編譯 | 李言
Nature, 30 October 2025, Volume 646 Issue 8087
《自然》2025年10月30日，第646卷，8087期
生物學(xué)Biology
Engineered prime editors with minimal genomic errors
基因組誤差最小化的工程化堿基編輯器
▲ 作者：Vikash P. Chauhan, Phillip A. Sharp & Robert Langer
▲鏈接：
https://www.nature.com/articles/s41586-025-09537-3
▲摘要：
在此，研究者發(fā)現(xiàn)，與5'鏈不穩(wěn)定性機制相一致，切口末端降解現(xiàn)象可通過改造Cas9切口酶實現(xiàn)——該酶突變體能夠放寬對切口位置的嚴(yán)格定位?；诖藱C制，研究者成功開發(fā)出具有極低插入/缺失錯誤率的高效堿基編輯器。
通過將該誤差抑制策略與最新增效架構(gòu)相結(jié)合，研究者設(shè)計出新一代堿基編輯器（vPE）。相較于前代編輯器，vPE在保持相當(dāng)編輯效率的同時，將插入/缺失錯誤率降低了60倍，實現(xiàn)了543:1的超高編輯/錯誤比。
▲ 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.
醫(yī)學(xué)Medicine
A neuronal architecture underlying autonomic dysreflexia
自主神經(jīng)反射障礙的神經(jīng)元結(jié)構(gòu)
▲ 作者：Jan Elaine Soriano, Remi Hudelle et al.
▲鏈接：
https://www.nature.com/articles/s41586-025-09487-w0
▲摘要：
研究者揭示了脊髓損傷后形成并引發(fā)自主神經(jīng)反射障礙的神經(jīng)元結(jié)構(gòu)。同時，他們發(fā)現(xiàn)了一種與之相抗衡卻又部分重疊的神經(jīng)結(jié)構(gòu)，該結(jié)構(gòu)通過脊髓硬膜外電刺激可安全調(diào)控脊髓損傷后的血壓。
這些對抗性神經(jīng)結(jié)構(gòu)最終匯聚于同一神經(jīng)元亞群的發(fā)現(xiàn)，為設(shè)計基于機制的干預(yù)方案提供了藍圖，該方案成功逆轉(zhuǎn)了小鼠、大鼠及人類脊髓損傷患者的自主神經(jīng)反射障礙。這些成果為開展關(guān)鍵性醫(yī)療器械臨床試驗開辟道路，將最終確立脊髓硬膜外電刺激治療脊髓損傷患者自主神經(jīng)反射障礙的安全性與有效性。
▲ 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
小細胞肺癌發(fā)病的神經(jīng)元活動依賴機制
▲ 作者：Solomiia Savchuk, Kaylee M. Gentry et al.
▲鏈接：
https://www.nature.com/articles/s41586-025-09492-z
▲摘要：
研究者揭示了，在肺部實施迷走神經(jīng)切斷術(shù)能顯著抑制原發(fā)性肺癌的發(fā)生與進展，表明神經(jīng)支配對小細胞肺癌（SCLC）生長具有關(guān)鍵調(diào)控作用。在大腦中，SCCLC細胞通過劫持神經(jīng)元活動調(diào)控機制促進腫瘤生長進程。谷氨酸能及伽馬氨基丁酸（γ-氨基丁酸能）皮質(zhì)神經(jīng)元活動分別通過旁分泌信號及突觸連接驅(qū)動SCLC增殖。
SCLC細胞與神經(jīng)元形成功能性突觸連接，在神經(jīng)元活動刺激下產(chǎn)生去極化電流并引發(fā)鈣瞬變；這種癌細胞膜去極化現(xiàn)象足以促進顱內(nèi)腫瘤生長。這些發(fā)現(xiàn)共同證實，神經(jīng)元活動在SCLC的發(fā)病機制中發(fā)揮著決定性作用。
▲ 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
線粒體鈣轉(zhuǎn)運蛋白NCLX的結(jié)構(gòu)與機制
▲ 作者：Minrui Fan, Chen-Wei Tsai et al.
▲鏈接：
https://www.nature.com/articles/s41586-025-09491-0
▲摘要：
在此，研究者通過冷凍電鏡解析了NCLX的結(jié)構(gòu)，揭示了其三維構(gòu)架、組裝方式、主要構(gòu)象狀態(tài)以及一個前所未有的交替存取機制。功能分析進一步發(fā)現(xiàn)了NCLX具有出人意料的轉(zhuǎn)運功能——它并非如廣泛認知的那樣作為鈉鈣交換體，而是扮演著質(zhì)子—鈣離子交換體的角色。
這些發(fā)現(xiàn)為理解線粒體鈣離子穩(wěn)態(tài)與信號傳導(dǎo)提供了關(guān)鍵認知，并為開發(fā)治療線粒體鈣紊亂相關(guān)疾病的療法提供了新線索。
▲ 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+.
地球科學(xué)Earth Science
Magnetotelluric evidence for a melt-rich magmatic reservoir beneath Mayotte
馬約特島下方富熔體巖漿儲層的大地電磁證據(jù)
▲ 作者：Pierre Wawrzyniak, Fabrice Gaillard et al.
▲鏈接：
https://www.nature.com/articles/s41586-025-09625-4
▲摘要：
研究者通過大地電磁成像發(fā)現(xiàn)，在馬約特島下方海平面以下23±1公里處存在一個高導(dǎo)帶電性體?；趯υ搷u熔巖電導(dǎo)率的實驗室測量數(shù)據(jù)，研究者認為這是巖漿儲層。
這一超過200立方千米的巨型巖漿儲層具有高熔融比例（22%—42%），其晶液比與重建的巖漿分異路徑高度吻合——正是這些分異作用形成了近期在馬約特島噴發(fā)的熔巖。該巖漿儲層很可能與造成2018—2019年法尼馬奧雷海底大噴發(fā)的巖漿供給系統(tǒng)相連。
▲ 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.
社會科學(xué)Social Sciences
Age and gender distortion in online media and large language models
在線媒體與大型語言模型中的年齡與性別扭曲
▲ 作者：Douglas Guilbeault, Solène Delecourt & Bhargav Srinivasa Desikan
▲鏈接：
https://www.nature.com/articles/s41586-025-09581-z
▲摘要：
在此，研究者突破了年齡相關(guān)性別偏見分析中的挑戰(zhàn)——年齡為評估刻板印象的準(zhǔn)確性提供了客觀參照基準(zhǔn)。盡管美國人口普查數(shù)據(jù)顯示勞動力市場中男女年齡并無系統(tǒng)性差異，但通過對谷歌、維基百科、IMDb、Flickr和YouTube中近140萬張圖片及視頻，以及九個基于互聯(lián)網(wǎng)海量文本訓(xùn)練的語言模型進行分析，研究者發(fā)現(xiàn)女性在各職業(yè)和社會角色中均被呈現(xiàn)得比男性更年輕。這種年齡差距在描繪高地位、高收入職業(yè)的內(nèi)容中最為顯著。
研究者進一步證實主流算法如何放大這種偏見。一項全美代表性預(yù)注冊實驗（n=459）表明，通過谷歌搜索職業(yè)圖像會強化受試者觀念及招聘偏好中的年齡相關(guān)性別偏見。
此外，ChatGPT在生成和評估簡歷時，會默認女性更年輕且經(jīng)驗不足，同時給年長男性求職者打出更高評分。這項研究揭示了性別與年齡偏見如何通過互聯(lián)網(wǎng)及其算法中介被系統(tǒng)性地扭曲，為對抗不平等提出了關(guān)鍵挑戰(zhàn)與改進契機。
▲ 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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