四川大学华西医院耳鼻咽喉头颈外科 Department of Otolaryngology-Head and Neck Surgery at West China Hospital, Sichuan University.

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Department of Otolaryngology-Head and Neck Surgery

科室：耳鼻咽喉头颈外科

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前沿速递

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华西耳鼻喉前沿学术速递——文献导读（第57期）

发布时间：2025-02-19

原创王欣怡华西医院耳鼻喉科

华西耳鼻喉前沿学术速递——文献导读（第57期）

【Science】2024年10月11日—2024年11月21日刊论文导读

期刊介绍：

《Science》杂志，创立于1880年，是美国科学促进会（AAAS）的官方刊物，被誉为世界上最顶级的科学杂志之一，代表了人类自然科学研究的最高水平。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。该杂志积极推行同行评议制度，通过严格的评审和编辑流程，确保所发表的每一项研究都具备高水平的学术价值和可靠性。除了高质量的研究论文，该杂志还定期发表涉及科学前沿探索、科学政策分析、科学教育改革以及科学社会议题探讨的评论文章。《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。因其在科学界拥有很高的声望和影响力，《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56.9。

Volume 386|Issue 6718|11 Oct 2024

在2024年10月11日，《Science》共发表文章34篇：7篇NEWS；11篇INSIGHTS，其中2篇EXPERT VOICES、3篇PERSPECTIVES、1篇POLICY FORUM、2本BOOK、3篇LETTERS；15篇RESEARCH，其中1篇REVIEWS、14篇RESEARCH ARTICLES；1篇CAREERS。

1.Temporal variability and cell mechanics control robustness in mammalian embryogenesis

时间变异性和细胞力学在哺乳动物胚胎发生过程中控制稳健性

奥地利科技学院联合荷兰乌特勒支Hubrecht研究所

How living systems achieve precision in form and function despite their intrinsic stochasticity is a fundamental yet ongoing question in biology. We generated morphomaps of preimplantation embryogenesis in mouse, rabbit, and monkey embryos, and these morphomaps revealed that although blastomere divisions desynchronized passively, 8-cell embryos converged toward robust three-dimensional shapes. Using topological analysis and genetic perturbations, we found that embryos progressively changed their cellular connectivity to a preferred topology, which could be predicted by a physical model in which actomyosin contractility and noise facilitate topological transitions, lowering surface energy. This mechanism favored regular embryo packing and promoted a higher number of inner cells in the 16-cell embryo. Synchronized division reduced embryo packing and generated substantially more misallocated cells and fewer inner-cell–mass cells. These findings suggest that stochasticity in division timing contributes to robust patterning.

生命系统如何在其固有的随机性中实现形态和功能的精确性，一直是生物学领域中的一个根本性且备受关注的问题。该研究通过绘制小鼠、兔子和猴子胚胎的囊胚发育形态图，发现尽管卵裂球的分裂呈现出被动失序的状态，但胚胎在发育至八细胞阶段时，却能趋向于形成高度稳定的三维结构。结合拓扑学分析和基因扰动实验，研究发现哺乳动物胚胎在发育过程中通过细胞去同步化和拓扑转变，逐步调整细胞连接方式，以达到物理模型所预测的优选拓扑构型。在这一过程中，肌动蛋白和肌球蛋白的收缩力与随机波动共同促进了拓扑转变的发生，从而降低了表面能量。此机制不仅确保了胚胎细胞的规则排列，而且在胚胎发育至十六细胞阶段时，促进了内层细胞数量的增加。相比之下，同步分裂则会扰乱这种规整性，导致细胞错位分布增多，并减少内细胞团的数量。这些发现揭示了分裂时序的随机性在胚胎稳健发育模式形成中的重要作用。

2.Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy

克隆性造血的表观遗传调控因子在免疫治疗过程中控制CD8 T细胞的干性

美国圣裘德儿童研究医院骨髓移植和细胞治疗科

Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy. CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 preserved a progenitor-exhausted (Tpex) population for more than 1 year during chronic antigen exposure without undergoing malignant transformation. Asxl1 controlled the self-renewal capacity of T cells and reduced CD8 T cell differentiation through H2AK119 ubiquitination and epigenetic modification of the polycomb group–repressive deubiquitinase pathway. Asxl1-deficient T cells synergized with anti–PD-L1 immunotherapy to improve tumor control in experimental models and conferred a survival advantage to mutated T cells from treated patients.

表观遗传学对T细胞耗竭的强化作用，已被公认为限制免疫治疗期间T细胞应答的主要障碍。然而，在长期抗原暴露的条件下，关于限制抗肿瘤免疫的核心表观遗传调控因子，目前仍不明确。该团队研究了三种常见的、能促进克隆性造血的表观遗传调控因子，旨在探讨它们是否影响T细胞的干性以及对抗检查点阻断免疫疗法的反应。研究发现，在慢性抗原暴露超过一年的过程中，缺失Dnmt3a、Tet2或Asxl1的CD8 T细胞，能够维持一个祖细胞耗竭（Tpex）群体。例如，敲除Asxl1的CD8 T细胞在慢性抗原暴露下保持了1年以上的耗竭T细胞前体/祖细胞(Tpex)，并且未发生恶性转化。在此基础上，Asxl1通过组蛋白H2AK119泛素化及多梳群抑制性去泛素化酶途径的表观遗传调控，不仅调控了T细胞的自我更新能力，还显著减少了CD8 T细胞的分化。在试验模型中，ASXL1基因突变的T细胞在与抗PD-L1免疫疗法协同作用时，不仅能在实验模型中显著提高肿瘤控制效果，还能赋予接受治疗患者的突变T细胞以生存优势，防止T细胞衰竭。

3. Helicase-assisted continuous editing for programmable mutagenesis of endogenous genomes

解旋酶介导的连续编辑用于内源基因组的可编程突变

美国麻省理工学院和哈佛大学Broad研究所

Deciphering the context-specific relationship between sequence and function is a major challenge in genomics. Existing tools for inducing locus-specific hypermutation and evolution in the native genome context are limited. Here we present a programmable platform for long-range, locus-specific hypermutation called helicase-assisted continuous editing (HACE). HACE leverages CRISPR-Cas9 to target a processive helicase-deaminase fusion that incurs mutations across large (>1000–base pair) genomic intervals. We applied HACE to identify mutations in mitogen-activated protein kinase kinase 1 (MEK1) that confer kinase inhibitor resistance, to dissect the impact of individual variants in splicing factor 3B subunit 1 (SF3B1)–dependent missplicing, and to evaluate noncoding variants in a stimulation-dependent immune enhancer of CD69. HACE provides a powerful tool for investigating coding and noncoding variants, uncovering combinatorial sequence-to-function relationships, and evolving new biological functions.

解析序列与功能在特定情境中的关联是基因组学范畴的一项重大挑战。当前，天然基因组背景下实现位点特异性超突变与进化的技术手段仍显匮乏。在此，研究团队推出了一个名为“解旋酶辅助连续编辑”（helicase-assisted continuous editing，HACE）的可编程平台，旨在达成长距离、特定位点的高突变率。HACE借助CRISPR-Cas9系统瞄准具有进程性的解旋酶-去氨酶融合蛋白，进而在较大的（>1000碱基对）基因间隔区域引发突变。研究团队运用HACE来识别赋予激酶抑制剂抗性的MEK1突变，剖析SF3B1亚基1（SF3B1）依赖性剪接过程中单个变异的影响，并评估刺激依赖性免疫增强子CD69中非编码变异的作用。目前，在天然基因组背景下诱导位点特异性超突变和进化的工具尚显不足。

4.Predicting pathogen mutual invasibility and co-circulation

预测病原体的互侵性和共循环

美国普林斯顿大学生态与进化生物学系

Observations of pathogen community structure provide evidence for both the coexistence and replacement of related strains. Despite many studies of specific host-pathogen systems, a unifying framework for predicting the outcomes of interactions among pathogens has remained elusive. We address this gap by developing a pathogen invasion theory (PIT) based on modern ecological coexistence theory and testing the resulting framework against empirical systems. Across major human pathogens, PIT predicts near-universal mutual susceptibility of one strain to invasion by another strain. However, predicting co-circulation from mutual invasion also depends on the degree to which susceptible abundance is reduced below the invasion threshold by overcompensatory epidemic dynamics, and the time it takes for susceptibles to replenish. The transmission advantage of an invading strain and the strength and duration of immunity are key determinants of susceptible dynamics. PIT unifies existing ideas about pathogen co-circulation, offering a quantitative framework for predicting the emergence of novel pathogen strains.

对于病原体群落结构的观测为同一种病原体的不同株系的共存及替代提供了有力证据。尽管既往研究已经针对特定宿主－病原体系统开展了众多研究，但预测病原体相互作用结果的统一框架始终未能形成。研究团队运用现代共存理论，创新性地构建了病原体入侵理论（PIT），旨在填补这一研究空白，并通过实证系统的测试验证了该框架的有效性。在主要的人类病原体中，PIT预测几乎所有株系之间均存在相互易感性，也就是说一个株系易被另一个株系入侵。然而，从相互入侵来预测共存，还取决于过度补偿的流行病动力学致使易感性降低的程度，以及易感人群补充所需的时间。入侵株系的传播优势以及免疫的强度和持续时间是易感性动态变化的关键决定因素。PIT整合了现有的有关病原体共存的理念，为预测新型病原体株系的出现提供了定量框架。

5. Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes

精神分裂症大脑中的体细胞嵌合现象揭示产前突变过程

哈佛医学院生物医学信息学系（美国）、麻省理工学院、哈佛大学Broad研究所及西奈山伊坎医学院遗传学和基因组科学系

Germline mutations modulate the risk of developing schizophrenia (SCZ). Much less is known about the role of mosaic somatic mutations in the context of SCZ. Deep (239×) whole-genome sequencing (WGS) of brain neurons from 61 SCZ cases and 25 controls postmortem identified mutations occurring during prenatal neurogenesis. SCZ cases showed increased somatic variants in open chromatin, with increased mosaic CpG transversions (CpG>GpG) and T>G mutations at transcription factor binding sites (TFBSs) overlapping open chromatin, a result not seen in controls. Some of these variants alter gene expression, including SCZ risk genes and genes involved in neurodevelopment. Although these mutational processes can reflect a difference in factors indirectly involved in disease, increased somatic mutations at developmental TFBSs could also potentially contribute to SCZ.

遗传变异能够调控罹患精神分裂症（SCZ）的风险。然而，关于SCZ中镶嵌型体细胞突变所发挥的作用，人们知之甚少。在迄今为止规模最大的精神分裂症全基因组测序研究中，研究团队对61例SCZ病例和25例对照者死后的大脑神经元进行了深度全基因组测序（WGS），揭示了罕见的结构遗传变异在精神分裂症中的潜在作用。在精神分裂症（SCZ）病例中，观察到开放染色质区域存在较多的体细胞变异，包括CpG颠换（CpG>GpG）和T>G突变。这些变异主要集中在开放染色质区域，并且在对照组中未发现类似情况。部分变异影响了基因表达，涉及与SCZ风险相关的基因以及参与神经发育的基因。单细胞级别的染色质开放区域测序技术揭示了这些变异的存在。尽管这些突变过程或许反映了与疾病相关的间接因素存在差异，但发育性转录因子结合位点（TFBSs）的体细胞突变，如德国马克斯·普朗克精神病学研究所Michael J. Ziller团队所报道的SCZ相关非编码基因变异，也有可能潜在地引发SCZ。

Volume 386|Issue 6719|18 Oct 2024

在2024年10月18日，《Science》共发表文章36篇：1篇EDITORIAL；9篇NEWS；10篇INSIGHTS，其中4篇PERSPECTIVES、1篇POLICY FORUM、2本BOOK、3篇LETTERS；15篇RESEARCH，其中1篇REVIEWS、14篇RESEARCH ARTICLES；1篇EDITORIAL。

1.In vivo dendritic cell reprogramming for cancer immunotherapy

体内树突状细胞重编程用于癌症免疫治疗

瑞典隆德大学瓦伦贝里分子医学中心

Immunotherapy can lead to long-term survival for some cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells; induced tumor regressions; and established long-term systemic immunity in multiple mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for human clinical trials of in vivo immune cell reprogramming for cancer immunotherapy.

免疫疗法已被证明能够使部分癌症患者实现长期生存，例如晚期乳腺癌患者通过免疫细胞疗法成功生存超过25年。然而，其疗效在某些情况下受到抗原呈递不足以及肿瘤微环境对免疫原性细胞排斥的限制。在此，研究团队利用重组腺相关病毒(rAAV)递送转录因子PU.1、IRF8和BATF3，成功在体内对肿瘤细胞进行重新编程，使它们能够呈递1型常规树突状细胞的抗原。这一策略在临床试验中已被证实具有安全性，并且在激活细胞毒性T淋巴细胞(CTL)方面显示出潜力。研究团队经过重新编程的肿瘤细胞重塑了其肿瘤微环境，招募并扩充了多克隆细胞毒性T细胞，诱导了肿瘤消退，并在多种小鼠黑色素瘤模型中建立了长期的系统性免疫。在人类肿瘤球体和异种移植模型中，向免疫原性树突状样细胞的重编程过程独立于常见的免疫抑制机制，这些机制通常限制免疫疗法的效果。研究团队的研究为用于癌症免疫疗法的体内免疫细胞重新编程的人类临床试验铺平了道路。

2.Mechanism of bacterial predation via ixotrophy

通过黏附摄食的细菌捕食机制

瑞士苏黎世联邦理工学院生物学系分子生物学与生物物理研究所

Ixotrophy is a contact-dependent predatory strategy of filamentous bacteria in aquatic environments for which the molecular mechanism remains unknown. We show that predator-prey contact can be established by gliding motility or extracellular assemblages we call “grappling hooks.” Cryo–electron microscopy identified the grappling hooks as heptamers of a type IX secretion system substrate. After close predator-prey contact is established, cryo–electron tomography and functional assays showed that puncturing by a type VI secretion system mediated killing. Single-cell analyses with stable isotope–labeled prey revealed that prey components are taken up by the attacker. Depending on nutrient availability, insertion sequence elements toggle the activity of ixotrophy. A marine metagenomic time series shows coupled dynamics of ixotrophic bacteria and prey. We found that the mechanism of ixotrophy involves multiple cellular machineries, is conserved, and may shape microbial populations in the environment.

黏附摄食是水生环境中丝状细菌所采用的一种依赖接触的捕食策略，其分子机制涉及通过滑动运动或称为“抓钩”的细胞外结构建立接触，并通过IX型分泌系统底物形成的七聚体进行捕食。此外，VI型分泌系统的穿刺介导了猎物的杀伤，而捕食者通过稳定同位素标记猎物的单细胞分析表明吸收了猎物的成分。研究团队发现，捕食者与猎物之间的接触能够通过滑行运动或者研究团队称作“抓钩”的细胞外结构来达成。通过冷冻电子显微镜技术，研究者们鉴定出IX型分泌系统(T9SS)底物的七聚体结构，揭示了其在细菌毒力因子分泌中的作用。在紧密的捕食者与猎物接触得以建立之后，冷冻电子断层技术和功能实验表明，由VI型分泌系统介导的穿刺致使了杀伤。通过使用稳定同位素标记的猎物进行单细胞分析揭示，攻击者摄取了猎物体成分。依据营养物质的可用性，插入序列元素会对摄食性的活性进行切换。一个海洋微生物组的时序表明，摄食性细菌和猎物之间存在着融合的动态变化。研究团队发现，摄食性机制涉及多种细胞机制，具有保守性，并且可能塑造环境中的微生物种群。

3.Neurotoxic mixture effects of chemicals extracted from blood of pregnant women

从孕妇血液中提取的化学物质的神经毒性混合效应

德国亥姆霍兹环境研究中心（UFZ）细胞毒理学系

Human biomonitoring studies typically capture only a small and unknown fraction of the entire chemical universe. We combined chemical analysis with a high-throughput in vitro assay for neurotoxicity to capture complex mixtures of organic chemicals in blood. Plasma samples of 624 pregnant women from the German LiNA cohort were extracted with a nonselective extraction method for organic chemicals. 294 of >1000 target analytes were detected and quantified. Many of the detected chemicals as well as the whole extracts interfered with neurite development. Experimental testing of simulated complex mixtures of detected chemicals in the neurotoxicity assay confirmed additive mixture effects at concentrations less than individual chemicals’ effect thresholds. The use of high-throughput target screening combined with bioassays has the potential to improve human biomonitoring and provide a new approach to including mixture effects in epidemiological studies.

人体生物监测研究通常仅能捕获整个化学世界中极小且未知的一部分。研究团队融合化学分析与高通量体外神经毒性检测技术，旨在捕获血液内复杂的有机化学混合物。研究团队运用一种非选择性的有机化学物提取方法，从德国LiNA队列的624名孕妇的血浆样本中提取有机化学物。从超过1000种目标分析物中，成功检测并定量了294种物质。检测到的众多化学物质及整体提取物均对神经突起发育产生干扰作用。针对模拟检测到的化学物质复杂混合物的神经毒性检测实验证实，在低于单个化学物质效应阈值的浓度下，存在混合物的叠加效应。结合高通量目标筛选与生物检测技术，有望优化人体生物监测，并为流行病学研究纳入混合物效应提供创新途径。

4.Description and functional validation of human enteroendocrine cell sensors

人类肠内分泌细胞传感器的描述和功能验证

荷兰乌特勒支大学医学中心（UMC Utrecht）荷兰皇家艺术与科学学院（KNAW）下属的Hubrecht研究所和Oncode研究所

Enteroendocrine cells (EECs) are gut epithelial cells that respond to intestinal contents by secreting hormones, including the incretins glucagon-like peptide 1 (GLP-1) and gastric inhibitory protein (GIP), which regulate multiple physiological processes. Hormone release is controlled through metabolite-sensing proteins. Low expression, interspecies differences, and the existence of multiple EEC subtypes have posed challenges to the study of these sensors. We describe differentiation of stomach EECs to complement existing intestinal organoid protocols. CD200 emerged as a pan-EEC surface marker, allowing deep transcriptomic profiling from primary human tissue along the stomach-intestinal tract. We generated loss-of-function mutations in 22 receptors and subjected organoids to ligand-induced secretion experiments. We delineate the role of individual human EEC sensors in the secretion of hormones, including GLP-1. These represent potential pharmacological targets to influence appetite, bowel movement, insulin sensitivity, and mucosal immunity.

肠内分泌细胞（EECs）属于肠道上皮细胞，受肠道内容物的刺激而分泌激素，其中包括对多种生理过程具有调节作用的促胰岛素释放肽1（GLP-1）和胃抑肽（GIP）。激素释放受代谢物感应蛋白调控。低表达水平、物种差异及多种EEC亚型，为感应蛋白研究带来挑战。研究团队阐述了胃EECs分化过程，补充了现有肠道类器官方案。CD200成为泛EEC表面标志物，能够从人的原始组织沿胃－肠道途径开展深度转录组分析。研究团队构建了22个受体失活突变体，并对类器官进行配体诱导分泌实验。研究团队明确了人类EEC感应蛋白在激素分泌（包括GLP-1）中的作用。这些感应蛋白为潜在药物靶点，影响食欲、排便、胰岛素敏感性及黏膜免疫。

Volume 386|Issue 6720|25 Oct 2024

在2024年10月25日，《Science》共发表文章37篇：1篇EDITORIAL；8篇NEWS；11篇INSIGHTS，其中1篇EXPERT VOICES、4篇PERSPECTIVES、1篇POLICY FORUM、3本BOOK、2篇LETTERS；15篇RESEARCH，其中1篇REVIEWS、14篇RESEARCH ARTICLES；1篇CAREERS。

1.The landscape of RNA binding proteins in mammalian spermatogenesis

哺乳动物精子发生过程中 RNA 结合蛋白的景观

南京医科大学公共卫生学院、基础医学科学院、附属常州第二人民医院

Despite continuous expansion of the RNA binding protein (RBP) world, there is a lack of systematic understanding of RBPs in the mammalian testis, which harbors one of the most complex tissue transcriptomes. We adapted RNA interactome capture to mouse male germ cells, building an RBP atlas characterized by multiple layers of dynamics along spermatogenesis. Trapping of RNA–cross-linked peptides showed that the glutamic acid–arginine (ER) patch, a residue-coevolved polyampholytic element present in coiled coils, enhances RNA binding of its host RBPs. Deletion of this element in NONO (non-POU domain-containing octamer-binding protein) led to a defective mitosis-to-meiosis transition due to compromised NONO-RNA interactions. Whole-exome sequencing of over 1000 infertile men revealed a prominent role of RBPs in the human genetic architecture of male infertility and identified risk ER patch variants.

尽管RNA结合蛋白（RBP）持续增多，然而，目前对于哺乳动物睾丸中的RBP，人们仍缺乏系统性的认知。睾丸是拥有最复杂组织转录组的器官之一。研究团队把RNA互作图谱捕获技术运用到小鼠雄性生殖细胞上，成功构建了一个反映精子发生过程中多层次动态特性的RBP图谱。对RNA交联肽段的捕获表明，存在于螺旋－环结构中的一种与残基共同进化的多聚阴离子元素——谷氨酸-精氨酸（ER）补丁，提升了宿主RBP对RNA的结合效能。在NONO（非POU域含八聚体结合蛋白）中删除此元素致使细胞从分裂期到减数分裂期的过渡出现缺陷，原因在于NONO-RNA相互作用遭到了破坏。对1000多位不育男性进行的全外显子测序揭示了RBP在人类男性不育遗传结构中的重要作用，并鉴定出了与ER补丁相关的风险变异。

2.Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function

通过维生素K前体的饮食促氧化剂疗法靶向PI 3－激酶VPS34功能

美国冷泉港实验室

Men taking antioxidant vitamin E supplements have increased prostate cancer (PC) risk. However, whether pro-oxidants protect from PC remained unclear. In this work, we show that a pro-oxidant vitamin K precursor [menadione sodium bisulfite (MSB)] suppresses PC progression in mice, killing cells through an oxidative cell death: MSB antagonizes the essential class III phosphatidylinositol (PI) 3-kinase VPS34—the regulator of endosome identity and sorting—through oxidation of key cysteines, pointing to a redox checkpoint in sorting. Testing MSB in a myotubular myopathy model that is driven by loss of MTM1—the phosphatase antagonist of VPS34—we show that dietary MSB improved muscle histology and function and extended life span. These findings enhance our understanding of pro-oxidant selectivity and show how definition of the pathways they impinge on can give rise to unexpected therapeutic opportunities.

服用抗氧化剂维生素E的男性的前列腺癌（PC）的患病风险增加。然而，抗氧化剂是否能够预防PC尚不明确。在此，研究团队发现一种抗氧化剂维生素K前体[二甲基亚砜（MSB）]于小鼠体内能够抑制PC的进展，通过氧化细胞死亡来杀灭细胞：MSB借助氧化关键半胱氨酸来对抗关键的Ⅲ类磷脂酰肌醇（PI）激酶VPS34（此为负责内体身份和分选的调节器），这指出了在分选过程中的一个氧化还原检查点。在由MTM1（VPS34的磷酸酶拮抗剂）缺失所驱动的肌管型肌营养不良模型中对MSB进行测试，研究团队发现饮食中的MSB改善了肌肉组织的结构和功能，并延长了生存期。这些发现增进了研究团队对抗氧化剂选择性的认识，并且展示了明确它们的作用途径如何带来意外的治疗契机。

3.Multi-omics landscape and molecular basis of radiation tolerance in a tardigrade

缓步动物辐射耐受性的多组学景观和分子基础

北京国家医学蛋白质组学重点实验室

Tardigrades are captivating organisms known for their resilience in extreme environments, including ultra-high-dose radiation, but the underlying mechanisms of this resilience remain largely unknown. Using genome, transcriptome, and proteome analysis of Hypsibius henanensis sp. nov., we explored the molecular basis contributing to radiotolerance in this organism. A putatively horizontally transferred gene, DOPA dioxygenase 1 (DODA1), responds to radiation and confers radiotolerance by synthesizing betalains—a type of plant pigment with free radical–scavenging properties. A tardigrade-specific radiation-induced disordered protein, TRID1, facilitates DNA damage repair through a mechanism involving phase separation. Two mitochondrial respiratory chain complex assembly proteins, BCS1 and NDUFB8, accumulate to accelerate nicotinamide adenine dinucleotide (NAD+) regeneration for poly(adenosine diphosphate–ribosyl)ation (PARylation) and subsequent poly(adenosine diphosphate–ribose) polymerase 1 (PARP1)–mediated DNA damage repair. These three observations expand our understanding of mechanisms of tardigrade radiotolerance.

水熊虫是一类因其在极端环境（包括超高剂量辐射）中的耐受能力而备受关注的生物，但其耐受能力的分子机制在很大程度上仍然未知。通过对Hypsibius henanensis sp. nov.的基因组、转录组和蛋白质组进行分析，研究团队探寻了该生物辐射耐受性的分子基础。一种可能经由水平转移获得的基因DODA1（DOPA二氧化酶1）对辐射作出反应，并通过合成一种具有自由基清除特性的植物色素——类胡萝卜素，赋予生物体辐射耐受性。一种水熊虫特有的辐射诱导无序蛋白TRID1借助一种涉及相分离的机制促进DNA损伤修复。两种线粒体呼吸链复合体装配蛋白BCS1和NDUFB8积聚，加快烟酰胺腺嘌呤二核苷酸（NAD+）的再生，以推动多聚（腺苷二磷酸-核糖）（PARylation）以及后续的多聚（腺苷二磷酸-核糖）聚合酶1（PARP1）介导的DNA损伤修复。这三项发现拓宽了研究团队对于水熊虫辐射耐受性机制的认知。

4.Hematopoietic aging promotes cancer by fueling IL-1⍺–driven emergency myelopoiesis

造血衰老通过促进IL-1⍺驱动的紧急髓系造血促进癌症

美国免疫学与免疫治疗系，西奈山伊坎医学院

Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. In this study, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor–like cells in lung tumors. These cells are a major source of interleukin (IL)–1⍺, which drives the enhanced myeloid response. The age-associated decline of DNA methyltransferase 3A enhances IL-1⍺ production, and disrupting IL-1 receptor 1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺–expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.

年龄是癌症的一项主要风险因素，然而衰老对肿瘤控制产生的影响尚不明确。在此，研究团队明确了无论基质与肿瘤的年龄状况如何，免疫系统的衰老皆会推动肺癌的发展进程。造血功能的衰老会强化应急性髓系造血，致使肺肿瘤局部大量聚集髓系祖细胞样细胞。这些细胞是IL-1α的主要来源，驱动髓系反应增强。与年龄相关的DNA甲基转移酶3A的降低会增进IL-1α的生成，在肿瘤发育的早期阶段阻断IL-1受体1信号能够使造血功能恢复正常，并减缓肺、结肠和胰腺肿瘤的生长。在人类肿瘤中，研究团队发现IL-1α表达的单核细胞来源的巨噬细胞的富集与年龄、较差的生存率以及复发存在关联，揭示了衰老促进癌症的方式，并提供了可行的治疗策略。

5.A human gut Faecalibacterium prausnitzii fatty acid amide hydrolase

类肠道普拉梭菌脂肪酸酰胺水解酶

美国华盛顿大学医学院爱迪生家族基因组科学和系统生物学中心

Undernutrition in Bangladeshi children is associated with disruption of postnatal gut microbiota assembly; compared with standard therapy, a microbiota-directed complementary food (MDCF) substantially improved their ponderal and linear growth. Here, we characterize a fatty acid amide hydrolase (FAAH) from a growth-associated intestinal strain of Faecalibacterium prausnitzii cultured from these children. This enzyme, expressed and purified from Escherichia coli, hydrolyzes a variety of N-acylamides, including oleoylethanolamide (OEA), neurotransmitters, and quorum sensing N-acyl homoserine lactones; it also synthesizes a range of N-acylamides, notably N-acyl amino acids. Treating germ-free mice with N-oleoylarginine and N-oleolyhistidine, major products of FAAH OEA metabolism, markedly affected expression of intestinal immune function pathways. Administering MDCF to Bangladeshi children considerably reduced fecal OEA, a satiety factor whose levels were negatively correlated with abundance and expression of their F. prausnitzii FAAH. This enzyme, structurally and catalytically distinct from mammalian FAAH, is positioned to regulate levels of a variety of bioactive molecules.

孟加拉国儿童的营养不良状况与产后肠道微生物群的失调存在关联；相较于标准疗法，基于微生物群的补充食品（MDCF）显著促进了儿童的体重和线性生长。在此，研究团队对从这些儿童体内分离培养出的与生长相关的类肠道普拉梭菌（Faecalibacterium prausnitzii）肠道菌株所产生的脂肪酸酰胺水解酶（FAAH）予以表征。该酶在大肠杆菌中表达并纯化，能够水解多种酰胺，涵盖油酰乙醇胺（OEA）、神经递质以及群体感应酰基同型半胱氨酸；同时还能合成多种酰胺，尤其是酰基氨基酸。使用由大肠杆菌酰基转移酶合成的N-酰基赖氨酸和N-酰基组氨酸（OEA代谢的主要产物）对无菌小鼠进行治疗，显著影响了肠道免疫功能途径的表达。为孟加拉国儿童提供MDCF显著降低了粪便中的OEA水平，OEA作为一种饱腹感因子，其水平与他们体内类肠道普拉梭菌FAAH的丰度和表达呈负相关。这种酶在结构和催化方面与哺乳动物的FAAH不同，具备调节多种生物活性分子水平的潜力。

6. A ubiquitous mobile genetic element changes the antagonistic weaponry of a human gut symbiont

一个无处不在的移动遗传元件改变了人类肠道共生菌的对抗性武器

美国芝加哥大学微生物系

DNA transfer is ubiquitous in the human gut microbiota, especially among species of the order Bacteroidales. In silico analyses have revealed hundreds of mobile genetic elements shared between these species, yet little is known about the phenotypes they encode, their effects on fitness, or pleiotropic consequences for the recipient’s genome. In this work, we show that acquisition of a ubiquitous integrative conjugative element (ICE) encoding a type VI secretion system (T6SS) shuts down the native T6SS of Bacteroides fragilis. Despite inactivating this T6SS, ICE acquisition increases the fitness of the B. fragilis transconjugant over its progenitor by arming it with the new T6SS. DNA transfer causes the strain to change allegiances so that it no longer targets ecosystem members with the same element yet is armed for communal defense.

DNA转移在人类肠道微生物群落中广泛存在，尤其在拟杆菌属（Bacteroidales）中。通过计算机模拟分析，研究人员揭示了这些物种间共享的数百个移动遗传元件，然而，对于它们所编码的表型、对适应性产生的影响以及对受体基因组的多效性后果，人们却知之甚少。在本次工作中，研究团队获取了一种普遍存在的编码一种Ⅵ型分泌系统（T6SS）的整合共轭接合元件（ICE），致使脆弱拟杆菌（Bacteroides fragilis）的天然T6SS关闭。尽管让T6SS失去活性，但ICE的获取使脆弱拟杆菌转导子的适应性高于其亲本，原因是为转导子配备了新的T6SS。DNA转移促使菌株改变归属倾向，使其不再针对生态系统中的相同成员，而是为集体防御做好了准备。

Volume 386|Issue 6721|1 Nov 2024

在2024年11月01日，《Science》共发表文章36篇：1篇EDITORIAL；9篇NEWS；12篇INSIGHTS，其中1篇EXPERT VOICES、4篇PERSPECTIVES、1篇POLICY FORUM、2本BOOK、4篇LETTERS；15篇RESEARCH；1篇CAREERS。

1.Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior

2型先天淋巴样细胞促进抑制性突触发育和社会行为

加州大学旧金山分校霍华德·休斯医学研究所、精神病学与行为科学系

The innate immune system shapes brain development and is implicated in neurodevelopmental diseases. It is critical to define the relevant immune cells and signals and their impact on brain circuits. In this work, we found that group 2 innate lymphoid cells (ILC2s) and their cytokine interleukin-13 (IL-13) signaled directly to inhibitory interneurons to increase inhibitory synapse density in the developing mouse brain. ILC2s expanded and produced IL-13 in the developing brain meninges. Loss of ILC2s or IL-13 signaling to interneurons decreased inhibitory, but not excitatory, cortical synapses. Conversely, ILC2s and IL-13 were sufficient to increase inhibitory synapses. Loss of this signaling pathway led to selective impairments in social interaction. These data define a type 2 neuroimmune circuit in early life that shapes inhibitory synapse development and behavior.

固有免疫系统对大脑发育具有塑造作用，且与神经发育性疾病存在关联。明确与脑回路相关的免疫细胞和信号，并洞悉其对大脑的影响，这一点至关重要。在此，研究团队发现2型固有淋巴细胞（ILC2s）及其细胞因子白细胞介素-13（IL-13）直接作用于抑制性中间神经元，从而增加发育中小鼠大脑内抑制性突触的密度。ILC2s在发育中的脑膜中扩增并生成IL-13。ILC2s或IL-13向中间神经元的信号缺失会减少抑制性皮层突触，而不会减少兴奋性皮层突触。反之，ILC2s和IL-13足以增加抑制性突触。该信号通路的缺失会致使社交互动能力出现选择性损伤。这些数据定义了一种在生命早期塑造抑制性突触发育和行为的2型神经免疫回路。

2.Exploring structural diversity across the protein universe with The Encyclopedia of Domains

使用域百科全书探索蛋白质宇宙中的结构多样性

伦敦大学学院结构与分子生物学研究所

The AlphaFold Protein Structure Database (AFDB) contains more than 214 million predicted protein structures composed of domains, which are independently folding units found in multiple structural and functional contexts. Identifying domains can enable many functional and evolutionary analyses but has remained challenging because of the sheer scale of the data. Using deep learning methods, we have detected and classified every domain in the AFDB, producing The Encyclopedia of Domains. We detected nearly 365 million domains, over 100 million more than can be found by sequence methods, covering more than 1 million taxa. Reassuringly, 77% of the nonredundant domains are similar to known superfamilies, greatly expanding representation of their domain space. We uncovered more than 10,000 new structural interactions between superfamilies and thousands of new folds across the fold space continuum.

AlphaFold折叠蛋白质结构数据库（AFDB）涵盖了超过2.14亿个预测的蛋白质结构，这些结构由在多种结构和功能背景下独立折叠的域所构成。对域的识别能够推动众多功能和演化分析，然而由于数据规模庞大，此过程充满挑战。研究团队运用深度学习方法，对AFDB中的每个域予以检测和分类，从而构建了域百科全书。他们总计检测到近3.65亿个域，比通过序列方法发现的数量多出1亿有余，涵盖了超过100万个分类群。令人欣喜的是，77%的非冗余域与已知超家族类似，极大地拓展了其域空间的表征。研究人员还发现了超过1万个超家族之间的新结构相互作用，以及在折叠空间连续体中的数千种新折叠形态。

3.Brain malformations and seizures by impaired chaperonin function of TRiC

由于TRiC分子伴侣功能受损导致的大脑畸形和癫痫

美国圣路易斯华盛顿大学医学院儿科系、斯坦福大学生物系、德国亚琛工业大学医院人类遗传学与基因组医学研究所

Malformations of the brain are common and vary in severity, from negligible to potentially fatal. Their causes have not been fully elucidated. Here, we report pathogenic variants in the core protein-folding machinery TRiC/CCT in individuals with brain malformations, intellectual disability, and seizures. The chaperonin TRiC is an obligate hetero-oligomer, and we identify variants in seven of its eight subunits, all of which impair function or assembly through different mechanisms. Transcriptome and proteome analyses of patient-derived fibroblasts demonstrate the various consequences of TRiC impairment. The results reveal an unexpected and potentially widespread role for protein folding in the development of the central nervous system and define a disease spectrum of “TRiCopathies”.

脑部畸形是一种常见的畸形，其严重程度各异，从微不足道到危及生命，其成因尚未完全阐释。在此，研究团队报告了在患有脑部畸形、智力障碍以及癫痫的个体中所发现的致病变异，这些变异存在于核心蛋白质折叠机制TRiC/CCT之中。TRiC属于一种必需的异源寡聚体，研究团队发现其八个亚基中的七个均存在变异，这些变异通过不同的机制对其功能或组装产生影响。对源自患者的成纤维细胞的转录组和蛋白质组进行分析表明，TRiC功能受损会引发各种后果。这些结果揭示了蛋白质折叠在中枢神经系统发育中未曾预料且可能广泛存在的作用，并定义了一种名为“TRiCopathies”的疾病谱。

4.Transcriptome-wide splicing network reveals specialized regulatory functions of the core spliceosome

全转录组剪接网络揭示核心剪接体的专门调节功能

西班牙庞培法布拉大学（UPF）、巴塞罗那科学技术研究院

The spliceosome is the complex molecular machinery that sequentially assembles on eukaryotic messenger RNA precursors to remove introns (pre-mRNA splicing), a physiologically regulated process altered in numerous pathologies. We report transcriptome-wide analyses upon systematic knock down of 305 spliceosome components and regulators in human cancer cells and the reconstruction of functional splicing factor networks that govern different classes of alternative splicing decisions. The results disentangle intricate circuits of splicing factor cross-regulation, reveal that the precise architecture of late-assembling U4/U6.U5 tri–small nuclear ribonucleoprotein (snRNP) complexes regulates splice site pairing, and discover an unprecedented division of labor among protein components of U1 snRNP for regulating exon definition and alternative 5′ splice site selection. Thus, we provide a resource to explore physiological and pathological mechanisms of splicing regulation.

剪接体是在真核信使RNA前体上依次进行组装，以实现内含子的移除（预mRNA剪接）的复杂分子机器，这一生理调控的过程在诸多病理过程中发生了变化。研究团队报告了对人类癌细胞中305个剪接体成分和调节因子予以系统性敲低后的转录组全方位分析，并重新构建了掌控不同类型选择性剪接决策的功能性剪接因子网络。这些成果揭示了剪接因子交叉调节的繁杂电路，阐明了晚期组装的U4/U6.U5三小核糖核蛋白（snRNP）复合物的精准结构对剪接位点配对的调节机制，还发现了U1snRNP蛋白成分在调节外显子定义和非标准5'剪接位点选择方面前所未有的分工情况。故而，研究团队提供了一种用以探索剪接调节的生理和病理机制的资源。

5.Two codependent routes lead to high-level MRSA

两条相互依赖的途径导致高水平的MRSA

英国谢菲尔德大学数学与物理科学学院、生物科学学院

Methicillin-resistant Staphylococcus aureus (MRSA), in which acquisition of mecA [which encodes the cell wall peptidoglycan biosynthesis component penicillin-binding protein 2a (PBP2a)] confers resistance to β-lactam antibiotics, is of major clinical concern. We show that, in the presence of antibiotics, MRSA adopts an alternative mode of cell division and shows an altered peptidoglycan architecture at the division septum. PBP2a can replace the transpeptidase activity of the endogenous and essential PBP2 but not that of PBP1, which is responsible for the distinctive native septal peptidoglycan architecture. Successful division without PBP1 activity requires the alternative division mode and is enabled by several possible chromosomal potentiator (pot) mutations. MRSA resensitizing agents differentially interfere with the two codependent mechanisms required for high-level antibiotic resistance, which provides opportunities for new interventions.

耐甲氧西林金黄色葡萄球菌(MRSA)是一种引起临床重点关注的细菌，其获得mecA基因(编码细胞壁肽聚糖合成成分青霉素结合蛋白2a(PBP2a)后对β-内酰胺类抗生素产生耐药性。研究团队发现，在抗生素存在的情况下，MRSA采用一种替代的细胞分裂模式，并在分裂缝隙处展现出不同的肽聚糖结构。PBP2a可以替代内源性且必需的PBP2的转肽酶活性，但不能替代PBP1的活性，后者负责独特的天然缝隙肽聚糖结构。在没有PBP1活性的情况下成功分裂需要采用替代的分裂模式，这可以通过几种可能的染色体增强因子(pot)突变实现。MRSA抗药性恢复剂通过干扰两种相互依赖的机制来降低其高水平抗药性，这为开发新的干预措施提供了机会。

Volume 386|Issue 6722|8 Nov 2024

在2024年11月8日，《Science》共发表文章40篇：1篇EDITORIAL；8篇NEWS；11篇INSIGHTS，其中1篇EXPERT VOICES、4篇PERSPECTIVES、1篇POLICY FORUM、2本BOOK、3篇LETTERS；3篇ESSAYS；15篇RESEARCH，其中1篇REVIEWS、14篇RESEARCH ARTICLES；1篇CAREERS。

1.Continuous evolution of user-defined genes at 1 million times the genomic mutation rate

以基因组突变率的100万倍速率持续演化用户定义的基因

美国加利福尼亚大学欧文分校分子生物学与生物化学系

When nature evolves a gene over eons at scale, it produces a diversity of homologous sequences with patterns of conservation and change that contain rich structural, functional, and historical information about the gene. However, natural gene diversity accumulates slowly and likely excludes large regions of functional sequence space, limiting the information that is encoded and extractable. We introduce upgraded orthogonal DNA replication (OrthoRep) systems that radically accelerate the evolution of chosen genes under selection in yeast. When applied to a maladapted biosynthetic enzyme, we obtained collections of extensively diverged sequences with patterns that revealed structural and environmental constraints shaping the enzyme’s activity. Our upgraded OrthoRep systems should support the discovery of factors influencing gene evolution, uncover previously unknown regions of fitness landscapes, and find broad applications in biomolecular engineering.

自然界历经数十亿年的大规模进化出一个基因时，会生成一系列具有保守与变化模式的同源序列，这些序列蕴含着有关该基因丰富的结构、功能及历史信息。然而，自然基因的多样性积累缓慢，很可能排除了功能序列空间的绝大部分区域，从而限制了可编码和可提取的信息含量。研究团队引入了改良的正交DNA复制（OrthoRep）系统，它能够在酵母中加快选择基因的进化进程。当研究团队把该系统应用于一种不适应的生物合成酶时，研究团队获取了一系列差异显著的序列，这些序列揭示了塑造酶活性的结构和环境制约因素。研究团队的改良型OrthoRep系统应当有助于发现影响基因进化的因素，揭示此前未知的适应度景观区域，并在生物分子工程中获得广泛应用。

2.Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis

逆转录转座子被重新利用以激活造血干细胞和红细胞生成

德国埃森大学医院皮肤科 & 德国癌症联盟，埃森，& 国家肿瘤疾病中心联合德克萨斯大学西南医学中心儿童医学研究所和儿科系

Hematopoietic stem cells (HSCs) and erythropoiesis are activated during pregnancy and after bleeding by the derepression of retrotransposons, including endogenous retroviruses and long interspersed nuclear elements. Retrotransposon transcription activates the innate immune sensors cyclic guanosine 3′,5′-monophosphate–adenosine 5′-monophosphate synthase (cGAS) and stimulator of interferon (IFN) genes (STING), which induce IFN and IFN-regulated genes in HSCs, increasing HSC division and erythropoiesis. Inhibition of reverse transcriptase or deficiency for cGAS or STING had little or no effect on hematopoiesis in nonpregnant mice but depleted HSCs and erythroid progenitors in pregnant mice, reducing red blood cell counts. Retrotransposons and IFN-regulated genes were also induced in mouse HSCs after serial bleeding and, in human HSCs, during pregnancy. Reverse transcriptase inhibitor use was associated with anemia in pregnant but not in nonpregnant people, suggesting conservation of these mechanisms from mice to humans.

在妊娠期间及出血后，造血干细胞（HSCs）和红细胞生成被激活，这归因于内源性逆转录病毒和长散布核元件等逆转录转座子的去抑制作用。逆转录转座子的转录激活了固有免疫感受器环鸟苷3′,5′-单磷酸-腺苷5′-单磷酸合成酶（cGAS）和干扰素刺激基因（STING），从而在HSCs中诱导出干扰素和干扰素调节基因，促进HSC的分裂以及红细胞的生成。在非妊娠小鼠中，逆转录酶的抑制或cGAS或STING的缺失对造血功能影响甚微，但在妊娠小鼠中却会耗尽HSCs和红系祖细胞，致使红细胞计数降低。在连续出血的小鼠和人类HSCs中，同样发现了逆转录转座子和干扰素调节基因的诱导现象。怀孕期间使用逆转录酶抑制剂与贫血相关，但在非妊娠人群中则无此关联，这表明这些机制在人类和小鼠之间具有保守性。

3.The interhemispheric amygdala-accumbens circuit encodes negative valence in mice

杏仁核至对侧脑半球伏隔核神经环路编码负性情绪效价

复旦大学基础医学院，医学神经生物学国家重点实验室

The structurally symmetric mammalian brain hemispheres are interconnected by commissural axons across the midline. However, the functions of interhemispheric connectivity remain largely unknown. We found that in mice, transection of the anterior commissure (AC), which connects the rostroventral forebrain, impaired avoidant behaviors. The basolateral amygdala (BLA) in the mouse projects to the contralateral nucleus accumbens (NAc) through the AC, independent of its ipsilateral projections. Aversive stimuli activated contralateral BLA-NAc projections. Positive stimuli, however, activated ipsilateral projections. Selective activation of contralateral BLA-NAc projections activated D2-positive medium spiny neurons (D2-MSNs), reduced NAc dopamine levels, and caused aversion, whereas selective activation of ipsilateral BLA-NAc projections activated D1-MSNs, increased NAc dopamine levels, and induced reward. The contralateral BLA-AC-NAc pathway is crucial for encoding negative valence, demonstrating distinct functions of intra- and interhemispheric circuits in brain physiology.

结构对称的哺乳动物脑半球借助中线处的连合纤维实现相互连接。然而，跨半球连接的功能在很大程度上仍然未知。研究团队发现，切断连接前额叶皮质（rostroventral forebrain）的前连合（anterior commissure，AC）会对小鼠模型的回避行为造成损害。小鼠的基底外侧杏仁核（basolateral amygdala，BLA）经由AC向对侧的伏隔核（nucleus accumbens，NAc）进行投射，此投射与向同侧的投射并无关联。厌恶性刺激会激活对侧BLA-NAc投射，而积极性刺激则会激活同侧投射。选择性激活对侧BLA-NAc投射会激活D2型中间神经元（D2-MSNs），降低NAc多巴胺水平，并引发厌恶；选择性激活同侧BLA-NAc投射会激活D1型中间神经元（D1-MSNs），提高NAc多巴胺水平，并产生奖励。对侧BLA-AC-NAc通路对于负性情绪价值的编码极为关键，这展现了大脑生理学中内侧和外侧脑回路存在的不同功能。

4.COVID-19 pandemic interventions reshaped the global dispersal of seasonal influenza viruses

COVID-19大流行干预措施重塑了季节性流感病毒的全球传播

复旦大学附属华山医院传染病科联合牛津大学流行病科学研究所

The global dynamics of seasonal influenza viruses inform the design of surveillance, intervention, and vaccination strategies. The COVID-19 pandemic provided a singular opportunity to evaluate how influenza circulation worldwide was perturbed by human behavioral changes. We combine molecular, epidemiological, and international travel data and find that the pandemic’s onset led to a shift in the intensity and structure of international influenza lineage movement. During the pandemic, South Asia played an important role as a phylogenetic trunk location of influenza A viruses, whereas West Asia maintained the circulation of influenza B/Victoria. We explore drivers of influenza lineage dynamics across the pandemic period and reasons for the possible extinction of the B/Yamagata lineage. After a period of 3 years, the intensity of among-region influenza lineage movements returned to pre-pandemic levels, with the exception of B/Yamagata, after the recovery of global air traffic, highlighting the robustness of global lineage dispersal patterns to substantial perturbation.

全球季节性流感病毒的动态情况为监测、干预及疫苗接种策略的规划提供了参考依据。COVID-19大流行提供了一个难得的契机，能够对全球流感传播受人类行为变化的影响方式进行评估。研究团队整合了分子、流行病学以及国际旅行方面的数据，发现大流行的出现致使国际流感谱系流动的强度和结构发生了转变。在大流行期间，南亚作为流感A病毒的谱系核心区域发挥了重要作用，而西亚维持着流感B/Victoria的传播。研究团队探究了整个大流行时期流感谱系动态的驱动因素以及B/Yamagata谱系可能灭绝的缘由。在全球航空交通恢复三年之后，除B/Yamagata外，各区域之间流感谱系流动的强度回归至大流行之前的水平，这凸显了全球谱系扩散模式对于重大干扰的强大适应性。

5.Hepatic vagal afferents convey clock-dependent signals to regulate circadian food intake

肝脏迷走神经传入纤维传递时钟依赖信号以调节昼夜节律食物摄入

美国宾夕法尼亚大学佩雷尔曼医学院医学部内分泌学、糖尿病和代谢学分部

Circadian desynchrony induced by shiftwork or jet lag is detrimental to metabolic health, but how synchronous or desynchronous signals are transmitted among tissues is unknown. We report that liver molecular clock dysfunction is signaled to the brain through the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a homeostatic feedback signal that relies on communication between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a potential therapeutic target for obesity in the setting of chronodisruption.

由轮班工作或时差所引发的昼夜节律失调对代谢健康具有不利影响，然而不同组织间如何传递同步或不同步信号仍未明晰。研究团队的研究表明，肝脏分子钟功能障碍通过肝脏迷走传入神经（HVAN）向大脑传递信号，从而导致进食模式发生改变，而切除HVAN能够对这种改变予以纠正。肝脏分支迷走神经切断术还能够预防高脂肪饮食喂养所引发的进食紊乱，并降低体重增加量。研究团队的研究成果揭示了一种依赖肝脏与大脑之间通信的内稳态反馈信号，用于控制昼夜节律性的进食模式。这表明肝脏迷走神经是因时差紊乱所致肥胖症的一个潜在治疗靶点。

6.C-LTMRs evoke wet dog shakes via the spinoparabrachial pathway

LTMRs通过脊髓旁脑桥路径引发甩水行为

美国哈佛医学院霍华德·休斯医学研究所神经生物学系

Many hairy mammals perform rapid oscillations of their body, called wet dog shakes, to remove water and irritants from their back hairy skin. The somatosensory mechanisms that underlie this behavior are unclear. We report that Piezo2-dependent mechanosensation mediates wet dog shakes evoked by water or oil droplets applied to back hairy skin of mice. Unmyelinated C-fiber low-threshold mechanoreceptors (C-LTMRs) were activated by oil droplets, and their optogenetic activation elicited wet dog shakes. Ablation of C-LTMRs attenuated this behavior. Moreover, C-LTMRs synaptically couple to spinoparabrachial neurons, and optogenetically inhibiting spinoparabrachial neuron synapses and excitatory neurons in the parabrachial nucleus impaired both oil droplet– and C-LTMR–evoked wet dog shakes. Thus, a C-LTMR–spinoparabrachial pathway promotes wet dog shakes for removal of water and mechanical irritants from back hairy skin.

许多多毛哺乳动物会进行快速的身体摆动，这种行为被称为甩水行为，以去除背部毛皮上的水分和刺激物。这种行为背后的体感机制尚不清楚。研究人员报告称，依赖Piezo2的机械感受介导了由水滴或油滴施加到小鼠背部毛皮而引发的甩水行为。无髓鞘的C型低阈值机械感受器（C-LTMRs）会被油滴激活，其光遗传学激活引发甩水行为。去除C-LTMRs会减弱这种行为。此外，C-LTMRs与脊髓旁臂核神经元在突触上耦合，光遗传学抑制脊髓旁臂核神经元突触和旁臂核内的兴奋性神经元会削弱由油滴和C-LTMR引发的甩水行为。因此，C-LTMR-脊髓旁臂核通路促进了甩水行为，以去除背部毛皮上的水分和机械刺激物。

Volume 386|Issue 6723|15 Nov 2024

在2024年11月15日，《Science》共发表文章41篇：2篇EDITORIAL；8篇NEWS；11篇INSIGHTS，其中1篇EXPERT VOICES、4篇PERSPECTIVES、1篇POLICY FORUM、2本BOOK、3篇LETTERS；4篇ESSAYS；16篇RESEARCH，其中1篇REVIEWS、15篇RESEARCH ARTICLES；1篇CAREERS。

1.Sequence modeling and design from molecular to genome scale with Evo

从分子到基因组尺度的序列建模和设计

美国加利福尼亚大学伯克利分校生物工程系和计算生物学中心联合斯坦福大学化学工程系

The genome is a sequence that encodes the DNA, RNA, and proteins that orchestrate an organism’s function. We present Evo, a long-context genomic foundation model with a frontier architecture trained on millions of prokaryotic and phage genomes, and report scaling laws on DNA to complement observations in language and vision. Evo generalizes across DNA, RNA, and proteins, enabling zero-shot function prediction competitive with domain-specific language models and the generation of functional CRISPR-Cas and transposon systems, representing the first examples of protein-RNA and protein-DNA codesign with a language model. Evo also learns how small mutations affect whole-organism fitness and generates megabase-scale sequences with plausible genomic architecture. These prediction and generation capabilities span molecular to genomic scales of complexity, advancing our understanding and control of biology.

基因组是对DNA、RNA及蛋白质进行编码的序列，而这些蛋白质负责对生物体的功能予以协调。研究团队提出了一种采用前瞻性架构、经过训练的长期上下文基因组基础模型——Evo，基于数百万种原核生物和噬菌体的基因组构建，并且报告了DNA的尺度定律，以此对语言和视觉方面的观察成果予以补充。Evo能够跨越DNA、RNA和蛋白质进行泛化，使其在零样本功能预测方面与特定领域的语言模型具有竞争力，还能够生成具备功能性的CRISPR-Cas和转座子系统，这是语言模型与蛋白质-RNA以及蛋白质-DNA协同设计的首例。Evo还学习了小突变如何对整个生物体的适应性产生影响，并生成了具有合理基因组架构的数百万碱基对序列。这些预测和生成能力涵盖了从分子到基因组复杂度的不同尺度，进而推进了研究团队对于生物学的理解和掌控。

2. Ribozyme-activated mRNA trans-ligation enables large gene delivery to treat muscular dystrophies

核糖酶激活的mRNA转连接实现大基因传递以治疗肌营养不良症

美国罗切斯特大学医学院和牙科学院Aab心血管研究所

Ribozymes are small catalytic RNA sequences capable of nucleotide-specific self-cleavage found widespread in nature. Ribozyme cleavage generates distinct 2′,3′-phosphate and 5′-hydroxyl termini that resemble substrates for recently characterized RNA repair pathways in cells. We report that ribozyme cleavage of two separate mRNAs activated their scarless trans-ligation and translation into full-length protein in eukaryotic cells, a process that we named StitchR (for Stitch RNA). Optimization of StitchR activity in mammalian cells resulted in a ~900-fold increase in protein expression that approached levels observed for genes expressed from single vectors. We demonstrate that StitchR can be harnessed for effective dual adeno-associated virus gene therapies to correct muscular dystrophies by restoring large functional muscle proteins to endogenous levels in vivo.

核酶是在自然界中广泛存在的小型催化RNA序列，具备特异性自我切割的能力。核酶的切割会产生类似于细胞中近期所描述的RNA修复途径底物的2'，3'-磷酸基和5'－羟基末端。研究团队发现，在真核细胞中，两个独立的mRNA的核酶切割激活了无疤痕的跨连接和翻译过程，从而生成完整的蛋白质，这一过程命名为StitchR（即Stitch RNA）。在哺乳动物细胞中对StitchR活性的优化，能够使蛋白质表达水平提高约900倍，接近由单个载体表达的基因所达到的水平。研究团队证实，StitchR可应用于有效的双重腺相关病毒基因疗法，通过在体内将大功能肌肉蛋白质恢复至内源水平，进而纠正肌营养不良症。

3.Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states

分离产生抗焦虑行为状态的迷幻反应神经

美国加州大学戴维斯分校医学院神经学系

Psychedelics hold promise as alternate treatments for neuropsychiatric disorders. However, the neural mechanisms by which they drive adaptive behavioral effects remain unclear. We isolated the specific neurons modulated by a psychedelic to determine their role in driving behavior. Using a light- and calcium-dependent activity integrator, we genetically tagged psychedelic-responsive neurons in the medial prefrontal cortex (mPFC) of mice. Single-nucleus RNA sequencing revealed that the psychedelic drove network-level activation of multiple cell types beyond just those expressing 5-hydroxytryptamine 2A receptors. We labeled psychedelic-responsive mPFC neurons with an excitatory channelrhodopsin to enable their targeted manipulation. We found that reactivation of these cells recapitulated the anxiolytic effects of the psychedelic without driving its hallucinogenic-like effects. These findings reveal essential insight into the cell-type–specific mechanisms underlying psychedelic-induced behavioral states.

迷幻药物作为治疗神经精神疾病的替代性疗法颇具潜力。然而，其驱动适应性行为效应的神经机制仍不明晰。研究团队确定了特定的神经元，以探究其在驱动行为方面所起的作用。研究团队运用一种光敏性和钙离子依赖的活动整合器，在小鼠的前额叶皮层（mPFC）中对迷幻药物敏感的神经元进行了遗传标记。单细胞RNA测序表明，迷幻药物激活了超出仅表达5-羟色胺2A受体的多种细胞类型所构成的网络。研究团队使用一种兴奋性通道视蛋白对迷幻药物敏感的mPFC神经元进行染色，以便对其实施有针对性的操控。研究团队发现，激活这些细胞重现了迷幻药物的镇静效果，且未引发类似致幻剂的效果。这些发现为迷幻药诱导行为状态的细胞类型特异性机制提供了重要的见解。

汇报人：王欣怡

导师：赵宇、任建君

审核：李向东、任建君

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