【Science】2025年6-7月刊论文导读
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 388 Issue 6754, June 2025
在2025年6月，Science共发表30篇文章，其中包括Editorial 1篇，News 5篇，Commentary 7篇，Reviews 1篇，Research highlights 1篇，Research summaries 5篇，Research articles 10篇。主要内容包括“糖笼”药物精准递送技术、哺乳动物再生基因遗传开关激活、BAX蛋白孔形成分子机制等内容。
Bespoke plant glycoconjugates for gut microbiota–mediated drug targeting
肠道微生物介导的药物靶向的定制植物糖缀合物
不列颠哥伦比亚大学：Michael Smith 实验室和化学系，儿科和BC儿童医院
The gut microbiota of mammals possess distinctive metabolic pathways with untapped therapeutic potential. Using molecular insights into dietary fiber metabolism by the human gut microbiota, we designed a targeted drug delivery system, called GlycoCaging, that is based on bespoke glycoconjugates of a complex plant oligosaccharide. GlycoCaging of exemplar anti-inflammatory drugs enabled release of active molecules triggered by specific glycosidases of autochthonous gut bacteria. GlycoCaging ensured that drug efficacy was potentiated, and off-target effects were eliminated in murine models of inflammatory bowel disease. Biochemical and metagenomic analyses of gut microbiota of individual humans confirmed the broad applicability of this strategy.
哺乳动物的肠道微生物群拥有独特的代谢通路，其治疗潜力尚未被充分挖掘。基于对人体肠道微生物群膳食纤维代谢的分子层面认知，研究团队设计了一种名为"糖笼"（GlycoCaging）的靶向药物递送系统。该系统依托复杂植物寡糖的定制化糖缀合物来构建，实现对典型抗炎药物的包裹，从而利于由固有肠道细菌特异性糖苷酶触发的活性分子释放。在小鼠炎症性肠病模型中，"糖笼"技术不仅增强了药物疗效，还消除了脱靶效应。同时研究通过对个体人类肠道微生物群的生物化学与宏基因组学分析，进一步证实了该策略的广泛适用性。
Event structure sculpts neural population dynamics in the lateral entorhinal cortex
事件结构塑造了外侧内嗅皮层的神经群体动力学
挪威科技大学 Kavli 系统神经科学研究所和皮层算法中心
Our experience of the world is a continuous stream of events that must be segmented and organized at multiple timescales. The neural mechanisms underlying this process remain unknown. In this work, we simultaneously recorded hundreds to thousands of neurons in the lateral entorhinal cortex of freely behaving rats. Neural population activity drifted continuously along a one-dimensional manifold during all behaviors and behavioral states, including sleep, which points to an intrinsic origin of the drift. In awake animals, boundaries between events were associated with discrete shifts in population dynamics, which segmented the neural activity into temporal units. During tasks with recurring temporal structure, activity traveled additionally in directions orthogonal to the drift, encoding event information across multiple timescales. The results identify a hierarchical coding scheme for organizing events in time.
我们对世界的体验是一连串的事件，必须在多个时间尺度上进行分割和组织。这个过程背后的神经机制仍然未知。在这项工作中，研究团队同时记录了在自由活动过程中大鼠外侧内嗅皮层中的数百到数千个神经元的动态变化。在所有行为和行为状态（包括睡眠）期间，神经群体活动沿一维流形不断漂移，这表明了漂移具有内在起源。在清醒的动物中，事件之间的边界与种群动态的离散变化有关，后者将神经活动分割成时间单元。在具有重复时间结构的任务中，活动还会沿着与漂移正交的方向传播，从而跨多个时间尺度编码事件信息。该结果确定了用于按时间组织事件的分层编码方案。
Reactivation of mammalian regeneration by turning on an evolutionarily disabled genetic switch
通过开启进化失活的基因开关来重新激活哺乳动物的再生
清华大学多学科生物医学研究院
Mammals display prominent diversity in the ability to regenerate damaged ear pinna, but the genetic changes underlying the failure of regeneration remain elusive. We performed comparative single-cell and spatial transcriptomic analyses of rabbits and mice recovering from pinna damage. Insufficient retinoic acid (RA) production, caused by the deficiency of rate-limiting enzyme Aldh1a2 and boosted RA degradation, was responsible for the failure of mouse pinna regeneration. Switching on Aldh1a2 or RA supplementation reactivated regeneration. Evolutionary inactivation of multiple Aldh1a2-linked regulatory elements accounted for the deficient Aldh1a2 expression upon injury in mice and rats. Furthermore, the activation of Aldh1a2 by a single rabbit enhancer was sufficient to improve ear pinna regeneration in transgenic mice. Our study identified a genetic switch involved in the evolution of regeneration.
哺乳动物在再生受损耳廓的能力方面表现出显着著的差异，但导致再生失败的遗传变化仍然难以捉摸。研究者对从耳廓损伤后恢复的兔子和小鼠进行了单细胞和空间转录组学的比较分析发现，由限速酶 Aldh1a2 缺乏和 RA 降解增强引起的视黄酸 （RA） 产生不足是导致小鼠耳廓再生失败的原因。激活Aldh1a2 或 补充RA可以重新激活再生，而多个Aldh1a2 相关调节元件的进化失活是小鼠和大鼠损伤后 Aldh1a2 表达缺陷的原因。此外，单个兔子增强子激活 Aldh1a2 足以改善转基因小鼠的耳廓再生。该研究确定了一个参与再生进化过程的遗传开关。
Volume 388 Issue 6753, June 2025
在2025年6月，Science共发表32篇文章，其中包括Editorial 1篇，News 7篇，Commentary 9篇，Reviews 1篇，Research highlights 1篇，Research summaries 5篇，Research articles 8篇。主要内容包括HIV预防药物的全球健康影响评估、病毒进化边界研究、胆固醇代谢通路、癌症免疫疗法工程化改造、转基因动物技术等内容。
Mechanism of release factor–mediated peptidyl-tRNA hydrolysis on the ribosome
核糖体上释放因子介导的肽基-tRNA 水解核糖体的机制
伊利诺伊大学芝加哥分校生物科学系
美国加尔维斯顿德克萨斯大学医学分部微生物学和免疫学系
Translation termination is essential in all living organisms because it ensures that proteins have lengths strictly defined by their genes. This universal process is mediated by peptide release factors (RFs) that recognize stop codons and catalyze the hydrolysis of peptidyl transfer RNA (peptidyl-tRNA) on the ribosome, presumably by activating a water molecule. We report structures of the bacterial ribosome in complex with peptidyl-tRNA and RFs in the prepeptide release state. No hydrolytic water molecule was seen in the peptidyl transferase center. Instead, RFs induced rearrangements of the peptidyl-tRNA adenine 76 (A76) ribose pucker that orient the 2'-OH for the nucleophilic attack onto the neighboring carbonyl group. These findings suggest a catalytic mechanism of RF-mediated peptide release and provide a structural basis for the universal conservation of the catalytic domain in peptide RFs.
翻译终止在所有生物体中都是必不可少的，因为它确保蛋白质的长度是由其基因严格定义的。这种普遍的过程是由肽释放因子 （RFs） 介导的，RFs 识别终止密码子并催化核糖体上肽基转移 RNA （peptidyl-tRNA） 的水解，这可能是通过激活水分子实现的。研究者报道了细菌核糖体与肽基-tRNA 和处于前肽释放状态的 RFs 复合物的结构，他们发现在肽基转移酶中心未观察到水解水分子。相反，RFs 诱导了肽基-tRNA 腺嘌呤 76 （A76） 核糖构象的重排，该构象将用于亲核攻击的 2'-OH 定向到邻近的羰基上。这些发现表明了 RFs 介导的肽释放的催化机制，并为肽 RFs 中催化结构域的普遍保守提供了结构基础。
Sleep need - dependent plasticity of a thalamic circuit promotes homeostatic recovery sleep
依赖睡眠需求的丘脑回路可塑性促进稳态恢复睡眠
美国马里兰州巴尔的摩市约翰霍普金斯大学神经病学系
Prolonged wakefulness leads to persistent, deep recovery sleep (RS). However, the neuronal circuits that mediate this process remain elusive. From a circuit screen in mice, we identified a group of thalamic nucleus reuniens (RE) neurons activated during sleep deprivation (SD) and required for sleep homeostasis. Optogenetic activation of RE neurons leads to an unusual phenotype: presleep behaviors (grooming and nest organizing) followed by prolonged, intense sleep that resembles RS. Inhibiting RE activity during SD impairs subsequent RS, which suggests that these neurons signal sleep need. RE neurons act upstream of sleep-promoting zona incerta cells, and SD triggers plasticity of this circuit to strengthen their connectivity. These findings reveal a circuit mechanism by which sleep need transforms the functional coupling of a sleep circuit to promote persistent, deep sleep.
长时间的清醒会导致持续的深度恢复睡眠 （RS）。然而，介导这一过程的神经元回路仍然难以捉摸。从小鼠的电路筛选中，研究者确定了一组在睡眠剥夺 （SD） 期间激活的丘脑核 （RE） 神经元，这是睡眠稳态所必需的。RE 神经元的光遗传学激活导致一种不寻常的表型——在睡前行为（梳理毛发和巢穴组织）后表现出类似于 RS 的长时间、高强度睡眠。在 SD 期间抑制 RE 活动会损害后续的 RS，这表明这些神经元发出睡眠需要的信号，这可能是因为RE 神经元作用于促进睡眠的不定带细胞的上游，SD 触发该回路的可塑性以加强它们的连接性。这些发现揭示了一种电路机制，而睡眠需求因其改变了睡眠回路的功能耦合，以促进持续的深度睡眠。
In vivo CAR T cell generation to treat cancer and autoimmune disease
用于治疗癌症和自身免疫性疾病的体内CAR T细胞产生
美国宾夕法尼亚大学
佩雷尔曼医学院细胞免疫疗法中心
Chimeric antigen receptor (CAR) T cell therapies have transformed treatment of B cell malignancies. However, their broader application is limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility. We present an in vivo engineering strategy using targeted lipid nanoparticles (tLNPs) for messenger RNA delivery to specific T cell subsets. These tLNPs reprogrammed CD8T cells in both healthy donor and autoimmune patient samples, and in vivo dosing resulted in tumor control in humanized mice and B cell depletion in cynomolgus monkeys. In cynomolgus monkeys, the reconstituted B cells after depletion were predominantly naïve, suggesting an immune system reset. By eliminating the requirements for complex ex vivo manufacturing, this tLNP platform holds the potential to make CAR T cell therapies more accessible and applicable across additional clinical indications.
嵌合抗原受体（CAR）T细胞疗法已彻底革新B细胞恶性肿瘤的治疗范式。然而，其临床广泛应用仍受限于复杂的体外制造流程及淋巴细胞清除性化疗的必要性，显著制约了患者可及性限制了患者的治疗可及性。本研究提出一种基于靶向脂质纳米颗粒（tLNPs）的体内工程化策略，通过tLNPs介导信使RNA（mRNA）向特定T细胞亚群的高效递送，实现CAR-T细胞的体内原位改造。实验结果显示，该tLNP系统可在健康供体及自身免疫性疾病患者来源的样本中实现CD8⁺ T细胞的功能重编程；体内给药后，不仅能有效控制人源化小鼠模型中的肿瘤进展，还可诱导食蟹猴模型中B细胞的特异性耗竭。值得关注的是，在食蟹猴模型中，B细胞耗竭后重建的B细胞群体以初始B淋巴细胞为主，提示该策略可能通过重置免疫系统状态实现更可控的免疫调控。通过规避传统CAR-T疗法对复杂体外制造流程的依赖，该tLNP平台有望显著提升CAR-T细胞疗法的可及性，并为拓展其在更多临床适应症中的应用提供新路径。
Cholinergic feedback for modality- and context-specific modulation of sensory representations
胆碱能反馈对感觉表征的模态和情境特异性调节
美国加利福尼亚州拉霍亚市加州大学圣地亚哥分校神经生物学系
The brain's ability to prioritize sensory information is crucial for adaptive behavior, yet its mechanisms remain unclear. We investigated basal forebrain cholinergic neurons modulating olfactory bulb (OB) circuits in mice. The activity of cholinergic feedback axons in OB correlated with orofacial movements, with little responses to passively experienced odors. When mice engaged in an olfactory task, OB cholinergic axons rapidly shifted their response patterns from movement correlated to odor aligned. This response shift was absent in cholinergic axons projecting to the dorsal cortex during olfactory task engagement, and in OB, during an auditory task. Inactivation of OB-projecting cholinergic neurons impaired olfactory task performance and reduced odor responses in OB granule cells. Thus, the cholinergic system dynamically modulates sensory processing in a modality-specific and context-dependent manner.
大脑优先处理感官信息的能力对适应性行为至关重要，但其神经机制仍不明确。本研究聚焦小鼠基底前脑胆碱能神经元对嗅球（OB）回路的调控作用，发现嗅球内胆碱能反馈轴突的活动模式与行为状态高度相关，其活动主要与口面部运动同步，而对被动暴露的气味刺激反应微弱。当小鼠主动执行嗅觉任务时，嗅球胆碱能轴突的反应模式迅速重构——从与运动相关的同步活动转变为与气味特征精确匹配的模式。值得注意的是，在嗅觉任务期间，这种反应模式的转变未在投射至背侧皮层的胆碱能轴突中观察到，也未在小鼠执行听觉任务时的嗅球中观察到。进一步实验证实，抑制投射至嗅球的胆碱能神经元会显著损害小鼠的嗅觉任务表现，并降低嗅球颗粒细胞对气味的反应强度。综上，胆碱能系统通过动态调整其神经投射的活动模式，以模态特异性（仅响应特定感官模态）和情境依赖性（随行为任务切换）的方式，实现对感官信息处理的精准调控。
Volume 388 Issue 6752, June 2025
在2025年6月，Science共发表35篇文章，其中包括Editorial 2篇，News 6篇，Commentary 10篇，Reviews 1篇，Research highlights 1篇，Research summaries 6篇，Research articles 9篇。主要内容包括血管生成信号、细菌免疫计算模型、染色体倒位、癌症基因组学、酶进化、疟疾耐药性等内容。
Catl forms filament networks to degrade NAD⁺ during the type III CRISPR - Cas antiviral response
Cat 1在III型CRISPR-Cas抗病毒反应期间形成细丝网络以降解NAD+
洛克菲勒大学细菌学实验室
Type III CRISPR-Cas systems defend against viral infection in prokaryotes by using an RNA-guided complex that recognizes foreign transcripts and synthesizes cyclic oligoadenylate (cOA) messengers to activate CRISPR-associated Rossmann-fold (CARF) immune effectors. In this study, we investigated a protein containing a CARF domain-fused Toll/interleukin-1 receptor (TIR) domain, Cat1. We found that Cat1 provides immunity by cleaving and depleting oxidized nicotinamide adenine dinucleotide (NAD) molecules from the infected host, inducing a growth arrest that prevents viral propagation. Cat1 forms dimers that stack upon each other to generate long filaments that are maintained by bound cOA ligands, with stacked TIR domains forming the NADcleavage catalytic sites. Furthermore, Cat1 filaments assemble into distinct trigonal and pentagonal networks that enhance NADdegradation. Cat1 presents an unprecedented chemistry and higher-order protein assembly for the CRISPR-Cas response.
III 型 CRISPR-Cas 系统通过使用 RNA 引导的复合物来防御原核生物中的病毒感染，该复合物识别外来转录本并合成环状寡腺苷酸 （cOA） 信使以激活 CRISPR 相关的罗斯曼折叠 （CARF） 免疫效应蛋白。在这项研究中，研究者构建了一种含有 CARF 结构域融合的 Toll/白细胞介素-1 受体 （TIR） 结构域 Cat1 的蛋白质。该研究发现 Cat1 通过裂解和消耗受感染宿主的氧化烟酰胺腺嘌呤二核苷酸 （NAD） 分子来提供免疫力，诱导生长停滞，从而阻止病毒传播。Cat1 形成二聚体，二聚体相互堆叠以产生由结合的 cOA 配体维持的长丝状结构，堆叠的 TIR 结构域形成 NAD切割催化位点。此外，Cat1 细丝组装成不同的三角形和五边形网络，从而增强 NAD降解。Cat1 为 CRISPR-Cas 响应提供了前所未有的化学和高阶蛋白质组装。
Aberrant basal cell clonal dynamics shape early lung carcinogenesis
异常的基底细胞克隆动力学塑造了早期肺癌发生
伦敦大学学院呼吸学研究中心
Preinvasive squamous lung lesions are precursors of lung squamous cell carcinoma (LUSC). The cellular events underlying lesion formation are unknown. Using a carcinogen-induced model of LUSC with no added genetic hits or cell type bias, we found that carcinogen exposure leads to non-neutral competition among basal cells, aberrant clonal expansions, and basal cell mobilization along the airways. Ultimately, preinvasive lesions developed from a few highly mutated clones that dominate most of the bronchial tree. Multisite sequencing in human patients confirmed the presence of clonally related preinvasive lesions across distinct airway regions. Our work identifies a transition in basal cell clonal dynamics, and an associated shift in basal cell fate, as drivers of field cancerization in the lung.
浸润性鳞状肺病变作为肺鳞状细胞癌（LUSC）的癌前病变，其发生发展的细胞生物学机制仍不明确。通过使用一种无需额外遗传打击或细胞类型偏倚的致癌物诱导的LUSC模型，研究团队发现致癌物暴露导致基底细胞之间的非中性竞争、异常的克隆扩增和沿气道的基底细胞迁移。最终，浸润前病变由一些高度突变的克隆发展而来，这些克隆在支气管树的大部分中占主导地位。人类患者的多位点测序证实了不同气道区域存在克隆相关的浸润前病变。本研究确定了基底细胞克隆动力学的转变以及基底细胞命运的相关转变，是肺部的“场效应癌化”的驱动因素。
A metabolite - based resistance mechanism against malaria
一种基于代谢物的抗疟机制
Gulbenkian 分子医学研究所 （GIMM）葡萄牙里斯本
Jaundice is a common presentation of Plasmodium falciparum malaria, which arises from the accumulation of circulating bilirubin. It is not understood whether it represents an adaptive or maladaptive response to Plasmodium spp. infection. We found that asymptomatic P. falciparum infection in humans was associated with a higher ratio of unconjugated over conjugated bilirubin and parasite burden compared with symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, through genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1), was protective against malaria in mice. Unconjugated bilirubin inhibited P. falciparum proliferation in red blood cells by a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin crystallization and compromised the parasite's food vacuole. Hence, jaundice appears to represent a metabolic response to Plasmodium spp. infection that limits malaria severity.
黄疸是恶性疟原虫疟疾的常见表现，由循环胆红素的积累引起。目前尚不清楚它是否代表对疟原虫属感染的适应性或适应不良反应。研究者发现，与有症状的疟疾相比，人类无症状的恶性疟原虫感染与未结合胆红素与结合胆红素和寄生虫负荷的比率更高有关。胆绿素还原酶 A （BVRA） 对胆红素合成的基因抑制增加了小鼠的寄生虫毒力和疟疾死亡率。通过 UDP 葡萄糖醛酸转移酶家族 1 成员 A1 （UGT1A1） 对肝脏结合的遗传抑制，未结合胆红素在血浆中积累，对小鼠的疟疾具有保护作用。未结合的胆红素通过抑制线粒体嘧啶合成的机制抑制恶性疟原虫在红细胞中的增殖。此外，未结合的胆红素抑制了血红素结晶并损害了寄生虫的食物液泡。因此，黄疸似乎代表了对疟原虫感染的代谢反应，限制了疟疾的严重程度。
Antagonism as a foraging strategy in microbial communities
拮抗作用作为微生物群落的觅食策略
苏黎世联邦理工学院 环境系统科学系 生物地球化学和污染物动力学研究所
In natural habitats, nutrient availability limits bacterial growth. We discovered that bacteria can overcome this limitation by acquiring nutrients by lysing neighboring cells through contact-dependent antagonism. Using single-cell live imaging and isotopic markers, we found that during starvation, the type VI secretion system (T6SS) lysed neighboring cells and thus provided nutrients from lysing cells for growth. Genomic adaptations in antagonists, characterized by a reduced metabolic gene repertoire, and the previously unexplored distribution of the T6SS across bacterial taxa in natural environments suggest that bacterial antagonism may contribute to nutrient transfer within microbial communities in many ecosystems.
在自然栖息地，养分的可用性限制了细菌的生长。本研究发现细菌可以通过接触依赖性拮抗作用裂解邻近细胞来获取营养物质，从而克服这一限制。实验者使用单细胞实时成像和同位素标记物，发现在饥饿期间，VI 型分泌系统 （T6SS） 裂解了邻近细胞，从而从裂解细胞中为生长提供营养。拮抗剂的基因组适应，其特征是代谢基因库减少，以及以前未探索的 T6SS 在自然环境中细菌类群中的分布，这表明细菌拮抗作用可能有助于许多生态系统中微生物群落内的营养转移。
RNA transcripts regulate G - quadruplex landscapes through G - loop formation
RNA转录物通过G环的形成调控G四链体的结构
荷兰莱顿大学 医学中心 人类遗传学系
G-quadruplexes (G4s) are prevalent DNA structures that regulate transcription but also threaten genome stability. How G4 dynamics are controlled remains poorly understood. Here, we report that RNA transcripts govern G4 landscapes through coordinated G-loop assembly and disassembly. G-loop assembly involves activation of the ATM and ATR kinases, followed by homology-directed invasion of RNA opposite the G4 strand mediated by BRCA2 and RAD51. Disassembly of the G-loop resolves the G4 structure through DHX36-FANCJ-mediated G4 unwinding, which triggers nucleolytic incision and subsequent hybrid strand renewal by DNA synthesis. Inhibition of G-loop disassembly causes global G4 and R-loop accumulation, leading to transcriptome dysregulation, replication stress, and genome instability. These findings establish an intricate G-loop assembly-disassembly mechanism that controls G4 landscapes and is essential for cellular homeostasis and survival.
G-四链体 （G4）是广泛存在的DNA结构，既能调控转录又可能威胁基因组稳定性。G4 动态调控机制仍然知之甚少。研究者报道了 RNA 转录本通过协调的G 环的组装和解离来控制 G4 景观。G 环组装涉及 ATM 和 ATR 激酶的激活，然后由 BRCA2 和 RAD51 介导的 RNA 同源定向侵袭与 G4 链相反的 RNA。G 环的分解通过 DHX36-FANCJ 介导的 G4 展开解析 G4 结构，从而触发核酸切口和随后通过 DNA 合成的杂交链更新。G环的解离通过DHX36-FANCJ介导的G4解旋实现，该过程触发核酸酶切割作用，并最终通过DNA合成实现杂交链更新。抑制 G 环分解会导致整体 G4 和 R 环积累，导致转录组失调、复制应激和基因组不稳定。这些发现建立了一种复杂的 G 环组装-解离机制，该机制控制 G4 景观，对细胞稳态和生存至关重要。
Volume 388 Issue 6751, June 2025
在2025年6月，Science共发表34篇文章，其中包括Editorial 1篇，News 7篇，Commentary 10篇，Research highlights 1篇，Research summaries 6篇，Research articles 9篇。主要内容包括纳米线视网膜修复技术、脑纤毛与肥胖关联、神经科学与生理学中多巴胺传感器应用、结构生物学染色质重塑机制等内容。
Gastruloids enable modeling of the earliest stages of human cardiac and hepatic vascularization
人类发育类胃腺激素类原肠胚能够模拟人类心脏和肝脏血管形成的最早阶段
斯坦福大学心血管研究所
Although model organisms have provided insight into the earliest stages of cardiac and hepatic vascularization, we know very little about this process in humans because of ethical restrictions and the technical difficulty of obtaining embryos during very early development. In this study, we demonstrate that micropatterned human pluripotent stem cell-derived gastruloids enable in vitro modeling of the earliest stages of vascularization. We identify a combination of vascular-inducing factors that give rise to cardiac vascularized organoids with a spatially organized and branched vascular network. To show the broader utility of our vascularization strategy, we use the same vascular-inducing factors to produce hepatic vascularized organoids. Our results suggest that a conserved developmental program generates the vasculature within different types of organs.
尽管模式生物已经提供了对心脏和肝脏血管形成最早阶段的见解，但由于伦理限制和获取早期人类胚胎的技术难度，目前对人类的这一过程知之甚少。在这项研究中，研究团队证明了微模式化的人类多能干细胞衍生的原肠菌能够对血管形成的最早阶段进行体外建模。他们确定了一种血管诱导因子的组合，这些因子能够生成具有空间组织和分支血管网络的心脏血管化类器官。为了展示血管化策略的更广泛用途，他们使用相同的血管诱导因子来产生肝脏血管化类器官。结果表明，不同类型器官的血管化是通过保守的发育程序生成的。
Is taurine an aging biomarker?
牛磺酸是一种衰老生物标志物吗？
美国国立卫生研究院 （NIH） 国家老龄化研究所校内研究计划转化老年学分部
Low circulating taurine concentrations have been proposed as a driver of the aging process. We found that circulating taurine concentrations increased or remained unchanged with age in three geographically distinct human cohorts as well as in nonhuman primates and mice when measured longitudinally (repeatedly in the same population) or cross-sectionally (sampling distinct populations at various ages). Moreover, considerable variability was observed in associations between taurine and age-related changes in health outcomes pertaining to gross motor function and energy homeostasis. Our results suggest that changes in circulating taurine are not a universal feature of aging and that its pleiotropic effects may be dependent on the temporal and physiological context of each individual.
低循环牛磺酸浓度被认为是衰老过程的驱动因素之一。本研究发现，在三个地理位置不同的人类群体中，以及在非人灵长类动物和小鼠中，循环牛磺酸浓度随着年龄增长要么增加，要么保持不变（通过纵向研究，即在同一群体中反复测量，或横断面研究，即在不同年龄的群体中采样）。此外，牛磺酸与年龄相关的健康变化（如粗大运动功能和能量稳态）的关系表现出相当大的差异。结果表明，循环牛磺酸的变化并不是衰老的普遍特征，其多效性作用可能取决于每个人的时间和生理环境。
GPR45 modulates Gαs at primary cilia of the paraventricular hypothalamus to control food intake
GPR45调节室旁下丘脑初级纤毛Gαs控制摄食
美国德克萨斯大学西南医学中心宿主防御遗传学中心、内分泌科
The melanocortin system centrally regulates energy homeostasis, with key components such as melanocortin-4 receptor (MC4R) and adenylyl cyclase 3 (ADCY3) in neuronal primary cilia. Mutations in MC4R and ADCY3 as well as ciliary dysfunction lead to obesity, but how melanocortin signaling works in cilia remains unclear. Using mouse random germline mutagenesis, we identified two missense mutations in G protein-coupled receptor 45 (Gpr45) that lead to obesity through hyperphagia. GPR45 was expressed in paraventricular nucleus of the hypothalamus (PVH), where it localized to cilia and recruited Gαsto increase ciliary cyclic adenosine monophosphate (cAMP) via ADCY3. GPR45 colocalized with MC4R in PVH cilia and promoted ciliary MC4R activation. Loss of GPR45 in the PVH or MC4Rneurons caused obesity. These findings establish GPR45 as a key regulator of the ciliary melanocortin system, bridging MC4R and ADCY3.
黑皮质素系统在中枢调控能量稳态中起关键作用，其主要成分包括位于神经元初级纤毛中的黑皮质素-4受体（MC4R）和腺苷酸环化酶3（ADCY3）。MC4R 和 ADCY3 突变以及纤毛功能障碍会导致肥胖，但黑皮质素信号转导如何在纤毛中发挥作用仍不清楚。使用小鼠随机种系诱变，研究者确定了 G 蛋白偶联受体 45 （Gpr45）中的两个错义突变，这些突变通过暴食行为导致肥胖。GPR45 在下丘脑室旁核（PVH）中表达，定位于纤毛并募集 Gαs通过 ADCY3 增加睫状环磷酸腺苷（cAMP）。GPR45 与 PVH 纤毛中的 MC4R 共定位并促进纤毛 MC4R 激活。PVH 或 MC4R 神经元中 GPR45 的缺失导致肥胖。这些发现确定 GPR45 是睫状黑皮质素系统的关键调节因子，将MC4R与ADCY3连接起来。
汇报人：代一冯
导师：赵宇、任建君
审核：庞文都、谢尔杰、任建君
