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【Science】2025年02月07日-03月21日期刊论文导读
期刊介绍：
《Science》（科学杂志）是一份由美国科学促进会（American Association for the Advancement of Science，简称AAAS）出版的著名科学杂志。该杂志创建于1880年，是全球最具影响力和知名度的跨学科科学期刊之一。该杂志以发表高质量、原创性的科学研究论文和评论而闻名，涵盖了各个科学领域，包括生命科学、物理学、化学、地球与环境科学、工程技术等。它是科学领域内同行评议制度的支持者，通过评审和编辑确保所发表的研究具有学术水平和可靠性。除了研究论文外，该杂志还经常刊发关于科学前沿、科学政策、科学教育和科学社会问题的评论文章。《Science》还定期发布一些专题特刊，深入探讨特定主题或领域的最新进展。因其在科学界的声望和影响力，《Science》成为科学家们追求学术卓越和科学创新的重要平台之一。最新影响因子为44.7。
VOLUME 387 | ISSUE 6734 | 7 FEB 2025
在2025年2月7日，《Science》共发表文章33篇：
7篇NEWS
10篇INSIGHTS
16篇RESEARCH
1.Nutrient-driven histone code determines exhausted CD8+ T cell fates
营养驱动的组蛋白编码决定了耗尽的CD8+ T细胞的命运
第一单位：美国加利福尼亚州拉霍亚市索尔克生物研究所诺米斯免疫生物学与微生物病原学中心
Abstract
Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by down-regulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.
在癌症和慢性病毒感染中，耗竭T细胞（TEX）会经历代谢与表观遗传重塑，削弱其保护能力。然而，营养物质代谢对调控TEX分化的表观遗传修饰的影响尚不明确。该研究表明，TEX细胞通过下调乙酰辅酶A合成酶2（ACSS2）同时维持ATP柠檬酸裂解酶（ACLY）活性，实现了从乙酸盐代谢向柠檬酸盐代谢的转变。这种代谢转换通过KAT2A-ACLY介导的组蛋白乙酰化作用，增加了TEX特征基因的柠檬酸盐依赖性组蛋白乙酰化；同时通过p300-ACSS2复合物依赖机制，降低了效应T细胞和记忆T细胞基因的乙酸盐依赖性组蛋白乙酰化。过表达核内ACSS2或抑制ACLY可阻止TEX分化并增强肿瘤特异性T细胞应答。这些发现揭示了营养物质指导的组蛋白密码对CD8+ T细胞分化的调控机制，为基于代谢和表观遗传的T细胞疗法提供了新思路。
通过ACLY和ACSS2实现的不同营养利用驱动位点特异性组蛋白乙酰化和CD8T细胞命运决定
TEFF和TEX细胞通过ACSS2和ACLY选择性利用醋酸盐和葡萄糖（上）。ACSS2与组蛋白乙酰转移酶（HAT）p300合作，而ACLY与HAT KAT2A相互作用，驱动位点特异性组蛋白乙酰化和T细胞分化（底部）。
2.Sequence-dependent activity and compartmentalization of foreign DNA in a eukaryotic nucleus
真核生物细胞核中外源DNA的序列依赖活性和区段化
第一单位：巴黎城市大学巴斯德研究所，法国科学院，法国巴黎
Abstract
In eukaryotes, DNA-associated protein complexes coevolve with genomic sequences to orchestrate chromatin folding. We investigate the relationship between DNA sequence and the spontaneous loading and activity of chromatin components in the absence of coevolution. Using bacterial genomes integrated into Saccharomyces cerevisiae, which diverged from yeast more than 2 billion years ago, we show that nucleosomes, cohesins, and associated transcriptional machinery can lead to the formation of two different chromatin archetypes, one transcribed and the other silent, independently of heterochromatin formation. These two archetypes also form on eukaryotic exogenous sequences, depend on sequence composition, and can be predicted using neural networks trained on the native genome. They do not mix in the nucleus, leading to a bipartite nuclear compartmentalization, reminiscent of the organization of vertebrate nuclei.
在真核生物中，DNA结合蛋白复合物与基因组序列协同进化，共同调控染色质折叠。研究者研究了在缺乏协同进化的条件下，DNA序列与染色质成分自发装载及活性之间的关系。通过将20多亿年前与酵母分化的细菌基因组整合至酿酒酵母中，研究者发现核小体、黏连蛋白及相关转录机器能独立于异染色质形成过程，引导产生两种不同的染色质原型：一种处于转录活跃状态，另一种则保持沉默。这两种原型同样能在真核外源序列上形成，其形成取决于序列组成，且可通过基于酵母自身基因组训练的神经网络进行预测。这两种染色质原型在细胞核内互不混合，导致核内形成二分区室化结构，该现象与脊椎动物细胞核的组织模式具有相似性。
酵母细胞核中外源染色体的不同命运
细菌或真核生物具有类似于酵母序列的GC含量的染色体（紫色）被积极地转录并与宿主染色体混合。相比之下，GC较低的外来染色体（蓝色）在细胞核内形成了一个独特的、转录沉默的球状隔间。这种分离需要活跃的转录，但独立于典型的异染色质形成。
3.Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants
基于肾脏多组学的遗传评分卡揭示了趋同的编码和调控变异
第一单位：美国宾夕法尼亚州费城宾夕法尼亚大学医学部肾电解质与高血压科。
Abstract
Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. In this study, we conducted a multiancestry genome-wide association study in 2.2 million individuals and identified 1026 (97 previously unknown) independent loci. Ancestry-specific analysis indicated an attenuation of newly identified signals on common variants in European ancestry populations and the power of population diversity for further discoveries. We defined genotype effects on allele-specific gene expression and regulatory circuitries in more than 700 human kidneys and 237,000 cells. We found 1363 coding variants disrupting 782 genes, with 601 genes also targeted by regulatory variants and convergence in 161 genes. Integrating 32 types of genetic information, we present the “Kidney Disease Genetic Scorecard” for prioritizing potentially causal genes, cell types, and druggable targets for kidney disease.
肾功能障碍是导致死亡的主要原因，但其遗传学机制尚未明晰。该研究通过对220万个体开展多祖先全基因组关联分析，鉴定出1026个独立基因座（其中97个为新发现的）。祖先特异性分析显示，欧洲血统人群中新发现的常见变异信号有所减弱，证实了群体多样性对进一步发现的推动作用。研究者系统分析了700多例人类肾脏样本和23.7万单细胞中基因型对等位基因特异性表达及调控网络的影响，发现1363个编码变异可破坏782个基因功能，其中601个基因同时受调控变异影响，并且有161个基因呈现双重作用机制。通过整合32类遗传学信息，研究者构建了"肾脏疾病遗传评分卡"，为优先筛选肾脏疾病的潜在致病基因、关键细胞类型及可成药靶点提供了系统工具。
肾脏疾病遗传记分卡揭示了肾功能的遗传结构和假定的靶基因
研究者在220万个体中进行了多祖先GWAS，鉴定了1026个（97个以前未知的）独立位点。结合32种类型的遗传信息，研究者提出了肾脏疾病遗传记分卡，用于优先排序潜在的致病基因、细胞类型和肾脏疾病的药物靶标。ASA，等位基因特异性可及性；ASE，等位基因特异性表达；bASA，基于转座酶可及染色质（ATAC）的等位基因特异性可及性；snASA，单核ATAC等位基因特异性染色质可及性；共定位；CDS，编码序列；ExWAS，外显子组全关联研究；PheWAS，全现象关联研究。
4.The essential genome of Plasmodium knowlesi reveals determinants of antimalarial susceptibility
诺氏疟原虫的基本基因组揭示了抗疟药物易感性的决定因素
第一单位：美国马萨诸塞州波士顿，哈佛大学陈曾熙公共卫生学院免疫及传染病学系
Abstract
Measures to combat the parasites that cause malaria have become compromised because of reliance on a small arsenal of drugs and emerging drug resistance. We conducted a transposon mutagenesis screen in the primate malaria parasite Plasmodium knowlesi, producing the most complete classification of gene essentiality in any Plasmodium spp. to date, with the resolution to define truncatable genes. We found conservation in the druggable genome between Plasmodium spp. and divergences in mitochondrial metabolism. Perturbation analyses with the frontline antimalarial artemisinin revealed modulators that both increase and decrease drug susceptibility. Our findings aid prioritization of drug and vaccine targets for the Plasmodium vivax clade and reveal mechanisms of resistance that can inform therapeutic development.
当前，由于过度依赖有限的药物库及日益严重的耐药性问题，针对疟原虫的防治措施正面临严峻挑战。研究者在灵长类疟原虫（诺氏疟原虫）中进行了转座子突变筛查，建立了迄今最完整的疟原虫基因必要性分类系统，其分辨率足以精确定义可截短基因。研究发现，不同疟原虫属间在可成药基因组上存在保守性，但线粒体代谢途径呈现显著差异。通过使用一线抗疟药物青蒿素进行扰动分析，研究者鉴定出既可增强也可降低药物敏感性的调控因子。这些发现不仅为间日疟原虫分支的药物与疫苗靶点优选提供了依据，同时揭示了耐药机制，这将为新疗法开发提供重要参考。
诺氏疟原虫的高分辨率转座子突变筛选揭示了抗疟药物的发现，并揭示了耐药性决定因素
5.Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes
肾上腺髓质素诱导的内皮细胞胰岛素抵抗介导了与肥胖相关的糖尿病
第一单位：德国巴特瑙海姆药学系马克斯·普朗克心肺研究所
Abstract
Insulin resistance is a hallmark of obesity-associated type 2 diabetes. Insulin’s actions go beyond metabolic cells and also involve blood vessels, where insulin increases capillary blood flow and delivery of insulin and nutrients. We show that adrenomedullin, whose plasma levels are increased in obese humans and mice, inhibited insulin signaling in human endothelial cells through protein-tyrosine phosphatase 1B–mediated dephosphorylation of the insulin receptor. In obese mice lacking the endothelial adrenomedullin receptor, insulin-induced endothelial nitric oxide–synthase activation and skeletal muscle perfusion were increased. Treating mice with adrenomedullin mimicked the effect of obesity and induced endothelial and systemic insulin resistance. Endothelial loss or blockade of the adrenomedullin receptor improved obesity-induced insulin resistance. These findings identify a mechanism underlying obesity-induced systemic insulin resistance and suggest approaches to treat obesity-associated type 2 diabetes.
胰岛素抵抗是肥胖相关2型糖尿病的典型特征。胰岛素的作用不仅限于代谢细胞，还涉及血管系统——它能增强毛细血管血流并促进胰岛素和营养物质的输送。该研究发现，肾上腺髓质素在肥胖人群和小鼠体内水平升高，可通过蛋白酪氨酸磷酸酶1B介导的胰岛素受体去磷酸化抑制人内皮细胞的胰岛素信号传导。在缺乏内皮细胞肾上腺髓质素受体的肥胖小鼠中，胰岛素诱导的内皮型一氧化氮合酶活化和骨骼肌血流灌注显著增强。使用肾上腺髓质素处理小鼠可模拟肥胖效应，并诱发内皮及全身性胰岛素抵抗。而敲除或阻断内皮细胞肾上腺髓质素受体则可改善肥胖诱导的胰岛素抵抗。这些发现揭示了肥胖引发全身性胰岛素抵抗的分子机制，为治疗肥胖相关2型糖尿病提供了新策略。
6.Overwriting an instinct: Visual cortex instructs learning to suppress fear responses
克服一种本能：视觉皮层指导学习抑制恐惧反应
第一单位：英国伦敦大学学院塞恩斯伯里惠康中心
Abstract
Fast instinctive responses to environmental stimuli can be crucial for survival but are not always optimal. Animals can adapt their behavior and suppress instinctive reactions, but the neural pathways mediating such ethologically relevant forms of learning remain unclear. We found that posterolateral higher visual areas (plHVAs) are crucial for learning to suppress escapes from innate visual threats through a top-down pathway to the ventrolateral geniculate nucleus (vLGN). plHVAs are no longer necessary after learning; instead, the learned behavior relies on plasticity within vLGN populations that exert inhibitory control over escape responses. vLGN neurons receiving input from plHVAs enhance their responses to visual threat stimuli during learning through endocannabinoid-mediated long-term suppression of their inhibitory inputs. We thus reveal the detailed circuit, cellular, and synaptic mechanisms underlying experience-dependent suppression of fear responses.
对环境刺激的快速本能反应对生存至关重要，但这些反应并非总是最优选择。动物能够通过行为适应来抑制本能反应，然而介导此类生态学相关学习行为的神经通路尚不明确。该研究发现，后外侧高级视觉区（plHVAs）通过一条自上而下的通路作用于腹外侧膝状体（vLGN），对学习抑制视觉威胁引发的本能逃跑行为起关键作用。学习完成后plHVAs便不再必要，取而代之的是vLGN群体内可塑性变化——这些神经元通过施加对逃跑反应的抑制性控制来维持习得行为。机制研究表明，接受plHVAs输入的vLGN神经元在学习过程中通过内源性大麻素介导的长时程抑制其抑制性输入，从而增强对视觉威胁刺激的反应。这项研究首次完整揭示了经验依赖性恐惧反应抑制所涉及的神经环路、细胞及突触机制。
VOLUME 387 | ISSUE 6735 | 14 FEB 2025
在2025年2月14日，《Science》共发表文章37篇：
1篇EDITORIAL
7篇NEWS
11篇INSIGHTS
18篇RESEARCH ARTICLES
1.KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection
在急性LCMV感染期间，KLF2维持谱系保真度并抑制CD8T细胞衰竭
第一单位：耶鲁大学医学院免疫生物学系，美国康涅狄格州纽黑文
Abstract
Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9–based perturbation sequencing to assess the role of ~40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.
幼稚CD8 T细胞在免疫应答过程中有潜力分化为多种功能状态，但其分化决策机制及抑制其他分化路径的调控方式仍不清楚。研究者采用基于CRISPR-Cas9的体内扰动测序技术，系统评估了约40个转录因子和表观遗传调控因子在T细胞命运决策中的作用。出乎意料的是，研究发现转录因子Klf2的敲除会导致急性感染期间CD8T细胞异常分化为类耗竭状态。KLF2通过双重机制发挥作用：一方面抑制促耗竭转录因子TOX的表达，另一方面确保转录因子TBET驱动效应T细胞分化。此外，KLF2对维持具有多功能的肿瘤特异性前体细胞状态也至关重要。这些发现表明，KLF2通过维持效应CD8T细胞谱系保真性和抑制耗竭程序，在T细胞分化调控中发挥核心作用。
KLF2可防止急性LCMV感染中CD8 T细胞的异常分化
幼稚CD8 T细胞在急性LCMV感染中发生功能效应分化。这种效应物的分化涉及到klf2依赖的TBET活性。在这种情况下，KLF2 KO导致CD8 T细胞异常分化为TOX+耗尽样状态。这一特征是与慢性感染中CD8 T细胞的标志性特征相似的表观遗传学和转录特征，并导致细胞溶解潜能和记忆回忆能力的降低。
2.Conformational ensembles reveal the origins of serine protease catalysis
构象系综揭示了丝氨酸蛋白酶催化的起源
第一单位：美国加州斯坦福大学生物化学系
Abstract
Enzymes exist in ensembles of states that encode the energetics underlying their catalysis. Conformational ensembles built from 1231 structures of 17 serine proteases revealed atomic-level changes across their reaction states. By comparing the enzymatic and solution reaction, we identified molecular features that provide catalysis and quantified their energetic contributions to catalysis. Serine proteases precisely position their reactants in destabilized conformers, creating a downhill energetic gradient that selectively favors the motions required for reaction while limiting off-pathway conformational states. The same catalytic features have repeatedly evolved in proteases and additional enzymes across multiple distinct structural folds. Our ensemble-function analyses revealed previously unknown catalytic features, provided quantitative models based on simple physical and chemical principles, and identified motifs recurrent in nature that may inspire enzyme design.
酶以动态构象集合体形式存在，其不同状态编码了催化过程的能量特征。基于17种丝氨酸蛋白酶的1231个结构构建的构象集合体，揭示了这些酶在反应过程中原子水平的结构变化。通过比较酶促反应与溶液反应，研究者鉴定出具有催化功能的分子特征，并量化了它们对催化的能量贡献。研究发现，丝氨酸蛋白酶通过将反应物精确定位于去稳定化构象中，形成下坡式能量梯度——这种机制选择性促进反应所需的构象变化，同时限制非反应路径的构象状态。这些催化特征在蛋白酶及其他酶类中多次独立进化出现，跨越多种不同的结构折叠类型。研究者的"构象集合体-功能"分析不仅发现了此前未知的催化特征，建立了基于简单物理化学原理的定量模型，更鉴定出自然界中反复出现的功能模体，这些发现将为酶设计提供重要启示。
集成功能方法为丝氨酸蛋白酶提供了一个定量的催化模型，并确定了反复进化的催化策略
（上图）集成函数方法的四个步骤。（左下）丝氨酸蛋白酶上的反应物相对于溶液中的反应物位置很高，距离更短，简化了反应路径，增加了反应概率。（右下）来自多个结构折叠的酶使用这里确定的催化策略。
3.RNA polymerase II at histone genes predicts outcome in human cancer
组蛋白基因上的RNA聚合酶II可以预测人类癌症的结果
第一单位：美国华盛顿州西雅图基础科学部弗雷德哈钦森癌症中心
Abstract
Genome-wide hypertranscription is common in human cancer and predicts poor prognosis. To understand how hypertranscription might drive cancer, we applied our formalin-fixed paraffin-embedded (FFPE)–cleavage under targeted accessible chromatin method for mapping RNA polymerase II (RNAPII) genome-wide in FFPE sections. We demonstrate global RNAPII elevations in mouse gliomas and assorted human tumors in small clinical samples and discover regional elevations corresponding to de novo HER2 amplifications punctuated by likely selective sweeps. RNAPII occupancy at S-phase-dependent histone genes correlated with WHO grade in meningiomas, accurately predicted rapid recurrence, and corresponded to whole-arm chromosome losses. Elevated RNAPII at histone genes in meningiomas and diverse breast cancers is consistent with histone production being rate-limiting for S-phase progression and histone gene hypertranscription driving overproliferation and aneuploidy in cancer, with general implications for precision oncology.
全基因组超转录现象在人类癌症中普遍存在，且与不良预后相关。为解析超转录驱动肿瘤的机制，研究者开发了基于福尔马林固定石蜡包埋（FFPE）样本的“靶向开放染色质切割”技术，实现了FFPE切片中RNA聚合酶II（RNAPII）的全基因组定位。研究发现：在小鼠胶质瘤和多种人类肿瘤小样本中均存在RNAPII全局性升高；与新生HER2基因扩增相关的局部区域的RNAPII富集，且可能伴随选择性清除现象。特别值得注意的是，脑膜瘤中S期依赖性组蛋白基因的RNAPII占据水平与WHO分级呈正相关，能准确预测肿瘤的快速复发情况，并与染色体整臂缺失显著相关。在脑膜瘤和多种乳腺癌中，组蛋白基因的RNAPII异常升高表明：组蛋白生成可能是S期进程的限速步骤，而组蛋白基因超转录通过驱动细胞过度增殖和非整倍体形成促进肿瘤发展——这一发现对精准肿瘤学具有广泛意义。
4.Thalamic opioids from POMC satiety neurons switch on sugar appetite
来自POMC饱腹神经元的丘脑阿片类药物开启了关于糖的食欲
第一单位：耶鲁大学
Abstract
High sugar–containing foods are readily consumed, even after meals and beyond fullness sensation (e.g., as desserts). Although reward-driven processing of palatable foods can promote overeating, the neurobiological mechanisms that underlie the selective appetite for sugar in states of satiety remain unclear. Hypothalamic pro-opiomelanocortin (POMC) neurons are principal regulators of satiety because they decrease food intake through excitatory melanocortin neuropeptides. We discovered that POMC neurons not only promote satiety in fed conditions but concomitantly switch on sugar appetite, which drives overconsumption. POMC neuron projections to the paraventricular thalamus selectively inhibited postsynaptic neurons through mu-opioid receptor signaling. This opioid circuit was strongly activated during sugar consumption, which was most notable in satiety states. Correspondingly, inhibiting its activity diminished high-sugar diet intake in sated mice.
高糖食物往往在饱餐后仍被持续食用（如餐后甜点），甚至超出饱腹感阈限。虽然美味食物的奖赏效应可促进过度进食，但饱食状态下对糖分选择性食欲的神经生物学机制尚不明确。下丘脑前阿黑皮素原（POMC）神经元作为饱食信号的主要调控者，通常通过释放兴奋性黑皮质素神经肽来抑制进食。该研究发现，POMC神经元在进食状态下不仅维持饱食信号，同时会激活糖分食欲驱动过食行为——该神经元通过μ-阿片受体信号通路，选择性抑制室旁丘脑突触后神经元活动。这条阿片能神经环路在糖分摄入时（尤其是饱食状态下）呈现显著激活，相应地在饱食小鼠中抑制该环路活动可有效减少高糖饮食摄入。
VOLUME 387 | ISSUE 6736 | 21 FEB 2025
在2025年2月21日，《Science》共发表文章35篇：
7篇NEWS
11篇INSIGHTS
17篇RESEARCH ARTICLES
1.Disease diagnostics using machine learning of B cell and T cell receptor sequences
使用机器学习的B细胞和T细胞受体序列进行疾病诊断
第一单位：美国加州斯坦福大学病理学系
Abstract
Clinical diagnosis typically incorporates physical examination, patient history, various laboratory tests, and imaging studies but makes limited use of the human immune system’s own record of antigen exposures encoded by receptors on B cells and T cells. We analyzed immune receptor datasets from 593 individuals to develop MAchine Learning for Immunological Diagnosis, an interpretive framework to screen for multiple illnesses simultaneously or precisely test for one condition. This approach detects specific infections, autoimmune disorders, vaccine responses, and disease severity differences. Human-interpretable features of the model recapitulate known immune responses to severe acute respiratory syndrome coronavirus 2, influenza, and human immunodeficiency virus, highlight antigen-specific receptors, and reveal distinct characteristics of systemic lupus erythematosus and type-1 diabetes autoreactivity. This analysis framework has broad potential for scientific and clinical interpretation of immune responses.
现有临床诊断主要依赖体格检查、病史采集、实验室检测和影像学检查，却很少利用B细胞和T细胞受体所编码的抗原暴露信息——这些信息记录了免疫系统自身的"病原接触史"。研究者分析了593名个体的免疫受体数据集，开发出"机器学习免疫诊断系统"（MAchine Learning for Immunological Diagnosis，MAID），该框架既能同时筛查多种疾病，也可针对单一病症进行精准检测。该系统可识别特定感染、自身免疫疾病、疫苗反应及疾病严重程度差异。模型的可解释特征不仅重现了机体对SARS-CoV-2、流感病毒和HIV的已知免疫应答模式，突出显示抗原特异性受体，并揭示了系统性红斑狼疮与1型糖尿病自身免疫反应的独特特征。这一分析框架为免疫应答的科学解析与临床应用提供了广阔前景。
2.A neural basis for prosocial behavior toward unresponsive individuals
一种对无反应个体的亲社会行为的神经基础
第一单位：美国加州大学洛杉矶分校David Geffen医学院神经生物系
Abstract
Humans often take actions to assist others experiencing unresponsiveness, such as transient loss of consciousness. How other animals react to unresponsive conspecifics—and the neural mechanisms driving such behaviors—remain largely unexplored. In this study, we demonstrated that mice exhibit rescue-like social behaviors toward unresponsive conspecifics, characterized by intense physical contact and grooming directed at the recipient’s facial and mouth areas, which expedite their recovery from unresponsiveness. We identified the medial amygdala (MeA) as a key region that encodes the unresponsive state of others and drives this head-directed physical contact. Notably, the behavioral responses toward unresponsive conspecifics differed from those directed at awake, stressed individuals, and these responses were differentially represented in the MeA. These findings shed light on the neural mechanisms underlying prosocial responses toward unresponsive individuals.
人类常会对意识丧失（如短暂昏厥）的同类实施救助行为，但其他动物对无意识同类的反应及其神经机制仍属未知。该研究发现，小鼠会对无意识同类表现出类救援行为——包括针对对方面部和口部的强烈身体接触及理毛行为，这些行为能加速其意识恢复。研究证实内侧杏仁核（MeA）是编码同类无意识状态并驱动此类头部定向接触的关键脑区。值得注意的是，小鼠对无意识同类的行为反应与对清醒应激个体的反应存在显著差异，且这两种行为在MeA中呈现不同的神经表征。这些发现揭示了动物对无意识个体产生亲社会反应的神经机制。
对无反应的同种动物的亲社会行为。
小鼠可以检测到其他个体的无反应状态，并表现出类似救援的行为，其特征是针对受者头部区域的强烈身体接触，这有助于从无反应中恢复。内侧杏仁核（MeA）的神经活动编码其他杏仁的无反应状态，并调节随后的亲社会行为。对无反应的同种个体表现出的行为与针对有压力的个体的行为不同，这些相互作用在MeA中有不同的表现。
3.Antiviral signaling of a type III CRISPR-associated deaminase
一种III型CRISPR相关脱氨酶的抗病毒信号传导
第一单位：中国药科大学药学院药学系
Abstract
Prokaryotes have evolved diverse defense strategies against viral infection, including foreign nucleic acid degradation by CRISPR-Cas systems and DNA and RNA synthesis inhibition through nucleotide pool depletion. Here, we report an antiviral mechanism of type III CRISPR-Cas–regulated adenosine triphosphate (ATP) depletion in which ATP is converted into inosine triphosphate (ITP) by CRISPR-Cas–associated adenosine deaminase (CAAD) upon activation by either cA4 or cA6, followed by hydrolysis into inosine monophosphate (IMP) by Nudix hydrolase, ultimately resulting in cell growth arrest. The cryo–electron microscopy structures of CAAD in its apo and activated forms, together with biochemical evidence, revealed how cA4 or cA6 binds to the CRISPR-associated Rossmann fold (CARF) domain and abrogates CAAD autoinhibition, inducing substantial conformational changes that reshape the structure of CAAD and induce its deaminase activity. Our results reveal the mechanism of a CRISPR-Cas–regulated ATP depletion antiviral strategy.
原核生物进化出多种抗病毒防御策略，包括CRISPR-Cas系统的外源核酸降解机制，以及通过耗竭核苷酸库来抑制DNA/RNA合成的策略。该研究报道了一种由III型CRISPR-Cas调控的ATP耗竭抗病毒机制：当cA4或cA6激活时，CRISPR-Cas关联腺苷脱氨酶（CAAD）将ATP转化为肌苷三磷酸（ITP），随后通过Nudix水解酶水解为肌苷单磷酸（IMP），最终导致细胞生长停滞。通过冷冻电镜解析的CAAD非激活态与激活态结构，结合生化证据揭示：cA4/cA6结合至CRISPR关联Rossmann折叠域（CARF）后，可解除CAAD的自抑制状态，诱导其发生显著构象变化从而重塑结构并激活脱氨酶活性。该研究阐明了一种CRISPR-Cas调控的ATP耗竭抗病毒作用机制。
III型CRISPR-CAAD-NH系统介导的抗病毒防御模型
在病毒感染后，由激活的III型CRISPR-Cas产生的cA4或cA6与CARF结构域结合，激活CAAD的脱氨酶活性，将ATP转化为ITP。ATP消耗和ITP积累导致细胞生长阻滞和病毒繁殖抑制。共存的Nudix水解酶（NUDIX）可以将ITP水解成IMP，从而缓解生长阻滞。
4.Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease
神经元FAM171A2介导α-突触核蛋白纤维的摄取并驱动帕金森病
第一单位：上海，复旦大学上海医学院，华山医院神经内科，国家神经疾病中心，医学神经生物学国家重点实验室，脑科学教育部前沿研究中心
Abstract
Neuronal accumulation and spread of pathological α-synuclein (α-syn) fibrils are key events in Parkinson's disease (PD) pathophysiology. However, the neuronal mechanisms underlying the uptake of α-syn fibrils remain unclear. In this work, we identified FAM171A2 as a PD risk gene that affects α-syn aggregation. Overexpressing FAM171A2 promotes α-syn fibril endocytosis and exacerbates the spread and neurotoxicity of α-syn pathology. Neuronal-specific knockdown of FAM171A2 expression shows protective effects. Mechanistically, the FAM171A2 extracellular domain 1 interacts with the α-syn C terminus through electrostatic forces, with >1000 times more selective for fibrils. Furthermore, we identified bemcentinib as an effective blocker of FAM171A2–α-syn fibril interaction with an in vitro binding assay, in cellular models, and in mice. Our findings identified FAM171A2 as a potential receptor for the neuronal uptake of α-syn fibrils and, thus, as a therapeutic target against PD.
病理性α-突触核蛋白（α-syn）纤维在神经元内的积聚与扩散是帕金森病（PD）病理生理学的关键事件，然而α-syn纤维被神经元摄取的分子机制尚不明确。该研究发现，FAM171A2作为影响α-syn聚集的PD风险基因，其过表达会促进α-syn纤维的内吞作用，加剧α-syn病理的扩散和神经毒性；而神经元特异性敲低FAM171A2则表现出保护效应。机制上，FAM171A2胞外结构域1通过静电力与α-syn C端相互作用，且对纤维形式的选择性高于单体1000倍以上。进一步通过体外结合实验、细胞模型和小鼠实验，研究者鉴定出Bemcentinib可作为FAM171A2–α-syn纤维相互作用的有效抑制剂。该研究确立FAM171A2是神经元摄取α-syn纤维的潜在受体，因而可作为PD治疗的靶点。
VOLUME 387 | ISSUE 6737 | 28 FEB 2025
在2025年2月28日，《Science》共发表文章38篇：
9篇NEWS
11篇INSIGHTS
18篇RESEARCH ARTICLES
1.CASTER: Direct species tree inference from whole-genome alignments
CASTER: 从全基因组比对中直接推断物种树
第一单位：加州大学圣地亚哥分校电气与计算机工程系
Abstract
Genomes contain mosaics of discordant evolutionary histories, challenging the accurate inference of the tree of life. Although genome-wide data are routinely used for discordance-aware phylogenomic analyses, because of modeling and scalability limitations, the current practice leaves out large chunks of genomes. As more high-quality genomes become available, we urgently need discordance-aware methods to infer the tree directly from a multiple genome alignment. In this study, we introduce Coalescence-Aware Alignment-Based Species Tree Estimator (CASTER), a theoretically justified site-based method that eliminates the need to predefine recombination-free loci. CASTER is scalable to hundreds of mammalian whole genomes. We demonstrate the accuracy and scalability of CASTER in simulations that include recombination and apply CASTER to several biological datasets, showing that its per-site scores can reveal both biological and artifactual patterns of discordance across the genome.
基因组包含着相互冲突的进化历史的马赛克式拼图，这对准确推断生命树提出了挑战。尽管目前常规使用全基因组数据进行"冲突感知"的系统发育分析，但由于建模和可扩展性的限制，现有方法往往会遗漏基因组中的大量区域。随着越来越多高质量基因组的出现，研究者迫切需要能够直接从多基因组比对中推断系统发育树的"冲突感知"方法。在该研究中，研究者引入了"基于比对的合并感知物种树估计器"(CASTER)，这是一种理论完备的位点分析方法，无需预先定义无重组位点。CASTER可扩展至数百个哺乳动物全基因组规模。研究者通过包含重组的模拟实验证明了CASTER的准确性和可扩展性，并将其应用于多个生物数据集，结果显示其位点特异性评分能够揭示全基因组范围内生物学真实的和人为造成的冲突模式。
CASTER概述
CASTER为输入比对中的每个位点针对任意四个物种（四联体）的任何树拓扑分配一个分数。选择在整个输入和所有四联体中得分最高的树拓扑。通过位点间的CASTER分数滑动窗口可以揭示位点特异性的不和谐信号。CASTER具有可扩展性和准确性。
2.Liver ALKBH5 regulates glucose and lipid homeostasis independently through GCGR and mTORC1 signaling
肝脏ALKBH5通过GCGR和mTORC1信号通路独立调节葡萄糖和脂质稳态
第一单位：哈尔滨工业大学郑州研究所，生命科学与技术学院生命科学中心，空间环境物质行为国家重点实验室，空间环境与物质相互作用前沿科学中心
Abstract
Maintaining glucose and lipid homeostasis is crucial for health, with dysregulation leading to metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction–associated fatty liver disease (MAFLD). This study identifies alkylation repair homolog protein 5 (ALKBH5), an RNA N6-methyladenosine (m6A) demethylase, as a major regulator in metabolic disease. ALKBH5 is up-regulated in the liver during obesity and also phosphorylated by protein kinase A, causing its translocation to the cytosol. Hepatocyte-specific deletion of Alkbh5 reduces glucose and lipids by inhibiting the glucagon receptor (GCGR) and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. Targeted knockdown of hepatic Alkbh5 reverses T2DM and MAFLD in diabetic mice, highlighting its therapeutic potential. This study unveils a regulatory mechanism wherein ALKBH5 orchestrates glucose and lipid homeostasis by integrating the GCGR and mTORC1 pathways, providing insight into the regulation of metabolic diseases.
维持血糖和血脂稳态对健康至关重要，其失调会导致代谢性疾病，如2型糖尿病（T2DM）和代谢功能障碍相关脂肪性肝病（MAFLD）。该研究发现：烷基化修复同源蛋白5（ALKBH5），一种RNA N6-甲基腺苷（m6A）去甲基化酶，是代谢性疾病的主要调节因子。在肥胖期间，ALKBH5在肝脏中上调，并被蛋白激酶A磷酸化，导致其转移到细胞质中。特异性敲除肝细胞中的Alkbh5基因可通过抑制胰高血糖素受体（GCGR）和哺乳动物雷帕霉素靶蛋白复合体1（mTORC1）信号通路，降低血糖和血脂水平。靶向敲低肝脏中Alkbh5基因可逆转糖尿病小鼠的T2DM和MAFLD，突显了其治疗潜力。该研究揭示了一种调控机制，即ALKBH5通过调节GCGR和mTORC1通路来协调血糖和血脂稳态，为代谢性疾病的调控机制提供了见解。
肝脏ALKBH5调节糖、脂稳态
ALKBH5通过GCGR信号通路调节葡萄糖稳态，这一过程依赖于其去甲基化酶活性和Ser362磷酸化。相比之下，它通过EGFR-mTORC1信号通路调节脂质稳态，而独立于其两个结构环的去甲基化酶活性。肝细胞特异性Alkbh5缺失通过不同的机制独立抑制GCGR和EGFR-mTORC1信号通路，改善肥胖患者的糖耐量，减轻肥胖中的MAFLD。
3.4D marmoset brain map reveals MRI and molecular signatures for onset of multiple sclerosis–like lesions
4D绒猴脑图显示了多发性硬化症样病变发作的MRI和分子特征
第一单位：美国马里兰州贝塞斯达国立卫生研究院国家神经疾病和中风研究所（NINDS）转化神经放射科
Abstract
Inferring cellular and molecular dynamics of multiple sclerosis (MS) lesions from postmortem tissue collected decades after onset is challenging. Using magnetic resonance image (MRI)–guided spatiotemporal RNA profiling in marmoset experimental autoimmune encephalitis (EAE), we mapped lesion dynamics and modeled molecular perturbations relevant to MS. Five distinct lesion microenvironments emerged, involving neuroglial responses, tissue destruction and repair, and brain border regulation. Before demyelination, MRI identified a high ratio of proton density–weighted signal to T1 relaxation time, capturing early hypercellularity, and elevated astrocytic and ependymal senescence signals marked perivascular and periventricular areas that later became demyelination hotspots. As lesions expanded, concentric glial barriers formed, initially dominated by proliferating and diversifying microglia and oligodendrocyte precursors, later replaced by monocytes and lymphocytes. We highlight SERPINE1+ astrocytes as a signaling hub underlying lesion onset in both marmoset EAE and MS.
从发病数十年后获取的尸检组织推断多发性硬化症（MS）病灶的细胞与分子动态具有挑战性。研究者通过狨猴实验性自身免疫性脑炎（EAE）模型的磁共振成像（MRI）引导时空转录组分析，绘制了与MS相关的病灶动态图谱并构建分子扰动模型。研究揭示了五种特征鲜明的病灶微环境，涉及神经胶质反应、组织破坏与修复、以及脑边界调控等过程。在脱髓鞘发生前，MRI检测到质子密度加权信号与T1弛豫时间的高比值，这一特征可捕捉早期细胞增殖；同时升高的星形胶质细胞和室管膜细胞衰老信号，标记了后期成为脱髓鞘热点区域的血管周围和脑室周围区域。随着病灶扩展，会形成同心圆状的胶质屏障——初期以增殖和多样化的微胶质细胞与少突胶质前体细胞为主，后期则被单核细胞和淋巴细胞取代。研究者鉴定出SERPINE1+星形胶质细胞作为狨猴EAE和MS病灶形成的共同信号枢纽。
血管周围区和脑室周围区细胞与微环境的动态变化
多发性硬化样病变在中央静脉和脑室附近形成并扩展，这些区域富含SASP标志物。分子和MRI生物标志物可时空定义病变分期。随着病变发展，EAE相关细胞（星形胶质细胞EAE、少突胶质细胞EAE、少突胶质前体细胞EAE、小胶质细胞EAE、室管膜细胞EAE和血管内皮细胞EAE）、增殖性细胞（增殖期白细胞、增殖期小胶质细胞和增殖期少突胶质前体细胞）以及髓鞘修复细胞（分化期少突胶质前体细胞）在不同病变区域占主导地位，其中SERPINE1阳性星形胶质细胞EAE在微环境转变过程中作为病变边缘的信号枢纽。缩写说明：Cyc：增殖期；CSF：脑脊液；DC：树突状细胞。
VOLUME 387 | ISSUE 6738 | 7 MAR 2025
在2025年3月7日，《Science》共发表文章39篇：
9篇NEWS
11篇INSIGHTS
19篇RESEARCH ARTICLES
Neonatal fungi promote lifelong metabolic health through macrophage-dependent β cell development
新生儿真菌通过巨噬细胞依赖性β细胞的发育促进终身代谢健康
第一单位：美国犹他州盐湖城犹他大学微生物与免疫学学系病理学系
Abstract
Loss of early-life microbial diversity is correlated with diabetes, yet mechanisms by which microbes influence disease remain elusive. We report a critical neonatal window in mice when microbiota disruption results in lifelong metabolic consequences stemming from reduced β cell development. We show evidence for the existence of a similar program in humans and identify specific fungi and bacteria that are sufficient for β cell growth. The microbiota also plays an important role in seeding islet-resident macrophages, and macrophage depletion during development reduces β cells. Candida dubliniensis increases β cells in a macrophage-dependent manner through distinctive cell wall composition and reduces murine diabetes incidence. Provision of C. dubliniensis after β cell ablation or antibiotic treatment improves β cell function. These data identify fungi as critical early-life commensals that promote long-term metabolic health.
婴儿期微生物多样性的丧失与糖尿病的发生有关，然而微生物影响疾病的具体机制仍然不明确。研究者在小鼠中报告了一个关键的新生儿窗口期，在此期间，微生物群落的破坏会导致终生的代谢后果，其根源在于胰岛β细胞发育减少。研究者提供了人类中存在类似机制的证据，并确定了特定的真菌和细菌，它们足以促进β细胞的生长。微生物群还对胰岛巨噬细胞的驻留发挥着重要作用，而在发育过程中耗竭巨噬细胞会导致β细胞减少。Candida dubliniensis（都柏林念珠菌）通过其独特的细胞壁组成，以巨噬细胞依赖性方式增加β细胞数量，并降低小鼠糖尿病的发病率。在β细胞消减或抗生素处理后补充都柏林念珠菌可以改善β细胞的功能。这些数据表明，真菌是促进长期代谢健康的关键婴儿期共生微生物。
都柏林念珠菌（C. dubliniensis）定植促进胰腺的产后发育
特定微生物可在断奶前的关键产后时期（出生后10-20天）促进小鼠β细胞增殖。这种真菌共生体通过巨噬细胞依赖性机制刺激β细胞团增长。该效应似乎是由都柏林念珠菌独特的细胞壁结构所激活——其甘露聚糖和几丁质含量均较低。这些生命早期的变化可带来长期的代谢健康效益。
A subcellular map of translational machinery composition and regulation at the single-molecule level
在单分子水平上的翻译机制组成和调控的亚细胞图谱
第一单位：美国加州斯坦福大学斯坦福医学院遗传学系
Abstract
Millions of ribosomes are packed within mammalian cells, yet we lack tools to visualize them in toto and characterize their subcellular composition. In this study, we present ribosome expansion microscopy (RiboExM) to visualize individual ribosomes and an optogenetic proximity-labeling technique (ALIBi) to probe their composition. We generated a super-resolution ribosomal map, revealing subcellular translational hotspots and enrichment of 60S subunits near polysomes at the endoplasmic reticulum (ER). We found that Lsg1 tethers 60S to the ER and regulates translation of select proteins. Additionally, we discovered ribosome heterogeneity at mitochondria guiding translation of metabolism-related transcripts. Lastly, we visualized ribosomes in neurons, revealing a dynamic switch between monosomes and polysomes in neuronal translation. Together, these approaches enable exploration of ribosomal localization and composition at unprecedented resolution.
哺乳动物细胞内紧密堆积着数百万个核糖体，但迄今仍缺乏工具来全面可视化和表征它们的亚细胞组成。该研究开发了核糖体膨胀显微技术（RiboExM）实现单核糖体可视化，并创建光遗传学邻近标记技术（ALIBi）用于分析其组成。通过构建超分辨率核糖体图谱，研究者发现了内质网（ER）附近多聚核糖体区存在60S亚基富集的翻译热点区，证实Lsg1蛋白可将60S亚基锚定于ER并调控特定蛋白翻译。此外，研究发现线粒体周边存在引导代谢相关mRNA翻译的异质性核糖体群。最后，研究者在神经元中观察到单核糖体与多聚核糖体在翻译过程中的动态转换。这些技术为在超高分辨率下探索核糖体定位与组成提供了全新工具。
两种互补的方法揭示了核糖体和mRNA翻译的亚细胞异质性
核糖体扩增显微镜（RiboExM）使核糖体群体、特化核糖体和相关mrna的各向同性单分子成像成为可能。avitag特异性位置限制照明增强生物素化（ALIBi）是一种光遗传控制技术，允许亚细胞核糖体群体的亲和纯化，用于多模态下游分析。在这里，研究者描述了使用这些技术来表征核糖体在亚细胞空间和神经元。
Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae
巨噬细胞过氧化物酶体引导肺泡再生，并限制SARS-CoV-2组织后遗症
第一单位：美国弗吉尼亚州夏洛茨维尔市弗吉尼亚大学贝妮·B·卡特免疫学研究中心
Abstract
Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8high dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.
过氧化物酶体是重要的代谢细胞器，但其作用常被忽视。该研究发现，过度的干扰素信号会重塑巨噬细胞中的过氧化物酶体，其功能缺失将损害严重呼吸道病毒感染期间的炎症消退和肺组织修复。过氧化物酶体以巨噬细胞类型特异性方式调节脂质代谢和线粒体功能，并能增强肺泡巨噬细胞介导的组织修复和病毒感染后的肺泡再生。此外，过氧化物酶体可抑制巨噬细胞炎症小体的过度激活及IL-1β的释放，从而减少病毒损伤后KRT8high表达型异常上皮祖细胞的积聚。在动物模型中，通过药物手段促进过氧化物酶体生物发生可同时缓解COVID-19的急性症状和急性后遗症（PASC）。这些发现表明，巨噬细胞过氧化物酶体功能障碍是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染后慢性肺部病变和纤维化的重要机制。
病毒损伤后巨噬细胞介导的肺泡再生中过氧化物酶体功能模型
肺泡巨噬细胞（AM）中的过氧化物酶体活性对于病毒感染后的AT2自我更新和肺泡修复至关重要。巨噬细胞过氧化物酶体功能障碍导致炎症小体过度激活，促进发育不良的KRT8移行细胞积累，导致急性感染后的慢性组织后遗症。4-PBA治疗促进巨噬细胞中过氧化物酶体的生物发生，以促进呼吸道病毒感染后的肺泡再生。
Macroevolutionary divergence of gene expression driven by selection on protein abundance
由蛋白质丰度选择驱动的基因表达的宏观进化差异
第一单位：加州洛杉矶美国南加州大学数量与计算生物系
Abstract
The regulation of messenger RNA (mRNA) and protein abundances is well-studied, but less is known about the evolutionary processes shaping their relationship. To address this, we derived a new phylogenetic model and applied it to multispecies mammalian data. Our analyses reveal (i) strong stabilizing selection on protein abundances over macroevolutionary time, (ii) mutations affecting mRNA abundances minimally impact protein abundances, (iii) mRNA abundances evolve under selection to align with protein abundances, and (iv) mRNA abundances adapt faster than protein abundances owing to greater mutational opportunity. These conclusions are supported by comparisons of model parameters with independent functional genomic data. By decomposing mutational and selective influences on mRNA-protein dynamics, our approach provides a framework for discovering the evolutionary rules that drive divergence in gene expression.
信使RNA（mRNA）和蛋白质丰度的调控已被广泛研究，但关于塑造它们之间关系的进化过程却知之甚少。为了解决这一问题，研究者提出了一个新的系统发育模型，并将其应用于多物种哺乳动物数据。研究者分析揭示了以下几点：（1）在宏观进化时间尺度上，蛋白质丰度受到强烈的稳定选择；（2）影响mRNA丰度的突变对蛋白质丰度的影响极小；（3）mRNA丰度在选择作用下进化，以与蛋白质丰度保持一致；（4）由于突变机会更多，mRNA丰度的适应速度比蛋白质丰度更快。这些结论得到了与独立的功能基因组学数据比较模型参数的支持。通过剖析突变和选择对mRNA-蛋白质动态的影响，研究者的方法为发现驱动基因表达差异的进化规律提供了一个框架。
VOLUME 387 | ISSUE 6739 | 14 MAR 2025
在2025年3月14日，《Science》共发表文章31篇：
9篇NEWS
9篇INSIGHTS
17篇RESEARCH ARTICLES
Tunneling nanotube–like structures regulate distant cellular interactions during heart formation
隧道纳米管样结构在心脏形成过程中调节远端细胞的相互作用
第一单位：休斯顿大学药学院药理学与药学，休斯顿，德克萨斯州，美国
Abstract
In the developing mammalian heart, the endocardium and the myocardium are separated by so-called cardiac jelly. Communication between the endocardium and the myocardium is essential for cardiac morphogenesis. How membrane-localized receptors and ligands achieve interaction across the cardiac jelly is not understood. Working in developing mouse cardiac morphogenesis models, we used a variety of cellular, imaging, and genetic approaches to elucidate this question. We found that myocardium and endocardium interacted directly through microstructures termed tunneling nanotube–like structures (TNTLs). TNTLs extended from cardiomyocytes (CMs) to contact endocardial cells (ECs) directly. TNTLs transported cytoplasmic proteins, transduced signals between CMs and ECs, and initiated myocardial growth toward the heart lumen to form ventricular trabeculae-like structures. Loss of TNTLs disturbed signaling interactions and, subsequently, ventricular patterning.
在发育中的哺乳动物心脏中，心内膜和心肌被所谓的心胶质分隔开。两者之间的信号交流对心脏形态发生至关重要。但膜定位受体与配体如何跨越心胶质实现互作尚不清楚。通过在发育中的小鼠心脏形态发生模型中工作，研究者使用了多种细胞、成像和遗传学方法来阐明这个问题。研究者发现心肌和心内膜通过称为隧道纳米管样结构（TNTLs）的微结构直接相互作用。TNTLs从心肌细胞（CMs）延伸出来，直接与心内膜细胞（ECs）接触。TNTLs运输细胞质蛋白，在CMs和ECs之间转导信号，并启动心肌向心腔生长，形成心室小梁样结构。TNTLs的缺失会干扰信号相互作用，进而影响心室模式形成异常。
微结构调节心肌细胞（CMs）和内皮细胞（ECs）之间的信号交互作用以及细胞质蛋白的转移
连接心肌细胞和内皮细胞的跨内皮连接丝（TNTLs）在心肌凝胶中起到桥梁作用，促进信号分子运输、细胞质蛋白转移以及肌球蛋白 X 的穿梭。运输囊泡和细胞质蛋白可以从心肌细胞转移到内皮细胞，但肌球蛋白 X 不能。跨内皮连接丝的破坏会影响 Notch1 信号激活以及心肌细胞和内皮细胞之间的其他几种信号交互作用，从而导致心肌小梁缺陷。NICD，Notch1 的细胞内结构域。
Direct sensing of dietary ω-6 linoleic acid through FABP5-mTORC1 signaling
通过FABP5-mTORC1信号通路直接感知饮食中ω-6亚油酸
第一单位：美国纽约威尔康奈尔医学桑德拉和爱德华迈耶癌症中心
Abstract
Diet influences macronutrient availability to cells, and although mechanisms of sensing dietary glucose and amino acids are well characterized, less is known about sensing lipids. We defined a nutrient signaling mechanism involving fatty acid–binding protein 5 (FABP5) and mechanistic target of rapamycin complex 1 (mTORC1) that is activated by the essential polyunsaturated fatty acid (PUFA) ω-6 linoleic acid (LA). FABP5 directly bound to the regulatory-associated protein of mTOR (Raptor) to enhance formation of functional mTORC1 and substrate binding, ultimately converging on increased mTOR signaling and proliferation. The amounts of FABP5 protein were increased in tumors and serum from triple-negative compared with those from receptor-positive breast cancer patients, which highlights its potential role as a biomarker that mediates cellular responses to ω-6 LA intake in this disease subtype.
饮食影响细胞对宏量营养素的可利用性，尽管感知饮食中葡萄糖和氨基酸的机制已被很好地描述，但对脂质的感知机制了解较少。研究者定义了一种涉及脂肪酸结合蛋白5（FABP5）和雷帕霉素靶蛋白复合体1（mTORC1）的营养信号机制，该机制可被必需多不饱和脂肪酸（PUFA）ω-6亚油酸（LA）激活。FABP5直接与mTOR的调节相关蛋白（Raptor）结合，增强功能性mTORC1的形成和底物结合，最终增加mTOR信号传导并促进细胞增殖。与受体阳性乳腺癌患者相比，三阴性乳腺癌患者的肿瘤和血清中FABP5蛋白的含量增加，这突显了其作为生物标志物的潜在作用，该生物标志物介导细胞对这种疾病亚型中ω-6亚油酸摄入的反应。
ω-6 LA促进了TNBC的增长
揭示了西方饮食中最丰富的多不饱和脂肪ω-6la激活细胞生长的主要调节因子mTORC1的机制。FABP5将这两种成分连接起来，形成一个营养信号轴，增强TNBC细胞的增殖，以响应膳食ω-6 LA的摄入。GβL，G蛋白亚基样；猛禽，mTOR的调节相关蛋白。
Identification of antigen-presenting cell–T cell interactions driving immune responses to food
识别驱动食物免疫应答的抗原呈递细胞-T细胞相互作用
第一单位：美国纽约洛克菲勒大学粘膜免疫学实验室
Abstract
The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Antigen-presenting cells (APCs) orchestrate these immune responses by presenting luminal antigens to CD4+ T cells and inducing their differentiation into regulatory (peripheral regulatory T cell) or inflammatory [T helper (Th) cell] subsets. We used a proximity labeling method (LIPSTIC) to identify APCs that presented dietary antigens under tolerizing and inflammatory conditions and to understand cellular mechanisms by which tolerance to food is induced and can be disrupted by infection. Helminth infections disrupted tolerance induction proportionally to the reduction in the ratio between tolerogenic APCs—including migratory dendritic cells (cDC1s) and Rorγt+ APCs—and inflammatory APCs, which were primarily cDC2s. These inflammatory cDC2s expanded by helminth infection did not present dietary antigens, thus avoiding diet-specific Th2 responses.
肠道免疫系统必须同时耐受食物与共生菌，并防御病原体侵袭。抗原呈递细胞（APCs）通过将管腔抗原呈递给CD4+ T细胞，诱导其分化为调节性（外周调节性T细胞）或炎症性[T辅助（Th）细胞]亚群，从而协调这些免疫应答。该研究采用邻近标记技术（LIPSTIC），在耐受状态和炎症状态下鉴定膳食抗原呈递APCs，并阐明食物耐受诱导及感染破坏该耐受的细胞机制。蠕虫感染会破坏耐受诱导，其破坏程度与耐受性APCs（包括迁移性树突细胞cDC1s和Rorγt+ APCs）和炎症性APCs（主要为cDC2s）的比例下降呈正相关。值得注意的是，蠕虫感染扩增的这些炎症性cDC2s并不呈递膳食抗原，从而避免了食物特异性Th2反应的发生。
不同抗原提呈细胞（APCs）对饮食来源抗原与病原体来源抗原的分隔呈递
抗原提呈细胞（APCs）指导 T 细胞分化为调节性（pTreg）和效应（Th）亚群。利用 LIPSTIC 技术，研究者发现，在稳态条件下，cDC1s 和 Rorγt+APCs 均呈递饮食来源抗原，从而诱导调节性 T 细胞（pTregs）的生成和口服耐受。委内瑞拉毛圆线虫感染消除了这些抗原提呈细胞对饮食来源抗原的呈递，损害了口服耐受。促炎性蠕虫诱导 Th2 反应的 cDC2s 不呈递饮食来源抗原，从而避免了食物特异性 Th2 反应。
VOLUME 387 | ISSUE 6740 | 21 MAR 2025
在2025年3月21日，《Science》共发表文章37篇：
8篇NEWS
11篇INSIGHTS
18篇RESEARCH ARTICLES
Regulatory T cells constrain T cells of shared specificity to enforce tolerance during infection
调节性T细胞通过限制共享特异性T细胞维持感染期间的免疫耐受
第一单位：美国伊利诺斯州芝加哥大学病理科
Abstract
During infections, CD4+ Foxp3+ regulatory T (Treg) cells must control autoreactive CD4+ conventional T (Tconv) cell responses against self-peptide antigens while permitting those against pathogen-derived “nonself” peptides. We defined the basis of this selectivity using mice in which Treg cells reactive to a single prostate-specific self-peptide were selectively depleted. We found that self-peptide–specific Treg cells were dispensable for the control of Tconv cells of matched specificity at homeostasis. However, they were required to control such Tconv cells and prevent autoimmunity toward the prostate after exposure to elevated self-peptide during infection. Notably, the Treg cell response to self-peptide did not affect protective Tconv cell responses to a pathogen-derived peptide. Thus, self-peptide–specific Treg cells promoted self-nonself discrimination during infection by selectively controlling Tconv cells of shared self-specificity.
在感染过程中，CD4+ Foxp3+ 调节性 T（Treg）细胞必须控制针对自身肽抗原的自身反应性 CD4+ 常规 T（Tconv）细胞反应，同时允许针对病原体来源的“非自身”肽的反应。研究者利用对单一前列腺特异性自身肽有反应的 Treg 细胞被选择性耗竭的小鼠模型，从而阐明了这种选择性反应的基础。研究者发现，在稳态条件下，针对自身肽的特异性Treg细胞对于控制具有匹配特异性的 Tconv细胞并非必需。然而，在感染期间暴露于升高的自身肽后，它们对于控制此类Tconv 细胞以及防止针对前列腺的自身免疫是必需的。值得注意的是，Treg细胞对自身肽的反应并不影响针对病原体来源肽的保护性Tconv细胞反应。因此，自身肽特异性Treg细胞通过选择性控制具有相同自身特异性的Tconv 胞，在感染期间促进了自身与非自身抗原的区分。
Treg细胞在感染过程中通过选择性地限制具有共享自我特异性的Tconv细胞来加强自我非自我辨别
在被表达自身肽的病原体感染的病原体相关表位模拟模型或自身抗原升高后，自身肽特异性Treg细胞通过减弱TCR刺激、IL-2信号和增殖，选择性地控制CD4+ Tconv细胞对同一肽的反应。这种选择性抑制同时阻止了自身免疫，并使Tconv对外源病原菌衍生肽产生强大的反应，以保护宿主。
Synaptic architecture of a memory engram in the mouse hippocampus
小鼠海马体中记忆印记的突触结构
第一单位：美国加利福尼亚州拉霍亚斯克利普斯研究所神经科学系
Abstract
Memory engrams are formed through experience-dependent plasticity of neural circuits, but their detailed architectures remain unresolved. Using three-dimensional electron microscopy, we performed nanoscale reconstructions of the hippocampal CA3-CA1 pathway after chemogenetic labeling of cellular ensembles recruited during associative learning. Neurons with a remote history of activity coinciding with memory acquisition showed no strong preference for wiring with each other. Instead, their connectomes expanded through multisynaptic boutons independently of the coactivation state of postsynaptic partners. The rewiring of ensembles representing an initial engram was accompanied by input-specific, spatially restricted upscaling of individual synapses, as well as remodeling of mitochondria, smooth endoplasmic reticulum, and interactions with astrocytes. Our findings elucidate the physical hallmarks of long-term memory and offer a structural basis for the cellular flexibility of information coding.
记忆印迹是通过神经回路的经验依赖性可塑性形成的，但其详细的结构特征仍未明确。利用三维电子显微镜技术，研究者在化学遗传学标记了在联想学习过程中被招募的细胞集合后，对海马体CA3-CA1通路进行了纳米级重建。具有与记忆获取同时活跃的远期活动史的神经元，并没有表现出彼此之间强烈连接的偏好。相反，它们的连接组通过多突触轴突末端扩展，而与突触后伙伴的共激活状态无关。代表初始印迹的细胞集合的重新连接伴随着输入特异性的、空间受限的单个突触的放大，以及线粒体、平滑内质网的重塑，以及与星形胶质细胞的相互作用。该研究阐明了长期记忆的物理特征，并为信息编码的细胞灵活性提供了结构基础。
小鼠海马体中记忆印记的物理基质的超微结构分析
(A)实验设计概述。(B)CA1背侧放射层兴奋性突触的饱和3D-EM重建。(C)图显示了在CA3和CA1区域的联想学习过程中激活的投射神经元之间没有优先连接，以及CA3神经元轴突网络的扩展。(D)图描述了通过非典型MSBs在初始记忆集合中轴突连接的扩展。还显示了连接三个树突分支（D1到D3）的单个MSB的三维视图。
Epithelial polarization by the planar cell polarity complex is exclusively non–cell autonomous
平面细胞极性复合物介导的上皮极化完全依赖非自主性细胞互作
第一单位：美国普林斯顿大学分子生物系
Abstract
For cells to polarize collectively along a tissue plane, asymmetrically localized planar cell polarity (PCP) complexes must form intercellular contacts between neighboring cells. Yet, it is unknown whether asymmetric segregation of PCP complexes requires cell-cell contact, or if cell autonomous, antagonistic interactions are sufficient for polarization. To test this, we generated mouse chimeras consisting of dual PCP-reporter cells mixed with unlabeled cells that cannot form PCP bridges. In the absence of intercellular interactions, PCP proteins failed to polarize cell autonomously. Rather, PCP-mediated contacts along single cell-cell interfaces were sufficient to sort PCP components to opposite sides of the junction, independent of junction orientation. Thus, intercellular binding of PCP complexes is the critical step that initiates sorting of opposing PCP complexes to generate asymmetry.
为了使细胞在组织平面内集体极化，不对称定位的平面细胞极性（PCP）复合体必须在相邻细胞之间形成细胞间接触。然而，目前尚不清楚不对称分离PCP复合体是否需要细胞间接触，或者细胞自主的拮抗性相互作用是否足以实现极化。为了测试这一点，研究者生成了小鼠嵌合体，其中包含双重PCP报告细胞与无法形成PCP桥的未标记细胞混合。在缺乏细胞间相互作用的情况下，PCP蛋白无法自主极化。相反，沿着单个细胞间界面的PCP介导的接触足以将PCP组分分选到连接的两侧，且与连接的方向无关。因此，PCP复合体的细胞间结合是启动对立PCP复合体分选以产生不对称性的关键步骤。
平面细胞极性（PCP）的建立是非细胞自主的，并且需要细胞间的Celsr1相互作用
（左下）嵌合体胚胎第15.5天（E15.5）小鼠表皮，包含来自Celsr1−/−和Fz6-3xGFP；tdTomato-Vangl2胚胎的细胞（左上）。 （右侧）通过检查被缺乏形成细胞间PCP桥能力的细胞（Celsr1−/−）包围的分离的双报告细胞，研究者发现PCP不能以细胞自主的方式建立（单细胞），Celsr1同型界面足以建立连接处的极性（细胞对），并且具有两个Celsr1同型界面的细胞能够建立细胞水平的极性（细胞三联体）。
4. Hippocampal encoding of memories in human infants
人类婴儿记忆的海马体编码
第一单位：美国康涅狄格州纽黑文耶鲁大学心理学系
Abstract
Humans lack memories for specific events from the first few years of life. We investigated the mechanistic basis of this infantile amnesia by scanning the brains of awake infants with functional magnetic resonance imaging while they performed a subsequent memory task. Greater activity in the hippocampus during the viewing of previously unseen photographs was related to later memory-based looking behavior beginning around 1 year of age, suggesting that the capacity to encode individual memories comes online during infancy. The availability of encoding mechanisms for episodic memory during a period of human life that is later lost from our autobiographical record implies that postencoding mechanisms, whereby memories from infancy become inaccessible for retrieval, may be more responsible for infantile amnesia.
人类无法忆起生命最初几年的特定事件。为探究这种婴儿期遗忘的神经机制，研究者在清醒婴儿执行记忆任务时对其脑部进行功能性磁共振成像（fMRI）扫描。研究发现：约1岁起，婴儿海马体在观看新照片时更强的活动与其后续基于记忆的注视行为相关，表明个体记忆编码能力在婴儿期开始形成。在人类这段后期会从自传体记忆中消失的时期，情景记忆编码机制已然存在——这意味着婴儿期记忆的不可提取性更可能源于编码后机制（即记忆虽被编码但无法检索），而非编码机制本身的缺失。
汇报人：胥飞宇
导师：刘世喜
审核：李朔、吴婷婷、任建君
