前沿速递 | ncs 集萃：2026-08-06 期
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1. 海洋铁施肥的气候效益与生态成本权衡
Climate benefit and ecological cost trade-offs for ocean iron fertilization
『Abstract』Ocean iron fertilization (OIF) is being discussed as a potential carbon dioxide removal (CDR) strategy. Yet the trade-offs between climate benefits and ecological costs remain poorly understood. Here we use a process-rich ocean biogeochemical model with validated representations of marine biodiversity and biogeochemistry to quantify fertilization potential and ecosystem impact across ten ocean biomes over 60 years. We find regional disparities in climate ecosystem trade-offs: biomes with comparable CDR efficiency have contrasting ecological outcomes. The Southern Ocean and the equatorial Pacific achieve the highest efficiencies through distinct pathways: the former through non-local downstream carbon export, the latter through local export with downstream loss, as fertilized blooms deplete macronutrients in source water, suppressing non-local productivity. Consequently, equatorial fertilization reduces energy flows to higher trophic levels, expands oxygen-minimum zones (OMZs) and reduces macrozooplankton biomass. These ecosystem impacts are potentially avoidable by shifting deployment to higher latitudes. Post-fertilization recovery experiments reveal ecosystem resilience in the Southern Ocean but persistent perturbations in the equatorial Pacific owing to regional iron retention. Balancing climate benefits and ecological risks yields three tiers: the Southern Ocean (higher efficiency/lower risk); the equatorial Pacific and global fertilization (higher efficiency/higher risk); and the subtropics (lower efficiency/moderate risk). Sixty years of fertilization yield net CDR of 1.1-5.3 ppm, with more than half re-emitted within decades post-fertilization. The disconnect between local interventions and global outcomes complicates robust carbon crediting and raises equity and governance concerns.
『摘要』
海洋铁施肥（OIF）正被讨论为一种潜在的二氧化碳移除（CDR）策略。然而，气候效益与生态成本之间的权衡仍未得到充分理解。本研究利用一个包含海洋生物多样性和生物地球化学验证表征的过程丰富的海洋生物地球化学模型，量化了60年间十个海洋生物群系的施肥潜力及其对生态系统的影响。研究发现，不同区域在气候-生态系统权衡方面存在差异：具有可比CDR效率的生物群系其生态结果截然相反。南大洋和赤道太平洋通过不同的途径实现了最高效率：前者通过非本地下游碳输出，后者则因施肥藻华消耗源水中的大量营养元素、抑制非本地生产力而通过本地输出伴随下游损失实现。因此，赤道施肥减少了向高营养级流动的能量，扩大了低氧区（OMZs），并降低了大型浮游动物的生物量。这些生态系统影响可通过将施肥地点转移至更高纬度地区来避免。施肥后的恢复实验显示，南大洋的生态系统具有弹性，而赤道太平洋由于区域铁滞留导致持续扰动。平衡气候效益与生态风险可划分为三个等级：南大洋（高效/低风险）；赤道太平洋和全球施肥（高效/高风险）；亚热带（低效/中等风险）。60年的施肥可使大气中二氧化碳浓度净减少1.1-5.3 ppm，但超过一半会在施肥后数十年内重新释放。局部干预措施与全球结果之间的脱节使稳健的碳信用机制复杂化，并引发了公平性与治理方面的担忧。
『总结』
研究用海洋生物地球化学模型量化海洋铁施肥的潜力及生态影响，发现不同区域在气候效益与生态成本间存在权衡，提出平衡二者的三等级方案，指出施肥有净减碳效果但部分会重释，且局部干预与全球结果的脱节带来诸多问题。
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2. 双轨擦除量子比特的纠缠门
An entangling gate for dual-rail erasure qubits
『Abstract』Quantum error correction (QEC) will likely be required to realize the full potential of quantum computing, but comes with daunting hardware overheads and demands low gate errors on the physical qubits. These requirements can be eased by engineering qubits with a strong error hierarchy, in which the most common noise channels are also the easiest to correct. Erasure qubits can achieve this when detectable leakage errors out of the computational subspace dominate over the residual Pauli errors, resulting in higher thresholds and improved scaling with code distance. In practice, these advantages come to fruition only if the error hierarchy is preserved as much as possible throughout all gates and operations. Here we design and realize a two-qubit entangling gate for dual-rail cavity qubits, a type of erasure qubit encoded in a pair of superconducting microwave cavities. Our experimental demonstration confirms that the error hierarchy is largely preserved during the gate. The gate is fast (about 500 ns duration) and shows low erasure rates of approximately 0.5% per gate, remaining Pauli errors below 0.1%, and a strong bias towards dephasing errors, in which bit-flips are practically non-existent at the 10-6 level. These results enable a faster path to error-corrected systems that rapidly suppress errors as they scale; a claim we support with our detailed surface code simulations.
『摘要』
要充分发挥量子计算的全部潜力，可能需借助量子纠错（QEC），但这会带来巨大的硬件开销，且要求物理量子比特的门错误率较低。通过设计具有强错误层级的量子比特可缓解这些需求，在这种层级中，最常见的噪声通道也是最容易纠正的。当计算子空间外可检测的泄漏错误占主导地位，超过剩余的泡利错误时，擦除量子比特就能实现这一点，从而获得更高的阈值和随编码距离改善的可扩展性。实际上，只有当所有门和操作都尽可能保持这种错误层级时，这些优势才能得以体现。在此，我们为双轨腔量子比特（一种编码在一对超导微波谐振器中的擦除量子比特）设计并实现了两量子比特纠缠门。我们的实验演示证实了该门操作在很大程度上保留了错误层级。此门速度快（约500纳秒持续时间），每门的擦除率低至约0.5%，剩余泡利错误低于0.1%，且相位翻转错误显著偏多，而位翻转错误在10-6水平上几乎不存在。这些结果为实现随着规模扩大能快速抑制错误的纠错系统提供了更快的途径；我们通过详细的表面码模拟支持了这一观点。
『总结』
充分发挥量子计算潜力或需量子纠错，但有硬件开销等难题，可通过设计强错误层级量子比特缓解，双轨腔量子比特的两量子比特纠缠门实验显示其保留了错误层级，具有多种优势，能为实现纠错系统提供更快途径且有模拟支持。
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3. 直流工作下的非外延钙钛矿极化激元激光二极管
Non-epitaxial perovskite polariton laser diode operating under direct current
『Abstract』Reaching lasing in electrically pumped microdevices based on solution-processed semiconductors poses a substantial scientific and technological challenge. Halide perovskites offer a promising platform for electrical injection, as their optically excited single-crystal cavities and predesigned or postprocessed microstructures have exhibited low lasing threshold. Indirect electrical pumping of a dual-cavity perovskite laser was recently obtained, using a well-established technological concept of embedding a high-luminosity light-emitting diode (LED) with a high-gain medium into an integrated device. Direct charge-carrier injection into a perovskite LED excited by auxiliary short, optical pulses resulted in amplified spontaneous emission (ASE). Other efforts for rational engineering of architectures that allow for high charge-carrier density are still to demonstrate lasing. Here we develop a new strategy for achieving direct electrical pumping of a perovskite laser. We integrate a solution-grown CsPbBr3 microplate with chemically inert single-walled carbon nanotube (SWCNT) electrodes and embed them into an optical microcavity. By cooling the microdevice down to 8 K at a constant current, a perovskite p-i-n diode is formed that facilitates a balanced carrier injection at high current densities. The perovskite microcavity diode operates in the strong coupling regime, exhibiting polariton lasing under a direct current of 65 μA.
『摘要』
在基于溶液处理半导体的电泵浦微器件中实现激光发射是一项重大的科学和技术挑战。卤化物钙钛矿为电注入提供了一个有前景的平台，因为其光激发单晶腔以及预先设计或后处理的微观结构已展现出低激光阈值特性。最近，通过将高亮度发光二极管（LED）与高增益介质嵌入集成器件这一成熟技术概念，实现了双腔钙钛矿激光器的间接电泵浦。向由辅助短光学脉冲激发的钙钛矿LED直接注入电荷载流子，产生了受激辐射放大（ASE）。然而，其他旨在合理设计能够实现高电荷载流子密度的结构的努力尚未实现激光发射。在此，我们开发了一种实现钙钛矿激光器直接电泵浦的新策略。我们将溶液生长的CsPbBr3微板与化学惰性的单壁碳纳米管（SWCNT）电极集成，并将其嵌入光学微腔中。在恒定电流下将该微器件冷却至8 K时，形成了一个钙钛矿p-i-n二极管，可在高电流密度下实现平衡的载流子注入。钙钛矿微腔二极管工作于强耦合区域，在65 μA直流条件下表现出极化激元激光现象。
『总结』
本文提出一种新策略实现钙钛矿激光器直接电泵浦，将溶液生长的CsPbBr3微板与单壁碳纳米管电极集成并嵌入光学微腔，冷却微器件形成钙钛矿p-i-n二极管，使其在高电流密度下平衡载流子注入，最终在65μA直流条件下实现极化激元激光。
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4. 嵌入卤化物的半导体和磁性镧系MXenes
Semiconducting and magnetic lanthanide MXenes from intercalated halides
『Abstract』Two-dimensional (2D) magnetic semiconductors are crucial for next-generation information storage and spintronic technologies. MXenes, owing to compositional diversity and tunable properties, provide a platform for designing functional materials. Incorporating lanthanides (Ln) introduces localized 4f electrons with strong spin polarization, while potentially enabling semiconducting behaviour, offering a viable route to magnetic semiconductors. However, the scarcity of MAX precursors and the susceptibility of Ln to dissolution in common etchants (for example, HF), compared with other M elements such as Mo, hinder the synthesis of lanthanide MXenes (Ln2CT2) by conventional 'top-down' etching. Here we propose a general 'bottom-up' methodology for synthesizing Ln2CT2 (Ln = Gd, Tb, Dy, Ho, Er, Lu; T = Cl, Br) using layered halides as van der Waals building blocks. Multilayer Ln2CT2 exhibits composition-tunable properties, characterized by optical absorption onsets spanning 1.26-1.71 eV, room-temperature resistivity of 0.329-36.1 Ω cm with a negative temperature coefficient, and low-temperature ferromagnetic hysteresis at 2 K accompanied by positive Curie-Weiss temperatures between 6 K and 59 K. Theoretical calculations show that the d-electron states around the Fermi level (Ef) are largely diminished in bare Ln2C, whereas surface terminals further exhaust these states to open band gaps. Meanwhile, the highly localized 4f electrons in Ln2CT2, located far from the Ef, contribute to the spin splitting for the observed ferromagnetic behaviour. This combination of semiconducting and magnetic properties makes Ln2CT2 a valuable candidate for spintronic device applications.
『摘要』
二维（2D）磁性半导体对于下一代信息存储和自旋电子学技术至关重要。MXenes因其成分多样性和可调特性，为设计功能材料提供了平台。引入稀土元素（Ln）会带来具有强自旋极化的局域4f电子，同时可能实现半导体行为，这为获得磁性半导体提供了一条可行途径。然而，与其他M元素（如钼）相比，MAX前驱体的稀缺以及稀土元素在常见蚀刻剂（例如氢氟酸）中易溶解的特性，阻碍了通过传统“自上而下”蚀刻法合成稀土MXenes（Ln₂CT₂）。在此，我们提出了一种通用的“自下而上”方法，利用层状卤化物作为范德华构建块来合成Ln₂CT₂（Ln = 钆、铽、镝、钬、铒、镥；T = 氯、溴）。多层Ln₂CT₂表现出随成分可调节的性质，其特点包括光学吸收起始点范围为1.26-1.71 eV，室温电阻率为0.329-36.1 Ω cm且温度系数为负值，以及在2 K低温下的铁磁滞后现象并伴有6 K至59 K之间的正居里-外斯温度。理论计算表明，裸露的Ln₂C中费米能级（Ef）附近的d电子态大幅减少，而表面终端进一步耗尽这些电子态以打开带隙。与此同时，Ln₂CT₂中远离Ef的高度局域化的4f电子有助于产生自旋分裂，从而出现观察到的铁磁行为。这种半导体与磁性的结合使Ln₂CT₂成为自旋电子器件应用的理想候选材料。
『总结』
二维磁性半导体对信息存储等重要，MXenes有潜力但传统方法难合成稀土MXenes，研究提出新方法合成Ln₂CT₂，其具多种可调性质，理论解释了相关特性，使其成自旋电子器件应用理想候选。
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5. 层状铁电体中极化的垂直转换
Perpendicular switching of polarization in layered ferroelectrics
『Abstract』Ferroelectric materials exhibit a spontaneous electric polarization that can be reversed by an electric field, a property central to non-volatile memories, sensors and actuators. In most conventional ferroelectrics, the polarization originates from a softening of a polar mode. The amplitude of the mode along a given direction couples with the applied field along the same direction. Ferroelectrics with a predominant in-plane polarization are harder to use in standard device geometries and therefore the field has mostly focused on out-of-plane ferroelectrics. Developing approaches that enable manipulation of the in-plane polarization component with an out-of-plane field would therefore provide new opportunities for device design and functionality. Here we have discovered that a trilinear coupling between the in-plane and out-of-plane polarization, mediated by means of the octahedral tilts and rotations in the layered ferroelectric Bi4Ti3O12, naturally fulfils this challenge and enables perpendicular switching of the polarization state. In its bulk monoclinic phase, this material hosts a large in-plane polarization (about 50 μC cm-2) driven by a proper ferroelectric instability, together with smaller out-of-plane polarization (about 5 μC cm-2) of improper origin, induced by oxygen octahedral distortions. We demonstrate that, in c-axis-oriented epitaxial films, the in-plane polarization switches deterministically under an out-of-plane electric field. This cross-coupling between orthogonal polarization components provides a route to transverse manipulation of ferroic order parameters and establishes layered ferroelectrics as a platform for capacitive computing concepts.
『摘要』
铁电材料具有一种自发电极化特性，该电极化可通过电场反转，这一特性是非易失性存储器、传感器和执行器的核心。在大多数传统铁电材料中，极化源于极性模式的软化。沿给定方向的模式振幅与同一方向的施加电场耦合。由于面内极化占主导的铁电材料难以应用于标准器件结构，因此研究领域主要聚焦于面外铁电材料。开发利用面外电场操纵面内极化分量的方法，将为器件设计和功能提供新机遇。本研究发现，层状铁电体Bi4Ti3O12中通过氧八面体的倾斜和旋转介导的面内与面外极化的三线性耦合，自然解决了这一挑战并实现了极化状态的垂直切换。在其块体单斜相中，该材料因本征铁电不稳定性产生较大的面内极化（约50 μC cm-2），同时因氧八面体畸变诱导出较小的非本征面外极化（约5 μC cm-2）。实验表明，在c轴取向的外延薄膜中，面内极化可在面外电场作用下确定性翻转。这种正交极化分量间的交叉耦合为横向调控铁性序参量提供了途径，并将层状铁电体确立为电容计算概念的平台。
『总结』
研究发现层状铁电体Bi4Ti3O12中存在面内与面外极化的三线性耦合机制，通过氧八面体运动实现极化状态垂直切换，为铁电器件设计开辟了新路径。
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6. CO<sub>2</sub>与双环烷烃交替共聚合成环状聚酯
Alternating CO<sub>2</sub> and bicycloalkane copolymerization to circular polyesters
『Abstract』Transforming abundant but inert CO2 into useful polymers has been pursued since the 1960s (ref. ) and has typically been achieved by copolymerization with a reactive comonomer, aided by a catalyst, which can address both thermodynamic constraints and high kinetic barriers associated with CO2 fixation and incorporation. However, making polyesters remains a challenge as alternating copolymerization of CO2 with alkenes is thermodynamically infeasible. Here we introduce a closed-loop CO2-based polyester platform for producing high-performance yet recyclable polyesters by direct alternating copolymerization of CO2 with bicycloalkanes, bicyclic butane (BCB) and pentane (BCP) monomers. This copolymerization is initiated by a simple organic catalyst and proceeds in a perfectly alternating fashion to high-molar-mass polyesters with maximum (50 mol%) CO2 incorporation and architecturally defined backbones, in which the in-chain ring structure enables tailorable thermal and mechanical properties. These polyesters exhibit desired orthogonal performance and end-of-life outcomes. Although the BCB-CO2 polyesters exhibit exceptional thermal and hydrolytic stability across the full pH range, they can be selectively depolymerized in bulk and base-catalysed conditions to regenerate pure BCB monomers in >90% isolated yield. The BCP-CO2 polyesters can also be selectively depolymerized but to bicyclolactones. Sequential depolymerization-repolymerization cycles establish circular lifecycles for BCB/BCP-CO2 high-performance polyesters.
『摘要』
自20世纪60年代以来，人们一直致力于将丰富但惰性的二氧化碳转化为有用的聚合物（参考文献），这通常通过与活性共聚单体在催化剂辅助下进行共聚来实现，该过程可解决与二氧化碳固定和掺入相关的热力学限制和高动力学能垒问题。然而，由于二氧化碳与烯烃的交替共聚在热力学上不可行，因此制备聚酯仍是一项挑战。在此，我们介绍了一种基于二氧化碳的闭环聚酯平台，该平台通过二氧化碳与双环烷烃、双环丁烷（BCB）和戊烷（BCP）单体的直接交替共聚来生产高性能且可回收的聚酯。这种共聚反应由一种简单的有机催化剂引发，以完美交替的方式进行，生成高分子量聚酯，其中二氧化碳的最大掺入量为50 mol%，主链结构明确，链内环状结构赋予其可调节的热性能和机械性能。这些聚酯表现出理想的正交性能和使用寿命结束后的处理结果。尽管BCB-CO₂聚酯在整个pH范围内均表现出优异的热稳定性和水解稳定性，但在本体和碱催化条件下可选择性地解聚，以超过90%的分离产率再生纯BCB单体。BCP-CO₂聚酯也可选择性地解聚为双环内酯。连续的解聚-再聚合循环为BCB/BCP-CO₂高性能聚酯建立了循环生命周期。
『总结』
自20世纪60年代起，人们就尝试将二氧化碳转化为有用聚合物，但因热力学限制等，制备聚酯有难度。本文介绍了基于二氧化碳的闭环聚酯平台，通过特定方式共聚制得高性能可回收聚酯，它们具有多种特性，还能经连续解聚 - 再聚合实现循环利用。
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7. 量子顺电体SrTiO<sub>3</sub>中纳米级极性纹理的成像
Imaging of nanoscale polar textures in quantum paraelectric SrTiO<sub>3</sub>
『Abstract』When cooling towards a ferroelectric phase transition, collective atomic motions (phonons) slow down (soften) until a static atomic displacement pattern forms, giving rise to spontaneous polarization throughout the material. However, in quantum paraelectrics such as strontium titanate (SrTiO3), long-range ferroelectric order does not develop at low temperatures due to persistent quantum fluctuations of ionic positions. In SrTiO3, quantum paraelectricity emerges below Tq ≈ 40 K refs. and is preceded by anomalous phonon dynamics: a transverse acoustic phonon mode partially softens at a finite wavevector, hinting at a modulated state at the nanoscale. The precise real-space structure of SrTiO3 at low temperature, however, has remained unresolved despite decades of study. Here we directly image the low-temperature polar structure of a SrTiO3 lamella using cryogenic scanning transmission electron microscopy down to 20 K. High-resolution imaging reveals a spatially fluctuating landscape of nanoscale domains. Below about 105 K, short-range polar domains initially self-organize into a periodic structure extending over tens of nanometres; however, upon entering the quantum paraelectric regime below Tq, the process reverses and the periodically ordered polar nanodomains fragment into smaller clusters. Quantum paraelectricity in SrTiO3 underlies remarkable properties, including large dielectric permittivity, proximity to ferroelectricity, multiferroicity and unconventional superconductivity. Our visualizations suggest that these phenomena may be linked to complex ordering and disordering of polar nanodomains at low temperature.
『摘要』
在向铁电相变冷却时，集体原子运动（声子）会减缓（软化），直至形成静态原子位移模式，使整个材料产生自发极化。然而，在钛酸锶（SrTiO3）等量子顺电体中，由于离子位置的持续量子涨落，低温下不会出现长程铁电有序。在 SrTiO3 中，量子顺电性出现在 Tq ≈ 40 K 以下，在此之前会出现反常的声子动力学：横声学声子模式在有限波矢处部分软化，暗示着纳米尺度上的调制态。尽管经过数十年的研究，SrTiO3 在低温下的精确实空间结构仍未得到解决。本研究利用低温扫描透射电子显微镜，直接对温度低至20K的SrTiO3薄片进行成像，揭示了其低温极性结构。高分辨率成像显示，存在空间波动的纳米级畴景观。在约105 K以下，短程极性畴最初自组织成延伸数十纳米的周期性结构；然而，当进入Tq以下的量子顺电区时，该过程逆转，周期性有序的极性纳米畴破碎为更小的簇。SrTiO3中的量子顺电性具有显著特性，包括大介电常数、接近铁电性、多铁性和非常规超导性。我们的可视化结果表明，这些现象可能与低温下极性纳米畴的复杂有序和无序有关。
『总结』
研究发现钛酸锶在低温下极性结构随温度变化呈现不同特征，其量子顺电性相关特性或与低温下极性纳米畴的有序无序状态有关。
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8. 无绝缘体拓扑光子多车道高速路
Insulator-free topological photonic multi-lane highways
『Abstract』Topological protection in photonic structures enables robust unidirectional propagation immune to structural disorder. However, conventional implementations obtain this protection from topological-insulator domains whose interfaces host narrow guiding channels, leaving much of the insulating bulk inactive for transport. This imposes a fundamental trade-off between topological robustness and spatial footprint. Here we introduce an insulator-free topological waveguide architecture that eliminates this trade-off, enabling multi-lane unidirectional light guiding with both 100% spatial utilization efficiency and topological protection. By strategically combining time-reversal and inversion-symmetry breaking in gyromagnetic honeycomb photonic crystals (PCs), we achieve four inequivalent photonic valley half-semimetals (PVHSMs) at distinct critical transition boundaries between trivial and Chern insulator phases. We arrange these four structures in a parallel, cyclic configuration, such that each domain simultaneously functions as a valley-selective waveguide and a topological barrier for the other valley in adjacent domains, circumventing the need for further topological insulating layers. Our experimental and theoretical results demonstrate that this multi-lane configuration transforms conventional edge states into densely packed, large-area one-way modes. These modes exhibit alternating unidirectionality across the four domains while maintaining robustness even under arbitrary sharp bends and pronounced shape variations. This work exemplifies a design strategy for ultracompact topological photonic circuits, with potential for high-density integrated optics.
『摘要』
光子结构中的拓扑保护可实现稳健的单向传播，且不受结构无序的影响。然而，传统方法通过拓扑绝缘体区域来实现这种保护，其界面处存在狭窄的导波通道，导致大部分绝缘体主体在传输过程中处于闲置状态。这就在拓扑鲁棒性和空间占用之间形成了根本性的权衡。本文介绍了一种无绝缘体的拓扑波导架构，消除了这一权衡，实现了具有100%空间利用效率和拓扑保护的多车道单向光引导。通过在旋磁蜂窝状光子晶体（PCs）中策略性地结合时间反演和反转对称性破缺，我们在平凡相与陈数绝缘体相之间的不同临界转变边界上实现了四种不等价的光子谷半半导体（PVHSMs）。我们将这四种结构以平行循环的方式排列，使得每个区域同时作为相邻区域其他谷的谷选择性波导和拓扑势垒，从而无需额外的拓扑绝缘层。实验和理论结果表明，这种多车道配置将传统的边缘态转变为密集分布的大面积单向模式。这些模式在四个区域间交替呈现单向性，即使在任意急弯和明显形状变化的情况下仍能保持稳健性。这项工作为超紧凑型拓扑光子电路提供了一种设计策略，在高密度集成光学领域具有应用潜力。
『总结』
本文提出一种无绝缘体的拓扑波导架构，消除拓扑鲁棒性与空间占用的权衡，实现高效多车道单向光引导，还介绍了相关原理、结构及优势，为超紧凑型拓扑光子电路提供设计策略。
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9. 脂肪变性塑造结直肠癌中决定预后的肝转移异质性
Steatosis shapes prognosis-defining liver metastasis heterogeneity in CRC
『Abstract』Patients with colorectal cancer (CRC) frequently develop liver metastases. The prognosis of these patients is skewed by the histopathological heterogeneity of their liver metastases. Patients with 'replacement' metastases have a 5-year overall survival of less than 44.2%, compared with 73.4% in patients with 'encapsulated' (previously known as desmoplastic) metastases; yet there are currently no approved therapies targeting replacement liver metastases. Here we show that treatment-naive patients with CRC with liver steatosis have an increased occurrence of replacement metastases compared with patients without steatosis. Mechanistically, we find that steatosis-promoted fatty acid oxidation increases formation of replacement metastases by increasing MYC stability through acetylation. In turn, MYC activates proline synthesis, fuelling collagen production, enabling growth of replacement metastases. Targeting MYC, P5CS or COL1A1 suppresses the occurrence and growth of replacement metastases in patient-derived organoids, mouse or patient-derived xenograft models. Spatial metabolite and protein analyses of liver metastases from patients with CRC further support this mechanism. In conclusion, we provide a mechanistic understanding of the emergence of liver metastases with poor prognosis in treatment-naive patients with CRC, identifying potential targets for therapeutic intervention.
『摘要』
结直肠癌（CRC）患者常发生肝转移。这些患者的预后因肝转移灶的组织病理学异质性而受到影响。与“包裹型”（既往称为硬纤维瘤型）肝转移患者73.4%的5年总生存率相比，“替代型”肝转移患者的5年总生存率低于44.2%；然而，目前尚无针对替代型肝转移的获批疗法。本研究发现，与无脂肪变性的结直肠癌患者相比，未经治疗的伴有肝脏脂肪变性的结直肠癌患者出现替代型肝转移的概率更高。从机制上讲，我们发现脂肪变性促进的脂肪酸氧化通过乙酰化作用增加MYC稳定性，进而增加替代型肝转移的形成。反过来，MYC激活脯氨酸合成，为胶原蛋白生成提供燃料，从而促进替代型肝转移的生长。在患者来源类器官、小鼠或患者来源移植模型中，靶向MYC、P5CS或COL1A1可抑制替代型肝转移的发生和生长。对结直肠癌患者肝转移灶的空间代谢物和蛋白质分析进一步支持了这一机制。总之，我们对未经治疗的结直肠癌患者预后不良的肝转移的出现提供了机制性理解，并确定了潜在的治疗干预靶点。
『总结』
研究发现未经治疗且伴肝脏脂肪变性的结直肠癌患者更易出现预后差的替代型肝转移，其机制是脂肪变性促脂肪酸氧化经乙酰化增加MYC稳定性，MYC激活脯氨酸合成助胶原生成以利转移生长，还确定了一些潜在治疗靶点。
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10. 通用细胞嵌入为细胞生物学提供了一个基础模型
Universal cell embedding provides a foundation model for cell biology
『Abstract』Developing a universal representation space for cells that encompasses the tremendous molecular diversity of cell types across species would be transformative for cell biology. Recent work using single-cell transcriptomic approaches to create molecular definitions of cell types in the form of cell atlases has provided the necessary data for such an endeavour. Here we present the universal cell embedding (UCE) foundation model. UCE was trained on a large corpus of cell data using self-supervision, creating a unified biological latent space that can represent cells across diverse tissues and species. This latent space captures important biological variation despite the presence of experimental noise. UCE's universality means that new cells can be embedded with no data labelling, model training or fine-tuning. We used UCE to create the Integrated Mega-scale Atlas, embedding 36 million cells, with more than 1,000 uniquely named cell types, from hundreds of experiments, dozens of tissues and eight species. We gain insights into the organization of cell types and tissues within the space. UCE's embedding space exhibits emergent behaviour, identifying biology that it was never trained for, such as identifying developmental lineages and embedding data from species that were not included in the training set. Overall, by enabling a universal representation for every cell state and type, UCE is a valuable tool for analysis, annotation and hypothesis generation over single-cell data.
『摘要』
开发一种涵盖跨物种细胞类型巨大分子多样性的通用细胞表征空间，将对细胞生物学产生变革性影响。近期利用单细胞转录组方法以细胞图谱形式对细胞类型进行分子定义的研究，为这一努力提供了必要的数据支持。本文提出通用细胞嵌入（UCE）基础模型。UCE通过自监督学习在大量细胞数据上进行训练，创建了一个统一的生物潜在空间，能够表征不同组织和物种的细胞。尽管存在实验噪声，该潜在空间仍能捕捉重要的生物学变异。UCE的通用性意味着无需数据标注、模型训练或微调即可嵌入新细胞。我们使用UCE构建了集成超大规模图谱，嵌入了来自数百项实验、数十种组织及八个物种的3600万个细胞，涵盖1000多种独特命名的细胞类型。我们在该空间中深入了解了细胞类型和组织的结构。UCE的嵌入空间展现出涌现行为，能够识别其从未接受过训练的生物学特征，例如确定发育谱系并嵌入未包含在训练集中的物种数据。总体而言，通过实现对每个细胞状态和类型的通用表征，UCE成为分析、注释单细胞数据以及生成假设的有力工具。
『总结』
开发通用细胞表征空间意义重大，研究提出UCE基础模型，经自监督学习训练可表征不同组织物种细胞，具通用性，用其构建集成超大规模图谱，其嵌入空间有涌现行为，是分析等单细胞数据的得力工具。
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11. 大型语言模型能够预测社会科学实验结果
Large language models can predict the results of social science experiments
『Abstract』There is growing interest in how large language models (LLMs) can advance social and behavioural science. Previous work has assessed LLMs' ability to predict survey responses, but less is known about whether they can predict the outcomes of social science experiments, particularly those absent from training data. Here we built an archive of 70 preregistered, nationally representative survey experiments in the USA involving 469 experimental effects and 119,330 participants. We prompted an LLM to simulate how representative samples from American individuals would respond to experimental stimuli, and then we inferred treatment effects by comparing simulated responses across conditions. Predictions derived from GPT-4, whose training-data cutoff predated the publication of many studies in our archive, were strongly correlated with actual treatment effects, achieving accuracy similar to pooled human forecasts. Correlations remained high for studies not published or publicly posted by the model's training-data cutoff date and for predictions from prominent open-weight models. Despite high correlations, predictions systematically overestimated effect sizes. In a secondary archive of 15 megastudies featuring 606 effects, correlations were lower but comparable to those of pooled expert forecasters. To assess implications for scientific practice, we surveyed 460 social scientists about probable uses and perceived risks and used our archives to assess several applications (pilot testing, intervention selection, identifying effects needing replication) and risks (bias, misuse). Together, these results indicate that LLMs can augment experimental methods in science and practice while raising important considerations for responsible use.
『摘要』
人们越来越关注大型语言模型（LLMs）如何推动社会和行为科学的发展。先前的研究评估了大型语言模型预测调查反应的能力，但对其能否预测社会科学实验的结果知之甚少，尤其是那些训练数据中未包含的实验结果。本研究构建了一个包含70项在美国进行的预注册、具有全国代表性的调查实验的档案库，涉及469个实验效应和119,330名参与者。我们提示一个大型语言模型模拟美国代表性样本对实验刺激的反应，然后通过比较不同条件下的模拟反应来推断处理效应。GPT-4的预测（其训练数据的截止日期早于本档案库中许多研究的发表时间）与实际处理效应高度相关，准确性与汇总的人类预测相当。对于在该模型训练数据截止日期前未发表或未公开发布的研究，以及来自知名开源权重模型的预测，相关性仍然很高。尽管相关性较高，但预测仍系统性地高估了效应量。在另一个包含15项大型研究（涉及606个效应）的次要档案库中，相关性较低但仍可与汇总专家预测相媲美。为评估其对科学实践的影响，我们对460名社会科学家进行了关于可能用途和感知风险的调查，并利用我们的档案库评估了几种应用（试点测试、干预选择、识别需要复制的效应）和风险（偏见、滥用）。总之，这些结果表明，大型语言模型可以增强科学和实践中的实验方法，同时也引发了对负责任使用的重要考量。
Sum: There's growing interest in how large language models (LLMs) advance social and behavioral science. This study built an archive of 70 nationally representative survey experiments in the USA. An LLM was prompted to simulate responses to experimental stimuli, and treatment effects were inferred. GPT-4's predictions correlated highly with actual effects, similar to human forecasts. Correlations remained high for unreleased studies and open-weight models. Predictions overestimated effect sizes. In a secondary archive, correlations were lower but comparable to expert forecasters. Surveys of social scientists and assessments of applications and risks show that LLMs can enhance experimental methods while raising considerations for responsible use.
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12. 通过神经迭代选择-扩展实现药物结合蛋白的零样本设计
Zero-shot design of drug-binding proteins via neural iterative selection-expansion
『Abstract』The design of proteins that bind to small molecules has been challenging because it requires simultaneous optimization of the protein sequence, protein structure and ligand conformation. Current deep-learning algorithms have struggled to navigate this landscape, precluding the zero-shot design of binders. Here we show that by combining two neural networks in an iterative design algorithm, small-molecule binding proteins can be created from scratch with high accuracy. We trained a graph neural network-ligand-aware sequence engineering message-passing neural network (LASErMPNN)-to design compatible protein sequences for an input protein backbone and docked ligand. We paired LASErMPNN with a structure predictor that models a three-dimensional protein-ligand complex for an input protein sequence and ligand identity. The closed-loop iteration of these reciprocal networks optimized sequence-structure-ligand compatibility, and outperformed a comparable design loop using a physics-based energy function. We used our strategy, termed neural iterative selection-expansion (NISE), to design proteins that, using different folds, specifically bind to two chemically distinct small-molecule drugs, exatecan and apixaban, with success rates of 100% and 83%, respectively. The tightest NISE binders had nanomolar-to-picomolar affinities, surpassing those of the next-leading method by 70-fold for exatecan and nearly 10,000-fold for apixaban. LASErMPNN then suggested two amino-acid substitutions that improved the affinity of the tightest exatecan binder by 100-fold without any experimental input. The optimized binder protected the labile lactone ring of exatecan from hydrolysis for days. Our work describes a general recipe for using neural networks to automate the design of small-molecule binding proteins for applications in drug delivery, sensing and catalysis.
『摘要』
设计能与小分子结合的蛋白质颇具挑战性，因为这需要同时优化蛋白质序列、蛋白质结构以及配体构象。当前的深度学习算法难以应对这一复杂局面，无法实现零样本结合物设计。本研究表明，通过在迭代设计算法中融合两个神经网络，可以高精度地从无到有创建小分子结合蛋白。我们训练了一个图神经网络——配体感知序列工程消息传递神经网络（LASErMPNN），用于为输入的蛋白质骨架和对接配体设计兼容的蛋白质序列。我们将LASErMPNN与一个结构预测器配对，该预测器可对输入的蛋白质序列和配体身份建模三维蛋白质-配体复合物。这些互惠网络的闭环迭代优化了序列-结构-配体的相容性，其表现优于使用基于物理的能量函数的可比设计循环。我们采用名为神经迭代选择扩展（NISE）的策略，设计了分别以不同折叠方式特异性结合两种化学性质截然不同的小分子药物依喜替康（exatecan）和阿哌沙班（apixaban）的蛋白质，成功率分别为100%和83%。最紧密的NISE结合物的亲和力处于纳摩尔至皮摩尔级别，对于依喜替康，其亲和力比次优方法高出70倍；对于阿哌沙班，则高出近10,000倍。随后，LASErMPNN提出了两个氨基酸替换方案，无需任何实验数据输入，便将最紧密的依喜替康结合物的亲和力提高了100倍。优化后的结合物可在数天内保护依喜替康不稳定的内酯环免受水解。我们的研究阐述了一种通用方法，即利用神经网络自动化设计小分子结合蛋白，应用于药物递送、传感和催化领域。
『总结』
当前深度学习算法难实现零样本小分子结合蛋白设计，本研究通过融合两个神经网络提出NISE策略，能高精度从无到有创建此类蛋白，所设计的蛋白对两种药物结合成功率高且亲和力强，还提出替换方案提高亲和力，阐述了用神经网络自动化设计这类蛋白的通用方法及多领域应用潜力。
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13. 菱面体石墨烯中磁场增强型超导体家族
Family of magnetic field-boosted superconductors in rhombohedral graphene
『Abstract』In some unconventional superconductors, time-reversal symmetry can be broken apart from the gauge symmetry, resulting in superconductivity that can be enhanced or induced by magnetic fields. However, field-enhanced superconductors are more vulnerable to impurities than their Bardeen-Cooper-Schrieffer counterparts. Crystalline rhombohedral multilayer graphene is a promising platform to explore them because of its superior material quality and gate-tunable strong correlation effects. Here we report transport measurements of rhombohedral tetralayer and pentalayer graphene, demonstrating a spectrum of clean-limit superconductivities. We found three different types of field-enhanced and field-induced superconductivities in the pentalayer. They are all robust against an in-plane field up to 8.5 T, exceeding the Pauli limit by tens of times. Compared with Bernal bilayer graphene showing only in-plane field-enhancement, pentalayer graphene features superconductors enhanced by out-of-plane as well as in-plane fields. They also reside at much lower gate electric fields owing to the intrinsically flatter band dispersion-facilitating their study and further engineering. Moreover, we observed that proximitized spin-orbit coupling generates multiple new superconductors without introducing additional disorder effects. Our work establishes a new family of magnetic field-boosted superconductors in rhombohedral graphene. Using the high accessibility with moderate gate voltages, this will pave the way for realizing non-Abelian quasiparticles through interfacial engineering in the extreme clean limit, in that proximitized spin-orbit coupling leads to topological states and maintains the ultrahigh quality of crystalline graphene.
『摘要』
在某些非常规超导体中，时间反演对称性可以与规范对称性分离，导致磁场能够增强或诱导出超导性。然而，场增强型超导体比其巴丁-库珀-施里弗（Bardeen-Cooper-Schrieffer）对应体更容易受到杂质的影响。菱面体多层石墨烯因其卓越的材料质量和栅极可调的强关联效应，成为探索这类超导体的理想平台。本研究报告了菱面体四层和五层石墨烯的输运测量结果，展示了清洁极限下的一系列超导现象。我们发现五层石墨烯中存在三种不同类型的场增强和场诱导超导性，它们在高达8.5特斯拉的面内磁场下仍保持稳定，超出泡利极限数十倍。与仅表现出面内场增强的伯纳尔双层石墨烯相比，五层石墨烯的超导性可通过面外和面内磁场共同增强。由于内在更平坦的能带色散，这些超导体所需的栅极电场更低，便于研究及进一步设计。此外，我们观察到近邻自旋轨道耦合可在不引入额外无序效应的情况下产生多种新型超导体。本研究在菱面体石墨烯中确立了一类新的磁场增强型超导体家族。借助中等栅压下的高可调控性，这将为在极端清洁极限下通过界面工程实现非阿贝尔准粒子铺平道路，因为近邻自旋轨道耦合可诱导拓扑态并维持晶体石墨烯的超高质量。
『总结』
菱面体多层石墨烯展现出多种由磁场增强或诱导的新型超导性，具有抗强磁场、低栅压需求及近邻自旋轨道耦合兼容性等优势，为探索非阿贝尔准粒子提供了新平台。
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14. 配体促进的脂肪族酸远端脱氢内酯化反应
Ligand-enabled distal desaturative lactonization of aliphatic acids
『Abstract』Transition-metal catalysis is a fundamental strategy for transforming inert C-H bonds into valuable functional motifs. However, achieving regioselective activation of remote C-H bonds remains challenging, particularly in unbiased hydrocarbon frameworks. In this context, distal C(sp)-H bonds are especially difficult to functionalize, as conformational flexibility favours proximal C-H activation. In this study, we demonstrate a ligand-enabled strategy using designed O-allyl amido ester ligands for palladium-catalysed activation of γ-methylene and methine C-H sites in unbiased aliphatic carboxylic acids, derived from readily available fatty and cyclic acid feedstocks. This protocol enables direct transformation of aliphatic carboxylic acid substrates into distal desaturated γ-lactones and double-dehydrogenated γ-spirolactones. Mechanistic studies are consistent with a pathway involving Pd(II)-mediated γ-C(sp)-H activation, followed by dehydrogenation and intramolecular cyclization. These lactones, with an unsaturated arm, serve as key intermediates for the formation of complex natural products and pharmaceuticals. For instance, muricatacin (from soursop/Laxman phal) and its analogue were rapidly assembled in three steps from margaric acid using this strategy and evaluated for anticancer activity, thereby demonstrating the potential of our approach for providing a rapid access to biologically relevant frameworks for traditional medicine. The introduced distal desaturation further opens up new avenues for remote functionalization, streamlining access to diverse bioactive molecules with improved step and atom economy.
『摘要』
过渡金属催化是将惰性C-H键转化为有价值官能团的基本策略。然而，实现远程C-H键的区域选择性活化仍具挑战，特别是在无偏向性的烃类骨架中。在此背景下，由于构象灵活性有利于近端C-H的活化，远端C(sp³)-H键的功能化尤为困难。本研究展示了一种配体辅助策略，即使用设计的O-烯丙基酰胺酯配体，实现了钯催化下由易得的脂肪酸和环酸原料衍生的无偏向性脂肪族羧酸中γ-亚甲基和次甲基C-H位点的活化。该方案可直接将脂肪族羧酸底物转化为远端脱饱和γ-内酯和双脱氢γ-螺内酯。机理研究表明，其反应路径涉及Pd(II)介导的γ-C(sp³)-H活化，随后进行脱氢和分子内环化。这些具有不饱和侧链的内酯是形成复杂天然产物和药物的关键中间体。例如，利用这一策略从十七烷酸出发经三步快速合成了刺果番荔枝素（来自刺果番荔枝/Laxman phal）及其类似物，并评估了它们的抗癌活性，从而证明了该方法在为传统医学提供快速获取生物相关框架方面的潜力。引入的远端脱饱和进一步开辟了远程功能化的新途径，简化了以改进步骤和原子经济性获得多种生物活性分子的过程。
『总结』
过渡金属催化转化惰性C-H键面临挑战，尤其远端C(sp³)-H键功能化难，本研究用特定配体实现钯催化无偏向性脂肪族羧酸中γ-C-H位点活化，生成特定内酯，机理表明有特定路径，这些内酯是关键中间体，还据此合成物质并评估抗癌活性，证明方法潜力，且远端脱饱和开辟新途径。
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15. 医疗人工智能带来的不同隐私风险
Disparate privacy risks from medical AI
『Abstract』Medical artificial intelligence (AI) models hold the promise to improve global access to high-quality diagnostics. However, the training data underlying these models often contain sensitive patient information that may be exposed through privacy attacks. Previous research has primarily quantified the success of these attacks in aggregate, across all records in a dataset. Thus, the privacy risk faced by individual patients, who often contribute multiple similar records to a training dataset, is poorly understood. Here we present one of the first patient-level privacy audits of AI models for medical diagnostic applications. We focus on membership inference attacks (MIAs), which seek to determine whether the data of a given individual were used to train a model. Across a diverse range of medical datasets, we show that MIAs can achieve near-perfect success rates for individual patients, even when the aggregate performance does not substantially deviate from random guessing. We further find that the number of patients with high attack success increases substantially with model capacity, and that underrepresented groups-stratified by disease status, self-reported race, insurance, sex or imaging protocol-face disproportionately high attack success. Together, our findings show that aggregate privacy metrics can severely underestimate individual privacy risk. Whether the disparate risk profiles we observe extend to attacks beyond MIAs remains an open question, motivating the further development of risk assessment and mitigation techniques that cater to all data-contributing patients.
『摘要』
医学人工智能（AI）模型有望改善全球获取高质量诊断的途径。然而，支撑这些模型的训练数据往往包含敏感的患者信息，可能通过隐私攻击泄露。先前的研究主要从整体上量化这些攻击在数据集所有记录中的成功率。因此，对于那些经常向训练数据集中贡献多条相似记录的个人患者所面临的隐私风险，人们知之甚少。本研究对医疗诊断应用的人工智能模型进行了首次针对患者层面的隐私审计。我们重点关注成员推理攻击（MIAs），这类攻击旨在确定某个特定个体的数据是否被用于训练模型。通过对多种医疗数据集的分析，我们发现即使总体表现与随机猜测无异，MIAs仍能实现对个体患者的近乎完美攻击成功率。我们还发现，随着模型容量的增加，高攻击成功率的病人数量大幅上升；此外，按疾病状态、自述种族、保险类型、性别或成像方案分层的代表性不足群体面临更高的攻击成功率。我们的研究结果表明，整体隐私指标可能会严重低估个人隐私风险。我们所观察到的不同风险状况是否会延伸到MIAs以外的攻击中仍是未解之谜，这促使我们进一步开发适用于所有提供数据的患者的风险评估和缓解技术。
『总结』
医学人工智能模型存在隐私泄露风险，当前研究多关注整体攻击成功率而忽视个体风险，研究发现成员推理攻击可实现个体患者的高成功率攻击，且某些群体更易受影响，表明整体隐私指标可能低估个体风险，需开发新风险评估和缓解技术。
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16. 激动性神经毒素在人类Na<sub>v</sub>1.6上的不同结合构象
Diverse binding poses of agonistic neurotoxins on human Na<sub>v</sub>1.6
『Abstract』Voltage-gated sodium (Nav) channels are key targets of various venomous toxins. Deciphering the binding poses and mechanisms of action of representative toxins will help to dissect the functional mechanism of the channels and facilitate therapeutic development targeting Nav channels. Here we present cryo-electron microscopy (cryo-EM) structures of distinct binding poses of three agonistic peptide toxins on the human Nav1.6-β1 channel complex. The globular β-scorpion toxin Cn2 nestles between the extracellular segment of voltage-sensing domain (VSD) in the second repeat of the Nav1.6 core α-unit (VSDII) and the pore extracellular loops in the third repeat of the Nav1.6 core α-unit (ECLIII), where it is stabilized by interactions with both protein regions and the branched N1372-glycan. Cone snail ι-conotoxin RXIA adopts an elongated conformation, spanning VSDI and VSDIV to wrap around the shoulder of the pore domain (PD). The bullet ant-derived toxin δ-paraponeritoxin-Pc1a exists as a transmembrane helix that stands between VSDII and PDIII. Our findings, corroborated by functional characterizations, illustrate the diversity in peptide toxin binding poses and mechanisms of action, link stabilization of the up state of VSDI or VSDII to channel activation, and provide clues to the rational design of selective Nav channel modulators.
『摘要』
电压门控钠（Nav）通道是多种毒液毒素的关键靶点。解析代表性毒素的结合构象和作用机制，有助于剖析通道的功能机制并促进针对Nav通道的药物开发。本研究展示了三种激动性肽类毒素在人类Nav1.6-β1通道复合体上的不同结合构象的冷冻电子显微镜（cryo-EM）结构。球状β-蝎毒素Cn2嵌合于Nav1.6核心α亚基第二重复序列电压传感域（VSDII）的胞外段与第三重复序列孔区胞外环（ECLIII）之间，通过与这两个蛋白区域及分支型N1372糖链相互作用实现稳定。芋螺ι-芋螺毒素RXIA呈长条形构象，横跨VSDI和VSDIV并环绕孔区（PD）肩部。子弹蚁来源的毒素δ-paraponeritoxin-Pc1a以跨膜螺旋形式存在于VSDII与PDIII之间。功能表征结果证实了这些发现，揭示了肽类毒素结合构象和作用机制的多样性，阐明了VSDI或VSDII"上态"稳定与通道激活之间的关联，并为选择性Nav通道调节剂的合理设计提供了线索。
『总结』
研究通过冷冻电镜技术解析了三种肽类毒素在Nav1.6通道上的不同结合模式，揭示其作用机制差异，为开发靶向钠通道的选择性药物提供新思路。
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17. 人体及癌症中蛋白质组的空间分布
Spatial distribution of the proteome in the human body and in cancers
『Abstract』A detailed, spatially resolved quantitative map of the human proteome is essential for a deeper understanding of human biology and disease. Here we present a comprehensive human proteomic landscape, generated by profiling more than 13,000 proteins across 2,856 samples using data-independent acquisition mass spectrometry. The dataset spans 58 major tissue types, 251 specific tissue subtypes and 25 distinct carcinomas. This resource enables the depiction of spatially resolved proteome trajectories across tissue types and physiological states, including fetal, tumour, adjacent non-tumour and healthy adult tissue, thereby providing insight into both developmental processes and oncogenic progression. Furthermore, quantitative proteomics comparisons across diverse tissue types and states facilitate the indication of organ-specific toxicity, the identification of repurposable anticancer drug candidates and the prioritization of therapeutic targets for cancers. This study establishes a quantitative resource for navigating the proteome in the human body and in common cancers.
『摘要』
人类蛋白质组的详细、空间分辨定量图谱对于深入理解人类生物学和疾病至关重要。本研究利用数据非依赖采集质谱技术，对2856个样本中的13000多种蛋白质进行剖析，构建了全面的人类蛋白质组图景。该数据集涵盖58种主要组织类型、251种特定组织亚型及25种不同癌种。这一资源能够描绘不同组织类型和生理状态（包括胎儿、肿瘤、邻近非肿瘤及健康成人组织）下的空间分辨蛋白质组动态轨迹，为发育过程和致癌进展提供洞见。此外，通过对不同组织类型和状态的定量蛋白质组学比较，有助于揭示器官特异性毒性、识别可重新用于抗癌的药物候选物以及确定癌症治疗靶点的优先级。本研究建立了探索人体和常见癌症中蛋白质组的定量资源。
『总结』
研究通过质谱技术绘制出覆盖多组织类型的全面人类蛋白质组图谱，揭示了蛋白质动态变化规律，并为疾病机制研究和药物开发提供了重要工具。
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18. 自闭症谱系障碍小鼠模型中的皮层发育动态
Cortical development dynamics across autism spectrum disorder mouse models
『Abstract』Despite the functional diversity of over 100 causal genes, phenotypic convergence across models may reveal common neurobiological processes in autism spectrum disorder (ASD). Here we profiled 251 samples from 11 monogenic mouse models of ASD using single-nucleus multi-omic sequencing across three developmental stages, both sexes and two brain regions. Despite genetic heterogeneity, ASD-linked mutations converged on perturbations of the radial glial cell lineage. These alterations reflect a transient developmental delay rather than lasting lineage misspecification and resolve by postnatal stages. Molecularly, the largest transcriptional differences emerged in neurons at early postnatal stages. These changes included downregulation of synaptic and ion channel-related genes, consistent with homeostatic adaptation or delayed maturation. Network analysis showed molecular convergence across models within each developmental stage, suggesting that diverse mutations linked to ASD impinge on common, stage-specific processes. Convergence becomes less pronounced by postnatal day 14, highlighting the dynamic nature of ASD-associated changes. Cross-genotype heterogeneity is superimposed on stage-specific effects. Electrophysiology corroborated this pattern: mutants generally showed altered neuronal excitability and synaptic properties with model-specific nuances. Our study also highlighted sex-specific gene expression alterations, with female mice often displaying larger effect sizes than male mice. Together, our findings provide a comprehensive view of developmental cellular and molecular dynamics across models of ASD.
『摘要』
尽管有超过100个致病基因功能多样，但不同模型间的表型趋同可能揭示出自闭症谱系障碍（ASD）中共同的神经生物学过程。本研究利用单核多组学测序技术，对来自11种单基因自闭症小鼠模型的251份样本进行了分析，这些样本涵盖了三个发育阶段、两种性别和两个脑区。尽管存在遗传异质性，与自闭症相关的突变均导致放射状胶质细胞谱系的扰动。这些改变反映的是暂时性的发育延迟而非持续的谱系异常分化，且在出生后阶段得到缓解。分子层面，最大的转录差异出现在早期出生后的神经元中，包括突触和离子通道相关基因的下调，这与稳态适应或成熟延迟一致。网络分析显示，每个发育阶段内各模型间存在分子趋同性，表明与自闭症相关的多种突变影响共同且具有阶段特异性的过程。到出生后第14天，这种趋同性变得不那么明显，凸显了自闭症相关变化的动态特性。跨基因型的异质性叠加于阶段特异性效应之上。电生理学研究证实了这一模式：突变体通常表现出神经元兴奋性和突触特性的改变，并带有模型特有的细微差别。本研究还强调了性别特异性的基因表达变化，雌性小鼠的影响程度往往大于雄性小鼠。总之，我们的研究全面呈现了自闭症模型在发育过程中的细胞和分子动态变化。
『总结』
研究通过单核多组学测序分析11种自闭症小鼠模型，发现尽管致病基因多样，但突变均引发放射状胶质细胞谱系的暂时性发育延迟，并在分子层面呈现阶段特异性趋同，同时揭示了性别差异及动态变化特征。
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19. 细胞类型解析的遗传变异影响炎症性肠病风险
Cell-type-resolved genetic variation shapes inflammatory bowel disease risk
『Abstract』Most genetic variants associated with complex diseases lie in non-coding regions, complicating efforts to identify effector genes and relevant cell types. Here we map cis-expression quantitative trait loci (eQTLs) across 2.2 million single cells using intestinal biopsies and blood from 421 individuals, including 125 with inflammatory bowel disease (IBD). Cell-type-level eQTLs were more distal to transcription start sites, enriched in enhancers, less likely to regulate the nearest gene, and more than 3.5-fold more likely to colocalize with IBD loci detected in genome-wide association studies (GWASs) than eQTLs detected at tissue-level resolution. We nominate effector genes at more than half of known IBD loci, including MAML2, PSEN2 and ZMIZ1 in myeloid cells, implicating reduced Notch signalling in intestinal immune dysfunction. We also identify Wnt-regulated genes, including MYC, in epithelial stem and progenitor cells, suggesting that impaired renewal contributes to barrier breakdown. Our results provide a mechanistic map that links genetic risk to specific genes and cell types in IBD, and a generalized framework for interpretation of GWAS loci using single-cell eQTL mapping of disease-relevant tissues in complex diseases.
『摘要』
与复杂疾病相关的大多数遗传变异位于非编码区域，这使得识别效应基因和相关细胞类型的工作变得复杂。本研究利用421名个体的肠道活检和血液样本（其中包括125例炎症性肠病(IBD)患者），在220万个单细胞中绘制了顺式表达数量性状位点（eQTLs）图谱。与组织水平分辨率检测到的eQTLs相比，细胞类型水平的eQTLs距离转录起始位点更远、富集于增强子区域、调控最近基因的可能性更低，且与全基因组关联研究(GWASs)中检测到的IBD位点共定位的可能性高出3.5倍以上。我们在超过半数的已知IBD位点中提名了效应基因，包括髓系细胞中的MAML2、PSEN2和ZMIZ1，提示Notch信号通路减少会导致肠道免疫功能障碍。我们还确定了上皮干细胞和祖细胞中受Wnt调控的基因（如MYC），表明再生能力受损会促进屏障破坏。我们的结果提供了一个机制图谱，将IBD的遗传风险与特定基因和细胞类型联系起来，并为通过复杂疾病中疾病相关组织的单细胞eQTL图谱来解释GWAS位点提供了通用框架。
『总结』
该研究通过单细胞eQTL图谱揭示了IBD遗传风险与特定基因及细胞类型的关联机制，为解析复杂疾病GWAS位点提供新方法。
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20. 激光（LASER）将损伤感应与ESCRT组装偶联以实现溶酶体修复
LASER couples damage sensing to ESCRT assembly for lysosome repair
『Abstract』Lysosomal membrane integrity is essential for cell survival, but how damage sensing is spatiotemporally coupled to repair remains poorly understood. Recruitment and assembly of endosomal sorting complex required for transport (ESCRT) I-III rapidly counteracts membrane damage, but it is unclear how ESCRT-I recognizes defective lysosomal membranes. Here, leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we identified LC3/GABARAP-assisted stimulator for ESCRT recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes and couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is TFG, an endoplasmic reticulum exit-site-resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3 and GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit TSG101 via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT-I-II-III polymerization and promotes membrane repair. TFG mutations that drive hereditary spastic paraplegia disrupt its oligomerization and impair lysosomal ESCRT recruitment and membrane resealing, implicating defective repair as a driver of TFG-associated neurodegeneration. Thus, LASER promotes ESCRT polymerization at damaged lysosomes and couples damage sensing to membrane repair.
『摘要』
溶酶体膜的完整性对于细胞存活至关重要，但损伤感应在时空上如何与修复相偶联仍知之甚少。内体分选转运所需复合物（ESCRT）I-III的招募和组装可迅速对抗膜损伤，但ESCRT-I如何识别有缺陷的溶酶体膜尚不清楚。本研究利用全基因组CRISPRi筛选技术，在损伤敏感遗传背景下确定了LC3/GABARAP辅助的ESCRT招募刺激因子（LASER），这是一种多成分蛋白质组合体，可在受损溶酶体释放钙离子时迅速形成，并将溶酶体膜损伤感应与ESCRT依赖性修复相偶联。LASER的核心是TFG，它是一种内质网出口位点驻留蛋白，通过与结合到溶酶体磷脂上的ATG8家族蛋白（LC3和GABARAP）相结合而转移到受损溶酶体。与ATG8结合的TFG形成寡聚体，该寡聚体通过由亲和力驱动相互作用增强的保守基序识别直接招募必需的ESCRT-I亚基TSG101。TFG与TSG101的结合会刺激ESCRT-I-II-III依次聚合并促进膜修复。导致遗传性痉挛性截瘫的TFG突变会破坏其寡聚化，损害溶酶体ESCRT的招募和膜再密封，这表明修复缺陷是TFG相关神经退行性疾病的驱动因素。因此，LASER可促进受损溶酶体的ESCRT聚合，并将损伤感应与膜修复相偶联。
『总结』
研究发现了LASER这一多成分蛋白质组合体，揭示了其在溶酶体膜损伤后通过TFG等机制促进ESCRT聚合、实现损伤感应与膜修复相偶联的过程，且TFG突变会导致相关疾病。
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21. 丘脑-脑干吸引子网络驱动具有历史偏好的决策
A thalamus-brainstem attractor network drives history-biased decisions
『Abstract』Natural environments often change gradually, making it adaptive to bias decisions on the basis of the recent past - a phenomenon known as serial dependence. Large-scale recordings during behaviour have identified that serial dependence is a common motif for decision-making, with neural representations of past experiences found throughout the brain. However, it remains unclear whether this bias arises from dedicated neural circuits with history-specific computations. Using whole-brain, cellular-resolution imaging in zebrafish performing memory-guided evasive manoeuvres, we identified a hierarchical circuit that maintains past information and biases future choices. Discrete attractors in the dorsal thalamus encoded the position of the most recent obstacle, maintaining a categorical memory via persistent activity lasting 10-20 s. Optogenetic manipulation of the dorsal thalamus abolished or imposed serial bias. A downstream hindbrain integrator received input from the thalamus and combined it with current sensory cues to produce graded responses reflecting multi-trial history. Leveraging a comprehensive brain atlas in zebrafish, we constructed a whole-brain computational model that recapitulated behaviour and also predicted a key role for heterogeneous inhibitory subtypes in enabling flexible state transitions. This attractor-integrator architecture reveals a hierarchical and modular computation that unifies robust memory retention with flexible sensory integration, providing a general principle for history-biased decisions.
『摘要』
自然环境通常会逐渐变化，这使得基于近期经历来做出有偏差的决策具有适应性——这种现象被称为序列依赖。行为期间的大规模记录表明，序列依赖是决策中常见的模式，整个大脑都能发现过去经历的神经表征。然而，目前尚不清楚这种偏差是否源于具有历史特定计算功能的专用神经回路。我们利用斑马鱼进行记忆引导的规避动作时，对其全脑、细胞分辨率成像，确定了一个维持过往信息并影响未来选择的层级回路。背侧丘脑中的离散吸引子编码最近障碍物的位置，通过持续10 - 20秒的活动维持分类记忆。对背侧丘脑的光遗传操作可消除或施加序列偏差。下游后脑整合器接收来自丘脑的输入，并将其与当前感觉线索相结合，产生反映多试次历史的分级反应。借助斑马鱼的全面脑图谱，我们构建了全脑计算模型，该模型重现了行为，还预测了异质抑制亚型在实现灵活状态转换中的关键作用。这种吸引子-整合器架构揭示了一种分层模块化计算方式，它将强大的记忆保持能力与灵活的感觉整合统一起来，为基于历史经验的决策提供了通用原则。
『总结』
自然环境渐变使基于近期经历做有偏差决策具适应性即序列依赖，其常见于决策但成因不明，研究通过对斑马鱼全脑成像等确定了相关层级回路，构建的全脑计算模型重现行为并揭示架构原理。
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22. 利用RNA触发的染色质碎裂靶向癌症特异性突变
Targeting cancer-specific mutations with RNA-triggered chromatin shredding
『Abstract』Genetic mutations that drive cancer often occur in tumour-suppressor proteins such as the p53 transcription factor, which is altered in 40-50% of cases. However, current therapies often fail to target these mutations because the mutant proteins typically lack defined drug-binding pockets and restoring their endogenous function has proven challenging. Here we program Cas12a2, an RNA-guided CRISPR nuclease with trans-nucleolytic cleavage activity, to kill cancer cells selectively by targeting cancer-specific transcripts. This approach limited cell growth by inducing trans shredding of chromatin and triggering DNA-damage responses and cell death. In contrast to existing methods, RNA-guided Cas12a2 senses cellular RNA signatures, enabling precise targeting of undruggable mutations. Transcript-activated chromatin shredding provides an innovative approach to precision disease treatments for undruggable targets.
『摘要』
驱动癌症的基因突变通常发生在肿瘤抑制蛋白中，例如p53转录因子，约40-50%的癌症病例存在该因子的变异。然而，当前疗法往往无法针对这些突变发挥作用，因为突变蛋白通常缺乏明确的药物结合位点，且恢复其内源性功能极具挑战性。本研究通过编程具有反式核酸酶切割活性的RNA引导CRISPR核酸酶Cas12a2，使其能够靶向癌细胞特异性转录本并选择性杀伤癌细胞。该方法通过诱导染色质反式剪切、触发DNA损伤反应和细胞死亡来限制细胞生长。与现有方法不同，RNA引导的Cas12a2可感知细胞RNA特征，从而实现对不可成药突变的精准靶向。转录激活型染色质剪切为针对不可成药靶点的精准疾病治疗提供了创新途径。
『总结』
研究利用RNA引导的Cas12a2核酸酶靶向癌细胞特异性转录本，通过染色质剪切机制实现不可成药癌症突变的选择性杀伤，为精准医疗提供新策略。
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23. 冷诱导肽信号传导确保花粉抗逆性和作物产量
Cold-induced peptide signalling secures pollen resilience and crop yield
『Abstract』Cold weather cause severe crop losses. Climate change exacerbates the unpredictability and frequency of such weather events, highlighting the need for cold-resilient crops. Cold-induced pollen abortion and reproductive failure during flowering are major causes of yield losses, yet the molecular mechanisms and signalling pathways that underlie cold resilience in pollen development remain unknown. Here we identify a subset of cold-responsive small signalling peptides in the RGF-GLV-CLEL family, SlRGF9 and SlRGF10, that control cold resilience in tomato pollen. After loss of function of SlRGF9 and SlRGF10, tomato plants (Solanum lycopersicum) showed no defects under normal conditions, but pollen abortion was observed after cold stress. The leucine-rich repeat receptor-like kinases, SlRGFR6 and SlSERK proteins, form cell-surface receptor complexes that bind to these cold-induced SlRGFs. Furthermore, SlRGF-SlRGFR6 signalling activates calcium influx through cyclic-nucleotide-gated channels, counteracting cold-delayed programmed cell death and ensuring tapetum degradation to support microspore development. Upregulating SlRGF9 and SlRGF10 in tomato plants prevents cold-induced yield losses by up to 52%. This cold-responsive peptide signalling pathway is conserved across dicots and monocots. For example, upregulation of RGF homologues in rice (Oryza sativa) boosts cold resilience in pollen and recovers 18.3% of grain yield loss. Our findings uncover a core peptide signalling axis that governs cold resilience in pollen and has broad potential for safeguarding crop productivity against cold stress.
『摘要』
低温天气会导致严重的作物减产。气候变化加剧了此类天气事件的不可预测性和发生频率，凸显出培育耐寒作物的必要性。开花期间低温导致的花粉败育和生殖失败是产量损失的主要原因，然而，花粉发育过程中耐寒性的分子机制和信号通路仍不为人知。本研究在RGF-GLV-CLEL家族中鉴定出一组冷响应小信号肽SlRGF9和SlRGF10，它们控制着番茄花粉的耐寒性。在SlRGF9和SlRGF10功能缺失后，番茄植株（Solanum lycopersicum）在正常条件下没有缺陷表现，但在寒冷胁迫下观察到花粉败育现象。富含亮氨酸重复序列的受体样激酶SlRGFR6和SlSERK蛋白形成细胞表面受体复合物，与这些由寒冷诱导产生的SlRGFs结合。此外，SlRGF-SlRGFR6信号通过环核苷酸门控通道激活钙离子内流，抵消因寒冷而延迟的程序性细胞死亡，确保绒毡层降解以支持小孢子发育。上调番茄植株中的SlRGF9和SlRGF10可防止因寒冷导致的产量损失高达52%。这种冷响应肽信号通路在双子叶植物和单子叶植物中均保守存在。例如，水稻（Oryza sativa）中RGF同源基因的上调增强了花粉的耐寒性，并恢复了18.3%的谷粒产量损失。我们的研究揭示了一个调控花粉耐寒性的核心肽信号轴，该轴在保护作物免受寒冷胁迫方面具有广泛潜力。
『总结』
低温致作物减产，气候变化使情况更严峻，目前花粉发育耐寒性的相关机制不明，研究发现一组冷响应小信号肽控制番茄花粉耐寒性，还阐述了其作用机制、效果及该通路的保守性，揭示的核心肽信号轴有保护作物抗寒的潜力。
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24. 高保真模块化骨骼证实了苔藓虫的寒武纪起源
High-fidelity modular skeletons authenticate a Cambrian origin for Bryozoa
『Abstract』The major animal body plans originated during the Cambrian explosion, yet the phylum Bryozoa has remained a conspicuous exception to this pattern. The initial discovery of Protomelission gatehousei provided compelling evidence for a Cambrian origin for the Bryozoa, together with other major metazoan phyla and compatible with independent molecular clock estimates. Nevertheless, the scarcity of definitive soft-tissue anatomy and diagnostic skeletal microstructure has left its phylogenetic affinities ambiguous and debated. Here we report exquisite fossils of P. gatehousei and a new taxon, Dayingomelission hexaclitia gen. et sp. nov., from the early Cambrian Xiannudong Formation of China. These specimens preserve in situ phosphatized soft tissues in modular skeletons, revealing critical anatomical structures, including styles, annular muscles, membranous sacs and ring septa. This suite of traits provides definitive evidence that these taxa belong to the Bryozoa. Phylogenetic analysis incorporating these new features identifies them as crown group stenolaemates. These results confirm a Cambrian origin for the phylum and reveal an unexpected early disparity in colonial architecture, demonstrating that bryozoan diversification was an integral component of the Cambrian radiation. Moreover, the early appearance of a differentiated stenolaemate crown group indicates a still deeper origin for the bryozoan stem lineage than was first apparent.
『摘要』
主要动物体型设计在寒武纪大爆发期间形成，但苔藓虫门（Bryozoa）却明显违背了这一模式。Protomelission gatehousei的首次发现为苔藓虫与其它主要后生动物门的寒武纪起源提供了有力证据，且与独立的分子钟估算结果相符。然而，由于缺乏明确的软组织解剖结构和诊断性骨骼微结构，其系统发育关系仍不明确并存在争议。本研究报告了来自中国早寒武世先奴东组（Xiannudong Formation）的精美P. gatehousei化石和一个新分类单元——Dayingomelission hexaclitia gen. et sp. nov.。这些标本在模块化骨骼中保存了原位的磷酸盐化软组织，揭示了关键解剖结构，包括口针、环肌、膜囊和环形隔板。这套特征为这些分类单元属于苔藓虫提供了确凿证据。结合这些新特征的系统发育分析表明它们属于冠群窄唇纲（stenolaemates）。这些结果证实了该门的寒武纪起源，揭示了群体结构的早期意外差异，表明苔藓虫多样化是寒武纪辐射的重要组成部分。此外，分化窄唇纲冠群的早期出现表明苔藓虫干系谱系的起源比最初认为的更为久远。
『总结』
研究发现了早寒武世的精美苔藓虫化石及新分类单元，揭示关键解剖结构，证实其寒武纪起源，还表明苔藓虫多样化是寒武纪辐射重要部分，且苔藓虫干系谱系起源更久远。
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25. 人类血液中与年龄相关的线粒体DNA突变累积机制
Mechanism of age-related accumulation of mtDNA mutations in human blood
『Abstract』Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH). Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.
『摘要』
突变线粒体DNA（mtDNA）异质性的积累是衰老最显著的特征之一。本研究利用约75万人的全基因组序列，通过分析人类血液中的线粒体DNA序列、丰度及异质性变异，探究其潜在机制。研究发现，线粒体DNA单核苷酸变异（mtSNVs）在60岁时急剧增加，异质性水平较低，无明显正向选择证据且可能主要为中性突变。mtSNVs的突变谱与常见的氧化损伤假说不符，而更符合线粒体DNA复制错误特征。为阐明mtSNVs随年龄增长可检测的原因，我们进行了异质性mtSNV负担的全基因组关联研究，发现TERT、TCL1A和SMC4附近的生殖细胞系变异均与克隆性造血（CH）相关。罕见变异分析还表明，高mtSNV负担与多个CH驱动基因的突变有关。即使在排除已知CH驱动突变的个体后，这些遗传关联仍然存在。我们的结果支持这样一种模型：最初“隐匿”的线粒体DNA突变作为复制错误随机产生，但在整体中无法被检测到；它们仅通过血液中细胞克隆的年龄相关性扩增才变得明显。我们认为，由于线粒体DNA的高拷贝数和高突变率，使其成为基于血液的、由克隆性造血导致的体细胞嵌合体的敏感标志物。我们的工作从机制上统一了三种显著的衰老特征：TERT中的常见生殖细胞系变异、克隆性造血以及观察到的线粒体DNA突变累积。
『总结』
研究揭示线粒体DNA突变随年龄增长而积累的现象，发现其与克隆性造血的遗传关联，提出线粒体DNA可作为反映体细胞嵌合的血液生物标志物，并统一解释了三种衰老特征间的内在联系。
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26. 因升温引发的火灾和甲烷生成作用，西伯利亚甲烷排放量每十年翻一番。
Decadal doubling of Siberian methane emissions due to warming-induced fires and methanogenesis.
『Abstract』The northern permafrost region, which stores double the amount of carbon in the atmosphere, is vulnerable to accelerated warming. Methane emissions from thawing permafrost may eventually result in a climate-carbon feedback. Our analysis of atmospheric methane data shows that Siberian growing-season methane emissions have increased by 12.0 ± 1.9 teragrams of methane (TgCH4) (5% per year) over the period 2010-2023. We reveal contrasting Siberian hydrological trends linked to high-pressure systems and distinct air-sea-land interactions. Warmer, drier conditions over eastern Siberia enhance fire-related emissions (0.7 ± 0.1 TgCH4 year-2), and wetter conditions over western Siberia promote wetland-related emissions (0.4 ± 0.1 TgCH4 year-2). Weakly nonlinear relationships between temperature maxima and emissions suggest that by 2050, higher Siberian emissions could offset about 20% of the global methane reduction required for climate targets, with eastern Siberia dominating the projected increase.
『摘要』
北部多年冻土区储存的碳量是大气中的两倍，极易受到加速变暖的影响。解冻多年冻土释放的甲烷最终可能导致气候-碳反馈。我们对大气甲烷数据的分析表明，2010年至2023年期间，西伯利亚生长季甲烷排放量增加了12.0 ± 1.9太克甲烷（TgCH4）（每年5%）。我们发现与高压系统和独特的气海陆相互作用相关的西伯利亚水文趋势截然不同。西伯利亚东部温暖干燥的条件加剧了火灾相关排放（每年0.7 ± 0.1 TgCH4），而西部湿润条件则促进了湿地相关排放（每年0.4 ± 0.1 TgCH4）。最高气温与排放之间呈弱非线性关系，这表明到2050年，西伯利亚更高的排放可能会抵消实现气候目标所需的全球甲烷减排量的约20%，其中东部的增长占主导地位。
『总结』
北部多年冻土区易受加速变暖影响，对西伯利亚大气甲烷数据分析显示其生长季甲烷排放量增加，且东西部因不同水文趋势导致排放类型有别，预计到2050年西伯利亚更高排放或抵消部分全球甲烷减排量。
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27. 大脑导航回路中θ波扫描的自适应调节。
Adaptive modulation of theta sweeps in the brain's navigation circuit.
『Abstract』Efficient navigation requires prioritizing information from behaviorally relevant locations. In rats, such selective sampling may arise from theta-paced sweeps in grid and place cell populations, which scan nearby space in a left-right alternating pattern coordinated by parasubicular direction signals. This alternation promotes uniform spatial coverage during exploration, but whether sweeps can be flexibly tuned to moment-to-moment demands remains unknown. Using large-scale Neuropixels recordings in freely behaving rats, we show that sweeps and direction signals are rapidly and dynamically modulated: They track moving targets during pursuit, precede orienting responses during immobility, and reverse during backward locomotion-all without prior spatial learning of goal locations. Comparable modulation occurs during rapid eye movement (REM) sleep. Together, these findings identify sweeps as a flexible, attention-like mechanism for selectively sampling allocentric cognitive maps.
『摘要』
高效导航需要优先处理来自与行为相关位置的信息。在大鼠中，这种选择性采样可能源于网格细胞和位置细胞群中的θ节律扫描，这些扫描以左右交替的模式在附近空间进行搜索，并由下副亚区方向信号协调。这种交替模式促进了探索过程中的均匀空间覆盖，但扫描是否能根据即时需求灵活调整尚不清楚。我们利用自由活动大鼠的大规模Neuropixels记录技术发现，扫描和方向信号能够快速且动态地调节：它们在追踪移动目标时跟随目标运动，在静止状态下先于定向反应出现，并在向后移动时反向扫描——所有这些都无需事先对目标位置进行空间学习。类似的调制现象也出现在快速眼动（REM）睡眠期间。这些发现共同表明，扫描是一种类似注意力的灵活机制，用于选择性地采样异我中心认知地图。
『总结』
研究发现大鼠的θ节律扫描及方向信号能根据即时任务需求灵活调整，揭示其作为注意力机制的认知功能。
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28. 常温环境下的磁强计悬浮传感器。
Levitated sensor for magnetometry in ambient environment.
『Abstract』Levitated particle systems have gained attention as a rapidly advancing platform for precision sensing, offering low-loss, highly isolated environments by eliminating mechanical contact and associated noise. Current room-temperature levitation techniques are primarily sensitive to acceleration, and it remains challenging to integrate them with high-sensitivity magnetic sensing. In this work, we demonstrate a diamagnetically stabilized magnetically levitated magnet magnetometer, where the motion of the magnet is detected optically. We achieved a sensitivity of 32 femtoteslas per square root of Hertz, which is adequate for a wide range of applications in biology, chemistry, and fundamental physics, matching the performance of superconducting quantum interference devices and atomic magnetometers, while offering the advantage of operating at room temperature and under Earth's magnetic field.
『摘要』
悬浮颗粒系统作为一种快速发展的精密传感平台，因其通过消除机械接触及相关噪声而提供低损耗、高度隔离的环境而备受关注。目前的室温悬浮技术主要对加速度敏感，将其与高灵敏度磁传感相结合仍具挑战性。本研究展示了一种抗磁稳定磁悬浮磁强计，其通过光学方式检测磁体的运动。我们实现了每平方根赫兹32飞特斯拉的灵敏度，足以满足生物学、化学和基础物理学中广泛的应用需求，性能可媲美超导量子干涉器件和原子磁强计，同时具备在室温和地球磁场下工作的优势。
『总结』
悬浮颗粒系统因能提供低损耗、高度隔离环境受关注，当前室温悬浮技术难与高灵敏度磁传感结合，该研究展示了抗磁稳定磁悬浮磁强计，实现较高灵敏度且能在室温和地球磁场下工作。
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29. 飓风登陆期间的湍动地震声学印记。
Turbulent seismoacoustic imprints during a hurricane landfall.
『Abstract』Hurricane evolution is affected by turbulence in the hurricane boundary layer (HBL), which is typically measured using aircraft flights and towers. Through a case study of a landfalling hurricane, we show that seismoacoustic data can also be used for HBL turbulence analysis. We identified contributions of HBL turbulence in infrasound pressure and seismic displacement, validating our interpretation by combining large-eddy simulation, calibrated with meteorological data, with quasi-static elastic deformation modeling. The convection velocity of the turbulent pressure field is key to this pressure-displacement coupling. For atmospheric studies, continuous infrasound pressure serves as a proxy for 10-meter wind speed, and the inertial subrange of pressure spectra provides an estimate of the turbulent dissipation rate near the top of the surface layer at ~100 to 200 meters, complementing portable tower data at ~10 meters.
『摘要』
飓风的发展演变受飓风边界层（HBL）湍流的影响，通常使用飞机飞行和观测塔来测量该湍流。通过对一个登陆飓风的案例研究，我们发现地震声学数据也可用于飓风边界层湍流分析。我们确定了飓风边界层湍流在次声压和地震位移中的贡献，通过结合用气象数据校准的大涡模拟与准静态弹性变形建模验证了我们的解释。湍流压力场的对流速度是这种压力-位移耦合的关键。对于大气研究而言，连续的次声压可作为10米高度风速的替代指标，而压力谱的惯性子区则可估算地表层顶部约100至200米处的湍流耗散率，补充了约10米处便携式观测塔的数据。
『总结』
研究发现地震声学数据可用于飓风边界层湍流分析，确定其在次声压和地震位移中的贡献，还指出连续次声压和压力谱惯性子区在大气研究中的作用。
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30. 协调驱动蛋白和动力蛋白进行线粒体货物运输的分子开关。
A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
『Abstract』The cellular distribution of mitochondria in response to stress and local energy needs is governed by the relative activities of the microtubule-based molecular motors kinesin and dynein. The mechanism for switching between these two opposite-polarity microtubule motors remains unknown. In this study, we coupled a cellular synthetic cargo transport assay with AlphaFold2-guided mutagenesis to identify a regulatory helix in the mitochondrial adaptor protein [trafficking kinesin-binding protein (TRAK)] that mediates switching between kinesin- and dynein-driven transport. Differences in the helix sequence explained why two near-identical TRAK isoforms transported mitochondria in predominantly opposite directions. Phosphorylation of the regulatory helix by stress-activated kinases caused the activation of dynein and dissociation of kinesin. Our results reveal a molecular mechanism for coordinating the directional transport of mitochondria in response to intracellular signals.
『摘要』
线粒体针对应激反应和局部能量需求的细胞分布受基于微管的分子马达驱动蛋白和动力蛋白的相对活性调控。这两种极性相反的微管马达之间的转换机制尚不清楚。本研究将细胞合成货物运输检测与AlphaFold2引导的突变分析相结合，确定了线粒体适配蛋白[驱动蛋白结合转运蛋白（TRAK）]中一个介导驱动蛋白和动力蛋白驱动运输之间切换的调控螺旋。该螺旋序列的差异解释了两种近乎相同的TRAK异构体为何主要沿相反方向运输线粒体。应激激活激酶对该调控螺旋的磷酸化会激活动力蛋白并使驱动蛋白解离。我们的研究结果揭示了一种响应细胞内信号协调线粒体定向运输的分子机制。
『总结』
研究发现线粒体适配蛋白TRAK中的调控螺旋介导驱动蛋白和动力蛋白间运输切换，其序列差异致异构体运输方向不同，且应激激活激酶对它的磷酸化可激活动力蛋白、使驱动蛋白解离，揭示了协调线粒体定向运输的分子机制。
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31. 古基因组学视角下美洲野牛的种群崩溃、恢复与管理
Paleogenomic insight into the collapse, recovery, and management of American bison.
『Abstract』American bison (Bison bison) were nearly hunted to extinction by the 20th century. This rapid decline and the fragmented nature of remnant populations pose challenges to their recovery and resilience, as does human-facilitated admixture between bison subspecies and cattle (Bos taurus). To contextualize current diversity, we sequenced 115 ancient and 45 modern bison genomes from the past ~20,000 years. Our results show that past bison populations were connected, in contrast to structured modern herds. Modern wood bison (B. b. athabascae), a northerly distributed subspecies, carry plains bison (B. b. bison) ancestry from 1920s translocations, and many sampled bison lack cattle ancestry. Our findings reveal the legacy of human impacts on bison and highlight the applicability of ancient DNA for guiding wildlife restoration.
『摘要』
到20世纪，美洲野牛（Bison bison）几乎被猎杀至灭绝。剩余种群数量迅速减少且分布零散，再加上人类促成的野牛亚种与家牛（Bos taurus）之间的杂交，给其恢复和适应能力带来了挑战。为了解当前多样性情况，我们对过去约2万年来的115个古代和45个现代野牛基因组进行了测序。结果显示，过去的野牛种群是相互连通的，而现代野牛群则结构分明。现代分布于北方的木野牛（B. b. athabascae）带有20世纪20年代迁移而来的平原野牛（B. b. bison）血统，而且许多样本中的野牛没有家牛血统。我们的研究结果揭示了人类活动对野牛的影响，并凸显了利用古DNA指导野生动物恢复的可行性。
『总结』
到20世纪美洲野牛几近灭绝，剩余种群面临诸多恢复难题，研究人员对其过去约2万年的基因组测序后发现古今野牛种群特征不同，还揭示了人类影响及古DNA在野生动物恢复方面的应用价值。
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32. 真菌病原体耳念珠菌暴露几丁质以触发γ干扰素并在毛囊中持续存在。
The fungal pathogen Candida auris exposes chitin to trigger IFNγ and persist in hair follicles.
『Abstract』Candida auris is a multidrug-resistant fungus of major public health concern whose mechanisms for persistence on skin, a major risk factor for deadly outbreaks, remain unclear. In this study, we compared skin colonization by C. auris versus C. albicans to illuminate distinct fungal-immune interactions in mice. C. auris exhibited enhanced skin persistence, hair follicle tropism, and direct hair binding. Whereas C. albicans triggered a type 3/17-skewed sterilizing antifungal immune response, C. auris triggered a type 1 interferon-γ (IFNγ)-driven response directed toward hair follicles. IFNγ enhanced C. auris colonization by signaling to keratinocytes and repressing epithelial antifungal defense programs. Genetic and biochemical approaches demonstrated that, in response to cues associated with the skin, C. auris increases cell wall chitin exposure, triggering type 1 immunity and promoting fungal persistence.
『摘要』
耳念珠菌（Candida auris）是一种多重耐药真菌，对公共卫生构成重大威胁。其能在皮肤上持续存在是导致致命性疫情暴发的主要风险因素，但其作用机制尚不明确。本研究通过比较小鼠体内耳念珠菌与白色念珠菌（C. albicans）的皮肤定植情况，揭示了两者在真菌-免疫相互作用方面的差异。耳念珠菌表现出更强的皮肤持久性、毛囊趋向性和直接毛发结合能力。白色念珠菌可引发以3型/17型为主的杀菌性抗真菌免疫反应，而耳念珠菌则触发由1型干扰素γ（IFNγ）驱动的针对毛囊的免疫反应。IFNγ通过向角质形成细胞发出信号并抑制上皮抗真菌防御程序来增强耳念珠菌的定植。遗传学和生物化学方法表明，耳念珠菌在响应皮肤相关信号时，会增加细胞壁几丁质的暴露，从而触发1型免疫反应并促进真菌的持续存在。
『总结』
研究揭示了耳念珠菌相较于白色念珠菌具有更强皮肤持久性的机制，发现其通过增加细胞壁几丁质暴露触发1型免疫应答，并通过IFNγ信号通路抑制宿主防御实现长期定植。
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33. 淘汰一辆可完全正常运行的内燃机汽车的气候效益
The climate benefits of retiring a fully operational internal combustion engine vehicle.
『Abstract』Internal combustion engine (ICE) vehicles represent the single largest source of carbon dioxide emissions for most US households. Although battery electric vehicles (BEVs) considerably reduce use-phase emissions, the transition poses a fundamental life cycle optimization challenge: Is there a net climate benefit to retiring a functional ICE vehicle before its end of life? Retiring a functioning ICE vehicle incurs a fundamental trade-off between BEV manufacturing emissions and decreased vehicle operation emissions. In this study, we evaluated this trade-off across a comprehensive range of retirement scenarios and found that scrappage-and-replacement yields consistent emissions reductions across most contexts, including the retirement of new ICE vehicles. Although scrapping a functional asset remains economically prohibitive under current market conditions, these results demonstrate a major mitigation potential for policy interventions, such as enhanced scrappage subsidies, to address the emissions of an increasingly durable ICE fleet.
『摘要』
对于大多数美国家庭而言，内燃机（ICE）汽车是二氧化碳排放的最大单一来源。尽管纯电动汽车（BEVs）可大幅减少使用阶段的排放，但向其过渡面临一个根本性的生命周期优化挑战：在功能性内燃机汽车使用寿命结束前将其淘汰是否会产生净气候效益？淘汰一辆仍在使用的内燃机汽车需要在纯电动汽车制造排放和车辆运营排放减少之间进行权衡。本研究评估了各种报废情景下的这种权衡关系，发现大多数情况下，报废并更换为纯电动汽车均能实现持续减排，包括新购内燃机汽车的提前报废。尽管在当前市场条件下报废仍具经济可行性的资产成本过高，但这些结果表明，通过政策干预（如提高报废补贴），对解决日益耐用的内燃机汽车车队的排放问题具有巨大的缓解潜力。
『总结』
研究表明多数情况下提前报废内燃机汽车并更换为纯电动汽车可实现持续减排，虽当前报废成本高，但政策干预有巨大减排潜力。
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34. 钙可调节蜗牛黏液基材料实现多种功能。
Calcium tunes snail mucus-based materials to multiple functions.
『Abstract』Mucus is known as a viscous fluid; yet, snails manufacture various mucus-based materials with much higher cohesion and tailored to different and even antagonistic functions, including lubrication, adhesion, protection, and defense. To gain insight into this versatility, we use a multidisciplinary approach to investigate five different mucus-based materials produced by the snail Cepaea nemoralis. Our results demonstrate that snails use collagen VI as a main structural component and add amorphous calcium carbonate (ACC) during mucus secretion. ACC functions as an ion source in wet mucus types, most likely for cross-linking, or as a mineral precursor in dry mucus types. These findings shed light on the versatility of these viscoelastic materials, which are able to switch between very different properties on the basis of calcium and protein content.
『摘要』
粘液是一种黏性流体，然而蜗牛能制造出各种基于粘液的材料，这些材料具有更高的内聚力，且针对不同甚至相互对立的功能进行定制，包括润滑、粘附、保护和防御。为了深入了解这种多功能性，我们采用多学科方法研究了由灰林蜗（Cepaea nemoralis）产生的五种不同的基于粘液的材料。我们的研究结果表明，蜗牛使用VI型胶原蛋白作为主要结构成分，并在分泌粘液时添加无定形碳酸钙（ACC）。在湿润的粘液类型中，ACC很可能作为离子源用于交联；而在干燥的粘液类型中，它则作为矿物前体。这些发现揭示了这些粘弹性材料的多功能性，它们能够根据钙和蛋白质含量在不同特性之间切换。
『总结』
蜗牛能制造多种基于粘液的具有更高内聚力的多功能材料，研究人员用多学科方法研究其五种此类材料，发现蜗牛以VI型胶原蛋白为主要结构成分并添加无定形碳酸钙，该物质在不同粘液类型中有不同作用，此发现揭示了这类粘弹性材料可根据钙和蛋白含量切换特性的多功能性。
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35. 重掺杂、高补偿的外延ScN薄膜突破了玻尔兹曼热电势极限。
Heavily doped, highly compensated epitaxial ScN thin films exceed Boltzmann thermopower limits.
『Abstract』The Seebeck effect converts a temperature gradient into an electric voltage. However, conventional transport theories constrain this thermopower to a few millivolts per Kelvin in crystalline materials. We present experimental evidence of a Seebeck coefficient exceeding -124 millivolts per Kelvin near room temperature in heavily doped, highly compensated (HDHC) epitaxial scandium nitride (ScN) thin films. Random distribution of charged dopants in HDHC ScN are known to generate potential fluctuations that distort the electronic bands and give rise to percolative transport, and our results further reveal a power-law scaling between thermopower and electrical conductivity. In ultrathin films, the Rytova-Keldysh modifications of the Coulomb potential further amplify the potential fluctuations and enhance the Seebeck response. Our findings reveal a solid-state analog of electrolyte-like thermopower in a crystalline semiconductor.
『摘要』
塞贝克效应将温度梯度转化为电动势。然而，传统输运理论限制了晶体材料中的热电势在每开尔文几毫伏的范围内。我们在重掺杂、高度补偿（HDHC）的外延氮化钪（ScN）薄膜中提供了实验证据，表明在接近室温时塞贝克系数超过-124毫伏/开尔文。已知HDHC ScN中带电掺杂剂的随机分布会产生电位波动，扭曲电子能带并引发渗流输运，我们的结果进一步揭示了热电势与电导率之间的幂律标度关系。在超薄膜中，库仑势的Rytova-Keldysh修正会进一步放大电位波动并增强塞贝克响应。我们的发现揭示了晶体半导体中类似电解质的固态热电势现象。
『总结』
研究发现在重掺杂、高度补偿的外延氮化钪薄膜中，接近室温时塞贝克系数远超传统理论值，且揭示了热电势与电导率的幂律关系及超薄膜中库仑势修正对塞贝克响应的增强作用，发现了晶体半导体中类似电解质的固态热电势现象。
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36. 化石证据支持视觉在灵长类新皮层模块化演化中发挥作用。
Fossil evidence favors a role for vision in the modular evolution of the primate neocortex.
『Abstract』Neocortical expansion is a key innovation of crown primates, although fossil evidence for how the neocortex has evolved remains elusive. We studied neocortical evolution using virtual brain endocasts from extant and Eocene-Miocene fossil primates. We found that neocortex size increased in parallel across crown primate clades, with rapid increases in tarsiers and anthropoids. Although the frontal lobe is commonly described as having expanded disproportionately in primates, we show that it evolved gradually, following a common pattern for allometric scaling. By contrast, nonfrontal neocortical regions underwent rapid increases relative to brain size in haplorhines. Neocortical expansion occurred in concert with increases in optic foramen area, suggesting that visual sensory inputs are functionally tied to modular evolution of the primate neocortex.
『摘要』
新皮层的扩张是冠群灵长类动物的一项关键创新，尽管关于新皮层如何演化的化石证据仍然难以捉摸。我们利用现生和始新世-中新世时期灵长类动物的虚拟脑内模研究了新皮层的演化情况。我们发现，在冠群灵长类的各个分支中，新皮层的大小呈平行增加趋势，其中眼镜猴和简鼻亚目灵长类的新皮层大小迅速增加。虽然额叶通常被描述为在灵长类动物中不成比例地扩张，但我们的研究表明，它遵循异速生长的共同模式而逐渐演化。相比之下，非额叶新皮质区域相对于大脑体积在简鼻亚目灵长类中经历了快速的增长。新皮质的扩张与视神经孔面积的增加同时发生，这表明视觉感觉输入与灵长类新皮质的模块化演化存在功能上的联系。
『总结』
研究发现冠群灵长类新皮层大小呈平行增加趋势，额叶渐变，非额叶新皮质区域在简鼻亚目中快速增长，且新皮质扩张与视神经孔面积增加相关，暗示视觉输入和新皮质模块化演化有功能联系。
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37. 基于基因组语言模型的噬菌体生成式设计
Generative design of bacteriophages with genome language models.
『Abstract』Many important biological functions arise not from single genes but from complex interactions encoded by entire genomes. We report the first generative design of complete bacteriophage genomes using genome language models. We generated viable bacteriophages with target host tropism, using the phage ΦX174 as our design template. Experimental testing yielded 16 phages with diverse fitness profiles in laboratory conditions. Cryo-electron microscopy confirmed that a generated phage utilizes an evolutionarily distant DNA packaging protein in its capsid. A cocktail of generated phages rapidly overcomes ΦX174-resistant Escherichia coli strains, demonstrating a path toward artificial intelligence-generated phage therapies against rapidly evolving bacterial pathogens. This work provides a blueprint for the design of diverse synthetic bacteriophages and useful biological systems at the genome scale.
『摘要』
许多重要的生物学功能并非源自单个基因，而是由整个基因组编码的复杂相互作用产生。我们报告了首次利用基因组语言模型对完整噬菌体基因组进行生成式设计的工作。以噬菌体ΦX174为设计模板，我们生成了具有目标宿主趋向性的可行噬菌体。实验测试在实验室条件下产生了16种适应性各异的噬菌体。冷冻电子显微镜证实，一种生成的噬菌体在其衣壳中使用了进化上距离较远的DNA包装蛋白。生成的噬菌体混合物可迅速克服对ΦX174有抗药性的大肠杆菌菌株，展示了针对快速进化的细菌病原体开发人工智能生成噬菌体疗法的途径。这项工作为在基因组尺度上设计多样化的合成噬菌体和有用的生物系统提供了蓝图。
『总结』
研究首次用基因组语言模型完成完整噬菌体基因组的生成式设计，生成多种噬菌体并验证其特性，还发现生成噬菌体可对抗耐药菌，为合成噬菌体及生物系统设计提供蓝图。
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38. 一种鸣禽的完整基因组。
The complete genome of a songbird.
『Abstract』Bird genomes are the smallest among amniotes; however, they remain challenging to assemble due to their structural complexity. This study presents a fully phased diploid telomere-to-telomere reference genome for the zebra finch (Taeniopygia guttata), a model organism for neuroscience and evolutionary genomics. Combining sequencing strategies allowed the closing of nearly all gaps, adding ∼90 Mbp of sequence (7.8%). The assembly contains gapless sequences for all microchromosomes, including the elusive dot chromosomes with their distinctive architecture. The genome was comprehensively annotated for genes, repeats, and structural variants. Complete centromeres were identified, along with candidate DNA-binding centromere protein B (CENP-B) homologs, suggesting that birds possess a kinetochore-associated CENP system similar to that of mammals. Relative to the previous reference generated by the Vertebrate Genomes Project, 2,710 (8.13%) previously unassembled or unannotated genes were identified. This complete genome of a songbird serves as a public reference and illuminates avian genome architecture and function.
『摘要』
鸟类基因组是羊膜动物中基因组最小的，但由于其结构复杂，组装起来仍然颇具挑战。本研究为斑胸草雀（Taeniopygia guttata）——一种神经科学和进化基因组学领域的模式生物，提供了一个完整的二倍体端粒到端粒参考基因组。通过结合多种测序策略，几乎填补了所有缺口，新增约90兆碱基对序列（占7.8%）。该组装包含了所有微小染色体的无缺口序列，包括那些难以捉摸的具有独特结构的点染色体。该基因组对基因、重复序列和结构变异进行了全面注释。确定了完整的着丝粒以及候选DNA结合着丝粒蛋白B（CENP-B）同源物，表明鸟类拥有与哺乳动物类似的动粒相关CENP系统。与脊椎动物基因组计划先前生成的参考基因组相比，新识别出2710个（占比8.13%）此前未组装或未注释的基因。这种鸣禽的完整基因组可作为公共参考，并阐明了鸟类的基因组结构和功能。
『总结』
研究提供了斑胸草雀完整的二倍体端粒到端粒参考基因组，填补了大部分缺口，完成全面注释，确定完整着丝粒等，还发现新基因，为公共参考并阐明鸟类基因组情况。
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39. 面向个性化基因组学的完整二倍体人类基因组基准
A complete diploid human genome benchmark for personalized genomics.
『Abstract』Human genome sequencing typically relies on mapping reads to a reference genome to call variants, but this approach introduces technical biases, excluding duplicated and structurally polymorphic regions of the genome. To overcome this, we present a telomere-to-telomere genome benchmark with near-perfect accuracy across 99.4% of the diploid HG002 genome. This benchmark adds 701.4 Mb of autosomal sequence and both sex chromosomes (216.8 Mb), which were absent from prior benchmarks. We annotated genes and repeats on both haplotypes, including 19,956 protein-coding genes on the maternal haplotype and 19,190 on the paternal haplotype, and developed new methods to measure the accuracy of reads, phased variant call sets, and assemblies against a diploid reference. Genome-wide analyses show that de novo assembly resolves 2%-7% more sequence and outperforms variant calling accuracy by an order of magnitude, expanding the reach of genomic medicine to the entire genome and enabling a new era of personalized genomics.
『摘要』
人类基因组测序通常依赖于将读长序列比对到参考基因组以识别变异，但这种方法会引入技术偏差，排除基因组中重复和结构多态性区域。为克服这一问题，我们提出了一个端粒到端粒的基因组基准，在99.4%的二倍体HG002基因组上具有近乎完美的准确性。该基准增加了701.4兆碱基的常染色体序列以及两条性染色体（216.8兆碱基）的序列，这些序列在先前的基准中均不存在。我们在两个单倍型上注释了基因和重复序列，包括母系单倍型上的19,956个蛋白质编码基因和父系单倍型上的19,190个蛋白质编码基因，并开发了新方法，以二倍体参考为对照来衡量读长、分相变异调用集和组装的准确性。全基因组分析表明，从头组装可解析多出2%-7%的序列，且变异检测准确率提高了一个数量级，从而将基因组医学的应用范围扩展至整个基因组，开启了个性化基因组学的新时代。
『总结』
人类基因组测序依赖比对参考基因组的方法存在技术偏差，研究提出端粒到端粒的基因组基准，增加此前缺失的序列并在两个单倍型上注释基因和重复序列，还开发新衡量方法；全基因组分析显示从头组装优势明显，能扩大基因组医学应用开启个性化基因组学新时代。
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40. 人类近端着丝粒染色体短臂的新发突变与重组。
Human acrocentric chromosome short-arm de novo mutation and recombination.
『Abstract』Highly repetitive short arms of human acrocentric chromosomes have remained largely inaccessible to studies of meiotic recombination and de novo mutation. Integrating long-read and complementary sequencing approaches, we created 156 phased short arms and assessed 107 transmissions from 23 samples in a four-generation human pedigree. We observed a significant depletion of p-arm allelic recombination, although one ectopic recombination was identified between chromosomes 13 and 21, mediated by a large segmental duplication near the SST1 array. In contrast, 18 maternal-biased q-arm allelic recombination events were significantly enriched near the centromere. Relative to autosomal euchromatin, acrocentric short arms showed a 10-fold higher single-nucleotide variant rate, with a distinct mutation spectrum marked by reduced C>T but increased C>G and A>C mutations. These findings suggest that acrocentric sequence composition biases and limited allelic recombination contribute to an elevated mutation rate and promote distinct mutational processes linked to mismatch repair defects and oxidative DNA damage.
『摘要』
人类近端着丝粒染色体高度重复的短臂在很大程度上难以进行减数分裂重组和新生突变的研究。我们整合了长读长测序和互补测序方法，构建了156个分相的短臂序列，并在一个四代家系中评估了来自23个样本的107次遗传传递情况。我们发现p臂等位基因重组显著减少，但在第13号和第21号染色体之间发现了一次由SST1阵列附近的大片段重复介导的异位重组事件。相比之下，在着丝粒附近发现了18例母源偏向性的q臂等位基因重组事件。与常染色质相比，近端着丝粒短臂的单核苷酸变异率高出10倍，其独特的突变谱表现为C>T减少但C>G和A>C增加。这些发现表明，近端着丝粒的序列组成偏差和有限的等位基因重组导致突变率升高，并促进了与错配修复缺陷和氧化性DNA损伤相关的独特突变过程。
『总结』
人类近端着丝粒染色体短臂因高度重复结构限制研究，通过整合测序技术发现其存在p臂重组匮乏、q臂母源偏向性重组、单核苷酸变异率高且突变谱特殊的现象，揭示序列组成与重组特征共同驱动高突变率的机制。
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41. 普通狨猴的全基因组。
A complete genome for the common marmoset.
『Abstract』The common marmoset is a New World monkey widely used to study primate evolution and human disease. We present a telomere-to-telomere (T2T) reference assembly for the species, plus three near-T2T haplotypes. These resolve previously inaccessible regions, including the centromeres, sex chromosomes, subterminal satellites, acrocentric chromosomes, and the major histocompatibility complex (MHC). We find marmoset centromeres carry dimeric alpha satellites with chromosomal specificity, flanked by inactive layers interpreted as ancestral centromere remnants. We assemble gene-poor, satellite-rich short arms of the acrocentrics and find that most can harbor rDNA and all share pseudo-homolog regions (PHRs). PHR-sharing chromosomes also share closely related centromeric satellites, consistent with a model of ongoing rDNA-facilitated recombinational exchange between heterologous chromosomes. We further identify over 500 marmoset-lineage-specific transcribed genes with previously unknown transcript models or expansions. These resources, along with a preliminary pangenome, improve the utility of the marmoset as a model organism and address gaps in primate genome evolution.
『摘要』
普通狨猴是一种广泛用于研究灵长类动物进化和人类疾病的新大陆猴。我们为该物种提供了一个端粒到端粒（T2T）参考基因组组装，以及三个接近T2T的单倍型。这些解决了先前无法获取的区域，包括着丝粒、性染色体、亚端粒卫星序列、近端着丝粒染色体和主要组织相容性复合体（MHC）。我们发现狨猴的着丝粒携带具有染色体特异性的二聚α卫星序列，其两侧是不活跃层，被解释为祖先着丝粒残余物。我们组装了近端着丝粒染色体上富含卫星序列但基因贫乏的短臂，发现大多数短臂可以容纳核糖体DNA（rDNA），且所有短臂都共享假同源区域（PHRs）。共享PHR的染色体也共享密切相关的着丝粒卫星序列，这与不同源染色体之间持续发生由rDNA促进的重组交换模型一致。我们还鉴定出500多个狨猴谱系特有的转录基因，这些基因具有此前未知的转录本模型或扩增情况。这些资源，连同一个初步的全基因组，提高了狨猴作为模式生物的实用性，并填补了灵长类动物基因组进化方面的空白。
『总结』
普通狨猴是新大陆猴，常用于相关研究，研究人员为其提供T2T参考基因组组装及单倍型，解决诸多先前难获取区域问题，还发现着丝粒等特性，鉴定出特定转录基因，这些资源和初步全基因组提升了其作为模式生物的效用并填补进化空白。
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42. 完整恒河猴参考基因组中的复杂亚端粒结构。
Complex subtelomeric architectures in a complete rhesus macaque reference genome.
『Abstract』We present T2T-MMU8v2.0, a near-perfect telomere-to-telomere assembly of the rhesus macaque (Macaca mulatta), representing high base-level accuracy reported in a primate genome. Our optimized assembly strategy exposes subtelomeric satellite-rich regions as the principal bottleneck in obtaining full assemblies, owing to long-read technological biases and limitations in hybrid assembly frameworks. By resolving ∼8 Mbp of SATR satellite arrays and discovering 268 previously unannotated repeat families, we define four distinct SATR genomic architectures, each with unique satellite composition, segmental duplication organization, and epigenetic signatures, which are distinct from the subtelomeric architectures observed in hominid genomes. These regions harbor 58 actively transcribed genes, suggesting gene innovation within these repetitive regions. Functionally, T2T-MMU8v2.0 improves alignment accuracy and chromatin accessibility detection, enabling a finer resolution in population variation and regulatory elements. Together, this work establishes a benchmark for primate genomics and illustrates the functional and evolutionary importance of previously inaccessible structures of the genome.
『摘要』
我们展示了恒河猴（Macaca mulatta）近乎完美的端粒到端粒组装T2T-MMU8v2.0，代表了灵长类动物基因组中报告的高碱基水平准确性。由于长读长技术的偏差和混合组装框架的局限性，我们优化的组装策略揭示了亚端粒富含卫星区域是获得完整组装的主要瓶颈。通过解析约8兆碱基对的SATR卫星阵列并发现268个先前未注释的重复家族，我们定义了四种独特的SATR基因组结构，每种结构都具有独特的卫星组成、节段性重复组织以及表观遗传特征，这些与人类近亲基因组中观察到的亚端粒结构不同。这些区域包含58个活跃转录的基因，表明这些重复区域内存在基因创新。从功能上讲，T2T-MMU8v2.0提高了比对准确性和染色质可及性检测能力，从而能够以更精细的分辨率分析群体变异和调控元件。总之，这项工作为灵长类动物基因组学树立了基准，并阐明了以前难以获取的基因组结构在功能和进化上的重要性。
『总结』
研究展示了恒河猴近乎完美的端粒到端粒组装T2T-MMU8v2.0，揭示了亚端粒富含卫星区域是组装主要瓶颈，定义了四种独特SATR基因组结构，该区域含58个活跃转录基因，此版本还提升了比对等能力，为灵长类动物基因组学树立了基准并阐明相关结构和功能的重要性。
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43. 通过烯烃自由基阳离子生成实现烷基C-X合成子的邻位二取代
Vicinal disubstitution of alkyl C-X synthons via alkene radical cation generation
『Abstract』In organic chemistry, functionalization of two adjacent carbons often starts from alkenes or already disubstituted precursors. Here, we report an exergonic activation mode that directly generates alkene radical cation intermediates from monofunctional C(sp)-X handles through a photoredox-triggered hydrogen-atom abstraction (HAT) and spin-center shift (SCS) process. Computations show that electron delocalization and a network of hydrogen-bonding solvent molecules facilitate a concerted [HAT+SCS] mechanism. The catalytic platform was used to design a transfer of electrophilic reactivity (C-X) from one carbon to another, which we refer to as electrophilic shuttling. Thus, two nucleophiles can be used in the construction of 1,2-difunctionalization adducts from homobenzylic C-X synthons, delivering bisazole architectures and demonstrating compatibility with other nucleophile classes. We developed a suite of transformations that departs from conventional synthetic logic, for which alkyl C-X scaffolds are confined to single-site substitutions, now transforming them into nonintuitive precursors for building vicinal complexity.
『摘要』
在有机化学中，对两个相邻碳原子进行功能化通常始于烯烃或已二取代的前体。本研究报告了一种放能活化模式，该模式通过光氧化还原触发的氢原子转移（HAT）和自旋中心位移（SCS）过程，直接从单官能团C(sp)-X基团生成烯烃自由基阳离子中间体。计算表明，电子离域和氢键溶剂分子网络促进了协同的[HAT+SCS]机制。利用该催化平台设计了一种将亲电反应性（C-X）从一个碳原子转移到另一个碳原子的方法，我们称之为“亲电穿梭”。因此，可以利用两种亲核试剂从苄位C-X合成子构建1,2-双官能化加合物，从而得到联唑结构并证明与其他类型亲核试剂的兼容性。我们开发了一系列不同于传统合成逻辑的转化方法，这些方法突破了烷基C-X骨架仅限于单一位点取代的限制，将其转化为构建邻位复杂性的非直观前体。
『总结』
研究提出一种放能活化模式，经光氧化还原触发相关过程生成烯烃自由基阳离子中间体，设计了亲电穿梭方法，可构建1,2-双官能化加合物，还开发系列新转化方法。
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44. 化学诱导的皮肤肿瘤源于上部毛囊中的长寿干细胞
Chemically induced skin tumors arise from long-lived stem cells of the upper hair follicle
『Abstract』The identification of the cancer cell of origin is a fundamental issue in cancer biology. We used fluorescent lineage tracing of independent mouse skin stem cell populations, single-cell transcriptomics, and duplex sequencing to identify the origin of chemically induced skin tumors. Tumors arose predominantly from Lgr6+ and/or Lrig1+ stem cells of the upper hair follicle but only very rarely from the Lgr5+ and Krt19+ hair follicle bulge. Lgr6+ stem cells initiated by dimethylbenzanthracene responded to tumor promoter treatment, resulting in clonal expansion of initiated cells carrying the canonical Hras Q61L mutation. Spontaneous mutations in Kras also clonally expanded but did not generate tumors unless the Hras gene was deleted, thus revealing a competitive interaction between the Hras and Kras pathways that influences clonal selection.
『摘要』
确定癌症的起源细胞是癌症生物学中的一个基本问题。我们利用独立小鼠皮肤干细胞群体的荧光谱系追踪、单细胞转录组学和双链测序技术，确定了化学诱导的皮肤肿瘤的起源。肿瘤主要起源于上部毛囊的Lgr6+和/或Lrig1+干细胞，但极少源于Lgr5+和Krt19+毛囊隆突部干细胞。由二甲基苯并蒽（DMBA）启动的Lgr6+干细胞对促癌剂处理产生响应，导致携带经典Hras Q61L突变的起始细胞克隆性扩增。Kras自发突变也发生克隆性扩增，但除非Hras基因被删除，否则不会形成肿瘤，这揭示了影响克隆选择的Hras和Kras通路之间的竞争相互作用。
『总结』
研究通过多种技术手段确定化学诱导的小鼠皮肤肿瘤主要起源于上部毛囊特定干细胞，还发现Hras和Kras通路间存在竞争相互作用影响克隆选择。
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45. 由双逆转录酶免疫系统协调进行的以RNA和蛋白质为模板的双链DNA合成
Coordinated RNA- and protein-templated synthesis of double-stranded DNA by a dual reverse transcriptase immune system
『Abstract』Defense-associated reverse transcriptase (DRT) systems mediate antiviral immunity through distinct modes of cDNA synthesis: class 1 DRTs catalyze untemplated synthesis, whereas class 2 DRTs polymerize non-coding RNA-templated products. However, how these distinct modes drive defense remains unclear. Here, we report that DRT3 immunity arises when class 1 and class 2 RT activities cooperate to produce self-complementary double-stranded DNA (dsDNA). DRT3a uses a 5'-ACACAC-3' RNA template to synthesize poly-(dTdG) repeats, whereas DRT3b synthesizes poly-(dCdA) repeats without any nucleic acid template. Cryo-electron microscopy reveals that DRT3b forms a hexamer and uses active-site-adjacent residues as deoxyadenosine and deoxycytidine gates to enforce alternating nucleotide addition, representing a unique example of amino-acid-templated DNA polymerization. DRT3 is toxic in cells lacking RecBCD, implicating host recombination machinery in limiting dsDNA accumulation, and the phage-encoded RecBCD inhibitor Gam triggers DRT3-mediated abortive infection. These findings reveal how two polymerases with distinct templating strategies generate complementary DNA for antiviral defense.
『摘要』
与防御相关的逆转录酶（DRT）系统通过不同的互补DNA（cDNA）合成模式介导抗病毒免疫：1类DRTs催化无模板的合成，而2类DRTs聚合非编码RNA为模板的产物。然而，这些不同模式如何驱动防御机制尚不清楚。本研究发现，当1类和2类逆转录酶活性协同作用产生自我互补的双链DNA（dsDNA）时，会触发DRT3介导的免疫反应。DRT3a利用5'-ACACAC-3' RNA模板合成聚(dTdG)重复序列，而DRT3b无需核酸模板即可合成聚(dCdA)重复序列。冷冻电镜显示，DRT3b形成六聚体结构，并利用活性位点附近的残基作为脱氧腺苷和脱氧胞苷通道，强制交替添加核苷酸，这代表了氨基酸模板化DNA聚合的独特案例。DRT3在缺乏RecBCD的细胞中具有毒性，表明宿主重组机制参与限制双链DNA积累；噬菌体编码的RecBCD抑制剂Gam可触发DRT3介导的流产感染。这些发现揭示了两种采用不同模板策略的聚合酶如何生成互补DNA以实现抗病毒防御。
『总结』
研究发现两类DRT通过协同生成自我互补双链DNA激活免疫应答，其中DRT3b通过氨基酸门控机制实现无模板DNA聚合，且其毒性受宿主RecBCD调控。
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46. UniPert-G2CP在从分子表征到表型建模的过程中架起了遗传筛选与化学筛选的桥梁
UniPert-G2CP bridges genetic and chemical screens from molecular representation to phenotype modeling
『Abstract』Systematically simulating and predicting phenotypic effects of diverse interventions across heterogeneous cellular environments is central to the vision of artificial intelligence virtual cell (AIVC). However, disparities in perturbagen modalities, assay formats, and data production efficiency hinder unified modeling and analysis of genetic and chemical screens. This study presents UniPert-G2CP, a two-stage deep learning framework that bridges genetic and chemical screens by unifying multimodal molecular perturbagen (cause) representations and enabling genetic-to-chemical perturbation phenotype (effect) transfer learning. Validated on large-scale genetic and chemical screening datasets, UniPert-G2CP enables more efficient, accurate, robust, interpretable, and generalizable simulation of multicellular and multidomain perturbation cause-effect spaces. Further joint analysis of these spaces reveals cellular heterogeneity underlying drug responses, providing mechanistic insights into drug action and resistance. Collectively, UniPert-G2CP advances universal biological causal modeling, accelerates AIVC realization, and expands the potential of AI-powered precision medicine.
『摘要』
在异质细胞环境中系统模拟和预测不同干预措施的表型效应是人工智能虚拟细胞（AIVC）愿景的核心。然而，扰动剂模式、检测格式和数据生成效率方面的差异阻碍了遗传和化学筛选的统一建模与分析。本研究提出了UniPert-G2CP，这是一个两阶段深度学习框架，通过统一多模态分子扰动剂（原因）表征并实现从基因到化学扰动的表型（结果）迁移学习，架起了遗传与化学筛选之间的桥梁。经大规模遗传和化学筛选数据集验证，UniPert-G2CP能够更高效、准确、稳健、可解释且通用地模拟多细胞和多领域扰动因果空间。对这些空间的进一步联合分析揭示了药物反应背后的细胞异质性，为药物作用机制及耐药性提供了见解。总体而言，UniPert-G2CP推动了通用生物因果建模的发展，加速了AIVC的实现，拓展了人工智能驱动精准医学的潜力。
『总结』
研究提出UniPert-G2CP两阶段深度学习框架，统一多模态扰动剂表征并实现跨模态迁移学习，能高效模拟多细胞扰动因果空间，揭示药物反应细胞异质性，推动生物因果建模发展。
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47. 利用MSA Pairformer将蛋白质语言建模范围扩展至蛋白质-蛋白质相互作用领域
Expanding the scope of protein language modeling to protein-protein interactions with MSA Pairformer
『Abstract』Protein-protein interactions underlie biological complexity, and modeling their coevolution is essential for characterizing and engineering molecular assemblies. While protein and genomic language models have excelled at modeling individual proteins, extending these capabilities to protein complexes remains challenging. We present multiple sequence alignment (MSA) Pairformer, a protein language model that builds on AlphaFold2/3's bidirectional refinement between sequence and pairwise residue representations to accurately model the evolution of protein-protein interactions, despite training exclusively on individual chains. MSA Pairformer achieves nearly 3-fold improvement over existing methods in predicting protein-protein interface contacts and better distinguishes binding from non-binding sequences. A learned attention mechanism selectively weights sequences by their inferred evolutionary relevance, enabling discovery of subfamily-specific contacts. On single-protein benchmarks, it achieves state-of-the-art contact prediction and strong variant effect prediction using only 111 million parameters, over two orders of magnitude smaller than frontier models. These results offer an evolutionarily grounded, computationally efficient alternative to the scaling paradigm.
『摘要』
蛋白质-蛋白质相互作用是生物复杂性的基础，对其协同进化进行建模对于表征和设计分子组装体至关重要。尽管蛋白质语言模型和基因组语言模型在单个蛋白质的建模方面表现出色，但将这些能力扩展到蛋白质复合物仍具有挑战性。我们提出了多序列比对（MSA）Pairformer，这是一种蛋白质语言模型，它基于AlphaFold2/3在序列与成对残基表示之间的双向优化机制，即使仅使用单链数据进行训练，也能准确模拟蛋白质-蛋白质相互作用的进化过程。相较于现有方法，MSA Pairformer在预测蛋白质-蛋白质界面接触点方面的性能提升了近3倍，并能更好地区分结合与非结合序列。其学习到的注意力机制可根据推断出的进化相关性对序列进行选择性加权，从而发现亚家族特异性接触点。在单一蛋白质基准测试中，该模型仅使用1.11亿个参数便实现了最先进的接触预测和强大的变异效应预测，参数量比前沿模型少两个数量级以上。这些结果为规模化范式提供了一种基于进化、计算高效的替代方案。
『总结』
MSA Pairformer是一种基于AlphaFold2/3双向优化机制的蛋白质语言模型，能准确模拟蛋白质-蛋白质相互作用进化，提升预测性能并实现亚家族特异性接触点发现，且参数量少，为规模化范式提供了新选择。
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48. 铁在过敏性气道疾病中驱动Gasdermin D的非蛋白酶依赖性裂解
Iron drives protease-independent cleavage of gasdermin D in allergic airway diseases
『Abstract』Gasdermin D (GSDMD)-mediated interleukin (IL)-33 secretion by lung epithelial cells initiates airway inflammation upon allergen challenge. How environmental allergens activate GSDMD remains elusive. Here, we demonstrate that exposing epithelial cells to allergens triggers protease-activated receptor 1 (PAR1)-dependent ferritinophagy, elevating intracellular labile iron. This iron pool is essential for noncanonical, protease-independent GSDMD activation. The iron chaperone poly(rC)-binding protein 2 (PCBP2) delivers iron directly to GSDMD, initiating a highly localized Fenton reaction. This generates constrained hydroxyl radicals that cleave GSDMD, releasing the active N-terminal p40 fragment to form pores for IL-33 release. Blocking any step of this iron-GSDMD pathway, via iron chelation or genetic ablation, abolishes IL-33 secretion, prevents group 2 innate lymphoid cell (ILC2) activation, and mitigates allergic airway inflammation and tissue damage in mice. Our findings reveal an unconventional, iron-catalyzed, and protease-independent mechanism for GSDMD activation, offering potential new therapeutic targets for allergic inflammatory diseases.
『摘要』
在过敏原刺激下，由肺上皮细胞通过Gasdermin D（GSDMD）介导的白细胞介素（IL）-33分泌会引发气道炎症。然而，环境过敏原如何激活GSDMD仍不明确。本研究表明，将上皮细胞暴露于过敏原可触发蛋白酶激活受体1（PAR1）依赖性铁自噬，提高胞内不稳定铁水平。该铁池对于非经典型、蛋白酶非依赖性的GSDMD激活至关重要。铁伴侣多聚胞嘧啶结合蛋白2（PCBP2）直接将铁递送至GSDMD，启动高度局部化的芬顿反应。此过程产生受限的羟基自由基，切割GSDMD，释放具有活性的N端p40片段以形成孔道，促进IL-33释放。通过螯合铁或基因敲除阻断该铁-GSDMD通路的任何步骤，均可消除IL-33分泌，防止2型固有淋巴细胞（ILC2）活化，并减轻小鼠过敏性气道炎症和组织损伤。本研究揭示了一种非常规的、铁催化和蛋白酶非依赖性的GSDMD激活机制，为过敏性炎性疾病提供了潜在的新治疗靶点。
『总结』
研究发现环境过敏原通过触发PAR1依赖性铁自噬升高胞内铁水平，进而经PCBP2介导的铁传递和局部芬顿反应实现非蛋白酶依赖性GSDMD激活，最终驱动IL-33分泌及过敏性气道炎症，为疾病干预提供新靶点。
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49. 人类海马神经元中双语语义表征的共享神经结构
Shared neural geometries for bilingual semantic representations in human hippocampal neurons
『Abstract』The human brain has the remarkable ability to comprehend and express similar concepts in multiple languages. To understand how it does so, we examined responses of hippocampal neurons during passive listening, directed speaking, and spontaneous conversation in both English and Spanish in a small group of balanced bilinguals. We found a small number of putative "cross-language neurons," whose responses to equivalent words (e.g., "tierra" and "earth") are correlated. However, neurons' semantic tunings differed substantially by language, suggesting language-specific neural implementations. Instead, the crucial driver of translation was a preserved geometric organization of neural responses between the two languages, one that did not depend on neuron-level functional overlap. Indeed, that geometry was implemented by a common set of neurons along distinct readout axes; this difference in readout may help prevent cross-language interference. Together, these results suggest that the hippocampus encodes a language-independent internal model for meaning.
『摘要』
人类大脑具有以多种语言理解和表达相似概念的非凡能力。为探究其运作机制，我们研究了一小群均衡双语者在被动聆听、定向说话以及英语和西班牙语自然对话过程中海马体神经元的反应。我们发现存在少量假定的“跨语言神经元”，它们对等义词（如“tierra”和“earth”）的反应具有相关性。然而，神经元的语义调谐在不同语言间差异显著，这表明存在特定语言的神经实现方式。相反，翻译的关键驱动因素是两种语言之间神经反应的几何组织结构得以保留，且这种结构不依赖于神经元层面的功能重叠。事实上，这种几何结构是通过一组共同神经元沿着不同读取轴实现的；读取方式的差异可能有助于防止跨语言干扰。综合来看，这些结果表明海马体编码了一个与语言无关的意义内部模型。
『总结』
研究发现人类大脑中存在少量“跨语言神经元”，但神经元语义调谐因语言而异，翻译关键在于神经反应几何组织结构的保留，海马体编码了与语言无关的意义内部模型。
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50. 与新发疾病相关的运动神经元状态先于肌萎缩侧索硬化症的细胞死亡出现
An emergent disease-associated motor neuron state precedes cell death in ALS
『Abstract』To define molecular determinants of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons together with spatial transcriptomics from the SOD1-G93A mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a distinct cell state we named "disease-associated motor neurons" (DMs). We identified transcription factor networks that govern how healthy cells transition into DMs and those associated with motor neuron subtype-selective vulnerability. Upregulation of DM-associated transcription factors in human motor neurons induced key features of DMs, demonstrating an active regulatory component. Human ALS spinal cord single-nucleus RNA sequencing data demonstrated conservation of the DM signature in alpha motor neurons, and human orthologs of regions differentially accessible in SOD1-G93A mouse motor neurons were enriched for ALS genetic risk variants. Together, these findings establish a conserved, genetically linked motor neuron signature in ALS.
『摘要』
为明确肌萎缩侧索硬化症（ALS）中运动神经元退化的分子决定因素，我们利用SOD1-G93A小鼠模型生成了脊髓运动神经元的纵向单核转录组和染色质可及性图谱，以及空间转录组数据。易受损的α运动神经元表现出数千种分子变化，标志着其向一种独特细胞状态转变，我们将这种状态命名为“疾病相关运动神经元”（DMs）。我们确定了调控健康细胞转变为DMs的转录因子网络，以及与运动神经元亚型选择性易损性相关的转录因子网络。在人类运动神经元中上调与DMs相关的转录因子会诱导出DMs的关键特征，这表明存在一个主动调控成分。人类ALS患者脊髓的单核RNA测序数据显示，α运动神经元中存在保守的DM特征，且在SOD1-G93A小鼠运动神经元中差异可及区域的同源区域富含ALS遗传风险变异。总之，这些发现确立了ALS中保守的、与遗传相关的运动神经元特征。
『总结』
研究通过多组学分析揭示了肌萎缩侧索硬化症中运动神经元退化的保守分子特征及其遗传关联机制。
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51. 桥状蛋白VPS13A和磷脂翻转酶XK介导的脂质转移机制
Mechanism of lipid transfer by bridge-like protein VPS13A and the scramblase XK
『Abstract』In eukaryotes, bridge-like lipid-transfer proteins (BLTPs) are central in mediating vesicle-independent lipid transfer between organelles. BLTPs span the cytosolic space between organelles at contact sites, featuring hydrophobic channels for lipids to travel between membranes. How BLTPs cooperate with partner proteins to orchestrate lipid delivery remains a mystery. Here, we used cryo-electron microscopy to visualize a complex comprising the prototypical BLTP VPS13A and the plasma membrane-localized scramblase XK at near-atomic resolution. VPS13A interacts with XK via its pleckstrin homology domain, priming VPS13A's bridge-like lipid-transfer domain to deliver lipids directly to the cytosolic leaflet of the acceptor membrane. In molecular dynamics simulations, this arrangement allows for robust lipid transfer. Newly delivered lipids can then be equilibrated between leaflets of the membrane bilayer by the scramblase, allowing for membrane growth. Mechanistic insights regarding lipid delivery by VPS13A are directly applicable to all VPS13 proteins and, more broadly, to all BLTP family members.
『摘要』
在真核生物中，桥状脂质转运蛋白（BLTPs）是介导细胞器间非囊泡依赖性脂质转运的核心因子。BLTPs横跨细胞器接触位点处的胞质空间，其特征为具有疏水通道，可供脂质在膜之间穿梭。然而，BLTPs如何与伴侣蛋白协同调控脂质递送仍是一个谜团。本研究利用冷冻电子显微镜技术，以近原子分辨率解析了典型BLTP蛋白VPS13A与定位在质膜上的磷脂翻转酶XK形成的复合物结构。VPS13A通过其普列克底物同源结构域与XK相互作用，促使VPS13A的桥状脂质转运结构域将脂质直接递送至受体膜的胞质侧小叶。分子动力学模拟表明，这种构象安排可实现高效的脂质转移。新递送的脂质随后可通过磷脂翻转酶在膜双层的小叶间达到平衡，从而促进膜的生长。关于VPS13A介导脂质递送的机制见解可直接应用于所有VPS13蛋白，更广泛地适用于所有BLTP家族成员。
『总结』
真核生物中的桥状脂质转运蛋白BLTPs介导细胞器间的非囊泡脂质转运，但它们与伴侣蛋白协同调控脂质递送的机制尚不清楚。研究利用冷冻电镜解析了VPS13A与磷脂翻转酶XK的复合物结构，发现VPS13A通过特定结构域与XK结合，将脂质直接递送到受体膜的胞质侧小叶，并通过分子动力学模拟验证了这一过程的效率，新递送的脂质再由磷脂翻转酶在膜双层间平衡以促进膜生长，该机制对理解所有VPS13蛋白及BLTP家族成员具有重要意义。
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52. 核蛋白质组揭示微管相关蛋白调控命运与疾病
Nuclear proteome reveals microtubule-associated protein regulating fate and disease
『Abstract』Cellular differentiation and morphogenesis require the coordination between cytoskeletal remodeling and transcriptional programs, raising the question of how cytoskeletal information is conveyed to the nucleus. Here, we profile the nuclear and cytosolic proteome of human and murine neural stem cells (NSCs) and uncover abundant cytoskeletal proteins in the nucleus, including the microtubule-associated protein 1B (MAP1B), implicated in disease. We find that MAP1B shuttles to the nucleus where it interacts with the BRG1-containing chromatin remodeling complex. MAP1B's nuclear enrichment promotes NSC fate, as opposed to its cytosolic function promoting neuronal differentiation. In vivo, increasing the nuclear/cytosol ratio disrupts neuronal positioning, reminiscent of patients with MAP1B mutations. Mutant human brain organoids show aberrant MAP1B nuclear enrichment, enhanced BRG1 chromatin binding, and neuronal ectopia formation. Our study uncovers a nuclear pool of cytoskeleton-associated proteins, revealing their role in fate regulation during brain development and reshaping our understanding of neurodevelopmental disease etiology.
『摘要』
细胞分化和形态发生需要细胞骨架重塑与转录程序之间的协调，这就引发了一个问题：细胞骨架信息是如何传递到细胞核的。在此，我们分析了人类和小鼠神经干细胞（NSCs）的细胞核和胞质蛋白组，发现细胞核中存在大量细胞骨架蛋白，包括与疾病相关的微管相关蛋白1B（MAP1B）。我们发现，MAP1B可穿梭至细胞核，并与含BRG1的染色质重塑复合物相互作用。与促进神经元分化的胞质功能相反，MAP1B在细胞核中的富集会促进神经干细胞的命运决定。在体内实验中，增加细胞核/胞质的比例会破坏神经元的定位，这与MAP1B突变患者的症状相似。突变的人类脑类器官显示出异常的MAP1B核富集、增强的BRG1染色质结合以及神经元异位形成。我们的研究揭示了细胞骨架相关蛋白的核池，阐明了它们在大脑发育过程中对细胞命运调控的作用，并重塑了我们对于神经发育疾病病因的理解。
『总结』
研究发现细胞骨架相关蛋白MAP1B可进入细胞核，通过与染色质重塑复合物作用影响神经干细胞命运及神经元定位，揭示其在大脑发育中的作用和对神经发育疾病病因的新认识。
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53. 异种吞噬作用阻断可增强种间嵌合性
Xenophagocytosis blockade enhances interspecies chimerism
『Abstract』Organ shortage remains a major challenge in transplantation medicine. Interspecies blastocyst complementation offers a promising strategy to generate human organs in livestock. However, efficient xenogeneic donor cell engraftment remains challenging. Here, we identify an innate immune barrier wherein host macrophages selectively eliminate viable xenogeneic donor cells, a process we term xenophagocytosis. Mechanistically, xenogeneic cells display elevated phosphatidylserine, an "eat-me" signal recognized by host macrophages through phagocytic receptor Axl. We demonstrate three orthogonal strategies for xenophagocytosis blockade: genetic ablation of macrophages or the Axl receptor in the host embryo or overexpression of the "don't-eat-me" signal CD47 or the phosphatidylserine-regulating flippase ATP11C in donor cells. Xenophagocytosis blockade enhances rat and human donor chimerism in mouse embryos and improves interspecies pancreas complementation efficiency. These findings reveal a previously unrecognized innate immune barrier that safeguards species integrity during early embryogenesis and provide mechanistic insights to enhance xenogeneic chimerism for generating human organs in livestock.
『摘要』
器官短缺仍是移植医学面临的主要挑战。种间囊胚互补为在牲畜体内生成人类器官提供了一种有前景的策略。然而，高效的异种供体细胞植入仍具挑战性。本研究发现一种先天免疫屏障，即宿主巨噬细胞会选择性清除存活的异种供体细胞，我们将这一过程称为异种吞噬作用。从机制上讲，异种细胞会暴露出较高的磷脂酰丝氨酸，这是一种“吃掉我”信号，可通过吞噬受体Axl被宿主巨噬细胞识别。我们展示了三种阻断异种吞噬作用的正交策略：基因敲除宿主胚胎中的巨噬细胞或Axl受体，或在供体细胞中过表达“别吃我”信号CD47或磷脂酰丝氨酸调节翻转酶ATP11C。阻断异种吞噬作用可增强小鼠胚胎中大鼠和人类供体的嵌合率，并提高种间胰腺互补效率。这些发现揭示了早期胚胎发育过程中维护物种完整性的先前未被识别的先天免疫屏障，并为通过增强异种嵌合来在牲畜体内生成人类器官提供了机制见解。
『总结』
研究发现宿主巨噬细胞会通过识别异种细胞的特定信号将其清除（异种吞噬作用），这是阻碍异种供体细胞植入的先天免疫屏障，并提出三种阻断该过程的策略以提升嵌合率和器官生成效率。
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54. 深海巨型动物借用微生物能量代谢基因以耐受超长期饥饿
Deep-sea megafauna co-opts microbial energy metabolism genes to withstand ultra-long starvation
『Abstract』The deep-sea supergiant isopod is renowned for surviving over 5 years without food, which is a crucial adaptive trait for megafauna inhabiting extreme environments. Here, morphological, physiological, and genomic comparisons of deep-sea isopods reveal a dual adaptive strategy underlying this trait: a distended, food-retentive stomach that enables episodic hyperphagia and a markedly reduced basal metabolic rate (BMR). Notably, central to this adaptation is the ancient horizontal acquisition of the microbial energy metabolism-related gene ND1, which thereafter achieved significant dosage enhancement via post-transfer duplication and ultra-high expression that is specifically regulated by histone acetylation at its promoter. Functional assays in transgenic zebrafish, nematodes, and cell lines demonstrate that ND1 reduces BMR by downregulating endogenous energy-production genes and thus extends starvation survival under cold-induced metabolic suppression. These findings uncover an exceptional evolutionary strategy whereby deep-sea megafauna co-opts and epigenetically optimizes exogenous microbial genes to reconcile the metabolic conflict between energy-demanding gigantism and extreme energy limitation.
『摘要』
深海巨型等足类动物以其能在无食物的情况下存活超过5年而闻名，这是栖息在极端环境中的大型生物至关重要的适应性特征。对深海等足类动物的形态、生理和基因组比较揭示了这一特性背后的双重适应策略：膨胀的、能保留食物的胃使其能够间歇性暴食，以及显著降低的基础代谢率（BMR）。值得注意的是，这种适应性的核心是古老的水平获取微生物能量代谢相关基因ND1，随后通过转移后复制实现了显著的剂量增强，并由其启动子处的组蛋白乙酰化特异性调控的超高效表达。转基因斑马鱼、线虫和细胞系的功能检测表明，ND1通过下调内源性能量产生基因来降低基础代谢率，从而在寒冷诱导的代谢抑制下延长饥饿生存时间。这些发现揭示了一种非凡的进化策略，即深海巨型生物利用并表观遗传优化外源微生物基因，以调和高能耗的大型化和极端能量限制之间的代谢冲突。
『总结』
研究发现深海巨型等足类动物通过膨胀的胃实现间歇性暴食及降低基础代谢率的双重策略得以长期绝食存活，其关键在于水平获得微生物基因ND1并通过复制和高表达进行优化，该基因可降低基础代谢率延长饥饿生存时间，展现了深海巨型生物利用外源基因解决代谢冲突的进化策略。
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55. 在量化亲和力图景上重现生发中心演化过程
Replaying germinal center evolution on a quantified affinity landscape
『Abstract』Darwinian evolution of immunoglobulin genes within germinal centers (GCs) underlies the progressive increase in antibody affinity following antigen exposure. Whereas the cellular mechanics of how competition between B cells increases affinity are well established, the evolutionary dynamics of this process are less clear. We developed an experimental evolution model in which we "replay" over one hundred monoclonal GC reactions, assigning affinities to each cell using deep mutational scanning. Our data reveal how GCs achieve predictable outcomes by means of noisy but persistent selection on an affinity landscape whose exploration is heavily constrained by somatic hypermutation biases. We infer a fitness landscape that quantitatively recapitulates the affinity maturation trajectory of our clone and find that apparent features of GC selection, such as permissiveness to low-affinity lineages and rapid plateauing of affinity, are likely artifacts of survivorship biases that distort our view of how B cell affinity progresses over time.
『摘要』
生发中心（GCs）内免疫球蛋白基因的达尔文式进化是抗原暴露后抗体亲和力逐步提高的基础。尽管B细胞间竞争如何提高亲和力的细胞机制已明确，但这一过程的进化动态尚不清楚。我们开发了一种实验进化模型，通过深度突变扫描为每个细胞分配亲和力，“重放”了一百多个单克隆生发中心反应。我们的数据揭示了生发中心如何在存在噪声但持续的选择压力下，通过对一个受体细胞高频突变偏倚严重限制探索的亲和力图景施加影响，从而实现可预测的结果。我们推断出一个定量再现克隆亲和力成熟轨迹的适应度图景，并发现生发中心选择的表观特征（如对低亲和力谱系的宽容和亲和力快速达到平台期）可能是幸存者偏差造成的假象，这些偏差扭曲了我们对于B细胞亲和力随时间进展的认知。
『总结』
研究通过实验进化模型揭示了生发中心内B细胞亲和力成熟的进化动态，指出传统观察到的选择特征可能源于幸存者偏差。
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56. 植物细胞壁-质膜连接通过纤维素合成酶复合体和雷莫蛋白介导抗逆性
Plant cell wall-plasma membrane attachments mediate stress resilience through cellulose synthase complexes and remorins
『Abstract』The outer cell surface of an organism is the frontline for detecting and responding to environmental stimuli. In plants, this interface consists of the plasma membrane that lies beneath the cell wall and remains associated with it through attachment sites. These wall-membrane attachments become evident upon hyperosmotic shock, when severe water loss causes the membrane to retract from the wall. Despite their long-standing observation, the molecular identity and function of these attachments remain poorly understood. Here, we identified two mechanisms governing wall-membrane attachments: one dependent on the cellulose synthase complex (CSC), whose density at the plasma membrane positively correlates with resistance to hyperosmotic stress, and the other on remorin (REM), which acts antagonistically to the CSC mechanism. Using proximity-labeling proteomics, we identified SHOU4/4L as REM-associated proteins that mediate this antagonism. Together, our findings reveal how wall-membrane attachments are patterned to mediate plant cell resilience under water stress.
『摘要』
生物体的外细胞表面是探测和响应环境刺激的前沿。在植物中，这一界面由位于细胞壁下方的质膜构成，并通过附着位点与细胞壁保持关联。当发生高渗冲击（严重失水导致质膜从细胞壁回缩）时，这些细胞壁-质膜的连接变得尤为明显。尽管人们早已观察到它们的存在，但对这些连接的分子身份和功能仍知之甚少。本研究发现了两种调控细胞壁-质膜连接机制：一种依赖于纤维素合成酶复合体（CSC），其在质膜上的密度与抗高渗透压胁迫能力呈正相关；另一种则依赖类朊蛋白（REM），其作用与CSC机制相反。通过邻近标记蛋白质组学技术，我们鉴定出SHOU4/4L为与REM相关的蛋白质，它们介导了这种拮抗作用。我们的研究结果共同揭示了细胞壁-质膜连接如何形成模式以在水胁迫下增强植物细胞的韧性。
『总结』
研究发现植物细胞壁-质膜连接受两种机制调控，即CSC机制和REM机制，且发现SHOU4/4L是与REM相关的介导拮抗作用的蛋白质，揭示了细胞壁 - 质膜连接在水胁迫下增强植物细胞韧性的模式。
『闲叙』
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