编译 | 李言
Nature, 30 October 2025, Volume 646 Issue 8087
《自然》2025年10月30日，第646卷，8087期
生物学Biology
Engineered prime editors with minimal genomic errors
基因组误差最小化的工程化碱基编辑器
▲ 作者：Vikash P. Chauhan, Phillip A. Sharp & Robert Langer
▲链接：
https://www.nature.com/articles/s41586-025-09537-3
▲摘要：
在此，研究者发现，与5'链不稳定性机制相一致，切口末端降解现象可通过改造Cas9切口酶实现——该酶突变体能够放宽对切口位置的严格定位。基于此机制，研究者成功开发出具有极低插入/缺失错误率的高效碱基编辑器。
通过将该误差抑制策略与最新增效架构相结合，研究者设计出新一代碱基编辑器（vPE）。相较于前代编辑器，vPE在保持相当编辑效率的同时，将插入/缺失错误率降低了60倍，实现了543:1的超高编辑/错误比。
▲ Abstract：
Here we discover that nicked end degradation, consistent with competing 5′ strand destabilization, can be promoted by Cas9-nickase mutations that relax nick positioning. We exploit this mechanism to engineer efficient prime editors with strikingly low indel errors. Combining this error-suppressing strategy with the latest efficiency-boosting architecture, we design a next-generation prime editor (vPE). Compared with previous editors, vPE features comparable efficiency yet up to 60-fold lower indel errors, enabling edit:indel ratios as high as 543:1.
医学Medicine
A neuronal architecture underlying autonomic dysreflexia
自主神经反射障碍的神经元结构
▲ 作者：Jan Elaine Soriano, Remi Hudelle et al.
▲链接：
https://www.nature.com/articles/s41586-025-09487-w0
▲摘要：
研究者揭示了脊髓损伤后形成并引发自主神经反射障碍的神经元结构。同时，他们发现了一种与之相抗衡却又部分重叠的神经结构，该结构通过脊髓硬膜外电刺激可安全调控脊髓损伤后的血压。
这些对抗性神经结构最终汇聚于同一神经元亚群的发现，为设计基于机制的干预方案提供了蓝图，该方案成功逆转了小鼠、大鼠及人类脊髓损伤患者的自主神经反射障碍。这些成果为开展关键性医疗器械临床试验开辟道路，将最终确立脊髓硬膜外电刺激治疗脊髓损伤患者自主神经反射障碍的安全性与有效性。
▲ Abstract：
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.
Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis
小细胞肺癌发病的神经元活动依赖机制
▲ 作者：Solomiia Savchuk, Kaylee M. Gentry et al.
▲链接：
https://www.nature.com/articles/s41586-025-09492-z
▲摘要：
研究者揭示了，在肺部实施迷走神经切断术能显著抑制原发性肺癌的发生与进展，表明神经支配对小细胞肺癌（SCLC）生长具有关键调控作用。在大脑中，SCCLC细胞通过劫持神经元活动调控机制促进肿瘤生长进程。谷氨酸能及伽马氨基丁酸（γ-氨基丁酸能）皮质神经元活动分别通过旁分泌信号及突触连接驱动SCLC增殖。
SCLC细胞与神经元形成功能性突触连接，在神经元活动刺激下产生去极化电流并引发钙瞬变；这种癌细胞膜去极化现象足以促进颅内肿瘤生长。这些发现共同证实，神经元活动在SCLC的发病机制中发挥着决定性作用。
▲ Abstract：
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.
Structure and mechanism of the mitochondrial calcium transporter NCLX
线粒体钙转运蛋白NCLX的结构与机制
▲ 作者：Minrui Fan, Chen-Wei Tsai et al.
▲链接：
https://www.nature.com/articles/s41586-025-09491-0
▲摘要：
在此，研究者通过冷冻电镜解析了NCLX的结构，揭示了其三维构架、组装方式、主要构象状态以及一个前所未有的交替存取机制。功能分析进一步发现了NCLX具有出人意料的转运功能——它并非如广泛认知的那样作为钠钙交换体，而是扮演着质子—钙离子交换体的角色。
这些发现为理解线粒体钙离子稳态与信号传导提供了关键认知，并为开发治疗线粒体钙紊乱相关疾病的疗法提供了新线索。
▲ Abstract：
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+/Ca2+ exchanger, rather than as a Na+/Ca2+ 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+.
地球科学Earth Science
Magnetotelluric evidence for a melt-rich magmatic reservoir beneath Mayotte
马约特岛下方富熔体岩浆储层的大地电磁证据
▲ 作者：Pierre Wawrzyniak, Fabrice Gaillard et al.
▲链接：
https://www.nature.com/articles/s41586-025-09625-4
▲摘要：
研究者通过大地电磁成像发现，在马约特岛下方海平面以下23±1公里处存在一个高导带电性体。基于对该岛熔岩电导率的实验室测量数据，研究者认为这是岩浆储层。
这一超过200立方千米的巨型岩浆储层具有高熔融比例（22%—42%），其晶液比与重建的岩浆分异路径高度吻合——正是这些分异作用形成了近期在马约特岛喷发的熔岩。该岩浆储层很可能与造成2018—2019年法尼马奥雷海底大喷发的岩浆供给系统相连。
▲ Abstract：
Here we image a bright electrical conductor at 23 ± 1 km below sea level beneath Mayotte island that we interpret as a magmatic reservoir, based on laboratory measurements of Mayotte’s melt conductivity. This large magmatic reservoir (more than 200 km3) contains a high melt fraction (22–42%). Such a crystal-to-liquid ratio matches the reconstructed differentiation paths producing the melts that recently erupted at Mayotte. This reservoir is possibly connected to the system that fed the large submarine eruption of Fani Maoré in 2018–2019.
社会科学Social Sciences
Age and gender distortion in online media and large language models
在线媒体与大型语言模型中的年龄与性别扭曲
▲ 作者：Douglas Guilbeault, Solène Delecourt & Bhargav Srinivasa Desikan
▲链接：
https://www.nature.com/articles/s41586-025-09581-z
▲摘要：
在此，研究者突破了年龄相关性别偏见分析中的挑战——年龄为评估刻板印象的准确性提供了客观参照基准。尽管美国人口普查数据显示劳动力市场中男女年龄并无系统性差异，但通过对谷歌、维基百科、IMDb、Flickr和YouTube中近140万张图片及视频，以及九个基于互联网海量文本训练的语言模型进行分析，研究者发现女性在各职业和社会角色中均被呈现得比男性更年轻。这种年龄差距在描绘高地位、高收入职业的内容中最为显著。
研究者进一步证实主流算法如何放大这种偏见。一项全美代表性预注册实验（n=459）表明，通过谷歌搜索职业图像会强化受试者观念及招聘偏好中的年龄相关性别偏见。
此外，ChatGPT在生成和评估简历时，会默认女性更年轻且经验不足，同时给年长男性求职者打出更高评分。这项研究揭示了性别与年龄偏见如何通过互联网及其算法中介被系统性地扭曲，为对抗不平等提出了关键挑战与改进契机。
▲ Abstract：
Here we overcame these challenges in the analysis of age-related gender bias, for which age provides an objective anchor for evaluating stereotype accuracy. Despite there being no systematic age differences between women and men in the workforce according to the US Census, we found that women are represented as younger than men across occupations and social roles in nearly 1.4 million images and videos from Google, Wikipedia, IMDb, Flickr and YouTube, as well as in nine language models trained on billions of words from the internet. This age gap is the starkest for content depicting occupations with higher status and earnings. We demonstrate how mainstream algorithms amplify this bias. A nationally representative pre-registered experiment (n = 459) found that Googling images of occupations amplifies age-related gender bias in participants’ beliefs and hiring preferences. Furthermore, when generating and evaluating resumes, ChatGPT assumes that women are younger and less experienced, rating older male applicants as of higher quality. Our study shows how gender and age are jointly distorted throughout the internet and its mediating algorithms, thereby revealing critical challenges and opportunities in the fight against inequality.
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