前沿速递 | NCS 集萃：2024-11-29 期

『Abstract』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.

『摘要』 在怀孕和出血后，血液干细胞（HSC）和红细胞生成将被激活，这是由于逆转录过程的去抑制作用所致；这些逆转录过程包括内源性逆转录病毒和长散在核元件（一类转座子）等逆转过程。逆转录元件的转录激活了先天免疫感知器环状鸟苷酸3′,5′-单磷酸合成酶（cGAS）和干扰素（IFN）基因刺激物（STING），从而在HSC中诱导IFN和IFN调节基因，增加HSC分裂和红细胞生成。在非怀孕小鼠中，逆转录酶抑制或cGAS缺陷或STING缺陷对血液生成没有明显影响，但在怀孕小鼠中，它们会耗尽HSC和红细胞祖细胞，降低红血球计数。小鼠血液干细胞中的逆转录元件和IFN调节基因也在连续出血后被诱导，人类造血干细胞中的这些元件则在怀孕期间被诱导。逆转录酶抑制剂的使用与怀孕人群中的贫血有关，但不影响非怀孕人群，表明这些机制从小鼠到人类都是保守的。

『总结』 怀孕和出血后，血液干细胞和红细胞生成将被激活；激活过程通过激活先天免疫感知器和干扰素信号通路让逆转录元件的去抑制而实现（也就是平时这些逆转录元件是处于被抑制状态）。
——小编注：蓝星上唯一一种流血7天还活蹦乱跳的……仙女们，果然有神秘力量加持，Science！

【严肃话】怀孕期间要避免逆转录抑制剂的使用，抗病毒药物常用逆转录抑制剂，如齐多夫定、拉米夫定、阿巴卡韦、替诺福韦、恩曲他滨、司他夫定等——新冠期间怀孕吃抗病毒药物的有没有影响？另：大家严肃了解一下逆转座子。

『Abstract』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.

『摘要』 形状对称的哺乳动物大脑半球之间通过中线交叉的联合轴突相互连接。然而，跨半球连接的功能仍然鲜为人知。我们在小鼠中发现，切断连接前侧支前脑的前联结（AC），会损害其回避行为。小鼠的基底外侧杏仁核（BLA）通过 AC 投射到对侧的伏隔核（NAc），独立于其同侧投射。厌恶刺激激活对侧 BLA-NAc 投射，而正性刺激则激活同侧投射。选择性激活对侧 BLA-NAc 投射激活 D2 阳性中等棘状神经元（D2-MSNs），降低 NAc 多巴胺水平，并引起厌恶；选择性激活同侧 BLA-NAc 投射激活 D1 阳性中等棘状神经元（D1-MSNs），增加 NAc 多巴胺水平，并引起奖励。对侧 BLA-AC-NAc 通路对于编码负性反馈至关重要，证明了脑生理学中半球内、半球间回路的不同功能。【人工校对】

『总结』 研究发现小鼠大脑中对侧基底外杏仁核到伏隔核的投射通路对编码负性反馈至关重要，并证明了脑生理学中半球内-、半球间-回路的不同功能。
——小编注：简单来讲“爱恨情仇”是受两个大脑半球控制的。个么做脑机接口的咖们想一想：未来有没有可能在人脑中植入一个遥控开关，远远地按一下，关闭对方大脑对你的“负面反馈”，就让恨你的人不再恨你甚至投怀送抱？婚前需要，婚后更需要……

『Abstract』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.

『摘要』 季节性流感病毒的全球动态为监测、干预和疫苗策略的设计提供了重要信息。 COVID-19 大流行提供了一个独特的机会来评估人类行为变化如何扰乱（居然“扰乱”我大流感的传播——你们人类居心大大地坏了啊！应为“扰动”）全球流感传播。我们结合了分子学、流行病学和国际旅行数据，发现大流行（COVID-19）的开始导致了国际流感谱系流动的强度和结构发生了变化。在大流行期间，南亚在流感A病毒的系统发育树上扮演了重要角色，而西亚则维持了流感B/Victoria谱系的传播。我们探索了大流行期间流感谱系动态的驱动因素，以及B/Yamagata谱系可能灭绝的原因。在3年大流行后，随着全球航空交通的恢复，地区之间流感谱系的流动的强度恢复到了大流行前的水平，唯一例外的是B/Yamagata谱系，这突出了全球谱系扩散模式对重大干扰的稳定性。【人工校对】

『总结』 研究发现，COVID-19 大流行期间人类行为变化对全球流感传播产生明显扰动，但全球流感谱系扩散模式在航空交通恢复后，又恢复到了大流行前的水平。
——小编注：他强任他强,清风拂山岗；他横由他横,明月照大江。大白话：你大爷（流感）还是你大爷。

『Abstract』(−)-Cylindrocyclophane A is a 22-membered C 2 -symmetric [7.7]paracyclophane that bears bis-resorcinol functionality and six stereocenters. We report a synthetic strategy for (−)-cylindrocyclophane A that uses 10 C−H functionalization reactions, resulting in a streamlined route with high enantioselectivity and efficiency (17 steps). The use of chiral dirhodium tetracarboxylate catalysis enabled the C–H functionalization of primary and secondary positions, which was complemented by palladium-catalyzed C(sp )–C(sp ) cross-couplings, resulting in the rapid formation of the macrocyclic core and all stereocenters with high regio-, diastereo-, and enantioselectivity. The use of a late-stage palladium-catalyzed fourfold C(sp )–H acetoxylation installed the bis-resorcinol moieties. This research exemplifies how multilaboratory collaborations can produce substantial modernizations of complex total synthesis endeavors.

『摘要』 (-)-环烷A是一种22元，C2对称[7.7]-对环取代芳烷结构，具有双酚羟基官能团和6个立体中心（手性中心）。我们报道了一种合成策略，通过10次C-H官能化反应，获得一条高效、高对映选择性的简化路线（17步）。使用手性二铑四羧酸催化剂促进了初级和次级C-H位点的功能化，并与钯催化的C(sp²)-C(sp²)交叉耦联反应相结合，实现了大环核心和所有立体中心的快速形成，并具有高位点选择性、非对映和对映选择性。最后通过后期钯催化四重C(sp²)-H 乙氧基化（乙酰化），修饰上双酚羟基官能团。这项研究展示了多实验室合作如何对复杂的全合成项目中实现实质性的现代化。【人工校对】

『总结』 研究人员报道了一种高效、高立体选择性的合成策略，使用10次C-H官能化反应，成功合成了(-)-环烷A。

『Abstract』 Wood constitutes the largest reservoir of terrestrial biomass. Composed of xylem, it arises from one side of the vascular cambium, a bifacial stem cell niche that also produces phloem on the opposing side. It is currently unknown which molecular factors endow cambium stem cell identity. Here we show that TRACHEARY ELEMENT DIFFERENTIATION INHIBITORY FACTOR (TDIF) ligand–activated PHLOEM INTERCALATED WITH XYLEM (PXY) receptors promote the expression of CAMBIUM-EXPRESSED AINTEGUMENTA-LIKE (CAIL) transcription factors to define cambium stem cell identity in the Arabidopsis root. By sequestrating the phloem-originated TDIF, xylem-expressed PXY confines the TDIF signaling front, resulting in the activation of CAIL expression and stem cell identity in only a narrow domain. Our findings show how signals emanating from cells on opposing sides ensure robust yet dynamically adjustable positioning of a bifacial stem cell layer.

『摘要』 木材是陆地生物质的最大储存库。它由木质部组成，起源于维管形成层的一侧，这是一个双面干细胞生态位，在其另一侧也产生韧皮部。目前，关于哪些分子因素赋予维管形成层干细胞特性尚不明确。我们在此展示了，TRACHEARY ELEMENT DIFFERENTIATION INHIBITORY FACTOR (TDIF) 配体激活的 PHLOEM INTERCALATED WITH XYLEM (PXY) 受体，通过促进 CAMBIUM-EXPRESSED AINTEGUMENTA-LIKE (CAIL) 转录因子的表达，来确定拟南芥根部维管形成层干细胞的身份。通过隔离来自韧皮部的TDIF，木质部表达的PXY受体限制了TDIF信号的传播范围，导致CAIL表达的激活和干细胞身份的形成仅发生在一个狭窄的区域内。我们的研究结果揭示了来自对侧细胞的信号如何确保双面干细胞层的定位既稳固又具动态可调性。

『总结』 研究发现了 TDIF 配体激活的 PXY 受体在拟南芥根中定义 cambium 干细胞身份的机理，并展示了来自对侧的细胞信号如何确保双面干细胞层的定位。

『Abstract』Existing separation technologies struggle to recover oil and water concurrently from surfactant-stabilized emulsions to achieve the goal of near-zero liquid discharge. We present a Janus channel of membranes (JCM) that features a confined architecture constructed of a pair of hydrophilic and hydrophobic membranes, which allows for concurrent, highly efficient recovery of oil and water from surfactant-stabilized emulsions. The confined Janus channel can amplify the interplay of the membrane pair through a feedback loop that involves enrichment and demulsification. Our JCM achieves exceptional oil and water recoveries of up to 97 and 75%, respectively, with near 99.9% purities. Moreover, its versatility in handling diverse emulsions may enable near-zero liquid discharge for a range of separations.

『摘要』 现有的分离技术难以从表面活性剂稳定的乳液中同时回收油和水，以实现近零液体排放的目标。本文展示一种 Janus 通道膜（JCM），它是由一对亲水和疏水膜组成的封闭架构，允许从表面活性剂稳定的乳液中同步、高效地回收油和水。封闭的 Janus 通道可以通过一个反馈循环来放大膜对的相互作用，该循环涉及到富集和去乳化。我们的 JCM 实现了卓越的油、水回收效果，其回收率分别高达 97% 和 75%，且达到近 99.9% 的回收纯度。此外，它在处理多种乳液方面的灵活性可能使得各种分离实现接近零液体排放。

『总结』 本文开发了一种 Janus 通道膜，可以高效地从表面活性剂稳定的乳液中同时回收油和水，实现近零液体排放。
——小编注：有机合成常加盐破乳，但之前在合成LNP 脂质原料（也是种表面活性剂）时就发现加盐破乳很困难，所以这个应该是挺有应用价值。不过，搞“地沟油”的是不是有更先进的技术？

『Abstract』Rational design of intricate multicomponent reticular structures is often hindered by the lack of suitable blueprint nets. We established the merged-net approach, proffering optimal balance between designability and complexity, as a systematic solution for the rational assembly of multicomponent structures. In this work, by methodically mapping node-net relationships among 53 basic edge-transitive nets, we conceived a signature net map to identify merging net pairs, resulting in the enumeration of 53 merged nets. We developed a practical design algorithm and proposed more than 100 multicomponent metal-organic framework platforms. The effectiveness of this approach is commended by the successful synthesis of four classes of materials, which is based on merging three-periodic nets with the four possible net periodicities. The construction of multicomponent materials based on derived nets of merged nets highlights the potential of the merged-net approach in accelerating the discovery of intricate reticular materials.

『摘要』 复杂多组分网状结构的合理设计常因缺乏合适的蓝图网而受阻。我们建立了合并网络方法，在可设计性与复杂性之间的提供最佳平衡，作为多组分结构合理组装的系统解决方案。在本研究中，通过系统地绘制53种基本边可迁移网的节点-网关系，我们构建了一个特征网图以识别合并网对，最终枚举出53种合并网。我们开发了一种实用设计算法，并提出了100多种多组分金属有机框架平台。这一方法的有效性通过成功合成四类材料得以验证，这些材料基于将三周期网与四种可能的网周期性进行合并而成。基于合并网的衍生网构建多组分材料，凸显了合并网方法在加速复杂网状材料发现方面的潜力。

『总结』 我们提出了合并网方法，以解决多组分网格结构的理性设计问题，并成功合成了四类材料，展示了该方法在加速复杂网格材料发现中的潜力。

『Abstract』One-fifth of human proteins are N-glycosylated in the endoplasmic reticulum (ER) by two oligosaccharyltransferases, OST-A and OST-B. Contrary to the prevailing view of N-glycosylation as a housekeeping function, we identified an ER pathway that modulates the activity of OST-A. Genetic analyses linked OST-A to HSP90B1, an ER chaperone for membrane receptors, and CCDC134, an ER luminal protein. During its translocation into the ER, an N-terminal peptide in HSP90B1 templates the assembly of a translocon complex containing CCDC134 and OST-A that protects HSP90B1 during folding, preventing its hyperglycosylation and degradation. Disruption of this pathway impairs WNT and IGF1R signaling and causes the bone developmental disorder osteogenesis imperfecta. Thus, N-glycosylation can be regulated by specificity factors in the ER to control cell surface receptor signaling and tissue development.

『摘要』 人类蛋白质的五分之一在内质网（ER）中通过两个寡糖基转移酶OST-A 和 OST-B，进行 N-糖基化。与传统观点认为 N-糖基化是一种“内务性”功能的普遍观点不同，我们识别出一个调节 OST-A 活性的内质网途径。遗传分析将OST-A与HSP90B1（一种内质网中负责膜受体的分子伴侣）和CCDC134（一种内质网腔蛋白）联系起来。在 HSP90B1 进入 ER 期间，其 N-端肽段模板组装了一个包含 CCDC134 和 OST-A 的转运复合物，该复合物保护 HSP90B1 在折叠过程中，免受过度糖基化和降解的影响。该途径的破坏会损害 WNT 和 IGF1R 信号通路，并导致骨发育障碍——成骨不全症。因此，N-糖基化可以通过内质网中的特异性因子来控制细胞表面受体信号传导和组织发育。

『总结』 研究揭示了一个通过调节OST-A活性和防止HSP90B1过度糖基化的内质网通路，影响细胞信号传导与组织发育，该通路的破坏可导致成骨不全症等疾病。

『Abstract』 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.

『摘要』 由轮班工作或时差引起的昼夜节律失调对代谢健康有害，但组织间如何传递同步或非同步节律信号仍不清楚。我们研究发现，肝脏分子时钟功能障碍通过肝迷走传入神经（HVAN）向大脑传递信号，导致进食模式的改变，而切除HVAN可以纠正这一现象。肝支迷走神经切断术还可防止高脂饮食诱导的进食紊乱，并减少体重增加。我们的研究揭示了一种依赖肝脏与大脑之间通信的稳态反馈信号，用于控制昼夜节律性的进食模式。这一发现表明肝迷走神经是解决时间紊乱背景下肥胖问题的潜在治疗靶点。

『总结』 研究发现肝脏迷走神经在昼夜节律失调引起的进食紊乱中扮演着关键角色，并将其作为时间紊乱背景下肥胖症潜在治疗靶标。
——小编注：当年一起跑马拉松的同学，后来做了996的程序员，就慢慢胖成球，之前觉得这不科学；现在看，这很科学。

『Abstract』Given the negative fitness effects that pathogens impose on their hosts, the benefits of resistance should be universal. However, there is marked variation across plant species in the number of nucleotide-binding leucine-rich repeat receptors, which form a cornerstone of defense. The growth–defense trade-off hypothesis predicts costs associated with defense investment to generate variation in these traits. Our analysis comparing features of the intracellular immune-receptor repertoires with trait data of 187 species shows that in wild plants, the size of the molecular defense repertoire correlates negatively with growth. By contrast, we do not find evidence for a growth–defense trade-off in agricultural plants. Our cross-species approach highlights the central role of defense investment in shaping ecological trait variation and its sensitivity to domestication.

『摘要』 鉴于病原体对其宿主的负面适应性效应，抗性（应该是宿主对病原体的抗性）的益处应该是普遍存在的。然而，不同植物物种之间，在核苷酸结合富含亮氨酸重复受体（NLR）的数量上，存在明显的差异，这些重复受体是防御的基石。“生长-防御权衡”假说预测，防御投入会产生与这些性状变化相关的成本。我们的分析比较了187种植物的细胞内免疫受体库特征与性状数据，发现野生植物的分子防御库的规模的确与生长呈负相关。但相反，我们没有在农作物中找到“生长-防御权衡”的证据。我们的跨物种研究方法突出了防御投入在塑造生态特性变化及驯化敏感性方面的核心作用。【人工校对】

『总结』 研究发现，野生植物中分子防御库规模与生长负相关，即存在“生长-防御权衡”关系，但农作物中却未发现此现象，凸显了防御投入在生态特性变化及其驯化敏感性中的关键作用。

『Abstract』The mid-Pleistocene transition (MPT) [~1.25 to 0.85 million years ago (Ma)] marks a shift in the character of glacial-interglacial climate. One prevailing hypothesis for the origin of the MPT is that glacial deep ocean circulation fundamentally changed, marked by a circulation “crisis” at ~0.90 Ma (marine isotope stages 24 to 22). Using high-resolution paired neodymium, carbon, and oxygen isotope data from the South Atlantic Ocean (Cape Basin) across the MPT, we find no evidence of a substantial change in deep ocean circulation. Before and during the early MPT (~1.30 to 1.12 Ma), the glacial deep ocean variability closely resembled that of the most recent glacial cycle. The carbon storage facilitated by developing deep ocean stratification across the MPT required only modest circulation adjustments.

『摘要』 中更新世过渡期（MPT，约125万年至85万年前）标志着冰期-间冰期气候特征的转变。一种广为接受的假说认为，MPT的起源与冰期深海环流的根本性变化有关，并且在约90万年前（海洋同位素阶段24至22）经历了一次“环流危机”。然而，通过分析南大西洋（海角盆地）跨越MPT的高分辨率钕、碳和氧同位素数据，我们未发现深海环流发生实质性变化的证据。在MPT早期（约130万年至112万年前）以及之前，冰期深海的变化与最近的冰期循环非常相似。MPT期间，随着深海分层的增强，碳储存的增加只需要对环流进行小幅调整。

『总结』 MPT期间南大西洋的深海环流变化幅度较小，碳储存的增加主要由深海分层的形成所推动，而非大规模环流危机。

『Abstract』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.

『摘要』 许多多毛哺乳动物会通过快速的身体摆动（称为“湿狗抖”）来去除背部毛发上的水分和刺激性物质。然而，这种行为背后的躯体感觉机制尚不清楚。本研究表明，由Piezo2依赖的机械感觉介导由水滴或油滴作用于小鼠背部毛发皮肤而引发的湿狗抖。无髓鞘C纤维低阈值机械感受器（C-LTMRs）可被油滴激活，其光遗传学激活可诱发湿狗抖。去除 C-LTMRs 会减弱了这种行为。此外，C-LTMRs通过突触连接到脊髓旁小脑核神经元（spinoparabrachial neurons），光遗传学抑制脊髓旁小脑核神经元的突触及小脑旁核中的兴奋性神经元会削弱油滴或C-LTMR引发的湿狗抖动行为。因此，C-LTMR-脊髓旁小脑核通路可促进湿狗抖行为，从而去除背部毛发皮肤上的水分和机械性刺激物。

『总结』 研究发现，Piezo2依赖的机械感知介导了湿狗抖动，通过C-LTMR-脊椎旁小脑通路来促进湿够抖动以去除背部毛发皮肤上的水和机械刺激物。
——小编注：我总觉得这个过程不是完全的应激，而是狗狗可以自觉控制的，不是湿身就抖，而是湿身后想抖才抖。大家可以试试。等等……科学家玩宠物能玩出 Science？

『Abstract』Developing porous materials with ultrahigh surface areas for gas storage (for example, methane) is attractive but challenging. Here, we report two isostructural three-dimensional covalent organic frameworks (COFs) with a rare self-catenated alb -3,6- Ccc 2 topology and a pore size of 1.1 nanometer. Notably, these imine-linked microporous COFs show both high gravimetric Brunauer–Emmett–Teller (BET) surface areas (~4400 square meters per gram) and volumetric BET surface areas (~1900 square meters per cubic centimeter). Moreover, their volumetric methane uptake reaches up to 264 cubic centimeter (standard temperature and pressure) per cubic centimeter [cm (STP) cm ] at 100 bar and 298 kelvin, and they exhibit the highest volumetric working capacity of 237 cm (STP) cm at 5 to 100 bar and 298 kelvin among all reported porous crystalline materials.

『摘要』 开发具有超高表面积的多孔材料用于气体储存（如甲烷）是非常吸引人但也极具挑战性。在此，我们报道了两个具有罕见的自交联 **alb-3,6-Ccc2** 拓扑结构和1.1纳米孔径的同构三维共价有机框架材料（COFs）。值得注意的是，这些亚胺键连接的微孔COFs同时表现出高的重量比布朗纳-埃米特-特勒（BET）表面积（约4400平方米/克）和体积比BET表面积（约1900平方米/立方厘米）。此外，它们的体积甲烷吸附量在100 bar气压、298K 温度下达到264立方厘米（标准温度和压力）/立方厘米，在5到100 bar、298 K 范围内展现出高达237立方厘米（标准温度和压力）/立方厘米的最高工作体积容量，超过所有已报道的多孔晶体材料。

『总结』 研究人员开发出具有超高表面积的共价有机框架（COFs），展示出极高的甲烷吸收能力，超过所有已报道的多孔晶体材料。（第2篇 COF 材料）
——小编注：我以液态二氧化碳密度0.77g/cm³估算了一下，从纯气态到纯液态压缩(22.4L*1000/(44/0.77) = 392倍，230~260倍吸附压缩接近完全液态化，这对于解决天然气的储存和运输是很有吸引力的。

『Abstract』Sleep is integral to cardiovascular health . Yet, the circuits that connect cardiovascular pathology and sleep are incompletely understood. It remains unclear whether cardiac injury influences sleep and whether sleep-mediated neural outputs contribute to heart healing and inflammation. Here we report that in humans and mice, monocytes are actively recruited to the brain after myocardial infarction (MI) to augment sleep, which suppresses sympathetic outflow to the heart, limiting inflammation and promoting healing. After MI, microglia rapidly recruit circulating monocytes to the brain’s thalamic lateral posterior nucleus (LPN) via the choroid plexus, where they are reprogrammed to generate tumour necrosis factor (TNF). In the thalamic LPN, monocytic TNF engages Tnfrsf1a -expressing glutamatergic neurons to increase slow wave sleep pressure and abundance. Disrupting sleep after MI worsens cardiac function, decreases heart rate variability and causes spontaneous ventricular tachycardia. After MI, disrupting or curtailing sleep by manipulating glutamatergic TNF signalling in the thalamic LPN increases cardiac sympathetic input which signals through the β2-adrenergic receptor of macrophages to promote a chemotactic signature that increases monocyte influx. Poor sleep in the weeks following acute coronary syndrome increases susceptibility to secondary cardiovascular events and reduces the heart’s functional recovery. In parallel, insufficient sleep in humans reprogrammes β2-adrenergic receptor-expressing monocytes towards a chemotactic phenotype, enhancing their migratory capacity. Collectively, our data uncover cardiogenic regulation of sleep after heart injury, which restricts cardiac sympathetic input, limiting inflammation and damage.

『摘要』 睡眠对心血管健康至关重要。然而，心血管疾病病理和睡眠之间的联系机制尚未完全明了。心脏损伤是否会影响睡眠，以及睡眠介导的神经输出是否有助于心脏愈合和减轻炎症，这些问题仍有待明确。在这里，我们报告了在人类和小鼠中，单核细胞在心肌梗死（MI）后被积极招募到大脑中，以增强睡眠，这个过程抑制了心脏的交感神经输出，限制炎症并促进愈合。在心肌梗死后，小胶质细胞通过脉络丛快速招募循环单核细胞（我理解应该是“招募外周循环中的单核细胞”）到大脑的丘脑后外侧核（LPN）， 在那里他们被重新编程以生成肿瘤坏死因子（TNF）。在丘脑LPN中，单核细胞表达的TNF与表达Tnfrsf1a的谷氨酸神经元相互作用，以增加慢波睡眠压力和丰度。心肌梗死后，扰乱睡眠会恶化心脏功能，降低心率变异性，并引发自发性室性心动过速。心肌梗死后，通过调控丘脑LPN中谷氨酸-TNF信号通路来干扰或减少睡眠，会增加心脏的交感神经输入，该输入通过巨噬细胞的β2-肾上腺素受体信号传递，促进趋化特征形成，增加单核细胞内流。在急性冠状动脉综合征后的几周内，睡眠不良增加了继发心血管事件的易感性，并降低了心脏的功能恢复能力。同时，在人类中，睡眠不足会促使表达β2-肾上腺素受体的单核细胞重编程，成为趋化表型，增强其迁移能力。总之，我们的数据揭示了心脏损伤后睡眠的心源性调节，该调节通过限制心脏的交感神经输入，进而减轻炎症和损害。【人工校对】

『总结』 研究发现，心脏损伤后，单核细胞被招募到大脑中，以增强睡眠，限制心脏交感输入，以减少炎症和损害。
——小编注：经常996的童鞋，发给你老板看看……看看他良心会不会痛

『Abstract』Atomic nuclei are self-organized, many-body quantum systems bound by strong nuclear forces within femtometre-scale space. These complex systems manifest a variety of shapes , traditionally explored using non-invasive spectroscopic techniques at low energies . However, at these energies, their instantaneous shapes are obscured by long-timescale quantum fluctuations, making direct observation challenging. Here we introduce the collective-flow-assisted nuclear shape-imaging method, which images the nuclear global shape by colliding them at ultrarelativistic speeds and analysing the collective response of outgoing debris. This technique captures a collision-specific snapshot of the spatial matter distribution within the nuclei, which, through the hydrodynamic expansion, imprints patterns on the particle momentum distribution observed in detectors . We benchmark this method in collisions of ground-state uranium-238 nuclei, known for their elongated, axial-symmetric shape. Our findings show a large deformation with a slight deviation from axial symmetry in the nuclear ground state, aligning broadly with previous low-energy experiments. This approach offers a new method for imaging nuclear shapes, enhances our understanding of the initial conditions in high-energy collisions and addresses the important issue of nuclear structure evolution across energy scales.

『摘要』 原子核是强核力束缚在费米尺度空间内的自组织多体量子系统，这些复杂系统表现出多种形状，传统上使用非侵入性光谱技术在低能量下探索。然而，在低能量状态下，它们的瞬时形状被长时间尺度的量子涨落所遮蔽，使得直接观察变得具有挑战性。在这里，我们引入了“集流辅助核成象”方法，该方法通过在超相对论速度下碰撞核并分析出射碎片的集体响应来成像核的全局形状。该技术捕捉核碰撞特定的空间物质分布快照，该快照通过在粒子动量分布上留下印记并被探测器观察到。我们在基态铀-238原子核的碰撞中对这种方法进行了基准测试，铀-238以其细长的轴对称形状而闻名。我们的发现表明核基态具有大的变形，略微偏离轴对称，总体上与之前的低能量实验结果一致。这种方法为成像核形状提供了一种新方法，增强了我们对高能碰撞初始条件的理解，并解决了核结构演化跨能量尺度的重要问题。

『总结』 科学家们开发了一种新的集流辅助核成象方法，可以在高能碰撞中直接观察原子核的形状，从而增强对核结构演化的理解。

『Abstract』Helicobacter pylori disturbs the stomach lining during long-term colonization of its human host, with sequelae including ulcers and gastric cancer . Numerous H. pylori virulence factors have been identified, showing extensive geographic variation . Here we identify a ‘Hardy’ ecospecies of H. pylori that shares the ancestry of ‘Ubiquitous’ H. pylori from the same region in most of the genome but has nearly fixed single-nucleotide polymorphism differences in 100 genes, many of which encode outer membrane proteins and host interaction factors. Most Hardy strains have a second urease, which uses iron as a cofactor rather than nickel , and two additional copies of the vacuolating cytotoxin VacA. Hardy strains currently have a limited distribution, including in Indigenous populations in Siberia and the Americas and in lineages that have jumped from humans to other mammals. Analysis of polymorphism data implies that Hardy and Ubiquitous coexisted in the stomachs of modern humans since before we left Africa and that both were dispersed around the world by our migrations. Our results also show that highly distinct adaptive strategies can arise and be maintained stably within bacterial populations, even in the presence of continuous genetic exchange between strains.

『摘要』 幽门螺杆菌在对人类宿主的长期定植过程中扰乱了胃粘膜功能，其后遗症包括胃溃疡和胃癌。已经鉴定出许多 H-型幽门螺旋杆菌致病因子，这些致病因子显示出明显的地域差异。在这里，我们鉴定出一种“Hardy”（有 AI 译成“硬朗型”，我理解是“耐受性”）生态种属的 H-幽门螺旋杆菌，它与同一地区的“Ubiquitous”（广泛型）H-幽门螺旋杆菌共享大部分基因组祖先，但在其100个基因中存在近乎固定的单核苷酸多态性差异，其中许多编码细菌外膜蛋白和宿主相互作用因子。大多数 Hardy 菌株具有第二个尿酶，这种尿酶使用铁作为辅因子而不是镍，并且具有两个额外的空泡细胞毒素 VacA 副本。Hardy 菌株目前分布有限，包括西伯利亚和美洲的土著人口，以及从人类跳到其他哺乳动物的谱系。多态性数据分析表明，Hardy 和 Ubiquitous 型自从人类离开非洲之前就在现代人类胃中共存，并且随着人类迁徙而全球分布。我们的结果还表明，即使在菌群之间存在连续的基因交流，细菌群体内仍然可以产生高度不同的适应性策略并稳定维持。【人工校对】

『总结』 研究人员鉴定出一种“Hardy”型 H-幽门螺旋杆菌生态种属，它与同地区常见的“Ubiquitous”生态种属共享祖先基因，但具有不同的致病因子和适应策略。
——小编注：幽门螺旋杆菌还有不 Hard 的吗？

『Abstract』Hyperspectral imaging provides high-dimensional spatial–temporal–spectral information showing intrinsic matter characteristics . Here we report an on-chip computational hyperspectral imaging framework with high spatial and temporal resolution. By integrating different broadband modulation materials on the image sensor chip, the target spectral information is non-uniformly and intrinsically coupled to each pixel with high light throughput. Using intelligent reconstruction algorithms, multi-channel images can be recovered from each frame, realizing real-time hyperspectral imaging. Following this framework, we fabricated a broadband visible–near-infrared (400–1,700 nm) hyperspectral image sensor using photolithography, with an average light throughput of 74.8% and 96 wavelength channels. The demonstrated resolution is 1,024 1,024 pixels at 124 fps. We demonstrated its wide applications, including chlorophyll and sugar quantification for intelligent agriculture, blood oxygen and water quality monitoring for human health, textile classification and apple bruise detection for industrial automation, and remote lunar detection for astronomy. The integrated hyperspectral image sensor weighs only tens of grams and can be assembled on various resource-limited platforms or equipped with off-the-shelf optical systems. The technique transforms the challenge of high-dimensional imaging from a high-cost manufacturing and cumbersome system to one that is solvable through on-chip compression and agile computation.

『摘要』 高光谱成像提供高维度时空光谱信息，展示物质的固有特征。在这里，我们报道了一种基于芯片的计算高光谱成像框架，具有高空间和时间分辨率。通过在图像传感器芯片上集成不同的宽带调制材料，目标谱信息被非均匀地和固有地耦合到每个像素上，具有高光通量。使用智能重建算法，可以从每帧中恢复多通道图像，实现实时高光谱成像。按照这个框架，我们使用光刻技术制备了一种“可见到近红外”（400-1,700 nm）宽度的高光谱图像传感器，平均光通量为74.8%，96个波长通道。所示的分辨率为1,024×1,024像素，124帧每秒。我们展示了其广泛的应用，包括智能农业中的叶绿素和糖含量测定，人类健康中的血氧和水质监测，工业自动化中的纺织品分类和苹果压痕检测，以及天文学中的遥感月球检测。集成的高光谱图像传感器仅重几十克，可以装配到各种资源受限的平台上或与现成的光学系统配套。这种技术将高维度成像的挑战从高成本制造和笨拙的系统转化为可以通过芯片压缩和敏捷计算解决的系统。

『总结』 研究人员开发了一种基于芯片的计算高光谱成像框架，具有高空间和时间分辨率，能够实时获取高维度时空-间光谱信息，可应用于智能农业、人类健康、工业自动化和天文学等领域。
——小编注：没明说，但近红外成像军事应用价值更高

『Abstract』Plasmids are major drivers of gene mobilization by means of horizontal gene transfer and play a key role in spreading antimicrobial resistance among pathogens . Despite various bacterial defence mechanisms such as CRISPR–Cas, restriction–modification systems and SOS-response genes that prevent the invasion of mobile genetic elements , plasmids robustly transfer within bacterial populations through conjugation . Here we show that the leading region of plasmids, the first to enter recipient cells, is a hotspot for an extensive repertoire of anti-defence systems, encoding anti-CRISPR, anti-restriction, anti-SOS and other counter-defence proteins. We further identified in the leading region a prevalence of promoters known to allow expression from single-stranded DNA , potentially facilitating rapid protection against bacterial immunity during the early stages of plasmid establishment. We demonstrated experimentally the importance of anti-defence gene localization in the leading region for efficient conjugation. These results indicate that focusing on the leading region of plasmids could lead to the discovery of diverse anti-defence genes. Combined, our findings show a new facet of plasmid dissemination and provide theoretical foundations for developing efficient conjugative delivery systems for natural microbial communities.

『摘要』 质粒是水平基因转移的主要驱动力，并在病原体间传播微生物抗性（耐药性）的过程中扮演关键角色。尽管细菌具有多种防御机制，如CRISPR-Cas、限制-修饰系统和SOS响应基因，以防止移动基因元件的入侵，但质粒仍然可以通过Conjugation （重组？接合？）过程作用在菌群中稳定传递。本研究表明，质粒的leading region（即首先进入受体细胞的区域，译成“先导区域”？）是抗防御系统的热点，包含抗CRISPR、抗限制、抗SOS和其他反防御蛋白的编码基因。我们进一步在先导区中发现了一些已知的启动子，这些启动子可以从单链DNA上表达，可能有助于在质粒建立的早期阶段快速防御细菌免疫。我们实验证明了抗防御基因在先导区中的定位对于高效重组中的重要性。这些结果表明，聚焦质粒的先导区可能会发现多种抗防御基因。综合来看，我们的发现揭示了质粒传播新的一面，并为开发天然微生物群体中的高效接合递送系统奠定了理论基础。【人工校对】

『总结』 本研究表明质粒的先导区是一个抗防御系统的热点，可编码多种抗防御蛋白以逃避细菌免疫，帮助质粒在菌群中传播。
——小编注：质粒在细胞间的传递不借助 DDS <药物递送系统>也可以实现——质粒转大肠杆菌其实就一直用的化学转染法；大自然做减法，人类做加法——高下立判。

『Abstract』α-FA1− x Cs x PbI3 is a promising absorbent material for efficient and stable perovskite solar cells (PSCs) . However, the most efficient α-FA 1− x Cs x PbI 3 PSCs require the inclusion of the additive methylammonium chloride , which generates volatile organic residues (methylammonium) that limit device stability at elevated temperatures . Previously, the highest certified power-conversion efficiency of α-FA 1− x Cs x PbI 3 PSCs without methylammonium chloride was only approximately 24%, and these PSCs have yet to exhibit any stability advantages. Here we identify interfacial contact loss caused by the accumulation of Cs in conventional α-FA 1− x Cs x PbI 3 PSCs, which deteriorates device performance and stability. Through in situ grazing-incidence wide-angle X-ray scattering analysis and density functional theory calculations, we demonstrate an intermediate-phase-assisted crystallization pathway enabled by acetate surface coordination to fabricate high-quality α-FA 1− x Cs x PbI 3 films, without using the methylammonium additive. We herein report a certified stabilized power output efficiency of 25.94% and a reverse-scanning power-conversion efficiency of 26.64% for α-FA 1− x Cs x PbI 3 PSCs. Moreover, the devices exhibited negligible contact losses and enhanced operational stability. They retained over 95% of their initial power-conversion efficiency after operating for over 2,000 h at the maximum power point under 1 sun, 85 °C and 60% relative humidity (ISOS-L-3).

『摘要』 α-FA_{1− x}Cs_xPbI₃ 是一种有前途的吸收材料，用于高效和稳定的钙钛矿太阳能电池（PSCs）。然而，最高效的 α-FA_{1− x}Cs_xPbI₃ 需要添加甲胺氯化物，这会生成易挥发的有机残留物（甲胺），限制设备在高温下的稳定性。之前，未使用甲胺氯化物的 α-FA_{1− x}Cs_xPbI₃ 的最高认证功率转换效率仅约为 24%，这些 PSCs 尚未展示出任何稳定性优势。在这里，我们确定了传统 α-FA_{1− x}Cs_xPbI₃中是因 Cs 的积累而引起界面接触损失，这会恶化设备性能和稳定性。通过原位掠入射广角-X射线散射分析和密度泛函理论计算，我们展示了一种通过乙酸表面配位促进的中间相辅助结晶路径，来制备高质量的 α-FA_{1− x}Cs_xPbI₃ 薄膜，而不无需使用甲胺添加剂。我们报告了的 α-FA_{1− x}Cs_xPbI₃的认证稳定功率输出效率为 25.94%，反向扫描光电转换功率为 26.64%。此外，设备显示出可忽略的接触损失和增强的操作稳定性。在 1 sun（大概一个太阳光照强度）、85°C 和 60% 相对湿度（ISOS-L-3）下，设备在超过 2,000 h 的操作中保留了超过 95% 的初始光电转换效率。【人工校对】

『总结』 研究人员发现了一种新的，不使用甲胺添加剂方法来制备高质量的 α-FA 1− x Cs x PbI 3 薄膜，实现了 25.94% 的认证稳定输出功率和增强的操作稳定性。
——小编注：钙钛矿太阳能电池还这么火热

『Abstract』Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer. Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.1% of tumour samples contain ecDNA. We reveal a pattern highly indicative of tissue-context-based selection for ecDNAs, linking their genomic content to their tissue of origin. We show that not only is ecDNA a mechanism for amplification of driver oncogenes, but it also a mechanism that frequently amplifies immunomodulatory and inflammatory genes, such as those that modulate lymphocyte-mediated immunity and immune effector processes. Moreover, ecDNAs carrying immunomodulatory genes are associated with reduced tumour T cell infiltration. We identify ecDNAs bearing only enhancers, promoters and lncRNA elements, suggesting the combinatorial power of interactions between ecDNAs in trans . We also identify intrinsic and environmental mutational processes linked to ecDNA, including those linked to its formation, such as tobacco exposure, and progression, such as homologous recombination repair deficiency. Clinically, ecDNA detection was associated with tumour stage, more prevalent after targeted therapy and cytotoxic treatments, and associated with metastases and shorter overall survival. These results shed light on why ecDNA is a substantial clinical problem that can cooperatively drive tumour growth signals, alter transcriptional landscapes and suppress the immune system.

『摘要』 外染色体DNA（ecDNA）是癌症治疗抗性和不良预后的主要原因。本文我们探讨了ecDNA在癌症中的多样性，揭示了其与相关组织、基因和突变背景的关联。通过分析来自《100,000基因组计划》项目的14,778名癌症患者、39种肿瘤类型的数据，我们证实了17.1%的肿瘤样本含有ecDNA。我们发现了一个高度指示组织背景选择性分布的模式，将ecDNA的基因组内容与其来源组织相关联。我们的研究表明，ecDNA不仅是驱动致癌基因扩增的机制，还经常扩增免疫调节基因和炎症基因，如调节淋巴细胞介导免疫和免疫效应过程的基因。此外，携带免疫调节基因的ecDNA与肿瘤T细胞浸润减少有关。我们还鉴定出了仅携带增强子、启动子和lncRNA（长链非编码 RNA）元件的ecDNA，表明ecDNA之间的交互作用具有组合性效应。此外，我们还识别出了与ecDNA相关的内在和环境导致的突变过程，包括其形成相关（如烟草暴露）和进展相关（如同源重组修复缺陷）的过程。临床上，ecDNA检测与肿瘤分期相关，在靶向治疗和细胞毒治疗后更为普遍，并且与癌症转移和较短的总生存期相关。这些结果揭示了为什么ecDNA是一个实质性的临床问题——可以协同驱动肿瘤生长信号、改变转录格局和抑制免疫系统。

『总结』 研究发现外染色体DNA（ecDNA）是癌症治疗抵抗和不良预后的主要贡献者，ecDNA可以扩增致癌基因、免疫调节基因，并抑制免疫系统。

『Abstract』Aqueous redox flow batteries with halide-based catholytes (where the halogen atom (X) is Br or I) are promising for sustainable grid energy storage. However, the formation of polyhalides during electrochemical charging and the associated phase separation into X2 limits the operable state of charge (SoC), results in vaporization and self-discharge inefficiencies, and spurs complete device failure . Here we introduce soft–hard zwitterionic trappers (SH-ZITs) as complexing agents composed of a polyhalide-complexing ‘soft’ cationic motif and a water-soluble ‘hard’ anionic motif to enable homogeneous halide cycling. More than 300 structures were designed and 13 were characterized, showcasing the ability to complex polyhalides in homogeneous aqueous solution, to deter cation-exchange membrane crossover and to alter the electrochemical electrode mechanism. In flow battery cycling at a standard catholyte SoC of 66.6 per cent (stoichiometrically X 3 ), an average coulombic efficiency of more than 99.9 per cent at 40 milliamperes per square centimetre with no apparent decay was observed after more than 1,000 cycles over 2 months, with stability at elevated temperatures also demonstrated. Interestingly, SH-ZITs enable homogeneous cycling of the halide catholyte up to 90 per cent SoC at 2 moles per litre (47.7 ampere-hours per litre) for bromide, revealing previously unknown polyhalide regimes to be studied. Ultimately, SH-ZIT enables ultrahigh catholyte capacity utilization up to over 120 ampere-hours per litre at 80 per cent SoC with homogeneous cycling as well as the ability to pair with a zinc anode in a hybrid flow battery.

『摘要』 基于卤化物（其中卤素原子 X 为溴（Br）或碘（I））的水系氧化还原液流电池在可持续电网储能方面极具潜力。然而，在电化学充电过程中形成的多卤化物及其相关的X2相分离限制了可操作的充电状态（SoC），导致蒸发和自放电效率低下，并可能引发设备完全失效。在此，我们引入了软-硬两性离子捕获剂（SH-ZITs）作为络合剂，该捕获剂由能与多卤化物络合的“软”阳离子基团和水溶性的“硬”阴离子基团组成，以实现卤化物的均匀循环。我们设计了300多种结构，并对其中13种进行了表征，证明了它们能够在均相水溶液中络合多卤化物，阻止阳离子交换膜的交叉渗透，并改变电化学电极机制。在标准阴极液SoC为66.6%（按化学计量比为X3）的液流电池循环中，以40毫安每平方厘米（mA/cm²）的电流密度进行超过1000次的循环（超过2个月），观察到平均库仑效率超过99.9%，且无明显衰减，同时也证明了在高温下的稳定性。有趣的是，SH-ZITs使溴化物阴极液能够在2摩尔每升（mol/L）的浓度下以高达90%的SoC（47.7安时每升（Ah/L））进行均匀循环，揭示了之前未知的多卤化物机制供进一步研究。最终，SH-ZITs实现了在80% SoC下阴极液容量利用率超过120 Ah/L的超高水平，同时实现了均匀循环，并能够在混合液流电池中与锌阳极配对。

『总结』 研究者开发了一种软硬两性离子捕获剂（SH-ZITs），可以实现基于卤素阴极液的水性氧化还原流动电池的均相卤素循环，提高电池的效率和稳定性。
——小编注：前面讲储存天然气，这里储电，储能是个很好的方向。

『Abstract』The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently . Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division . Distinct ecDNA sequences, termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells . How multiple ecDNA species within a tumour cell are assorted and maintained across somatic cell generations is unclear. Here we show that cooperative ecDNA species are coordinately inherited through mitotic co-segregation. Imaging and single-cell analyses show that multiple ecDNAs encoding distinct oncogenes co-occur and are correlated in copy number in human cancer cells. ecDNA species are coordinately segregated asymmetrically during mitosis, resulting in daughter cells with simultaneous copy-number gains in multiple ecDNA species before any selection. Intermolecular proximity and active transcription at the start of mitosis facilitate the coordinated segregation of ecDNA species, and transcription inhibition reduces co-segregation. Computational modelling reveals the quantitative principles of ecDNA co-segregation and co-selection, predicting their observed distributions in cancer cells. Coordinated inheritance of ecDNAs enables co-amplification of specialized ecDNAs containing only enhancer elements and guides therapeutic strategies to jointly deplete cooperating ecDNA oncogenes. Coordinated inheritance of ecDNAs confers stability to oncogene cooperation and novel gene regulatory circuits, allowing winning combinations of epigenetic states to be transmitted across cell generations.

『摘要』 染色体遗传理论指出，同一染色体上的基因一起分离，而不同染色体上的基因独立分配。外染色体DNA（ecDNA）在癌症中很常见，并通过细胞分裂中的随机分配驱动肿瘤基因扩增、基因表达紊乱和肿瘤内异质性。不同的ecDNA序列，称为ecDNA种类，可以共存以促进癌细胞中的分子间合作。然而，肿瘤细胞中多个ecDNA种类如何被分配和维持在体细胞世代中尚不清楚。这里我们展示了，协作的ecDNA种类通过有丝分裂共同分配被协调继承。成像和单细胞分析表明，人类癌细胞中编码不同肿瘤基因的多个ecDNA同时出现，并且他们的拷贝数呈正相关。ecDNA种类在有丝分裂期间不对称地协调分配，导致子细胞在任何选择之前同时获得多个ecDNA种类的拷贝数增加。在有丝分裂开始时，分子间近距离和活跃转录促进了ecDNA种类的协调分配，而转录抑制减少了共同分配。计算机模型揭示了ecDNA共同分配和共同选择的定量原则，预测了它们在癌细胞中观察到的分布情况。ecDNA的协调遗传使得只含有增强子元件的专门ecDNA得以共同扩增，并为联合消除合作性ecDNA癌基因的治疗策略提供了指导。ecDNA的协调遗传赋予癌基因合作和新型基因调控回路稳定性，使得表观遗传状态的获胜组合能够跨细胞世代传递。

『总结』 研究发现，肿瘤细胞中的多个外染色体DNA种类通过有丝分裂共同分配被协调继承，促进肿瘤基因合作和新基因调控回路的稳定性。

『Abstract』Capture of CO2 from the air offers a promising approach to addressing climate change and achieving carbon neutrality goals . However, the development of a durable material with high capacity, fast kinetics and low regeneration temperature for CO2 capture, especially from the intricate and dynamic atmosphere, is still lacking. Here a porous, crystalline covalent organic framework (COF) with olefin linkages has been synthesized, structurally characterized and post-synthetically modified by the covalent attachment of amine initiators for producing polyamines within the pores. This COF (termed COF-999) can capture CO2 from open air. COF-999 has a capacity of 0.96 mmol g under dry conditions and 2.05 mmol g under 50% relative humidity, both from 400 ppm CO 2 . This COF was tested for more than 100 adsorption–desorption cycles in the open air of Berkeley, California, and found to fully retain its performance. COF-999 is an exceptional material for the capture of CO 2 from open air as evidenced by its cycling stability, facile uptake of CO 2 (reaches half capacity in 18.8 min) and low regeneration temperature (60 °C).

『摘要』 从空气中捕获 CO₂ 为解决气候变化和实现碳中和目标提供了一种很有前景的方法。然而，开发一种耐用、高容量、快速动力学和低再生温度的材料，以捕获空气中的CO₂，特别是在复杂和动态的大气环境中，仍然未能实现。这里，我们合成了一个多孔的共价有机框架材料（COF），其具有烯烃键（我估计是交联剂），并通过共价键修饰上胺基引发剂，在孔隙中引发聚合生成聚胺。这种COF（称为COF-999）可以从开放空气中捕获CO₂。在干燥条件下，COF-999的捕获能力为0.96 mmol/g，在50%相对湿度下为2.05 mmol/g，均是从400 ppm的 CO₂中进行吸附。我们在加州伯克利的开放空气中对COF-999进行了超过100次吸附-解吸循环测试，并发现它完全保留了其性能。COF-999是捕获开放空气中CO2的优异材料，具有循环稳定、CO₂快速吸附（达到半容量需18.8分钟）和低再生温度（60°C）特征。

『总结』 研究人员开发了一种多孔共价有机框架材料，该材料可以从开放空气中捕获CO₂，具有高容量、快速吸附、低再生温度、良好的循环稳定性和捕获性能。

『Abstract』Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival . At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription–replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses of ecDNA transcription reveal pervasive RNA transcription and associated single-stranded DNA, leading to excessive transcription–replication conflicts and replication stress compared with chromosomal loci. Nucleotide incorporation on ecDNA is markedly slower, and replication stress is significantly higher in ecDNA-containing tumours regardless of cancer type or oncogene cargo. pRPA2-S33, a mediator of DNA damage repair that binds single-stranded DNA, shows elevated localization on ecDNA in a transcription-dependent manner, along with increased DNA double strand breaks, and activation of the S-phase checkpoint kinase, CHK1. Genetic or pharmacological CHK1 inhibition causes extensive and preferential tumour cell death in ecDNA-containing tumours. We advance a highly selective, potent and bioavailable oral CHK1 inhibitor, BBI-2779, that preferentially kills ecDNA-containing tumour cells. In a gastric cancer model containing FGFR2 amplified on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription–replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer.

『摘要』 外染色体DNA（ecDNA）对癌症患者构成了主要挑战。ecDNA通过促进大量肿瘤基因转录和快速基因组演化，使肿瘤对治疗产生抵抗，从而导致患者生存率不佳。目前，没有针对 ecDNA的治疗方法。在这里，我们展示了增强转录-复制冲突可以实现含ecDNA癌症的靶向消除。对ecDNA转录的逐步分析揭示了普遍的RNA转录和相关的单链DNA，从而导致与染色体loci相比的过度转录-复制冲突和复制压力。ecDNA上的核苷酸合成速度明显较慢，无论癌症类型或肿瘤基因载体，含ecDNA肿瘤的复制压力都明显增加。pRPA2-S33，一种结合单链DNA的 DNA损伤修复介质，在ecDNA上显示出增强的定位，并伴随着DNA双链断裂和S期检查点激酶CHK1的激活。CHK1的基因或药理学抑制导致含ecDNA肿瘤细胞的大量的、优先性死亡。我们开发了一种高选择性、高活性和高生物利用度的口服CHK1抑制剂BBI-2779，该抑制剂选择性地杀死含ecDNA的肿瘤细胞。在一个胃癌模型中，FGFR2在ecDNA上被扩增，BBI-2779抑制肿瘤生长，并防止ecDNA介导的泛FGFR抑制剂infigratinib获得性抵抗，从而在小鼠中实现强效且持久的肿瘤消退。转录-复制冲突成为面向ecDNA定向治疗的靶标，利用过量的合成致死效应来治疗癌症。

『总结』 研究人员发现了一种新的治疗策略，即增强转录-复制冲突，以靶向消除含有外染色体DNA（ecDNA）的癌症细胞，并开发了一种高选择性、强效的口服CHK1抑制
——ecDNA 第三篇了

『Abstract』Oil has long been the dominant feedstock for producing fuels and chemicals, but coal, natural gas and biomass are increasingly explored alternatives . Their conversion first generates syngas, a mixture of CO and H 2 , which is then processed further using Fischer–Tropsch (FT) chemistry. However, although commercial FT technology for fuel production is established, using it to access valuable chemicals remains challenging. A case in point is linear α-olefins (LAOs), which are important chemical intermediates obtained by ethylene oligomerization at present . The commercial high-temperature FT process and the FT-to-olefin process under development at present both convert syngas directly to LAOs, but also generate much CO2 waste that leads to a low carbon utilization efficiency . The efficiency is further compromised by substantially fewer of the converted carbon atoms ending up as valuable C5 –C10 LAOs than are found in the C2 –C4 olefins that dominate the product mixtures. Here we show that the use of the original phase-pure χ-iron carbide can minimize these syngas conversion problems: tailored and optimized for the process of FT to LAOs, this catalyst exhibits an activity at 290 °C that is 1–2 orders higher than dedicated FT-to-olefin catalysts can achieve above 320 °C , is stable for 200 h, and produces desired C2 –C10 LAOs and unwanted CO2 with carbon-based selectivities of 51% and 9% under industrially relevant conditions. This higher catalytic performance, persisting over a wide temperature range (250–320 °C), demonstrates the potential of the system for developing a practically relevant technology.

『摘要』 石油长期以来一直是生产燃料和化学品的主要原料，但煤、天然气和生物质正在被越来越多地探索作为替代方案。这些替代方案的转换首先生成合成气，一种一氧化碳和氢气的混合物，然后使用费歇尔-特罗普什（FT）化学进行进一步处理。然而，尽管用于燃料生产的商业FT技术已经建立起来，但使用它来获得有价值的化学品仍然具有挑战性。一个典型的例子是线性α-烯烃（LAOs），它们是通过乙烯齐聚反应获得的重要化学中间体。目前的商业高温FT过程和正在开发的FT-to-olefin过程都将合成气直接转化为LAOs，但也生成了大量的CO₂废料，从而导致了较低的碳利用效率。由于转化后的碳原子中进入有价值的C5-C10线性α-烯烃（LAOs）的比例显著低于占主导地位的C2-C4烯烃，效率进一步降低。这里我们发现，使用原相纯的χ-铁碳化物（作催化剂）可以最大限度地减少合成气转化中的问题：这种催化剂专为费托（FT）合成线性α-烯烃（LAOs）工艺而优化，在290°C下的活性比专用的FT制烯烃催化剂在320°C以上的活性高出1-2个数量级；且在工业相关条件下可以稳定工作200小时，分别产生以基于碳原子计量51%的C2-C10 LAOs目标产物、仅9%的不需要的CO₂。这种在宽温度范围（250-320°C）内持续保持高催化活性的特性，显示了该系统在开发实际应用相关技术方面的潜力。【人工校对】

『总结』 研究人员发现了一种新的催化剂，可以高效地将合成气转化为线性α-烯烃，解决了传统FT技术的低碳利用效率和产品选择性问题。

『Abstract』Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity . In this study, we investigated the evolution of genomic signatures caused by endogenous and external mutagenic processes and their interplay with complex structural variants (SVs). We superimposed mutational signatures and phylogenetic analyses of matched serial tumours from patients with urothelial cancer to define the evolutionary dynamics of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas chemotherapy induces mutational bursts of hundreds of late subclonal mutations. Using a genome graph computational tool , we observed frequent high copy-number circular amplicons characteristic of extrachromosomal DNA (ecDNA)-forming SVs. We characterized the distinct temporal patterns of APOBEC3-induced and chemotherapy-induced mutations within ecDNA-forming SVs, gaining new insights into the timing of these mutagenic processes relative to ecDNA biogenesis. We discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA-forming SVs. ecDNA-forming SVs persisted and increased in complexity, incorporating additional DNA segments and contributing to the evolution of treatment resistance. Oxford Nanopore Technologies long-read whole-genome sequencing followed by de novo assembly mapped out CCND1 ecDNA structure. Experimental modelling of CCND1 ecDNA confirmed its role as a driver of treatment resistance. Our findings define fundamental mechanisms that drive urothelial cancer evolution and have important therapeutic implications.

『摘要』 晚期尿路上皮癌是一种具有明显基因异质性的致命疾病。在本文研究中，我们调查了内源性和外源性致突变过程引起的基因组特征演变及其与复杂结构变异（SVs）的相互作用。我们同时运用突变特征分析和系统发育分析方法对匹配的连续分期（机翻及 AI 译为“匹配连续肿瘤样本”，我理解应该是“不同肿瘤分期的肿瘤样本”）尿路上皮癌患者肿瘤样本进行研究，以定义这些过程的演变（evolutionary，机译“进化”，对于个体我想到不了进化层面，也无方向性；所以用“演变”、“演化”，比较合适）动力学。我们的研究表明，APOBEC3诱导的突变是克隆性的和早期的，而化疗会导致数百个晚期亚克隆突变的爆发。借助基因组图计算工具，我们观察到由外染色体DNA（ecDNA）形成的SVs常表现为高拷贝数的环形扩增子。我们描述了APOBEC3诱导和化疗诱导突变在ecDNA形成SVs中的不同时间模式，获得了这些诱变过程相对于ecDNA生物发生的新见解。我们发现，尿路上皮癌中大多数CCND1扩增来自环形ecDNA形成SVs。ecDNA形成的SVs在治疗过程中持续存在并增加复杂性，整合更多的DNA段，并推动治疗抵抗进化（大多数treatment resistance我翻译成“治疗抵抗”而非“耐药”，除非原文为 drug resistance，因为肿瘤的治疗手段不只化疗）。通过牛津纳米孔技术长读全基因组测序后进行de novo assembly（可能是一种分析方法），描绘出了CCND1 ecDNA结构。实验模型CCND1 ecDNA证实了其作为治疗抵抗的驱动因素。我们的发现定义了尿路上皮癌演化的基本机理，具有重要的治疗意义。

『总结』 研究发现尿路上皮癌的演化是由APOBEC3诱导的早期突变和化疗诱导的晚期突变爆发所驱动的，并且ecDNA形成SVs在治疗抵抗的演化中扮演着关键角色。
——小编注：这篇值得深思……

『Abstract』The Greenland ice sheet (GrIS) is at present the largest single contributor to global-mass-induced sea-level rise, primarily because of Arctic amplification on an increasingly warmer Earth . However, the processes of englacial water accumulation, storage and ultimate release remain poorly constrained. Here we show that a noticeable amount of the summertime meltwater mass is temporally buffered along the entire GrIS periphery, peaking in July and gradually reducing thereafter. Our results arise from quantifying the spatiotemporal behaviour of the total mass of water leaving the GrIS by analysing bedrock elastic deformation measured by Global Navigation Satellite System (GNSS) stations. The buffered meltwater causes a subsidence of the bedrock close to GNSS stations of at most approximately 5 mm during the melt season. Regionally, the duration of meltwater storage ranges from 4.5 weeks in the southeast to 9 weeks elsewhere. We also show that the meltwater runoff modelled from regional climate models may contain systematic errors, requiring further scaling of up to about 20% for the warmest years. These results reveal a high potential for GNSS data to constrain poorly known hydrological processes in Greenland, forming the basis for improved projections of future GrIS melt behaviour and the associated sea-level rise .

『摘要』 格陵兰冰盖（GrIS）目前是全球海平面上升的最大单一贡献者，主要是由于全球变暖的北极放大效应。然而，对于冰川内水的积累、存储和最终释放的过程仍然不太确定。在本研究中，我们发现，夏季融水质量的一部分在格陵兰冰盖周边明显地被暂存，其峰值在七月，然后逐渐减少。我们的结果基于对全球导航卫星系统（GNSS）站点测量的基岩弹性变形的分析，来量化格陵兰冰盖离开的总水质量的时空行为。在融水季节，暂存的融水引起了GNSS站附近基岩的沉降，最大沉降约5毫米。在区域上，融水存储的持续时间从东南部的4.5周到其他地区的9周不等。此外，我们还发现，区域气候模型模拟的融水径流可能包含系统性误差，在最温暖的年份需要进一步放大约20%。这些结果揭示了GNSS数据对约束格陵兰尚不确定的水文过程具有重要潜力，为改进未来GrIS融水行为和相关海平面上升的预测奠定基础。

『总结』 格陵兰冰盖周边的融水暂存现象可能会影响海平面上升的预测，GNSS数据可以约束这种过程，提高未来融水行为和海平面上升的预测准确性。

『Abstract』The ribonuclease FttA (also known as aCPSF and aCPSF1) mediates factor-dependent transcription termination in archaea . Here we report the structure of a Thermococcus kodakarensis transcription pre-termination complex comprising FttA, Spt4, Spt5 and a transcription elongation complex (TEC). The structure shows that FttA interacts with the TEC in a manner that enables RNA to proceed directly from the TEC RNA-exit channel to the FttA catalytic centre and that enables endonucleolytic cleavage of RNA by FttA, followed by 5′→3′ exonucleolytic cleavage of RNA by FttA and concomitant 5′→3′ translocation of FttA on RNA, to apply mechanical force to the TEC and trigger termination. The structure further reveals that Spt5 bridges FttA and the TEC, explaining how Spt5 stimulates FttA-dependent termination. The results reveal functional analogy between bacterial and archaeal factor-dependent termination, functional homology between archaeal and eukaryotic factor-dependent termination, and fundamental mechanistic similarities in factor-dependent termination in bacteria, archaea, and eukaryotes.

『摘要』 核糖核酸酶FttA（也称为aCPSF或aCPSF1）介导古菌中依赖因子的转录终止。我们报道了一个来自Thermococcus kodakarensis的转录预终止复合物的结构，其中包含FttA、Spt4、Spt5和转录延伸复合物（TEC）。结构显示，FttA与TEC相互作用，使RNA可以直接从TEC的RNA出口通道进入FttA的催化中心，并允许FttA对RNA进行内切核酸酶裂解，随后进行5’→3’外切核酸酶裂解，同时FttA沿RNA的5’→3’转移，对TEC施加机械力，从而触发终止。结构还揭示了Spt5在FttA与TEC之间的桥梁作用，解释了Spt5如何促进FttA依赖的终止过程。这些结果表明了细菌和古菌依赖因子终止的功能相似性，古菌和真核生物依赖因子终止的功能同源性，以及细菌、古菌和真核生物中依赖因子终止的基本机制相似性。

『总结』 研究揭示了FttA通过与TEC和Spt5协作触发古菌转录终止的分子机制，并展示了其与细菌和真核中依赖因子终止的共同特性和进化联系。

『Abstract』The fast increase of convergence rate between India and Eurasia around 65 million years ago (Ma)—from approximately 8 cm yr to a peak rate of approximately 18 cm yr —remains a complex geological event to explain , given the inherent uncertainty surrounding the tectonic history and the intricate interplay of forces influencing plate speed . Here we use a combination of geochemical analysis and geodynamic modelling to propose that this rapid convergence can be explained by sediment subduction derived from the northern Indian passive margin. Through isotope and trace element analysis, we find an enhanced contribution of terrigenous sediment melt to the mantle source of the Gangdese magmatic rocks around 65 Ma, concurrent with the acceleration of India–Eurasia convergence. Numerical experiments suggest that subduction of sediments more than 1 km thick covering an approximately 1,000-km-wide ocean basin abutting the northern Indian passive margin starting from 65 Ma could have spurred the increased convergence rate and further led to significant crustal extension, consistent with empirical observations. Our study implies that the acceleration of India–Eurasia convergence marks the arrival of passive-margin-derived sediments, constraining the initial India–Eurasia collision to be around 60 Ma. It further suggests that temporary accelerations in subduction rates might be a common feature at the final stage of continental assembly.

『摘要』 印度与欧亚板块之间的融合速率在约6500万年前（Ma）从约8厘米/年快速增加到约18厘米/年的峰值，这一复杂的地质事件仍难以解释，因为与板块运动历史相关的不确定性及影响板块速度的多种力的复杂交互作用。在本研究中，我们结合地球化学分析和地球动力学模型提出，这一快速融合可以通过源自印度北部被动大陆边缘的沉积物俯冲来解释。通过同位素和微量元素分析，我们发现，约6500万年前，源自陆源沉积物熔体对冈底斯岩浆岩地幔来源的贡献显著增加，与印度-欧亚板块融合加速相一致。数值实验表明，从6500万年开始，覆盖约1,000公里宽的海洋盆地、厚度超过1公里的沉积物俯冲，可能引发了融合速率的增加，并进一步导致显著的地壳伸展，这与实证观测结果一致。我们的研究表明，印度-欧亚板块融合加速标志着被动大陆边缘沉积物的到达，并将初始印度-欧亚碰撞时间约束在6000万年前。此外，研究还表明，在大陆拼合的最终阶段，俯冲速率的短暂加速可能是一个常见特征。

『总结』 本研究通过沉积物俯冲机制解释印度与欧亚板块6500万年前的融合加速，并将初始碰撞时间约束在6000万年前，同时揭示大陆拼合晚期可能普遍存在短暂的俯冲速率加速现象。
——三哥心里的压迫感，源于6000万年前

『Abstract』The interplay between translation and mRNA decay is widespread in human cells . In quality-control pathways, exonucleolytic degradation of mRNA associated with translating ribosomes is mediated largely by the cytoplasmic exosome , which includes the exoribonuclease complex EXO10 and the helicase complex SKI238. The helicase can extract mRNA from the ribosome and is expected to transfer it to the exoribonuclease core through a bridging factor, HBS1L3 (also known as SKI7), but the mechanisms of this molecular handover remain unclear . Here we reveal how human EXO10 is recruited by HBS1L3 (SKI7) to an active ribosome-bound SKI238 complex. We show that rather than a sequential handover, a direct physical coupling mechanism takes place, which culminates in the formation of a cytoplasmic exosome–ribosome supercomplex. Capturing the structure during active decay reveals a continuous path in which an RNA substrate threads from the 80S ribosome through the SKI2 helicase into the exoribonuclease active site of the cytoplasmic exosome complex. The SKI3 subunit of the complex directly binds to HBS1L3 (SKI7) and also engages a surface of the 40S subunit, establishing a recognition platform in collided disomes. Exosome and ribosome thus work together as a single structural and functional unit in co-translational mRNA decay, coordinating their activities in a transient supercomplex.

『摘要』 翻译与mRNA降解之间的相互作用在人体细胞中广泛存在。在质量控制通路中，与翻译核糖体相关的mRNA的外切核酸酶降解主要由胞质外体（cytoplasmic exosome，在细胞内发挥功能， 我想译成“外泌体”可能不合适，就简单用“外体”表示）介导，该外体包括外切核糖核酸酶复合物EXO10和解旋酶复合物SKI238。解旋酶可以从核糖体中提取mRNA，并预期通过桥接因子HBS1L3（也称为SKI7）将其转移到外切核酸酶核心，但这种分子交接的机制尚不清楚。在本研究中，我们揭示了人类外切核糖核酸酶复合物EXO10如何通过桥接因子HBS1L3（SKI7）被招募到一个活跃的、与核糖体结合的解旋酶复合物SKI238复合物中。我们发现，与其说是一个顺序交接过程，不如说是一种直接的物理耦合机制，最终形成一个胞质外体-核糖体超级复合物。捕捉活跃降解过程中的结构显示了一个连续的路径，其中RNA底物从80S核糖体通过SKI2解旋酶进入胞质外体复合物的外切核酸酶活性位点。SKI238复合物的SKI3亚基直接与HBS1L3（SKI7）结合，并与40S亚基的一个表面接触，在碰撞二聚体中建立了一个识别平台。外体和核糖体因此作为一个单一的结构和功能单位在协同翻译mRNA降解中协同工作，通过短暂的超级复合物协调它们的活动。

『总结』 研究发现人类细胞中的翻译和mRNA降解之间存在直接的物理耦合机理，形成细胞质外体-核糖体超复合体，协调翻译和衰变活动。
——小编注：也就是说 mRNA的降解本身与翻译过程也有关，如何利用这一点？可能是 mRNA 设计忽略的一个考量点！！

『Abstract』Natural disasters trigger complex chains of events within human societies . Immediate deaths and damage are directly observed after a disaster and are widely studied, but delayed downstream outcomes, indirectly caused by the disaster, are difficult to trace back to the initial event . Tropical cyclones (TCs)—that is, hurricanes and tropical storms—are widespread globally and have lasting economic impacts , but their full health impact remains unknown. Here we conduct a large-scale evaluation of long-term effects of TCs on human mortality in the contiguous United States (CONUS) for all TCs between 1930 and 2015. We observe a robust increase in excess mortality that persists for 15 years after each geophysical event. We estimate that the average TC generates 7,000–11,000 excess deaths, exceeding the average of 24 immediate deaths reported in government statistics . Tracking the effects of 501 historical storms, we compute that the TC climate of CONUS imposes an undocumented mortality burden that explains a substantial fraction of the higher mortality rates along the Atlantic coast and is equal to roughly 3.2–5.1% of all deaths. These findings suggest that the TC climate, previously thought to be unimportant for broader public health outcomes, is a meaningful underlying driver for the distribution of mortality risk in CONUS, especially among infants (less than 1 year of age), people 1–44 years of age, and the Black population. Understanding why TCs induce this excess mortality is likely to yield substantial health benefits.

『摘要』 自然灾害会在人类社会中引发复杂的事件链。灾后直接观察到的死亡和损失被广泛研究，但灾害间接引起的延迟性后果却难以追溯到最初的事件。热带气旋（TCs），即飓风和热带风暴——在全球范围内广泛存在，并对经济产生持久影响，但它们对公共健康的影响仍不明确。本文对1930年至2015年期间美国本土所有热带气旋的长期健康影响进行大规模评估。我们观察到，在每次地质事件发生后，超额死亡率显著增加，并持续15年。我们估算，平均每次热带气旋会导致7,000到11,000例超额死亡，超过政府统计的即时死亡数平均24例。通过追踪501场历史风暴，我们计算出，美国本土的热带气旋气候带来了未被记录的死亡负担，解释了大西洋沿岸更高的死亡率，并占所有死亡的约3.2%至5.1%。这些发现表明，之前被认为与公共健康结果无关的热带气旋气候，是美国本土死亡风险分布的重要驱动因素，尤其是在婴儿（1岁以下）、1-44岁人群和黑人群体中。理解为何热带气旋引发这些超额死亡可能带来显著的公共健康益处。

『总结』 热带气旋对人类死亡率的影响远远超过直接死亡，平均每个热带气旋会导致7,000-11,000例超额死亡，尤其在婴儿、年轻人和黑人群体中更为显著。

『Abstract』Complex multicellularity has emerged independently across a few eukaryotic lineages and is often associated with the rise of elaborate, tightly coordinated developmental processes . How multicellularity and development are interconnected in evolution is a major question in biology. The hourglass model of embryonic evolution depicts how developmental processes are conserved during evolution, and predicts morphological and molecular divergence in early and late embryogenesis, bridged by a conserved mid-embryonic (phylotypic) period linked to the formation of the basic body plan . Initially found in animal embryos , molecular hourglass patterns have recently been proposed for land plants and fungi . However, whether the hourglass pattern is an intrinsic feature of all complex multicellular eukaryotes remains unknown. Here we tested the presence of a molecular hourglass in the brown algae, a eukaryotic lineage that has evolved multicellularity independently from animals, fungi and plants . By exploring transcriptome evolution patterns of brown algae with distinct morphological complexities, we uncovered an hourglass pattern during embryogenesis in morphologically complex species. Filamentous algae without canonical embryogenesis display transcriptome conservation in multicellular stages of the life cycle, whereas unicellular stages are more rapidly evolving. Our findings suggest that transcriptome conservation in brown algae is associated with cell differentiation stages, but is not necessarily linked to embryogenesis. Together with previous work in animals, plants and fungi, we provide further evidence for the generality of a developmental hourglass pattern across complex multicellular eukaryotes.

『摘要』 复杂多细胞化在几个真核生物谱系中独立出现，并且通常与伴随精细、紧密协调的发育过程的相关联。多细胞化和发育在进化上如何相互关联是生物学中的一个主要问题。胚胎发育的沙漏模型描绘了发育过程在进化中是如何保持不变的，并预测了早期和晚期胚胎发育中的形态和分子差异，这些差异通过一个与基本体型形成相关的保守的中胚期（种型期）连接起来。沙漏模式最初是在动物胚胎中发现的，但最近也有人在陆生植物和真菌中提出了分子沙漏模式。然而，沙漏模式是否是所有复杂多细胞真核生物的内在特征仍不得而知。在这里，我们测试了棕色藻类（一种独立于动物、真菌和植物进化出多细胞性的真核生物谱系）中是否存在分子沙漏模式。通过探索具有不同形态复杂性的棕色藻类的转录组进化模式，我们在形态复杂的物种的胚胎发育过程中发现了沙漏模式。没有典型胚胎发育的丝状藻类在其生命周期的多细胞阶段显示出转录组的保守性，而单细胞阶段的进化速度则更快。我们的研究结果表明，棕色藻类的转录组保守性与细胞分化阶段有关，但不一定与胚胎发育有关。结合之前在动物、植物和真菌中的研究，我们为复杂多细胞真核生物中发育沙漏模式的普遍性提供了进一步的证据。

『总结』 本研究在棕色藻类中发现了发育沙漏模式，表明复杂多细胞真核生物的转录组保守性可能与细胞分化阶段相关，而不一定与胚胎发育直接相关，为发育沙漏模式在复杂多细胞真核生物中的普遍性提供了进一步证据。

『Abstract』Now extinct, the aurochs ( Bos primigenius ) was a keystone species in prehistoric Eurasian and North African ecosystems, and the progenitor of cattle ( Bos taurus ), domesticates that have provided people with food and labour for millennia . Here we analysed 38 ancient genomes and found 4 distinct population ancestries in the aurochs—European, Southwest Asian, North Asian and South Asian—each of which has dynamic trajectories that have responded to changes in climate and human influence. Similarly to Homo heidelbergensis , aurochsen first entered Europe around 650 thousand years ago , but early populations left only trace ancestry, with both North Asian and European B. primigenius genomes coalescing during the most recent glaciation. North Asian and European populations then appear separated until mixing after the climate amelioration of the early Holocene. European aurochsen endured the more severe bottleneck during the Last Glacial Maximum, retreating to southern refugia before recolonizing from Iberia. Domestication involved the capture of a small number of individuals from the Southwest Asian aurochs population, followed by early and pervasive male-mediated admixture involving each ancestral strain of aurochs after domestic stocks dispersed beyond their cradle of origin.

『摘要』 现已灭绝的原始牛（Bos primigenius）是史前欧亚大陆和北非生态系统的关键物种，也是数千年来为人们提供食物和劳力的家畜——家牛（Bos taurus）的祖先。在本文中，我们分析了38个古代基因组，并在原始牛中发现了4个不同的种群起源——欧洲、西南亚、北亚和南亚，每个起源的动态轨迹都反映了对气候变化和人类影响的响应。与海德堡人（Homo heidelbergensis）类似，原始牛大约在65万年前首次进入欧洲，但早期种群只留下极少的祖先痕迹，北亚和欧洲的Bos primigenius基因组在最近一次冰河时期汇聚。然后，北亚和欧洲种群出现分离，直到全新世早期气候改善后才再次混合。欧洲原始牛在末次冰盛期经历了更为严重的瓶颈期，它们先退到南部避难所，然后从伊比利亚半岛重新定居。驯化过程涉及从西南亚原始牛种群中捕获少数个体，随后在家畜离开其起源地后，每个原始牛祖先种群都发生了早期且普遍的雄性介导的混合。

『总结』 原始牛作为史前关键物种，其不同种群起源反映了气候和人类影响，驯化则涉及从西南亚种群捕获少量个体及后续各祖先种群的雄性介导混合。

『Abstract』Mate recognition systems evolve rapidly to reinforce the reproductive boundaries between species, but the underlying neural mechanisms remain enigmatic. Here we leveraged the rapid coevolution of female pheromone production and male pheromone perception in Drosophila to gain insight into how the architecture of mate recognition circuits facilitates their diversification. While in some Drosophila species females produce unique pheromones that act to arouse their conspecific males, the pheromones of most species are sexually monomorphic such that females possess no distinguishing chemosensory signatures that males can use for mate recognition . We show that Drosophila yakuba males evolved the ability to use a sexually monomorphic pheromone, 7-tricosene, as an excitatory cue to promote courtship. By comparing key nodes in the pheromone circuits across multiple Drosophila species, we reveal that this sensory innovation arises from coordinated peripheral and central circuit adaptations: a distinct subpopulation of sensory neurons has acquired sensitivity to 7-tricosene and, in turn, selectively signals to a distinct subset of P1 neurons in the central brain to trigger courtship. Such a modular circuit organization, in which different sensory inputs can independently couple to parallel courtship control nodes, may facilitate the evolution of mate recognition systems by allowing novel sensory modalities to become linked to male arousal. Together, our findings suggest how peripheral and central circuit adaptations can be flexibly coordinated to underlie the rapid evolution of mate recognition strategies across species.

『摘要』 配偶识别系统进化迅速，以强化物种间的生殖隔离，但其潜在的神经机制仍是个谜。本研究利用了果蝇中雌性信息素产生和雄性信息素感知的快速协同进化，来深入了解配偶识别系统的结构如何促进其多样化。在一些果蝇物种中，雌性会释放独特的信息素来激发同物种雄性的交配欲望，但大多数物种的信息素在性别上是单态（单一，没有区分度）的，即雌性没有可供雄性用于配偶识别的独特化学感官特征。本研究表明，雅库巴果蝇（Drosophila yakuba）雄性进化出了利用性别单态信息素7-二十三碳烯（7-tricosene）作为性兴奋线索来促进交配行为的能力。通过比较多个果蝇物种信息素回路中的关键节点，本研究发现这种感官创新源于外周回路和中枢回路的协同适应：一个特定的感觉神经元亚群已对7-二十三碳烯变得敏感，并转而选择性地向中央大脑中的特定P1神经元亚群发送信号，以触发交配行为。在这种模块化回路组织中，不同的感官输入可以独立地与平行的交配控制节点结合，这可能通过使新的感官模态与雄性交配欲望相关联，从而促进配偶识别系统的进化。综上所述，本研究结果揭示了外周回路和中枢回路适应如何灵活协调，以支撑物种间配偶识别策略的迅速进化。

『总结』 本研究通过果蝇信息素回路的分析，揭示了配偶识别系统进化迅速的原因，即外周和中枢回路适应的灵活协调。

『Abstract』Behavioural time scale plasticity (BTSP) is non-Hebbian plasticity induced by integrating presynaptic and postsynaptic components separated by a behaviourally relevant time scale (seconds) . BTSP in hippocampal CA1 neurons underlies place cell formation. However, the molecular mechanisms that enable synapse-specific plasticity on a behavioural time scale are unknown. Here we show that BTSP can be induced in a single dendritic spine using two-photon glutamate uncaging paired with postsynaptic current injection temporally separated by a behavioural time scale. Using an improved Ca /calmodulin-dependent kinase II (CaMKII) sensor, we did not detect CaMKII activation during this BTSP induction. Instead, we observed dendritic, delayed and stochastic CaMKII activation (DDSC) associated with Ca influx and plateau potentials 10–100 s after BTSP induction. DDSC required both presynaptic and postsynaptic activity, which suggests that CaMKII can integrate these two signals. Also, optogenetically blocking CaMKII 15–30 s after the BTSP protocol inhibited synaptic potentiation, which indicated that DDSC is an essential mechanism of BTSP. IP 3 -dependent intracellular Ca release facilitated both DDSC and BTSP. Thus, our study suggests that non-synapse-specific CaMKII activation provides an instructive signal with an extensive time window over tens of seconds during BTSP.

『摘要』 行为时间尺度可塑性（BTSP）是一种通过整合以行为相关时间尺度（秒级）分隔的突触前和突触后成分而诱导的非Hebbian型可塑性。在海马CA1神经元中，BTSP是定位细胞形成的基础。然而，支持在行为时间尺度上实现突触特异性可塑性的分子机制尚不清楚。本研究表明，使用双光子谷氨酸光解结合与突触后电流注入，并在行为时间尺度上分离，可以在单一树突棘中诱导BTSP。通过改进的钙/钙调蛋白依赖性激酶II（CaMKII）传感器，我们在BTSP诱导过程中未检测到CaMKII激活，而是观察到与钙流入和平台电位相关的树突延迟随机CaMKII激活（DDSC），其发生于BTSP诱导后10-100秒内。DDSC需要突触前和突触后活动，这表明CaMKII可以整合这两种信号。此外，通过光遗传学在BTSP方案后15-30秒阻断CaMKII活动会抑制突触增强，这表明DDSC是BTSP的关键机制。IP3依赖性胞内钙释放促进了DDSC和BTSP的发生。因此，本研究表明，非突触特异性的CaMKII激活在BTSP过程中提供了一个跨越数十秒的广泛时间窗口的指导信号。

『总结』 研究揭示了CaMKII的延迟随机激活是行为时间尺度可塑性的重要机制，为理解突触可塑性提供了新的时间尺度上的分子视角。

『Abstract』Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD. In mouse tumor models, pulsed and low-level pyroptosis induced by DMB suppresses tumor growth without harming GSDMD-expressing immune cells. Protection is immune-mediated and abrogated in mice lacking lymphocytes. Vaccination with DMB-treated cancer cells protects mice from secondary tumor challenge, indicating that immunogenic cell death is induced. DMB treatment synergizes with anti-PD-1. DMB treatment does not alter circulating proinflammatory cytokine or leukocyte numbers or cause weight loss. Thus, our studies reveal a strategy that relies on a low level of tumor cell pyroptosis to induce antitumor immunity and raise the possibility of exploiting pyroptosis without causing overt toxicity.

『摘要』 Gasdermin介导的炎性细胞死亡（焦亡）可以在免疫冷肿瘤中激活保护性免疫。在这里，我们进行了一次高通量筛选，以寻找能够激活广泛表达于肿瘤中的Gasdermin D（GSDMD）的化合物。我们鉴定出6,7-二氯-2-甲基磺基-3-N-叔丁基氨基喹诺沙林（DMB）是一种直接和选择性的GSDMD激动剂，可以激活GSDMD孔洞的形成和焦亡，而不裂解GSDMD。在小鼠肿瘤模型中，DMB诱导的脉冲式和低水平的焦亡抑制了肿瘤生长，而不损害表达GSDMD的免疫细胞。保护是免疫介导的，在缺乏淋巴细胞的小鼠中，这种保护作用被清除。用DMB处理的癌细胞疫苗可以保护小鼠免受次级肿瘤挑战，表明诱导了免疫原细胞死亡。DMB治疗与抗PD-1治疗具有协同作用。DMB治疗不改变循环的炎性细胞因子或白细胞数量，也不引起体重减轻。因此，我们的研究揭示了一种依赖肿瘤细胞低水平焦亡来诱导抗肿瘤免疫的策略，并提出了利用焦亡而不引起明显毒性的可能性。

『总结』 研究发现了一种激活GSDMD的化合物DMB，可以诱导肿瘤细胞焦亡，从而激活抗肿瘤免疫，而不引起明显毒性。 （Gasdermin D具体指什么还没细查，保留原单词；ChatGPT 译成“气道素”）

『Abstract』Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor β (TGF-β) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-β and RAS inputs. RREB1 localizes to H4K16acK20ac marks in histone H2A.Z-loaded nucleosomes at enhancers in the fibrogenic genes interleukin-11 ( IL11 ), platelet-derived growth factor-B ( PDGFB ), and hyaluronan synthase 2 ( HAS2 ), as well as the EMT transcription factor SNAI1 , priming these enhancers for activation by a SMAD4-INO80 nucleosome remodeling complex in response to TGF-β. These regulatory properties segregate the fibrogenic EMT program from RAS-independent TGF-β gene responses and illuminate the operation and vulnerabilities of a bifunctional program that promotes metastatic outgrowth.

『摘要』 上皮到间质转化（EMT）和细胞外基质（ECM）重塑是在癌症侵袭和转移过程中既独立又重要的过程。转化生长因子β（TGF-β）和RAS通过SMAD和RAS反应元件结合蛋白1（RREB1）信号共同触发癌症细胞中EMT和成纤维因子表达，这两者作为共同转录反应的两个独立途径。在本研究中，我们证明了这两个途径共同作用，形成了肺腺癌转移的程序，并识别了将组成基因的表达与TGF-β和RAS输入联系起来的染色质决定因子。RREB1定位于纤维化基因（如白介素-11（IL11）、血小板源性生长因子-B（PDGFB）和透明质酸合酶2（HAS2））以及EMT转录因子SNAI1的增强子上，这些区域的组蛋白H2A.Z负载核小体上有H4K16acK20ac标记，准备通过SMAD4-INO80核小体重塑复合体在TGF-β刺激下激活这些增强子。这些调控特性将纤维化EMT程序与RAS独立的TGF-β基因反应区分开，揭示了一个促进转移性生长的双功能程序的运作机制及其脆弱性。

『总结』 TGF-β和RAS共同触发EMT和成纤维因子的表达，形成了肺腺癌转移的程序，并且RREB1在染色质水平上调节了该程序的运作机制和脆弱性。

『Abstract』TGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvβ8 activates L-TGF-β1/GARP. The dogma is that mature TGF-β must physically dissociate from L-TGF-β1 for signaling to occur. Our previous studies discovered that αvβ8-mediated TGF-β autocrine signaling can occur without TGF-β1 release from its latent form. Here, we show that mice engineered to express TGF-β1 that cannot release from L-TGF-β1 survive without early lethal tissue inflammation, unlike those with TGF-β1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-β1 signaling without release where αvβ8 binding redistributes the intrinsic flexibility of L-TGF-β1 to expose TGF-β1 to its receptors. Dynamic allostery explains the TGF-β3 latency/activation mechanism and why TGF-β3 functions distinctly from TGF-β1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.

『摘要』 TGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvβ8 activates L-TGF-β1/GARP. The dogma is that mature TGF-β must physically dissociate from L-TGF-β1 for signaling to occur. Our previous studies discovered that αvβ8-mediated TGF-β autocrine signaling can occur without TGF-β1 release from its latent form. Here, we show that mice engineered to express TGF-β1 that cannot release from L-TGF-β1 survive without early lethal tissue inflammation, unlike those with TGF-β1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-β1 signaling without release where αvβ8 binding redistributes the intrinsic flexibility of L-TGF-β1 to expose TGF-β1 to its receptors. Dynamic allostery explains the TGF-β3 latency/activation mechanism and why TGF-β3 functions distinctly from TGF-β1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems. TGF-β，对于发育和免疫至关重要，作为潜在复合体（L-TGF-β）与其前结构域非共价结合，并通过与GARP的共价结合展示在免疫细胞表面。与整合素 αvβ8 结合可激活L-TGF-β1/GARP。传统观点认为，成熟的TGF-β必须从L-TGF-β1中物理分离以发生信号传递。然而，我们之前的研究发现，αvβ8介导的TGF-β自分泌信号传导可以在不释放TGF-β1的情况下发生。我们用基因工程小鼠实验，发现与TGF-β1缺陷的小鼠不同，表达不能从L-TGF-β1中释放的TGF-β1的小鼠可以存活下来，没有发生早期致命性组织炎症（这句意译的）。通过结合低温电子显微镜与基于细胞的检测，我们揭示了一种动态的别构机制，使TGF-β1信号传导能够在没有释放的情况下进行，其中αvβ8的结合重新分布L-TGF-β1的固有灵活性，以暴露TGF-β1与其受体的结合位点。动态别构机制解释了TGF-β3的潜伏/激活机制，并解释了为什么TGF-β3的功能不同于TGF-β1，表明它广泛适用于其他灵活的细胞表面受体/配体系统。【人工校对】

『总结』 TGF-β可以通过动态别构机制在不释放TGF-β的情况下发生自分泌信号传导，挑战了传统的TGF-β信号传递机制。

『Abstract』The genome duplication program is affected by multiple factors in vivo , including developmental cues, genotoxic stress, and aging. Here, we monitored DNA replication initiation dynamics in regenerating livers of young and old mice after partial hepatectomy to investigate the impact of aging. In young mice, the origin firing sites were well defined; the majority were located 10–50 kb upstream or downstream of expressed genes, and their position on the genome was conserved in human cells. Old mice displayed the same replication initiation sites, but origin firing was inefficient and accompanied by a replication stress response. Inhibitors of the ATR checkpoint kinase fully restored origin firing efficiency in the old mice but at the expense of an inflammatory response and without significantly enhancing the fraction of hepatocytes entering the cell cycle. These findings unveil aging-dependent replication stress and a crucial role of ATR in mitigating the stress-associated inflammation, a hallmark of aging.

『摘要』 基因组复制程序在体内受到多种因素的影响，包括发育信号、基因毒性应激和衰老。在这里，我们监测了年轻和老鼠（Ai 我谢谢你，young and old mice——你就给我这么译？）肝脏再生后的DNA复制起始动态，以研究衰老的影响。在年轻鼠中，复制起始位点十分明确，大多数位于表达基因的上、下游10-50 kb 位置，并且这些位点在人类细胞的基因组位置也具有保守性（相似度高）。老年小鼠（可能AI 眼里，“小鼠”不应该老？）显示相同的复制启始位点，但起始（启动？）效率低下，并伴随着复制应激反应。ATR检查点激酶的抑制剂能够完全恢复老年小鼠起始位点的启动效率，但以引发炎症反应为代价，并且没有显著增强肝细胞进入细胞周期的比例。这些发现揭示了衰老依赖性的复制应激，并强调了ATR在缓解应激相关炎症中的关键作用，而这种炎症是衰老的标志之一。

『总结』 研究发现，衰老会导致DNA复制启动效率下降和复制应激反应，而ATR检查点激酶在缓解衰老相关炎症中起着关键作用。

『Abstract』Phytochrome B (phyB) and phytochrome-interacting factors (PIFs) constitute a well-established signaling module critical for plants adapting to ambient light. However, mechanisms underlying phyB photoactivation and PIF binding for signal transduction remain elusive. Here, we report the cryo-electron microscopy (cryo-EM) structures of the photoactivated phyB or the constitutively active phyB mutant in complex with PIF6, revealing a similar trimer. The light-induced configuration switch of the chromophore drives a conformational transition of the nearby tongue signature within the phytochrome-specific (PHY) domain of phyB. The resulting α-helical PHY tongue further disrupts the head-to-tail dimer of phyB in the dark-adapted state. These structural remodelings of phyB facilitate the induced-fit recognition of PIF6, consequently stabilizing the N-terminal extension domain and a head-to-head dimer of activated phyB. Interestingly, the phyB dimer exhibits slight asymmetry, resulting in the binding of only one PIF6 molecule. Overall, our findings solve a key question with respect to how light-induced remodeling of phyB enables PIF signaling in phytochrome research.

『摘要』 植物色素B（phyB）和植物色素互作因子（PIFs）构成了一个已确立的信号传导模块，该模块对植物适应环境光照至关重要。然而，phyB的光活化机制以及PIFs结合进行信号传导的机制仍不清楚。在这里，我们报告了光活化phyB或与PIF6结合的组成型活性phyB突变体的冷冻电子显微镜（cryo-EM）结构，揭示了它们形成了一个相似的三聚体。光诱导的色素构象转变驱动了phyB中植物色素特异性（PHY）域附近特征性“舌部”的构象转变。由此产生的α-螺旋PHY舌部进一步破坏了暗适应状态下phyB的头尾二聚体。phyB的这些结构重塑促进了PIF6的诱导契合识别，从而稳定了N端延伸域和活化的phyB头对头二聚体。有趣的是，phyB二聚体表现出轻微的不对称性，导致仅结合一个PIF6分子。总体而言，我们的研究结果解决了光诱导phyB重塑如何促进植物色素研究中PIF信号传导的关键问题。

『总结』 研究揭示了光激活植物色素 B 的结构重塑如何促进 PIF信号传递，解决了植物色素研究中一个关键问题。

『Abstract』The small intestine contains a two-front nutrient supply environment created by luminal dietary and microbial metabolites (enteral side) and systemic metabolites from the host (serosal side). Yet, it is unknown how each side contributes differentially to the small intestinal physiology. Here, we generated a comprehensive, high-resolution map of the small intestinal two-front nutrient supply environment. Using in vivo tracing of macronutrients and spatial metabolomics, we visualized the spatiotemporal dynamics and cell-type tropism in nutrient absorption and the region-specific metabolic heterogeneity within the villi. Specifically, glutamine from the enteral side fuels goblet cells to support mucus production, and the serosal side loosens the epithelial barrier by calibrating fungal metabolites. Disorganized feeding patterns, akin to the human lifestyle of skipping breakfast, increase the risk of metabolic diseases by inducing epithelial memory of lipid absorption. This study improves our understanding of how the small intestine is spatiotemporally regulated by its unique nutritional environment.

『摘要』 小肠的营养供给环境由腔内膳食和微生物代谢物（肠腔侧）以及宿主的全身代谢物（浆膜侧）共同构成，但目前尚不清楚两侧如何在小肠生理功能中发挥不同作用。在本研究中，我们生成了小肠双重营养供给环境的全面高分辨率图。通过体内追踪宏营养素和空间代谢组学，我们可视化了营养吸收的时空动态、细胞类型的特异性倾向，以及绒毛内特定区域的代谢异质性。具体而言，肠腔侧的谷氨酰胺为杯状细胞提供能量以支持黏液生成，而浆膜侧通过调节真菌代谢物削弱上皮屏障。类似于人类跳过早餐的不规律进食模式，会通过诱导脂质吸收的上皮记忆增加代谢疾病的风险。本研究加深了对小肠如何被其独特营养环境时空调控的理解。

『总结』 研究揭示小肠双重营养供给环境对时空代谢调控的机制，不规律进食（如不吃早餐）则增加代谢疾病风险。
——小编提醒：看完记得吃早餐哦！

『Abstract』Identifying the properties of the rapid eye movement (REM) sleep circuitry and its relation to diseases has been challenging due to the neuronal heterogeneity of the brainstem. Here, we show in mice that neurons in the pontine sublaterodorsal tegmentum (SubLDT) that express corticotropin-releasing hormone-binding protein ( Crhbp neurons) and project to the medulla promote REM sleep. Within the medullary area receiving projections from Crhbp neurons, neurons expressing nitric oxide synthase 1 ( Nos1 neurons) project to the SubLDT and promote REM sleep, suggesting a positively interacting loop between the pons and the medulla operating as a core REM sleep circuit. Nos1 neurons also project to areas that control wide forebrain activity. Ablating Crhbp neurons reduces sleep and impairs REM sleep atonia. In Parkinson’s disease patients with REM sleep behavior disorders, CRHBP-immunoreactive neurons are largely reduced and contain pathologic α-synuclein, providing insight into the mechanisms underlying the sleep deficits characterizing this disease.

『摘要』 由于脑干神经元的异质性，识别快速眼动（REM）睡眠神经回路的特性及其与疾病的关系一直充满挑战。在本研究中，我们发现，小鼠脑桥的后外侧被盖区（SubLDT）中表达促肾上腺皮质激素释放激素结合蛋白（Crhbp）的神经元并投射至延髓的神经元可以促进REM睡眠。在接受Crhbp神经元投射的延髓区域中，表达一氧化氮合酶1（Nos1）的神经元会投射至SubLDT并促进REM睡眠，提示脑桥与延髓之间存在一个正反馈循环，构成核心的REM睡眠回路。Nos1神经元还投射到调控广泛前脑活动的区域。破坏Crhbp神经元会减少睡眠并损害REM睡眠时的肌肉失张力。在患有REM睡眠行为障碍的帕金森病患者中，Crhbp免疫反应性神经元显著减少，并含有病理性α-突触核蛋白，这为该疾病的睡眠障碍机制提供了新的见解。

『总结』 研究揭示脑桥SubLDT区的Crhbp神经元与延髓Nos1神经元通过正反馈回路调控REM睡眠机制，这为患有REM睡眠行为障碍的帕金森病患者的睡眠障碍机制提供新的见解。（第二篇关于睡眠）

『Abstract』Locomotion involves rhythmic limb movement patterns that originate in circuits outside the brain. Purposeful locomotion requires descending commands from the brain, but we do not understand how these commands are structured. Here, we investigate this issue, focusing on the control of steering in walking Drosophila . First, we describe different limb “gestures” associated with different steering maneuvers. Next, we identify a set of descending neurons whose activity predicts steering. Focusing on two descending cell types downstream of distinct brain networks, we show that they evoke specific limb gestures: one lengthens strides on the outside of a turn, while the other attenuates strides on the inside of a turn. Our results suggest that a single descending neuron can have opposite effects during different locomotor rhythm phases, and we identify networks positioned to implement this phase-specific gating. Together, our results show how purposeful locomotion emerges from specific, coordinated modulations of low-level patterns.

『摘要』 移动涉及源于大脑外部神经回路的规律性肢体运动模式，而有目的的移动需要来自大脑的下行指令，但这些指令的结构尚不清楚。在本研究中，我们聚焦于行走果蝇的转向控制以探讨这一问题。首先，我们描述了与不同转向动作相关的肢体“姿势”。接着，我们识别了一组下行神经元，这些神经元的活动可预测行走转向。重点研究了两种位于不同脑神经网络下游的下行神经元类型，发现它们引发特定的肢体姿势：一种神经元延长转向外侧的步幅，而另一种神经元减弱转向内侧的步幅。我们的研究表明，单一的下行神经元在不同运动节律相位中可能具有相反的作用，并确定了能够实现这种相位特异性调节的神经网络。总体而言，我们的结果展示了有目的的运动如何通过低层次运动模式的特定、协调控制而产生。

『总结』 研究揭示果蝇转向运动中，特定下行神经元通过相位特异性调控肢体手势，协调低层次运动模式以实现有目的运动。
——小编注：简单来讲，无意识运动不需要大脑的控制，有目的运动需要大脑下达指令来完成。别再说“四肢发达头脑简单”了，运动也是要脑子的；运动&学习神经都发达算最强大脑了吧？

『Abstract』In this high-throughput proteomic study of autosomal dominant Alzheimer’s disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers.

『摘要』 在这项针对常染色体显性阿尔茨海默病（ADAD）的高通量蛋白质组学研究中，我们旨在通过脑脊液（CSF）发现早期生物标志物，以监测疾病和制定治疗策略。我们分析了286名突变携带者（MCs）和177名非携带者（NCs）的CSF蛋白，使用多层回归模型区分了这些群体中蛋白的不同伪轨迹。通过独立的ADAD和散发性AD数据集验证了研究结果，并利用机器学习开发和验证预测模型。研究识别了137种在MCs和NCs之间表现出不同轨迹的蛋白质，其中8种在传统AD生物标志物变化之前发生改变。这些蛋白质分为三个阶段：早期阶段（压力反应、谷氨酸代谢、神经线粒体损伤）、中期阶段（神经元死亡、凋亡）和晚期无症状阶段（小胶质细胞变化、细胞通讯）。预测模型揭示了一个由六种蛋白质组成的子集，与传统生物标志物相比，更有效地区分携带者和非携带者。

『总结』 本研究通过高通量蛋白质组学分析，鉴定了137个阿尔茨海默病早期生物标志物，用于监测和制定治疗策略，并开发了一个六蛋白质子集预测模型，优化了疾病预测模型。

『Abstract』Diet is a major determinant of gut microbiome composition, and variation in diet-microbiome interactions may contribute to variation in their health consequences. To mechanistically understand these relationships, here we map interactions between ∼150 small-molecule dietary xenobiotics and the gut microbiome, including the impacts of these compounds on community composition, the metabolic activities of human gut microbes on dietary xenobiotics, and interindividual variation in these traits. Microbial metabolism can toxify and detoxify these compounds, producing emergent interactions that explain community-specific remodeling by dietary xenobiotics. We identify the gene and enzyme responsible for detoxification of one such dietary xenobiotic, resveratrol, and demonstrate that this enzyme contributes to interindividual variation in community remodeling by resveratrol. Together, these results systematically map interactions between dietary xenobiotics and the gut microbiome and connect toxification and detoxification to interpersonal differences in microbiome response to diet.

『摘要』 饮食是肠道微生物菌群组成的主要决定因素，饮食-微生物相互作用的变化可能会导致健康状态的变化。为了从机制上理解这些关系，我们在此绘制了约150种膳食性小分子与肠道微生物组之间的相互作用图，包括这些化合物对微生物群群组成的影响、人体肠道微生物对膳食小分子的代谢活动，以及这些特征的个体差异。微生物代谢可以使这些化合物产生毒性或解毒，从而产生新的相互作用，解释了食用外源性物质如何通过这些相互作用特异性地重塑菌群。我们鉴别出一个解毒白藜芦醇的基因和酶，并证明了该酶可导致白藜芦醇对微生物群落重塑贡献的个体差异。总之，这些结果系统地绘制了膳食性外源物质与肠道微生物组之间的相互作用，并将毒化和解毒作用与微生物组对饮食响应的个体差异联系起来。

『总结』 研究揭示了膳食性外源物质与肠道微生物组之间的相互作用，以及毒化和解毒过程如何导致微生物组对饮食反应的个体差异。

『Abstract』Pharmaceuticals can directly inhibit the growth of gut bacteria, but the degree to which such interactions manifest in complex community settings is an open question. Here, we compared the effects of 30 drugs on a 32-species synthetic community with their effects on each community member in isolation. While most individual drug-species interactions remained the same in the community context, communal behaviors emerged in 26% of all tested cases. Cross-protection during which drug-sensitive species were protected in community was 6 times more frequent than cross-sensitization, the converse phenomenon. Cross-protection decreased and cross-sensitization increased at higher drug concentrations, suggesting that the resilience of microbial communities can collapse when perturbations get stronger. By metabolically profiling drug-treated communities, we showed that both drug biotransformation and bioaccumulation contribute mechanistically to communal protection. As a proof of principle, we molecularly dissected a prominent case: species expressing specific nitroreductases degraded niclosamide, thereby protecting both themselves and sensitive community members.

『摘要』 药物可以直接抑制肠道细菌的生长，但这种相互作用在复杂的群落中表现程度是一个没有定论的问题。本研究比较了30种药物对包含32种细菌的合成群落的影响及其对每个群落成员的影响（隔离环境）。虽然在群落背景下，大多数单个药物-物种相互作用保持不变，但在所有测试案例中，有26%的案例出现了群落行为。交叉保护，即药物敏感物种在群落中受到保护的现象，是交叉敏化（即相反的现象）的6倍。在高药物浓度下，交叉保护减少，交叉敏化增加，这表明当扰动增强时，微生物群落的恢复力可能会崩溃。通过对药物治疗后的群落进行代谢特征分析，我们发现药物生物转化和生物累积在机制上均有助于群落保护。作为原理验证，我们从分子层面对一个典型案例进行了剖析：表达特定硝基还原酶的物种能够降解尼克罗酰胺，从而保护自己和其他敏感群落成员。

『总结』 研究发现肠道细菌在药物的影响下出现交叉保护和交叉敏化群落行为，但高药物浓度时微生物群落的的恢复力可能崩溃，而药物生物转化和生物累积机制有助于群落保护。

『Abstract』In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin’s influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin’s effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.

『摘要』 在一项为期40个月的严谨研究中，我们评估了二甲双胍对成年雄性食蟹猴的抗衰老作用，填补了灵长类动物衰老研究领域的空白。该研究涵盖了一系列全面的生理、成像、组织学和分子学评估，证实了二甲双胍在生物体层面延缓年龄相关表型的影响。具体而言，我们利用全组织转录组学、DNA甲基组学、血浆蛋白质组学和代谢组学开发了创新的猴类衰老时钟，并将其应用于评估二甲双胍对衰老的影响。研究结果显示，衰老指标显著减缓，尤其是大脑衰老出现了大约6年的逆转。二甲双胍具有显著的神经保护作用，能够保护大脑结构并增强认知能力。二甲双胍对灵长类动物神经元的抗衰老作用部分是通过激活具有抗氧化能力的转录因子Nrf2介导的。我们的研究开创了通过二甲双胍系统性降低灵长类动物多维生物年龄的新纪元，为推进人类抗衰老制药策略铺平了道路。

『总结』 本研究发现二甲双胍能显著减缓成年雄性食蟹猴的衰老过程，并通过激活具有抗氧化能力的转录因子保护神经并逆转大脑衰老，为开发人类抗衰老药物策略提供了新途径。（神药）

『Abstract』The family of Ras-like GTPases consists of over 150 different members, regulated by an even larger number of guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs) that comprise cellular switch networks that govern cell motility, growth, polarity, protein trafficking, and gene expression. Efforts to develop selective small molecule probes and drugs for these proteins have been hampered by the high affinity of guanosine triphosphate (GTP) and lack of allosteric regulatory sites. This paradigm was recently challenged by the discovery of a cryptic allosteric pocket in the switch II region of K-Ras. Here, we ask whether similar pockets are present in GTPases beyond K-Ras. We systematically surveyed members of the Ras, Rho, and Rab family of GTPases and found that many GTPases exhibit targetable switch II pockets. Notable differences in the composition and conservation of key residues offer potential for the development of optimized inhibitors for many members of this previously undruggable family.

『摘要』 Ras样GTP酶家族包含超过150种不同成员，这些成员由更多数量的鸟嘌呤交换因子（GEFs）和GTP酶激活蛋白（GAPs）调控，组成了控制细胞运动、生长、极性、蛋白质运输和基因表达的细胞开关网络。然而，由于鸟嘌呤三磷酸（GTP）的高亲和性以及缺乏变构调控位点，为这些蛋白质开发选择性的小分子探针和药物一直面临困难。最近，这一模式被挑战——在K-Ras的开关II区发现了一个隐秘的变构口袋。在此，我们探讨了这种口袋是否也存在于K-Ras以外的GTP酶中。通过系统地研究Ras、Rho和Rab家族的GTP酶，我们发现许多GTP酶确实存在可作为靶点的开关II口袋。关键残基的组成和保守性上的显著差异为许多此前被认为无法成药的家族成员，提供了优化抑制剂的开发的可能。

『总结』 研究发现，之前许多被认为无法成药的 Ras样酶家族成员存在可作为靶点的开关II变构口袋，为开发针对这些蛋白的新型抑制剂提供了可能性。

『Abstract』The interplay between translation and mRNA decay is widespread in human cells . In quality-control pathways, exonucleolytic degradation of mRNA associated with translating ribosomes is mediated largely by the cytoplasmic exosome , which includes the exoribonuclease complex EXO10 and the helicase complex SKI238. The helicase can extract mRNA from the ribosome and is expected to transfer it to the exoribonuclease core through a bridging factor, HBS1L3 (also known as SKI7), but the mechanisms of this molecular handover remain unclear . Here we reveal how human EXO10 is recruited by HBS1L3 (SKI7) to an active ribosome-bound SKI238 complex. We show that rather than a sequential handover, a direct physical coupling mechanism takes place, which culminates in the formation of a cytoplasmic exosome–ribosome supercomplex. Capturing the structure during active decay reveals a continuous path in which an RNA substrate threads from the 80S ribosome through the SKI2 helicase into the exoribonuclease active site of the cytoplasmic exosome complex. The SKI3 subunit of the complex directly binds to HBS1L3 (SKI7) and also engages a surface of the 40S subunit, establishing a recognition platform in collided disomes. Exosome and ribosome thus work together as a single structural and functional unit in co-translational mRNA decay, coordinating their activities in a transient supercomplex.

『摘要』 翻译与mRNA降解之间的相互作用在人体细胞中广泛存在。在质量控制通路中，与翻译核糖体相关的mRNA的外切核酸酶降解主要由胞质外体（cytoplasmic exosome，在细胞内发挥功能， 我想译成“外泌体”可能不合适，就简单用“外体”表示）介导，该外体包括外切核糖核酸酶复合物EXO10和解旋酶复合物SKI238。解旋酶可以从核糖体中提取mRNA，并预期通过桥接因子HBS1L3（也称为SKI7）将其转移到外切核酸酶核心，但这种分子交接的机制尚不清楚。在本研究中，我们揭示了人类外切核糖核酸酶复合物EXO10如何通过桥接因子HBS1L3（SKI7）被招募到一个活跃的、与核糖体结合的解旋酶复合物SKI238复合物中。我们发现，与其说是一个顺序交接过程，不如说是一种直接的物理耦合机制，最终形成一个胞质外体-核糖体超级复合物。捕捉活跃降解过程中的结构显示了一个连续的路径，其中RNA底物从80S核糖体通过SKI2解旋酶进入胞质外体复合物的外切核酸酶活性位点。SKI238复合物的SKI3亚基直接与HBS1L3（SKI7）结合，并与40S亚基的一个表面接触，在碰撞二聚体中建立了一个识别平台。外体和核糖体因此作为一个单一的结构和功能单位在协同翻译mRNA降解中协同工作，通过短暂的超级复合物协调它们的活动。

『总结』 研究发现人类细胞中的翻译和mRNA降解之间存在直接的物理耦合机理，形成细胞质外体-核糖体超复合体，协调翻译和衰变活动。
——小编注：也就是说 mRNA的降解本身与翻译过程也有关，如何利用这一点？可能是 mRNA 设计忽略的一个考量点！！