【Nature】2025年10-11月刊论文导读

期刊介绍：

《Nature》创刊于1869年，是一本国际性周刊，致力于发表各领域科学和技术中最优质的经同行评审的研究，基于其原创性、重要性、跨学科兴趣、时效性和可读性的结论。《Nature》还提供快速、权威、深刻且引人注目的新闻报道与解读，涵盖影响科学、科学家和更广泛公众的热门趋势和未来趋势。最新影响因子为48.5。

Volume 646 Issue 8085, 16 October 2025

本期Nature共发表59篇文章，其中包括8篇This Week，9篇News in Focus，2篇Books & Arts，7篇Opinion，3篇Work，30篇Research。

1.Parent-of-origin effects on complex traits in up to 236,781 individuals

亲本来源对复杂性状的影响：基于多达236,781名个体的分析

瑞士洛桑大学、爱沙尼亚基因组中心、挪威卑尔根大学等机构合作发表

Abstract

Parent-of-origin effects (POEs) occur when the effect of a genetic variant depends on its parental origin. Traditionally linked to genomic imprinting, POEs are believed to occur due to parental conflict over resource allocation to offspring, resulting in opposing parental influences. Despite their importance, POEs remain underexplored in complex traits, owing to the lack of parental genomes. Here we present an approach to infer the parent of origin of alleles without parental genomes, leveraging interchromosomal phasing, mitochondrial and X chromosome data, and sex-specific crossover in siblings. Applied to the UK Biobank, this enabled parent-of-origin inference for up to 109,385 individuals. Genome-wide association study scans for 59 complex traits and over 14,000 protein quantitative trait loci contrasting maternal and paternal effects identified over 30 POEs and confirmed more than 50% of known associations. More than one third of these showed opposite parental influences, especially for traits related to growth (for example, IGF1 and height) and metabolism (for example, type 2 diabetes and triglyceride levels). Replication in up to 85,050 individuals from the Estonian Biobank and 42,346 offspring from the Norwegian Mother, Father and Child Cohort Study (MoBa) validated 87% of testable associations. Overall, our findings highlight the contribution of POEs to complex traits and support the parental conflict hypothesis, providing compelling evidence for this understudied evolutionary phenomenon.

摘要：

亲本来源效应（POEs）指基因变异的效果取决于其亲本来源。传统上与基因组印记相关，POEs被认为源于父母在后代资源分配上的冲突，导致亲本影响相互抵消。尽管其重要性显著，但由于缺乏父母基因组数据，POEs在复杂性状研究中仍未得到充分探索。该研究提出一种无需亲本基因组即可推断等位基因亲本来源的方法，该方法融合了染色体间相位分析、线粒体与X染色体数据，以及同胞间性别特异性交叉互换信息。应用于英国生物样本库后，该方法成功为109,385名个体推断出亲本来源。针对59种复杂性状及14,000余个蛋白质数量性状位点开展的全基因组关联分析，通过对比母系与父系效应，共识别出30余个POE位点，并验证了超过50%的已知关联。其中逾三分之一位点呈现相反的亲本效应，尤其在生长相关性状（如IGF1与身高）及代谢相关性状（如2型糖尿病与甘油三酯水平）中表现显著。通过爱沙尼亚生物库中多达85,050名个体及挪威父母子女队列研究（MoBa）中42,346名后代的验证，87%的可验证关联得到确认。总体而言，该发现凸显了POE对复杂性状的贡献，支持亲代冲突假说，为这一研究不足的进化现象提供了有力证据。

2.Single-cell transcriptomic and genomic changes in the ageing human brain

衰老人类大脑中的单细胞转录组与基因组变化

美国马萨诸塞大学

Abstract

Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process. In the human brain, the prefrontal cortex undergoes age-related changes that can affect cognitive functioning later in life. Here, using single-nucleus RNA sequencing (snRNA-seq), single-cell whole-genome sequencing (scWGS) and spatial transcriptomics, we identify gene-expression and genomic changes in the human prefrontal cortex across lifespan, from infancy to centenarian. snRNA-seq identified infant-specific cell clusters enriched for the expression of neurodevelopmental genes, as well as an age-associated common downregulation of cell-essential homeostatic genes that function in ribosomes, transport and metabolism across cell types. Conversely, the expression of neuron-specific genes generally remains stable throughout life. These findings were validated with spatial transcriptomics. scWGS identified two age-associated mutational signatures that correlate with gene transcription and gene repression, respectively, and revealed gene length- and expression-level-dependent rates of somatic mutation in neurons that correlate with the transcriptomic landscape of the aged human brain. Our results provide insight into crucial aspects of human brain development and ageing, and shed light on transcriptomic and genomic dynamics.

摘要：

随着时间推移，大脑和身体中的细胞会积累损伤，这会加速衰老进程。在人类大脑中，前额叶皮层会发生与年龄相关的变化，这些变化可能影响晚年的认知功能。该研究通过单核RNA测序（snRNA-seq）、单细胞全基因组测序（scWGS）和空间转录组学技术，揭示了人类前额叶皮层从婴儿期到百岁老人整个生命周期中的基因表达和基因组变化。snRNA-seq技术发现婴儿特异性细胞群富集神经发育相关基因表达，同时跨细胞类型普遍存在与年龄相关的细胞稳态基因下调现象——这些基因在核糖体、运输和代谢通路中发挥关键作用。相反，神经元特异性基因的表达水平在整个生命周期中通常保持稳定。空间转录组学验证了上述发现。单细胞全基因组测序识别出两种与年龄相关的突变特征，分别关联基因转录与基因抑制过程，并揭示神经元中存在依赖基因长度与表达水平的体细胞突变速率，该速率与衰老人类大脑的转录组图谱呈相关性。该研究揭示了人类大脑发育与衰老的关键机制，并为转录组与基因组动态变化提供了新见解。

3.Microglia regulate GABAergic neurogenesis in prenatal human brain through IGF1

小胶质细胞通过IGF1调节人类胎儿大脑中的γ-氨基丁酸能神经发生

美国加州大学旧金山分校

Abstract

GABAergic neurons are essential cellular components of neural circuits. Their abundance and diversity have increased significantly in the human brain, contributing to the expanded cognitive capacity of humans. However, the developmental mechanism underlying the extended production of GABAergic neurons in the human brain remains elusive. Here we uncovered the microglial regulation of the sustained proliferation of GABAergic progenitors and neuroblasts in the human medial ganglionic eminence (hMGE). We showed that microglia are preferentially distributed in the proliferating zone and identified insulin-like growth factor 1 (IGF1) and its receptor IGR1R as the predicted top ligand–receptor pair underlying microglia–progenitor communication in the prenatal hMGE. Using our newly developed neuroimmune hMGE organoids, which mimic the hMGE cytoarchitecture and developmental trajectory, we demonstrated that microglia-derived IGF1 promotes progenitor proliferation and production of GABAergic neurons. Conversely, IGF1-neutralizing antibodies and IGF1 knockout human embryonic stem-cell-induced microglia abolish the induced microglia-mediated progenitor proliferation. Together, these findings revealed a previously unappreciated role of microglia-derived IGF1 in promoting the proliferation of neural progenitors and the development of GABAergic neurons in the human brain.

摘要：

γ-氨基丁酸能神经元是神经回路的关键细胞组分。其在人类大脑中的丰度与多样性显著增加，推动了人类认知能力的拓展。然而，人类大脑中γ-氨基丁酸能神经元持续增殖的发育机制仍未明晰。该研究揭示了小胶质细胞对人类内侧丘状隆起（hMGE）中γ-氨基丁酸能前体细胞与神经母细胞持续增殖的调控作用。研究发现小胶质细胞优先分布于增殖区，并鉴定出胰岛素样生长因子1（IGF1）及其受体IGF1R是胎期hMGE中小胶质细胞与前体细胞间通信的核心配体-受体对。通过新开发的神经免疫hMGE类器官（其模拟了hMGE的细胞结构和发育轨迹），证明小胶质细胞衍生的IGF1能促进前体细胞增殖和GABA能神经元的产生。相反，IGF1中和抗体和IGF1敲除的人胚胎干细胞诱导的小胶质细胞则消除了由诱导小胶质细胞介导的前体细胞增殖。综合而言，这些发现揭示了小胶质细胞衍生的IGF1在促进神经前体细胞增殖和人脑中GABA能神经元发育方面具有此前未被重视的作用。

4.Haematopoietic stem cell number is not solely defined by niche availability

造血干细胞数量并非仅由生态位可用性决定

美国阿尔伯特爱因斯坦医学院、圣达菲研究所等机构合作发表

Abstract

Haematopoietic stem cells (HSCs) reside in specialized microenvironments, referred to as niches, and the classical model suggests that HSC numbers are predominantly determined by the niche size. However, the vast excess of niche cells relative to HSCs challenges this perspective. To rigorously define the role of niche size in regulating HSC numbers, we developed a femur-transplantation system, enabling us to increase available HSC niches. Notably, the addition of niches did not alter the total HSC numbers in the body, suggesting the presence of a systemic mechanism that limits HSC numbers. Additionally, HSC numbers in transplanted wild-type femurs did not exceed physiological levels when HSCs were mobilized from defective endogenous niches to the periphery, indicating that HSC numbers are constrained at the local level as well. The notion of dual restrictions at systemic and local levels was further supported by other experimental approaches, including parabiosis and non-conditioned transfer of HSCs after bone transplantation. Moreover, we found that thrombopoietin has a pivotal role in determining the total number of HSCs in the body, even in the context of increased niche availability. Our study redefines key principles underlying HSC number regulation, providing insights into this critical biological process.

摘要：

造血干细胞（HSCs）栖息于被称为“生态位”的特殊微环境中，经典模型认为HSC数量主要由生态位容量决定。然而，生态位细胞数量远超HSC的现象对此观点提出挑战。为精确界定生态位容量在调控HSC数量中的作用，该研究建立了股骨移植模型，从而增加可用HSC生态位数量。值得注意的是，增加生态位数量并未改变体内HSC总量，表明存在限制HSC数量的系统性机制。此外，当缺陷性内源性生态位中的HSC被动员至外周时，移植至野生型股骨中的HSC数量仍未超过生理水平，表明HSC数量在局部层面同样受到限制。通过异体共生实验及骨移植后非预处理造血干细胞转移等方法，进一步证实了系统性与局部双重限制的理论。更关键的是，研究发现血小板生成素在决定体内造血干细胞总量方面具有核心作用，即使在生态位环境改善的条件下亦然。该研究重新定义了造血干细胞数量调控的核心机制，为理解这一关键生物学过程提供了新视角。

5.Amygdala–liver signalling orchestrates glycaemic responses to stress

杏仁核-肝脏信号传导协调应激状态下的血糖反应

美国纽约西奈山伊坎医学院、阿尔伯特爱因斯坦医学院

Abstract

Behavioural adaptations to environmental threats are crucial for survival and necessitate rapid deployment of energy reserves. The amygdala coordinates behavioural adaptations to threats, but little is known about its involvement in underpinning metabolic adaptations. Here we show that acute stress activates medial amygdala (MeA) neurons that innervate the ventromedial hypothalamus (MeAVMH neurons), which precipitates hyperglycaemia and hypophagia. The glycaemic actions of MeAVMH neurons occur independently of adrenal or pancreatic glucoregulatory hormones. Using whole-body virus tracing, we identify a polysynaptic connection from MeA to the liver that promotes the rapid synthesis of glucose by hepatic gluconeogenesis. Repeated stress exposure disrupts MeA control of blood glucose, resulting in diabetes-like dysregulation of glucose homeostasis. Our findings reveal an amygdala–liver axis that regulates rapid glycaemic adaptations to stress and links recurrent stress to metabolic dysfunction.

摘要：

行为适应对环境威胁至关重要，需快速调动能量储备以确保生存。杏仁核虽能协调威胁应对行为，但其在代谢适应中的作用尚不明确。该研究发现急性应激可激活内侧杏仁核（MeA）神经元，这些神经元通过支配腹内侧下丘脑（MeAVMH神经元）引发高血糖与食欲减退。MeAVMH神经元的血糖调节作用独立于肾上腺或胰腺的血糖调节激素。通过全身病毒追踪技术，发现从杏仁核到肝脏的多突触连接可促进肝脏糖异生快速合成葡萄糖。反复应激暴露会破坏杏仁核对血糖的调控，导致类似糖尿病的葡萄糖稳态失调。该研究揭示了杏仁核-肝轴在调节应激反应的快速血糖适应机制中的作用，并阐明了反复应激与代谢功能障碍之间的关联。

6.Reprogramming neuroblastoma by diet-enhanced polyamine depletion

通过饮食增强的多胺耗竭重编程神经母细胞瘤

瑞士苏黎世大学、美国费城儿童医院、宾夕法尼亚大学等机构合作发表

Abstract

Neuroblastoma is a highly lethal childhood tumour derived from differentiation-arrested neural crest cells. Like all cancers, its growth is fuelled by metabolites obtained from either circulation or local biosynthesis. Neuroblastomas depend on local polyamine biosynthesis, and the inhibitor difluoromethylornithine has shown clinical activity. Here we show that such inhibition can be augmented by dietary restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumour differentiation and profound survival gains in the Th-MYCN mouse model. Specifically, an arginine- and proline-free diet decreases the amount of the polyamine precursor ornithine and enhances tumour polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at codons with adenosine in the third position. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by combined dietary and pharmacological intervention, favours a pro-differentiation proteome. These results suggest that the genes of specific cellular programmes have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of paediatric cancers.

摘要：

神经母细胞瘤是一种致死率极高的儿童肿瘤，源自分化受阻的神经嵴细胞。与所有癌症一样，其生长依赖于通过循环系统或局部生物合成获得的代谢物。该肿瘤依赖于局部多胺生物合成，且抑制剂二氟甲基鸟氨酸已展现出临床活性。该研究揭示：通过饮食限制上游氨基酸底物可增强此类抑制作用，从而破坏致癌蛋白翻译、促进肿瘤分化，并在Th-MYCN小鼠模型中显著延长生存期。具体而言，精氨酸-脯氨酸双重限制饮食可降低多胺前体鸟氨酸含量，并增强二氟甲基鸟氨酸对肿瘤多胺的耗竭作用。这种多胺耗竭意外地导致核糖体停滞，且特异性集中于第三位点含腺嘌呤的密码子。此类密码子在细胞周期基因中富集，而在神经分化基因中稀缺。因此，通过饮食与药物联合干预导致的密码子翻译障碍，促进了促分化蛋白质组的形成。这些结果表明：特定细胞程序的基因已进化出标志性的密码子使用偏好，使其能在代谢应激下实现协调的翻译重编程；该过程可被靶向利用以激活儿童癌症的分化。

7.The Virtual Lab of AI agents designs new SARS-CoV-2 nanobodies

人工智能虚拟实验室设计新型SARS-CoV-2纳米抗体

美国斯坦福大学、Chan Zuckerberg Biohub

Abstract

Science frequently benefits from teams of interdisciplinary researchers, but many scientists do not have easy access to experts from multiple fields. Although large language models (LLMs) have shown an impressive ability to aid researchers across diverse domains, their uses have been largely limited to answering specific scientific questions rather than performing open-ended research. Here we expand the capabilities of LLMs for science by introducing the Virtual Lab, an artificial intelligence (AI)–human research collaboration to perform sophisticated, interdisciplinary science research. The Virtual Lab consists of an LLM Principal Investigator agent guiding a team of LLM scientist agents through a series of research meetings, with a human researcher providing high-level feedback. We applied the Virtual Lab to design nanobody binders to recent variants of SARS-CoV-2. The Virtual Lab created a novel computational nanobody design pipeline that incorporates the protein language model ESM, the protein folding model AlphaFold-Multimer and the computational biology software Rosetta and designed 92 new nanobodies. Experimental validation reveals a range of functional nanobodies with promising binding profiles across SARS-CoV-2 variants. In particular, two new nanobodies exhibit improved binding to the recent JN.1 or KP.3 variants while maintaining strong binding to the ancestral viral spike protein, suggesting that these are suitable candidates for further investigation. This work demonstrates how the Virtual Lab can rapidly make an impactful, real-world scientific discovery.

摘要：

科学研究常受益于跨学科团队协作，但许多科学家难以接触到多领域专家。尽管大型语言模型（LLMs）展现出协助多领域研究的卓越能力，其应用却主要局限于解答特定科学问题，而非开展开放式研究。该研究通过引入“虚拟实验室”——一种人工智能与人类研究者协作开展复杂跨学科科学研究的模式，拓展了LLMs在科学领域的应用边界。虚拟实验室由LLM首席研究员代理主导，通过系列研究会议引导LLM科学家代理团队开展工作，并由人类研究员提供高层次反馈。该研究运用虚拟实验室针对新型冠状病毒近期变异株设计纳米抗体结合物。该系统构建了创新的计算纳米抗体设计流程，整合了蛋白质语言模型ESM、蛋白质折叠模型AlphaFold-Multimer及计算生物学软件Rosetta，成功设计出92种新型纳米抗体。实验验证揭示了多种功能性纳米抗体，其在SARS-CoV-2变异株中展现出极具前景的结合特性。其中两种新型纳米抗体在保持对原始病毒刺突蛋白强结合力的同时，对近期出现的JN.1或KP.3变异株展现出增强的结合能力，表明这些抗体是值得深入研究的理想候选物。这项工作证明了虚拟实验室如何快速实现具有重大现实意义的科学突破。

8.Thymic epithelial cells amplify epigenetic noise to promote immune tolerance

胸腺上皮细胞通过放大表观遗传噪声促进免疫耐受

美国芝加哥大学、斯坦福大学、Chan Zuckerberg Biohub等机构合作发表

Abstract

Cellular plasticity is a principal feature of vertebrate adaptation, tissue repair and tumorigenesis. However, the mechanisms that regulate the stability of somatic cell fates remain unclear. Here, we use the somatic plasticity of thymic epithelial cells, which facilitates the selection of a self-discriminating T cell repertoire, as a physiological model system to show that fluctuations in background chromatin accessibility in nucleosome-dense regions are amplified during thymic epithelial maturation for the ectopic expression of genes restricted to other specialized cell types. This chromatin destabilization was not dependent on AIRE-induced transcription but was preceded by repression of the tumour suppressor p53. Augmenting p53 activity indirectly stabilized chromatin, inhibited ectopic transcription, limited cellular plasticity and caused multi-organ autoimmunity. Genomic regions with heightened chromatin accessibility noise were selectively enriched for nucleosome-destabilizing polymeric AT tracts and were associated with elevated baseline DNA damage and transcriptional initiation. Taken together, our findings define molecular levers that modulate cell fate integrity and are used by thymic epithelial cells for immunological tolerance.

摘要：

细胞可塑性是脊椎动物适应性、组织修复和肿瘤发生的核心特征。然而，调控体细胞命运稳定性的机制仍不明确。该研究以胸腺上皮细胞的体细胞可塑性（该特性有助于筛选具有自我识别能力的T细胞谱系）作为生理模型系统，揭示胸腺上皮细胞成熟过程中，核小体密集区域的染色质可及性背景波动会得到放大，从而促进其他特殊细胞类型特异性基因的异位表达。这种染色质不稳定性并非依赖于AIRE诱导的转录，而是由肿瘤抑制因子p53的抑制作用先行引发。增强p53活性可间接稳定染色质、抑制异位转录、限制细胞可塑性并引发多器官自身免疫。染色质可及性噪声增强的基因组区域富集了破坏核小体稳定性的聚合AT序列，并与基线DNA损伤及转录起始水平升高相关。综合而言，该研究揭示了调控细胞命运完整性的分子杠杆机制，这些机制被胸腺上皮细胞用于实现免疫耐受。

9.Targeting G1-S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors

使用细胞周期蛋白A/B RxL抑制剂靶向G1-S检查点受损的癌症

美国哈佛医学院、Circle Pharma、德克萨斯大学西南医学中心等机构合作发表

Abstract

Small-cell lung cancers (SCLCs) contain near-universal loss-of-function mutations in RB1 and TP53, compromising the G1–S checkpoint and leading to dysregulated E2F activity. Other cancers similarly disrupt the G1–S checkpoint through loss of CDKN2A or amplification of cyclin D or cyclin E, also resulting in excessive E2F activity. Although E2F activation is essential for cell cycle progression, hyperactivation promotes apoptosis, presenting a therapeutic vulnerability. Cyclin proteins use a conserved hydrophobic patch to bind to substrates bearing short linear RxL motifs. Cyclin A represses E2F through an RxL-dependent interaction, which, when disrupted, hyperactivates E2F. However, this substrate interface has remained difficult to target. Here we developed cell-permeable, orally bioavailable macrocyclic peptides that inhibit RxL-mediated interactions of cyclins with their substrates. Dual inhibitors of cyclin A and cyclin B RxL motifs (cyclin A/Bi) selectively kill SCLC cells and other cancer cells with high E2F activity. Genetic screens revealed that cyclin A/Bi induces apoptosis through cyclin B- and CDK2-dependent spindle assembly checkpoint activation. Mechanistically, cyclin A/Bi hyperactivates E2F and cyclin B by blocking cyclin A–E2F and cyclin B–MYT1 RxL interactions. Notably, cyclin A/Bi promoted the formation of neomorphic cyclin B–CDK2 complexes, which drive spindle assembly checkpoint activation and mitotic cell death. Finally, orally administered cyclin A/Bi showed robust anti-tumour activity in chemotherapy-resistant SCLC patient-derived xenografts. These findings reveal gain-of-function mechanisms through which cyclin A/Bi triggers apoptosis and support their development for E2F-driven cancers.

摘要：

小细胞肺癌（SCLC）普遍存在RB1和TP53基因的失活突变，这破坏了G1-S期检查点功能，导致E2F活性失调。其他癌症也常通过CDKN2A缺失或周期素D/E扩增破坏G1-S期检查点，同样导致E2F过度活化。尽管E2F激活对细胞周期进展至关重要，但过度激活会促进凋亡，形成治疗靶点。周期蛋白通过保守疏水区段与携带短线性RxL基序的底物结合。周期蛋白A通过RxL依赖性相互作用抑制E2F，该相互作用一旦中断将导致E2F过度激活。然而该底物界面始终难以靶向。该研究开发出可渗透细胞且口服有效的巨环肽，能抑制周期蛋白通过RxL介导的底物结合。这种针对周期蛋白蛋白A/B的RxL基序的双重抑制剂（cyclin A/Bi），可选择性杀伤小细胞肺癌细胞及其他高E2F活性的癌细胞。基因筛选揭示，cyclin A/Bi通过激活环磷酸腺苷B-依赖性及CDK2依赖性纺锤体组装检查点诱导凋亡。其作用机制在于：cyclin A/Bi通过阻断周期蛋白A-E2F及周期蛋白B-MYT1的RxL相互作用，过度激活E2F和周期蛋白B。值得注意的是，cyclin A/Bi促进了新形态周期素B-CDK2复合物的形成，该复合物驱动纺锤体组装检查点激活并引发有丝分裂细胞死亡。最终，口服cyclin A/Bi在化疗耐药的小细胞肺癌患者来源异种移植瘤模型中展现出强效抗肿瘤活性。这些发现揭示了cyclin A/Bi通过获得功能机制触发细胞凋亡的途径，为其在E2F驱动型癌症中的开发提供了依据。

10.Cocaine chemogenetics blunts drug-seeking by synthetic physiology

可卡因化学遗传学通过合成生理学抑制药物渴求行为

美国国家药物滥用研究所、霍华德休斯医学研究所、加州大学等机构合作发表

Abstract

Chemical feedback is ubiquitous in physiology but is challenging to study without perturbing basal functions. One example is addictive drugs, which elicit a positive-feedback cycle of drug-seeking and ingestion by acting on the brain to increase dopamine signalling. However, interfering with this process by altering basal dopamine also adversely affects learning, movement, attention and wakefulness. Here, inspired by physiological control systems, we developed a highly selective synthetic physiology approach to interfere with the positive-feedback cycle of addiction by installing a cocaine-dependent opposing signalling process into this body–brain signalling loop. We used protein engineering to create cocaine-gated ion channels that are selective for cocaine over other drugs and endogenous molecules. Expression of an excitatory cocaine-gated channel in the rat lateral habenula, a brain region that is normally inhibited by cocaine, suppressed cocaine self-administration without affecting food motivation. This artificial cocaine-activated chemogenetic process reduced the cocaine-induced extracellular dopamine rise in the nucleus accumbens. Our results show that cocaine chemogenetics is a selective approach for countering drug reinforcement by clamping dopamine release in the presence of cocaine. In the future, chemogenetic receptors could be developed for additional addictive drugs or hormones and metabolites, which would facilitate efforts to probe their neural circuit mechanisms using a synthetic physiology approach. As these chemogenetic ion channels are specific for cocaine over natural rewards, they may also offer a route towards gene therapies for cocaine addiction.

摘要：

化学反馈在生理学中无处不在，但若不干扰基础功能则难以研究。成瘾性药物便是典型例证——它们通过作用于大脑增强多巴胺信号传导，从而诱发寻求药物与摄入的正反馈循环。然而，通过改变基础多巴胺水平来干扰此过程，也会对学习、运动、注意力和觉醒状态产生负面影响。受生理调控系统启发，该研究开发了一种高度特异性的合成生理学方法，通过在体脑信号回路中植入可卡因依赖性对抗信号过程，干扰成瘾的正反馈循环。研究通过蛋白质工程构建出可卡因门控离子通道，该通道对可卡因具有选择性，能特异性响应可卡因而非其他药物及内源性分子。在大鼠外侧丘脑（该脑区通常受可可因抑制）表达兴奋性可卡因门控通道后，可抑制可卡因自我给药行为而不影响食物动机。这种人工构建的可卡因激活型化学遗传学过程显著降低了伏隔核中可卡因诱导的细胞外多巴胺升高。研究结果表明，可卡因化学遗传学通过在可卡因存在时锁定多巴胺释放，成为对抗药物强化作用的选择性策略。未来可开发针对其他成瘾药物、激素及代谢物的化学遗传学受体，助力通过合成生理学方法探究其神经回路机制。鉴于这些化学遗传学离子通道对可卡因的专一性优于天然奖赏物质，它们亦可能为可卡因成瘾的基因治疗开辟新路径。

11.Crystal structures of agonist-bound human cannabinoid receptor CB1

激动剂结合的人源大麻素受体CB1的晶体结构

上海科技大学、中国科学院大学、美国东北大学等机构合作发表

Abstract

Cannabinoid receptor 1 (CB1) is the primary target of the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive constituent of marijuana. Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841). The two CB1–agonist complexes reveal important conformational changes in the overall structure relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G protein-binding region. Furthermore, a twin toggle switch of Phe2003.36 and Trp3566.48 (where the superscripts denote Ballesteros–Weinstein numbering) is experimentally observed and seems to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Δ9-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

摘要：

大麻素受体1（CB1）是大麻精神活性成分Δ9-四氢大麻酚（Δ9-THC）的主要作用靶点。该研究报道了人源CB1与四氢大麻酚（AM11542）及六氢大麻酚（AM841）形成的两种激动剂结合晶体结构。这两种CB1-激动剂复合物相较于拮抗剂结合态，其整体结构发生了显著构象变化：配体结合口袋体积缩小53%，G蛋白结合区域表面积增大。此外，实验观察到由Phe2003.36和Trp3566.48（上标表示Ballesteros-Weinstein编号）构成的双重拨动开关，该结构似乎对受体激活至关重要。这些结构揭示了CB1激活机制的重要线索，为预测Δ9-THC及内源性/合成大麻素的结合模式提供了分子基础。CB1结合口袋的可塑性似乎是某些A类G蛋白偶联受体的共同特征。这些发现将推动具有独特药理特性的多样化化学配体设计。

Volume 646 Issue 8086, 23 October 2025

本期Nature共发表60篇文章，其中包括6篇This Week，8篇News in Focus，1篇Books & Arts，7篇Opinion，2篇Work，30篇Research，5篇Amendments & Corrections，1篇Nature Index。

1. Rate and noise in human amygdala drive increased exploration in aversive learning

人类杏仁核中的速率与噪声驱动厌恶性学习中的探索行为增强

以色列雷霍沃特魏茨曼科学研究所、特拉维夫大学医学院、特拉维夫Sourasky医疗中心等机构合作发表

Abstract

To cope in uncertain environments, animals must balance their actions between using current resources and searching for new ones. This exploration–exploitation dilemma has been studied extensively in paradigms involving positive outcomes, and neural correlates have been identified in frontal cortices and subcortical structures, including the amygdala. Importantly, exploration is just as essential for survival or well-being when trying to avoid negative outcomes, yet we do not know whether the single-neuron mechanisms that drive exploration are shared across positive and negative environments. Here we examined the dynamics of exploration when human participants engaged in a probabilistic learning task with intermixed loss and gain trials, while simultaneously recording single-neuron activity. We show that neurons of the amygdala and temporal cortex modulate their activity before a decision to explore in both loss and gain. Moreover, we find that humans exhibit more exploration when trying to avoid losses, and that an increase in the levels of noise in amygdala neurons contributes to this behaviour. Overall, we report that human exploration is driven by two distinct neural mechanisms, a valence-independent rate signal and a valence-dependent global noise signal. The results suggest a link between the heightened amygdala activity observed in mood disorders and higher exploration rates that underlie maladaptive and even pathological behaviours.

摘要：

为应对不确定环境，动物必须在利用现有资源与探索新资源之间取得行动平衡。这种探索与开发两难困境已在涉及积极结果的范式中得到广泛研究，其神经关联已被识别于前额叶皮层及杏仁核等皮层下结构中。值得注意的是，当试图规避负面结果时，探索行为对生存或福祉同样至关重要。然而尚不清楚驱动探索的单神经元机制是否适用于正负环境。该研究通过让受试者参与混合损失与收益试次的概率学习任务，同时记录单神经元活动，考察了探索行为的动态变化。研究发现，无论面临损失或收益，杏仁核和颞叶皮层的神经元在探索决策前都会调节其活动。此外，研究发现人类在规避损失时表现出更强的探索倾向，而杏仁核神经元噪声水平的增加对此行为具有促进作用。总体而言，研究发现人类探索行为由两种独立神经机制驱动：一种是价值无关的速率信号，另一种是价值相关的全局噪声信号。研究结果揭示了情绪障碍中观察到的杏仁核活动增强与探索率升高之间的关联，这种探索率升高正是导致适应不良甚至病理行为的基础机制。

2.Human gastroids to model regional patterning in early stomach development

利用人源胃类器官模拟早期胃发育中的区域模式形成

清华大学、中国科学院大学、美国密歇根大学等机构合作发表

Abstract

The human stomach features distinct, regionalized functionalities along the anterior–posterior axis. Historically, studies on stomach patterning have used animal models to identify the underlying principles. Recently, human pluripotent stem (hPS)-cell-based gastric organoids for modelling domain-specific development of the fundic and antral epithelium are emerging. However, recapitulating self-organized fundic–antral patterning in early stomach organogenesis remains challenging, presenting a considerable barrier for advancing knowledge of stomach organogenesis. Here we report human gastroids—a self-organized multilineage gastric organoid derived from hPS cells—to model gastric fundic–antral patterning in vitro. Through multi-germ-layer co-development, we generate gastroids that feature an epithelial chamber with bipolar fundic–antral patterning, annexed with neural populations near the fundic domain while enveloped by mesenchymal cells, therefore showing molecular, cellular, structural and anatomical similarity to stomach development in vivo. Non-endodermal cells, especially neural populations, function as a critical signalling centre to instruct fundic–antral patterning in gastroids through WNT-mediated crosstalk. Single-cell transcriptomic profiling and genetic silencing further reveal NR2F2 as a key mediator of fundic–antral patterning in gastroid development. This study reveals a principle for instructing gastric patterning and provides a higher-fidelity platform for advancing knowledge of stomach organogenesis and gastric organoid development.

摘要：

人类胃部沿前后轴呈现出独特的区域化功能。历史上，胃部模式形成的研究主要通过动物模型来揭示其基本原理。近年来，基于人类多能干细胞（hPS）的胃类器官模型开始涌现，用于模拟胃底和胃窦上皮的区域特异性发育。然而，重现早期胃器官发生过程中自发形成的胃底-胃窦区域模式仍具挑战性，这成为推进胃器官发生研究的重要障碍。该研究首次报道基于hPS细胞构建的自发性多谱系胃类器官——人胃类器官，用于体外模拟胃底-胃窦区域模式。通过多胚层协同发育，构建出具有双极性胃底-胃窦模式的上皮腔室，该腔室在胃底区域邻近神经细胞群，同时被间充质细胞包裹，从而在分子、细胞、结构和解剖层面均呈现与体内胃发育相似的特征。非内胚层细胞（尤其是神经细胞群）通过WNT介导的交叉通讯，在胃类器官中发挥关键信号中枢作用，指导胃底-胃窦区域的模式形成。单细胞转录组测序与基因沉默实验进一步揭示NR2F2是胃类器官发育中底端-窦端模式形成的关键调控因子。该研究阐明了胃部模式形成的调控原理，并为推进胃器官发生与胃类器官发育研究提供了更高保真度的实验平台。

3.Therapeutic genetic restoration through allogeneic brain microglia replacement

通过异体脑小胶质细胞置换实现治疗性基因修复

美国斯坦福大学、德国汉堡-埃彭多夫大学医学中心

Abstract

Migration of transplanted allogeneic myeloid cells into the brain following systemic haematopoietic stem and progenitor cell transplantation (HCT) holds great promise as a therapeutic modality to correct genetic deficiencies in the brain such as lysosomal storage diseases. However, the toxic myeloablation required for allogeneic HCT can cause serious, life-threatening side effects, limiting its applicability. Moreover, transplanted allogeneic myeloid cells are highly vulnerable to rejection even in an immune-privileged organ like the brain. Here we report a brain-restricted, high-efficiency microglia replacement approach without myeloablative preconditioning. Contrary to previous assumptions, we found that haematopoietic stem cells are not required to repopulate the myeloid compartment of the brain environment, and Sca1− committed progenitor cells were highly efficient in replacing microglia following intracerebral injection. This finding enabled the development of brain-restricted preconditioning and avoided long-term peripheral engraftment, thus eliminating complications such as graft-versus-host disease. Evaluating its therapeutic potential, we found that our allogeneic microglia replacement method rescued the mouse model of Sandhoff disease, a lysosomal storage disease caused by hexosaminidase B deficiency. In support of the translational relevance of this approach, we discovered that human embryonic stem cell-derived myeloid progenitor cells display a similar engraftment potential following brain-restricted conditioning. Our results overcome current limitations of conventional HCT and may pave the way for the development of allogeneic microglial cell therapies for the brain.

摘要：

全身性造血干细胞和祖细胞移植（HCT）后，移植的异基因髓系细胞向脑部的迁移，为纠正脑部遗传缺陷（如溶酶体贮积症）提供了极具前景的治疗模式。然而，异基因HCT所需的毒性骨髓清除会引发严重且危及生命的副作用，限制了其应用范围。此外，即使在脑部这类免疫豁免器官中，移植的异体髓系细胞仍极易遭受排斥。该研究报道了一种无需骨髓清除预处理的脑特异性高效小胶质细胞替代方案。与既往认知相反，研究发现脑内环境的髓系细胞重建无需造血干细胞参与，而Sca1-定向分化前体细胞经脑内注射后能高效替代小胶质细胞。这一发现促成了脑特异性预处理方案的开发，避免了长期外周移植物嵌合，从而规避移植物抗宿主病等并发症。在评估其治疗潜力时，研究发现该异体小胶质细胞替代方法成功挽救了桑德霍夫病小鼠模型——该病症由己糖胺酶B缺乏引发的溶酶体贮积症。为验证该方法的转化医学意义，研究发现经脑部限定预处理的人胚胎干细胞衍生的髓系前体细胞具有相似的植入潜力。该研究突破了传统造血干细胞移植的局限性，有望为异体小胶质细胞脑部治疗的开发开辟新路径。

4.Microglia–neuron crosstalk through Hex–GM2–MGL2 maintains brain homeostasis

小胶质细胞与神经元通过Hex-GM2-MGL2通路的相互作用维持脑稳态

德国弗莱堡大学、曼海姆应用科学大学、海德堡大学、哥廷根大学等机构合作发表

Abstract

As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations. They primarily interact with neurons by means of synaptic engulfment and through the rapid elimination of apoptotic cells and non-functional synapses. Here, by combining unbiased lipidomics and high-resolution spatial lipid imaging, deep single-cell transcriptome analysis and novel cell-type-specific mutants, we identified a previously unknown mode of microglial interaction with neurons. During homeostasis, microglia deliver the lysosomal enzyme β-hexosaminidase to neurons for the degradation of the ganglioside GM2 that is integral to maintaining cell membrane organization and function. Absence of Hexb, encoding the β subunit of β-hexosaminidase, in both mice and patients with neurodegenerative Sandhoff disease leads to a massive accumulation of GM2 derivatives in a characteristic spatiotemporal manner. In mice, neuronal GM2 gangliosides subsequently engage the macrophage galactose-type lectin 2 receptor on microglia through N-acetylgalactosamine residues, leading to lethal neurodegeneration. Notably, replacement of microglia with peripherally derived microglia-like cells is able to break this degenerative cycle and fully restore central nervous system homeostasis. Our results reveal a mode of bidirectional microglia–neuron communication centred around GM2 ganglioside turnover, identify a microgliopathy and offer therapeutic avenues for these maladies.

摘要：

作为中枢神经系统实质组织中的常驻巨噬细胞，小胶质细胞在稳态与扰动期间执行多种关键功能。它们主要通过突触吞噬作用与神经元相互作用，并能快速清除凋亡细胞和失效突触。该研究通过整合无偏向脂质组学与高分辨率空间脂质成像技术、深度单细胞转录组分析及新型细胞类型特异性突变体，发现了小胶质细胞与神经元之间一种前所未知的交互模式。在稳态条件下，小胶质细胞向神经元输送溶酶体酶β-己糖胺酶，用于降解神经节苷脂GM2——该物质对维持细胞膜结构与功能至关重要。在小鼠和神经退行性桑德霍夫病患者中，编码β-己糖胺酶β亚基的Hexb基因缺失，导致GM2衍生物以特征性的时空模式大量积累。在小鼠模型中，神经元GM2神经节苷脂通过N-乙酰半乳糖胺残基与小胶质细胞表面的巨噬细胞半乳糖型凝集素2受体结合，最终引发致命性神经退行性病变。值得注意的是，用外周来源的小胶质细胞样细胞替代原有小胶质细胞，可打破该退行性循环并完全恢复中枢神经系统稳态。研究揭示了以GM2神经节苷脂代谢为核心的双向小胶质细胞-神经元通信模式，确立了小胶质细胞病这一病理机制，并为相关疾病提供了治疗新途径。

5.Dynamic fibroblast–immune interactions shape recovery after brain injury

动态成纤维细胞-免疫细胞相互作用塑造脑损伤后的恢复过程

美国加州大学、格拉德斯通研究所、澳大利亚莫纳什大学

Abstract

Fibroblasts and immune cells coordinate tissue regeneration and necessary scarring after injury. In the brain, fibroblasts are border-enriched cells whose dynamic molecular states and immune interactions after injury remain unclear. Here we define the shared fibroblast–immune response to brain injury. Early profibrotic myofibroblasts develop from pre-existing brain fibroblasts and infiltrate brain lesions, orchestrated by fibroblast TGFβ signalling, profibrotic macrophages and microglia, and perilesional glia. Myofibroblasts transition into several late fibroblast states, including lymphocyte-interactive fibroblasts. Interruption of the early myofibroblast state exacerbated sub-acute brain injury, tissue loss and secondary neuroinflammation, with increased mortality in the transient middle cerebral artery occlusion stroke model. Disruption of late lymphocyte–fibroblast niches via selective loss of fibroblast chemokine CXCL12 led to late brain-specific innate inflammation and lymphocyte dispersal with increased IFNγ production. These data indicate the response to brain injury is coordinated by evolving temporal and spatial fibroblast states that limit functional tissue loss and chronic neuroinflammation.

摘要：

成纤维细胞与免疫细胞协同调控损伤后的组织再生及必要瘢痕形成。在大脑中，成纤维细胞是边界富集细胞，其损伤后的动态分子状态及免疫相互作用尚不明确。该研究揭示了脑损伤中成纤维细胞与免疫反应的共同机制。早期促纤维化肌成纤维细胞由原有脑成纤维细胞分化而来，在成纤维细胞TGFβ信号通路、促纤维化巨噬细胞与小胶质细胞及病灶周围胶质细胞的协同调控下浸润脑损伤区域。肌成纤维细胞可向多种晚期成纤维细胞状态转化，包括与淋巴细胞相互作用的成纤维细胞。在瞬时性中大脑动脉闭塞性卒中模型中，阻断早期肌成纤维细胞状态会加剧亚急性脑损伤、组织缺失及继发性神经炎症，并导致死亡率上升。通过选择性丧失成纤维细胞趋化因子CXCL12破坏晚期淋巴细胞-成纤维细胞生态位，导致晚期脑特异性先天性炎症和淋巴细胞扩散，并增加IFNγ的产生。这些数据表明，对脑损伤的反应是由不断演变的时空成纤维细胞状态协调的，这些状态限制了功能性组织损失和慢性神经炎症。

6.In vivo CRISPR screens identify modifiers of CAR T cell function in myeloma

体内CRISPR筛选识别出影响骨髓瘤中CAR-T细胞功能的调节因子

美国哈佛医学院马萨诸塞州总医院、麻省理工学院

Abstract

Chimeric antigen receptor (CAR) T cells are highly effective in haematological malignancies. However, progressive loss of CAR T cells contributes to relapse in many patients. Here we performed in vivo loss-of-function CRISPR screens in CAR T cells targeting B cell maturation antigen to investigate genes that influence CAR T cell persistence and function in a human multiple myeloma model. We tracked the expansion and persistence of CRISPR library-edited T cells in vitro and at early and late time points in vivo to track the performance of gene-modified CAR T cells from manufacturing to survival in tumours. The screens revealed context-specific regulators of CAR T cell expansion and persistence. Ablation of RASA2 and SOCS1 enhanced T cell expansion in vitro, whereas loss of PTPN2, ZC3H12A and RC3H1 conferred early growth advantages to CAR T cells in vivo. Notably, we identified cyclin-dependent kinase inhibitor 1B (encoded by CDKN1B), a cell cycle regulator, as the most important factor limiting CAR T cell fitness at late time points in vivo. CDKN1B ablation increased CAR T cell proliferation and effector function, significantly enhancing tumour clearance and overall survival. Our findings reveal differing effects of gene perturbation on CAR T cells over time and in different environments, highlight CDKN1B as a promising target to generate highly effective CAR T cells for multiple myeloma and underscore the potential of in vivo screening for identifying genes to enhance CAR T cell efficacy.

摘要：

嵌合抗原受体（CAR）T细胞在血液系统恶性肿瘤中疗效显著。然而，CAR T细胞的持续耗竭导致许多患者复发。该研究通过在靶向B细胞成熟抗原的CAR T细胞中进行体内功能缺失性CRISPR筛选，在人源化多发性骨髓瘤模型中探究影响CAR T细胞存活与功能的基因。研究通过体外及体内早期/晚期时间点的追踪，监测了CRISPR文库编辑T细胞的扩增与存活状态，从而全面评估基因修饰CAR T细胞从制备到肿瘤内存活的全过程表现。筛选揭示了CAR T细胞扩增与存活的特定环境调控因子。RASA2和SOCS1的缺失增强了体外T细胞扩增，而PTPN2、ZC3H12A和RC3H1的缺失则赋予CAR-T细胞体内早期生长优势。值得注意的是，研究发现细胞周期调节因子周期蛋白依赖性激酶抑制剂1B（CDKN1B所编码）是限制CAR-T细胞体内晚期适应性的关键因素。CDKN1B缺失可增强CAR-T细胞增殖与效应功能，显著提升肿瘤清除率及总体生存率。该研究揭示基因扰动对CAR-T细胞在不同时间点和环境中的差异化影响，强调CDKN1B是开发高效多发性骨髓瘤CAR-T细胞的潜在靶点，并证实体内筛选技术在识别增强CAR-T细胞疗效基因方面的潜力。

7.Systematic discovery of CRISPR-boosted CAR T cell immunotherapies

CRISPR增强型CAR-T细胞免疫疗法的系统性发现

奥地利科学院分子医学 CeMM 研究中心、维也纳医科大学

Abstract

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in treating blood cancers, but CAR T cell dysfunction remains a common cause of treatment failure. Here we present CELLFIE, a CRISPR screening platform for enhancing CAR T cells across multiple clinical objectives. We performed genome-wide screens in human primary CAR T cells, with readouts capturing key aspects of T cell biology, including proliferation, target cell recognition, activation, apoptosis and fratricide, and exhaustion. Screening hits were prioritized using a new in vivo CROP-seq method in a xenograft model of human leukaemia, establishing several gene knockouts that boost CAR T cell efficacy. Most notably, we discovered that RHOG knockout is a potent and unexpected CAR T cell enhancer, both individually and together with FAS knockout, which was validated across multiple in vivo models, CAR designs and sample donors, and in patient-derived cells. Demonstrating the versatility of the CELLFIE platform, we also conducted combinatorial CRISPR screens to identify synergistic gene pairs and saturation base-editing screens to characterize RHOG variants. In summary, we discovered, validated and biologically characterized CRISPR-boosted CAR T cells that outperform standard CAR T cells in widely used benchmarks, establishing a foundational resource for optimizing cell-based immunotherapies.

摘要：

嵌合抗原受体（CAR）T细胞疗法在治疗血液癌症方面取得了显著成效，但CAR T细胞功能障碍仍是导致治疗失败的常见原因。该研究介绍了CELLFIE——一种基于CRISPR的筛选平台，可针对多个临床目标增强CAR T细胞功能。对人源原代CAR-T细胞开展全基因组筛选，通过检测T细胞生物学关键指标（包括增殖、靶细胞识别、活化、凋亡、自杀及耗竭）进行评估。通过新型体内CROP-seq方法在人白血病异种移植模型中对筛选结果进行优先级排序，确立了多个可增强CAR T细胞疗效的基因敲除方案。尤为重要的是，研究发现RHOG基因敲除是强效且出人意料的CAR T细胞增强因子——无论是单独敲除还是与FAS基因敲除联合使用。该发现已在多种体内模型、CAR设计方案、捐赠者样本及患者来源细胞中得到验证。为展现CELLFIE平台的多功能性，同时开展了组合式CRISPR筛选以识别协同基因对，并通过饱和碱基编辑筛选表征RHOG变异体。综上所述，该研究成功发现、验证并生物学表征了经CRISPR增强的CAR-T细胞，其在广泛采用的基准测试中显著优于标准CAR-T细胞，为优化细胞免疫疗法奠定了基础性资源。

8.Molecular subtypes of human skeletal muscle in cancer cachexia

癌症恶病质中人类骨骼肌的分子亚型

加拿大阿尔伯塔大学、卡尔加里大学、法国人类营养学部（UNH）

Abstract

Cancer-associated muscle wasting is associated with poor clinical outcomes, but its underlying biology is largely uncharted in humans. Unbiased analysis of the RNAome (coding and non-coding RNAs) with unsupervised clustering using integrative non-negative matrix factorization provides a means of identifying distinct molecular subtypes and was applied here to muscle of patients with colorectal or pancreatic cancer. Rectus abdominis biopsies from 84 patients were profiled using high-throughput next-generation sequencing. Integrative non-negative matrix factorization with stringent quality metrics for clustering identified two highly coherent molecular subtypes within muscle of patients with cancer. Patients with subtype 1 (versus subtype 2) showed clinical manifestations of cachexia: high-grade weight loss, low muscle mass, atrophy of type IIA and type IIX muscle fibres, and reduced survival. On the basis of differential expression between the subtypes, we identified biological processes that may contribute to cancer-associated loss of muscle mass and function, including altered posttranscriptional regulation and perturbation of neuronal systems; cytokine storm and cellular immune response; pathways related to extracellular matrix; and metabolic abnormalities spanning xenobiotic metabolism, haemostasis, signal transduction, embryonic and/or pluripotent stem cells, and amino acid metabolism. Differential expression between subtypes indicated the involvement of multiple intertwined higher-order gene regulatory networks, suggesting that network interactions of (hub) long non-coding RNAs, microRNAs and mRNAs could represent targets for future research.

摘要：

癌症相关的肌肉萎缩与不良临床预后相关，但其在人类中的基础生物学机制尚未被充分探索。通过整合非负矩阵分解技术进行无监督聚类分析，对RNA组（编码RNA与非编码RNA）进行无偏分析，可识别出独特的分子亚型。该研究将该方法应用于结直肠癌或胰腺癌患者的肌肉组织。通过高通量新一代测序技术对84名患者的腹直肌活检样本进行分析。采用严格质量指标的集成非负矩阵分解聚类技术，在癌症患者肌肉组织中识别出两种高度一致的分子亚型。与亚型2相比，亚型1患者呈现恶病质临床表现：高度体重减轻、肌肉质量低下、IIA型和IIX型肌纤维萎缩，以及生存期缩短。基于亚型间的差异表达，研究识别出可能导致癌症相关肌肉质量与功能丧失的生物学过程，包括：转录后调控改变与神经系统紊乱；细胞因子风暴及细胞免疫反应；与细胞外基质相关的通路；以及涉及异物代谢、凝血、信号转导、胚胎/多能干细胞及氨基酸代谢的代谢异常。亚型间的差异表达表明存在多重交织的高阶基因调控网络，提示（枢纽）长非编码RNA、microRNA与mRNA的网络交互可作为未来研究靶点。

9.CRISPR activation for SCN2A-related neurodevelopmental disorders

CRISPR激活技术在SCN2A相关神经发育疾病中的应用

美国加州大学旧金山分校、布罗德研究所、密歇根大学、英国牛津大学

Abstract

Most neurodevelopmental disorders with single gene diagnoses act via haploinsufficiency, in which only one of the two gene copies is functional. SCN2A haploinsufficiency is one of the most frequent causes of neurodevelopmental disorder, often presenting with autism spectrum disorder, intellectual disability and, in a subset of children, refractory epilepsy. Here, using SCN2A haploinsufficiency as a proof-of-concept, we show that upregulation of the existing functional gene copy through CRISPR activation (CRISPRa) can rescue neurological-associated phenotypes in Scn2a haploinsufficient mice. We first show that restoring Scn2a expression in adolescent heterozygous Scn2a conditional knock-in mice rescues electrophysiological deficits associated with Scn2a haploinsufficiency (Scn2a+/−). Next, using an adeno-associated virus CRISPRa-based treatment in adolescent mice, we show that we can correct intrinsic and synaptic deficits in neocortical pyramidal cells, a major cell type that contributes to neurodevelopmental disorders and seizure aetiology in SCN2A haploinsufficiency. Furthermore, we find that systemic delivery of CRISPRa protects Scn2a+/− mice against chemoconvulsant-induced seizures. Finally, we also show that adeno-associated virus CRISPRa treatment rescues excitability in SCN2A haploinsufficient human stem-cell-derived neurons. Our results showcase the potential of this therapeutic approach to rescue SCN2A haploinsufficiency and demonstrates that rescue even at adolescent stages can ameliorate neurodevelopmental phenotypes.

摘要：

大多数单基因诊断的神经发育障碍通过单倍体不足机制发挥作用，即两个基因拷贝中仅有一个具有功能。SCN2A单倍体不足是最常见的神经发育障碍病因之一，常表现为自闭症谱系障碍、智力障碍，部分患儿还会出现难治性癫痫。该研究以SCN2A单倍体不足作为概念验证模型，证明通过CRISPR激活技术（CRISPRa）上调现有功能性基因拷贝，可挽救Scn2a单倍体不足小鼠的神经相关表型缺陷。首先证明了在青春期杂合Scn2a条件性敲入小鼠中恢复Scn2a表达，可挽救与Scn2a单倍体不足（Scn2a+/−）相关的电生理缺陷。随后，通过对青春期小鼠实施腺相关病毒CRISPRa治疗，证实可纠正新皮质锥体细胞的内在及突触缺陷——该细胞类型是导致SCN2A单倍体不足相关神经发育障碍和癫痫病因的关键细胞类型。此外，研究发现全身性CRISPRa递送能保护Scn2a+/−小鼠免受化学致痫剂诱发的癫痫发作。最后，证实腺相关病毒CRISPRa治疗能恢复SCN2A单倍体不足的人源干细胞衍生的神经元兴奋性。该研究结果彰显了该治疗策略在挽救SCN2A单倍体不足方面的潜力，并证明即使在青春期阶段进行干预，也能改善神经发育表型。

10.DNA2 enables growth by restricting recombination-restarted replication

DNA2通过限制重组重启的复制来促进生长

英国萨塞克斯大学

Abstract

Nuclease–helicase DNA2 is a multifunctional genome caretaker that is essential for cell proliferation in a range of organisms, from yeast to human. Bi-allelic DNA2 mutations that reduce DNA2 concentrations cause a spectrum of primordial dwarfism disorders, including Seckel and Rothmund–Thomson-related syndromes. By contrast, cancer cells frequently express high concentrations of DNA2. The mechanism that precludes cell proliferation in the absence of DNA2 and the molecular aetiology of DNA2-linked diseases remain elusive. Here we used yeast and human cells to demonstrate that DNA2 suppresses homologous recombination-restarted replication and checkpoint activation at stalled DNA replication forks. Loss of this control mechanism upon degradation of DNA2 in human cells causes recombination-dependent DNA synthesis and build-up of RPA-bound single-stranded DNA in the G2 phase of the cell cycle. Consequently, DNA2 deprivation triggers the DNA damage checkpoint and invariably leads to ATR–p21-dependent cell-cycle exit before mitosis. These findings explain why DNA2 is essential for cell proliferation and reveal that replication fork processing to restrict recombination is indispensable for avoiding cellular senescence. Stochastic entry into senescence stifles the proliferative potential of cells following the expression of a Seckel syndrome patient-derived DNA2 hypomorph or partial degradation of DNA2, providing a conceptual framework to explain global growth failure in DNA2-linked primordial dwarfism disorders.

摘要：

核酸酶-解旋酶DNA2是一种多功能基因组守护者，对从酵母到人类等多种生物的细胞增殖至关重要。导致DNA2浓度降低的双等位基因突变会引发一系列原始侏儒症疾病，包括塞克尔综合征和罗特蒙德-汤姆森相关综合征。相反，癌细胞常高表达DNA2。DNA2缺失时抑制细胞增殖的机制及DNA2相关疾病的分子病因仍不明晰。该研究通过酵母与人类细胞模型证实：DNA2能抑制同源重组启动的复制过程，并在停滞的DNA复制叉处激活检查点机制。在人类细胞中，DNA2降解导致该调控机制失效，引发重组依赖性DNA合成，并在细胞周期G2期积累RPA结合的单链DNA。最终，DNA2缺失触发DNA损伤检查点，不可避免地导致有丝分裂前通过ATR-p21依赖性机制退出细胞周期。这些发现阐明了DNA2对细胞增殖的必需性，并揭示限制重组的复制叉处理机制对避免细胞衰老不可或缺。当表达源自塞克尔综合征患者的DNA2低表达突变体或DNA2部分降解时，随机进入衰老状态会抑制细胞增殖能力，这为解释DNA2相关原发性侏儒症中全身性生长障碍提供了理论框架。

11.Multiple overlapping binding sites determine transcription factor occupancy

多个重叠的结合位点决定转录因子的占据情况

美国马萨诸塞州波士顿布莱根妇女医院、哈佛医学院

Abstract

Transcription factors (TFs) regulate gene expression by interacting with DNA in a sequence-specific manner. High-throughput in vitro technologies, such as protein-binding microarrays and HT-SELEX (high-throughput systematic evolution of ligands by exponential enrichment), have revealed the DNA-binding specificities of hundreds of TFs. However, they have limited ability to reliably identify lower-affinity DNA binding sites, which are increasingly recognized as important for precise spatiotemporal control of gene expression. Here, to address this limitation, we developed protein affinity to DNA by in vitro transcription and RNA sequencing (PADIT-seq), with which we comprehensively assayed the binding preferences of six TFs to all possible ten-base-pair DNA sequences, detecting hundreds of novel, lower-affinity binding sites. The expanded repertoire of lower-affinity binding sites revealed that nucleotides flanking high-affinity DNA binding sites create overlapping lower-affinity sites that together modulate TF genomic occupancy in vivo. We propose a model in which TF binding is not determined by individual binding sites, but rather by the sum of multiple, overlapping binding sites. The overlapping binding model explains how competition between paralogous TFs for shared high-affinity binding sites is determined by flanking nucleotides that create differential numbers of overlapping, lower-affinity binding sites. Critically, the model transforms our understanding of noncoding-variant effects, revealing how single nucleotide changes simultaneously alter multiple overlapping sites to additively influence gene expression and human traits, including diseases.

摘要：

转录因子（TFs）通过与DNA进行序列特异性相互作用来调控基因表达。高通量体外技术（如蛋白质结合微阵列和HT-SELEX技术）已揭示了数百种转录因子的DNA结合特异性。然而，这些技术难以可靠地识别低亲和力DNA结合位点——这类位点对基因表达的精确时空调控日益受到重视。为突破这一局限，该研究开发了基于体外转录与RNA测序的蛋白质DNA亲和力测定技术（PADIT-seq），通过该技术全面检测了六种转录因子对所有可能十碱基对DNA序列的结合偏好，发现了数百个新型低亲和力结合位点。扩展的低亲和力结合位点谱系揭示：高亲和力DNA结合位点两侧的核苷酸会形成重叠的低亲和力位点，共同调控转录因子在体内的基因组占位。该研究提出新模型：转录因子结合并非由单个位点决定，而是由多个重叠结合位点的综合效应决定。该重叠结合模型阐释了：当同源转录因子竞争共享的高亲和力结合位点时，其竞争关系由侧翼核苷酸决定——这些核苷酸会形成数量不等的重叠低亲和力结合位点。该模型关键性地重塑了对非编码变异效应的认知，揭示单个核苷酸变化如何同时改变多个重叠位点，从而累积性地影响基因表达及人类性状（包括疾病）。

Volume 646 Issue 8087, 30 October 2025

本期Nature共发表67篇文章，其中包括8篇This Week，9篇News in Focus，2篇Books & Arts，7篇Opinion，2篇Work，33篇Research，5篇Amendments & Corrections，1篇Spotlight。

1.Polygenic and developmental profiles of autism differ by age at diagnosis

自闭症的多基因特征与发育特征因诊断年龄而异

英国剑桥大学、丹麦奥胡斯大学、英国惠康桑格研究所等机构合作发表

Abstract

Although autism has historically been conceptualized as a condition that emerges in early childhood, many autistic people are diagnosed later in life. It is unknown whether earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Using longitudinal data from four independent birth cohorts, we demonstrate that two different socioemotional and behavioural trajectories are associated with age at diagnosis. In independent cohorts of autistic individuals, common genetic variants account for approximately 11% of the variance in age at autism diagnosis, similar to the contribution of individual sociodemographic and clinical factors, which typically explain less than 15% of this variance. We further demonstrate that the polygenic architecture of autism can be broken down into two modestly genetically correlated (rg = 0.38, s.e. = 0.07) autism polygenic factors. One of these factors is associated with earlier autism diagnosis and lower social and communication abilities in early childhood, but is only moderately genetically correlated with attention deficit–hyperactivity disorder (ADHD) and mental-health conditions. Conversely, the second factor is associated with later autism diagnosis and increased socioemotional and behavioural difficulties in adolescence, and has moderate to high positive genetic correlations with ADHD and mental-health conditions. These findings indicate that earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Our findings have important implications for how we conceptualize autism and provide a model to explain some of the diversity found in autism.

摘要：

尽管自闭症历来被视为一种在幼儿期显现的疾病，但许多自闭症患者是在成年后才被确诊的。目前尚不清楚早期确诊与晚期确诊的自闭症是否存在不同的发展轨迹和基因特征。该研究通过分析四个独立出生队列的纵向数据，发现两种不同的社会情感与行为发展轨迹与确诊年龄存在关联。在独立的自闭症个体队列中，常见遗传变异约解释了自闭症诊断年龄差异的11%，与个体社会人口学及临床因素的贡献相当——后者通常仅能解释该差异的15%以下。研究进一步证实，自闭症的多基因结构可分解为两个遗传相关性适中的自闭症多基因因子（rg=0.38, s.e.=0.07）。其中一个因子与早期自闭症诊断及幼儿期较低的社交沟通能力相关，但仅与注意力缺陷多动障碍（ADHD）及心理健康状况存在中等遗传相关性。相反，第二个因素与较晚的自闭症诊断及青春期社会情感与行为困难加剧相关，并与ADHD及心理健康状况存在中度至高度的正向遗传相关性。这些发现表明，早期诊断与晚期诊断的自闭症具有不同的发展轨迹和遗传特征。该研究结果对自闭症的概念化具有重要意义，并为解释自闭症多样性提供了一个模型。

2.Transitions in dynamical regime and neural mode during perceptual decisions

感知决策过程中动态模式与神经模式的转换

美国普林斯顿大学

Abstract

Perceptual decision-making is thought to be mediated by neuronal networks with attractor dynamics. However, the dynamics underlying the complex neuronal responses during decision-making remain unclear. Here we use simultaneous recordings of hundreds of neurons, combined with an unsupervised, deep-learning-based method, to discover decision-related neural dynamics in the rat frontal cortex and striatum as animals accumulate pulsatile auditory evidence. We found that trajectories evolved along two sequential regimes: an initial phase dominated by sensory inputs, followed by a phase dominated by autonomous dynamics, with the flow direction (that is, neural mode) largely orthogonal to that in the first regime. We propose that this transition marks the moment of decision commitment, that is, the time when the animal makes up its mind. To test this, we developed a simplified model of the dynamics to estimate a putative neurally inferred time of commitment (nTc) for each trial. This model captures diverse single-neuron temporal profiles, such as ramping and stepping. The estimated nTc values were not time locked to stimulus or response timing but instead varied broadly across trials. If nTc marks commitment, evidence before this point should affect the decision, whereas evidence afterwards should not. Behavioural analysis aligned to nTc confirmed this prediction. Our findings show that decision commitment involves a rapid, coordinated transition in dynamical regime and neural mode and suggest that nTc offers a useful neural marker for studying rapid changes in internal brain state.

摘要：

感知决策被认为由具有吸引子动力学的神经网络介导。然而，决策过程中复杂神经反应背后的动力学机制仍不清楚。该研究通过同步记录数百个神经元，结合基于深度学习的无监督方法，在大鼠积累脉冲式听觉证据时，发现了其前额叶皮层和纹状体中与决策相关的神经动力学。研究发现神经轨迹沿两个序列性阶段演化：初始阶段由感觉输入主导，随后进入自主动力学主导阶段，其流动方向（即神经模式）与前一阶段基本正交。研究提出这种转变标志着决策承诺的时刻，即动物最终下定决心的时间点。为验证这一假说，构建了动态简化模型，用于估算每次试验中神经推断的承诺时间（nTc）。该模型能捕捉单神经元多样化的时序特征，如渐变式和阶跃式变化。估算的nTc值并未与刺激或反应时间同步，而是在不同试验中呈现显著波动。若nTc标志着决策承诺，则该节点前的证据应影响决策，而之后的证据则不应产生影响。基于nTc的时间轴进行的行为分析验证了这一预测。该发现表明，决策承诺涉及动态状态与神经模式的快速协调转换，并指出nTc可作为研究大脑内部状态快速变化的有效神经标记。

3.A neuronal architecture underlying autonomic dysreflexia

自主神经反射异常的基础神经元结构

加拿大卡尔加里大学卡明医学院、瑞士联邦理工学院等机构合作发表

Abstract

Autonomic dysreflexia is a life-threatening medical condition characterized by episodes of uncontrolled hypertension that occur in response to sensory stimuli after spinal cord injury (SCI). The fragmented understanding of the mechanisms underlying autonomic dysreflexia hampers the development of therapeutic strategies to manage this condition, leaving people with SCI at daily risk of heart attack and stroke. Here we expose the neuronal architecture that develops after SCI and causes autonomic dysreflexia. In parallel, we uncover a competing, yet overlapping neuronal architecture activated by epidural electrical stimulation of the spinal cord that safely regulates blood pressure after SCI. The discovery that these adversarial neuronal architectures converge onto a single neuronal subpopulation provided a blueprint for the design of a mechanism-based intervention that reversed autonomic dysreflexia in mice, rats and humans with SCI. These results establish a path towards essential pivotal device clinical trials that will establish the safety and efficacy of epidural electrical stimulation for the effective treatment of autonomic dysreflexia in people with SCI.

摘要：

自主神经反射异常是一种危及生命的病症，其特征为脊髓损伤（SCI）后对感觉刺激产生无法控制的高血压发作。由于对该病症机制的认知尚不完整，阻碍了治疗策略的开发，导致脊髓损伤患者每日面临心脏病发作和中风的风险。该研究揭示了脊髓损伤后形成并引发自主神经反射亢进的神经元结构。同时发现，通过脊髓硬膜外电刺激激活的竞争性（但存在重叠）神经元结构，可在脊髓损伤后安全调节血压。发现这两种对抗性神经网络结构汇聚于单一神经亚群，为设计基于机制的干预方案提供了蓝图——该方案成功逆转了脊髓损伤小鼠、大鼠及人类患者的自主神经反射亢进。这些成果为关键性设备临床试验铺平道路，将验证硬膜外电刺激在有效治疗脊髓损伤患者自主神经反射亢进方面的安全性和有效性。

4.PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia

PICALM阿尔茨海默病风险等位基因导致小胶质细胞中脂滴异常

美国埃文斯顿奋进健康研究所、芝加哥大学、南佛罗里达大学等机构合作发表

Abstract

Despite genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (LOAD) having identified many genetic risk loci, the underlying disease mechanisms remain largely unclear. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Here, using our approach for identifying functional GWAS risk variants showing allele-specific open chromatin, we systematically identified putative causal LOAD-risk variants in human induced pluripotent stem (iPS)-cell-derived neurons, astrocytes and microglia, and linked a PICALM LOAD-risk allele to a microglial-specific role of PICALM in lipid droplet (LD) accumulation. Allele-specific open-chromatin mapping revealed functional risk variants for 26 LOAD-risk loci, mostly specific to microglia. At the microglial-specific PICALM locus, the LOAD-risk allele of the single-nucleotide polymorphism rs10792832 reduced transcription factor (PU.1) binding and PICALM expression, impairing the uptake of amyloid beta (Aβ) and myelin debris. Notably, microglia carrying the PICALM risk allele showed transcriptional enrichment of pathways for cholesterol synthesis and LD formation. Genetic and pharmacological perturbations of microglia further established a causal link between reduced PICALM expression, LD accumulation and phagocytosis deficits. Our work elucidates the selective LOAD vulnerability in microglia at the PICALM locus through detrimental LD accumulation, providing a neurobiological basis that can be exploited for developing clinical interventions.

摘要：

尽管全基因组关联研究（GWAS）已识别出许多晚发性阿尔茨海默病（LOAD）的遗传风险位点，其潜在疾病机制仍基本不明。确定致病性变异及其与LOAD相关的细胞表型始终是重大挑战。该研究采用识别具有等位基因特异性开放染色质的功能性GWAS风险变异的方法，系统性地在人诱导多能干细胞（iPS）衍生的神经元、星形胶质细胞和小胶质细胞中鉴定出潜在的致病性LOAD风险变异，并将PICALM LOAD风险等位基因与PICALM在脂滴（LD）积累中的小胶质细胞特异性功能相关联。等位基因特异性开放染色质图谱揭示了26个LOAD风险位点中的功能性风险变异，其中多数特异性存在于小胶质细胞中。在小胶质细胞特异性PICALM位点，单核苷酸多态性rs10792832的LOAD风险等位基因削弱了转录因子PU.1的结合及PICALM表达，从而损害β淀粉样蛋白（Aβ）和髓鞘碎片的吞噬作用。值得注意的是，携带PICALM风险等位基因的小胶质细胞在胆固醇合成与脂滴形成通路中呈现转录富集现象。通过基因和药理学手段扰动小胶质细胞，进一步确立了PICALM表达下降、脂滴积累与吞噬功能缺陷之间的因果关联。该研究阐明了PICALM位点通过有害脂滴积累导致小胶质细胞对LOAD的特殊易感性，为开发临床干预措施提供了神经生物学基础。

5.Energy deficiency selects crowded live epithelial cells for extrusion

能量匮乏促使拥挤的活上皮细胞被挤出

英国伦敦国王学院、弗朗西斯·克里克研究所、美国犹他大学、西班牙庞培法布拉大学

Abstract

Epithelial cells work collectively to provide a protective barrier, yet they turn over rapidly through cell division and death. If the numbers of dividing and dying cells do not match, the barrier can vanish, or tumours can form. Mechanical forces through the stretch-activated ion channel Piezo1 link both of the processes; stretch promotes cell division, whereas crowding triggers live cells to extrude and then die. However, it was not clear what selects a given crowded cell for extrusion. Here we show that the crowded cells with the least energy and membrane potential are selected for extrusion. Crowding triggers sodium (Na+) entry through the epithelial Na+ channel (ENaC), which depolarizes cells. While those with sufficient energy repolarize, those with limited ATP remain depolarized, which, in turn, triggers water egress through the voltage-gated potassium (K+) channels Kv1.1 and Kv1.2 and the chloride (Cl−) channel SWELL1. Transient water loss causes cell shrinkage, amplifying crowding to activate crowding-induced live cell extrusion. Thus, our findings suggest that ENaC acts as a tension sensor that probes for cells with the least energy to extrude and die, possibly damping inadvertent crowding activation of Piezo1 in background cells. We reveal crowding-sensing mechanisms upstream of Piezo1 that highlight water regulation and ion channels as key regulators of epithelial cell turnover.

摘要：

上皮细胞通过集体协作形成保护性屏障，但它们又通过细胞分裂和死亡实现快速更新。若分裂细胞与死亡细胞的数量失衡，屏障便会崩溃，或形成肿瘤。机械力通过张力激活离子通道Piezo1调控这两种过程：张力促进细胞分裂，而拥挤则触发活细胞外排并最终死亡。然而，具体机制尚不明确——究竟是什么因素决定了特定拥挤细胞被选中进行外排？该研究揭示：能量最低且膜电位最弱的拥挤细胞会被优先选中进行外排。拥挤状态会触发钠离子通过上皮钠通道（ENaC）进入细胞，导致细胞去极化。能量充足的细胞可重新极化，而ATP储备有限的细胞则持续去极化，进而通过电压门控钾通道K+++v1.1和Kv1.2以及氯离子通道SWELL1引发水分外流。短暂性水分流失导致细胞收缩，进而放大拥挤效应以激活活细胞挤出机制。因此，该研究发现表明ENaC作为张力传感器，能识别能量最低的细胞进行挤出并致死，可能抑制背景细胞中Piezo1的意外激活。揭示了Piezo1上游的拥挤感知机制，强调水分调节与离子通道是上皮细胞更新的关键调控因子。

6.Monoclonal antibodies protect against pandrug-resistant Klebsiella pneumoniae

单克隆抗体可预防泛耐药性肺炎克雷伯菌感染

意大利单克隆抗体发现（MAD）实验室、锡耶纳大学、比萨大学等机构合作发表

Abstract

The ‘silent pandemic’ caused by antimicrobial resistance requires innovative therapeutic approaches. Human monoclonal antibodies (mAbs), which are among the most transformative and safe drugs in oncology and autoimmunity, are rarely used for infectious diseases and not yet used for antimicrobial resistance. Here we applied an antigen-agnostic strategy to isolate extremely potent human mAbs against Klebsiella pneumoniae sequence type 147 (ST147), a hypervirulent and pandrug-resistant lineage that is spreading globally. Isolated mAbs target the KL64 capsule and the O-antigen. However, although mAbs displayed bactericidal activity in the picomolar range in vitro, only the capsule-specific mAbs were protective against fulminant bloodstream infection by ST147 and two geographically and genetically distant carbapenem-resistant KL64-bearing K. pneumoniae. Protection observed in vivo correlated with in vitro bacterial uptake by macrophages and enchained bacterial growth. Our study thus describes a mAb that protects against pandrug-resistant K. pneumoniae and provides a strategy to isolate mAbs and identify mAbs that confer protection against bacteria with antimicrobial resistance.

摘要：

由抗菌药物耐药性引发的“沉默大流行”亟需创新性治疗方案。人源单克隆抗体（mAbs）作为肿瘤学和自身免疫领域最具变革性且安全的药物之一，在传染病治疗中应用甚少，且尚未用于抗微生物耐药性领域。该研究采用抗原无关策略，成功分离出针对肺炎克雷伯菌序列型147（ST147）的高效人源单克隆抗体。该菌株具有超高毒性且对多种药物耐药，正呈全球蔓延趋势。所分离的mAbs靶向KL64荚膜及O抗原。尽管mAbs在体外展现出皮摩尔级别的杀菌活性，但仅有荚膜特异性mAbs能有效预防ST147及两种地理与基因上相距甚远的碳青霉烯耐药KL64阳性肺炎克雷伯菌引发的暴发性血流感染。体内观察到的保护作用与体外巨噬细胞摄取细菌及链状细菌生长相关。该研究揭示了一种能抵御泛耐药肺炎克雷伯菌的单克隆抗体，并为筛选单克隆抗体及识别具有抗耐药菌保护功能的抗体提供了策略。

7.Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours

髓系祖细胞失调助长肿瘤中免疫抑制性巨噬细胞的形成

美国西奈山伊坎医学院、哈佛医学院、法国Gustave Roussy研究所等机构合作发表

Abstract

Monocyte-derived macrophages (mo-macs) often drive immunosuppression in the tumour microenvironment (TME) and tumour-enhanced myelopoiesis in the bone marrow fuels these populations. Here we performed paired transcriptome and chromatin accessibility analysis over the continuum of myeloid progenitors, circulating monocytes and tumour-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. We show that lung tumours prime accessibility for Nfe2l2 (NRF2) in bone marrow myeloid progenitors as a cytoprotective response to oxidative stress, enhancing myelopoiesis while dampening interferon response and promoting immunosuppression. NRF2 activity is amplified during monocyte differentiation into mo-macs in the TME to regulate stress and drive immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced the survival and immunosuppression of mo-macs in the TME, restoring natural killer and T cell anti-tumour immunity and enhancing checkpoint blockade efficacy. Our findings identify a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the lung TME and highlight the potential of early interventions to reprogram macrophage fate for improved immunotherapy outcomes.

摘要：

单核细胞衍生的巨噬细胞（mo-macs）常在肿瘤微环境（TME）中驱动免疫抑制，而骨髓中肿瘤增强的髓系造血过程则为这些细胞群提供能量。该研究通过对小鼠及肺癌患者的髓系祖细胞、循环单核细胞和肿瘤浸润性单核细胞来源巨噬细胞进行配对转录组与染色质可及性分析，识别出促进促肿瘤性单核细胞来源巨噬细胞的髓系祖细胞调控程序。研究表明，肺肿瘤通过激活骨髓髓系祖细胞中Nfe2l2（NRF2）的可及性作为抗氧化应激的细胞保护性反应，在增强髓系造血的同时抑制干扰素反应并促进免疫抑制。单核细胞分化为TME中单核细胞来源巨噬细胞期间，NRF2活性被放大以调控应激反应并驱动免疫抑制表型。通过基因敲除及药物抑制NRF2，显著降低了肿瘤微环境中巨噬细胞的存活率与免疫抑制作用，恢复了自然杀伤细胞和T细胞的抗肿瘤免疫功能，并增强了免疫检查点抑制剂的疗效。该研究揭示了维持肺部肿瘤微环境中免疫调节型巨噬细胞的关键表观遗传调控节点——髓系祖细胞失调，强调了通过早期干预重编程巨噬细胞命运以改善免疫疗法疗效的潜力。

8.Peroxisomal metabolism of branched fatty acids regulates energy homeostasis

过氧化物酶体对支链脂肪酸的代谢调节能量稳态

美国华盛顿大学、犹他大学、密苏里大学等机构合作发表

Abstract

Brown and beige adipocytes express uncoupling protein 1 (UCP1), a mitochondrial protein that dissociates respiration from ATP synthesis and promotes heat production and energy expenditure. However, UCP1−/− mice are not obese, consistent with the existence of alternative mechanisms of thermogenesis. Here we describe a UCP1-independent mechanism of thermogenesis involving ATP-consuming metabolism of monomethyl branched-chain fatty acids (mmBCFA) in peroxisomes. These fatty acids are synthesized by fatty acid synthase using precursors derived from catabolism of branched-chain amino acids and our results indicate that β-oxidation of mmBCFAs is mediated by the peroxisomal protein acyl-CoA oxidase 2 (ACOX2). Notably, cold exposure upregulated proteins involved in both biosynthesis and β-oxidation of mmBCFA in thermogenic fat. Acute thermogenic stimuli promoted translocation of fatty acid synthase to peroxisomes. Brown-adipose-tissue-specific fatty acid synthase knockout decreased cold tolerance. Adipose-specific ACOX2 knockout also impaired cold tolerance and promoted diet-induced obesity and insulin resistance. Conversely, ACOX2 overexpression in adipose tissue enhanced thermogenesis independently of UCP1 and improved metabolic homeostasis. Using a peroxisome-localized temperature sensor named Pexo-TEMP, we found that ACOX2-mediated fatty acid β-oxidation raised intracellular temperature in brown adipocytes. These results identify a previously unrecognized role for peroxisomes in adipose tissue thermogenesis characterized by an mmBCFA synthesis and catabolism cycle.

摘要：

棕色和米色脂肪细胞表达解偶联蛋白1（UCP1），这种线粒体蛋白能使呼吸作用与ATP合成分离，从而促进产热和能量消耗。然而，UCP1−/−小鼠并未出现肥胖，这表明存在替代性的产热机制。该研究揭示了一种UCP1独立的产热机制，涉及过氧化物酶体中单甲基支链脂肪酸（mmBCFA）的ATP消耗性代谢。这些脂肪酸由脂肪酸合成酶利用支链氨基酸代谢产生的前体合成，研究表明mmBCFA的β-氧化由过氧化物酶体蛋白酰基辅酶A氧化酶2（ACOX2）介导。值得注意的是，低温暴露可上调产热脂肪组织中参与mmBCFA生物合成与β-氧化的相关蛋白。急性产热刺激促进脂肪酸合成酶向过氧化物酶体的转运。棕色脂肪组织特异性敲除脂肪酸合成酶会降低耐寒性。脂肪组织特异性敲除ACOX2同样损害耐寒性，并促进饮食诱导的肥胖和胰岛素抵抗。相反，脂肪组织中过量表达ACOX2可独立于UCP1增强产热作用，并改善代谢稳态。通过过氧化物酶体定位温度传感器Pexo-TEMP发现，ACOX2介导的脂肪酸β-氧化可提升棕色脂肪细胞的细胞内温度。研究结果揭示了过氧化物酶体在脂肪组织产热中的全新作用机制——其特征在于微量长链脂肪酸的合成与分解代谢循环。

9.Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis

小细胞肺癌发病机制的神经元活动依赖性机制

美国斯坦福大学、布莱根妇女医院、哈佛医学院等机构合作发表

Abstract

Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth through paracrine mechanisms and by electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses. Outside of the central nervous system, innervation of tumours such as prostate, head and neck, breast, pancreatic, and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates small cell lung cancer (SCLC) progression, either in the lung or when growing within the brain, is less well understood. SCLC is a lethal high-grade neuroendocrine tumour that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that in the lung, vagus nerve transection markedly inhibits primary lung tumour development and progression, highlighting a critical role for innervation in SCLC growth. In the brain, SCLC cells co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity each drive proliferation of SCLC in the brain through paracrine and synaptic neuron–cancer interactions. SCLC cells form bona fide neuron-to-SCLC synapses and exhibit depolarizing currents with consequent calcium transients in response to neuronal activity; such SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumours. Together, these findings illustrate that neuronal activity has a crucial role in dictating SCLC pathogenesis.

摘要：

神经活动日益被公认为癌症生长的关键调控因子。在大脑中，神经元活动通过旁分泌机制，以及通过神经元-胶质瘤突触将恶性细胞电化学整合进神经回路，对胶质瘤生长产生显著影响。在中枢神经系统之外，外周神经对前列腺癌、头颈癌、乳腺癌、胰腺癌及胃肠癌等肿瘤的支配同样调控着癌症进展。然而，神经系统在肺部或脑内调控小细胞肺癌（SCLC）进展的程度尚不明确。SCLC是一种致命性高级别神经内分泌肿瘤，具有强烈向脑转移的倾向。该研究发现：在肺部，迷走神经切断显著抑制原发性肺肿瘤的发生与进展，凸显神经支配对SCLC生长的关键作用；而在脑部，SCLC细胞通过征用神经元活动调控机制来刺激自身生长与进展。谷氨酸能与γ-氨基丁酸能（GABA能）皮质神经元活动分别通过旁分泌及突触神经元-癌细胞相互作用，驱动脑内SCLC增殖。小细胞肺癌细胞形成真实的神经元-癌细胞突触连接，并在神经活动刺激下产生去极化电流及随之而来的钙离子瞬变；这种癌细胞膜去极化现象足以促进颅内肿瘤生长。综合而言，这些发现表明神经活动在决定小细胞肺癌发病机制中具有关键作用。

10.Functional synapses between neurons and small cell lung cancer

神经元与小细胞肺癌之间的功能性突触

德国科隆大学、埃森大学、哥廷根大学等机构合作发表

Abstract

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, frequent early relapse and a high mortality rate. Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer. Cancer-to-neuron synapses have been reported in gliomas, but whether peripheral tumours can form such structures is unknown. Here we show that SCLC cells can form functional synapses and receive synaptic transmission. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified neuronal, synaptic and glutamatergic signalling gene sets in mouse and human SCLC. Further experiments revealed the ability of SCLC cells to form synaptic structures with neurons in vitro and in vivo. Electrophysiology and optogenetic experiments confirmed that cancer cells can receive NMDA receptor- and GABAA receptor-mediated synaptic inputs. Fitting with a potential oncogenic role of neuron–SCLC interactions, we showed that SCLC cells derive a proliferation advantage when co-cultured with vagal sensory or cortical neurons. Moreover, inhibition of glutamate signalling had therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells seem to hijack synaptic signalling to promote tumour growth, thereby exposing a new route for therapeutic intervention.

摘要：

小细胞肺癌（SCLC）是一种侵袭性极强的肺癌类型，其特征为快速增殖、早期转移扩散、频繁早期复发及高死亡率。最新证据表明，神经支配在多种癌症的发生发展中起着重要作用。虽然胶质瘤中已发现癌-神经元突触结构，但外周肿瘤能否形成此类结构尚不明确。该研究首次证实SCLC细胞可形成功能性突触并接收突触传递。通过体内插入突变筛选结合跨物种基因组与转录组验证，在小鼠和人类SCLC中鉴定出神经元、突触及谷氨酸能信号通路相关基因集。后续实验揭示SCLC细胞在体外及体内均能与神经元形成突触结构。电生理学与光遗传学实验证实癌细胞可接收NMDA受体和GABAA受体介导的突触输入。与神经元-SCLC相互作用潜在致癌作用相符，研究发现SCLC细胞与迷走神经感觉神经元或皮质神经元共培养时具有增殖优势。此外，在原发性小鼠SCLC模型中抑制谷氨酸信号传导具有治疗效果。因此，恶性转化后的SCLC细胞似乎通过劫持突触信号促进肿瘤生长，从而揭示了治疗干预的新途径。

11.Spatial joint profiling of DNA methylome and transcriptome in tissues

组织中DNA甲基组与转录组的空间联合分析

美国宾夕法尼亚大学、费城儿童医院

Abstract

The spatial resolution of omics analyses is fundamental to understanding tissue biology. The capacity to spatially profile DNA methylation, which is a canonical epigenetic mark extensively implicated in transcriptional regulation, is lacking. Here we introduce a method for whole-genome spatial co-profiling of DNA methylation and the transcriptome of the same tissue section at near single-cell resolution. Applying this technology to mouse embryogenesis and the postnatal mouse brain resulted in rich DNA–RNA bimodal tissue maps. These maps revealed the spatial context of known methylation biology and its interplay with gene expression. The concordance and distinction in spatial patterns of the two modalities highlighted a synergistic molecular definition of cell identity in spatial programming of mammalian development and brain function. By integrating spatial maps of mouse embryos at two different developmental stages, we reconstructed the dynamics that underlie mammalian embryogenesis for both the epigenome and transcriptome, revealing details of sequence-, cell-type- and region-specific methylation-mediated transcriptional regulation. This method extends the scope of spatial omics to include DNA cytosine methylation, enabling a more comprehensive understanding of tissue biology across development and disease.

摘要：

组学分析的空间分辨率是理解组织生物学的基础。目前尚缺乏对DNA甲基化进行空间测绘的能力——这种经典表观遗传标记广泛参与转录调控。该研究提出一种方法，可在近单细胞分辨率下对同一组织切片进行全基因组DNA甲基化与转录组的空间联合测绘。将该技术应用于小鼠胚胎发育及出生后脑组织，成功绘制出丰富的DNA-RNA双模态组织图谱。这些图谱揭示了已知甲基化生物学现象的空间背景及其与基因表达的交互作用。两种模态在空间模式上的共性与差异，凸显了哺乳动物发育与脑功能空间编程中，细胞身份通过协同分子机制实现的定义。通过整合小鼠胚胎两个发育阶段的空间图谱，重建了哺乳动物胚胎发育过程中表观基因组与转录组的动态调控机制，揭示了序列特异性、细胞类型特异性及区域特异性甲基化介导的转录调控细节。该方法将空间组学研究范围扩展至DNA胞嘧啶甲基化领域，为深入理解发育与疾病过程中的组织生物学提供了更全面的视角。

12.Structure and mechanism of the mitochondrial calcium transporter NCLX

线粒体钙转运蛋白NCLX的结构和机制

美国斯坦福大学、弗吉尼亚大学、科罗拉多大学等机构合作发表

Abstract

As a key mitochondrial Ca2+ transporter, NCLX regulates intracellular Ca2+ signalling and vital mitochondrial processes. The importance of NCLX in cardiac and nervous-system physiology is reflected by acute heart failure and neurodegenerative disorders caused by its malfunction. Despite substantial advances in the field, the transport mechanisms of NCLX remain unclear. Here we report the cryo-electron microscopy structures of NCLX, revealing its architecture, assembly, major conformational states and a previously undescribed mechanism for alternating access. Functional analyses further reveal an unexpected transport function of NCLX as a H/Ca+2+ exchanger, rather than as a Na/Ca+2+ exchanger as widely believed. These findings provide critical insights into mitochondrial Ca2+ homeostasis and signalling, offering clues for developing therapies to treat diseases related to abnormal mitochondrial Ca2+.

摘要：

作为关键的线粒体钙离子转运蛋白，NCLX调控着细胞内钙信号传导及至关重要的线粒体功能。其功能失调引发的急性心力衰竭和神经退行性疾病，彰显了NCLX在心血管及神经系统生理中的重要性。尽管该领域已取得重大进展，NCLX的转运机制仍未完全阐明。该研究通过冷冻电镜技术解析了NCLX的结构，揭示其空间构象、组装模式、主要构象状态，并发现了此前未知的交替通道机制。功能分析进一步揭示NCLX具有出人意料的H/Ca²⁺交换功能，而非普遍认知的Na/Ca²⁺交换功能。这些发现为线粒体钙稳态与信号传导提供了关键认识，为开发治疗线粒体钙异常相关疾病的疗法提供了线索。

汇报人：张宇阳

导师：赵宇

审核：厚媛、吴婷婷、任建君