【Science】2025年4-5月刊论文导读

期刊介绍：

Science创刊于1880年，由美国科学促进会（AAAS）出版，被誉为世界上最顶级的科学杂志之一。该期刊每周出版一期，覆盖自然科学全领域，包括生物学、化学、物理学、地球科学、天文学等基础学科，同时延伸至科技政策、科学伦理及跨学科研究，致力于推动科学前沿突破与社会应用结合。最新影响因子指数为44.7。

Volume 387|Issue 6741|28 Mar 2025

2025年3月28日，Science共发表40篇文章， 其中包括Editorial 1篇；News 9篇；Perspectives 5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、Telomeric transposons are pervasive in linear bacterial genomes

端粒转座子在线性细菌基因组中普遍存在

美国康奈尔大学微生物学系

Abstract

Eukaryotes have linear DNA, and their telomeres are hotspots for transposons, which in some cases took over telomere maintenance. We identified several families of independently evolved telomeric transposons in linear chromosomes and plasmids of cyanobacteria and Streptomyces. Although these elements have one specific transposon end sequence, with the second boundary being the telomere, we can show that they move using two transposon ends, likely when transiently bridged by the telomere maintenance systems. Mobilization of the element and the associated telomere allows replacement of native telomeres, making the host cell dependent on the new transposon telomere system for genome maintenance. This work indicates how telomeric transposons can promote gene transfer both between and within genomes, substantially influencing the evolutionary dynamics of linear genomes.

摘要

真核生物具有线性DNA，其端粒是转座子的富集区域。在某些情况下，这些转座子接管了端粒的维持功能。该研究在蓝藻菌和链霉菌的线性染色体和质粒中鉴定出了几个独立进化而来的端粒转座子家族。虽然这些转座子元件一端具有特定的转座子末端序列，另一端以端粒为界，但它们可通过两个转座子末端进行移动，这很可能是在端粒维持系统暂时将它们连接起来时发生的。该元件及其相关端粒的移动，能够替换宿主原有的端粒，从而使宿主细胞依赖于这种新的转座子端粒系统来维持基因组稳定。这项工作揭示了端粒转座子如何促进基因组之间和基因组内部的基因转移，从而极大地影响线性基因组的进化动力学。

2、Chromatin accessibility landscape of mouse early embryos revealed by single-cell NanoATAC-seq2

单细胞NanoATAC-seq2揭示的小鼠早期胚胎染色质可及性景观

北京大学生命科学学院

Abstract

In mammals, fertilized eggs undergo genome-wide epigenetic reprogramming to generate the organism. However, our understanding of epigenetic dynamics during preimplantation development at single-cell resolution remains incomplete. Here, we developed scNanoATAC-seq2, a single-cell assay for transposase-accessible chromatin using long-read sequencing for scarce samples. We present a detailed chromatin accessibility landscape of mouse preimplantation development, revealing distinct chromatin signatures in the epiblast, primitive endoderm, and trophectoderm during lineage segregation. Differences between zygotes and two-cell embryos highlight reprogramming in chromatin accessibility during the maternal-to-zygotic transition. Single-cell long-read sequencing enables in-depth analysis of chromatin accessibility in noncanonical imprinting, imprinted X chromosome inactivation, and low-mappability genomic regions, such as repetitive elements and paralogs. Our data provide insights into chromatin dynamics during mammalian preimplantation development and lineage differentiation.

摘要

在哺乳动物中，受精卵会经历全基因组范围的表观遗传重编程，从而发育成一个完整的有机体。然而，对于单细胞分辨率下着床前胚胎发育过程中的表观遗传动态的理解仍然不完整。该研究开发了一种名为scNanoATAC-seq2的单细胞分析方法，该方法利用长读长测序技术检测转座酶可及染色质，适用于样本量稀少的情况。作者展示了小鼠着床前胚胎发育的详细染色质可及性图谱，揭示了在谱系分离过程中，上胚层、原始内胚层和滋养外胚层具有不同的染色质特征。受精卵与二细胞胚胎之间的差异凸显了母源-合子转换过程中染色质可及性的重编程事件。单细胞长读长测序技术能够深入分析非典型印记、印记X染色体失活以及低可比对性基因组区域（如重复元件和旁系同源基因）中的染色质可及性。该研究为哺乳动物着床前发育和谱系分化过程中的染色质动态提供了见解。

3、Leucine aminopeptidase LyLAP enables lysosomal degradation of membrane proteins

亮氨酸氨肽酶LyLAP介导膜蛋白的溶酶体降解

美国加州大学伯克利分校分子和细胞生物学系

Abstract

Breakdown of every transmembrane protein trafficked to lysosomes requires proteolysis of their hydrophobic helical transmembrane domains. Combining lysosomal proteomics with functional genomic datasets, we identified lysosomal leucine aminopeptidase (LyLAP; formerly phospholipase B domain-containing 1) as the hydrolase most tightly associated with elevated endocytosis. Untargeted metabolomics and biochemical reconstitution demonstrated that LyLAP is a processive monoaminopeptidase with preference for amino-terminal leucine. This activity was necessary and sufficient for the breakdown of hydrophobic transmembrane domains. LyLAP was up-regulated in pancreatic ductal adenocarcinoma (PDA), which relies on macropinocytosis for nutrient uptake. In PDA cells, LyLAP ablation led to the buildup of undigested hydrophobic peptides, lysosomal membrane damage, and growth inhibition. Thus, LyLAP enables lysosomal degradation of membrane proteins and protects lysosomal integrity in highly endocytic cancer cells.

摘要

每个被运输到溶酶体的跨膜蛋白的降解都需要对其疏水的螺旋跨膜结构域进行蛋白水解。通过结合溶酶体蛋白质组学和功能性基因组学数据集，该研究鉴定出溶酶体亮氨酸氨肽酶（LyLAP）是与内吞作用增强关系最为密切的水解酶。非靶向代谢组学和生化重建实验证实，LyLAP是一种偏好作用于氨基末端亮氨酸的进程性单氨肽酶。这种活性对于疏水跨膜结构域的降解是必要且充分的。在依赖巨胞饮作用摄取营养的胰腺导管腺癌（PDA）中，LyLAP表达上调。在PDA细胞中，LyLAP的缺失导致未降解的疏水肽积累、溶酶体膜损伤以及细胞生长抑制。因此，LyLAP能够介导膜蛋白的溶酶体降解，并在高内吞活性的癌细胞中维持溶酶体的完整性。

4、Running a genetic stop sign accelerates oxygen metabolism and energy production in horses

基因终止密码子突变可加速马的氧气代谢和能量产生

美国范德比尔特大学生物科学系

Abstract

Horses are among nature's greatest athletes, yet the ancestral molecular adaptations fueling their energy demands are poorly understood. Within a clinically important pathway regulating redox and metabolic homeostasis (NRF2/KEAP1), we discovered an ancient mutation-conserved in all extant equids-that increases mitochondrial respiration while decreasing tissue-damaging oxidative stress. This mutation is a de novo premature opal stop codon in KEAP1 that is translationally recoded into a cysteine through previously unknown mechanisms, producing an R15C mutation in KEAP1 that is more sensitive to electrophiles and reactive oxygen species. This recoding enables increased NRF2 activity, which enhances mitochondrial adenosine 5'-triphosphate production and cellular resistance to oxidative damage. Our study illustrates how recoding of a de novo stop codon, a strategy thought restricted to viruses, can facilitate adaptation in vertebrates.

摘要

马是自然界中最伟大的运动员之一，然而驱动它们能量需求的祖先分子适应性尚未研究清楚。该研究在调节氧化还原和代谢稳态的重要途径(NRF2/KEAP1)中，发现了一个在所有现存马类动物中都得以保留的古老突变，该突变能够增加线粒体呼吸作用，同时减少组织损伤性的氧化应激。这种突变是KEAP1基因中新出现的一个提前终止密码子，它通过一种此前未知的机制被重新编码为半胱氨酸，导致 KEAP1 蛋白发生 R15C 突变。这一突变的 KEAP1 对亲电物质和活性氧更加敏感。这种重新编码使得NRF2活性增强，进而提高了线粒体三磷酸腺苷的产生以及细胞对氧化损伤的抵抗力。该研究表明，对从头产生的终止密码子进行翻译重编——这一曾被认为仅限于病毒的策略——同样能够促进脊椎动物的适应性进化。

5、Canine genome-wide association study identifies DENND1B as an obesity gene in dogs and humans

犬类全基因组关联研究鉴定DENND1B为犬类和人类的肥胖基因

英国剑桥大学生理学、发育和神经科学系

Abstract

Obesity is a heritable disease, but its genetic basis is incompletely understood. Canine population history facilitates trait mapping. We performed a canine genome-wide association study for body condition score-a measure of obesity-in 241 Labrador retrievers. Using a cross-species approach, we showed that canine obesity genes are also associated with rare and common forms of obesity in humans. The lead canine association was within the gene DENN domain containing 1B (DENND1B). Each copy of the alternate allele was associated with ~7.5% greater body fat. We demonstrate a role for this gene in regulating signaling and trafficking of melanocortin 4 receptor, a critical controller of energy homeostasis. Thus, canine genetics identified obesity genes and mechanisms relevant to both dogs and humans.

摘要

肥胖是一种具有遗传性的疾病，但其遗传基础尚未研究清楚。犬类的种群历史有助于性状定位。该研究对241只拉布拉多寻回犬进行了全基因组关联研究（GWAS），以体况评分（衡量肥胖的指标）作为表型。通过跨物种的研究方法，该研究发现与犬类肥胖相关的基因同样也与人类罕见及常见的肥胖形式相关。犬类肥胖的主要关联基因是含有DENN结构域的1B基因（DENND1B）。替代等位基因每增加一个拷贝，约与体脂增加 7.5% 相关。该研究证实了该基因在调节黑皮质素4受体的信号传导和运输方面起作用，而黑皮质素4受体是能量稳态的关键调控因子。因此，犬类遗传学研究识别了对犬类和人类都具有相关性的肥胖基因和机制。

6、Hedonic eating is controlled by dopamine neurons that oppose GLP-1R satiety

享乐性进食由拮抗 GLP-1R 饱腹感信号的多巴胺神经元所控制

美国加州大学圣地亚哥分校神经科学系

Abstract

Hedonic eating is defined as food consumption driven by palatability without physiological need. However, neural control of palatable food intake is poorly understood. We discovered that hedonic eating is controlled by a neural pathway from the peri-locus ceruleus to the ventral tegmental area (VTA). Using photometry-calibrated optogenetics, we found that VTA dopamine (VTADA) neurons encode palatability to bidirectionally regulate hedonic food consumption. VTADA neuron responsiveness was suppressed during food consumption by semaglutide, a glucagon-like peptide receptor 1 (GLP-1R) agonist used as an antiobesity drug. Mice recovered palatable food appetite and VTADA neuron activity during repeated semaglutide treatment, which was reversed by consumption-triggered VTADA neuron inhibition. Thus, hedonic food intake activates VTADA neurons, which sustain further consumption, a mechanism that opposes appetite reduction by semaglutide.

摘要

享乐性进食是指由食物美味性驱动而非基于生理需求的食物摄取行为。然而，对于享乐性进食的神经调控机制尚不清楚。该研究发现，享乐性进食受一条从蓝斑旁核到腹侧被盖区（VTA）的神经通路调控。通过采用光度计量校准的光遗传学技术，该研究发现腹侧被盖区多巴胺能神经元（VTADA）能够编码食物的美味性，进而双向调节享乐性食物摄取。在食物摄取过程中，GLP-1R激动剂司美格鲁肽（一种抗肥胖药物）可抑制VTADA神经元的反应性。在重复司美格鲁肽治疗期间，小鼠恢复了对美味食物的食欲以及VTADA神经元的活性，而这一过程可通过摄取触发的VTADA神经元抑制而逆转。因此，享乐性食物摄取激活了VTADA神经元，这些神经元维持了进一步的摄食行为，这一机制与司美格鲁肽减少食欲的作用相对抗。

Volume 388|Issue 6742|4 Apr 2025

2025年4月4日，Science共发表42篇文章， 其中包括Editorial 1篇；News 9篇；Expert Voices 1篇；Perspectives 4篇；Policy Forum 1篇；Books 2篇；Letters 1篇；Essays 3篇； Research Highlights 2篇；Reviews 1篇；Research Articles 15篇；Careers 1篇；Products & Materials 1篇。

1、A geological timescale for bacterial evolution and oxygen adaptation

细菌进化和氧气适应的地质时间表

澳大利亚昆士兰大学化学和分子生物科学学院

Abstract

Microbial life has dominated Earth's history but left a sparse fossil record, greatly hindering our understanding of evolution in deep time. However, bacterial metabolism has left signatures in the geochemical record, most conspicuously the Great Oxidation Event (GOE). We combine machine learning and phylogenetic reconciliation to infer ancestral bacterial transitions to aerobic lifestyles, linking them to the GOE to calibrate the bacterial time tree. Extant bacterial phyla trace their diversity to the Archaean and Proterozoic, and bacterial families prior to the Phanerozoic. We infer that most bacterial phyla were ancestrally anaerobic and adopted aerobic lifestyles after the GOE. However, in the cyanobacterial ancestor, aerobic metabolism likely predated the GOE, which may have facilitated the evolution of oxygenic photosynthesis.

摘要

微生物生命主导了地球历史，但留下的化石记录却极为稀少，这极大地阻碍了对深时（地质时间表）进化的理解。然而，细菌的代谢活动在地球化学记录中留下了痕迹，其中最为显著的是大氧化事件（GOE）。该研究结合机器学习和系统发育校正方法，推断出细菌祖先向有氧生活方式的转变，并将其与GOE联系起来，以校准细菌的地质时间表。现存细菌门的多样性可追溯至太古代和元古代，而细菌科则可追溯至显生宙之前。作者推断，大多数细菌门最初是厌氧的，并在GOE之后才采用了有氧生活方式。然而，在蓝藻的祖先中，有氧代谢可能早于GOE出现，这可能促进了氧光合作用的进化。

2、Human high-order thalamic nuclei gate conscious perception through the thalamofrontal loop

人类高阶丘脑核通过丘脑前额叶环控制意识感知

北京师范大学认知神经科学与学习国家重点实验室

Abstract

Human high-order thalamic nuclei activity is known to closely correlate with conscious states. However, it is not clear how those thalamic nuclei and thalamocortical interactions directly contribute to the transient process of human conscious perception. We simultaneously recorded stereoelectroencephalography data from the thalamic nuclei and prefrontal cortex (PFC), while patients with implanted electrodes performed a visual consciousness task. Compared with the ventral nuclei and PFC, the intralaminar and medial nuclei presented earlier and stronger consciousness-related activity. Transient thalamofrontal neural synchrony and cross-frequency coupling were both driven by the θ phase of the intralaminar and medial nuclei during conscious perception. The intralaminar and medial thalamic nuclei thus play a gate role to drive the activity of the PFC during the emergence of conscious perception.

摘要

人脑的高阶丘脑核团活动已知与意识状态密切相关。然而，目前尚不清楚这些丘脑核团以及丘脑皮层相互作用是如何直接促成人类意识知觉的瞬态过程的。研究人员在患者植入电极期间执行了一项视觉意识任务，同时记录了来自丘脑核团和前额叶皮层（PFC）的立体脑电图数据。与腹侧核团和前额叶皮层相比，内髓层核团和内侧核团表现出更早且更强的与意识相关的活动。在意识感知过程中，瞬态的丘脑-前额叶神经同步以及跨频耦合均由内髓层核团和内侧核团的θ相位所驱动。因此，内髓层核团和内侧丘脑核团在意识感知的出现过程中起着闸门作用，驱动前额叶皮层的活动。

3、Nonlinear sound-sheet microscopy: Imaging opaque organs at the capillary and cellular scale

非线性声片显微镜：在毛细血管和细胞尺度上成像不透明器官

荷兰代尔夫特理工大学成像物理系

Abstract

Light-sheet fluorescence microscopy has revolutionized biology by visualizing dynamic cellular processes in three dimensions. However, light scattering in thick tissue and photobleaching of fluorescent reporters limit this method to studying thin or translucent specimens. In this study, we applied nondiffractive ultrasound beams in conjunction with a cross-amplitude modulation sequence and nonlinear acoustic reporters to enable fast and volumetric imaging of targeted biological functions. We reported volumetric imaging of tumor gene expression at the cubic centimeter scale using genetically encoded gas vesicles and localization microscopy of cerebral capillary networks using intravascular microbubble contrast agents. Nonlinear sound-sheet microscopy provides a ~64× acceleration in imaging speed, ~35× increase in imaged volume, and ~4× increase in classical imaging resolution compared with the state of the art in biomolecular ultrasound.

摘要

光片荧光显微镜通过可视化三维动态细胞过程，彻底革新了生物学研究。然而，厚组织中的光散射以及荧光报告分子的光漂白限制了这种方法仅能用于研究薄的或半透明的标本。研究人员联合应用非衍射超声波束、交叉振幅调制序列以及非线性声学报告分子，实现了对靶向生物功能的快速且三维化的成像。作者利用基因编码的气囊泡和血管内微泡对比剂，分别在立方厘米尺度上对肿瘤基因表达进行体积成像以及对脑毛细血管网络进行定位成像。与生物分子超声成像领域的现有技术相比，非线性声片显微镜在成像速度上实现了约64倍的加速，在成像体积上实现了约35倍的增加，以及在经典成像分辨率上实现了约4倍的提升。

4、Exogenous RNA surveillance by proton-sensing TRIM25

质子感知蛋白 TRIM25 介导的外源 RNA 监视

韩国首尔基础科学研究所RNA研究中心

Abstract

Exogenous messenger RNAs (mRNAs) require cellular machinery for delivery and translation but also encounter inhibitory factors. To investigate their regulation, we performed genome-wide CRISPR screens with in vitro-transcribed mRNAs in lipid nanoparticles (LNPs). Heparan sulfate proteoglycans (HSPGs) and vacuolar adenosine triphosphatase (V-ATPase) were identified as mediators of LNP uptake and endosomal escape, respectively. TRIM25-an RNA binding E3 ubiquitin ligase-emerged as a key suppressor inducing turnover of both linear and circular mRNAs. The endoribonucleases N4BP1 and KHNYN, along with the antiviral protein ZAP, act redundantly in TRIM25-dependent surveillance. TRIM25 specifically targets mRNAs delivered by endosomes, and its RNA affinity increases at acidic pH, suggesting activation by protons released from ruptured endosomes. N1-methylpseudouridine modification reduces TRIM25's RNA binding, helping RNAs evade its suppressive effect. This study comprehensively maps cellular pathways regulating LNP-mRNAs, offering insights into RNA immunity and therapeutics.

摘要

外源信使RNA（mRNA）需要细胞内机制来实现递送和翻译，但同时也面临着抑制因素。为了研究它们的调控机制，该研究对脂质纳米粒(LNPs)中的体外转录mRNAs进行了全基因组CRISPR筛选。硫酸软骨素蛋白多糖（HSPGs）和液泡型腺苷酸三磷酸酶（V-ATPase）分别被鉴定为介导LNP摄取和内质网逃逸的关键因子。TRIM25是一种RNA结合的E3泛素连接酶，可作为一种关键的抑制因子出现，诱导线性mRNA和环状mRNA的降解。内切核糖核酸酶N4BP1和KHNYN，以及抗病毒蛋白ZAP，在TRIM25依赖的监视通路中发挥协同作用。TRIM25特异性地靶向由内质网递送的mRNA，并且其RNA亲和力在酸性pH下增加，这表明它可能被破裂内质网释放的质子激活。N1-甲基伪尿苷修饰降低了TRIM25对RNA的结合能力，帮助RNA逃避其抑制效应。该研究全面绘制了调节LNP-mRNA的细胞通路图谱，为RNA免疫学和治疗学提供了见解。

5、Osteoarthritis treatment via the GLP-1–mediated gut-joint axis targets intestinal FXR signaling

通过GLP-1介导的肠-关节轴靶向肠道FXR信号通路治疗骨关节炎

中南大学湘雅医院骨科

Abstract

Whether a gut-joint axis exists to regulate osteoarthritis is unknown. In two independent cohorts, we identified altered microbial bile acid metabolism with reduced glycoursodeoxycholic acid (GUDCA) in osteoarthritis. Suppressing farnesoid X receptor (FXR)-the receptor of GUDCA-alleviated osteoarthritis through intestine-secreted glucagon-like peptide 1 (GLP-1) in mice. GLP-1 receptor blockade attenuated these effects, whereas GLP-1 receptor activation mitigated osteoarthritis. Osteoarthritis patients exhibited a lower relative abundance of Clostridium bolteae, which promoted the formation of ursodeoxycholic acid (UDCA), a precursor of GUDCA. Treatment with C. bolteae and Food and Drug Administration-approved UDCA alleviated osteoarthritis through the gut FXR-joint GLP-1 axis in mice. UDCA use was associated with lower risk of osteoarthritis-related joint replacement in humans. These findings suggest that orchestrating the gut microbiota-GUDCA-intestinal FXR-GLP-1-joint pathway offers a potential strategy for osteoarthritis treatment.

摘要

是否存在一个肠道-关节轴来调节骨关节炎尚不清楚。在两个独立的队列中，作者发现骨关节炎患者存在微生物胆汁酸代谢紊乱，其特征是甘氨熊去氧胆酸（GUDCA）水平降低。在小鼠模型中，抑制法尼醇X受体（FXR）——GUDCA的受体——可通过肠道分泌的胰高血糖素样肽1（GLP-1）缓解骨关节炎。GLP-1受体阻断减弱了这些效应，而GLP-1受体激活则缓解了骨关节炎。骨关节炎患者中梭菌属的博尔特菌（Clostridium bolteae）相对丰度较低，该菌促进了胆汁酸（UDCA）的形成，而UDCA是GUDCA的前体。用博尔特菌和美国食品药品监督管理局批准的UDCA治疗小鼠，通过肠道FXR-关节GLP-1轴减轻了骨关节炎。在人群中，使用UDCA与较低的骨关节炎相关关节置换术风险相关。这些发现表明，调节肠道微生物群-GUDCA-肠道FXR-GLP-1-关节通路为骨关节炎治疗提供了一种潜在策略。

6、Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes

转录因子调控网络在血细胞表型遗传力中呈现不成比例的富集。

美国哈佛医学院Dana-Farber癌症研究所波士顿儿童医院血液肿瘤科和儿科肿瘤科

Abstract

Most phenotype-associated genetic variants map to noncoding regulatory regions of the human genome, but their mechanisms remain elusive in most cases. We developed a highly efficient strategy, Perturb-multiome, to simultaneously profile chromatin accessibility and gene expression in single cells with CRISPR-mediated perturbation of master transcription factors (TFs). We examined the connection between TFs, accessible regions, and gene expression across the genome throughout hematopoietic differentiation. We discovered that variants within TF-sensitive accessible chromatin regions in erythroid differentiation, although representing<0.3% of the genome, show a ~100-fold enrichment for blood cell phenotype heritability, which is substantially higher than that for other accessible chromatin regions. Our approach facilitates large-scale mechanistic understanding of phenotype-associated genetic variants by connecting key cis-regulatory elements and their target genes within gene regulatory networks.

摘要

大多数与表型相关的遗传变异都定位于人类基因组的非编码调控区域，但其机制在大多数情况下仍不明确。作者开发了一种高效率的方法，即Perturb-multiome，通过CRISPR介导的对关键转录因子（TFs）的扰动，同时在单细胞水平上分析染色质可及性和基因表达。该研究分析了转录因子、可及区域和基因表达在整个基因组水平上与造血分化过程中的联系。结果发现，在红细胞分化过程中，位于TF敏感的可及染色质区域内的变异，尽管仅占基因组的不到0.3%，但显示出与血细胞表型遗传力相关的约100倍富集度，这比其他可及染色质区域的富集度要高得多。该研究通过将基因调控网络中的关键顺式调控元件与其靶基因关联起来，促进了对表型相关遗传变异的大规模机制性理解。

7、Ectoderm barcoding reveals neural and cochlear compartmentalization

外胚层标记示踪技术揭示神经和耳蜗的区室化分隔

瑞典卡罗林斯卡学院细胞和分子生物学系

Abstract

Placodes and the neural crest are defining features of vertebrates. In this study, we investigate their lineages in mice using in utero approaches. We demonstrated that nanoinjection at embryonic day 7.5 targeted the ectoderm, including the future nervous system, placodes, and neural crest, allowing highly efficient manipulation of the future nervous system and inner ear. By using heritable DNA barcodes and high-throughput next-generation single-cell lineage tracing, we elucidated convergent differentiation pathways and identified distinct nervous system-, neural crest-, and otic placode-derived lineages. Clonal analyses identified early neural and cochlear compartmentalization, linking differentiated cell types to their progenitors or cellular siblings. This provides foundational insights for neuroscience and developmental biology.

摘要

基板和神经嵴是脊椎动物的标志性特征。作者利用子宫内操作技术探究了小鼠胚胎中这些结构的谱系。研究结果发现在胚胎第7.5天进行纳米注射能够靶向包括未来将发育为神经系统、基板和神经嵴在内的外胚层区域，从而实现对未来的神经系统和内耳的高效操控。通过使用可遗传的DNA条形码和高通量下一代单细胞谱系追踪技术，该研究阐明了趋同的分化路径，并识别了不同的神经系统、神经嵴和耳基板衍生的谱系。克隆分析确定了早期神经和耳蜗的区室化分隔现象，将分化的细胞类型与其祖细胞或同源细胞联系起来。该研究为神经科学和发育生物学提供了基础性见解。

8、Vaccine-enhanced competition permits rational bacterial strain replacement in the gut

疫苗增强的竞争作用可驱动肠道内细菌菌株的有序替代

瑞士苏黎世联邦理工学院食品、营养和健康研究所

Abstract

Colonization of the intestinal lumen precedes invasive infection for a wide range of enteropathogenic and opportunistic pathogenic bacteria. We show that combining oral vaccination with engineered or selected niche-competitor strains permits pathogen exclusion and strain replacement in the mouse gut lumen. This approach can be applied either prophylactically to prevent invasion of nontyphoidal Salmonella strains, or therapeutically to displace an established Escherichia coli. Both intact adaptive immunity and metabolic niche competition are necessary for efficient vaccine-enhanced competition. Our findings imply that mucosal antibodies have evolved to work in the context of gut microbial ecology by influencing the outcome of competition. This has broad implications for the elimination of pathogenic and antibiotic-resistant bacterial reservoirs and for rational microbiota engineering.

摘要

肠道定植是多种肠道致病菌和机会致病菌侵入性感染的前奏。该研究发现，将口服疫苗与工程化或筛选的生态位竞争菌株相结合，可以在小鼠肠道腔内实现病原体的清除和菌株的替代。这种方法既可以预防非伤寒沙门氏菌菌株的侵入，也可以治疗性地取代已定植的大肠杆菌。完整的适应性免疫和代谢生态位竞争对于有效的疫苗增强竞争都是必要的。研究表明，黏膜抗体已经进化到通过影响竞争的结果而在肠道微生物生态环境中发挥作用。该研究结果对于消除致病菌和耐药菌的储存库以及合理设计微生物群落具有广泛的意义。

Volume 388|Issue 6743|11 Apr 2025

2025年4月11日，Science共发表40篇文章， 其中包括Editorial 1篇；News 9篇；Expert Voices 1篇；Perspectives 4篇；Policy Forum 1篇；Books 2篇；Letters 4篇；Research Highlights 2篇；Research Articles 15篇；Careers 1篇。

1、Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues

逆行性线粒体信号传导主导调控代谢组织的特性和成熟度

美国密歇根大学代谢、内分泌和糖尿病学部及内科

Abstract

Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. In this work, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Pharmacologic blockade of the integrated stress response in vivo restored β cell identity after the loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.

摘要

线粒体损伤是包括糖尿病在内的代谢性疾病的标志，然而代谢组织中受损线粒体的后果尚不清楚。作者发现，线粒体质量控制功能失调会启动一种逆向（线粒体-核）信号传导程序，从而损害β细胞、肝细胞和棕色脂肪细胞的细胞特性和成熟度。在整个线粒体质量控制途径中，包括基因组完整性、动态性或周转的靶向缺陷，会损害氧化磷酸化机制，进而激活线粒体综合应激反应，引发染色质重塑，并促进细胞呈现未成熟状态而非走向凋亡，最终导致代谢功能障碍。在体内药理学阻断综合应激反应可在线粒体质量控制丧失后恢复β细胞功能。因此，靶向线粒体逆向信号传导可能在代谢性疾病的治疗或预防中具有前景。

2、Structural pathway for PI3-kinase regulation by VPS15 in autophagy

自噬中VPS15调节PI3-激酶的结构途径

美国加州大学伯克利分校生物物理学研究所

Abstract

The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and PI3KC3-C2) have vital roles in macroautophagy and endosomal maturation, respectively. We elucidated a structural pathway of enzyme activation through cryo-electron microscopy analysis of PI3KC3-C1. The inactive conformation of the VPS15 pseudokinase stabilizes the inactive conformation, sequestering its N-myristate in the N-lobe of the pseudokinase. Upon activation, the myristate is liberated such that the VPS34 lipid kinase catalyzes phosphatidylinositol-3 phosphate production on membranes. The VPS15 pseudokinase domain binds tightly to guanosine triphosphate and stabilizes a web of interactions to autoinhibit the cytosolic complex and promote activation upon membrane binding. These findings show in atomistic detail how the VPS34 lipid kinase is activated in the context of a complete PI3K complex.

摘要

III类磷脂酰肌醇-3激酶复合体I和II（PI3KC3-C1和PI3KC3-C2）分别在巨自噬和内体成熟中发挥着至关重要的作用。作者通过冷冻电镜分析PI3KC3-C1，阐明了酶激活的结构途径。VPS15假激酶的非活性构象维持了复合体的失活状态，将其N端豆蔻酰基（N-myristate）锚定在假激酶结构域的N叶（N-lobe）中。在激活时，肌醇酰基被释放出来，从而使VPS34脂质激酶在膜上催化磷脂酰肌醇-3磷酸的产生。VPS15假激酶结构域紧密结合鸟苷酸三磷酸，并稳定一个相互作用网络，该网络在胞质中实现复合体的自抑制（autoinhibition）。这些发现展示了VPS34脂质激酶在完整的PI3K复合体背景下是如何被激活的。

3、A neuroimmune circuit mediates cancer cachexia-associated apathy

神经免疫回路介导癌症恶病质相关的冷漠行为

美国华盛顿大学医学院神经科学系

Abstract

Cachexia, a severe wasting syndrome associated with inflammatory conditions, often leads to multiorgan failure and death. Patients with cachexia experience extreme fatigue, apathy, and clinical depression, yet the biological mechanisms underlying these behavioral symptoms and their relationship to the disease remain unclear. In a mouse cancer model, cachexia specifically induced increased effort-sensitivity, apathy-like symptoms through a cytokine-sensing brainstem-to-basal ganglia circuit. This neural circuit detects elevated interleukin-6 (IL-6) at cachexia onset and translates inflammatory signals into decreased mesolimbic dopamine, thereby increasing effort sensitivity. We alleviated these apathy-like symptoms by targeting key circuit nodes: administering an anti-IL-6 antibody treatment, ablating cytokine sensing in the brainstem, and optogenetically or pharmacologically boosting mesolimbic dopamine. Our findings uncovered a central neural circuit that senses systemic inflammation and orchestrates behavioral changes, providing mechanistic insights into the connection between chronic inflammation and depressive symptoms.

摘要

恶病质是一种与炎症状态相关的严重消耗综合征，常常导致多器官衰竭和死亡。患有恶病质的患者会经历极度疲劳、冷漠和临床抑郁，然而这些行为症状背后的生物学机制及其与疾病的关系仍然不明确。在一个小鼠癌症模型中，恶病质特异性诱导了“努力敏感性”（effort-sensitivity）增加，并通过一条感应细胞因子的“脑干-基底神经节”（brainstem-to-basal ganglia）神经回路导致了类冷漠症状（apathy-like symptoms）。这一神经回路在恶病质发作时检测到白细胞介素-6（IL-6）水平升高，并将炎症信号转化为中脑边缘多巴胺的减少，从而增加努力敏感性。研究人员通过靶向关键回路节点来缓解冷漠样症状：给予抗IL-6抗体治疗、消除脑干中的细胞因子感知，以及通过光遗传学或药理学手段增强中脑边缘多巴胺。研究发现揭示了一个能够感知全身炎症并协调行为变化的中枢神经回路，为慢性炎症与抑郁症状之间的联系提供了机制上的见解。

4、A distinct priming phase regulates CD8 T cell immunity by orchestrating paracrine IL-2 signals

一个独特的启动阶段通过协调旁分泌IL-2信号调节CD8 T细胞免疫应答

德国维尔茨堡大学免疫学研究所

Abstract

T cell priming is characterized by an initial activation phase that involves stable interactions with dendritic cells (DCs). How activated T cells receive the paracrine signals required for their differentiation once they have disengaged from DCs and resumed their migration has been unclear. We identified a distinct priming phase that favors CD8 T cells expressing receptors with high affinity for antigen. CXCR3 expression by CD8 T cells was required for their hours-long reengagement with DCs in specific subfollicular niches in lymph nodes. CD4 T cells paused briefly at the sites of CD8 T cell and DC interactions and provided Interleukin-2 (IL-2) before moving to another DC. Our results highlight a previously unappreciated phase of cell-cell interactions during T cell priming and have direct implications for vaccinations and cellular immunotherapies.

摘要

T细胞的启动过程以与树突状细胞（DCs）的稳定相互作用为特征的初始激活阶段为标志。然而，T细胞在与DCs脱离接触并恢复迁移后，如何接收其分化所需的旁分泌信号一直不明确。该研究发现了一个独特的启动阶段，该阶段有利于表达对抗原具有高亲和力受体的CD8 T细胞。CD8 T细胞上CXCR3的表达对于它们在淋巴结中特定的副滤泡生态位与DCs进行数小时的重新接触是必需的。CD4 T细胞在CD8 T细胞和DC相互作用的位点短暂停留，并在转移到另一个DC之前分泌白细胞介素-2（IL-2）。研究结果强调了T细胞启动过程中一个之前未被充分认识的细胞间相互作用阶段，并对疫苗接种和细胞免疫疗法有直接的启示。

5、Commander complex regulates lysosomal function and is implicated in Parkinson’s disease risk

commander复合物调节溶酶体功能并与帕金森病风险有关

美国费恩伯格医学院西北大学神经病学系

Abstract

Variants in GBA1 resulting in decreased lysosomal glucocerebrosidase (GCase) activity are a common risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Incomplete penetrance of GBA1 variants suggests that additional genes contribute to PD and DLB manifestation. By using a pooled genome-wide CRISPR interference screen, we identified copper metabolism MURR1 domain-containing 3 (COMMD3) protein, a component of the COMMD/coiled-coil domain-containing protein 22 (CCDC22)/CCDC93 (CCC) and Commander complexes, as a modifier of GCase and lysosomal activity. Loss of COMMD3 increased the release of lysosomal proteins through extracellular vesicles, leading to their impaired delivery to endolysosomes and consequent lysosomal dysfunction. Rare variants in the Commander gene family were associated with increased PD risk. Thus, COMMD genes and related complexes regulate lysosomal homeostasis and may represent modifiers in PD and other neurodegenerative diseases associated with lysosomal dysfunction.

摘要

GBA1基因的变异导致溶酶体葡萄糖脑苷脂酶（GCase）活性降低，是帕金森病（PD）和路易体痴呆（DLB）的常见风险因素。GBA1变异的不完全外显率表明，其他基因也参与了PD和DLB的发病过程。通过应用全基因组CRISPR干扰筛选技术，研究者鉴定出铜代谢MURR1结构域蛋白3（COMMD3）——它是COMMD/卷曲螺旋结构域蛋白22（CCDC22）/CCDC93（CCC）和Commander复合体的组分——作为调节GCase和溶酶体活性的修饰因子。COMMD3的缺失增加了溶酶体蛋白通过细胞外囊泡的释放，导致它们无法有效地递送至内溶酶体，从而引发溶酶体功能障碍。Commander基因家族中的罕见变异与PD风险增加相关。因此，COMMD基因及相关复合体调节溶酶体稳态，可能在PD及其他与溶酶体功能障碍相关的神经退行性疾病中起修饰作用。

Volume 388|Issue 6744|18 Apr 2025

2025年4月18日，Science共发表39篇文章， 其中包括Editorial 1篇；News 9篇；Expert Voices 1篇；Perspectives 4篇；Policy Forum 1篇；Books 2篇；Letters 3篇；Research Highlights 2篇；Research Articles 15篇；Careers 1篇。

1、Casz1 is required for both inner hair cell fate stabilization and outer hair cell survival

Casz1是内毛细胞命运稳定和外毛细胞存活所必需的

中国科学院脑科学与智能技术卓越中心神经科学国家重点实验室神经科学研究所

Abstract

Cochlear inner hair cells (IHCs) and outer hair cells (OHCs) require different transcription factors for their cell fate stabilization and survival, which suggests that separate mechanisms are involved. In this study, we found that the transcription factor Casz1 is crucial for early IHC fate consolidation and for OHC survival during mouse development. Loss of Casz1 resulted in transdifferentiation of IHCs into OHCs, without affecting OHC production. However, long-term OHC survival was compromised in Casz1 mutant mice. In addition, the transcription factor Gata3 was down-regulated in Casz1-deleted IHCs, and overexpressing Gata3 partially rescued IHC properties, OHC numbers, and hearing in Casz1-deleted mice. Thus, Casz1 plays critical roles in early IHC fate stabilization and OHC survival and could potentially provide a lead for therapies aimed at regenerating both IHCs and OHCs.

摘要

耳蜗内毛细胞（IHCs）和外毛细胞（OHCs）需要不同的转录因子来稳定其细胞命运和维持存活，这表明其涉及的机制是不同的。作者发现转录因子Casz1 不仅在小鼠发育早期对内毛细胞 (IHC) 的命运决定至关重要，而且对外毛细胞 (OHC) 的存活也起着关键作用。Casz1的缺失导致IHC转分化为OHC，但不影响OHC的产生。然而，Casz1突变小鼠的长期OHC存活受到损害。此外，Casz1缺失的IHC中转录因子Gata3表达下调，而在Casz1缺失的小鼠中过表达Gata3部分恢复了IHC的特性、OHC的数量和听力。因此，Casz1在IHC早期命运稳定和OHC存活中发挥关键作用，并可能为旨在再生IHC和OHC的治疗策略提供线索。

2、Deep-tissue transcriptomics and subcellular imaging at high spatial resolution

高空间分辨率的深层组织转录组学和亚细胞成像

美国霍华德休斯医学研究所

Abstract

Limited color channels in fluorescence microscopy have long constrained spatial analysis in biological specimens. We introduce cycle hybridization chain reaction (cycleHCR), a method that integrates multicycle DNA barcoding with HCR to overcome this limitation. cycleHCR enables highly multiplexed imaging of RNA and proteins using a unified barcode system. Whole-embryo transcriptomics imaging achieved precise three-dimensional gene expression and cell fate mapping across a specimen depth of ~310 μm. When combined with expansion microscopy, cycleHCR revealed an intricate network of 10 subcellular structures in mouse embryonic fibroblasts. In mouse hippocampal slices, multiplex RNA and protein imaging uncovered complex gene expression gradients and cell-type-specific nuclear structural variations. cycleHCR provides a quantitative framework for elucidating spatial regulation in deep tissue contexts for research and has potential diagnostic applications.

摘要：

荧光显微镜中有限的颜色通道长期以来限制了生物样本的空间分析。作者开发了一种名为循环杂交链反应（cycleHCR）的方法，该方法将多循环DNA条形码技术与HCR相结合，以克服这一限制。cycleHCR能够利用统一的条形码系统实现RNA和蛋白质的高通量同步成像。全胚胎转录组学成像在约310微米的样本深度范围内实现了精确的三维基因表达和细胞命运图谱绘制。当与扩展显微镜技术结合时，cycleHCR揭示了小鼠胚胎成纤维细胞中10种亚细胞结构的复杂网络。在小鼠海马切片中，多重RNA和蛋白质成像揭示了复杂的基因表达梯度和细胞类型特异性的核结构变异。cycleHCR为深入组织环境中阐明空间调控提供了定量研究框架，并具有潜在的诊断应用价值。

3、Structure of human PINK1 at a mitochondrial TOM-VDAC array

人类PINK1在线粒体TOM-VDAC阵列上的结构

澳大利亚沃尔特和伊丽莎·霍尔医学研究所

Abstract

Mutations in the ubiquitin kinase PINK1 cause early-onset Parkinson's disease, but how PINK1 is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-angstrom resolution cryo-electron microscopy structure of dimeric human PINK1 stabilized at an endogenous array of mitochondrial translocase of the outer membrane (TOM) and voltage-dependent anion channel (VDAC) complexes. Symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, both of which also bind PINK1 kinase C-lobes. PINK1 enters mitochondria through the proximal TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22. Our structure explains how human PINK1 is stabilized at the TOM complex and regulated by oxidation, uncovers a previously unknown TOM-VDAC assembly, and reveals how a physiological substrate traverses TOM40 during translocation.

摘要

泛素激酶PINK1的突变可导致早发性帕金森病，但PINK1如何在线粒体去极化转位复合体中得以稳定，尚不清楚。作者通过冷冻电镜技术解析了二聚体人源PINK1稳定锚定于内源性线粒体外膜转位酶（TOM）-电压依赖性阴离子通道（VDAC）复合体阵列的结构（分辨率3.1埃）。研究发现：中央VDAC2二聚体周围对称排布着两个TOM核心复合体，该组装由TOM5和TOM20介导，二者同时结合PINK1激酶的C端结构域。在TOM7和TOM22的引导下，PINK1经TOM核心复合体近端的TOM40桶状通道进入线粒体。研究结果揭示了人源PINK1如何在TOM复合体中得以稳定以及如何受到氧化调节，发现了一种新的TOM-VDAC组装形式，并阐明了生理底物在转运过程中穿越TOM40通道的分子路径。

4、Distinct synaptic plasticity rules operate across dendritic compartments in vivo during learning

学习过程中体内不同树突区室遵循独特的突触可塑性规则

美国加州大学圣地亚哥分校神经生物学系

Abstract

Synaptic plasticity underlies learning by modifying specific synaptic inputs to reshape neural activity and behavior. However, the rules governing which synapses will undergo different forms of plasticity in vivo during learning and whether these rules are uniform within individual neurons remain unclear. Using in vivo longitudinal imaging with single-synapse resolution in the mouse motor cortex during motor learning, we found that apical and basal dendrites of layer 2/3 (L2/3) pyramidal neurons showed distinct activity-dependent synaptic plasticity rules. The strengthening of apical and of basal synapses is predicted by local coactivity with nearby synapses and activity coincident with postsynaptic action potentials, respectively. Blocking postsynaptic spiking diminished basal synaptic potentiation without affecting apical plasticity. Thus, individual neurons use multiple activity-dependent plasticity rules in a compartment-specific manner in vivo during learning.

摘要

突触可塑性通过修饰特定的突触输入来重塑神经活动和行为，从而构成学习的基础。然而，关于在学习过程中体内哪些突触会经历不同形式的可塑性变化，以及这些规则是否在单个神经元内保持一致，目前尚不清楚。通过在小鼠运动皮层中进行具有单突触分辨率的纵向体内成像，研究者发现L2/3锥体神经元的顶树突和基底树突表现出不同的活动依赖性突触可塑性规则。顶树突突触的增强取决于与附近突触的局部共活动，而基底树突突触的增强则取决于与突触后动作电位的同步性。阻断突触后放电会削弱基突触的强化效应，而对顶树突的可塑性无影响。因此，在学习过程中，单个神经元在体内以区域特异性的方式使用多种活动依赖性可塑性规则。

Volume 388|Issue 6745|25 Apr 2025

2025年4月25日，Science共发表43篇文章， 其中包括Editorial 1篇；News 10篇；Expert Voices 1篇；Perspectives 4篇；Policy Forum 1篇；Books 3篇；Letters 4篇；Reviews 1篇； Research Highlights 2篇；Research Articles 15篇；Careers 1篇。

1、Distinct adipose progenitor cells emerging with age drive active adipogenesis

随着年龄增长而出现的独特脂肪祖细胞驱动活跃的脂肪生成过程

美国希望之城医疗中心亚瑟里格斯糖尿病和代谢研究所

Abstract

Starting at middle age, adults often suffer from visceral adiposity and associated adverse metabolic disorders. Lineage tracing in mice revealed that adipose progenitor cells (APCs) in visceral fat undergo extensive adipogenesis during middle age. Thus, despite the low turnover rate of adipocytes in young adults, adipogenesis is unlocked during middle age. Transplantations quantitatively showed that APCs in middle-aged mice exhibited high adipogenic capacity cell-autonomously. Single-cell RNA sequencing identified a distinct APC population, the committed preadipocyte, age-enriched (CP-A), emerging at this age. CP-As demonstrated elevated proliferation and adipogenesis activity. Pharmacological and genetic manipulations indicated that leukemia inhibitory factor receptor signaling was indispensable for CP-A adipogenesis and visceral fat expansion. These findings uncover a fundamental mechanism of age-dependent adipose remodeling, offering critical insights into age-related metabolic diseases.

摘要

从成年中期开始，成年人常患内脏脂肪过多及相关的不良代谢性疾病。小鼠的谱系追踪研究表明，在成年中期，内脏脂肪中的脂肪祖细胞（APCs）会经历显著的脂肪生成过程。由此可见，尽管青年期脂肪细胞更新率较低，但脂肪生成机制在中年期被重新激活。移植实验定量显示，中年小鼠APCs具有细胞自主性的强效成脂分化能力。单细胞RNA测序鉴定出一种独特的APC群体，即在该时期出现的年龄富集型的前脂肪细胞（CP-A）。CP-As表现出很强的增殖和脂肪生成活性。药理学和遗传学方法表明，白血病抑制因子受体信号对于CP-A的脂肪生成和内脏脂肪扩张是不可或缺的。该研究揭示了年龄依赖性脂肪重塑的基本机制，为理解与年龄相关的代谢性疾病提供了关键见解。

2、Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity

肿瘤衍生的红细胞生成素在癌症免疫中充当免疫抑制开关

美国斯坦福大学病理学系

Abstract

Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell-rich or a noninflamed T cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.

摘要：

成功的癌症免疫疗法需要患者能够对肿瘤产生有效的免疫反应；然而，许多癌症能够逃避机体的免疫系统。为了探究治疗失败的基础原因，作者研究了具有炎症性T细胞丰富或非炎症性T细胞匮乏的肿瘤微环境（TME）的自发性小鼠肝细胞癌（HCC）模型。研究表明，肿瘤细胞分泌的促红细胞生成素（EPO）决定了肿瘤的免疫类型。肿瘤来源的EPO通过与肿瘤相关巨噬细胞（TAMs）上的其相应受体EPOR相互作用，自主地产生非炎症性TME。EPO信号经由NRF2介导的血红素耗竭途径，促使TAMs转化为免疫调节表型。基因型非依赖性实验证实，清除肿瘤源性EPO或阻断TAMs表面EPOR可重建炎性TME并诱导肿瘤消退，此效应源于增强的抗肿瘤T细胞免疫。因此，EPO/EPOR轴构成抗肿瘤免疫的免疫抑制性开关。

3、Base-modified nucleotides mediate immune signaling in bacteria

碱基修饰的核苷酸介导细菌中的免疫信号

华中农业大学湖北洪山实验室农业微生物国家重点实验室

Abstract

Signaling from pathogen sensing to effector activation is a fundamental principle of cellular immunity. Whereas cyclic (oligo)nucleotides have emerged as key signaling molecules, the existence of other messengers remains largely unexplored. In this study, we reveal a bacterial antiphage system that mediates immune signaling through nucleobase modification. Immunity is triggered by phage nucleotide kinases, which, combined with the system-encoded adenosine deaminase, produce deoxyinosine triphosphates (dITPs) as immune messengers. The dITP signal activates a downstream effector to mediate depletion of cellular nicotinamide adenine dinucleotide (oxidized form), resulting in population-level defense through the death of infected cells. To counteract immune signaling, phages deploy specialized enzymes that deplete cellular deoxyadenosine monophosphate, the precursor of dITP messengers. Our findings uncover a nucleobase modification-based antiphage signaling pathway, establishing noncanonical nucleotides as a new type of immune messengers in bacteria.

摘要

从病原体感知到效应器激活的信号传导是细胞免疫的基本原理。虽然环状（寡）核苷酸已被确认为关键信号分子，但其他信使的存在仍属未知领域。该研究揭示了一种细菌抗噬菌体系统，该系统通过核苷酸碱基修饰介导免疫信号传导。当噬菌体核苷酸激酶与系统编码的腺苷脱氨酶协同作用时，会生成脱氧肌苷三磷酸（dITP）作为免疫信使；dITP信号激活下游效应因子，介导细胞氧化型烟酰胺腺嘌呤二核苷酸（NAD⁺）耗竭，通过感染细胞死亡实现群体水平防御。为对抗此信号通路，噬菌体利用特异性酶清除胞内dITP信使前体——脱氧腺苷一磷酸（dAMP）。该发现揭示了基于核碱基修饰的抗噬菌体信号通路，确立了非常规核苷酸作为细菌新型免疫信使的地位。。

4、Bottom-up reconstruction of functional death fold signalosomes reveals a requirement for polymer stability and avidity

通过自下而上重构功能性死亡折叠信号体，揭示聚合物稳定性与亲合力是该类复合物形成的必备条件

德国马克斯普朗克感染生物学研究所

Abstract

Protein polymer scaffolds composed of death fold (DF) proteins are critical to the formation of signalosomes in immune signaling. The biophysical properties that these polymeric scaffolds require for signal transduction are not clearly defined. Here, we engineered single-component DF signalosomes. We found that functionality depends on the stability provided by the DF polymer, which could also be achieved with a bacterial DF domain, a synthetic filament-forming domain, and amyloid-like sequences. This demonstrates the importance of polymer stability and inducibility irrespective of the motif's origin. By varying the number of included TRAF6 interaction motifs, we demonstrate that avidity is a tunable property that can control the amplitude of signaling outputs. This work lays out a reductionist framework to elucidate the required signaling properties through polymeric scaffolds by adjusting their assembly kinetics, stability, and avidity.

摘要

由死亡折叠（DF）蛋白组成的蛋白质聚合物支架对于免疫信号传导中信号体的形成至关重要。然而，这些聚合物支架在信号转导中所需的生物物理特性尚未明确。本研究通过工程化构建单组分DF信号体，发现其功能依赖于DF聚合物提供的稳定性——该特性亦可由细菌DF结构域、人工合成的纤丝形成结构域及类淀粉样序列实现，表明聚合物稳定性与可诱导性是功能核心，与结构基序来源无关。通过调控TRAF6相互作用基序的数量，本研究证明了亲和力是一种可调节的特性，能够控制信号输出的幅度。此项工作构建了通过调控聚合物支架的组装动力学、稳定性及亲合力来阐明信号传导特性的简化研究框架。

Volume 388|Issue 6746|1 May 2025

2025年5月1日，Science共发表42篇文章， 其中包括Editorial 1篇；News 8篇；Expert Voices 1篇；Perspectives 5篇；Policy Forum 1篇；Books 2篇；Letters 4篇；Reviews 1篇；Research Highlights 2篇；Research Articles 15篇；Careers 1篇；Products & Materials 1篇。

1、Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis

神经酰胺通过FPR2受体介导的代谢信号传导对脂肪细胞产热产生抑制作用

山东大学齐鲁医院新基石科学实验室

Abstract

Ceramides play a central role in human health and disease, yet their role as systemic signaling molecules remain poorly understood. In this work, we identify formyl peptide receptor 2 (FPR2) as a membrane receptor that specifically binds long-chain ceramides (C14 to C20). In brown and beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis through Gi cyclic adenosine monophosphate signaling pathways, an effect that is reversed in the absence of FPR2. We present three cryo-electron microscopy structures of FPR2 in complex with Gi trimers bound to C16:0, C18:0, and C20:0 ceramides. The hydrophobic tails are deeply embedded in the orthosteric ligand pocket, which has a limited amount of plasticity. Modification of the ceramide binding motif in closely related receptors, such as FPR1 or FPR3, converts them from inactive to active ceramide receptors. Our findings provide a structural basis for adipocyte thermogenesis mediated by FPR2.

摘要

神经酰胺在人类健康和疾病中发挥着核心作用，然而其作为系统性信号分子的作用尚不清楚。作者发现甲酰肽受体2（FPR2）是一种能特异性结合长链神经酰胺（C14至C20）的膜受体。在棕色和米色脂肪细胞中，C16:0神经酰胺与FPR2结合，通过Gi环磷酸腺苷信号通路抑制产热作用，这种效应在FPR2缺失时被逆转。作者分析了FPR2与Gi三聚体结合C16:0、C18:0和C20:0神经酰胺的三种冷冻电镜结构，发现神经酰胺疏水链深埋于正构配体结合腔内，且该腔隙构象柔性有限。通过修饰FPR1/FPR3等同源受体的神经酰胺结合基序，可将其从非活性状态转化为活性神经酰胺受体。本研究为FPR2介导的脂肪细胞产热机制提供了结构基础。

2、A symbiotic filamentous gut fungus ameliorates MASH via a secondary metabolite–CerS6–ceramide axis

丝状共生肠道真菌通过次级代谢物-CerS6-神经酰胺轴干预治疗代谢相关脂肪性肝炎（MASH）MASH

北京大学第三医院生殖医学中心

Abstract

The gut microbiota is known to be associated with a variety of human metabolic diseases, including metabolic dysfunction-associated steatohepatitis (MASH). Fungi are increasingly recognized as important members of this community; however, the role of fungal symbionts in metabolic diseases is unknown. We have systematically isolated and characterized gut fungi, identifying Fusarium foetens as an intestinal symbiotic filamentous fungus in mice. F. foetens reverses MASH progression in mouse models through an intestinal ceramide synthetase 6 (CerS6)-ceramide axis. Moreover, we identified FF-C1, a secondary metabolite from F. foetens, as a CerS6 inhibitor that has an endogenous protective effect on MASH progression.

摘要：

肠道微生物群已知与多种人类代谢性疾病相关，包括代谢功能障碍相关脂肪性肝炎（MASH）。然而，真菌共生体在代谢性疾病中的作用尚不清楚。研究人员系统地分离并鉴定肠道真菌，发现Fusarium foetens是小鼠肠道中的一种共生丝状真菌。F. foetens通过肠道神经酰胺合成酶6（CerS6）-神经酰胺轴在小鼠模型中逆转MASH的进展。此外，研究发现F. foetens产生的次级代谢产物FF-C1是一种CerS6抑制剂，对MASH的进展具有内源性保护作用。

3、Intracellular protein editing enables incorporation of noncanonical residues in endogenous proteins

细胞内蛋白质编辑可以将非经典残基编辑入内源性蛋白质中

美国宾夕法尼亚大学佩雷尔曼医学院生物化学和生物物理系

Abstract

The ability to study proteins in their native cellular context is crucial to our understanding of biology. In this work, we report a technology for intracellular protein editing, drawing from split intein-mediated protein splicing, genetic code expansion, and endogenous protein tagging. This approach enables us to rapidly and site-specifically install residues and chemical handles into a protein. We demonstrate the power of this platform to edit cellular proteins, inserting epitopes, protein-specific sequences, and noncanonical amino acids. Notably, we use an endogenous tagging approach to apply our protein editing technology to endogenous proteins with minimal perturbation. We anticipate that the protein editing technology presented in this work will be applied to a diverse set of problems and phenomena in live mammalian cells.

摘要

在细胞的天然环境中研究蛋白质对于理解生物学至关重要。作者开发了一种用于细胞内蛋白质编辑的技术，该技术结合了分裂内含肽介导的蛋白质剪接、遗传密码扩展和内源性蛋白质标记技术。这种方法能够快速且位点特异地在蛋白质中插入残基和化学基团。该研究展示了这个平台用于编辑细胞蛋白质的强大能力，成功引入了表位、蛋白质特异性序列和非典型氨基酸。值得注意的是，本研究采用内源性标记的方法将该蛋白质编辑技术应用于内源性蛋白质，干扰程度达到最小。该蛋白质编辑技术未来可被应用于活体哺乳动物细胞中各种问题和现象的研究。

4、TIGR-Tas: A family of modular RNA-guided DNA-targeting systems in prokaryotes and their viruses

TIGR-Tas：原核生物及其病毒中的一类模块化RNA引导的DNA靶向系统家族

美国霍华德休斯医学研究所

Abstract

RNA-guided systems provide remarkable versatility, enabling diverse biological functions. Through iterative structural and sequence homology-based mining starting with a guide RNA-interaction domain of Cas9, we identified a family of RNA-guided DNA-targeting proteins in phage and parasitic bacteria. Each system consists of a tandem interspaced guide RNA (TIGR) array and a TIGR-associated (Tas) protein containing a nucleolar protein (Nop) domain, sometimes fused to HNH (TasH)- or RuvC (TasR)-nuclease domains. We show that TIGR arrays are processed into 36-nucleotide RNAs (tigRNAs) that direct sequence-specific DNA binding through a tandem-spacer targeting mechanism. TasR can be reprogrammed for precise DNA cleavage, including in human cells. The structure of TasR reveals striking similarities to box C/D small nucleolar ribonucleoproteins and IS110 RNA-guided transposases, providing insights into the evolution of diverse RNA-guided systems.

摘要

RNA引导系统能够实现多样的生物学功能。通过从Cas9的引导RNA相互作用结构域开始，基于结构和序列同源性的迭代挖掘，作者在噬菌体和寄生细菌中鉴定出一个RNA引导的DNA靶向蛋白家族。每个系统由一个串联间隔的引导RNA（TIGR）阵列和一个含有核仁蛋白（Nop）结构域的TIGR相关（Tas）蛋白组成，该Tas蛋白有时还与HNH核酸酶结构域（形成TasH）或RuvC核酸酶结构域（形成TasR）融合。研究结果证明，TIGR阵列会被加工成长度为36个核苷酸的RNA（tigRNA），这些tigRNA通过一种串联间隔序列靶向机制（tandem-spacer targeting mechanism）指导序列特异性的DNA结合。TasR可以被重新编程以实现精确的DNA切割，包括在人类细胞中。TasR的结构揭示了其与box C/D小核仁核糖核蛋白和IS110 RNA引导的转座酶的显著相似性，为理解多样化RNA引导系统的进化提供了见解。

5、Dimensionality reduction simplifies synaptic partner matching in an olfactory circuit

降维技术简化了嗅觉回路中的突触匹配

美国斯坦福大学生物系

Abstract

A navigating axon faces complex choices when selecting postsynaptic partners in a three-dimensional (3D) space. In this work, we discovered a principle that can establish the 3D glomerular map of the fly antennal lobe by reducing the higher dimensionality serially to 1D projections. During development, olfactory receptor neuron (ORN) axons first contact their partner projection neuron dendrites on the spherical surface of the antennal lobe, regardless of whether the adult glomeruli lie near the surface or inside. Along this 2D surface, axons of each ORN type take a specific, arc-shaped trajectory that precisely intersects with their partner dendrites. Altering axon trajectories compromises synaptic partner matching. A 3D search is thus reduced to one dimension, simplifying partner matching.

摘要

在三维空间中选择突触后伙伴时，轴突面临着复杂的选择。在本研究中，研究者发现了一个能够通过将高维信息逐级降至一维投影，从而确立果蝇触角叶三维嗅小球空间排布图的原则。在发育过程中，嗅觉感受神经元（ORN）的轴突首先在触角叶的球形表面上与它们的伙伴投射神经元树突接触，无论成体嗅小球最终位置是位于表面附近还是内部。沿着这个二维表面，每种ORN类型的轴突都采取一个特定的、弧形的轨迹，精确地与它们的伙伴树突相交。改变轴突的轨迹会破坏突触伙伴的匹配。因此，三维搜索被降低到一个维度，简化了突触伙伴的匹配。

Volume 388|Issue 6747|8 May 2025

2025年5月8日，Science共发表41篇文章， 其中包括Editorial 1篇；News 10篇；Expert Voices 2篇；Perspectives 5篇；Books 2篇；Letters 3篇；Policy Articles 1篇；Research Highlights 2篇；Research Articles 14篇；Careers 1篇。

1、Pancreatic cancer–restricted cryptic antigens are targets for T cell recognition

胰腺癌-限制性隐性抗原是T细胞识别的靶标

美国麻省理工学院科赫学院

Abstract

Translation of the noncoding genome in cancer can generate cryptic (noncanonical) peptides capable of presentation by human leukocyte antigen class I (HLA-I); however, the cancer specificity and immunogenicity of noncanonical HLA-I-bound peptides (ncHLAp) are incompletely understood. Using high-resolution immunopeptidomics, we discovered that cryptic peptides are abundant in the pancreatic cancer immunopeptidome. Approximately 30% of ncHLAp exhibited cancer-restricted translation, and a substantial subset were shared among patients. Cancer-restricted ncHLAp displayed robust immunogenic potential in a sensitive ex vivo T cell priming platform. ncHLAp-reactive, T cell receptor-redirected T cells exhibited tumoricidal activity against patient-derived pancreatic cancer organoids. These findings demonstrate that pancreatic cancer harbors cancer-restricted ncHLAp that can be recognized by cytotoxic T cells. Future therapeutic strategies for pancreatic cancer, and potentially other solid tumors, may include targeting cryptic antigens.

摘要

在癌症中，非编码基因组的翻译可以产生隐秘的（非典型）肽段，这些肽段能够被人类白细胞抗原I类（HLA-I）呈递；然而，非典型HLA-I结合肽段（ncHLAp）的癌症特异性和免疫原性尚未被完全理解。通过高分辨率免疫肽组学，发现隐秘肽段在胰腺癌免疫肽组中大量存在。大约30%的ncHLAp表现出癌症限制性翻译，且相当一部分在患者之间共享。这些癌症限制性的ncHLAp在一种灵敏的体外T细胞启动平台中展现出强大的免疫原性潜能。针对ncHLAp反应的、经T细胞受体（TCR）重定向的T细胞，对患者来源的胰腺癌类器官表现出杀伤活性。这些发现表明，胰腺癌含有能够被细胞毒性T细胞识别的癌症限制性ncHLAp。未来的胰腺癌治疗策略，以及可能的其他实体瘤治疗策略，可能包括靶向隐秘抗原。

2、Sedentary chromosomal integrons as biobanks of bacterial antiphage defense systems

固定染色体整合子：细菌抗噬菌体防御系统的基因储备库

法国巴斯德研究院

Abstract

Integrons are genetic systems that drive bacterial adaptation by acquiring, expressing, and shuffling gene cassettes. While mobile integrons are well known for spreading antibiotic resistance genes, the functions of the hundreds of cassettes carried by sedentary integrons remain largely unexplored. We show that many of these cassettes encode small variants of known antiphage systems that favor their inclusion in the integron. We also demonstrate that nearly 10% of the integron cassettes in the pandemic Vibrio cholerae strain encode novel antiphage functions. Most of these novel systems have little or no similarity to previously known ones, with several providing defense through cell lysis or growth arrest. Our work highlights the stabilization and prevalence of small antiphage systems within integrons, making them an untapped biobank of defense mechanisms.

摘要：

整合子是一种通过获取、表达和重组基因盒来推动细菌适应性的遗传系统。尽管可移动性整合子因其传播抗生素抗性基而广为人知，但固定整合子所携带的数百种基因盒的功能在很大程度上仍未被探索。研究发现，其中许多基因盒编码了已知抗噬菌体系统的小型变体，这种小型化特性有利于它们被整合子纳入。研究还证明，在流行性霍乱弧菌菌株中，近10%的整合子基因盒编码了新型抗噬菌体功能。这些新的系统大多与已知的系统几乎没有相似之处，其中几个通过细胞裂解或生长停滞提供防御。该研究突出了小型抗噬菌体系统在整合子中的稳定性和普遍性，使它们成为一个尚未被开发的、蕴藏丰富防御机制的基因储备库。

3、Mobile integrons encode phage defense systems

移动整合子编码噬菌体防御系统

西班牙马德里康普顿斯大学兽医学院

Abstract

Integrons are bacterial genetic elements that capture, stockpile, and modulate the expression of genes encoded in integron cassettes. Mobile integrons (MIs) are borne on plasmids, acting as a vehicle for hundreds of antimicrobial resistance genes among key pathogens. These elements also carry gene cassettes of unknown function (gcus) whose role and adaptive value remain unexplored. In this work, we show that gcus encode phage resistance systems, many of which are newly discovered. Bacteriophage resistance integron cassettes (BRiCs) can be combined and mixed with resistance cassettes to produce multiphage or drug and phage resistance. The fitness costs of BRiCs are variable and dependent on the genetic context and can be modulated by changing the order of cassettes in the array. Hence, MIs act as highly mobile, low-cost defense islands.

摘要

整合子是细菌的遗传元件，能够捕获、储存并调节整合子基因盒中编码基因的表达。移动性整合子（MIs）存在于质粒上，作为数百种抗微生物耐药基因在关键病原体之间传播的载体。这些元件还携带未知功能的基因盒（gcus），其作用和适应性价值尚未被探索。该研究发现gcus编码噬菌体抗性系统，其中许多属于新近发现。噬菌体抗性整合子基因盒（BRiCs）可以与抗性基因盒结合并混合，从而产生针对多种噬菌体或兼具药物与噬菌体抗性的能力。BRiCs的适应性成本是可变的，取决于遗传背景，并且可以通过改变基因盒在阵列中的顺序来调节。因此，可移动整合子（MIs）发挥着高度移动、低成本的“防御岛”作用。

4、Imaging-guided deep tissue in vivo sound printing

成像引导的体内深层组织声学打印技术

美国加州理工学院工程与应用科学部医学工程系

Abstract

Three-dimensional printing offers promise for patient-specific implants and therapies but is often limited by the need for invasive surgical procedures. To address this, we developed an imaging-guided deep tissue in vivo sound printing (DISP) platform. By incorporating cross-linking agent-loaded low-temperature-sensitive liposomes into bioinks, DISP enables precise, rapid, on-demand cross-linking of diverse functional biomaterials using focused ultrasound. Gas vesicle-based ultrasound imaging provides real-time monitoring and allows for customized pattern creation in live animals. We validated DISP by successfully printing near diseased areas in the mouse bladder and deep within rabbit leg muscles in vivo, demonstrating its potential for localized drug delivery and tissue replacement. DISP's ability to print conductive, drug-loaded, cell-laden, and bioadhesive biomaterials demonstrates its versatility for diverse biomedical applications.

摘要

三维打印在患者特异性植入物和治疗方面具有巨大潜力，但常常受限于需要进行侵入性外科手术。为了解决这一问题，作者开发了一种影像引导的体内深部组织声学打印（DISP）平台。通过将交联剂负载的低温敏感脂质体纳入生物墨水，DISP能够利用聚焦超声实现多种功能性生物材料的精确、快速、按需交联。基于气体囊泡的超声成像技术提供了实时监测能力，并能在活体动物体内创建定制化图案。通过在小鼠膀胱附近和兔子腿部肌肉深处成功打印，验证了DISP的有效性，展示了其在局部药物递送和组织替代方面的潜力。DISP能够打印导电、载药、含细胞和具有生物粘附性生物材料，证明了其在多种生物医学应用中的多功能性。

5、Enhanced ERK activity extends ketamine’s antidepressant effects by augmenting synaptic plasticity

ERK活性增强可通过提升突触可塑性而延长氯胺酮的抗抑郁作用

美国范德比尔特大学药理学系

Abstract

Repeated ketamine treatment to maintain a rapid antidepressant effect can lead to side effects over time, highlighting an unmet clinical need for sustaining this drug's antidepressant action from a single administration. Ketamine-induced synaptic potentiation at CA3-CA1 synapses has been proposed to be a key synaptic substrate for antidepressant action. Here, we found that ketamine-induced CA3-CA1 synaptic potentiation could be augmented by transiently increasing extracellular signal-regulated kinase (ERK) activity through pharmacological inhibition of dual-specificity phosphatases 6 (DUSP6). The antidepressant-like behavioral effects of acute ketamine treatment were extended by DUSP6 inhibition for up to 2 months. The selective deletion of tropomyosin receptor kinase B (TrkB) in excitatory neurons abolished these DUSP6 inhibition-mediated synaptic and behavioral effects. These data suggest that ketamine's rapid antidepressant effects can be sustained by selectively targeting downstream intracellular signaling.

摘要

为维持氯胺酮的快速抗抑郁疗效而进行的重复给药，长期可能导致副作用，这凸显了临床上一个亟待解决的问题：如何通过单次给药即可持续发挥该药物的抗抑郁作用。氯胺酮诱导的CA3-CA1突触的增强被认为是抗抑郁作用的关键突触基础。研究发现，通过药理学抑制双重特异性磷酸酶6（DUSP6）来短暂增加细胞外信号调节激酶（ERK）活性，可以增强氯胺酮诱导的CA3-CA1突触的增强。通过DUSP6抑制，急性氯胺酮治疗的抗抑郁样行为效应可延长至多2个月。在兴奋性神经元中选择性敲除神经营养因子受体酪氨酸激酶B（TrkB）会消除这些由DUSP6抑制介导的突触和行为效应。这些数据表明，通过选择性靶向下游细胞内信号传导，可以维持氯胺酮的快速抗抑郁效果。

Volume 388|Issue 6748|15 May 2025

2025年5月15日，Science共发表38篇文章， 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；Research Highlights 2篇；Research Articles 16篇；Careers 1篇。

1、Molecular basis of influenza ribonucleoprotein complex assembly and processive RNA synthesis

流感病毒核糖核蛋白复合物组装和RNA合成的分子基础

美国宾夕法尼亚大学佩雷尔曼医学院生物化学和生物物理系

Abstract

Influenza viruses replicate and transcribe their genome in the context of a conserved ribonucleoprotein (RNP) complex. By integrating cryo-electron microscopy single-particle analysis and cryo-electron tomography, we define the influenza RNP as a right-handed, antiparallel double helix with the viral RNA encapsidated in the minor groove. Individual nucleoprotein subunits are connected by a flexible tail loop that inserts into a conserved pocket in its neighbor. We visualize the viral polymerase in RNP at different functional states, revealing how it accesses the RNA template while maintaining the double-helical architecture of RNP by strand sliding. Targeting the tail loop binding interface, we identify lead compounds as potential anti-influenza inhibitors. These findings elucidate the molecular determinants underpinning influenza virus replication and highlight a promising target for antiviral development.

摘要

流感病毒在其保守的核糖核蛋白（RNP）复合体环境中进行其基因组的复制与转录。通过整合冷冻电镜单颗粒分析和冷冻电镜断层扫描技术，研究者确定流感病毒RNP呈右手反平行双螺旋结构，其中病毒RNA被包裹在小沟内。各个核蛋白亚基通过一个灵活的尾环相互连接，该尾环插入其相邻亚基的一个保守口袋中。研究人员在不同功能状态下可视化了RNP中的病毒聚合酶，揭示了它如何通过链滑动机制在保持RNP双螺旋结构的同时获取RNA模板。作者针对尾环结合界面，鉴定出一些可作为潜在的抗流感抑制剂的先导化合物。这些发现阐明了流感病毒复制的分子决定因素，并强调了抗病毒药物开发的一个有前景的靶点。

2、Programmable gene insertion in human cells with a laboratory-evolved CRISPR-associated transposase

利用实验室定向进化的CRISPR相关转座酶实现在人类细胞中的可编程基因插入

美国麻省理工学院和哈佛大学博德研究所

Abstract

Programmable gene integration in human cells has the potential to enable mutation-agnostic treatments for loss-of-function genetic diseases and facilitate many applications in the life sciences. CRISPR-associated transposases (CASTs) catalyze RNA-guided DNA integration but thus far demonstrate minimal activity in human cells. Using phage-assisted continuous evolution (PACE), we generated CAST variants with >200-fold average improved integration activity. The evolved CAST system (evoCAST) achieves ~10 to 30% integration efficiencies of kilobase-size DNA cargoes in human cells across 14 tested genomic target sites, including safe harbor loci, sites used for immunotherapy, and genes implicated in loss-of-function diseases, with undetected indels and low levels of off-target integration. Collectively, our findings establish a platform for the laboratory evolution of CASTs and advance a versatile system for programmable gene integration in living systems.

摘要：

人体细胞内可编程的基因整合有助于实现对功能丧失性遗传疾病的“突变不可知”疗法，并促进生命科学领域的许多应用。CRISPR相关转座酶（CASTs）能够催化RNA引导的DNA整合，但迄今为止在人类细胞中表现出的活性极低。利用噬菌体辅助连续进化（PACE）技术，作者生成了平均整合活性提高超过200倍的CAST变体。进化后的CAST系统（evoCAST）在人类细胞中实现了约10%到30%的千碱基大小DNA货物的整合效率，覆盖了14个测试的基因组靶点，包括安全港位点、用于免疫治疗的位点以及与功能丧失型疾病相关的基因，且未检测到插入缺失突变，非靶向整合水平低。总体而言，研究结果建立了一个用于CASTs实验室进化的平台，并推进了一个在活体系统中用于可编程基因整合的多功能系统。

3、GPCR signaling gates astrocyte responsiveness to neurotransmitters and control of neuronal activity

GPCR信号控制星形胶质细胞对神经递质的反应和对神经元活动的控制

美国俄勒冈健康与科学大学沃尔伦研究所

Abstract

How astrocytes regulate neuronal circuits is a fundamental question in neurobiology. Specifically, how astrocytes respond to different neurotransmitters in vivo and how they affect downstream circuit modulation are questions that remain to be fully elucidated. Here, we report a mechanism in Drosophila by which G protein-coupled adrenergic signaling in astrocytes can control-or "gate"-their ability to respond to other neurotransmitters. Further, we show that manipulating this pathway potently regulates neuronal circuit activity and animal behavior. This gating mechanism is conserved in cultured primary mammalian astrocytes, suggesting that it might be an ancient feature of astrocyte circuit function. Our work establishes a mechanism by which astrocytes dynamically respond to and modulate neuronal activity in different brain regions and in different behavioral states.

摘要

星形胶质细胞如何调节神经回路是神经生物学中的一个基本问题。具体来说，星形胶质细胞在体内如何响应不同的神经递质，以及它们如何影响下游回路的调节，这些问题尚未得到充分阐明。作者报告了果蝇中的一种神经机制，即星形胶质细胞中的G蛋白偶联肾上腺素能信号可以控制或“调控”它们对其他神经递质的响应能力。此外，研究还表明，操纵这一通路可以强有力地调节神经回路活动和动物行为。这种调控机制在培养的原代哺乳动物星形胶质细胞中得以保留，表明它可能是星形胶质细胞回路功能的一个古老特征。总之，该研究发现了一种机制，通过该机制，星形胶质细胞在不同的脑区和不同的行为状态下动态响应并调节神经活动。

4、Norepinephrine changes behavioral state through astroglial purinergic signaling

去甲肾上腺素通过星形胶质细胞嘌呤能信号改变行为状态

美国霍华德休斯医学研究所

Abstract

Both neurons and glia communicate through diffusible neuromodulators; however, how neuron-glial interactions in such neuromodulatory networks influence circuit computation and behavior is unclear. During futility-induced behavioral transitions in the larval zebrafish, the neuromodulator norepinephrine (NE) drives fast excitation and delayed inhibition of behavior and circuit activity. We found that astroglial purinergic signaling implements the inhibitory arm of this motif. In larval zebrafish, NE triggers astroglial release of adenosine triphosphate (ATP), extracellular conversion of ATP into adenosine, and behavioral suppression through activation of hindbrain neuronal adenosine receptors. Our results suggest a computational and behavioral role for an evolutionarily conserved astroglial purinergic signaling axis in NE-mediated behavioral and brain state transitions and position astroglia as important effectors in neuromodulatory signaling.

摘要

神经元和胶质细胞都通过可扩散的神经调节因子进行通信；然而，神经调节网络中的神经元-胶质细胞相互作用如何影响回路计算和行为尚不清楚。在斑马鱼幼虫经历无效尝试诱导的行为状态转变过程中，神经调质去甲肾上腺素（NE） 可驱动行为的快速兴奋以及行为与回路活动的延迟抑制。研究发现，星形胶质细胞的嘌呤能信号传导介导了该调控模式的抑制性环节。在斑马鱼中，NE触发星形胶质细胞释放三磷酸腺苷（ATP），ATP在细胞外转化为腺苷，并通过激活延髓神经元的腺苷受体来抑制行为。结果表明，在NE介导的行为和大脑状态转变中，进化上保守的星形胶质细胞嘌呤能信号传导轴具有计算和行为作用，并将星形胶质细胞定位为神经调节信号传导中的重要效应器。

5、Norepinephrine signals through astrocytes to modulate synapses

去甲肾上腺素信号通过星形胶质细胞调节突触

美国圣路易斯华盛顿大学神经科学系

Abstract

Locus ceruleus (LC)-derived norepinephrine (NE) drives network and behavioral adaptations to environmental saliencies by reconfiguring circuit functional connectivity, but the underlying synapse-level mechanisms are elusive. Here, we show that NE remodeling of synaptic function is completely independent from its binding on neuronal receptors. Instead, astrocytic adrenergic receptors and calcium dynamics fully gate the effect of NE on synapses. Additionally, we found that NE suppression of synaptic strength results from an adenosine 5'-triphosphate (ATP)-derived and A1 adenosine receptor-mediated control of presynaptic efficacy. These findings suggest that astrocytes are a core component of neuromodulatory systems and the circuit effector through which NE produces network and behavioral adaptations.

摘要

蓝斑（LC）源性的去甲肾上腺素（NE）通过重构回路的功能性连接，驱动网络和行为对环境显著性的适应，但其背后的突触水平机制尚不清楚。在此，研究发现NE对突触功能的重塑完全独立于其与神经元受体的结合。相反，星形胶质细胞的肾上腺素能受体和钙动态变化完全调控了NE对突触的影响。此外，研究还发现NE对突触强度的抑制作用源于一种由腺苷酸三磷酸（ATP）衍生并通过A1腺苷受体介导的对突触前效能的控制。这些发现表明，星形胶质细胞是神经调节系统的核心组成部分，也是NE产生网络和行为适应的回路效应器。

Volume 388|Issue 6749|22 May 2025

2025年5月22日，Science共发表37篇文章， 其中包括Editorial 1篇；News 7篇；Perspectives 4篇；Books 2篇；Letters 3篇；Policy Articles 1篇；Reviews 1篇；Research Highlights 2篇；Research Articles 15篇；Careers 1篇。

1、Actin organizes chromosomes and microtubules to ensure mitotic fidelity in the preimplantation embryo

胚胎植入前胚胎中肌动蛋白通过组织染色体与微管确保有丝分裂保真度

美国宾夕法尼亚大学佩雷尔曼医学院再生医学研究所细胞和发育生物学系

Abstract

Following fertilization, the preimplantation embryo undergoes successive rounds of cell division and must accurately propagate the genetic material to ensure successful development. However, early mammalian embryos lack efficient spindle assembly mechanisms, and it remains unclear how error-free chromosome segregation is achieved. In this work, we imaged early mouse embryos and identified a network of nuclear actin cables that organize prophase chromosomes at the nuclear periphery. Following nuclear envelope breakdown, the network contracts and gathers chromosomes toward the cell center. Network contraction was driven by filament disassembly in a myosin II-independent manner. Additionally, we identified a network of branched actin filaments that attenuates metaphase spindle elongation. We also visualized nuclear actin in human embryos, suggesting a conserved role for actin in ensuring mitotic fidelity during early mammalian development.

摘要

受精后，植入前胚胎经历连续的细胞分裂过程，并必须准确地传递遗传物质以确保成功的发育。然而，早期哺乳动物胚胎缺乏有效的纺锤体组装机制，如何实现无误的染色体分离仍不清楚。作者通过对早期小鼠胚胎进行了成像，识别出一个核肌动蛋白纤维网络，该网络存在于核周缘组织前期染色体。核膜破裂后，该网络收缩并将染色体聚集到细胞中心。网络的收缩是由肌动蛋白丝的解聚驱动的，这一过程不依赖于肌球蛋白II。此外，作者还识别出一个分支肌动蛋白丝网络，该网络抑制中期纺锤体的延长。研究人员还在人类胚胎中观察到了核肌动蛋白，这表明肌动蛋白在确保早期哺乳动物发育过程中的有丝分裂保真度方面具有保守的作用。

2、Deep learning–guided design of dynamic proteins

深度学习指导下的动态蛋白质设计

美国加州大学伯克利-UCSF分校生物工程系

Abstract

Deep learning has advanced the design of static protein structures, but the controlled conformational changes that are hallmarks of natural signaling proteins have remained inaccessible to de novo design. Here, we describe a general deep learning-guided approach for de novo design of dynamic changes between intradomain geometries of proteins, similar to switch mechanisms prevalent in nature, with atomic-level precision. We solve four structures that validate the designed conformations, demonstrate modulation of the conformational landscape by orthosteric ligands and allosteric mutations, and show that physics-based simulations are in agreement with deep-learning predictions and experimental data. Our approach demonstrates that new modes of motion can now be realized through de novo design and provides a framework for constructing biology-inspired, tunable, and controllable protein signaling behavior de novo.

摘要

深度学习推动了静态蛋白质结构的设计，但天然信号蛋白的标志性特征——受控的构象变化——长期以来难以通过从头设计实现。该研究描述了一种由深度学习引导的通用方法，用于从头设计蛋白质内部结构域几何形状之间的动态变化。该方法以原子级别的精度，实现了类似于自然界中普遍存在的开关机制。作者解析了四个结构，验证了设计的构象，展示了正构配体和变构突变对构象景观的调节，并证明基于物理的模拟与深度学习预测和实验数据一致。研究结果表明，现在可以通过从头设计实现新的运动模式，并为从头构建受生物学启发的、可调节的和可控的蛋白质信号传导行为提供了框架。

汇报人：周菁

导师：刘世喜

审核：冯兰、任建君