【Science】2025年09月04日-2025年10月23日刊论文导读

期刊介绍：

《Science》（科学杂志）是一份由美国科学促进会（American Association for the Advancement of Science，简称AAAS）出版的著名科学杂志。该杂志创建于1880年，是全球最具影响力和知名度的跨学科科学期刊之一。该杂志以发表高质量、原创性的科学研究论文和评论而闻名，涵盖了各个科学领域，包括生命科学、物理学、化学、地球与环境科学、工程技术等。它是科学领域内同行评议制度的支持者，通过评审和编辑确保所发表的研究具有学术水平和可靠性。除了研究论文外，该杂志还经常刊发关于科学前沿、科学政策、科学教育和科学社会问题的评论文章。《Science》还定期发布一些专题特刊，深入探讨特定主题或领域的最新进展。因其在科学界的声望和影响力，《Science》成为科学家们追求学术卓越和科学创新的重要平台之一。最新影响因子为45.8。

VOLUME 389|ISSUE 6764|4 SEP 2025

2025年09月04日，《Science》共发表文章37篇。其中包括Editorial 1篇；News 6篇；Perspectives 4篇；Policy Forum 1篇；Books 2篇；Letters 3篇；Reviews 1篇； Research Highlights 2篇；Research Articles 15篇；Careers 1篇；Products & Materials 1篇。

1.Epithelial tension controls intestinal cell extrusion

上皮张力控制肠细胞挤压

荷兰皇家艺术与科学院（KNAW）和乌得勒支大学医学中心（UMC），

乌得勒支，荷兰

Abstract

Cell extrusion is essential for homeostatic self-renewal of the intestinal epithelium. Extrusion is thought to be triggered by crowding-induced compression of cells at the intestinal villus tip. In this study, we found instead that a local "tug-of-war" competition between contractile cells regulated extrusion in the intestinal epithelium. We combined quantitative live microscopy, optogenetic induction of tissue tension, genetic perturbation of myosin II activity, and local disruption of the basal cortex in mouse intestines and intestinal organoids. These approaches revealed that a dynamic actomyosin network generates tension throughout the intestinal villi, including the villus tip region. Mechanically weak cells unable to maintain this tension underwent extrusion. Thus, epithelial barrier integrity depends on intercellular mechanics.

摘要：

细胞挤出对于肠上皮的稳态性自我更新至关重要。挤出被认为是由肠绒毛尖端细胞的拥挤引起的细胞受压所触发。本研究则发现肠上皮中的挤出由具收缩性的细胞之间的局部“拔河”式竞争所调控。本研究结合了定量活体显微成像、光遗传学诱导组织张力、对肌球蛋白II活性的遗传扰动，以及在小鼠肠道和肠道类器官中对基底皮层的局部破坏。这些方法揭示出，一个动态的肌动蛋白-肌球蛋白网络在整个肠绒毛（包括绒毛顶端区域）产生张力。无法维持该张力的力学薄弱细胞会发生挤出。因此，上皮屏障的完整性取决于细胞间力学。

2.Lewy body dementia promotion by air pollutants

空气污染物引发路易体痴呆

神经再生和干细胞项目，约翰霍普金斯大学医学院细胞工程研究所，

美国马里兰州巴尔的摩

Abstract

Evidence links air pollution to dementia, yet its role in Lewy body dementia (LBD) remains unclear. In this work, we showed in a cohort of 56.5 million individuals across the United States that fine particulate matter (PM2.5) exposure raises LBD risk. Mechanistically, we found that PM2.5exposure led to brain atrophy in wild-type mice, an effect not seen in α-synuclein (αSyn)-deficient mice. PM2.5exposure generated a highly pathogenic αSyn strain, PM2.5-induced preformed fibril (PM-PFF), with enhanced proteinase K resistance and neurotoxicity, resembling αSyn LBD strains. PM2.5samples from China, the United States, and Europe consistently induced proteinase-resistant αSyn strains and in vivo pathology. Transcriptomic analyses revealed shared responses between PM2.5-exposed mice and LBD patients, underscoring PM2.5's role in LBD and stressing the need for interventions to reduce air pollution and its associated neurological disease burden.

摘要：

已有证据表明空气污染与痴呆相关，但其在路易体痴呆（LBD）中的作用尚不清楚。本研究通过对美国5650万人的队列研究显示，细颗粒物（PM2.5）暴露会增加路易体痴呆风险。从机制上讲，本研究发现PM2.5暴露导致了野生型小鼠的脑萎缩，而在α-突触核蛋白（αSyn）缺失的小鼠中未观察到这一效应。PM2.5暴露产生了一种高致病性的αSyn菌株，即PM2.5诱导的预制原纤维（PM-PFF），其具有增强的蛋白酶K抗性和神经毒性，类似于LBD中的αSyn菌株。来自中国、美国和欧洲的PM2.5样本均能一致地诱导产生具有蛋白酶抗性的αSyn菌株及体内病理变化。转录组分析揭示了PM2.5暴露的小鼠与LBD患者之间存在共同应答反应，这突显了PM2.5在路易体痴呆中的作用，并强调了采取干预措施以减少空气污染及其相关的神经系统疾病负担的必要性。

Divergent FOXA1 mutations drive prostate tumorigenesis and therapy-resistant cellular plasticity

分化型FOXA1突变驱动前列腺肿瘤发生和治疗抵抗性细胞可塑性

美国密歇根州安娜堡市密歇根大学病理学系

Abstract

FOXA1 is altered in 10 to 40% of prostate cancers, yet its oncogenic mechanisms remain uncharacterized in vivo. We developed knock-in mouse models representing distinct classes of FOXA1 mutations. Histopathological and multiomic analyses of prostate tissues and organoids revealed that Class 1 mutations, in conjunction with p53 inactivation, drive androgen-dependent adenocarcinomas through coactivation of mTORC1/2 and oncogenic AR signaling stemming from chimeric AR-half enhancers. By contrast, Class 2 mutations induce intraluminal plasticity by reprogramming differentiated luminal cells into a progenitor-like state through activation of KLF5 and AP-1 neo-enhancer circuitries, which enables enhanced survival and proliferation even under castrate androgen levels. Our findings establish FOXA1 as a multifaceted oncogene, with distinct mutational classes divergently evolving to drive prostate tumorigenesis or therapy-resistant progression.

FOXA1在10-40%的前列腺癌中发生改变，但其体内致癌机制仍未得到充分阐释。 本研究建立了代表不同类别FOXA1突变的基因敲入小鼠模型。对前列腺组织和类器官的组织病理学和多组学分析显示，1类突变与p53失活协同，通过共激活mTORC1/2和源于嵌合AR半增强子的致癌性AR信号传导来驱动雄激素依赖性腺癌。相比之下，2类突变通过激活KLF5和AP-1新增强子回路，将分化的管腔细胞重编程为祖细胞样状态，从而诱导管腔内可塑性，这使得细胞即使在去势雄激素水平下也能增强存活和增殖能力。本研究结果确立了FOXA1作为一个多效性致癌基因，其不同的突变类别分化演进以驱动前列腺肿瘤发生或治疗抵抗性进展。

Cooperative actions of interneuron families support the hippocampal spatial code

中间神经元家族的协同作用支撑海马空间编码

神经科学研究所，纽约大学格罗斯曼医学院，美国纽约州纽约市

Abstract

Identifying the computational roles of different neuron families is crucial for understanding neural networks. Most neural diversity is embodied in various types of γ-aminobutyric acid-mediated (GABAergic) interneurons, grouped into four major families. We collected datasets of opto-tagged neurons from all four families, along with excitatory neurons, from both the neocortex and hippocampus. The physiological features of these neurons were used to train a machine learning classifier, which subsequently inferred specific interneuron families in large-scale recordings. This combined approach enabled the reconstruction of synaptic connectivity motifs across interneuron family members. We further showed that these motifs differentially control the place field features of pyramidal neurons. Our findings attribute a prominent role to interneurons in the formation of a flexible cognitive map.

摘要：

识别不同神经元家族的计算功能对于理解神经网络至关重要。神经多样性主要体现在多种类型的γ-氨基丁酸能（GABA能）中间神经元中，可分为四个主要家族。本研究从新皮层和海马体采集了来自全部四个家族的光标记神经元数据集，以及兴奋性神经元。利用这些神经元的生理特征训练机器学习分类器，随后在大规模记录中推断特定中间神经元家族。这种联合方法使得中间神经元家族成员间的突触连接模式得以重构。本研究进一步证明这些连接模式差异性地调控锥体神经元的位置野特征。本研究表明中间神经元在形成灵活认知地图方面发挥着重要作用。

5.Relative importance of the anti-apoptotic versus apoptosis-unrelated functions of MCL-1 in vivo

MCL-1在体内抗凋亡功能相对于凋亡无关功能的相对重要性

澳大利亚墨尔本沃尔特和伊丽莎·霍尔医学研究所

Abstract

The anti-apoptotic protein MCL-1 (myeloid cell leukemia-1) is essential for embryogenesis and the survival of many cell types that tolerate loss of its relatives, BCL-XL and BCL-2. Apoptosis-unrelated roles of MCL-1 in metabolism may contribute to this requirement, although their relevance for embryogenesis and postnatal life remains unclear. We hypothesized that BCL-XL and BCL-2 may substitute MCL-1's anti-apoptotic but not its apoptosis-unrelated functions. Replacing MCL-1 with BCL-XL or BCL-2 supported embryo development by rescuing the Mcl-1-/- preimplantation lethality. Mcl-1Bcl-xL/Bcl-xL but not Mcl-1Bcl-2/Bcl-2 mice were born on a mixed background, although they showed metabolic defects. Thus MCL-1's apoptosis-unrelated functions appear critical in later development, with BCL-XL, but not BCL-2, partially compensating. These findings clarify MCL-1's distinct physiological roles, critically informing MCL-1 inhibitor development as cancer therapeutics.

摘要：

抗凋亡蛋白MCL-1（髓细胞白血病蛋白-1）对于胚胎发育以及那些能够耐受其同源蛋白BCL-XL和BCL-2缺失的多种细胞的存活至关重要。MCL-1在代谢中与凋亡无关的作用可能与其必要性有关，但这些作用在胚胎发育和出生后生命中的意义仍不明确。本研究假设BCL-XL和BCL-2或许可以替代MCL-1的抗凋亡功能，但不能替代其凋亡无关的功能。用BCL-XL或BCL-2替代MCL-1能够通过拯救Mcl-1基因敲除（Mcl-1-/-）造成的植入前致死来支持胚胎发育。在混合遗传背景下，Mcl-1Bcl-xL/Bcl-xL小鼠（而非Mcl-1Bcl-2/Bcl-2小鼠）能够出生，但表现出代谢缺陷。因此，MCL-1的凋亡无关功能在后期发育中似乎至关重要，而BCL-XL（而非BCL-2）能够部分补偿这一功能。这些发现阐明了MCL-1独特的生理作用，为将MCL-1抑制剂开发为癌症治疗药物提供了关键参考。

6.Estrogen-regulated renal progenitors determine pregnancy adaptation and preeclampsia

雌激素调节的肾祖细胞决定妊娠适应和先兆子痫

佛罗伦萨大学"马里奥·塞里奥"生物医学、实验和临床科学系，

佛罗伦萨，意大利

Abstract

The global burden of kidney disease displays marked sexual dimorphism. Lineage tracing and single-cell RNA-sequencing revealed that starting from puberty, estrogen signaling in female mice supports self-renewal and differentiation of renal progenitors to increase filtration capacity, reducing sensitivity to glomerular injury compared with that of males. This phenomenon accelerated as female kidneys adapted to the workload of pregnancy. Deletion of estrogen receptor α in renal progenitors disrupted this adaptation, leading to preeclampsia, fetal growth restriction, and increased maternal risk of hypertension and chronic kidney disease. Offspring from affected mothers had fewer nephrons, resulting in early-life hypertension and greater susceptibility to kidney disease. These results highlight the fundamental role of kidney fitness and renal progenitors for pregnancy and preeclampsia and as a determinant of sexual dimorphism in kidney disease

摘要：

肾脏疾病全球负担呈现出显著的性别二态性。谱系追踪与单细胞RNA测序显示，自青春期开始，雌性小鼠的雌激素信号支持肾祖细胞的自我更新与分化，从而提高滤过能力，使其相较于雄性对肾小球损伤的敏感性降低。随着雌性肾脏为适应妊娠的工作负荷，这一现象进一步加速。若在肾祖细胞中缺失雌激素受体α（ERα），这种适应将被破坏，导致子痫前期、胎儿生长受限，并增加母体发生高血压和慢性肾病的风险。受影响母体所生的后代肾单位数量减少，因而在生命早期即出现高血压，并更易罹患肾脏疾病。这些结果强调了肾脏功能与肾祖细胞对妊娠和子痫前期的关键作用，以及作为决定肾脏疾病性别差异的重要因素。

7.Resistin-like molecule γ attacks cardiomyocyte membranes and promotes ventricular tachycardia

抵抗素样分子γ攻击心肌细胞膜并促进室性心动过速

美国马萨诸塞州波士顿马萨诸塞总医院和哈佛医学院系统生物学中心

Abstract

Ventricular tachycardia disrupts the heart's coordinated pump function, leading to sudden cardiac death. Neutrophils, which are recruited in high numbers to the ischemic myocardium, promote these arrhythmias. Comparing neutrophils with macrophages, we found that resistin-like molecule γ (Retnlg or RELMγ) was the most differentially expressed gene in mouse infarcts. RELMγ is part of a pore-forming protein family that defends the host against bacteria by perforating their membranes. In mice with acute infarcts, leukocyte-specific Retnlg deletion reduced ventricular tachycardia. RELMγ elicited membrane defects that allowed cell exclusion dyes to enter the cardiomyocyte interior and also caused delayed afterdepolarizations and later cardiomyocyte death, both of which are strong arrhythmogenic triggers. Human resistin likewise attacked membranes of liposomes and mammalian cells. We describe how misdirected innate immune defense produces membrane leaks and ventricular arrhythmia.

摘要：

室性心动过速破坏心脏的协调泵血功能，导致心源性猝死。大量募集到缺血心肌的中性粒细胞促进了这些心律失常的发生。通过比较中性粒细胞和巨噬细胞，本研究发现抵抗素样分子γ（Retnlg或RELMγ）是小鼠心肌梗死中差异表达最显著的基因。RELMγ属于成孔蛋白家族的一部分，通过穿孔细菌膜来保护宿主抵御细菌。在急性心肌梗死小鼠中，白细胞特异性Retnlg缺失减少了室性心动过速的发生。RELMγ引起的膜缺陷允许细胞排斥染料进入心肌细胞内部，并导致延迟后除极和随后的心肌细胞死亡，这两者都是强烈的致心律失常触发因素。人抵抗素同样攻击脂质体和哺乳动物细胞的膜。本研究阐述了错误定向的先天免疫防御如何产生膜泄漏和室性心律失常。

VOLUME 389|ISSUE 6765|11 SEP 2025

2025年09月11日，《Science》共发表文章38篇。其中包括Editorial 1篇；News 7篇；Expert Voice 1篇；Perspectives 4篇；Policy Forum 1篇；Books 2篇；Letters 3篇；Reviews 1篇； Research Highlights 2篇；Research Articles 15篇；Careers 1篇。

1.Oxytocin signaling regulates maternally directed behavior during early life

催产素信号传导调控早期发育阶段的趋母行为

脑科学系，魏茨曼科学研究所，以色列雷霍沃特

Abstract

Oxytocin is essential in shaping social behavior across the lifespan. Although the role of oxytocin signaling in parental care has been widely investigated, little is known about its function in social behavior during early life. We studied the role of oxytocin in mouse pup social behavior during acute separation from the mother as well as upon reunion. The activity of oxytocin neurons was increased by acute maternal separation. Behaviorally, maternally separated pups emitted more ultrasonic vocalizations upon reunion, which were further modulated by nipple attachment behavior. These effects were attenuated by blocking the oxytocin receptor during maternal separation. Optogenetic silencing of oxytocin neurons during maternal separation disrupted vocal behavior during separation and reunion. Our findings reveal an important role of oxytocin in context-dependent vocal communication in mouse pups.

摘要：

催产素在塑造整个生命周期的社会行为中至关重要。尽管催产素信号在亲代抚育中的作用已被广泛研究，但对其在生命早期社会行为中的功能却知之甚少。本研究探索了催产素在小鼠幼崽与母亲急性分离期间以及重聚时社会行为中的作用。催产素神经元的活性因急性母子分离而增加。在行为上，与母亲分离的幼崽在重聚时发出了更多超声波发声，这些发声进一步受到乳头附着行为的调节。通过在母子分离期间阻断催产素受体，这些效应被减弱。在母子分离期间对催产素神经元进行光遗传学沉默，破坏了分离和重聚期间的发声行为。本研究结果揭示了催产素在小鼠幼崽依赖情境的声音交流中的重要作用。

2.Visual objects refine head direction coding

视觉对象精化头部方向编码

全脑网络研究组，眼科学系，哥廷根大学医学中心，艾尔莎·克勒纳·弗雷泽纽斯光遗传治疗中心，德国哥廷根

Abstract

Animals use visual objects to guide navigation-related behaviors. However, visual object-preferring areas have yet to be described in the mouse brain, limiting our understanding of how visual objects affect spatial navigation system processing. Using functional ultrasound imaging, we identified brain areas that were preferentially activated by images of objects compared with their scrambled versions. Whereas visual cortex did not show a preference, areas associated with spatial navigation were preferentially activated by visual objects. Electrophysiological recordings in postsubiculum, the cortical head direction (HD) system hub, confirmed a preference for visual objects in both HD cells and fast-spiking interneurons. In freely moving animals, visual objects increased firing rates of HD cells aligned with a visual object but decreased activity in HD cells coding for other directions.

摘要：

动物利用视觉对象来指导导航相关行为。然而，小鼠大脑中的视觉对象偏好区域尚未得到描述，这限制了人们对视觉对象如何影响空间导航系统处理的理解。使用功能超声成像，本研究识别出相比于其打乱版本，优先被物体图像激活的脑区。虽然视觉皮层未显示出偏好性，但与空间导航相关的区域优先被视觉对象激活。在海马后下托（皮层头部方向HD系统的枢纽）进行的电生理记录证实了HD细胞和快速放电中间神经元对视觉对象的偏好。在自由移动的动物中，视觉对象增加了与视觉对象对齐的HD细胞的放电频率，但降低了编码其他方向的HD细胞的活性。

3.E. coli transcription factors regulate promoter activity by a universal, homeostatic mechanism

大肠杆菌转录因子通过通用的稳态机制调节启动子活性

系统生物学系，马萨诸塞大学陈医学院，美国马萨诸塞州伍斯特

Abstract

Transcription factors (TFs) may activate or repress gene expression through an interplay of different mechanisms, including RNA polymerase (RNAP) recruitment, exclusion, and initiation. However, depending on the regulated promoter identity, TF function can vary, and the principles underlying this context dependence remain unclear. We demonstrate an inverse scaling relationship between the promoter's basal activity and its regulation by a given TF. Specifically, activation is weaker and repression is stronger on stronger promoters. This scaling applies to both activators and repressors, which suggests a common underlying mechanism where TFs regulate expression by stabilizing RNAP binding at the promoter. The consequence of this relationship is that TFs buffer expression by affecting constant regulated expression levels across promoters of different basal activity, ensuring homeostatic control despite genetic or environmental changes.

摘要：

转录因子(TFs)可通过不同机制的相互作用激活或抑制基因表达，包括RNA聚合酶(RNAP)的招募、排斥和起始。然而，根据所调控启动子的身份，转录因子功能可能发生变化，而这种情境依赖性的基本原理仍不清楚。本研究证明了启动子的基础活性与其被特定转录因子调控之间存在反向标度关系。具体而言，在较强的启动子上，激活作用较弱而抑制作用较强。这种标度关系适用于激活子和抑制子，提示了一个共同的潜在机制，即转录因子通过稳定RNA聚合酶在启动子处的结合来调节表达。这种关系的结果是，转录因子通过在不同基础活性的启动子间产生恒定的调控表达水平来缓冲表达，确保在遗传或环境变化的情况仍能维持稳态控制。

4.Cryo-EM structure of endogenous Plasmodium falciparum Pfs230 and Pfs48/45 fertilization complex

内源性恶性疟原虫Pfs230和Pfs48/45受精复合体的冷冻电镜结构

沃尔特和伊丽莎·霍尔医学研究所，澳大利亚帕克维尔

Abstract

Malaria parasite fertilization occurs in the midgut of a female Anopheles mosquito. Blocking fertilization within the mosquito can prevent malaria transmission. Plasmodium falciparum Pfs230 and Pfs48/45 proteins are critical for male fertility and transmission of the malaria parasite. They form a core fertilization complex, but it is unknown how they interact. We determined a cryo-electron microscopy structure of the endogenous Pfs230-Pfs48/45 complex showing that Pfs48/45 interacts with Pfs230 domains 13 and 14. Transgenic parasite lines with these domains removed were defective in Pfs230 gamete localization and showed reduced oocyst formation. Nanobodies against domains 13 and 14 inhibited Pfs230-Pfs48/45 complex formation and reduced transmission, and structural analyses revealed their epitopes. These Pfs230 domains were targets of naturally acquired immunity and immune sera from messenger RNA lipid nanoparticle immunizations blocked parasite transmission.

摘要：

疟原虫的受精发生在雌性按蚊的中肠内。阻断蚊体内的受精可预防疟疾传播。恶性疟原虫的Pfs230和Pfs48/45蛋白对雄性生育力和疟原虫传播至关重要。它们形成一个核心受精复合物，但其相互作用方式尚不清楚。本研究通过冷冻电子显微镜解析了内源性Pfs230-Pfs48/45复合物的结构，发现Pfs48/45与Pfs230的第13和第14结构域相互作用。去除这些结构域的转基因寄生虫株在Pfs230配子定位方面存在缺陷，并表现出卵囊形成减少。针对第13和第14结构域的纳米抗体抑制了Pfs230-Pfs48/45复合物的形成并降低了传播，结构分析揭示了它们的表位。这些Pfs230结构域是自然获得性免疫的靶标，而由信使RNA脂质纳米颗粒免疫产生的免疫血清可阻断寄生虫传播。

5.Structural basis for LZTR1 recognition of RAS GTPases for degradation

LZTR1识别RAS GTPases用于降解的结构基础

美国国立癌症研究所RAS计划，癌症研究技术项目，弗雷德里克国立癌症研究实验室，美国马里兰州弗雷德里克

Abstract

The RAS family of small guanosine triphosphatases (GTPases) are tightly regulated signaling molecules that are further modulated by ubiquitination and proteolysis. Leucine Zipper-like Transcription Regulator 1 (LZTR1), a substrate adapter of the Cullin-3 RING E3 ubiquitin ligase, binds specific RAS GTPases and promotes their ubiquitination and proteasomal degradation. We present structures of LZTR1 Kelch domains bound to RIT1, MRAS, and KRAS, revealing interfaces that govern RAS isoform selectivity and nucleotide specificity. Biochemical and structural analyses of disease-associated Kelch domain mutations revealed three types of alterations: impaired substrate interaction, loop destabilization, and blade-blade repulsion. In cellular and mouse models, mutations disrupting substrate binding phenocopied LZTR1 loss, underscoring its substrate specificity. These findings define RAS recognition mechanisms by LZTR1 and suggest a molecular glue strategy to degrade oncogenic KRAS.

摘要：

RAS家族小型鸟苷三磷酸酶(GTPases)是受到严格调控的信号分子，通过泛素化和蛋白水解进一步调节。亮氨酸拉链样转录调节因子1(LZTR1)作为Cullin-3 RING E3泛素连接酶的底物适配器，能结合特定的RAS GTPases并促进其泛素化和蛋白酶体降解。本研究提供了与RIT1、MRAS和KRAS结合的LZTR1的Kelch结构域结构，揭示了决定RAS亚型选择性和核苷酸特异性的界面。对疾病相关Kelch结构域突变的生化和结构分析显示了三类改变：底物相互作用受损、环状结构不稳定化和叶片间排斥。在细胞和小鼠模型中，破坏底物结合的突变表现出与LZTR1缺失相同的表型，强调了其底物特异性。这些发现定义了LZTR1识别RAS的机制，并提出了一种分子胶策略来降解致癌的KRAS。

6.Genomic signatures indicate biodiversity loss in an endemic island ant fauna

基因组特征表明特有岛屿蚂蚁动物群的生物多样性丧失

生物多样性与生物复杂性研究单元，冲绳科学技术大学院大学，日本冲绳恩纳

Abstract

Insect populations have declined worldwide, but the extent and drivers of these declines are debated. Most studies rely on field surveys performed in the past century, leaving gaps in our understanding of longer-term trends. Using a "community genomics" approach, we estimated community assembly over millions of years and more recent demographic trends of ant species in the Fijian archipelago. We found that 79% of endemic species are in decline, starting after the arrival of humans approximately 3000 years ago and accelerating in the past 300 years, whereas recent arrivals are expanding. The primary correlate of population decline among endemic species was found to be sensitivity to habitat disturbance. This study demonstrates the value of contemporary collections for estimating long-term community trends and highlights the vulnerability of endemic island species to anthropogenic change.

摘要：

昆虫种群在全球范围内呈现下降趋势，但这些下降的程度和驱动因素仍存在争议。大多数研究依赖于上个世纪进行的实地调查，导致人们对长期趋势的理解存在缺口。利用"群落基因组学"方法，本研究估计了斐济群岛蚂蚁物种数百万年来的群落构建过程及其近期的种群动态统计趋势。本研究现79%的特有物种正在减少，这一趋势始于人类约3000年前到达之后，并在过去300年中加速，而近期抵达的物种则呈扩张趋势。特有物种种群减少的主要相关因素被发现是对栖息地干扰的敏感性。这项研究展示了现代收集样本对估计长期群落趋势的价值，并强调了特有岛屿物种对人为变化的脆弱性。

VOLUME 389|ISSUE 6766|18 SEP 2025

2025年09月18日，《Science》共发表文章37篇。其中包括Editorial 1篇；News 6篇；Expert Voice 1篇；Perspectives 4篇；Policy article 1篇；Books 2篇；Letters 3篇；Reviews 1篇； Research Highlights 2篇；Research Articles 15篇；Careers 1篇。

1.1206 genomes reveal origin and movement of Aedes aegypti driving increased dengue risk

1206个基因组揭示埃及伊蚊的起源和迁移导致登革热风险增加

Verily生命科学公司，美国加利福尼亚州南旧金山市

Abstract

The emergence and global expansion of Aedes aegypti puts more than half of all humans at risk of arbovirus infection, but the origin of this mosquito and the impact of contemporary gene flow on arbovirus control are unclear. We sequenced 1206 genomes from 73 globally distributed locations. After evolving a preference for humans in Sahelian West Africa, the invasive subspecies Ae. aegypti aegypti (Aaa) emerged in the Americas after the Atlantic slave trade era and expanded globally. Recent back-to-Africa Aaa migration introduced insecticide resistance and anthropophily into regions with recent dengue outbreaks, raising concern that Aaa movement could increase arbovirus risk in urban Africa. These data underscore developing complexity in the fight against dengue, Zika, and chikungunya and provide a platform to further study this important mosquito vector.

摘要：

埃及伊蚊的出现和全球扩散使超过一半的人类面临虫媒病毒感染风险，但这种蚊子的起源以及当代基因流对虫媒病毒防控的影响尚不清楚。本研究对来自全球73个地区的1206个基因组进行了测序。在萨赫勒西非地区进化出对人类的偏好后，具有侵袭性的埃及伊蚊埃及亚种(Aaa)在大西洋奴隶贸易时期后出现在美洲并在全球扩散。最近Aaa回流非洲在近期登革热爆发地区引入了杀虫剂抗性和嗜人性，引发了对Aaa迁移可能增加非洲城市地区虫媒病毒风险的担忧。这些数据凸显了抗击登革热、寨卡和基孔肯雅热斗争中日益复杂的情况，并为进一步研究这种重要的蚊媒提供了平台。

2.Functional maps of a genomic locus reveal confinement of an enhancer by its target gene

基因组位点功能图谱揭示增强子受靶基因约束

基因调控研究室，荷兰癌症研究所，荷兰阿姆斯特丹

Abstract

Genes are often activated by enhancers located at large genomic distances, and the importance of this positioning is poorly understood. By relocating promoter-reporter constructs into thousands of alternative positions within a single locus, we dissected the positional relationship between the mouse Sox2 gene and its distal enhancer. This revealed an intricate, sharply confined activation landscape in which the native Sox2 gene occupies an optimal position for its activation. Deletion of the gene relaxes this confinement and broadly increases reporter activity. The confining effect of the Sox2 gene is partially conferred by its ~1-kilobase coding region. Our local relocation approach provides high-resolution functional maps of a genomic locus and reveals that a gene can strongly constrain the realm of influence of its enhancer.

摘要：

基因常常被位于基因组远距离的增强子激活，而这种定位的重要性尚未被充分理解。通过将启动子-报告基因构建体重新定位到单一位点内数千个不同位置，本研究解析了小鼠Sox2基因与其远端增强子之间的位置关系。这揭示了一个复杂且边界清晰的激活景观，其中原生Sox2基因占据了最适合其激活的位置。删除该基因会放松这种限制，并广泛增加报告基因活性。Sox2基因的限制效应部分由其约1千碱基的编码区域赋予。本研究的局部重定位方法提供了基因组位点的高分辨率功能图谱，并揭示基因可以强烈限制其增强子的影响范围。

3.Genomic diversity of the African malaria vector Anopheles funestus

非洲疟疾媒介弗氏按蚊的基因组多样性

韦尔科姆桑格研究所，欣克斯顿，英国

Abstract

Anopheles funestus s.s. is a major human malaria vector across Africa. To study its evolution, especially under vector control pressure, we sequenced 656 modern specimens (collected 2014 to 2018) and 45 historic specimens (collected 1927 to 1967) from 16 African countries. Despite high genetic diversity, the species shows stable but considerable continental population structure. Although one population showed little differentiation over a century and 4000 kilometers, nearby, we found two genetically distinct ecotypes. Vector control has resulted in strong signals of selection, with some resistance alleles shared across populations through gene flow and others arising independently. Fortunately, we found that a promising gene drive target in Anopheles gambiae is highly conserved in An. funestus. These insights will enable more strategic insecticide usage and gene drive deployment, supporting malaria elimination.

摘要：

弗氏按蚊是整个非洲的主要人类疟疾媒介。为了研究其进化，特别是在媒介控制压力下的进化，本研究对来自16个非洲国家的656个现代样本（采集于2014年至2018年）和45个历史样本（采集于1927年至1967年）进行了测序。尽管具有高度的遗传多样性，该物种仍表现出稳定但显著的大陆种群结构。尽管一个种群在一个世纪和4000公里的范围内几乎没有分化，但在附近，本研究发现了两个遗传上不同的生态型。媒介控制导致了强烈的选择信号，一些抗性等位基因通过基因流动在种群间共享，而另一些则独立产生。幸运的是，本研究发现冈比亚按蚊中一个有前景的基因驱动靶点在弗氏按蚊中高度保守。这些见解将有助于更具战略性地使用杀虫剂和部署基因驱动，支持疟疾消除。

4.Kinetic organization of the genome revealed by ultraresolution multiscale live imaging

超分辨率多尺度活细胞成像揭示的基因组动力学组织

美国加利福尼亚州斯坦福，斯坦福大学发育生物学系

Abstract

Genome function requires regulated genome motion. However, tools to directly observe this motion in vivo have been limited in coverage and resolution. Here we introduce an approach to tile mammalian chromosomes with self-mapping fluorescent labels and track them at ultraresolution. We find that sequences separated by submegabase distances transition to proximity in tens of seconds. This rapid search is dependent on cohesin and is exhibited only within domains. Domain borders act as kinetic impediments to this search process, rather than structural boundaries. The genomic separation-dependent scaling of the search time for cis interactions violated predictions of diffusion, suggesting motor-driven folding. We also uncover cohesin-dependent processive motion at 2.7 kilobases per second. Together, these multiscale dynamics reveal the organization of the genome into kinetically associated domains.

摘要：

基因组功能依赖于受调控的基因组运动。然而，在活体内直接观察这种运动的工具在覆盖范围和分辨率方面一直受到限制。在此，本研究提出一种新方法，通过在哺乳动物染色体上铺设自我定位荧光标记，实现超高分辨率的动态追踪。本研究发现，相隔小于兆碱基距离的序列在数十秒内转变为邻近。这种快速搜索依赖于黏连蛋白，并且仅在结构域内表现出来。结构域边界作为这一搜索过程的动力学障碍，而非结构边界。顺式相互作用搜索时间的基因组分离依赖性标度违反了扩散预测，表明存在马达驱动的折叠。本研究还揭示了依赖于黏连蛋白的持续运动，速度为每秒2.7千碱基。总之，这些多尺度动力学揭示了基因组组织成动力学相关结构域。

VOLUME 389|ISSUE 6767|25 SEP 2025

2025年09月25日，《Science》共发表文章37篇。其中包括Editorial 1篇；News 7篇；Perspectives 4篇；Books 3篇；Letters 3篇；Policy article 1篇；Reviews 1篇； Research Highlights 2篇；Research Articles 14篇；Careers 1篇。

1.Dynamic U2AF cycling defines two phases of cotranscriptional pre-mRNA splicing

动态U2AF循环定义了共转录前体mRNA剪接的两个阶段

西湖生命科学与生物医学实验室，西湖大学生命科学学院，中国杭州

Abstract

Distinguishing functional splice sites from abundant cryptic sites in precursor messenger RNAs (pre-mRNAs) represents a fundamental challenge in decoding mammalian genomes. We demonstrate that the specific RNA polymerase II (Pol II) subunit RPB9 directly interacts with the 3' AG dinucleotide binding factor U2AF1 to initiate 3' splice site recognition. Combined with recent structural insights into Pol II-mediated 5' splice site selection, these findings support a cotranscriptional mechanism to recognize paired 3' and 5' splice sites across individual exons. These initial exon definition events facilitate the recruitment of U2AF2 to heterodimerize with U2AF1, which also triggers U2AF1 release from elongating Pol II. Collectively, these results reveal dynamic U2AF cycling that partitions Pol II subunit-facilitated splice site recognition and subsequent Pol II-independent spliceosome assembly steps during cotranscriptional splicing.

摘要：

在前体信使RNA（pre-mRNAs）中区分功能性剪接位点和大量隐匿位点是解码哺乳动物基因组的基本挑战。本研究证明特定的RNA聚合酶II（Pol II）亚基RPB9直接与3' AG二核苷酸结合因子U2AF1相互作用，启动3'剪接位点识别。结合最近关于Pol II介导的5'剪接位点选择的结构见解，这些发现支持了一种共转录机制，用于识别跨越单个外显子的成对3'和5'剪接位点。这些初始外显子定义事件促进了U2AF2的招募，使其与U2AF1形成异二聚体，这也触发了U2AF1从延伸中的Pol II释放。总体而言，这些结果揭示了动态U2AF循环，该循环在共转录剪接过程中分割了Pol II亚基促进的剪接位点识别和随后的Pol II非依赖性剪接体组装步骤。

2.Dual transposon sequencing profiles the genetic interaction landscape in bacteria

双转座子测序描绘细菌中的遗传相互作用图谱

传染病转化研究项目及微生物学与免疫学系，杨潞龄医学院，新加坡国立大学，新加坡

Abstract

Gene redundancy complicates systematic characterization of gene function as single-gene deletions may not produce discernible phenotypes. We report dual transposon sequencing (dual Tn-seq), a platform for assaying the fitness of a comprehensive double mutant pool in parallel. Dual Tn-seq couples random barcode transposon site sequencing with the Cre-lox system, enabling deep sampling of 73% of the 1.3 million possible double gene deletions in Streptococcus pneumoniae. The genetic interactions identified span a wide range of biochemical processes, revealing new factors in presumably well-studied pathways, exemplified by a cytidine triphosphate synthase PyrJ. Moreover, this approach should permit further investigation of growth condition-specific genetic interactions. Because dual Tn-seq does not require the construction of a large array of single mutants, it should be readily adaptable to various microorganisms.

摘要：

基因冗余使基因功能的系统性表征变得复杂，因为单基因缺失可能不会产生可辨别的表型。本研究报道了双转座子测序（dual Tn-seq），一种可并行检测大规模双突变体库适应性的平台。双转座子测序将随机条形码转座子位点测序与Cre-lox系统相结合，实现了对肺炎链球菌中130万个可能的双基因缺失组合中73%的深度采样。所鉴定的遗传相互作用跨越广泛的生化过程，在已被认为充分研究的通路中揭示了新的因子，三磷酸胞苷合成酶PyrJ就是一个例证。此外，该方法还能够进一步研究生长条件特异性的遗传相互作用。由于双转座子测序不需要构建大量单突变体阵列，因此应该很便捷地适用于各种微生物。

3.Deazaguanylation is a nucleobase-protein conjugation required for type IV CBASS immunity

去氮鸟苷酰化是IV型CBASS免疫所需的核碱基-蛋白质偶联反应

美国马萨诸塞州波士顿,哈佛医学院布拉瓦特尼克研究所微生物学系

Abstract

7-Deazapurines are nucleobase analogs essential for nucleic acid modifications in nearly all cellular life. In this study, we discovered a role for 7-deazapurines in protein modification within type IV cyclic oligonucleotide-based antiviral signaling system (CBASS) antiphage defense and defined functions for CBASS ancillary proteins Cap9 and Cap10 in nucleobase-protein conjugation. A structure of Cap10 revealed a transfer RNA transglycosylase family enzyme remodeled to bind a partner cGAS/DncV-like nucleotidyltransferase that is modified with an N-terminal 7-amido-7-deazaguanine (NDG) nucleobase. A structure of Cap9 explained how this QueC-like enzyme co-opts a 7-deazapurine biosynthetic reaction to install NDG. We show that Cap9, Cap10, and protein deazaguanylation are essential for host defense against phage infection. Our results define a 7-deazapurine protein modification and explain how nucleobase biosynthetic machinery has been repurposed for antiviral immunity.

摘要：

7-去氮嘌呤是核碱基类似物，对几乎所有细胞生命中的核酸修饰至关重要。本研究发现了7-去氮嘌呤在IV型基于环状寡核苷酸的抗病毒信号系统(CBASS)抗噬菌体防御中的蛋白质修饰作用，并确定了CBASS辅助蛋白Cap9和Cap10在核碱基-蛋白质偶联中的功能。Cap10的结构揭示了一种经过重塑的转运RNA转糖基酶家族酶，该酶可与伴侣cGAS/DncV样核苷酸转移酶结合，而该转移酶的N端被7-氨基-7-去氮鸟嘌呤(NDG)核碱基修饰。Cap9的结构解释了这种QueC样酶如何利用7-去氮嘌呤生物合成反应来加载NDG。本研究证明Cap9、Cap10和蛋白质去氮鸟苷酰化对宿主防御噬菌体感染至关重要。本研究结果定义了一种7-去氮嘌呤蛋白质修饰方法，并解释了核碱基生物合成机制如何被重新利用于抗病毒免疫。

4.Lysosomes signal through the epigenome to regulate longevity across generations

溶酶体通过表观基因组信号调控跨代寿命

美国德克萨斯州休斯顿，贝勒医学院赫芬顿老龄化研究中心

Abstract

The epigenome is sensitive to metabolic inputs and is crucial for aging. Lysosomes act as a signaling hub to sense metabolic cues and regulate longevity. We found that lysosomal metabolic pathways signal through the epigenome to regulate transgenerational longevity in Caenorhabditis elegans. Activation of lysosomal lipid signaling and lysosomal adenosine monophosphate-activated protein kinase (AMPK) or reduction of lysosomal mechanistic target of rapamycin (mTOR) signaling increased the expression of a histone H3.3 variant and increased its methylation on K79, leading to life-span extension across multiple generations. This transgenerational prolongevity effect required intestine-to-germline transportation of histone H3.3 and a germline-specific H3K79 methyltransferase and was recapitulated by overexpressing H3.3 or the H3K79 methyltransferase. Thus, signals from a lysosome affect the epigenome and link the soma and germ line to mediate transgenerational inheritance of longevity.

摘要：

表观基因组对代谢输入敏感，并且对衰老至关重要。溶酶体作为信号枢纽感知代谢信号并调控寿命。本研究发现溶酶体代谢通路通过表观基因组发出信号，调控秀丽隐杆线虫的跨代寿命。激活溶酶体脂质信号传导和溶酶体腺苷酸活化蛋白激酶(AMPK)，或降低溶酶体雷帕霉素机制靶蛋白(mTOR)信号传导，可增加组蛋白H3.3变体的表达并增加其K79位点的甲基化，从而导致多代寿命延长。这种跨代延寿效应需要组蛋白H3.3以及生殖系特异性H3K79甲基转移酶从肠道向生殖系的运输，并且可通过过表达H3.3或H3K79甲基转移酶来重现。因此，来自溶酶体的信号影响表观基因组，并连接体细胞和生殖系以介导寿命的跨代遗传。

VOLUME 390|ISSUE 6768|2 OCT 2025

2025年10月02日，《Science》共发表文章37篇。其中包括Editorial 1篇；News 7篇；Expert Voices 1篇; Perspectives 4篇；Policy forum 1篇；Books 2篇；Letters 1篇；Research Highlights 2篇；Research Articles16篇；Careers 1篇；Products & Materials 1篇。

1.ATP-dependent remodeling of chromatin condensates reveals distinct mesoscale outcomes

染色质凝聚体的ATP依赖性重塑揭示了不同的中尺度结果

美国加利福尼亚州旧金山，加州大学旧金山分校，生物化学与生物物理系

Abstract

Adenosine triphosphate (ATP)-dependent chromatin remodeling enzymes mobilize nucleosomes, but how such mobilization affects chromatin condensation is unclear. We investigate effects of two major remodelers, ACF and RSC, using chromatin condensates and single-molecule footprinting. We find that both remodelers inhibit the formation of condensed chromatin. However, the remodelers have distinct effects on preformed chromatin condensates. ACF spaces nucleosomes without decondensing the chromatin, explaining how ACF maintains nucleosome organization in transcriptionally repressed genomic regions. By contrast, RSC catalyzes ATP-dependent decondensation of chromatin. RSC also drives micron-scale movements of entire chromatin condensates. These additional activities of RSC may contribute to its central role in transcription. The biological importance of remodelers may thus reflect both their effects on nucleosome mobilization and the corresponding consequences on chromatin dynamics at the mesoscale.

摘要：

三磷酸腺苷（ATP）依赖的染色质重塑酶能够动员核小体，但这种动员如何影响染色质凝聚尚不清楚。本研究利用染色质凝聚体和单分子足迹分析技术研究了两种主要重塑酶ACF和RSC的效应。本研究发现这两种重塑酶均抑制凝聚态染色质的形成。然而，这两种重塑酶对预先形成的染色质凝聚体具有截然不同的作用。ACF能够调整核小体间距而不解凝聚染色质，这解释了ACF如何在转录抑制的基因组区域维持核小体组织结构。相比之下，RSC催化ATP依赖的染色质解凝聚过程。RSC还驱动整个染色质凝聚体的微米尺度运动。RSC的这些额外活性可能有助于其在转录过程中发挥核心作用。因此，重塑酶的生物学重要性可能既体现在其对核小体动员的效应上，也体现在其对中尺度染色质动力学的相应影响上。

2.A comprehensive genetic catalog of human double-strand break repair

人类双链断裂修复的综合基因图谱

拓扑学与DNA断裂研究组，西班牙国家癌症研究中心（CNIO），西班牙马德里

Abstract

The analysis of DNA sequence outcomes provides molecular insights into double-strand break (DSB) repair mechanisms. Using parallel in-pool profiling of Cas9-induced insertions and deletions (indels) within a genome-wide knockout library, we present a comprehensive catalog that assesses the influence of nearly every human gene on DSB repair outcomes. This REPAIRome resource uncovers uncharacterized mechanisms, pathways, and factors involved in DSB repair, including opposing roles for XLF and PAXX, a molecular explanation for Cas9-induced multinucleotide insertions, HLTF functions in Cas9-induced DSB repair, the involvement of the SAGA complex in microhomology-mediated end joining, and an indel mutational signature linked to VHL loss, renal carcinoma, and hypoxia. These results exemplify the potential of REPAIRome to drive future discoveries in DSB repair, CRISPR-Cas gene editing and the etiology of cancer mutational signatures.

摘要：

DNA序列结果分析为双链断裂（DSB）修复机制提供了分子层面的见解。通过在全基因组敲除文库中对Cas9诱导的插入与缺失（indel）进行并行池内分析，本研究提出了一份全面的图谱，评估几乎所有人类基因对DSB修复结果的影响。这一REPAIRome资源揭示了参与DSB修复的未被表征的机制、途径和因子，包括XLF和PAXX的对立作用、Cas9诱导的多核苷酸插入的分子解释、HLTF在Cas9诱导的DSB修复中的功能、SAGA复合体在微同源介导的末端连接中的参与，以及与VHL缺失、肾癌和缺氧相关的indel突变特征。这些结果展示了REPAIRome在推动DSB修复、CRISPR-Cas基因编辑和癌症突变特征病因学方面未来发现的潜力。

3.Intercellular communication in the brain through a dendritic nanotubular network

通过树突纳米管网络实现的大脑细胞间通讯

美国约翰斯·霍普金斯大学医学院所罗门·H·斯奈德神经科学系

Abstract

Intercellular nanotubular networks mediate material exchange, but their existence in neurons remains to be explored in detail. We identified long, thin dendritic filopodia forming direct dendrite-dendrite nanotubes (DNTs) in mammalian cortex. Super-resolution microscopy in dissociated neurons revealed DNTs' actin-rich composition and dynamics, enabling long-range calcium ion (Ca2+) propagation. Imaging and machine learning-based analysis validated in situ DNTs as anatomically distinct from synaptic spines. DNTs actively transported small molecules and human amyloid-β (Aβ); DNT density increased before plaque formation in the medial prefrontal cortex of APP/PS1 mice (APP, Aβ precursor protein; PS1, presenilin-1), suggesting that the dendrite-DNT network might play a role in Alzheimer's disease pathology. Computational models of DNT-mediated Aβ propagation recapitulated early amyloidosis, predicting selective intracellular accumulation. These findings uncover a nanotubular connectivity layer in the brain, extending neuronal communication beyond classical synapses.

摘要：

细胞间纳米管网络介导物质交换，但其在神经元中的存在仍有待详细探索。本研究在哺乳动物皮层中发现了长而细的树突伪足，形成直接的树突-树突纳米管（DNTs）。在分离的神经元中进行的超分辨率显微镜检查揭示了DNTs富含肌动蛋白的组成和动态特性，使长程钙离子（Ca2+）传播成为可能。基于成像和机器学习的分析验证了原位DNTs在解剖学上与突触棘不同。DNTs主动运输小分子和人类淀粉样蛋白-β（Aβ）；在APP/PS1小鼠（APP，Aβ前体蛋白；PS1，早老素-1）的内侧前额叶皮层中，DNT密度在斑块形成之前增加，表明树突-DNT网络可能在阿尔茨海默病病理中发挥作用。DNT介导的Aβ传播的计算模型再现了早期淀粉样变性，预测了选择性细胞内积累。这些发现揭示了大脑中的纳米管连接层，将神经元通讯扩展到经典突触之外。

4.GCN1 couples GCN2 to ribosomal state to initiate amino acid response pathway signaling

GCN1 将 GCN2 与核糖体状态偶联以启动氨基酸应答途径信号传导

发育生物学系，哈佛大学牙医学院，美国马萨诸塞州波士顿

Abstract

During nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular stresses. GCN2 activation has been linked to its association with uncharged tRNAs, specific ribosomal proteins, and conditions of translational arrest, but their relative contribution to activation is unclear. Here, we used in vitro translation to reconstitute GCN2 activation by amino acid stress and compared collided ribosome populations induced by diverse translational stressors. Initiation of GCN2 signaling required the di-ribosome sensor GCN1, which recruits GCN2 to ribosomes in a collision-dependent manner, where GCN2 becomes activated by key ribosomal interactions and stably associated with collided ribosomes. Our findings define the molecular requirements and dynamics of GCN2 activation.

摘要：

在营养匮乏期间，蛋白激酶GCN2的激活调节着细胞存活和代谢稳态。除了氨基酸应激外，GCN2 还能被多种细胞应激所激活。GCN2 的激活与其和未携带氨基酸的 tRNA、特定核糖体蛋白的结合以及翻译停滞条件相关，但它们对激活的相对贡献尚不清楚。本研究利用体外翻译系统重建了氨基酸应激诱导的 GCN2 激活过程，并比较了由不同翻译应激源诱导的碰撞核糖体群体。GCN2 信号传导的启动需要双核糖体传感器 GCN1，GCN1 以依赖碰撞的方式将 GCN2 募集到核糖体上，在此过程中 GCN2 通过关键的核糖体相互作用被激活，并与碰撞的核糖体稳定结合。本研究结果阐明了 GCN2 激活的分子要求和动态过程。

VOLUME 390|ISSUE 6769|9 OCT 2025

2025年10月09日，《Science》共发表文章40篇。其中包括Editorial 1篇；News 7篇；Expert Voices 1篇; Perspectives 4篇；Policy forum 1篇；Books 2篇；Letters 3篇；Reviews1篇；Research Highlights 2篇；Research Articles 17篇；Careers 1篇。

1.MTAP deficiency confers resistance to cytosolic nucleic acid sensing and STING agonists

MTAP缺陷赋予对胞质核酸感应和STING激动剂的抵抗性

中国医药大学生物医学科学研究所，台湾台中

Abstract

Cytosolic nucleic acid-sensing pathways are potential targets for cancer immunotherapy. Although stimulator of interferon genes (STING) agonists have shown substantial antitumor effects in animal models, their clinical efficacy in human tumors remains unclear. Deletion of methylthioadenosine phosphorylase (MTAP) is a common genomic alteration in human tumors but is rare in preclinical syngeneic mouse models. We found that homozygous MTAP deletion in human tumors creates a tumor microenvironment that obstructs cytosolic nucleic acid-sensing pathways by down-regulating interferon regulatory factor 3 (IRF3), leading to resistance to STING agonists. Targeting polyamine biosynthesis reverses IRF3 down-regulation, restoring sensitivity to STING agonists in MTAP-deficient tumors. Our findings suggest that MTAP genetic status may inform patient responses to STING agonist therapy and offer an alternative strategy for boosting antitumor immune responses using STING agonists in MTAP-deleted tumors.

摘要：

胞质核酸感应通路是癌症免疫治疗的潜在靶点。尽管干扰素基因刺激因子(STING)激动剂在动物模型中显示出显著的抗肿瘤效应，但其在人类肿瘤中的临床疗效仍不明确。甲硫腺苷磷酸化酶(MTAP)缺失是人类肿瘤中常见的基因组改变，但在临床前同基因小鼠模型中较为罕见。本研究发现，人类肿瘤中MTAP纯合缺失会形成一种肿瘤微环境，通过下调干扰素调节因子3 (IRF3)来阻碍胞质核酸感应通路，从而导致对STING激动剂产生抵抗性。靶向多胺生物合成可逆转IRF3的下调，恢复MTAP缺陷型肿瘤对STING激动剂的敏感性。本研究结果表明，MTAP基因状态可能有助于预测患者对STING激动剂治疗的反应，并为在MTAP缺失型肿瘤中使用STING激动剂增强抗肿瘤免疫应答提供了一种替代策略。

2.mRNA initiation and termination are spatially coordinated

mRNA起始和终止具有空间协调性

RNA治疗研究所，马萨诸塞大学陈氏医学院，伍斯特，马萨诸塞州，美国

Abstract

Transcriptional initiation and termination decisions drive messenger RNA (mRNA) isoform diversity but the relationship between them remains poorly understood. By systematically profiling joint usage of transcription start and end sites, we observed that mRNA using upstream starts preferentially use upstream end sites and that the usage of downstream sites is similarly coupled. Our results suggest a positional initiation termination axis (PITA), in which usage of alternative terminal sites are coupled based on their genomic order. PITA is enriched in longer genes with distinct chromatin features. We find that mRNA 5' start choice directly influences 3' ends depending on RNA polymerase II trafficking speed. Our results indicate that spatial organization and transcriptional dynamics couple transcription initiation and mRNA 3' end decisions to define mRNA isoform expression.

摘要：

转录起始和终止决策驱动着信使RNA（mRNA）异构体的多样性，但它们之间的关系仍然知之甚少。通过系统性分析转录起始位点和终止位点的联合使用情况，本研究观察到使用上游起始位点的mRNA优先使用上游终止位点，而下游位点的使用也同样存在偶联。本研究结果表明存在一个位置依赖的起始-终止轴（PITA），其中可变终端位点的使用根据其基因组顺序相互偶联。PITA在具有独特染色质特征的较长基因中富集。本研究发现mRNA 5'起始位点的选择通过RNA聚合酶II的运行速度直接影响3'端终止位点的选择。本研究结果表明，空间组织和转录动力学将转录起始与mRNA 3'端决策偶联起来，从而定义mRNA异构体的表达。

3.A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging

裸鼹鼠中cGAS介导的机制增强DNA修复并延缓衰老

中国上海，同济大学生命科学与技术学院，干细胞研究前沿科学中心，上海市第一妇婴保健院临床与转化研究中心，上海市母胎医学重点实验室

Abstract

Efficient DNA repair might make possible the longevity of naked mole-rats. However, whether they have distinctive mechanisms to optimize functions of DNA repair suppressors is unclear. We find that naked mole-rat cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) lacks the suppressive function of human or mouse homologs in homologous recombination repair through the alteration of four amino acids during evolution. The changes enable cGAS to retain chromatin longer upon DNA damage by weakening TRIM41-mediated ubiquitination and interaction with the segregase P97. Prolonged chromatin binding of cGAS enhanced the interaction between repair factors FANCI and RAD50 to facilitate RAD50 recruitment to damage sites, thereby potentiating homologous recombination repair. Moreover, the four amino acids mediate the function of cGAS in antagonizing cellular and tissue aging and extending life span. Manipulating cGAS might therefore constitute a mechanism for life-span extension.

摘要：

高效的DNA修复可能是裸鼹鼠长寿的原因。然而，它们是否具有独特的机制来优化DNA修复抑制因子的功能尚不清楚。本研究发现裸鼹鼠的环鸟苷酸-腺苷酸合成酶（cGAS）通过进化过程中四个氨基酸的改变，失去了人类或小鼠同源物在同源重组修复中的抑制功能。这些变化通过削弱TRIM41介导的泛素化以及与分离酶P97的相互作用，使cGAS在DNA损伤时能够在染色质上滞留更长时间。cGAS在染色质上的延长结合增强了修复因子FANCI和RAD50之间的相互作用，促进RAD50招募到损伤位点，从而增强同源重组修复。此外，这四个氨基酸介导了cGAS在抵抗细胞和组织衰老以及延长寿命方面的功能。因此，调控cGAS可能构成一种延长寿命的机制。

4.Acidosis orchestrates adaptations of energy metabolism in tumors

酸中毒调控肿瘤的能量代谢适应

细胞信号与代谢研究部，德国癌症研究中心（DKFZ）及DKFZ-ZMBH联盟，

德国海德堡

Abstract

Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal-regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.

摘要：

恶性肿瘤的特征是面临多样的代谢应激，包括营养物质短缺、缺氧以及代谢副产物的累积。为了理解癌细胞如何适应这些挑战，本研究进行了序贯CRISPR筛选，以鉴定在细胞培养中特定代谢应激条件下影响细胞适应性的基因，并进一步探究它们在胰腺肿瘤中的相关性。对数百个适应性基因的比较分析揭示，体内癌症代谢是由对肿瘤酸中毒的生物能量适应所塑造的。从机制上讲，酸中毒抑制了细胞外信号调节激酶（ERK）在细胞质中的活性，从而阻止了癌基因诱导的线粒体碎裂并促进线粒体融合。由此产生的线粒体呼吸增强支持了癌细胞对各种代谢应激的适应。因此，酸中毒是一种通过改变能量代谢来促进癌症应激耐受的环境因素。

5.T cell cholesterol transport links intestinal immune responses to dietary lipid absorption

T细胞胆固醇转运连接肠道免疫反应与膳食脂质吸收

美国加利福尼亚州洛杉矶市，加州大学洛杉矶分校，病理学与实验室医学系

Abstract

The intrinsic pathways that control membrane organization in immune cells and their impact on cellular functions are poorly defined. We found that the nonvesicular cholesterol transporter Aster-A linked plasma membrane (PM) cholesterol availability in CD4 T cells to systemic metabolism. Aster-A was recruited to the PM during T cell receptor (TCR) activation, where it facilitated the removal of accessible cholesterol. Loss of Aster-A increased cholesterol accumulation in the PM, which enhanced TCR nanoclustering and signaling. Aster-A associated with stromal interaction molecule 1 (STIM1) and negatively regulated calcium (Ca2+) flux. Aster-A deficiency promoted CD4 T cells to acquire a T helper 17 (TH17) phenotype and stimulated interleukin-22 production, which reduced intestinal fat absorption and conferred resistance to diet-induced obesity. These findings delineate how immune cell membrane homeostasis links to systemic physiology.

摘要：

控制免疫细胞膜组织的内在途径及其对细胞功能的影响尚未明确阐明。本研究发现，非囊泡性胆固醇转运蛋白Aster-A将CD4 T细胞质膜中胆固醇的可利用性与全身代谢联系起来。在T细胞受体(TCR)激活过程中，Aster-A被募集至质膜，在那里促进可接近胆固醇的清除。Aster-A缺失会增加质膜中胆固醇的积累，从而增强TCR纳米簇集和信号转导。Aster-A与基质相互作用分子1(STIM1)结合，并负向调控钙离子(Ca²⁺)流动。Aster-A缺陷促使CD4 T细胞获得辅助性T细胞17(TH17)表型，并刺激白细胞介素-22的产生，从而减少肠道脂肪吸收，并赋予对饮食诱导性肥胖的抵抗力。这些发现阐明了免疫细胞膜稳态如何与全身生理机能相关联。

6.A genome-to-proteome map reveals how natural variants drive proteome diversity and shape fitness

基因组-蛋白质组图谱揭示自然变异驱动蛋白质组多样性并影响适应性的机制

斯坦福大学医学院化学与系统生物学系，美国加州斯坦福

Abstract

Understanding how genetic variation translates into complex phenotypes remains a fundamental challenge. In this work, we address this by mapping genome-to-proteome relationships in 800 progeny of a cross between two yeast strains adapted to distinct environments. Despite the modest genetic distance between the parents, we observed notable proteomic diversity and mapped more than 6400 genotype-protein associations, with more than 1600 linked to individual genetic variants. Proteomic adaptation emerged from a conserved network of cis- and trans-regulatory variants, often originating from proteins not traditionally linked to gene regulation. This atlas allowed us to forecast organismal fitness effects across diverse conditions. By connecting genomic and proteomic landscapes at unprecedented resolution, our study provides a framework for predicting the phenotypic outcomes of natural genetic variation.

摘要：

理解遗传变异如何转化为复杂表型仍然是一个基本挑战。本研究通过绘制800个后代的基因组-蛋白质组关系来解决这一问题，这些后代来自适应不同环境的两个酵母菌株的杂交。尽管亲本之间的遗传距离不大，但本研究中观察到了显著的蛋白质组多样性，并绘制了超过6400个基因型-蛋白质关联图谱，其中超过1600个与单个遗传变异相关联。蛋白质组适应源于顺式和反式调控变异的保守网络，这些变异通常来源于传统上与基因调控无关的蛋白质。该图谱使人们能够预测在不同条件下生物体的适应性效应。通过以前所未有的分辨率连接基因组和蛋白质组景观，本研究为预测自然遗传变异的表型结果提供了一个框架。

7.Mechanism of DNA targeting by human LINE-1

人类LINE-1 DNA靶向机制

表观遗传调控与干预国家重点实验室，中国科学院生物物理研究所，中国北京

Abstract

Long interspersed nuclear element-1 (LINE-1 or L1), the only autonomously active retrotransposon in humans today, constitutes a large proportion of the genome and continues to evolve the genome and impact fundamental biological processes. L1 retrotransposition critically depends on its endonuclease and reverse transcriptase subunit open reading frame 2 protein (ORF2p), which targets genomic loci and nicks DNA using an evolutionarily distinct yet not fully understood mechanism. Our structural and biochemical analyses revealed that ORF2p is a structure-dependent endonuclease. It binds a double-stranded DNA region upstream of the nicking site and recognizes a downstream forked or flap structure for efficient DNA nicking. This discovery suggests that L1 mobilization piggybacks on chromosomal processes with noncanonical DNA structure intermediates.

摘要：

长散在核元件-1（LINE-1或L1）是目前人类体内唯一具有自主活性的逆转座子，占据基因组的很大比例，并持续推动基因组演化和影响基本生物学过程。L1的逆转座关键依赖于其核酸内切酶和逆转录酶亚基——开放阅读框2蛋白（ORF2p），该蛋白通过一种进化上独特但尚未完全阐明的机制靶向基因组位点并切割DNA。我们的结构和生化分析揭示了ORF2p是一种结构依赖性核酸内切酶。它结合切割位点上游的双链DNA区域，并识别下游的分叉或襟翼结构以实现高效的DNA切割。这一发现表明L1的转移搭载于具有非经典DNA结构中间体的染色体过程。

8.Targeted protein evolution in the gut microbiome by diversity-generating retroelements

多样性生成逆转录元件在肠道微生物组中的靶向蛋白质进化

美国加利福尼亚州洛杉矶市，加州大学洛杉矶分校大卫·格芬医学院儿科学系新生儿学与发育生物学科

Abstract

Diversity-generating retroelements (DGRs) accelerate evolution by rapidly diversifying variable proteins. The human gastrointestinal microbiota harbors the greatest density of DGRs known in nature, suggesting that they play adaptive roles in this environment. We identified >1100 distinct DGRs among human-associated Bacteroides species and discovered a subset that diversify adhesive components of type V pili and related proteins. We show that Bacteroides DGRs are horizontally transferred across species, display activity levels ranging from high to low, and preferentially alter the functional characteristics of ligand-binding residues on adhesive organelles. Specific variable protein sequences are enriched when Bacteroides strains compete with other commensal bacteria in gnotobiotic mice. Analysis of >2700 DGRs from diverse phyla in mother-infant pairs shows that Bacteroides DGRs are disproportionately transferred to vaginally delivered infants where they actively diversify. Our observations provide a foundation for understanding the potential roles of targeted genome plasticity in shaping host-associated microbial communities.

摘要：

多样性生成逆转录元件（DGRs）通过快速分化可变蛋白来加速进化。人类胃肠道微生物群含有自然界已知的最高密度的DGRs，这表明它们在该环境中发挥适应性作用。本研究在人类相关拟杆菌属物种中鉴定出超过1100个不同的DGRs，并发现其中一个亚群可使V型菌毛的粘附组分及相关蛋白多样化。本研究证明拟杆菌属DGRs可在物种间水平转移，表现出从高到低的活性水平，并优先改变粘附细胞器上配体结合残基的功能特性。当拟杆菌菌株在无菌小鼠中与其他共生菌竞争时，特定的可变蛋白序列会富集。对母婴配对中来自不同门类的超过2700个DGRs的分析表明，拟杆菌属DGRs不成比例地转移到经阴道分娩的婴儿体内，并在其中保持活跃分化状态。本研究结果为理解靶向基因组可塑性在塑造宿主相关微生物群落中的潜在作用奠定了基础。

9.Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations

泛素介导的线粒体自噬调控线粒体DNA突变的遗传

英国剑桥，剑桥大学临床医学院临床神经科学系，剑桥生物医学园区

Abstract

Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders

摘要：

线粒体合成三磷酸腺苷对真核生物的生命至关重要，但依赖于两个基因组的协作：核基因组和线粒体DNA（mtDNA）。mtDNA的突变速率约为核基因组的15倍，这对这种共生关系构成了挑战。生物体必然进化出了某些机制来减轻mtDNA突变的影响，但人们对此知之甚少。本研究观察到在母源-合子转换期间，泛素特异性肽酶30（Usp30）调控了小鼠mtDNA突变的纯化选择。在体外实验中，抑制Usp30通过增强泛素介导的线粒体自噬（线粒体自噬）重现了这些发现。本研究还发现高突变负荷，即异质性，会损害泛素-蛋白酶体系统，这解释了突变如何逃避质量控制从而导致疾病。抑制USP30可释放潜在的线粒体自噬活性，降低高异质性细胞中的突变型mtDNA。这些发现提示了一种预防线粒体疾病的潜在策略。

10.Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations

异质性线粒体DNA突变积累对生理韧性的可逆性损害

美国哈佛医学院贝斯以色列女执事医疗中心内科学系肾脏科

Abstract

Somatically acquired mitochondrial DNA (mtDNA) mutations accumulate with age, but the mechanisms and consequences of this accumulation are poorly understood. Here we show that transient injuries induce a burst of persistent mtDNA mutations that impair resilience to future injuries. mtDNA mutations suppressed energy-intensive nucleotide metabolism. Repletion of adenosine, but not other nucleotides, restored adenosine triphosphate generation, which required a nuclear-encoded purine biosynthetic enzyme, adenylate kinase 4 (AK4). Analysis of 369,912 UK Biobank participants revealed a graded association between mutation burden and chronic kidney disease severity as well as an independent increase in the risk of future acute kidney injury events (P < 10-7). Heteroplasmic mtDNA mutations may therefore reflect the cumulative effect of acute injuries to metabolically active cells, impairing major functions in a fashion amenable to nuclear-controlled purine biosynthesis.

摘要：

体细胞获得性线粒体DNA（mtDNA）突变随年龄增长而积累，但这种积累的机制和后果尚不清楚。本研究显示，短暂性损伤诱导产生大量持续性mtDNA突变，从而削弱了机体对未来损伤的恢复能力。mtDNA突变抑制了高能耗的核苷酸代谢。补充腺苷（而非其他核苷酸）可恢复三磷酸腺苷（ATP）的生成，这一过程需要核基因编码的嘌呤生物合成酶——腺苷酸激酶4（AK4）。对369,912名英国生物样本库参与者的分析揭示，突变负荷与慢性肾脏病严重程度之间存在分级关联，并且未来发生急性肾损伤事件的风险独立增加（P < 10⁻⁷）。因此，异质性mtDNA突变可能反映了急性损伤对代谢活跃细胞的累积效应，以一种可通过核控制的嘌呤生物合成加以改善的方式损害主要功能。

VOLUME 390|ISSUE 6770|16 OCT 2025

2025年10月16日，《Science》共发表文章37篇。其中包括Editorial 1篇；News6篇；Expert Voices 1篇; Perspectives 4篇；Policy forum 1篇；Books 2篇；Letters 3篇； Research Highlights 2篇；Research Articles 16篇；Careers 1篇。

1.A mosaic of modular variation at a single gene underpins convergent plumage coloration

单个基因上的模块化变异镶嵌是趋同羽色的基础

瑞士伯尔尼大学生态学与进化研究所进化生态学系

Abstract

The reshuffling of genomic variation from multiple origins is an important contributor to phenotypic diversification, yet insights into the evolutionary trajectories of this combinatorial process and their interplay with genetic architecture remain scarce. We show that convergent plumage color evolution in wheatears involves a monogenic architecture with modular variation introgressed at the agouti signaling protein (ASIP) locus. Introgression of a new transposable element insertion and linked protein-coding variation underpin a transspecific throat color polymorphism, which stable isotopes suggest is associated with alternative foraging niches. Cointrogression of linked regulatory ASIP variation resulted in mantle color convergence in one species, whereas convergent color evolution at the genus level required new variation. Our results demonstrate evolutionary trajectories from introgressed variation realized within the constraints of a monogenic architecture.

摘要：

基因组变异的多源重组是表型多样化的重要贡献因素，然而关于这一组合过程的进化轨迹及其与遗传结构相互作用的认识仍然很少。本研究表明，麦翁（wheatears）趋同的羽色进化涉及一种单基因结构，其模块化变异通过在刺鼠信号蛋白（ASIP）基因座上渗入实现。一个新的转座元件插入以及与之连锁的蛋白质编码变异的渗入，是跨物种喉部颜色多态性的基础，稳定同位素分析表明这与不同的觅食生态位相关。连锁的ASIP调控变异的共同渗入导致了一个物种背羽颜色的趋同，而在属水平上的趋同颜色进化则需要新的变异。本结果展示了在单基因结构限制下，通过渗入变异实现的进化轨迹。

2.Mapping early human blood cell differentiation using single-cell proteomics and transcriptomics

基于单细胞蛋白质组学和转录组学的人类早期血细胞分化图谱构建

芬森实验室，哥本哈根国家医院（哥本哈根大学医院），哥本哈根大学健康科学学院，丹麦哥本哈根

Abstract

Single-cell RNA sequencing (scRNA-seq) has facilitated the characterization of cell state heterogeneity and recapitulation of differentiation trajectories. However, the exclusive use of messenger RNA (mRNA) measurements comes at the risk of missing important biological information. We leveraged recent technological advances in single-cell proteomics by mass spectrometry (scp-MS) to generate an scp-MS dataset of an in vivo differentiation hierarchy encompassing >2500 human CD34+ hematopoietic stem and progenitor cells. Through integration with scRNA-seq, we identified proteins important for stem cell function, which were not indicated by their mRNA transcripts. Further, we showed that modeling translation dynamics can infer cell progression during differentiation and explain substantially more protein variation from mRNA than linear correlation. Our work offers a framework for single-cell multiomics studies across biological systems.

摘要：

单细胞RNA测序（scRNA-seq）促进了细胞状态异质性的表征和分化轨迹的重现。然而，仅使用信使RNA（mRNA）测量存在遗漏重要生物学信息的风险。本研究利用基于质谱的单细胞蛋白质组学（scp-MS）的最新技术进展，生成了一个体内分化层级的scp-MS数据集，涵盖了超过2500个人类CD34+造血干细胞和祖细胞。通过与scRNA-seq整合，本研究鉴定出对干细胞功能重要的蛋白质，而这些蛋白质未能从其mRNA转录本中体现出来。此外，本研究证明了翻译动力学建模可以推断分化过程中的细胞进程，并且相比线性相关性分析，能够从mRNA中解释更多的蛋白质变异。本研究的工作为跨生物系统的单细胞多组学研究提供了一个框架。

3.“Kiss-shrink-run” unifies mechanisms for synaptic vesicle exocytosis and hyperfast recycling

"吻合-收缩-逃逸"机制统一了突触囊泡的胞吐与超快速回收

中国科学技术大学生命科学与医学部生命科学学院,无膜细胞器与细胞动力学教育部重点实验室,合肥微尺度物质科学国家研究中心,生物医学成像中心,中国合肥

Abstract

Synaptic vesicle (SV) exocytosis underpins neuronal communication, yet its nanoscale dynamics remain poorly understood owing to limitations in visualizing rapid events in situ. Here, we used optogenetics-coupled, time-resolved cryo-electron tomography to capture SV exocytosis in rat hippocampal synapses. Within 4 milliseconds of synaptic activation, SVs transiently "kiss" the plasma membrane, forming a ~4-nanometer lipidic fusion pore flanked by putative soluble NSF-attachment protein receptor (SNARE) complexes and then rapidly "shrink" to approximately half of their original surface area. By 70 milliseconds, most shrunken SVs recycle via a "run-away" pathway, whereas others collapse into the presynaptic membrane. Ultrafast endocytosis retrieves the expanded presynaptic membrane after 100 milliseconds. These findings reveal a "kiss-shrink-run" mechanism of SV exocytosis and hyperfast recycling, reconciling conflicting models and elucidating the efficiency and fidelity of synaptic transmission.

摘要：

突触囊泡（SV）的胞吐作用是神经元通讯的基础，然而由于原位观察快速事件的技术局限，其纳米尺度的动态过程仍知之甚少。本研究运用光遗传学耦合的时间分辨冷冻电子断层扫描技术，捕获了大鼠海马突触中突触囊泡的胞吐过程。在突触激活后4毫秒内，突触囊泡短暂地"吻合"质膜，形成一个约4纳米的脂质融合孔，融合孔两侧分布着推测的可溶性NSF附着蛋白受体（SNARE）复合物，随后囊泡迅速"收缩"至原表面积的约一半。到70毫秒时，大多数收缩的突触囊泡通过"逃逸"途径进行再循环，而其他囊泡则塌陷进入突触前膜。超快速内吞作用在100毫秒后回收扩张的突触前膜。这些发现揭示了突触囊泡胞吐和超快速回收的"吻合-收缩-逃逸"机制，调和了相互矛盾的模型，并阐明了突触传递的高效性和精确性。

4.High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer

利用PEtracer实现体内细胞状态和谱系动态的高分辨率空间图谱绘制

怀特海德生物医学研究所，美国马萨诸塞州剑桥市

Abstract

Charting the spatiotemporal dynamics of cell fate determination in development and disease is a long-standing objective in biology. Here, we present the design, development, and extensive validation of PEtracer, a prime editing (PE)-based, evolving lineage tracing technology compatible with both single-cell sequencing and multimodal imaging methodologies, created to jointly profile cell state and lineage in dissociated cells or while preserving cellular context in tissues with high spatial resolution. Using PEtracer coupled with MERFISH spatial transcriptomic profiling in a syngeneic mouse model of tumor metastasis, we reconstructed the growth of individually seeded tumors in vivo and uncovered distinct modules of cell-intrinsic and -extrinsic factors that coordinate tumor growth. More generally, PEtracer enables systematic characterization of cell state and lineage relationships in intact tissues over biologically relevant temporal and spatial scales.

摘要：

绘制发育和疾病过程中细胞命运决定的时空动态是生物学领域的一个长期目标。本研究介绍了PEtracer的设计、开发和广泛验证。PEtracer是一种基于先导编辑（PE）的演化谱系追踪技术，与单细胞测序和多模态成像方法兼容，旨在对解离细胞进行细胞状态和谱系的联合分析，或在保持组织细胞背景的同时实现高空间分辨率的分析。通过在同基因小鼠肿瘤转移模型中使用PEtracer结合MERFISH空间转录组学分析，本研究重建了体内单个种植肿瘤的生长过程，并揭示了协调肿瘤生长的细胞内在和外在因素的不同模块。更广泛地说，PEtracer能够在生物学相关的时间和空间尺度上系统表征完整组织中的细胞状态和谱系关系。

VOLUME 390|ISSUE 6771|23 OCT 2025

2025年10月23日，《Science》共发表文章41篇。其中包括Editorial 1篇；News 8篇；Expert Voices 1篇; Perspectives 4篇；Policy forum 1篇；Books 2篇；Letters 3篇；Reviews 1篇； Research Highlights 2篇；Research Articles 17篇；Careers 1篇。

1.Unsaturated fat alters clock phosphorylation to align rhythms to the season in mice

不饱和脂肪改变生物钟磷酸化以调节小鼠生物节律适应季节变化

美国加州大学旧金山分校神经病学系

Abstract

The circadian clock maintains synchrony between biological processes and light/dark cycles by integrating environmental cues. How the clock adapts to seasonal variations in the environment is incompletely understood. We found that a high-fat diet increased phosphorylation of the clock protein PERIOD2 (PER2) on serine 662 (S662), which was necessary and sufficient for regulating phase shifting of daily locomotor activity to entrain to seasonal light cycles. PER2-S662 phosphorylation correlated with genome-wide expression pathways that regulate polyunsaturated fatty acid (PUFA) conversion into oxylipins in the hypothalamus. Partial hydrogenation of dietary PUFAs increased hypothalamic PER2-S662 phosphorylation and entrainment to a summer photoperiod in control mice, but not in mice for which PER2-S662 could not be phosphorylated. PER2-S662 phosphorylation is influenced by, and alters the regulation of, unsaturated fat to control circadian phase shifting across the seasons.

摘要：

昼夜节律生物钟通过整合环境信号来维持生物过程与光/暗周期之间的同步性。然而，生物钟如何适应环境中的季节性变化尚未完全阐明。本研究发现，高脂饮食增加了生物钟蛋白PERIOD2（PER2）在丝氨酸662位点（S662）的磷酸化，这对于调节日常运动活动的时相转移以同步于季节性光周期是必要且充分的。PER2-S662磷酸化与下丘脑中调控多不饱和脂肪酸（PUFA）转化为氧脂素的全基因组表达通路相关。膳食多不饱和脂肪酸的部分氢化增加了对照组小鼠下丘脑中的PER2-S662磷酸化水平以及对夏季光周期的同步化，但在PER2-S662无法被磷酸化的小鼠中则没有这种效应。PER2-S662磷酸化受不饱和脂肪的影响，同时也改变了不饱和脂肪的调控，从而控制昼夜节律在不同季节间的时相转移。

2.Nematode telomerase RNA hitchhikes on introns of germline-up-regulated genes

线虫端粒酶RNA搭载于生殖系上调基因的内含子中

日本兵库县神户市中央区，理化学研究所（RIKEN）生命系统动态研究中心（BDR），配子发生实验室

Abstract

Telomerase is a ribonucleoprotein complex that elongates telomeric DNA, ensuring germline immortality. In this study, we identified the Caenorhabditis elegans telomerase RNA component 1 (terc-1), as the first known telomerase RNA expressed as an intronic long noncoding RNA (lncRNA), embedded in an intron of germline-up-regulated gene nmy-2. terc-1 undergoes splicing, polyadenylation, and nuclear RNA exosome-dependent maturation, stabilized by H/ACA small nucleolar ribonucleoproteins, thus co-opting the H/ACA small nucleolar RNA (snoRNA) biogenesis machinery. Mutations in terc-1 led to progressive telomere shortening and sterility in successive generations. Artificially transplanting the nmy-2 intron into the introns of germline-expressed genes but not non-germline-expressed genes restored germline immortality, highlighting the importance of genomic context. Our findings suggest that nematode telomerase RNA is a snoRNA-like intronic lncRNA that exploits the introns of germline-up-regulated genes to ensure species survival.

摘要：

端粒酶是一种核糖核蛋白复合物，可延长端粒DNA，确保生殖系的永生性。本研究鉴定了秀丽隐杆线虫端粒酶RNA组分1（terc-1），这是首个已知的以内含子长非编码RNA（lncRNA）形式表达的端粒酶RNA，嵌入在生殖系上调基因nmy-2的内含子中。terc-1经历剪接、多聚腺苷酸化和依赖核RNA外泌体的成熟过程，并由H/ACA小核仁核糖核蛋白稳定，从而利用了H/ACA小核仁RNA（snoRNA）的生物合成机制。terc-1的突变导致连续世代中端粒进行性缩短和不育。人工将nmy-2内含子移植到生殖系表达基因（而非非生殖系表达基因）的内含子中可恢复生殖系永生性，这突显了基因组背景的重要性。本研究结果表明，线虫端粒酶RNA是一种类似snoRNA的内含子lncRNA，利用生殖系上调基因的内含子来确保物种生存。

3.Predicting protein-protein interactions in the human proteome

人类蛋白质组中蛋白质相互作用的预测

尤金·麦克德莫特人类生长与发育中心，德克萨斯大学西南医学中心，美国德克萨斯州达拉斯市

Abstract

Protein-protein interactions (PPIs) are essential for biological function. Coevolutionary analysis and deep-learning (DL)-based protein structure prediction have enabled comprehensive PPI identification in bacteria and yeast, but these approaches have had limited success for the more complex human proteome. We overcame this challenge by enhancing the coevolutionary signals with sevenfold-deeper multiple sequence alignments harvested from 30 petabytes of unassembled genomic data and developing a new DL network trained on augmented datasets of domain-domain interactions from 200 million predicted protein structures. We systematically screened 200 million human protein pairs and predicted 17,849 interactions with an expected precision of 90%, of which 3631 interactions were not identified in previous experimental screens. Three-dimensional models of these predicted interactions provide numerous hypotheses about protein function and mechanisms of human diseases.

摘要：

蛋白质-蛋白质相互作用（PPIs）对生物学功能至关重要。共进化分析和基于深度学习（DL）的蛋白质结构预测已能够在细菌和酵母中全面鉴定PPI，但这些方法在更为复杂的人类蛋白质组中取得的成功有限。本研究通过以下方式克服了这一挑战：一方面从30PB未组装的基因组数据中挖掘出深度提升七倍的多序列比对以增强共进化信号；另一方面基于2亿个预测蛋白质结构中的结构域-结构域相互作用增强数据集，训练了新型深度学习网络本研究系统地筛选了2亿对人类蛋白质，预测出17,849个相互作用，预期精确度达90%，其中3,631个相互作用在以往的实验筛选中未被发现。这些预测相互作用的三维模型为蛋白质功能和人类疾病机制提供了大量研究假说。

4.Escherichia coli with a 57-codon genetic code

具有57个密码子遗传密码的大肠杆菌

英国剑桥弗朗西斯·克里克大道，医学研究委员会分子生物学实验室

Abstract

The near-universal genetic code uses 64 codons to encode the 20 canonical amino acids and protein synthesis. Here, we designed and generated Escherichia coli with a 4-megabase synthetic genome in which we replaced known occurrences of six sense codons and a stop codon with synonymous codons. The resulting organism, Syn57, uses 55 codons to encode the 20 canonical amino acids.

摘要：

近似通用的遗传密码使用64个密码子来编码20种标准氨基酸并进行蛋白质合成。在这里，本研究设计并构建了具有4兆碱基合成基因组的大肠杆菌，在其中研究者用同义密码子替换了已知的6个有义密码子和1个终止密码子的所有出现位点。由此产生的生物体Syn57使用55个密码子来编码20种标准氨基酸。

汇报人：李朔

导师：任建君

审核:倪恬、肖瑶、任建君