. Viral-targeting SPIRs responded to infectious clones of plant viruses, and transgenic plants expressing SPIRs conferred disease resistance. This work establishes a versatile platform for the efficient engineering of plant immunity.

『摘要』 天然植物免疫受体的有限多样性和识别范围阻碍了针对快速进化病原体的抗性育种。本研究报道了合成植物免疫受体（SPIRs）的可编程设计，将靶向病原体蛋白的从头设计结合模块嫁接到植物免疫受体的整合诱饵结构域中；SPIRs可识别来自病毒、细菌、真菌和卵菌病原体的蛋白质，通过人工智能引导的蛋白质设计与体内定向进化相结合改善其性能，增强免疫激活并减少自身激活；SPIRs具有高靶标特异性且可叠加用于多重识别病原体蛋白，靶向病毒的SPIRs对植物病毒感染性克隆产生响应，表达SPIRs的转基因植物表现出抗病性，该研究为高效工程化植物免疫建立了多功能平台。

『总结』 可编程设计的合成植物免疫受体能识别多种病原体蛋白，经优化后具高特异性与多重识别能力，转基因植物表达后可获抗病性，为植物免疫工程提供新平台。

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54. 胚胎衍生肽信号指导拟南芥胚乳极性

An embryo-derived peptide signal directs endosperm polarity in Arabidopsis

Creff A, Rhodes J, Salaun C, ... , Landrein B, Zipfel C, Ingram G.; science; (393, 6815)

『Abstract』Angiosperm seed formation requires the coordinated development of the products of double fertilization-the embryo and the endosperm. The endosperm mediates efficient nutrient transfer from surrounding maternal tissues to the developing embryo. This function requires a polarized tissue organization, which manifests as early polar gene expression and polar cellularization dynamics. We show that the receptor kinase HAIKU2 (IKU2) acts in coordination with the transcription factor WRKY10/MINISEED3 (MINI3) to ensure robust endosperm polarity establishment through the activity of the homeodomain transcription factors WUSCHEL-RELATED HOMEOBOX 8 (WOX8) and WOX9. This process depends on egg cell fertilization and is mediated through the peptide PATHOGEN-INDUCED PEPTIDE-LIKE 7 (PIPL7), which acts as a potential IKU2 ligand. Our results reveal how a molecular paracrine dialog between the embryo and endosperm ensures optimal seed developmental coordination.

『摘要』 被子植物种子形成需要双受精产物胚和胚乳的协同发育，其中胚乳通过极性组织实现营养从母体组织向胚胎的高效转移，这种极性表现为早期极性基因表达及细胞化动态。研究发现受体激酶HAIKU2（IKU2）与转录因子WRKY10/MINISEED3（MINI3）协同作用，通过同源结构域转录因子WUSCHEL-RELATED HOMEOBOX 8（WOX8）和WOX9的活性确保胚乳极性的稳健建立；该过程依赖卵细胞受精并由病原诱导肽样7（PIPL7）介导，其可能作为IKU2配体发挥作用；研究揭示了胚胎与胚乳间分子旁分泌对话如何保障种子发育的最优协调。

『总结』 IKU2与MINI3通过WOX8/WOX9调控胚乳极性建立，依赖卵细胞受精及PIPL7配体介导的胚胎-胚乳旁分泌信号实现种子发育协调。

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55. 化学气相沉积聚合物薄膜中的自发极化产生强电场

Spontaneous polarization in chemical vapor-deposited polymer films creates large electric fields

Schroder S, Hartig T, Clausen KU, Strunskus T, Faupel F.; science; (393, 6815)

『Abstract』Controlled surface potentials in permanently polarized polymer films are of increasing interest for electronics, sensing, and biomedical devices. Conventional polymer films require external electric fields or postdeposition treatments, limiting precision and scalability. Here, we report a spontaneous polarization in polymer thin films polymerized through initiated chemical vapor deposition (iCVD). Surface potentials emerge spontaneously during film growth, scale linearly with film thickness, and remain stable under ambient conditions. Their magnitude is tunable through deposition parameters, and polymerization initiator choice determines the polarity. The solvent-free, single-step iCVD process enables mechanically robust, uniform coatings on complex geometries and large areas. Our findings establish a simple, versatile route to intrinsically polarized polymer films without postprocessing, opening new opportunities for direct integration of electric fields into functional devices or surface-driven processes at the nanoscale.

『摘要』 永久极化聚合物薄膜中受控的表面电位在电子、传感和生物医学设备领域的应用日益受到关注，但传统方法依赖外部电场或后处理，限制了精度与可扩展性。本研究通过引发式化学气相沉积（iCVD）制备的聚合物薄膜展现出自发电极化特性，其表面电位在成膜过程中自发形成，随膜厚线性增加且在环境条件下稳定存在，电位大小可通过沉积参数调控，聚合引发剂的选择决定极性方向；无溶剂的单步iCVD工艺可在复杂几何结构和大面积基底上实现机械性能优异且均匀的涂层。该发现为无需后处理的固有极化聚合物薄膜提供了简单通用的制备路径，为将电场直接集成到功能器件或纳米级表面驱动过程开辟了新机遇。

『总结』 通过引发式化学气相沉积制备的聚合物薄膜具有自发电极化特性，表面电位可控且稳定，工艺兼容复杂结构并支持大面积应用。

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56. 不均衡的TCR链配对约束调控表位识别

Uneven TCR chain pairing constraints govern epitope recognition

Minervina AA, Pogorelyy MV, Mayer-Blackwell K, ... , Mora T, Bradley P, Thomas PG.; science; (393, 6815)

『Abstract』Combinatorial pairing of independently recombined T cell receptor (TCR) α- and β-chains is central to diversifying the TCR repertoire. Although sequence motifs in one chain correlate with epitope recognition, the extent to which a single chain dictates specificity remains unclear. Here, we systematically tested TCR chain coupling constraints by enforcing the pairing of individual chains with hundreds of thousands of partners. Although most chains paired stably, the preservation of epitope specificity was rare and highly variable, with the frequency of compatible partners ranging from ~10 to <0.1%. This approach identified >70,000 epitope-specific TCRs across 10 epitopes. Our work illuminates the distinct contributions of TCR chains, highlights the limitations of single-chain data, and provides an experimental and analytical framework for refining TCR-peptide-major histocompatibility complex specificity inference.

『摘要』 T细胞受体（TCR）α链和β链的独立重组组合配对是TCR库多样化的核心机制，尽管单条链中的序列基序与表位识别相关，但单条链对特异性的决定程度尚不明确。本研究通过强制将单个TCR链与数十万种不同伙伴配对，系统测试了TCR链的耦合限制，发现虽然大多数链能稳定配对，但表位特异性保留罕见且高度可变，兼容伴侣的频率范围约为10%至<0.1%，此方法在10个表位中鉴定出超过70,000种表位特异性TCR。

『总结』 强制配对揭示TCR链对表位特异性的贡献有限且高度可变，为优化TCR-肽-MHC特异性推断提供了实验和分析框架。

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57. 裸盖菇素通过维持线粒体转运预防化疗诱导的周围神经病变

Psilocybin prevents chemotherapy-induced peripheral neuropathy through mitochondrial trafficking preservation

Heles M, Pasvolsky L, Sathishkumar H, ... , Jones GH, Dougherty PM, Amit M.; science; (393, 6815)

『Abstract』Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling, often irreversible toxicity that affects millions of patients, limits life-saving cancer therapy, and lacks proven treatment. In this work, we show that as little as two doses of psilocybin before chemotherapy durably prevented the onset of CIPN across platinum- and taxane-based models, including repeated chemotherapy cycles, without impairing antitumor efficacy. Peripherally, psilocybin maintained tactile sensitivity and intraepidermal nerve fiber endings through axonal mitochondrial trafficking and distribution preservation, through the TrkB-Akt-PAK5-MAP2-KIF5B pathway and remobilization of syntaphilin-anchored mitochondria. Centrally, it normalized medial prefrontal cortical synaptic activity and cortical alpha and beta electroencephalography power. This stabilization of peripheral axonal energy balance establishes psilocybin as a first-in-class prophylactic agent for CIPN while also preserving central neural function. Given psilocybin's established safety, these discoveries support clinical evaluation as a strategy to prevent CIPN.

『摘要』 化疗诱导的周围神经病变（CIPN）是一种致残性且常不可逆的毒性反应，影响数百万患者、限制救命性癌症治疗且缺乏有效疗法；本研究发现化疗前仅需两剂裸盖菇素即可在铂类和紫杉烷类模型中持久预防CIPN发生，包括重复化疗周期，且不影响抗肿瘤疗效；其机制为外周通过TrkB-Akt-PAK5-MAP2-KIF5B通路维持轴突线粒体运输与分布并重新动员syntaphilin锚定的线粒体，从而保护触觉敏感性和表皮内神经纤维末梢，中枢则通过稳定内侧前额叶皮层突触活动及调节α/β脑电波功率实现神经功能保护。

『总结』 裸盖菇素可安全预防化疗诱导的周围神经病变并维护中枢神经功能，支持其作为首创预防药物的临床评估。

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前沿速递 | NCS 集萃：2026-09-03 期

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The complete gustatory connectome of adult Drosophila reveals how taste guides feeding, foraging, and social behavior

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Atomic-scale double-slit interferometry with a focused electron probe

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Luminescent-reaction-enabled super-resolution imaging

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An expanded codebook of human transcription factor DNA-binding specificity

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Pyridoxal photoenzymes for asymmetric radical-radical cross-couplings

Exceptional brain and ecological diversity in the earliest snakes

Efficient and precise programmable DNA knock-in without double-strand breaks

Phase-homogeneous mixed-halide perovskites for stable tandem photovoltaics

CRISPR-Cas regulates expression of embedded anti-phage defence systems

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Modular in vivo antibody-ADC click to reverse drug resistance in tumours

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A global molecular code for birth order and neuronal identity in Drosophila

Cell-type signatures of Alzheimer's disease shared across population groups

Non-genotoxic transplantation and in vivo selection through epitope editing

In vivo feasibility study of humanoid robots in surgery

An encyclopedia of human enhancer-gene regulatory interactions

An intrinsic cytoskeletal oscillator establishes neuronal polarity

Measurement of the Λ electric dipole moment with an entangled baryon-antibaryon system

Rising plant extinction rates on European mountain summits

Conformational asymmetry of replicated human chromosomes

Monomer-biased manufacture of industrial-scale colloidal photonic films

Spatially resolved single-cell atlas reveals the macroevolutionary trajectory of animal hearts

Thalamic NRXN1-mediated input to human cortical progenitors drives excitatory neurogenesis

Programmable design of synthetic plant immune receptors for pathogen protein recognition

An embryo-derived peptide signal directs endosperm polarity in Arabidopsis

Spontaneous polarization in chemical vapor-deposited polymer films creates large electric fields

Uneven TCR chain pairing constraints govern epitope recognition

Psilocybin prevents chemotherapy-induced peripheral neuropathy through mitochondrial trafficking preservation

贡献排行榜

Targeting peripheral 5-HT<sub>2A</sub>R enhances antitumor immunity in colorectal cancer