前沿速递 | ncs 集萃：2026-07-22 期
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1. 利用公民科学为适应机制发现提供背景支持
Harnessing citizen science to contextualize adaptation mechanism discovery
『Abstract』Species occupying broad geographic regions have evolved multiple mechanisms to regulate phenological characteristics, enabling adaptations to diverse native habitats. By developing computer vision AI to process citizen science observations across native habitats over North America, we uncovered a consistent latitudinal trend of earlier flowering at higher latitudes in warm-season perennial grasses. To explore the underlying mechanisms of adaptation, we conducted common garden experiments with one species (switchgrass) and discovered the opposite latitudinal flowering-time trend. Integration of differential plasticity of GI-Hd1-FTL1 haplotypes of flowering time regulatory genes, haplotype range, and local environmental profiles found that observations from native habitats capture only part of the genotype-environment-phenotype spectrum established in common garden experiments, therefore reconciling the discrepancy. Two mechanisms emerged as key forces shaping current haplotype ranges and influencing future shifts. Our study highlights the power of combining citizen science observations with designed experiments to uncover mechanisms of adaptation across spatiotemporal scales.
『摘要』
分布范围广泛的物种已经进化出多种机制来调节物候特征，使其能够适应不同的原生栖息地。通过开发计算机视觉人工智能来处理北美原生栖息地公民科学观测数据，我们发现暖季多年生草本植物在高纬度地区开花更早，呈现出一致的纬度趋势。为探究其适应的潜在机制，我们对一种物种（柳枝稷）进行了共同园试验，发现其开花时间纬度趋势与之相反。综合开花时间调控基因GI-Hd1-FTL1单倍型的差异可塑性、单倍型范围和当地环境特征，发现原生栖息地的观测结果仅捕捉到了共同园试验中建立的基因型-环境-表型图谱的一部分，从而调和了这一差异。两种机制成为塑造当前单倍型范围和影响未来变化的关键力量。我们的研究强调了将公民科学观测与精心设计的实验相结合，对于揭示跨时空尺度适应机制的重要性。
『总结』
研究通过结合公民科学数据和共同园试验，揭示了暖季多年生草本植物开花时间的纬度趋势差异，并发现基因型差异可塑性和环境因素共同作用，解释了这一差异，同时强调了结合公民科学观测与实验研究在揭示跨时空尺度适应机制中的重要性。
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2. 基因组不稳定性会触发人类细胞间的细胞间DNA转移
Genome instability triggers intercellular DNA transfer between human cells
『Abstract』The mammalian genome is safeguarded within the confines of the interphase nucleus. However, genomic instability can trigger the mislocalization of nuclear DNA to the cytoplasm within micronuclei or as fragmented chromosomes. Beyond activating cell-autonomous signaling programs, whether such cytoplasmic DNA can elicit non-cell-autonomous consequences to nearby cells remains unclear. Here, we show that cytoplasmic DNAs undergo intercellular transfer through contact-dependent, cytoskeleton-based nanotube structures connecting adjacent human cells. Diverse sources of genomic instability-including exposure to mitotic spindle poisons, ionizing radiation, and Cas9-induced chromosome breakage-promote nanotube-mediated DNA transfer in both cancerous and non-cancerous cells. Transferred DNA fragments are stably inherited as functional extrachromosomal genetic elements in the recipient host genome, thereby conferring heritable phenotypic traits to the recipient cell. Our findings uncover a horizontal gene transfer-like mechanism through which direct cell-cell contact can propagate genomic instability and reshape mammalian genomes.
『摘要』
哺乳动物基因组在间期细胞核内得到保护。然而，基因组不稳定性可能导致细胞核DNA错位至细胞质中，形成微核或染色体碎片。除激活细胞自主信号通路外，这种细胞质DNA是否会对邻近细胞产生非细胞自主性后果尚不清楚。本研究表明，细胞质DNA通过连接相邻人类细胞的基于细胞骨架的纳米管结构，以接触依赖的方式进行细胞间转移。多种基因组不稳定性来源（包括暴露于有丝分裂纺锤体毒物、电离辐射和Cas9诱导的染色体断裂）均会促进癌细胞和非癌细胞中纳米管介导的DNA转移。转移的DNA片段作为功能性染色体外遗传元件在受体宿主基因组中稳定遗传，从而使受体细胞获得可遗传的表型特征。本研究揭示了一种类似水平基因转移的机制，通过该机制，直接细胞间接触可传播基因组不稳定性并重塑哺乳动物基因组。
『总结』
哺乳动物基因组不稳定性导致细胞质DNA形成，这些DNA通过纳米管结构在细胞间转移，并作为染色体外遗传元件稳定遗传，传播基因组不稳定性并重塑基因组。
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3. 在一颗恒星的次恒星伴星周围探测到行星质量的系外卫星
Planetary-mass exosatellite detected around the substellar companion of a star
『Abstract』Brown dwarfs occupy the mass regime between planets and stars. In systems containing both a star and a substellar companion (be it a brown dwarf or an exoplanet), a third object orbiting the companion can be called an exosatellite. Exoplanet satellites can be easily described as exomoons, but it is not clear if satellites of brown dwarf companions can be called the same, as the term lacks a formal definition. Despite more than 6,000 exoplanets being discovered, no exomoon has ever been confidently detected. Although there are candidates, they lack confirmation and remain controversial. In this work, we present evidence of an exosatellite orbiting the directly imaged brown dwarf companion CD-35 2722 B. Applying radial velocity analysis, the same technique used to discover the first exoplanet around a Solar-type star, to VLT/CRIRES+ spectra of this brown dwarf, we find what appears to be the periodic signal of at least one orbiting satellite. This is the first time, to our knowledge, this technique has produced evidence of satellites around a companion brown dwarf. Our best-fitting model includes a satellite with a minimum mass of about 0.9 Jupiter masses and a period of around 170 days. Although it is uncertain whether this exosatellite will fulfil the presently undefined criteria for qualifying as an exomoon, it is a marked step towards that first uncontroversial detection, as advancing technology will allow the same method to be applied to less massive targets.
『摘要』
褐矮星的质量介于行星和恒星之间。在包含一颗恒星和一个亚恒星伴星（无论是褐矮星还是系外行星）的系统中，围绕伴星运行的第三个天体可称为系外卫星。系外行星的卫星可轻松描述为系外卫星（exomoon），但尚不清楚褐矮星伴星的卫星是否也可如此称呼，因为该术语缺乏正式定义。尽管已发现超过6000颗系外行星，但从未确凿地探测到系外卫星。尽管存在一些候选天体，但缺乏确认且仍存在争议。本研究中，我们提供了证据，证明在直接成像的褐矮星伴星CD-35 2722 B周围存在一颗系外卫星。我们采用径向速度分析方法（即发现首颗围绕类太阳恒星运行的系外行星所用的技术），对欧洲南方天文台甚大望远镜（VLT）的CRIRES+光谱仪观测到的这颗褐矮星的光谱进行分析，发现了至少一颗围绕其运行的卫星发出的周期性信号。据我们所知，这是首次利用该技术为褐矮星伴星周围存在卫星提供证据。我们拟合的最佳模型中，这颗卫星的最小质量约为0.9个木星质量，公转周期约为170天。尽管尚不确定这颗系外卫星是否符合目前尚未定义的系外卫星（exomoon）判定标准，但这是向首次无争议探测迈出的重要一步，因为随着技术进步，同样的方法将可用于质量更小的目标。
『总结』
褐矮星质量介于行星与恒星间，其伴星卫星称呼尚无正式定义，虽发现超6000颗系外行星却未确凿探测到系外卫星，本研究通过径向速度分析发现褐矮星伴星CD-35 2722 B周围存在系外卫星，其最佳模型显示卫星最小质量约0.9个木星质量、公转周期约170天，虽不确定是否符合系外卫星标准，但为首次无争议探测迈出重要一步。
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4. 锌中低能增强的磁性特征
Magnetic character of the low-energy enhancement in Zn
『Abstract』The transition of an atomic nucleus from an excited state to a state of lower energy is typically accompanied by the emission of photons. The likelihood of photon emission is a function of the photon energy and of properties of the initial and final nuclear states and is known as the photon (or γ-ray) strength function (γSF). Of the features present in the γSF, an enhancement in the low-energy region has been observed in some nuclei, but the electromagnetic nature of this enhancement remains an open question. This low-energy enhancement in the γSF significantly impacts our understanding of how elements are created in stars and the structure of the nucleus. Here we present the results from an experiment on the γSF of Zn that show that the enhancement in the γSF of this nucleus is of magnetic nature. This observation helps address a long-open question about γSFs in atomic nuclei and directly impacts our predictive capabilities in nuclear science.
『摘要』
原子核从激发态向低能态转变时，通常会伴随光子的发射。光子发射的可能性取决于光子能量以及初始和最终核态的性质，这一可能性被称为光子（或γ射线）强度函数（γSF）。在γSF的特征中，某些原子核的低能区出现了增强现象，但这种增强的电磁性质仍是一个未解之谜。γSF的低能增强现象显著影响我们对恒星中元素形成以及原子核结构的理解。本研究展示了锌的γSF实验结果，表明该原子核的γSF增强具有磁性特征。这一发现有助于解答关于原子核γSF长期未解的问题，并直接影响核科学中的预测能力。
『总结』
本研究通过实验证实锌的γ射线强度函数低能区增强为磁性特征，解决了原子核γSF的长期疑问并提升了核科学的预测能力。
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5. 量子统计等离子体超晶格
Quantum statistical plasmonic metacrystals
『Abstract』Engineering materials that control quantum many-body dynamics remains challenging, as multiparticle interactions typically produce complex emergent behaviour that is difficult to predict. Here we introduce quantum statistical plasmonic metacrystals, structures in which the multiparticle dynamics mediated by optical near fields produce forbidden quantum statistical bands that enable selective transmission of different types of light. This functionality arises from a plasmonic structure composed of nanoantennas acting as meta-atoms. Multiphoton fields with statistics within the allowed bands propagate without distortion, whereas fields in forbidden bands are suppressed or driven towards the nearest accessible statistical state. We show that these bands are determined by the geometry and collective arrangement of the meta-atoms, providing a deterministic route to engineering quantum statistical transport. This platform establishes a room-temperature quantum material intrinsically sensitive to the quantum coherence of many-body photonic systems, enabling their robust manipulation and transport. Our results have implications for coherence-sensitive photonic materials for energy harvesting and scalable many-body quantum technologies.
『摘要』
控制量子多体动力学的工程材料仍具挑战性，因为多粒子相互作用通常会产生难以预测的复杂涌现行为。在此，我们引入了量子统计等离子体元晶体，在这种结构中，由光学近场介导的多粒子动力学产生了禁阻量子统计能带，使得不同类型的光能够选择性传输。这种功能源于由作为超原子的纳米天线组成的等离子体结构。允许能带内的统计多光子场传播时不会失真，而禁阻能带内的场则会被抑制或驱动至最近的可及统计状态。我们发现，这些能带由超原子的几何形状和集体排列决定，为工程量子统计传输提供了确定性途径。该平台建立了一种在室温下对多体光子系统的量子相干性具有内在敏感性的量子材料，能够实现对它们的稳健操控和传输。我们的研究结果对用于能量收集和可扩展多体量子技术的相干敏感光子材料具有重要意义。
『总结』
本文提出量子统计等离子体元晶体，其多粒子动力学产生禁阻量子统计能带，实现不同类型光选择性传输，该能带由超原子特性决定，为量子统计传输提供确定性途径，此平台对多体光子系统量子相干敏感，研究结果对相关光子材料有重要意义。
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6. 高度分散且恢复需求不均的欧洲湿地
Highly fragmented European wetlands with uneven restoration needs
『Abstract』European wetlands store large carbon reserves, but centuries of land use have eroded carbon stocks and biodiversity. The European Union (EU) Nature Restoration Law (NRL) requires at least 30% of wetland ecosystems not in 'good condition' to be restored by 2030, yet spatially consistent information on wetland types and condition remains scarce. Using 10-m satellite imagery and machine learning, we map six seminatural open wetland types and land-use disturbance across 38 European countries. Wetlands are highly fragmented, with an estimated 27-33% of wetland area occurring in map-defined patches <25 ha and 7-11% in patches <1 ha, exposing many small sites missed by coarser products. We estimate that human activities affect 20.4 ± 3.4% of wetland areas (95% confidence interval), with inland wetland types most affected, and up to 5 Gt CO2-eq of soil carbon potentially lost relative to an undisturbed baseline. Translating disturbed area into NRL restoration targets, we find that several countries' pledges are broadly consistent with our 2030 estimates, whereas others lack quantified commitments despite substantial candidate areas identified by our maps. The resulting standardized, high-resolution products provide an EU-wide baseline tailored to the NRL and a reproducible template for linking satellite mapping to restoration targets, supporting progress tracking.
『摘要』
欧洲湿地储存着大量的碳储备，但几个世纪以来的土地利用已侵蚀了碳储量和生物多样性。欧盟《自然恢复法》（NRL）要求，到2030年，至少30%的“状况不佳”的湿地生态系统需得到恢复，然而，关于湿地类型和状况的空间一致信息依然稀缺。我们利用10米分辨率的卫星图像和机器学习技术，绘制了38个欧洲国家六种半自然开放湿地类型及土地利用干扰情况的地图。湿地高度破碎化，估计有27-33%的湿地面积分布在小于25公顷的斑块中，7-11%分布在小于1公顷的斑块中，许多小型湿地因分辨率较低的产品而未被发现。我们估计，人类活动影响了20.4±3.4%的湿地面积（95%置信区间），其中内陆湿地类型受影响最大，相对于未受干扰的基线，土壤碳可能最多损失50亿吨二氧化碳当量。将受干扰面积转化为NRL恢复目标，我们发现，部分国家的承诺与我们的2030年估计大致相符，而另一些国家尽管我们的地图已识别出大量候选区域，但仍缺乏量化承诺。由此产生的标准化、高分辨率产品为整个欧盟提供了适合NRL的基线，并为将卫星测绘与恢复目标联系起来提供了可复制的模板，有助于追踪进展。
『总结』
研究利用卫星图像和机器学习绘制了欧洲湿地类型及干扰情况地图，发现湿地高度破碎化且受人类活动影响显著，部分国家恢复承诺与估计相符，研究提供了适合NRL的基线及可复制模板。
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7. 扭曲菱面体石墨烯中的分数量子高陈数绝缘体
Fractional high-Chern insulator in twisted rhombohedral graphene
『Abstract』The realization of fractional Chern insulators opens the possibility of exploring fractionally charged excitations and anyonic statistics in the absence of a magnetic field. A central question is whether lattice-based systems can give rise to radically new states, distinct from those observed in traditional fractional quantum Hall systems. Here we investigate a type of moire flat-band system composed of Bernal bilayer graphene and rhombohedral tetralayer graphene. We discover an unprecedented richness of quantum anomalous Hall insulators with Chern numbers from |C| = 1 to |C| = 7 at a moire filling factor v = 1 and around v = 3. Remarkably, we observe an exotic fractional Chern insulator with C = 7/3 around v = 2/3, which is beyond all known fractional Chern insulators described by either the Jain sequence or current high-Chern theory. Our work expands the understanding of fractionally charged excitations beyond the Landau-level basis and offers a moire platform for exploring anyons.
『摘要』
分数陈绝缘体的实现为在无磁场情况下探索分数电荷激发和任意子统计提供了可能性。一个核心问题是，基于晶格的系统能否产生与传统分数量子霍尔系统中观察到的截然不同的全新状态。本研究对一种由伯纳尔双层石墨烯和菱形四层石墨烯组成的莫尔平带系统进行了探索。我们发现，在莫尔填充因子ν=1和ν≈3时，存在从|C|=1到|C|=7的量子反常霍尔绝缘体，其丰富性前所未有。值得注意的是，我们在ν≈2/3附近观察到一个具有C=7/3的奇异分数陈绝缘体，这超出了所有已知的由Jain序列或当前高陈数理论描述的分数陈绝缘体。我们的研究拓展了基于朗道能级的分数电荷激发理解，并为探索任意子提供了一个莫尔平台。
『总结』
研究发现了莫尔平带系统中丰富的量子反常霍尔绝缘体，并观察到一种超出已知理论的奇异分数陈绝缘体，拓展了分数电荷激发的理解并提供了探索任意子的新平台。
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8. 无催化剂、微液滴介导的废旧塑料转化为二元酸
Catalyst-free, microdroplet-mediated waste plastic conversion to diacids
『Abstract』Plastic waste accumulation poses a global threat to both the environment and public health. Although catalytic upcycling to value-added chemicals holds promise, its industrial adoption is hindered by additive-induced catalyst deactivation, feedstock heterogeneity, process inflexibility and limited economic viability. Here we report a catalyst-free upcycling strategy that makes use of in situ generation of hydroxyl radicals at microdroplet interfaces to enable oxidative cleavage of diverse waste plastics-from polyolefins to rubbers-into carboxylic acids under mild conditions. By eliminating catalyst-dependent pathways, this approach circumvents key challenges of catalyst design and poisoning, while substantially lowering technical barriers and costs. Our method achieves complete conversion of polyethylene (PE) with selectivity to short-chain diacids approaching 69% under relatively mild conditions and demonstrated broad applicability to mixed commercial plastics, with scalability demonstrated up to the 300-g scale. Radical intermediate analysis reveals the crucial role of H2O in mediating a unique oxidative degradation mechanism: sequential hydroxyl radical addition to alkyl radicals, distinct from classical liquid-phase aerobic oxidation of alkane. This interfacial radical-mediated strategy enables sustainable polymer upcycling with minimal infrastructure. More broadly, this work provides a scalable blueprint for the first, to our knowledge, industrial implementation of microdroplet chemistry, with transformative implications for oxidation processes in organic acid synthesis and beyond.
『摘要』
塑料废弃物的积累对环境和公共健康构成了全球性威胁。尽管催化升级再造为高附加值化学品前景广阔，但添加剂导致的催化剂失活、原料异质性、工艺灵活性不足以及经济可行性有限等问题阻碍了其工业化应用。本文报道了一种无需催化剂的升级再造策略，该策略利用微液滴界面原位生成的羟基自由基，在温和条件下实现从聚烯烃到橡胶等各类废弃塑料的氧化裂解，最终生成羧酸。通过消除对催化剂的依赖，该方法规避了催化剂设计和中毒等关键挑战，同时大幅降低了技术门槛和成本。在相对温和的条件下，该方法可实现聚乙烯（PE）的完全转化，短链二元酸的生成选择性接近69%，且对混合商业塑料具有广泛的适用性，并已成功实现300克规模的放大实验。自由基中间体分析揭示了水在介导独特氧化降解机制中的关键作用：羟基自由基连续加成至烷基自由基，这一过程与经典的烷烃液相需氧氧化机制截然不同。这种界面自由基介导策略以最小的基础设施需求实现了可持续聚合物升级再造。更广泛地说，据我们所知，这项工作为微液滴化学的首次工业化应用提供了可扩展的蓝图，对有机酸合成及其他氧化过程具有变革性意义。
『总结』
本文提出了一种无需催化剂的微液滴界面羟基自由基介导策略，实现各类废弃塑料在温和条件下的氧化裂解，规避了传统催化升级再造的关键挑战，具备工业化应用潜力。
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9. 用于高效节能气体分离的可扩展准纯金属有机框架（MOF）膜
Scalable quasi-pure MOF membranes for energy-efficient gas separations
『Abstract』Metal-organic framework (MOF) membranes offer great potential to address the energy penalties of energy-intensive gas separations. Deriving convenient scalable protocols is essential for the successful translation and deployment of MOF-based membranes into practical applications. Here we report a new membrane architecture, the quasi-pure MOF membrane (>90 vol% MOF), manufacturable at scale using industry-reliable solution-processing techniques and offering separation performance approaching that of associated pure MOF membranes, fully realizing the MOF intrinsic potential. This advance is enabled by a merged-phase approach fusing MOFs and polymers into a single pseudo-continuous phase and proffering MOFs with polymer-like surface properties, allowing rheologically controlled flocculated networks even at extreme solid concentrations. Representative benchmark MOFs (ZIF-67, CALF-20 and CuBDC) were fabricated into quasi-pure membranes and evaluated for essential separations, including propylene/propane, ethylene/ethane, carbon capture and hydrogen purification. Demonstrating industrial relevance, continuous roll-to-roll fabrication of quasi-pure (110)-oriented ZIF-67 membranes was achieved at an industrial plant. For propylene/propane separation, these membranes achieve a propylene permeability of about 160 barrer and mixed-gas selectivity of about 100-sufficient to produce polymer-grade propylene, offering an 80% purification cost reduction compared with distillation based on techno-economic analysis. This study addresses the long-standing gap between performance and scalability of crystalline membranes for demanding molecular separations.
『摘要』
金属有机框架（MOF）膜在解决高能耗气体分离的能源损耗问题上具有巨大潜力。开发便捷的可扩展方案对于将基于MOF的膜成功转化并应用于实际至关重要。本文报道了一种新的膜结构——准纯MOF膜（MOF含量>90 vol%），该膜可采用工业可靠的溶液加工技术大规模制造，分离性能接近相关纯MOF膜，充分实现了MOF的内在潜力。这一进步得益于一种融合相方法，该方法将MOF和聚合物融合成单一的拟连续相，并赋予MOF类似聚合物的表面特性，即使在极端固含量下也能形成流变可控的絮凝网络。代表性基准MOF（ZIF-67、CALF-20和CuBDC）被制成准纯膜，并用于评估丙烯/丙烷、乙烯/乙烷、碳捕获和氢气纯化等重要分离过程。具有工业相关性的准纯（110）取向ZIF-67膜在工业工厂中实现了连续卷对卷制造。对于丙烯/丙烷分离，这些膜的丙烯渗透性约为160 barrer，混合气体选择性约为100，足以生产聚合物级丙烯，与基于技术经济分析的蒸馏相比，净化成本降低了80%。本研究解决了苛刻分子分离中晶体膜性能与可扩展性之间长期存在的差距。
『总结』
本文报道了一种新的准纯MOF膜结构，该膜可通过工业可靠的溶液加工技术大规模制造，分离性能优异，在重要气体分离过程中表现出色，且实现了连续卷对卷制造，降低了净化成本，解决了晶体膜性能与可扩展性之间的差距。
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10. 可重构毫米波微芯片，在氮化镓上共集成氮化硼开关
Reconfigurable mmWave microchips co-integrating hBN switches on GaN
『Abstract』Monolithic microwave integrated circuits (MMICs) are an emerging technology that is expected to substantially improve telecommunications in the next few years. MMICs use application-specific semiconductors to meet the performance needs of 5G standards and beyond; however, integrating high-frequency switches into these platforms is very demanding in terms of area and cost and doing so is also a bottleneck for performance. Memristive radio-frequency switches are an appealing alternative due to their easy fabrication and high device-level electrical performance, but their use in circuit implementations of MMICs has never been realized. Here we demonstrate programmable millimetre-wave (mmWave) gallium nitride (GaN) MMICs fabricated with memristive radio-frequency switches made from two-dimensional layered hexagonal boron nitride (hBN) integrated directly on the back-end-of-line. We fabricated back-end-of-line wideband switches operating up to 100 GHz with insertion losses as low as 0.3 dB and isolation better than 15 dB. The switches delivered long-term state retention (2 weeks), stable on-state resistance at 175 °C, linear power handling within 0.28 dB measured up to 18 dBm, and an extrapolated 1-dB compression point mean of 30.52 dBm. We use one-transistor, one-memristor cell integration for the switch drivers, achieving 3,250 cycles of endurance, an improvement for two-dimensional-material-based memristive radio-frequency switches. Finally, we demonstrate the implementation of memristive-configurable attenuators, power dividers and programmable resonators on the GaN MMIC platform.
『摘要』
单片微波集成电路（MMICs）是一项有望在未来几年大幅提升电信性能的新兴技术。MMICs使用专用半导体以满足5G及更高标准的性能需求；然而，将高频开关集成到这些平台中，对面积和成本要求极高，且是性能提升的瓶颈。忆阻射频开关因其易于制造和器件级的高电气性能而成为颇具吸引力的替代方案，但其在MMIC电路实现中的应用却从未实现。本研究展示了采用直接集成在后端工艺线上的二维层状六方氮化硼（hBN）忆阻射频开关制造的可编程毫米波（mmWave）氮化镓（GaN）MMIC。我们制造了工作频率高达100 GHz的后端工艺线宽带开关，其插入损耗低至0.3 dB，隔离度优于15 dB。这些开关具有长期状态保持能力（2周），在175°C时导通电阻稳定，在0.28 dB内线性处理功率（测量值高达18 dBm），且外推的1 dB压缩点平均值为30.52 dBm。我们采用单晶体管-单忆阻器单元集成技术来驱动开关，实现了3250次循环耐久性，提高了基于二维材料的忆阻射频开关的性能。最后，我们在GaN MMIC平台上展示了忆阻可配置衰减器、功率分配器和可编程谐振器的实现。
『总结』
本文展示了采用二维六方氮化硼忆阻射频开关制造的可编程毫米波氮化镓单片微波集成电路，并验证了其高性能特性，同时实现了多种忆阻可配置微波器件。
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11. 量子纠错的强化学习控制
Reinforcement learning control of quantum error correction
『Abstract』Quantum error correction (QEC) is the primary strategy for protecting a quantum computer from the environment. The prerequisite of QEC is that errors must remain sufficiently rare, which requires perpetually adapting the control parameters of the computer to the drifting environmental conditions. The current solution to this problem is to terminate the entire quantum computation for recalibration, but it is incompatible with the long runtimes of future quantum algorithms. Here we address this challenge by unifying calibration with computation. We grant the QEC process a dual role: its error-detection events are not only used to correct the logical quantum state but are also repurposed as a learning signal, teaching a reinforcement learning agent to continuously steer the control parameters and stabilize the quantum system during computation. We experimentally demonstrate this framework on a Willow superconducting processor, improving the logical stability of the surface code 3.5-fold against injected drift. By synthesizing our full suite of technological advances, we achieve record performance of the surface and colour codes, with average logical error per cycle of 7.72(9) × 10-4 and 8.19(14) × 10-3, respectively. Numerical simulations of large codes with tens of thousands of control parameters confirm the scalability of our RL framework, revealing an optimization speed that is independent of system size. This work thus enables a new paradigm: a quantum computer that learns from its errors and never stops computing.
『摘要』
量子纠错（QEC）是保护量子计算机免受环境干扰的主要策略。QEC的前提是错误必须足够罕见，这就要求计算机不断调整控制参数以适应不断变化的环境条件。目前解决这一问题的方法是终止整个量子计算过程以进行重新校准，但这与未来量子算法所需的长时间运行不兼容。本文通过将校准与计算相结合来应对这一挑战。我们赋予QEC过程双重作用：其错误检测事件不仅用于纠正逻辑量子态，还被重新用作学习信号，指导强化学习智能体在计算过程中持续调整控制参数并稳定量子系统。我们在Willow超导处理器上实验验证了这一框架，将表面码的逻辑稳定性相对于注入的漂移提高了3.5倍。通过整合全套技术进步，我们实现了表面码和颜色码的创纪录性能，每周期平均逻辑错误率分别为7.72(9) × 10-4和8.19(14) × 10-3。对具有数万个控制参数的大型代码的数值模拟证实了我们的强化学习框架的可扩展性，揭示了优化速度与系统规模无关。这项工作因此开启了一种新范式：一种从错误中学习且永不停机的量子计算机。
『总结』
本文提出了一种将量子纠错校准与计算相结合的新方法，通过强化学习智能体持续调整控制参数，实现了量子计算机的稳定运行和创纪录性能，为未来长时间运行的量子算法提供了可能。
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12. 热触发磷脂翻转稳定质膜流动性
Heat-triggered phospholipid flipping stabilizes plasma membrane fluidity
『Abstract』Cells must rapidly counteract heat stress-induced hyperfluidization of the plasma membrane to prevent membrane damage, yet how cells achieve such early protection remains unknown. Here we show that in rice (Oryza sativa), the P4-ATPase OsALA5, together with its β-subunit OsALIS2, mediates a heat-responsive flipping of saturated phosphatidylcholines that rapidly stabilizes plasma membrane fluidity. Using leaflet-resolved lipidomics and complementary transport assays, we demonstrate that heat exposure induces a minute-timescale shift in OsALA5 transport activity that leads to selective enrichment of saturated phosphatidylcholines in the cytoplasmic plasma membrane leaflet. This OsALA5-mediated saturated phosphatidylcholine flipping prevents plasma membrane hyperfluidization upon heat stress, thus mitigating ion leakage and cell death. Our analyses of OsALA5 orthologues in Arabidopsis thaliana and yeast support functional conservation of a rapid heat-associated response within a subset of plasma membrane-localized, phosphatidylcholine-transporting P4-ATPases. We identified a rare haplotype of OsALA5 that confers both heat tolerance and yield stability in multi-year, multi-location field trials. Thus, beyond identifying this P4-ATPase-mediated flipping of saturated phosphatidylcholines in response to heat stress and providing genetic resources to advance breeding of heat-tolerant crops, our study reveals how cells counteract heat stress-driven plasma membrane hyperfluidization at an earlier stage than the previously known transcription-dependent lipid remodelling response.
『摘要』
细胞必须迅速抵消热应激引起的质膜过度流动化，以防止膜损伤，但细胞如何实现这种早期保护仍不得而知。本研究表明，在水稻（Oryza sativa）中，P4-ATP酶OsALA5与其β亚基OsALIS2共同介导了饱和磷脂酰胆碱的热响应翻转，从而快速稳定质膜流动性。通过小叶解析脂质组学和互补转运实验，我们发现热暴露会在分钟尺度上改变OsALA5的转运活性，导致细胞质质膜小叶中饱和磷脂酰胆碱的选择性富集。这种由OsALA5介导的饱和磷脂酰胆碱翻转可防止热应激引起的质膜过度流动化，从而减少离子渗漏和细胞死亡。我们对拟南芥和酵母中OsALA5直系同源物的分析表明，在质膜定位的磷脂酰胆碱转运P4-ATP酶亚集中，快速热响应具有功能保守性。我们在多年、多地田间试验中鉴定出一种罕见的OsALA5单倍型，该单倍型可赋予水稻耐热性和产量稳定性。因此，本研究不仅确定了这种P4-ATP酶介导的饱和磷脂酰胆碱在热应激下的翻转，为耐热作物的育种提供了遗传资源，还揭示了细胞在比先前已知的转录依赖性脂质重塑反应更早的阶段，如何抵消热应激驱动的质膜过度流动化。
『总结』
研究揭示了水稻中OsALA5与OsALIS2通过翻转饱和磷脂酰胆碱快速稳定质膜流动性，防止热应激损伤，为耐热作物育种提供了遗传资源，并揭示了细胞早期应对热应激的新机制。
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13. 3I/ATLAS冷而遥远起源的同位素证据
Isotopic evidence for a cold and distant origin of 3I/ATLAS
『Abstract』Interstellar objects provide the only directly observable samples of icy planetesimals formed around other stars, and can therefore provide insight into the diversity of physical and chemical conditions occurring during exoplanet formation. Here we report isotopic measurements of the interstellar comet 3I/ATLAS, which reveal an elemental composition unlike any Solar System body. The water in 3I/ATLAS is enriched in deuterium, at a level of D/H = (0.98 ± 0.06)%, which is more than an order of magnitude higher than in known comets, and its range of C/C ratios (141-191 for CO2 and 123-172 for CO) exceeds typical values found in the Solar System, as well as nearby interstellar clouds and protoplanetary disks. Such extreme isotopic signatures indicate formation at temperatures ≲30 K in a relatively metal-poor environment. When interpreted with respect to models for Galactic chemical evolution, the carbon isotopic composition implies that 3I/ATLAS may have accreted as long ago as 12 billion years, following a period of intense, early star formation. 3I/ATLAS thus represents a preserved fragment of an ancient planetary system.
『摘要』
星际天体是唯一可直接观测到的围绕其他恒星形成的冰质星子样本，因而能够为系外行星形成过程中物理和化学条件的多样性提供线索。本研究报告了对星际彗星3I/ATLAS的同位素测量结果，发现其元素组成与太阳系任何天体均不相同。3I/ATLAS中的水富含氘，氘氢比（D/H）为(0.98 ± 0.06)%，比已知彗星高出一个数量级以上；其碳同位素比值范围（CO2的C/C为141-191，CO的C/C为123-172）也远超太阳系、邻近星际云和原行星盘的典型值。这种极端同位素特征表明其形成于温度≲30 K且金属丰度相对较低的环境。结合银河系化学演化模型分析，其碳同位素组成暗示3I/ATLAS可能诞生于120亿年前早期恒星剧烈形成阶段之后，是古老行星系统的保存片段。
『总结』
星际彗星3I/ATLAS的同位素特征显示其形成于低温贫金属环境，可能源自120亿年前早期恒星形成阶段后的古老行星系统，其元素组成与太阳系天体存在显著差异。
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14. 细胞核内多聚腺苷酸化RNA命运决定的分子基础
Molecular basis of polyadenylated RNA fate determination in the nucleus
『Abstract』Eukaryotic genomes generate a plethora of polyadenylated (pA+) RNAs, which are packaged into ribonucleoprotein particles (RNPs). To ensure faithful gene expression, functional pA+ RNPs, including protein-coding RNPs, are exported to the cytoplasm, whereas transcripts within non-functional pA+ RNPs are degraded in the nucleus. How cells distinguish these opposing fates remains unknown. The DExD-box ATPase UAP56 (also known as DDX39B) is a central component of functional pA+ RNPs, and promotes their docking to the nuclear pore complex-anchored TREX-25,6, which triggers transcript release from UAP56 to facilitate export. Here we reveal that the poly(A) tail exosome targeting (PAXT) connection binds a TREX-2-like module, which releases pA+ RNAs from UAP56 for decay by the nuclear exosome. The core of this module consists of a LENG8-PCID2-SEM1 trimer, which we show is structurally and biochemically equivalent to the central GANP-PCID2-SEM1 trimer of TREX-2. Mutagenesis and transcriptomic data demonstrate that the nuclear fate of pA+ RNPs is governed by the contending actions of nucleoplasmic PAXT and nuclear pore complex-associated TREX-2, which interpret RNA-bound UAP56 as a signal for RNA decay or export, respectively. As RNA targets of PAXT are generally short and intron-poor, we propose an overall model for pA+ RNP fate determination whereby the distinct sub-nuclear localizations of PAXT and TREX-2 govern the degradation of short non-functional pA+ RNAs while allowing export of their longer and functional counterparts.
『摘要』
真核生物基因组会产生大量多聚腺苷酸化（pA+）的RNA，这些RNA会被包装成核糖核蛋白颗粒（RNPs）。为确保基因表达的准确性，包括蛋白质编码RNP在内的功能性pA+ RNP会被转运至细胞质，而非功能性pA+ RNP中的转录本则在细胞核内降解。细胞如何区分这些截然不同的命运尚不清楚。DExD-box ATP酶UAP56（也称为DDX39B）是功能性pA+ RNP的核心成分，可促进其与锚定在核孔复合体上的TREX-25,6结合，进而触发转录本从UAP56释放，以促进其输出。本研究揭示，多聚（A）尾外泌体靶向（PAXT）连接体可结合一个类似TREX-2的模块，该模块从UAP56释放pA+ RNA，供核外泌体降解。该模块的核心由LENG8-PCID2-SEM1三聚体组成，结构与生化特性与TREX-2的核心GANP-PCID2-SEM1三聚体相当。突变分析和转录组数据显示，pA+ RNP的核内命运由核质中的PAXT和核孔复合体相关TREX-2的竞争作用决定，二者分别将RNA结合的UAP56解读为RNA降解或输出的信号。鉴于PAXT的RNA靶点通常较短且内含子较少，我们提出了一个关于pA+ RNP命运决定的整体模型，即PAXT和TREX-2在核内的不同定位决定了短的非功能性pA+ RNA的降解，同时允许其更长的功能性对应物输出。
『总结』
真核生物中，功能性pA+ RNP被转运至细胞质，非功能性则被降解，细胞区分机制不明，本研究揭示PAXT连接体与类似TREX-2的模块结合，使pA+ RNA被核外泌体降解，且PAXT和TREX-2的竞争作用决定pA+ RNP命运，基于此提出pA+ RNP命运决定模型。
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15. 全钙钛矿叠层太阳能电池组件的纳米晶定制复合
Nanocrystal-tailored recombination for all-perovskite tandem solar modules
『Abstract』The commercialization of all-perovskite tandem solar modules is hindered by the reliance on the conventional gold-based tunnel recombination junction. Specifically, this tunnel recombination junction introduces substantial near-infrared parasitic absorption and suffers from interfacial instability, limiting both photocurrent generation and operational durability. Here, we develop a solution-processed interconnecting layer based on surface-engineered indium oxide nanocrystals featuring high optical transparency, in which controlled nanocrystal morphology and tailored ligand chemistry enable smooth interfacial contact and favourable energy-level alignment. We introduce a phosphonic acid additive into the lead-tin perovskite precursor, which synergistically improves the electronic contact with the indium oxide recombination layer, thereby enhancing hole extraction. Moreover, the additive regulates perovskite crystallization to mitigate residual strain during film formation, ensuring high-quality large-area deposits. This coordinated interfacial and crystallization engineering strategy simultaneously enhances carrier recombination efficiency at the interconnection layer, improves carrier extraction and promotes large-area film uniformity in all-perovskite tandems. As a result, a 65-cm all-perovskite tandem solar module achieves a certified power conversion efficiency of 26.2% (ref. ), with an open-circuit voltage of 2.182 V, a fill factor of 77.4% and a short-circuit current density of 15.6 mA cm-2 in terms of averaged subcell performance, measured by the Japan Electrical Safety and Environment Technology Laboratories. This marks a notable advance towards scalable perovskite tandem photovoltaics.
『摘要』
全钙钛矿叠层太阳能电池组件的商业化因依赖传统的金基隧道复合结而受到阻碍。具体而言，这种隧道复合结会引入大量的近红外寄生吸收，且存在界面不稳定性问题，限制了光电流的产生和运行耐久性。在此，我们开发了一种基于表面工程氧化铟纳米晶体的溶液处理互连层，该互连层具有高光学透明度，其中受控的纳米晶体形态和定制的配体化学可实现光滑的界面接触和有利的能级排列。我们在铅锡钙钛矿前驱体中引入了磷脂酸添加剂，该添加剂协同改善了与氧化铟复合层的电子接触，从而增强了空穴提取。此外，该添加剂可调控钙钛矿结晶过程，减轻薄膜形成过程中的残余应力，确保大面积高质量沉积。这种协同的界面和结晶工程策略同时提高了互连层的载流子复合效率，提高了载流子提取能力，并促进了全钙钛矿叠层太阳能电池组件的大面积薄膜均匀性。因此，一个65平方厘米的全钙钛矿叠层太阳能电池组件经日本电气安全与环境技术实验室测定，基于平均子电池性能，实现了26.2%的认证功率转换效率，开路电压为2.182伏，填充因子为77.4%，短路电流密度为15.6毫安每平方厘米。这标志着可扩展钙钛矿叠层光伏技术取得了显著进展。
『总结』
全钙钛矿叠层太阳能电池组件因依赖传统金基隧道复合结而受限，研究开发了基于表面工程氧化铟纳米晶体的溶液处理互连层，引入磷脂酸添加剂改善电子接触和调控结晶，提高了载流子复合效率和提取能力，促进了大面积薄膜均匀性，实现了显著的技术进展。
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16. 栉水母的原肠胚孔组织者
A blastoporal organizer in a ctenophore
『Abstract』In an iconic experiment in 1924, Hilde Mangold and Hans Spemann established that the dorsal blastopore lip of amphibian embryos functions as an organizer and induces a secondary body axis when transplanted into a host embryo. This discovery demonstrated that specific embryonic regions can regulate embryonic patterning and lead to the establishment of an entire body axis. Subsequent studies have revealed that cnidarians, the sister group to Bilateria, also possess a blastoporal embryonic organizer. However, the evolutionary origin of the organizer remains unclear. Here we report that the blastopore lip of the ctenophore Mnemiopsis leidyi, a member of the evolutionary sister group to all other metazoans, exhibits organizer activity. We show that transplanted fragments of blastopore lip tissue from M. leidyi gastrula induce secondary pharynx and mouth formation. Moreover, transphyletic transplantation experiments show that the blastopore lip of M. leidyi leads to the generation of a secondary body axis in embryos of the cnidarian Nematostella vectensis. Organizer function in M. leidyi requires both β-catenin and TGFβ signalling, and the TGFβ-family ligands probably provide this inductive capacity. These findings reveal the deep homology of the blastoporal organizer in ctenophores, cnidarians and vertebrates, implying the ancestral organizer role of the blastopore lip. We propose that the emergence of the organizer was an essential innovation that facilitated the change from the temporal cell differentiation of unicellular relatives to the spatial cell differentiation of the first multicellular embryo.
『摘要』
1924年的一项标志性实验中，希尔德·曼戈尔德（Hilde Mangold）和汉斯·斯佩曼（Hans Spemann）证实，两栖动物胚胎的背侧胚孔唇可作为组织者，当移植到宿主胚胎中时，可诱导次级体轴的形成。这一发现表明，特定胚胎区域能够调控胚胎模式形成，并促成整个体轴的建立。后续研究揭示，两侧对称动物的姐妹类群——刺胞动物也拥有胚孔胚胎组织者。然而，组织者的进化起源尚不清楚。本研究报告，栉水母Mnemiopsis leidyi（所有其他后生动物的进化姐妹类群成员）的胚孔唇具有组织者活性。研究显示，从M. leidyi原肠胚移植的胚孔唇组织片段可诱导次级咽部和口部形成。此外，跨门类移植实验表明，M. leidyi的胚孔唇可在刺胞动物Nematostella vectensis胚胎中诱导次级体轴的形成。M. leidyi的组织者功能需要β-连环蛋白和TGFβ信号通路，且TGFβ家族配体可能提供了这种诱导能力。这些发现揭示了栉水母、刺胞动物和脊椎动物胚孔组织者的深层同源性，暗示胚孔唇具有祖先性组织者作用。我们提出，组织者的出现是一项关键创新，促进了从单细胞近亲的时序细胞分化到首个多细胞胚胎的空间细胞分化的转变。
『总结』
研究发现栉水母Mnemiopsis leidyi的胚孔唇具有组织者活性，揭示了栉水母、刺胞动物和脊椎动物胚孔组织者的深层同源性，并指出组织者的出现是促进细胞分化方式转变的关键创新。
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17. SIRT7调控剂量补偿并保护雌性X染色体
SIRT7 regulates dosage compensation and safeguards the female X chromosome
『Abstract』Sirtuins are deacetylases implicated in stress responses and longevity in mammals. Although their differential impact on disease for the two sexes has been noted, the underlying reasons are unclear. Here, using Sirt7 as a model in mice, we examine the mechanisms leading to sex differences and find that Sirt7-/- female mice have decreased fitness throughout their lifespan. Notably, SIRT7 preferentially localizes to the sex chromosomes. In female individuals, SIRT7 loss affects X-chromosome inactivation, the first arm of dosage compensation that equalizes X-linked gene expression between males and females. Xist is overexpressed and gene silencing becomes more efficient. However, SIRT7 loss has greatest impact on the active X (Xa) chromosome. The Xa chromosome becomes hyperacetylated at Lys36 of histone H3, structurally disorganized, prone to DNA damage and overexpressed. Increased Xa-chromosome expression leads to genome imbalance and augmented X-chromosome upregulation-the second arm of dosage compensation that balances X-chromosome versus autosomal gene expression. These data reveal an essential crosstalk between sirtuins and the sex chromosomes, with SIRT7 safeguarding X-chromosome integrity and dosage balance with autosomes. We propose that the sex bias in SIRT7 biology can be explained in part by unequal effects on the sex chromosomes.
『摘要』
Sirtuins是一类去乙酰化酶，参与哺乳动物的应激反应和寿命调控。尽管已发现其对两性疾病的影响存在差异，但潜在原因尚不明确。本研究以小鼠Sirt7为模型，探讨导致性别差异的机制，发现Sirt7-/-雌性小鼠在整个生命周期内健康状况下降。值得注意的是，SIRT7优先定位于性染色体。在雌性个体中，SIRT7缺失影响X染色体失活（这是使男女X连锁基因表达相等的剂量补偿的第一条途径），Xist表达上调，基因沉默效率提高。然而，SIRT7缺失对活性X（Xa）染色体的影响最大。Xa染色体组蛋白H3第36位赖氨酸（Lys36）发生超乙酰化，结构紊乱，易受DNA损伤，且表达上调。Xa染色体表达上调导致基因组失衡，并加剧X染色体上调（这是使X染色体与常染色体基因表达相等的剂量补偿的第二条途径）。这些数据揭示了Sirtuins与性染色体之间的关键相互作用，其中SIRT7维护X染色体完整性和与常染色体的剂量平衡。我们提出，SIRT7生物学中的性别差异可部分归因于其对性染色体的影响不均。
『总结』
研究揭示了SIRT7在维护雌性小鼠X染色体完整性和剂量平衡中的关键作用，并解释了SIRT7生物学中的性别差异部分源于其对性染色体的不均等影响。
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18. IDH突变型胶质瘤进展过程中获得的遗传与细胞状态变化
Acquired genetic and cell-state changes in IDH-mutant glioma progression
『Abstract』Gliomas with mutant isocitrate dehydrogenase (IDH) are malignant brain tumours that typically arise in early to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular-state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA and RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumour types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH wild-type glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell-state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were enriched in gliomas that acquired recurrence-associated genetic events. These included treatment-associated hypermutation, increased copy number changes and cell cycle alterations. Second, increased mesenchymal-like-state abundance occurred independently of acquired genetic alterations and instead coincided with elevated macrophage expression. Overall, our findings provide an integrative model that traces the cell intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
『摘要』
异柠檬酸脱氢酶（IDH）突变的胶质瘤是恶性脑肿瘤，通常在成年早期到中期发病，且治疗后几乎总会复发。然而，驱动IDH突变型胶质瘤在治疗过程中进展的遗传和细胞状态变化仍未得到完全阐明。本研究整合了75例来自35名患者的、时间上分离的胶质瘤的单核转录组谱、染色质可及性谱以及批量DNA和RNA测序数据，这些患者涵盖了少突胶质细胞瘤和星形细胞瘤两种IDH突变型胶质瘤类型。我们发现，恶性细胞状态在转录上与正常胶质-神经元谱系发育阶段或反应性间充质样状态相似，与先前在IDH野生型胶质母细胞瘤中描述的状态相呼应。两种IDH突变型胶质瘤的恶性细胞状态均显示出独特的染色质可及性谱。随着肿瘤级别升高和出现如PDGFRA扩增等遗传变异，分化程度较低的恶性细胞数量增加。纵向分析揭示了两种主要的恶性细胞状态转变模式。首先，复发时谱系分化减少和增殖性恶性细胞增加的情况在获得复发相关遗传事件的胶质瘤中更为常见。这些事件包括治疗相关超突变、拷贝数变化增加和细胞周期改变。其次，间充质样状态数量的增加独立于获得的遗传变异，而是与巨噬细胞表达升高同时发生。总体而言，我们的研究结果提供了一个综合模型，该模型追踪了IDH突变型胶质瘤疾病进展过程中塑造细胞状态的细胞内在和外在因素。
『总结』
研究整合了多种数据，揭示了IDH突变型胶质瘤恶性细胞状态与正常细胞发育的相似性，以及两种主要的恶性细胞状态转变模式，为理解其疾病进展提供了综合模型。
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19. 大刍草等位基因可增强玉米氮同化能力及种子蛋白质含量
Teosinte alleles enhance nitrogen assimilation and seed protein in maize
『Abstract』During maize (Zea mays L.) domestication, seed protein content sharply declined. In plants, glutamine and asparagine levels are closely correlated with protein content. Asparagine is synthesized from glutamine, a process catalysed by asparagine synthase. Teosinte harbours a superior haplotype of asparagine synthase 4 (ASN4). Here, we report that teosinte also possesses a superior haplotype gene promoting glutamine synthesis. We identify and clone teosinte high protein 3 (THP3), which encodes glutamate-oxaloacetate transaminase 1 (GOT1), a key enzyme involved in nitrogen assimilation and carbon-nitrogen balance. The superior THP3-T allele, subjected to negative selection during domestication, has natural variations that boost both its expression and enzymatic activity. Overexpressing THP3-T, but not the modern THP3-B allele, significantly increases seed protein, representing altered carbon-nitrogen composition. Pyramiding THP3-T with THP9-T (the latter encoding asparagine synthase 4 (ASN4)) synergistically elevates both seed and whole-plant protein in elite hybrids while maintaining yield. Our findings demonstrate a powerful strategy for crop improvement by reintroducing beneficial rare alleles disfavoured during domestication from wild relatives.
『摘要』
在玉米（Zea mays L.）驯化过程中，种子蛋白质含量急剧下降。在植物中，谷氨酰胺和天冬酰胺水平与蛋白质含量密切相关。天冬酰胺由谷氨酰胺合成，该过程由天冬酰胺合成酶催化。大刍草拥有天冬酰胺合成酶4（ASN4）的优异单倍型。本文报道大刍草还拥有一个促进谷氨酰胺合成的优异单倍型基因。研究鉴定并克隆了大刍草高蛋白3（THP3），该基因编码谷氨酸-草酰乙酸转氨酶1（GOT1），是参与氮同化和碳氮平衡的关键酶。在驯化过程中受到负选择的优异THP3-T等位基因具有自然变异，可增强其表达和酶活性。过表达THP3-T（而非现代THP3-B等位基因）可显著提高种子蛋白质含量，改变碳氮组成。将THP3-T与THP9-T（后者编码天冬酰胺合成酶4（ASN4））叠加，可在保持产量的同时协同提高优良杂交种的种子和全株蛋白质含量。本研究表明，通过从野生近缘种中重新引入驯化过程中被淘汰的有益稀有等位基因，可实现作物改良。
『总结』
研究通过重新引入驯化过程中被淘汰的大刍草有益稀有等位基因THP3-T，实现了玉米种子和全株蛋白质含量的协同提升，为作物改良提供了新策略。
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20. 共生物来源的乙酰胆碱增强黏膜免疫调节
Commensal-derived acetylcholine enhances mucosal immune education
『Abstract』The microbiota produces thousands of potentially bioactive small molecules. High-throughput bioactivity screens of in vitro commensal cultures have exposed microbiota metabolites that shape host physiology by activating diverse G-protein-coupled receptors (GPCRs). However, owing to technical limitations, the GPCRome-wide bioactivities of in vivo metabolomes, which result from complex diet-microorganism-host interactions, remain unclear. Here we used a multiplexed GPCR screening technology to assess GPCRome-wide bioactivities of 100 commensal strains grown in vivo in monoassociated germ-free mice or in vitro in bacterial culture medium. In vivo and in vitro commensal metabolomes exhibited distinct GPCR activation patterns due to (1) host-mediated metabolite degradation; (2) in vivo microbial metabolic reprogramming; and (3) biotransformation of dietary substrates. Notably, we found that multiple commensal strains produced acetylcholine (ACh) in vivo through the conversion of dietary choline, including select Bifidobacterium strains that dominate the microbiome in early life and a probiotic Pediococcus strain. Mechanistically, we identified and characterized the bacterial enzymes that mediate this biotransformation in Bifidobacterium breve and Pediococcus pentosaceus, and generated an isogenic mutant B. breve strain lacking ACh production. Mice colonized with ACh-producing B. breve exhibited enhanced intestinal immunoglobulin A (IgA) production, altered microbiota composition and increased resistance to enteric infection. These findings underscore the profound impacts of the in vivo environment on microbiota metabolism and reveal a diet-microbiome-host axis that strengthens mucosal immune defences and reinforces host-microbiota mutualism.
『摘要』
微生物群会产生数千种潜在具有生物活性的小分子。体外共生菌群培养的高通量生物活性筛选揭示了通过激活多种G蛋白偶联受体（GPCR）来影响宿主生理的微生物群代谢物。然而，由于技术限制，由复杂的饮食-微生物-宿主相互作用产生的体内代谢组的整个GPCR组生物活性仍不清楚。本研究采用多重GPCR筛选技术，评估了在无菌单关联小鼠体内或细菌培养基中体外生长的100种共生菌株的整个GPCR组生物活性。体内和体外共生代谢组表现出不同的GPCR激活模式，原因在于：（1）宿主介导的代谢物降解；（2）体内微生物代谢重编程；（3）饮食底物的生物转化。值得注意的是，研究发现多种共生菌株在体内通过转化饮食中的胆碱产生乙酰胆碱（ACh），包括早期生命中主导微生物组的某些双歧杆菌菌株和一种益生菌片球菌菌株。从机制上讲，研究鉴定并表征了短双歧杆菌和戊糖片球菌中介导这种生物转化的细菌酶，并生成了缺乏ACh产生的同源突变短双歧杆菌菌株。携带产生ACh的短双歧杆菌的小鼠肠道免疫球蛋白A（IgA）产生增强、微生物群组成改变、对肠道感染的抵抗力增加。这些发现强调了体内环境对微生物群代谢的深远影响，并揭示了饮食-微生物组-宿主轴可增强黏膜免疫防御，强化宿主-微生物群互利共生。
『总结』
研究揭示了体内环境对微生物群代谢的显著影响，发现了共生菌株在体内产生乙酰胆碱的新机制，并证实了饮食-微生物组-宿主轴对增强黏膜免疫和宿主-微生物互利共生的重要作用。
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21. 重新设计算法以在国家选举期间干预社会规范误解
Redesigning algorithms to intervene on social norm misperceptions during a national election
『Abstract』For the first time in history, civic discourse commonly occurs in digital environments in which algorithms influence exposure to social information. It is increasingly important to understand whether and how these algorithms affect political discourse. Here we built custom feed-ranking algorithms with full control over their features, and randomly assigned 2,000 participants to use them for 8 weeks (before and after the 2024 US presidential election). We tested whether an engagement-based algorithm (used on major social media platforms) amplifies intergroup, moralized and emotional (IME) information in ways that skew perceptions of social norms around political dialogue, and whether it increased engagement with IME content and perceptions of partisan animosity (compared with a reverse-chronological feed). We also developed and tested a 'diversified extremity' algorithm to reduce the influence of extreme users to improve the accuracy of social norm perception and reduce perceptions of partisan animosity. We found that engagement-based feeds amplified IME and toxic content relative to reverse-chronological feeds, with the largest increases in moral outrage and political content. Engagement-based feeds also reduced prescriptive norm perception accuracy (albeit in an unexpected direction) and increased perceived partisan animosity. However, they did not significantly alter users' own engagement behaviours. The diversified extremity algorithm reduced IME and toxic content exposure, improved prescriptive norm accuracy, yet maintained comparable platform enjoyment-suggesting that reducing the influence of extreme users can curb algorithmic distortions without diminishing user experience.protocol registration The Stage 1 protocol for this Registered Report was accepted in principle on 17 September 2024. The protocol, as accepted by the journal, can be found at https://osf.io/c9a3m .
『摘要』
历史上首次，公民话语普遍存在于算法影响社会信息接触的数字环境中。理解这些算法是否以及如何影响政治话语变得越来越重要。为此，我们构建了可完全控制其特征的定制信息流排序算法，并随机指定2000名参与者在2024年美国总统大选前后使用这些算法8周。我们测试了基于参与度的算法（主要社交媒体平台所使用）是否会以扭曲政治对话社会规范认知的方式放大群体间、道德化和情绪化（IME）信息，以及与按时间倒序排列的信息流相比，它是否会增加对IME内容的参与度和对党派敌意的感知。我们还开发并测试了一种“多样化极端”算法，以减少极端用户的影响，提高社会规范认知的准确性，并减少对党派敌意的感知。我们发现，与按时间倒序排列的信息流相比，基于参与度的信息流放大了IME和有害内容，其中道德愤慨和政治内容的增幅最大。基于参与度的信息流还降低了规范性规范认知的准确性（尽管方向出乎意料），并增加了感知到的党派敌意。然而，它们并未显著改变用户自身的参与行为。“多样化极端”算法减少了IME和有害内容的接触，提高了规范性规范的准确性，同时保持了相当的平台愉悦度，这表明减少极端用户的影响可以抑制算法扭曲，同时不会降低用户体验。方案注册 本注册报告的第一阶段方案于2024年9月17日被期刊原则上接受。经期刊接受的方案可在https://osf.io/c9a3m查阅。
『总结』
本研究通过构建定制算法并测试其影响，发现基于参与度的算法会放大IME和有害内容、降低规范性规范认知准确性并增加党派敌意感知，而“多样化极端”算法可减少这些负面影响且不降低用户体验。
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22. 黑暗与体型塑造了白垩纪末期的海洋灭绝模式
Darkness and body size shaped end-Cretaceous marine extinction patterns
『Abstract』The Chicxulub asteroid impact at the Cretaceous-Paleogene (K-Pg) boundary (66 Ma) is thought to have caused the extinction of around 75% of species in the fossil record by triggering catastrophic environmental changes. However, despite decades of research, the mechanisms linking the environmental changes to the selective extinction patterns observed in the marine fossil record remain unresolved. Here we use a global trait-based ecosystem model to establish this causality for the marine plankton community beyond the fossilized groups. Our model simulates diversity dynamics during the initial 100 years after the K-Pg boundary and represents explicitly extinction based on biomass thresholds that scales with body size. Under K-Pg climatic forcings, the model reproduces successfully key observed extinction patterns, including the high vulnerability of planktic foraminifera and other zooplankton, the survival of small mixotrophs and phytoplankton, and potential for reduced diversity loss in high-latitude settings. Our analysis suggests that impact-driven darkness and body-size-dependent extinction thresholds drove most of the observed extinction patterns. These results suggest that plankton ecologies enhance survival through differences in energy demand and acquisition. Our study bridges the gap between fossil evidence of extinction patterns and the K-Pg impact winter hypothesis, highlighting the value of trait-based models for understanding past biodiversity crises.
『摘要』
白垩纪-古近纪（K-Pg）界线（6600万年前）的希克苏鲁伯小行星撞击事件被认为引发了灾难性的环境变化，导致化石记录中约75%的物种灭绝。然而，尽管经过数十年的研究，将环境变化与海洋化石记录中观察到的选择性灭绝模式联系起来的机制仍未得到解决。本研究采用基于全球性状的生态系统模型，针对化石记录以外的海洋浮游生物群落，建立了这种因果关系。该模型模拟了K-Pg界线之后最初100年的多样性动态，并基于与体型相关的生物量阈值明确表示灭绝。在K-Pg气候强迫下，该模型成功再现了观察到的关键灭绝模式，包括浮游有孔虫和其他浮游动物的易灭绝性、小型混合营养生物和浮游植物的存活，以及高纬度地区多样性损失可能减少的情况。分析表明，撞击引发的黑暗和与体型相关的灭绝阈值是导致观察到的灭绝模式的主要原因。研究结果表明，浮游生物通过能量需求和获取方式的差异来提高生存能力。本研究弥合了灭绝模式的化石证据与K-Pg撞击冬季假说之间的差距，突出了基于性状的模型在理解过去生物多样性危机中的价值。
『总结』
研究采用全球性状生态系统模型，揭示了K-Pg小行星撞击事件引发的环境变化与海洋浮游生物灭绝模式之间的因果关系，强调了基于性状的模型对理解过去生物多样性危机的价值。
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23. 619,372名个体循环代谢特征的遗传分析
Genetic analysis of circulating metabolic traits in 619,372 individuals
『Abstract』Interpreting the association of genetic variants with complex traits can be improved by gaining a greater understanding of the molecular consequences of these variants. Although genome-wide association studies (GWAS) for complex diseases routinely profile over one million individuals, studies of molecular traits have lagged behind. Here we performed a GWAS meta-analysis for 249 circulating metabolic traits in the Estonian Biobank and the UK Biobank in up to 619,372 individuals. We identified 88,127 common and low-frequency locus-trait associations from 8,398 loci that converged on shared genes and pathways. Using statistical fine mapping, systematic phenome-wide colocalization and cis-Mendelian randomization, we explored putative causal links between metabolic traits and disease outcomes. We predict that although plasma branched-chain amino acids (BCAAs) have been associated with type 2 diabetes in observational studies, lowering BCAA levels by targeting the BCAA catabolism pathway is unlikely to reduce type 2 diabetes risk. Leveraging our large sample size and high-quality genotype imputation, we found that 19.4% of the confidently fine-mapped variants had minor allele frequencies between 0.1 and 1%, and these variants were twofold enriched for predicted missense and splice-altering variants. Our results highlight the value of integrating low-frequency variants into genetic association studies.
『摘要』
通过更深入地了解这些遗传变异的分子后果，可以更好地阐释遗传变异与复杂性状之间的关联。尽管针对复杂疾病的全基因组关联研究（GWAS）通常会涉及超过一百万人的样本，但针对分子性状的此类研究却相对滞后。本研究在爱沙尼亚生物银行和英国生物银行中针对多达619,372名个体的249种循环代谢性状进行了GWAS荟萃分析。我们从8398个位点中确定了88,127个常见和低频位点-性状关联，这些关联集中在共享基因和通路上。利用统计精细定位、系统性表型组共定位和顺式孟德尔随机化方法，我们探究了代谢性状与疾病结局之间的潜在因果关系。我们预测，尽管观察性研究显示血浆支链氨基酸（BCAAs）与2型糖尿病相关，但通过靶向BCAA分解代谢途径降低BCAA水平不太可能降低2型糖尿病风险。借助大样本量和高质量的基因型推断，我们发现19.4%的精细定位变异体的次要等位基因频率在0.1%至1%之间，且这些变异体中预测的错义和剪接改变变异体富集了两倍。我们的研究结果强调了将低频变异纳入遗传关联研究的重要性。
『总结』
研究通过对爱沙尼亚和英国生物银行的大样本数据进行GWAS荟萃分析，揭示了代谢性状与疾病间的潜在因果关系，并强调了低频变异在遗传研究中的重要性。
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24. 线粒体L-2-羟基戊二酸是一种生理信号代谢物
Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite
『Abstract』L-2-Hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals because the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH) oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation. In humans, a lack of L2HGDH activity leads to L-2-HG accumulation and causes L-2-hydroxyglutaric aciduria. Thus, L-2-HG is often classified as a toxic metabolite. However, whether L-2-HG has any physiological function is unclear. Here we investigate whether L-2-HG qualifies as a physiological signalling metabolite by testing three criteria: regulated levels, defined molecular targets and a measurable physiological function. We report that an increase in mitochondrial NADH/NAD+ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-OG into L-2-HG. Moreover, L2HGDH oxidizes L-2-HG back to 2-OG in the mitochondrial matrix without requiring a functional electron transport chain. Through proteome integral solubility alteration assays, we show that the KDM4 family of H3K9 demethylases are L-2-HG-responsive targets. L-2-HG represses the nascent transcription of specific genes in mouse embryonic stem cells and increases H3K9me3 (a repressive histone mark) at these loci. In vivo, early embryonic L2HGDH overexpression in mice systemically reduces L-2-HG levels, impairs postnatal growth, causes mortality and produces selective functional and histological renal vulnerabilities. In postnatal kidneys, this reduction in L-2-HG causes H3K9me3 loss at L1MdTf retrotransposons and their derepression, which coincides with the activation of the integrated stress response and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiological signalling metabolite and indicate that metabolites previously regarded as toxic may also have crucial physiological functions.
『摘要』
L-2-羟基戊二酸（L-2-HG）在哺乳动物体内是一种低丰度的代谢物，因为线粒体酶L-2-HG脱氢酶（L2HGDH）会将L-2-HG氧化为2-酮戊二酸（2-OG），以防止其积累。在人类中，L2HGDH活性缺乏会导致L-2-HG积累，引发L-2-羟基戊二酸尿症。因此，L-2-HG常被归类为有毒代谢物。然而，L-2-HG是否具有任何生理功能尚不清楚。本研究通过测试三个标准——调控水平、明确的分子靶点和可测量的生理功能，探究L-2-HG是否具备作为生理信号代谢物的资格。研究发现，线粒体NADH/NAD+比值的升高会驱动苹果酸脱氢酶2（MDH2）将2-OG还原为L-2-HG。此外，L2HGDH无需功能性电子传递链即可在线粒体基质中将L-2-HG氧化回2-OG。通过蛋白质组整体溶解度改变实验，我们证实H3K9去甲基化酶KDM4家族是L-2-HG的响应靶点。L-2-HG抑制小鼠胚胎干细胞中特定基因的新生转录，并增加这些基因位点的H3K9me3（一种抑制性组蛋白标记）。在体内，小鼠早期胚胎中L2HGDH的过表达会系统性降低L-2-HG水平，阻碍出生后生长，导致死亡，并产生选择性的功能和组织学肾脏脆弱性。在出生后肾脏中，L-2-HG的减少导致L1MdTf逆转录转座子处H3K9me3的丢失及其去抑制，这与整合应激反应和炎症通路的激活同时发生。我们的研究结果确立了线粒体L-2-HG作为一种生理信号代谢物的地位，并表明先前被认为有毒的代谢物也可能具有关键的生理功能。
『总结』
研究证实线粒体L-2-HG是生理信号代谢物，具有调控基因表达和组蛋白修饰的功能，并表明先前被认为有毒的代谢物也可能具有关键的生理功能。
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25. 深度学习框架揭示细胞层面的全身性扰动
A deep-learning framework reveals whole-body perturbations at cell level
『Abstract』Many diseases, including obesity, have systemic effects that perturb multiple organ systems throughout the body. However, tools for comprehensive, high-resolution analysis of disease-associated changes at the whole-body scale have been lacking. Here we developed MouseMapper, a suite of foundation-model-based deep-learning algorithms enabling multi-system analysis of disease across the entire mouse body. MouseMapper enables whole-body quantitative analysis of nerves and immune cells, resolving fine axonal branches and immune-cell clusters while automatically segmenting 31 organs and tissues. We used MouseMapper to study diet-induced obesity, and identified structural alterations of the infraorbital branch of the trigeminal ganglia. This structural impairment in infraorbital nerves was associated with functional sensory deficits in whisker sensing. Furthermore, we identified proteomic changes in the trigeminal ganglion affecting axon remodelling and complement pathways both in mice and humans. MouseMapper also generated detailed three-dimensional inflammation maps by characterizing immune cell cluster compositions across tissues. The MouseMapper framework demonstrates robust generalizability across different imaging resolutions and datasets. Our study provides a powerful, scalable approach for identifying and quantifying systemic pathologies, bridging molecular insights from animal models to human conditions.
『摘要』
包括肥胖在内的许多疾病具有系统性影响，会扰乱全身多个器官系统。然而，目前缺乏在全身范围内对疾病相关变化进行全面、高分辨率分析的工具。为此，我们开发了MouseMapper，这是一套基于基础模型的深度学习算法，可对整个小鼠身体进行多系统疾病分析。MouseMapper能够对神经和免疫细胞进行全身定量分析，解析精细的轴突分支和免疫细胞簇，同时自动分割31个器官和组织。我们利用MouseMapper研究饮食诱导的肥胖，并发现了三叉神经节眶下支的结构改变。眶下神经的这种结构损伤与触须感觉的功能性感觉缺陷有关。此外，我们在小鼠和人类中均发现三叉神经节中影响轴突重塑和补体通路的蛋白质组变化。MouseMapper还通过表征各组织中的免疫细胞簇组成，生成了详细的三维炎症图谱。MouseMapper框架在不同成像分辨率和数据集中均表现出强大的泛化能力。我们的研究提供了一种强大且可扩展的方法，用于识别和量化全身性病理，将动物模型的分子见解与人类疾病联系起来。
『总结』
研究开发了名为MouseMapper的深度学习算法工具，可对小鼠全身进行多系统疾病分析，在研究饮食诱导的肥胖时发现相关结构改变、蛋白质组变化及生成炎症图谱，且该工具具有强大泛化能力，为识别和量化全身性病理提供方法。
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26. 鸣唱学习的突触位点
A synaptic locus of song learning
『Abstract』Learning by imitation is the foundation for verbal and musical expression, but its neural basis remains unclear. A juvenile male zebra finch imitates the multisyllabic song of an adult tutor in a process that depends on a song-specialized cortico-basal ganglia circuit, affording a powerful system to identify the synaptic substrates of imitative motor learning. Plasticity at a particular set of cortico-basal ganglia synapses is hypothesized to drive rapid learning-related changes in song before these changes are subsequently consolidated in downstream circuits. Nevertheless, this hypothesis is untested and the synaptic locus where learning initially occurs is unclear. Here, by combining a computational framework to quantify song learning with synapse-specific optogenetic and chemogenetic manipulations within and downstream of the cortico-basal ganglia circuit, we identified the specific cortico-basal ganglia synapses that drive the acquisition and expression of rapid vocal changes during juvenile song learning and characterized the hours-long timescale over which these changes consolidate. Furthermore, transiently augmenting postsynaptic activity in the basal ganglia briefly accelerates learning rates and persistently alters song, demonstrating a direct link between basal ganglia activity and rapid learning. These results localize the specific cortico-basal ganglia synapses that enable a juvenile songbird to learn to sing and reveal the circuit logic and behavioural timescales of this imitative learning paradigm.
『摘要』
通过模仿进行学习是语言和音乐表达的基础，但其神经基础仍不明确。幼年雄性斑胸草雀通过模仿成年导师的多音节歌声来学习，这一过程依赖于专门用于歌曲处理的皮质-基底神经节回路，为确定模仿性运动学习的突触基质提供了强大的系统。有人假设，皮质-基底神经节特定突触的可塑性会驱动歌声中与快速学习相关的变化，随后这些变化会在下游回路中得到巩固。然而，这一假设尚未得到验证，且最初发生学习的突触位点尚不明确。本研究结合计算框架来量化歌曲学习，并利用皮质-基底神经节回路内部及下游的突触特异性光遗传学和化学遗传学操控技术，确定了在幼鸟歌曲学习过程中驱动快速发声变化获取和表达的具体皮质-基底神经节突触，并描述了这些变化得以巩固的数小时时间尺度。此外，短暂增强基底神经节突触后活动可短暂加快学习速度并持久改变歌声，这表明基底神经节活动与快速学习之间存在直接联系。这些结果确定了幼鸟鸣禽学会唱歌的具体皮质-基底神经节突触，并揭示了这种模仿性学习范式的回路逻辑和行为时间尺度。
『总结』
研究确定了幼年斑胸草雀在歌曲学习过程中驱动快速发声变化的具体皮质-基底神经节突触，揭示了模仿性学习范式的回路逻辑和行为时间尺度。
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27. 生物神经网络的关键初始化
A critical initialization for biological neural networks
『Abstract』Intrinsically generated, brainwide neural activity displays macroscopic coordination among large populations of neurons that persists beyond the biophysical timescales of individual neurons. It is not well understood how these macroscopic behaviours arise from microscopic, short-lived interactions between pairs of neurons. Here we show that the eigenvalue spectrum and dynamical properties of large-scale neural recordings in mice are similar to those produced by linear dynamics governed by a random symmetric matrix that is critically normalized. An exception was population activity in hippocampal area CA1, which resembled an efficient, uncorrelated neural code that may be optimized for information storage capacity. High-dimensional, global activity modes emerged in critically normalized artificial networks and persisted under sparse, clustered or spatial connectivity. These dynamics were useful for solving time-dependent tasks such as a zero-shot working memory task.
『摘要』
在大脑内部自发产生的、全脑范围的神经活动显示出，在大量神经元群体中存在超越单个神经元生物物理时间尺度的宏观协调。目前尚不清楚这些宏观行为是如何从成对神经元之间的微观、短暂相互作用中产生的。本研究表明，小鼠大规模神经记录的特征值谱和动力学特性与由临界归一化的随机对称矩阵控制的线性动力学所产生的特征值谱和动力学特性相似。海马体CA1区的群体活动是个例外，其类似于高效、无相关的神经编码，可能针对信息存储容量进行了优化。在临界归一化的人工网络中出现了高维全局活动模式，并且在稀疏、聚类或空间连接的情况下仍能持续存在。这些动力学特性有助于解决与时间相关的任务，如零样本工作记忆任务。
『总结』
研究揭示小鼠大规模神经活动特性与临界归一化随机对称矩阵控制的线性动力学相似，海马体CA1区群体活动除外，且临界归一化人工网络中的高维全局活动模式对解决时间相关任务有帮助。
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28. 人类生命周期白质微观与宏观结构脑图谱
White matter micro- and macrostructure brain charts for the human lifespan
『Abstract』The human brain relies on a complex network of connections to function, with white matter acting as the primary communication highway between different brain regions. Disruptions in these critical communication pathways are linked to several neurological, psychiatric and developmental disorders. Although clinicians have long used standard growth charts to track physical development, with more recent work translating these to whole-brain and grey matter measurements, there has been no equivalent reference standard for white matter. Establishing a readily available normative reference is an imperative first step if we hope to utilize these white matter structural biomarkers clinically. Here we present lifespan reference charts for human brain white matter. By processing and standardizing 35,120 brain scans from diverse global studies, we mapped the typical growth, maturation and age-related decline of specific brain pathways from birth to 100 years of age. These reference charts establish a fundamental benchmark for healthy brain development and ageing, allowing researchers and clinicians to quantify how an individual's brain deviates from typical patterns and highlighting disorder-related alterations. Furthermore, the accompanying open access charts enable the scientific and clinical communities to evaluate new patient and research data against these normative baselines, facilitating future clinical and neuroscience studies.
『摘要』
人类大脑依赖复杂的连接网络来运作，其中白质是不同脑区之间主要的通信通道。这些关键通信路径的中断与多种神经、精神和发展障碍有关。尽管临床医生长期以来一直使用标准生长图表来跟踪身体发育情况，并且近期也有研究将这些图表转化为全脑和灰质测量数据，但目前还没有针对白质的等效参考标准。如果希望在临床上利用这些白质结构生物标志物，建立一个现成可用的规范性参考是首要步骤。在此，我们展示了人类大脑白质的生命周期参考图表。通过对来自全球不同研究的35120份脑部扫描进行处理和标准化，我们绘制了从出生到100岁特定脑通路典型生长、成熟和与年龄相关的衰退情况。这些参考图表为健康的大脑发育和衰老建立了基本基准，使研究人员和临床医生能够量化个体大脑与典型模式的偏差，并突出与障碍相关的变化。此外，随附的开放获取图表使科学和临床界能够根据这些规范性基准评估新的患者和研究数据，为未来的临床和神经科学研究提供便利。
『总结』
研究展示了人类大脑白质的生命周期参考图表，为大脑健康发育和衰老提供基准，有助于评估个体大脑与典型模式的差异并推动临床和神经科学研究。
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29. 全新世期间语言多样性的兴衰
The rise and fall of language diversity through the Holocene
『Abstract』Characterizing the factors that have shaped linguistic diversity is fundamental for understanding human history, culture, and cognition. In this study, we combined statistical and social computational modeling, ethnographic data, and paleodemographic inference to model trajectories of global linguistic diversity. Before the onset of plant and animal domestication, the number of languages was smaller than it is today (4500 to 6000 compared with 7500). Subsequent increases in global population precipitated increased linguistic diversity. We uncovered a linguistic "golden age" with tens of thousands of languages 3000 to 1000 years ago. Great loss of linguistic diversity did not begin with recent colonial expansion but as multinational empires first spread along with their languages, pathogens, and cultures. Thus, extinction has likely played a much greater role in shaping linguistic and cultural diversity than previously thought.
『摘要』
确定影响语言多样性的因素，对于理解人类历史、文化和认知至关重要。本研究结合统计与社会计算建模、民族志数据及古人口统计学推断，对全球语言多样性的演变轨迹进行建模。在动植物驯化开始之前，语言数量少于现今（4500至6000种，而现今为7500种）。随后全球人口的增长促进了语言多样性的增加。我们发现了3000至1000年前存在一个拥有数万种语言的“语言黄金时代”。语言多样性的大幅减少并非始于近期的殖民扩张，而是随着跨国帝国的首次扩张及其语言、病原体和文化的传播而开始的。因此，灭绝在塑造语言和文化多样性方面所起的作用可能比之前认为的要大得多。
『总结』
该研究通过多学科方法建模全球语言多样性演变，发现语言数量随人口增长而增加，存在“语言黄金时代”，且语言多样性减少早于殖民扩张，灭绝作用被低估。
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30. 雀形目鸟类鸣唱的全世界生物地理学研究
The global biogeography of passerine songs
『Abstract』Although bird songs are classic models for understanding the evolution of vocal communication, their global diversity has long made the development of a unifying framework challenging. By analyzing the acoustic architecture of songs from more than 3000 passerine species worldwide, we show that this acoustic space can be structured around eight elemental motifs. The differential use of these motifs is driven by a combination of species' biological traits (social organization, morphology, and mating system) and the physics of sound propagation. In tropical rainforests, environmental filtering for transmission efficiency favors structurally simple motifs, such as flat whistles. Conversely, in temperate regions, where high population densities facilitate close-range communication and short breeding seasons intensify sexual selection, the balance shifts toward complex, information-rich motifs, such as ultrafast trills, despite their susceptibility to acoustic degradation. Ultimately, the global geography of birdsong reflects a spatially varying equilibrium between physical environmental constraints and the biological drive for complex communication.
『摘要』
虽然鸟鸣是理解发声交流进化的经典模型，但因其全球多样性，长期以来建立统一框架颇具挑战性。通过对全球3000多种雀形目鸟类鸣声的声学结构进行分析，我们发现这一声学空间可围绕八个基本音型构建。这些音型的差异使用由物种的生物学特征（社会结构、形态和交配系统）以及声音传播的物理特性共同驱动。在热带雨林中，环境对传播效率的筛选作用有利于结构简单的音型，如平调口哨声。相反，在温带地区，高人口密度促进了近距离交流，短暂的繁殖季节加剧了性选择，尽管复杂、信息丰富的音型（如超快颤音）易受声学衰减影响，但这种平衡仍倾向于选择此类音型。最终，鸟鸣的全球地理分布反映了物理环境限制与生物对复杂交流需求之间的空间动态平衡。
『总结』
全球雀形目鸟类鸣声的声学结构可归纳为八个基本音型，其差异使用受物种生物学特征和声音传播物理特性共同影响，不同环境下的选择压力导致音型复杂度呈现地理差异，最终形成物理限制与生物交流需求之间的动态平衡。
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31. 单细胞多组学揭示阿尔茨海默病中3D基因组与转录组的变化关联
Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer's disease
『Abstract』Alzheimer's disease (AD) disrupts brain function through cell type-specific transcriptomic and epigenomic alterations, yet the contribution of three-dimensional (3D) genome organization to AD remains poorly understood. We applied GAGE-seq (genome architecture and gene expression by sequencing) to jointly profile gene expression and 3D chromatin structure in single cells from postmortem brain tissue from AD patients and age-matched individuals without AD, revealing chromatin reorganization linked to cell type-specific dysregulation. Integrations with spatial transcriptomics and chromatin accessibility data uncovered altered niches reflecting genome compartment remodeling and regulatory element reorganization. Hicformer, a deep learning framework, showed that 3D genome features are essential for predicting disease-relevant, cell type-specific gene expression changes. Our results establish higher-order chromatin alterations as a component of AD-associated molecular pathology, providing a multiscale view of transcriptional regulation and 3D genome organization in neurodegeneration.
『摘要』
阿尔茨海默病（AD）通过细胞类型特异性转录组和表观基因组改变破坏大脑功能，但三维（3D）基因组组织对阿尔茨海默病的贡献仍知之甚少。我们应用GAGE-seq（通过测序分析基因组结构与基因表达）技术，对阿尔茨海默病患者和年龄匹配的非阿尔茨海默病患者的死后脑组织单细胞中的基因表达和三维染色质结构进行联合分析，揭示了与细胞类型特异性失调相关的染色质重组。与空间转录组学和染色质可及性数据的整合揭示了反映基因组区室重塑和调控元件重组的改变的细胞微环境。深度学习框架Hicformer表明，3D基因组特征对于预测与疾病相关的细胞类型特异性基因表达变化至关重要。我们的研究结果证实了高阶染色质改变是阿尔茨海默病相关分子病理学的一个组成部分，为神经退行性变中的转录调控和三维基因组组织提供了多尺度视角。
『总结』
研究利用GAGE-seq技术分析阿尔茨海默病患者及非患者脑组织单细胞，揭示了三维基因组组织对阿尔茨海默病的影响，证实了高阶染色质改变是阿尔茨海默病相关分子病理学的一个组成部分。
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32. 单细胞多组学与染色质结构揭示心力衰竭中的基因调控动态
Single-cell multiomics and chromatin structure reveal gene-regulatory dynamics in heart failure
『Abstract』Heart failure is a leading cause of morbidity and mortality, yet gene-regulatory mechanisms driving cell type-specific pathologic responses remain undefined. Here, we present the cell type-resolved transcriptomes, chromatin accessibility, histone modifications, and chromatin organization of 13 nonfailing and 23 failing human hearts across all cardiac chambers. Integrative analyses revealed dynamic changes in cell type composition, gene-regulatory programs, and chromatin organization, particularly in cardiomyocytes and fibroblasts. Mapping cell type-specific enhancer-gene interactions from these analyses enabled the illumination of likely causal genetic contributors to heart failure from genetic association data. Together, these findings provide multimodal gene-regulatory maps of the human heart in health and disease, offering a framework for designing precise, cell type-targeted therapies for treating heart failure.
『摘要』
心力衰竭是导致发病率和死亡率的主要原因，然而驱动细胞类型特异性病理反应的基因调控机制仍未明确。在此，我们展示了来自所有心腔的13个非衰竭和23个衰竭人类心脏的细胞类型分辨转录组、染色质可及性、组蛋白修饰和染色质组织。综合分析揭示了细胞类型组成、基因调控程序和染色质组织的动态变化，特别是在心肌细胞和成纤维细胞中。通过这些分析绘制细胞类型特异性增强子-基因相互作用图，能够从遗传关联数据中阐明可能导致心力衰竭的遗传因素。这些发现共同提供了健康和患病状态下人类心脏的多模式基因调控图谱，为设计治疗心力衰竭的精确细胞靶向疗法提供了框架。
『总结』
研究揭示了健康和衰竭人类心脏的多模式基因调控图谱及动态变化，为设计治疗心力衰竭的精准细胞靶向疗法提供了框架。
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33. 单分子反应锥体的空间分辨
Spatially resolving the cone of reaction for a single molecule
『Abstract』Collisions of atoms and molecules are required for bond formation and are thus key to any chemical reaction. Their outcome is determined by the collision energy, relative orientation, and impact parameter of the reactants. Collision studies in the gas phase have shown that energies are easily controlled, whereas it is difficult to steer the molecular orientations and completely impossible to control the impact parameter. Here, we study the collision of individual molecules at a surface where each involved compound is imaged before and after collision by scanning tunneling microscopy, allowing precise control of orientations and impact parameter. We observe that the molecules must collide in a narrow cone of reaction and that surface atom displacements can enable a reaction even for disfavored pathways.
『摘要』
原子和分子的碰撞是形成化学键的必要条件，因此是任何化学反应的关键。其碰撞结果由反应物的碰撞能量、相对取向和碰撞参数决定。气相中的碰撞研究表明，能量易于控制，但难以控制分子取向，且完全无法控制碰撞参数。本研究通过扫描隧道显微镜对单个分子在表面碰撞前后的状态进行成像，实现了对分子取向和碰撞参数的精确控制。研究发现，分子必须在狭窄的反应锥内碰撞才能发生反应，且表面原子的位移可使原本不利的反应路径得以实现。
『总结』
研究通过扫描隧道显微镜精确控制分子碰撞的取向和参数，揭示了反应锥和表面原子位移对化学反应的关键作用。
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34. 人类扁桃体三维基因组图谱及环挤出作用在B细胞体细胞高频突变中的角色
A 3D genome atlas of human tonsil and the role of loop extrusion in B cell somatic hypermutation
『Abstract』B cell maturation within the germinal center tissue microenvironment involves immunoglobulin gene diversification by somatic hypermutation (SHM). How three-dimensional (3D) genome architecture influences SHM is not fully understood. We leveraged sequencing-based and image-based 3D genomics and transcriptomics to map single-cell 3D genome organization and gene expression across cell types and states in human tonsils and in B cell lymphoma cell lines. These analyses revealed trajectories of compartment, looping, and nuclear position changes during the B cell immune response and activation of SHM. Targeted protein degradation of cohesin component RAD21 revealed its contribution to enabling SHM. Our results provide a single-cell 3D genome atlas of human tonsil cells and outline the links between the chromatin loop extrusion machinery and SHM.
『摘要』
生发中心组织微环境中B细胞的成熟涉及通过体细胞超突变（SHM）进行的免疫球蛋白基因多样化。三维（3D）基因组结构如何影响SHM尚未完全明确。我们利用基于测序和基于图像的3D基因组学和转录组学，绘制了人类扁桃体和B细胞淋巴瘤细胞系中不同细胞类型和状态的细胞单细胞3D基因组组织及基因表达图谱。这些分析揭示了B细胞免疫反应和SHM激活过程中区室、环化和核位置变化的轨迹。通过靶向降解黏连蛋白成分RAD21，揭示了其对SHM的促进作用。我们的研究结果提供了人类扁桃体细胞的单细胞3D基因组图谱，并概述了染色质环挤出机制与SHM之间的联系。
『总结』
本研究利用3D基因组学和转录组学绘制了人类扁桃体和B细胞淋巴瘤细胞系的单细胞3D基因组图谱，揭示了B细胞免疫反应和SHM激活过程中基因组结构的变化，并通过靶向降解RAD21证实了其对SHM的促进作用，同时概述了染色质环挤出机制与SHM之间的联系。
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35. 人类三维染色质对与心脏病相关转录因子的剂量依赖性敏感性
Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease-linked transcription factor
『Abstract』Dosage-sensitive transcription factors (TFs) underlie altered gene regulation in human developmental disorders, and cell type-specific gene regulation is linked to the reorganization of three-dimensional (3D) chromatin during cellular differentiation. In this work, we show dose-dependent regulation of chromatin organization by the congenital heart disease (CHD)-linked, lineage-restricted TF TBX5 in human cardiomyocyte differentiation. Genome organization, including compartments, topologically associated domains, and chromatin loops, was sensitive to reduced TBX5 dosage in a human model of CHD, with variations in response across individual cells. Cohesin binding was reduced at TBX5-bound enhancer elements in a TBX5 dose-dependent manner, providing a potential mechanism for disrupted loop formation. These results highlight the importance of lineage-restricted TF dosage in cell type-specific 3D chromatin dynamics, suggesting a mechanism for TF-dependent disease.
『摘要』
剂量敏感转录因子（TFs）是人类发育障碍中基因调控改变的基础，细胞类型特异性基因调控与细胞分化过程中三维（3D）染色质的重组有关。本研究表明，在人类心肌细胞分化过程中，与先天性心脏病（CHD）相关、谱系限制性转录因子TBX5以剂量依赖性方式调控染色质组织。在CHD的人类模型中，包括区域、拓扑关联结构域和染色质环在内的基因组组织对TBX5剂量减少敏感，且单个细胞的反应存在差异。TBX5剂量依赖性地降低了其在TBX5结合增强子元件上的粘连蛋白结合，这为环形成受阻提供了潜在机制。这些结果强调了谱系限制性转录因子剂量在细胞类型特异性三维染色质动力学中的重要性，提示了一种转录因子依赖性疾病的机制。
『总结』
研究表明与先天性心脏病相关的转录因子TBX5以剂量依赖性方式调控人类心肌细胞分化中的染色质组织，强调了谱系限制性转录因子剂量在细胞类型特异性三维染色质动力学中的重要性，并提示了转录因子依赖性疾病的机制。
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36. 人类机体三维基因组组织与DNA甲基化的单细胞图谱
Human body single-cell atlas of three-dimensional genome organization and DNA methylation
『Abstract』Higher-order chromatin structure and DNA methylation are critical for gene regulation, but how these vary across the human body remains unclear. We performed multiomic profiling of three-dimensional (3D) genome structure and DNA methylation for 86,689 single nuclei across 16 tissues, identifying 35 major and 206 cell subtypes. We revealed extensive changes in CG and non-CG methylation across cell types and characterized 3D chromatin structure at an unprecedented cellular resolution. Extensive discrepancies exist between cell types delineated by DNA methylation and genome structure, which indicates that the role of distinct epigenomic features in maintaining cell identity may vary by lineage. This study expands our understanding of the diversity of DNA methylation and chromatin structure and offers a reference for exploring gene regulation in human health and disease.
『摘要』
高级染色质结构和DNA甲基化对基因调控至关重要，但这些特征在人体各部位如何变化仍不明确。我们对来自16种组织的86,689个单细胞核进行了三维（3D）基因组结构和DNA甲基化的多组学分析，鉴定出35种主要细胞类型和206种细胞亚型。我们揭示了不同细胞类型间CG和非CG甲基化的广泛变化，并以前所未有的细胞分辨率刻画了三维染色质结构。通过DNA甲基化和基因组结构划分的细胞类型之间存在广泛差异，这表明不同表观基因组特征在维持细胞身份中的作用可能因谱系而异。该研究拓展了我们对DNA甲基化和染色质结构多样性的认识，为探索人类健康与疾病中的基因调控提供了参考。
『总结』
该研究通过单细胞多组学分析揭示了人体16种组织中DNA甲基化和三维染色质结构的细胞类型特异性变化，发现不同表观遗传特征在维持细胞身份中的作用具有谱系依赖性，为基因调控研究提供了新视角。
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37. 抗压气囊使昆虫幼虫能够在极端深度的水生栖息地生存
Crush-resistant air sacs allow insect larvae to exploit aquatic habitats at extreme depth
『Abstract』The absence of aquatic insects from pelagic marine habitats has been attributed to their air-filled tracheal respiratory system, which could implode at depth while undertaking diel vertical migrations to escape predatory fish. However, we found that the aquatic larvae of the lake fly Chaoborus edulis in Lake Malawi have modified their tracheal system into reinforced buoyancy-regulating air-filled sacs, allowing them to escape predatory fish by undertaking these migrations well over 200 meters deep into the lake's anoxic hypolimnion during the day. The crush depth of their air sacs increases with each instar, with final instars resisting implosion at depths greater than half a kilometer. Contrary to expectations, these insects adapt to the extreme hydrostatic pressures of deep-water habitats, allowing them to coexist with pelagic fish.
『摘要』
人们认为远洋海洋栖息地没有水生昆虫，是因为它们充满空气的气管呼吸系统在进行昼夜垂直迁徙以躲避捕食性鱼类时，可能会在深处破裂。然而，我们发现马拉维湖中的湖蝇幼虫Chaoborus edulis已经将其气管系统改造成加固的、可调节浮力的充气囊，使它们能够在白天深入湖中超过200米的缺氧底层，从而躲避捕食性鱼类。它们的气囊抗压深度随龄期增加而增加，末龄幼虫在超过半公里深的水下也不会破裂。与预期相反，这些昆虫适应了深水栖息地的极端流体静压力，得以与远洋鱼类共存。
『总结』
湖蝇幼虫Chaoborus edulis通过改造气管系统为加固充气囊，适应了深水高压环境，实现了与远洋鱼类的共存。
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38. 阶梯形貌引导的菱方石墨烯生长
Step geometry-guided growth of rhombohedral graphene
『Abstract』Rhombohedral (ABC)-stacked graphene has emerged as a platform for exploring correlated and topological physics. However, its large-scale, pure-phase synthesis has been hindered by intrinsic thermodynamic metastability and kinetic instability. In this work, we introduce a step geometry-guided epitaxial strategy to deterministically control interlayer slip, enabling the synthesis of pure-phase rhombohedral graphene. Using this approach, we obtained pure (phase purity > 99%) rhombohedral graphene with an area reaching 160 micrometers by 80 micrometers and thickness ranging from ~15 layers to ~120 nanometers. The resulting samples establish the first comprehensive reference dataset of Raman fingerprints and intrinsic band structures from few-layer films to ~200-layer bulk. Electronic transport measurements reveal a layer-antiferromagnetic state and the quantum anomalous Hall effect, enabling scalable exploration of next-generation quantum science and technology applications.
『摘要』
菱方（ABC）堆叠石墨烯已成为探索关联物理和拓扑物理的平台。然而，其大规模纯相合成受到内在热力学亚稳性和动力学不稳定性的阻碍。在本工作中，我们引入了一种台阶几何引导外延策略，确定性地控制层间滑移，从而实现纯相菱方石墨烯的合成。利用这种方法，我们获得了纯度（相纯度 > 99%）的菱方石墨烯，面积达160微米乘80微米，厚度从约15层到约120纳米不等。所得样品建立了从少层薄膜到约200层块体的拉曼指纹和本征能带结构的首个综合参考数据集。电子输运测量揭示了层反铁磁态和量子反常霍尔效应，为下一代量子科学和技术应用的可扩展探索提供了可能。
『总结』
研究提出台阶几何引导外延策略合成出大面积纯相菱方石墨烯，建立了拉曼指纹和本征能带结构参考数据集，且电子输运测量揭示了层反铁磁态和量子反常霍尔效应。
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39. 入侵物种对全球南方的环境影响更为严重
Invasive species' environmental impacts are more severe in the Global South
『Abstract』Invasive alien species (IAS) are a major threat to biodiversity, yet their impact distribution remains poorly understood. Global biodiversity assessments suggest the highest impacts in wealthy countries of the Global North, but this is only inferred from IAS numbers, reflecting research bias. Using a new global database of standardized impact measures, we calculated average impact severity per country and found that it is higher in the Global South despite more than twice as many reports in the Global North. Weak governance and limited management capacity are the main drivers of high impact severity. Emerging economies with rapid economic growth but poor governance are particularly vulnerable. Failure to recognize the Global South as facing the highest IAS impacts diverts attention away from the most threatened regions.
『摘要』
外来入侵物种（IAS）是对生物多样性的主要威胁，但人们对它们的影响分布仍知之甚少。全球生物多样性评估显示，全球北方富裕国家受到的影响最大，但这仅是根据外来入侵物种数量推断得出的，反映了研究偏差。利用新的全球标准化影响度量数据库，我们计算了每个国家的平均影响严重程度，发现尽管全球北方报告的数量是全球南方的两倍多，但全球南方的影响严重程度更高。治理薄弱和管理能力有限是影响严重程度高的主要驱动因素。经济快速增长但治理不善的新兴经济体尤为脆弱。未能认识到全球南方正面临最严重的外来入侵物种影响，会使人们的注意力从受威胁最严重的地区转移开。
『总结』
全球南方外来入侵物种影响严重程度高于北方，治理薄弱和管理能力有限是主因，不重视此情况会使注意力偏离受威胁最严重地区。
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40. 后期使用张力释放弹头的官能化可实现可调节的共价抑制
Late-stage functionalization with strain-release warheads enables tunable covalent inhibition
『Abstract』Covalent inhibition continues to gain momentum as a strategy for selective protein modulation in both therapeutic and chemical biology contexts. Covalent reactive groups (CRGs) typically engage nucleophilic residues such as cysteine, resulting in targeted protein inactivation. However, common electrophiles such as acrylamides often suffer from nonselective reactivity, leading to off-target effects and toxicity. To overcome these limitations, we developed a modular sulfur(IV) reagent platform for the mild, late-stage installation of sulfonyl- and sulfonimidoyl-bicyclobutane motifs with complete cysteine selectivity. This methodology enables access to diverse sulfur(VI) CRGs with tunable strain-release reactivity. Incorporation into US Food and Drug Administration-approved covalent inhibitors demonstrated effective bioisosteric replacement of acrylamides and the potential of strain-release CRGs for selective protein targeting. Preclinical studies in mice have validated this approach, highlighting its promise for next-generation covalent drug design.
『摘要』
在治疗和化学生物学领域，共价抑制作为一种选择性蛋白质调控策略正持续获得关注。共价反应基团（CRGs）通常与半胱氨酸等亲核残基结合，导致目标蛋白质失活。然而，丙烯酰胺等常见亲电试剂常因反应缺乏选择性而产生脱靶效应和毒性。为克服这些局限，我们开发了一个模块化四价硫试剂平台，可在温和条件下后期安装磺酰基和磺酰亚氨基双环丁烷基序，并具有完全的半胱氨酸选择性。该方法可制备具有可调应变释放反应活性的多样化六价硫共价反应基团。将其引入美国食品药品监督管理局批准的共价抑制剂中，证实可有效替代丙烯酰胺，并展示了应变释放共价反应基团用于选择性蛋白质靶向的潜力。小鼠临床前研究验证了该策略的可行性，凸显了其在下一代共价药物设计中的前景。
『总结』
开发模块化四价硫试剂平台可实现温和条件下高选择性共价修饰，通过应变释放机制克服传统亲电试剂的脱靶毒性，为新一代共价药物设计提供新策略。
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41. 人类海马体衰老过程中的表观遗传与三维基因组重编程
Epigenetic and 3D genome reprogramming during the aging of the human hippocampus
『Abstract』Changes in gene expression have been observed in the aging human brain, but our understanding of the underlying regulatory mechanisms remains limited. To unravel these complexities, we analyzed single-nucleus gene expression, chromatin accessibility, DNA methylation, and three-dimensional (3D) chromatin architecture from human hippocampal tissues spanning the adult lifespan. We identified both linear and nonlinear dynamic gene regulatory programs during aging. Between the ages of 50 to 75, embryonic yolk sac-derived microglia were depleted and replaced by cells resembling peripheral blood monocyte-derived microglia. Hippocampal astrocytes decreased substantially with age, including those regulating synaptic transmission. Across cell types, 3D genome architecture underwent global erosion. Our analysis provides insights for how altered gene regulatory programs promote cell type-specific aging phenotypes in the human brain.
『摘要』
在衰老的人类大脑中已观察到基因表达的变化，但我们对潜在调控机制的了解仍然有限。为揭示这些复杂性，我们分析了涵盖成年期的人类海马体组织中的单核基因表达、染色质可及性、DNA甲基化以及三维（3D）染色质结构。我们确定了衰老过程中线性和非线性的动态基因调控程序。在50至75岁之间，胚胎卵黄囊来源的小胶质细胞逐渐耗竭，并被类似外周血单核细胞来源的小胶质细胞所取代。海马星形胶质细胞随年龄增长显著减少，包括调节突触传递的细胞。在各类细胞中，三维基因组结构均发生全局性侵蚀。我们的分析为基因调控程序改变如何促进人类大脑中细胞类型特异性衰老表型提供了见解。
『总结』
研究分析了人类海马体组织在衰老过程中的基因调控机制，发现基因调控程序动态变化，特定细胞类型数量改变，三维基因组结构全局性侵蚀，为理解大脑衰老表型提供了新见解。
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42. 利用恒星-行星相互作用约束系外行星的磁场
Constraining an exoplanet's magnetic field using star-planet interactions
『Abstract』Theory predicts that a planet with a sufficiently strong magnetic field orbiting close to its host star could induce star-planet magnetic interactions. This is potentially observable as an optical or radio stellar activity signal synchronized with the planet's orbital period. We analyzed 18 years of high-resolution optical spectroscopy of GJ 436, a low-mass star orbited by a Neptune-sized exoplanet on a polar eccentric orbit. Stellar activity indicators show enhancements at a period corresponding to the exoplanet orbit, modulated by stellar rotation, and the star's 8-year magnetic cycle. We interpret this as a signal of star-planet magnetic interaction. Using a geometric model, we reproduced these periods if GJ 436 b has a magnetic field strength of 6 to 110 gauss.
『摘要』
理论预测，一颗具有足够强磁场且围绕主星近距离运行的行星，可能会引发恒星-行星磁场相互作用。这可能表现为与行星轨道周期同步的光学或射电恒星活动信号。我们对GJ 436进行了18年的高分辨率光学光谱分析，这是一颗低质量恒星，有一颗海王星大小的系外行星围绕其进行极偏心轨道运行。恒星活动指标显示，在与系外行星轨道相对应的周期内出现增强，并受到恒星自转和恒星8年磁场周期的调制。我们将其解释为恒星-行星磁场相互作用的信号。利用几何模型，如果GJ 436 b的磁场强度为6至110高斯，我们重现了这些周期。
『总结』
理论预测近距离运行且磁场足够强的行星可引发恒星-行星磁场相互作用，表现为同步光学或射电信号，对GJ 436进行18年分析后发现其活动指标增强，被解释为磁场相互作用信号，且用几何模型推测出其行星GJ 436 b磁场强度范围。
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43. 氧化物薄膜在基底上印制的动态非对称应变
Dynamic asymmetric strain imprinted into substrates by an oxide thin film
『Abstract』In film-substrate systems, the substrate role is often considered to be limited to providing static mechanical constraints. Dynamic film-substrate interactions when a structural change in the film modifies the substrate are generally disregarded. Using combined x-ray and electron microscopies, we observed that an electrically induced filament in a vanadium dioxide film created strong asymmetric strain in an underlying sapphire substrate. This asymmetric substrate strain fed back into the film and defined the filament expansion direction, revealing the importance of film-substrate dynamic interactions in determining film functionality. Furthermore, the strain imprint propagated at least tens of micrometers deep into the substrate, exceeding the film thickness by more than 200-fold, potentially enabling substrate functionalization as an active mechanical coupling media in three-dimensional integrated microelectronic architectures.
『摘要』
在薄膜-基底系统中，基底的作用通常被认为仅限于提供静态机械约束。而当薄膜结构变化改变基底时产生的动态薄膜-基底相互作用通常被忽视。通过结合X射线与电子显微镜技术，我们发现二氧化钒薄膜中电致丝状结构会在下方蓝宝石基底中产生强不对称应变。这种不对称基底应变反馈至薄膜并决定了丝状结构的扩展方向，揭示了薄膜-基底动态相互作用在决定薄膜功能方面的重要性。此外，应变印记至少向基底内传播了数十微米，深度超过薄膜厚度200倍以上，这有可能使基底在三维集成微电子架构中作为主动机械耦合介质实现功能化。
『总结』
薄膜-基底动态相互作用通过应变反馈决定薄膜功能，且应变可深入基底超薄膜厚度200倍，为三维微电子架构提供新可能。
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44. 通过完全去除内含子产生的非剪接体依赖型真核生物
A spliceosome-independent eukaryote generated by complete intron removal
『Abstract』Spliceosomal introns impose a universal processing burden on eukaryotes and obstruct genome minimization because their essentiality remains unresolved. By exploiting Spo11-independent meiosis in synthetic single-chromosome Saccharomyces cerevisiae, the complete deletion of all 300 spliceosomal introns was achieved, generating an intron-free strain, SYNE27α. Whole-genome sequencing confirmed precise excision. Unexpectedly, spliceosomal components (all five small nuclear RNAs [snRNAs], Prp8, Prp9, Prp19, Yhc1, and Luc7) were no longer required for viability, demonstrating that a eukaryotic cell can exist independently of spliceosomal function. U3 small nucleolar RNA (snoRNA) splicing bypassed the requirements for Yhc1, Luc7, Prp9, and Prp19, revealing a mechanistic divergence from pre-mRNA splicing. Cumulative intron loss caused slow growth via ribosomal dysregulation, yet SYNE27α maintained genetic stability. Fitness costs were fully recessive in diploids, confirming intron loss as the primary driver. These findings establish an intron-free, spliceosome-independent eukaryote, resolving the essential function of the spliceosome and enabling minimal-system studies of genome evolution.
『摘要』
真核生物中剪接体内含子给所有真核生物带来普遍的加工负担，并且阻碍基因组最小化，因为其重要性仍未得到解决。通过利用合成单染色体酿酒酵母中不依赖Spo11的减数分裂，实现了全部300个剪接体内含子的完全删除，生成了无内含子菌株SYNE27α。全基因组测序证实了精确切除。出乎意料的是，剪接体组分（全部五种小核RNA [snRNAs]、Prp8、Prp9、Prp19、Yhc1和Luc7）不再是生存所必需，这表明真核细胞可独立于剪接体功能而存在。U3小核仁RNA（snoRNA）剪接绕过了对Yhc1、Luc7、Prp9和Prp19的需求，揭示了与前体mRNA剪接的机制差异。累积的内含子缺失通过核糖体失调导致生长缓慢，然而SYNE27α保持了遗传稳定性。在二倍体中，适应性代价完全隐性，证实内含子缺失是主要驱动因素。这些发现确立了一种无内含子、不依赖剪接体的真核生物，解决了剪接体的基本功能问题，并使基因组进化的最小系统研究成为可能。
『总结』
通过删除酿酒酵母全部剪接体内含子，发现剪接体组分非生存必需，揭示了snoRNA与前体mRNA剪接的机制差异，证实内含子缺失是主要驱动因素，解决了剪接体基本功能问题并助力基因组进化研究。
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45. 小鼠视觉系统中变化检测所依赖的神经元放电活动图
Map of spiking activity underlying change detection in the mouse visual system
『Abstract』Visual behavior requires coordinated activity across hierarchically organized brain circuits. Understanding this complexity demands datasets that are both large-scale (sampling many areas) and dense (recording many neurons in each area). Here, we present a database of spiking activity across the mouse visual system-including the cortex, thalamus, and midbrain-while mice perform an image change detection task. Using Neuropixels probes, we record from >75,000 high-quality units in 54 mice, mapping area-, cortical-layer-, and cell-type-specific coding of sensory and motor information. Modulation by task engagement increased across the thalamocortical hierarchy but was strongest in the midbrain. Novel images recruited an expanded cortical population and modulated late cortical (but not thalamic) responses. Population decoding and optogenetics identified a critical time window for change detection and were consistent with mice using an adaptation-based rather than image-comparison strategy. This comprehensive resource provides a valuable substrate for understanding sensorimotor computations in neural networks.
『摘要』
视觉行为需要层次分明的大脑回路间协调活动。理解这种复杂性需要既大规模（对多个区域进行采样）又密集（在每个区域记录多个神经元）的数据集。本研究展示了小鼠视觉系统（包括皮层、丘脑和中脑）在小鼠执行图像变化检测任务时的尖峰活动数据库。利用Neuropixels探针，我们在54只小鼠中记录了超过75000个高质量单元，绘制了区域、皮层层和细胞类型特定的感觉和运动信息编码图。丘脑-皮层层级中任务参与度的调节作用逐渐增强，但在中脑最强。新图像激活了更多的皮层神经元，并调节了晚期皮层（而非丘脑）反应。群体解码和光遗传学确定了变化检测的关键时间窗口，且与小鼠采用基于适应而非图像比较的策略一致。这一综合资源为理解神经网络中的感觉运动计算提供了有价值的基质。
『总结』
本研究展示了小鼠视觉系统在执行图像变化检测任务时的尖峰活动数据库，揭示了感觉和运动信息编码特征，确定了变化检测的关键时间窗口，为理解神经网络中的感觉运动计算提供了有价值的资源。
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46. 噬菌体全基因组转座子诱变
Bacteriophage genome-wide transposon mutagenesis
『Abstract』Bacteriophage genomes are densely packed with coding sequences and frequently encode genes of unknown function. Unbiased phage functional genomics approaches are therefore needed, particularly for large lytic phages. Here, we harness the mariner transposase to develop phage transposon mutagenesis and sequencing (phage TnSeq), which enables pooled sequencing to identify both fitness-conferring and dispensable genes. Using the Pseudomonas aeruginosa-infecting nucleus-forming jumbo phage ΦKZ (280,334 bp; 371 predicted genes), we show that ∼110 genes are fitness-conferring via phage TnSeq, identifying many known and previously unknown essential genes. Moreover, this phage harbors ∼261 non-essential genes, including some capsid and tail proteins, many of which are important for fitness across different clinical isolates or conditions. Phage TnSeq was also extended to a base-modified phage. Together, phage TnSeq is a scalable technology that can identify essential phage genes, generate knockouts in all non-essential genes, and sensitively assign the quantitative fitness contributions of every gene in parallel.
『摘要』
噬菌体基因组中编码序列高度密集，且常编码未知功能的基因。因此，尤其对于大型裂解性噬菌体而言，需要采用无偏倚的噬菌体功能基因组学方法。本研究利用mariner转座酶开发了噬菌体转座子诱变测序技术（phage TnSeq），该技术通过混合测序能够同时鉴定赋予适应性的基因和可有可无的基因。以感染铜绿假单胞菌的成核型巨型噬菌体ΦKZ（280,334 bp；预测基因371个）为模型，通过phage TnSeq鉴定出约110个赋予适应性的基因，其中包含许多已知和先前未知的必需基因。此外，该噬菌体含有约261个非必需基因，包括部分衣壳和尾部蛋白基因，其中许多基因在不同临床分离株或条件下对适应性具有重要作用。该技术还扩展应用于碱基修饰噬菌体。总之，phage TnSeq是一种可扩展的技术，能够鉴定噬菌体必需基因，敲除所有非必需基因，并同步量化每个基因的适应性贡献。
『总结』
本研究开发了一种基于转座子诱变测序的噬菌体功能基因组学技术（phage TnSeq），通过混合测序同时鉴定噬菌体必需基因与非必需基因，并揭示了巨型噬菌体ΦKZ中适应性相关基因的分布特征，为噬菌体基因功能研究提供了可扩展的量化分析平台。
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47. 基于4D晶格光片显微镜数据的全细胞粒子数字孪生模拟
Whole-cell particle-based digital twin simulations from 4D lattice light-sheet microscopy data
『Abstract』We introduce a whole-cell digital twin framework that integrates four-dimensional (4D) (x, y, z, and t) lattice light-sheet microscopy with particle-based reaction-diffusion simulations in ReaDDy to model mesoscale intracellular organelle dynamics. Using fluorescence microscopy data from live Cal27 cells, we construct spatially resolved digital twins incorporating mitochondrial networks, microtubule networks, dynein and kinesin motors, the plasma membrane, and the nucleus. Mitochondrial dynamics include fusion/fission remodeling, diffusion, and motor-driven active transport along microtubules. Our simulations reproduce experimental trends in mitochondrial dynamics across control and two microtubule-perturbed conditions, demonstrating predictive capability without reparameterization. We then use stress-mimicking to predict emergent perinuclear mitochondrial clustering. Crucially, these simulations reveal that microtubule topology acts as a structural gate for this reorganization, demonstrating that upregulated retrograde motor kinetics alone are insufficient to drive clustering without permissive filament connectivity. This digital twin framework provides an approach for investigating intracellular dynamics and perturbation effects in an interpretable and biologically grounded manner.
『摘要』
我们引入了一个全细胞数字孪生框架，该框架将四维（4D）（x、y、z和t）晶格光片显微镜与ReaDDy中的基于粒子的反应扩散模拟相结合，用于模拟介观尺度下细胞内细胞器的动态变化。利用活体Cal27细胞的荧光显微镜数据，我们构建了包含线粒体网络、微管网络、驱动蛋白和动力蛋白马达、细胞膜以及细胞核的空间分辨数字孪生模型。线粒体动态包括融合/分裂重塑、扩散以及沿微管的马达驱动主动运输。我们的模拟再现了对照组和两种微管受干扰条件下线粒体动态的实验趋势，无需重新参数化即展示了预测能力。随后，我们利用应激模拟预测了核周线粒体聚集的出现。至关重要的是，这些模拟揭示了微管拓扑结构是这种重新组织化的结构屏障，表明仅上调逆行马达动力学，若没有允许的纤维连接性，则不足以驱动聚集。该数字孪生框架为以可解释且基于生物学的方式研究细胞内动态和扰动效应提供了一种方法。
『总结』
本文介绍了全细胞数字孪生框架，结合显微成像与模拟技术构建模型，模拟再现线粒体动态实验趋势，揭示微管拓扑结构对线粒体重组的影响，为研究细胞内动态和扰动效应提供方法。
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48. 弧蛋白通过细胞外囊泡介导细胞间tau蛋白传播
Arc mediates intercellular tau transmission via extracellular vesicles
『Abstract』Tau pathology spreads cell to cell, but the mechanisms of intercellular tau transmission remain unclear. We find that the neuronal gene Arc is critical for the release of tau in neuronal extracellular vesicles (EVs) via a direct protein-protein interaction. Brain EVs purified from transgenic rTg4510 mutant tau mice (rTgWT) crossed with Arc knockout mice (rTgArc KO) contain less tau and reduced tau seeding potential. Both Arc and tau are co-packaged in mouse and human brain-derived EVs. Moreover, Arc levels in brain-derived EVs isolated from human Alzheimer's disease (AD) brains show a strong positive correlation with phosphorylated EV-tau levels. rTgArc KO mice have increased accumulation of intracellular tau and a modest increase in cell toxicity early in disease progression. Strikingly, intercellular tau transmission is almost absent in Arc KO mice. These results show that Arc is critical for the packaging of tau in EVs, which plays a significant role in intercellular tau transmission.
『摘要』
tau病理在细胞间传播，但细胞间tau传播的机制尚不清楚。研究发现，神经元基因Arc通过直接蛋白质-蛋白质相互作用，对神经元细胞外囊泡（EVs）中tau的释放至关重要。从小鼠转基因rTg4510突变tau鼠（rTgWT）与Arc基因敲除鼠（rTgArc KO）杂交得到的后代中提取并纯化脑细胞外囊泡，发现其tau含量较低，tau播种潜力降低。Arc和tau在小鼠和人类大脑衍生的细胞外囊泡中共同包装。此外，从人类阿尔茨海默病（AD）患者大脑中分离出的脑细胞外囊泡中，Arc水平与磷酸化细胞外囊泡tau水平呈强正相关。rTgArc KO小鼠在疾病早期，细胞内tau积累增加，细胞毒性略有上升。值得注意的是，Arc基因敲除小鼠中细胞间tau传播几乎不存在。这些结果表明，Arc对于tau在细胞外囊泡中的包装至关重要，在细胞间tau传播中发挥重要作用。
『总结』
研究发现Arc基因对tau在细胞外囊泡中的包装至关重要，在细胞间tau传播中起重要作用。
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49. 同一神经元的基因表达、形态和活性的多模态成像
Multimodal imaging of gene expression, morphology, and activity of the same neuron
『Abstract』Elucidating the relationships among in vivo activity, brain-wide projection, and gene expression is critical for understanding neuronal functions, but characterizing these modalities for the same neuron remains technically challenging. Here, we developed a trimodal platform combining in vivo Ca2+ imaging, morphological reconstruction of single neurons in cleared whole brains, and post hoc imaging-based in situ transcriptomic profiling in thick brain sections. We applied this platform to the mouse primary visual cortex (VISp) and obtained trimodal profiles for 141 intratelencephalic (IT) and pyramidal tract (PT) neurons. We found that regional axonal arborization, soma location, transcriptomic signatures, and subcellular RNA localization emerged as informative predictors for distinguishing neurons preferentially responsive to different visual stimuli. Importantly, morphological and transcriptomic features are complementary and, when integrated, can better predict neuronal function. Thus, this trimodal platform enables a comprehensive understanding of the relationships among gene expression, morphological diversity, and functional properties of single neurons.
『摘要』
阐明体内活性、全脑投射和基因表达之间的关系对于理解神经元功能至关重要，但对同一神经元的这些特征进行表征在技术上仍具有挑战性。在此，我们开发了一个三模态平台，该平台结合了体内钙离子（Ca2+）成像、在透明全脑中单神经元的形态重建以及在厚脑切片中基于成像的事后原位转录组分析。我们将该平台应用于小鼠初级视觉皮层（VISp），获得了141个大脑内（IT）和锥体束（PT）神经元的三模态特征。我们发现，区域轴突分支、胞体位置、转录组特征以及亚细胞RNA定位可作为区分优先响应不同视觉刺激的神经元的有力预测指标。重要的是，形态学和转录组特征是互补的，整合后能够更好地预测神经元功能。因此，该三模态平台有助于全面理解单个神经元基因表达、形态多样性和功能特性之间的关系。
『总结』
研究开发三模态平台，应用于小鼠初级视觉皮层，发现区域轴突分支等特征可预测神经元对视觉刺激的响应，且形态学和转录组特征互补，该平台有助于全面理解单个神经元基因表达、形态多样性和功能特性间的关系。
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50. 两个不同原因导致人类植入前发育效率低下
Two distinct causes contribute to the low efficiency of human pre-implantation development
『Abstract』∼50% of fertilized eggs arrest during human pre-implantation development, representing a major bottleneck for assisted reproductive technology. The underlying causes remain controversial. By imaging ∼150 live human and monkey fertilized eggs for up to 5 days, we uncovered that the second mitotic divisions are the most error-prone, accounting for early embryonic arrest. Stochastic centriole overduplication, which could be effectively suppressed by transient treatment with PLK4 inhibitor centrinone, predisposed 2-cell blastomeres to assembling multipolar spindles and missegregating chromosomes. Missegregated chromosomes in turn resulted in the formation of most micronuclei in human embryos and led to the arrest or death of daughter blastomeres. By contrast, late embryonic arrest was largely independent of chromosome missegregations but involved the activation of endoplasmic reticulum stress response, which could impair the expression of subsets of junctional and cell polarity proteins required for blastocyst formation. Thus, two distinct causes contribute to the low efficiency of human pre-implantation development.
『摘要』
约50%的受精卵在人类植入前发育过程中停止发育，这是辅助生殖技术面临的一个主要瓶颈，其潜在原因仍存在争议。通过对约150个存活的人类和猴子受精卵进行长达5天的成像观察，我们发现第二次有丝分裂是最易出错的阶段，是导致早期胚胎发育停滞的主要原因。随机性中心粒过度复制（可通过PLK4抑制剂centrinone的短暂处理有效抑制）使2细胞期卵裂球易形成多极纺锤体并发生染色体错分离。染色体错分离进而导致人类胚胎中大多数微核的形成，并导致子代卵裂球的发育停滞或死亡。相比之下，晚期胚胎发育停滞在很大程度上与染色体错分离无关，而是涉及内质网应激反应的激活，该反应会损害囊胚形成所需的连接和细胞极性蛋白亚群表达。因此，人类植入前发育效率低下的原因有两个。
『总结』
人类植入前发育中约50%受精卵停止发育，原因包括第二次有丝分裂易出错致染色体错分离，以及晚期胚胎发育停滞涉及内质网应激反应激活。
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51. 从全能性到早期器官发生的灵长类胚胎发生的连续建模
Continuous modeling of primate embryogenesis from totipotency to early organogenesis
『Abstract』Embryo-like structures, or embryoids, are powerful models to investigate early embryonic development. Yet, previous models cover only partial developmental stages, restricting their applications. Here, we successfully generate primate organogenetic embryoids from cynomolgus totipotent blastomere-like stem cells (cTBLCs). cTBLCs, reprogrammed from pluripotent stem cells and stably maintained, can display key totipotent-like molecular and functional features resembling zygotes/2-4-cell blastomeres. cTBLCs spontaneously generate well-organized blastoids that further progress through gastrulation to early organogenesis, thus exhibiting neural-tube-like structures and cardiac-like beating activity. Using single-cell RNA sequencing (scRNA-seq), we visualized stepwise cell-state transitions from cTBLCs to organogenetic lineages and identified an intermediate 8-cell/morula-like state. Interestingly, we uncovered a dynamic cascade of regulatory networks originating from cTBLCs, which represented an intrinsic developmental initiation program occurring independently of classical fertilization-associated events. Together, the cTBLC platform provides a unified in vitro framework to investigate developmental initiation, early lineage specification, and organogenesis.
『摘要』
类胚胎结构或胚胎样体是研究早期胚胎发育的有力模型。然而，以往的模型仅涵盖部分发育阶段，限制了其应用。本研究中，我们成功利用食蟹猴全能卵裂球样干细胞（cTBLCs）生成灵长类器官发生胚胎样体。cTBLCs由多能干细胞重编程而来并稳定维持，可表现出类似合子/2-4细胞卵裂球的关键全能样分子和功能特征。cTBLCs可自发形成组织良好的胚泡样结构，并进一步通过原肠胚形成进展至早期器官发生阶段，从而表现出神经管样结构和心脏样跳动活动。我们利用单细胞RNA测序（scRNA-seq）技术，直观呈现了从cTBLCs到器官发生谱系的逐步细胞状态转变，并鉴定出一个中间8细胞/桑椹胚样状态。有趣的是，我们发现了一个源自cTBLCs的动态调控网络级联，其代表了一种独立于经典受精相关事件的内在发育启动程序。总之，cTBLC平台为研究发育启动、早期谱系特化和器官发生提供了一个统一的体外研究框架。
『总结』
该研究利用食蟹猴全能卵裂球样干细胞成功生成灵长类器官发生胚胎样体，揭示了其发育过程及调控网络，为研究发育启动、早期谱系特化和器官发生提供了统一体外研究框架。
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52. mRNA 3'非翻译区辅助内源性无序区域调控蛋白质活性
mRNA 3' UTRs chaperone intrinsically disordered regions to control protein activity
『Abstract』More than 2,700 human mRNA 3' UTRs have hundreds of highly conserved nucleotides, but their biological roles are unclear. These mRNAs encode proteins strongly enriched for long intrinsically disordered regions (IDRs) with hydrophobic amino acid clusters. For MYC, UTX, and JMJD3, we show that their mRNA 3' UTRs control protein activity. Rather than affecting protein abundance or localization, we find that the KDM6B 3' UTR co-translationally changes the folding of JMJD3 protein. It promotes IDR-IDR interactions and suppresses folding between domains, suggesting that RNA has IDR chaperone activity that prevents interference between hydrophobic clusters in the IDR with folding of the structured domain. 3' UTRs with chaperone activity are multivalent and mesh-like condensate-enriched, indicating the presence of localized folding environments for IDR-containing proteins. We show here that the protein sequence is insufficient for the biogenesis of fully active IDR-containing transcriptional regulators in cells, suggesting that mRNA 3' UTRs control their activity by preventing co-translational misfolding.
『摘要』
超过2700个人类信使核糖核酸（mRNA）的3'非翻译区（UTR）含有数百个高度保守的核苷酸，但其生物学作用尚不明确。这些信使核糖核酸编码的蛋白质富含长无序区域（IDR），且含有疏水性氨基酸簇。对于MYC、UTX和JMJD3，研究发现其信使核糖核酸3'非翻译区能够控制蛋白质活性。研究发现，KDM6B 3'非翻译区并非通过影响蛋白质丰度或定位，而是在共翻译过程中改变JMJD3蛋白的折叠。它促进无序区域间相互作用，抑制结构域间折叠，这表明核糖核酸具有无序区域伴侣活性，可防止无序区域中的疏水簇干扰结构域的折叠。具有伴侣活性的3'非翻译区是多价的，且富含网状凝聚物，这表明无序区域蛋白存在局部折叠环境。本研究表明，蛋白质序列不足以使细胞中含无序区域的转录调控因子完全生物合成，这表明信使核糖核酸3'非翻译区通过防止共翻译错误折叠来控制其活性。
『总结』
研究发现人类mRNA 3' UTR含高度保守核苷酸，其编码蛋白富含长无序区域，部分基因的mRNA 3' UTR能控制蛋白活性，KDM6B 3' UTR可改变JMJD3蛋白折叠，具有伴侣活性的3' UTR表明存在局部折叠环境，且蛋白质序列不足以使含无序区域的转录调控因子完全生物合成，mRNA 3' UTR通过防止共翻译错误折叠来控制其活性。
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53. 凝聚体形态中功能扰动的深度学习
Deep learning of functional perturbations from condensate morphology
『Abstract』Biomolecular condensates compartmentalize the interior of cells to organize complex functions, yet linking molecular interactions within condensates to their mesoscale organization remains a major challenge. To bridge this gap, we developed a neural-network-based framework-Deep-Phase (deep learning of phase-separated condensates)-that uses microscopy images to directly measure condensate morphology changes resulting from pharmacological alterations in associated biochemical processes. We use Deep-Phase to precisely quantify time- and concentration-dependent structural perturbations to the multiphase nucleolus and show that they are tightly coupled to potencies of drugs inhibiting ribosomal RNA (rRNA) transcription and processing. Applying Deep-Phase in a chemical screen, we identify a unique nucleolar morphology and discover a role for a DNA topoisomerase in rRNA processing. Mechanistic studies of this morphology provide insights into how the interfaces between nucleolar sub-compartments are maintained. We demonstrate Deep-Phase's adaptability to diverse cell lines, labeling techniques, and condensates, offering a powerful platform for connecting molecular pathways to cellular mesoscale organization.
『摘要』
生物分子凝聚体将细胞内部区域化，以组织复杂的功能，然而，将凝聚体内的分子相互作用与其介观组织联系起来仍是一大挑战。为填补这一空白，我们开发了一种基于神经网络的框架——Deep-Phase（相分离凝聚体的深度学习），它利用显微镜图像直接测量因相关生化过程的药理学改变而导致的凝聚体形态变化。我们使用Deep-Phase精确量化多相核仁随时间和浓度变化的结构扰动，并表明这些扰动与抑制核糖体RNA（rRNA）转录和加工的药物效力紧密相关。在化学筛选中应用Deep-Phase，我们识别出一种独特的核仁形态，并发现了DNA拓扑异构酶在rRNA加工中的作用。对该形态的机制研究揭示了核仁亚区室之间界面如何维持。我们证明了Deep-Phase对不同细胞系、标记技术和凝聚体的适应性，为将分子通路与细胞介观组织联系起来提供了一个强大的平台。
『总结』
为填补将凝聚体内分子相互作用与其介观组织联系起来的空白，研究开发了基于神经网络的框架Deep-Phase，利用其进行相关研究，并证明了其对不同细胞系等的适应性，提供了连接分子通路与细胞介观组织的强大平台。
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54. 神经元蛋白示踪揭示的生理性脑清除结构
Physiological brain clearance architecture revealed by neuronal protein tracing
『Abstract』The brain must efficiently clear protein waste to maintain homeostasis, yet physiological drainage pathways remain poorly defined. Standard tracer injection approaches may not reflect endogenous efflux. Here, we develop a non-invasive genetic system to trace neuron-derived protein clearance from the brain to cerebrospinal fluid (CSF) and border tissues. We identify distinct drainage routes and border hotspots missed by tracer injection, confirmed by bioorthogonal labeling of endogenous neuronal proteins. Pulse-chase kinetics reveal slow skull outflow versus rapid dural and nasal clearance. Transcriptomic analyses uncover border cells sampling neuronal antigens, including tolerogenic skull-resident B cells. Region-restricted reporter expression demonstrates compartmentalized clearance following a "nearest exit" principle, where anatomical origin dictates drainage pathway. Disease disrupts clearance through distinct mechanisms: inflammation drives vascular leakage into blood, while amyloid pathology causes parenchymal retention and border exit obstruction. These findings define brain clearance as a compartmentalized system of organized pathways and immune niches whose dysfunction may underlie regional vulnerability in neurological disease.
『摘要』
大脑必须高效清除蛋白质废物以维持内环境稳态，但生理性引流途径仍不明确。标准示踪剂注射方法可能无法反映内源性外排情况。本研究开发了一种非侵入性遗传系统，用于追踪从大脑到脑脊液（CSF）及边界组织的神经元源性蛋白质清除过程。我们确定了示踪剂注射所遗漏的独特引流途径和边界热点区域，并通过内源性神经元蛋白质的生物正交标记加以证实。脉冲追踪动力学显示，颅骨外流缓慢，而硬脑膜和鼻腔清除迅速。转录组分析揭示了采样神经元抗原的边界细胞，包括具有免疫耐受性的颅骨驻留B细胞。区域限制性报告基因表达表明，清除遵循“就近出口”原则的分区模式，即解剖学起源决定引流途径。疾病通过不同机制破坏清除过程：炎症促使血管渗漏至血液，而淀粉样蛋白病变导致实质潴留和边界出口阻塞。这些发现将大脑清除定义为由有序通路和免疫微环境组成的分区系统，其功能障碍可能是神经系统疾病区域脆弱性的根源。
『总结』
研究揭示大脑蛋白质废物清除依赖分区化引流途径和免疫微环境，并发现疾病通过不同机制破坏该系统，这可能解释神经系统疾病的区域脆弱性。
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55. TPPP/p25淀粉样蛋白成核活性作为多系统萎缩的特异性生物标志物
TPPP/p25 amyloid seeding activity as a specific biomarker for multiple system atrophy
『Abstract』Detection of α-synuclein (α-syn) amyloid seeds in human biofluids has attracted great interest for clinical diagnosis of synucleinopathies. However, as a common biomarker, α-syn lacks specificity in reliably differentiating distinct disorders. Here, we report tubulin polymerization promoting protein (TPPP/p25) as a cerebrospinal fluid (CSF) biomarker for the specific diagnosis of multiple system atrophy (MSA). We demonstrate that native TPPP/p25 is self-protected against amyloid aggregation, while disease-related mutation disrupts this protection, triggering TPPP/p25 aggregation. Cryo-electron microscopy (cryo-EM) analysis reveals that the well-folded core domain (CORE) undergoes large conformational changes to mediate amyloid formation. Based on this insight, we developed a seed amplification assay using a minimized CORE (miniCORE) monomer, which detects TPPP/p25 amyloid seeds in CSF and robustly differentiates MSA from Parkinson's disease (PD) and other neurodegenerative diseases. Our findings establish misfolded TPPP/p25 as a promising, specific biomarker in biofluids for MSA diagnosis.
『摘要』
在人体生物流体中检测α-突触核蛋白（α-syn）淀粉样蛋白种子，对于突触核蛋白病的临床诊断具有重大意义。然而，作为常见生物标志物，α-syn在可靠区分不同疾病方面缺乏特异性。本研究报告微管相关蛋白（TPPP/p25）可作为脑脊液（CSF）生物标志物，用于多系统萎缩症（MSA）的特异性诊断。研究证实，天然TPPP/p25可自我保护免受淀粉样蛋白聚集的影响，而疾病相关突变会破坏这种保护作用，从而引发TPPP/p25聚集。冷冻电子显微镜（cryo-EM）分析显示，结构良好的核心结构域（CORE）会发生较大的构象变化，从而介导淀粉样蛋白的形成。基于这一发现，我们开发了一种种子扩增试验，使用最小化的CORE（miniCORE）单体，可检测脑脊液中的TPPP/p25淀粉样蛋白种子，并有效区分MSA与帕金森病（PD）和其他神经退行性疾病。本研究结果表明，错误折叠的TPPP/p25有望成为生物流体中用于MSA诊断的特异性生物标志物。
『总结』
TPPP/p25可作为脑脊液生物标志物用于MSA特异性诊断，其错误折叠形式有望成为MSA诊断的特异性生物标志物。
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56. 解码人类脑膜的时空发育过程
Decoding the spatiotemporal development of human meninges
『Abstract』The human meninges are essential regulators of central nervous system (CNS) development and homeostasis. However, a comprehensive spatiotemporal characterization of the cellular and molecular dynamics during human meninges development is currently lacking. Using single-cell spatiotemporal transcriptomics across 6-23 gestational weeks (GWs), we identify asynchronous meningeal layer development, with the pia mater forming earliest. We define layer-specific fibroblast states from the three meningeal layers, including the expression of barrier-related genes, neurotransmitter transporter-related and synapse-related genes, and lipid metabolism-related genes. We further characterize spatiotemporal heterogeneity in meningeal immune cells, identifying a meningeal-specific macrophage population. The pia mater recruits and spatially organizes immune cells, particularly macrophages in the leptomeninges via CXCL12-CXCR4 signaling. Moreover, Trem2+ macrophages, in turn, regulate the development of Cajal-Retzius (CR) cells in the cerebral cortex. These findings establish a spatiotemporal framework for human meningeal development, uncover neuro-immune interactions that shape cortical development, and identify potential therapeutic targets.
『摘要』
人类脑膜是中枢神经系统（CNS）发育和稳态的重要调节器。然而，目前尚缺乏对人类脑膜发育过程中细胞和分子动态变化的全面时空特征描述。通过在妊娠6至23周（GWs）期间进行单细胞时空转录组学分析，我们发现了脑膜各层发育的异步性，其中软脑膜形成最早。我们从三个脑膜层中确定了各层特异性的成纤维细胞状态，包括屏障相关基因、神经递质转运体相关基因和突触相关基因以及脂质代谢相关基因的表达。我们进一步表征了脑膜免疫细胞的时空异质性，并确定了脑膜特异性的巨噬细胞群。软脑膜通过CXCL12-CXCR4信号通路招募并空间组织免疫细胞，尤其是软脑膜中的巨噬细胞。此外，Trem2+巨噬细胞反过来调节大脑皮层中Cajal-Retzius（CR）细胞的发育。这些发现为人类脑膜发育建立了时空框架，揭示了塑造皮层发育的神经免疫相互作用，并确定了潜在的治疗靶点。
『总结』
通过单细胞时空转录组学分析，研究揭示了人类脑膜发育的时空异步性、脑膜各层特异性的成纤维细胞状态、免疫细胞的时空异质性，以及神经免疫相互作用对皮层发育的影响，并确定了潜在治疗靶点。
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57. 利用CRISPR筛选测序揭示空间分辨功能基因组学
Uncovering spatially resolved functional genomics with CRISPR screen sequencing
『Abstract』Spatial omics has advanced our understanding of tissue-level biology, yet tools to systematically link gene functional perturbations to spatial phenotypes and signaling pathways remain limited. To address this, we developed spatial CRISPR screen sequencing (SPAC-seq), a high-throughput spatial CRISPR screen platform, and TARDIS (target prioritization toolkit for perturbation data in spatial omics), a statistical spatial perturbation analysis toolkit. Using SPAC-seq and TARDIS, we linked gene perturbations to spatial phenotypes and pathways, uncovering how Icam1 loss in tumor cells promotes metastasis via immune suppression and macrophage polarization. In CD8+ T cells, we revealed Cd44's role in regulating spatial phenotypes by interacting with Spp1 on macrophages. We also demonstrated the model of the transcription factor-chemokine receptor axis coupling cell states with chemotaxis. SPAC-seq and TARDIS provide an effective framework to study spatially resolved functional genomics and pathways across diverse biological and disease contexts.
『摘要』
空间组学增进了我们对组织层面生物学的理解，但目前仍缺乏能系统地将基因功能扰动与空间表型和信号通路联系起来的工具。为解决这一问题，我们开发了空间CRISPR筛选测序（SPAC-seq）这一高通量空间CRISPR筛选平台，以及TARDIS（空间组学中扰动数据的目标优先级工具包）这一统计空间扰动分析工具包。利用SPAC-seq和TARDIS，我们将基因扰动与空间表型和通路联系起来，揭示了肿瘤细胞中Icam1的缺失如何通过免疫抑制和巨噬细胞极化促进转移。在CD8+T细胞中，我们发现Cd44通过与巨噬细胞上的Spp1相互作用来调控空间表型。我们还展示了转录因子-趋化因子受体轴将细胞状态与趋化作用相耦合的模型。SPAC-seq和TARDIS为研究各种生物学和疾病背景下空间分辨的功能基因组和通路提供了有效的框架。
『总结』
研究开发了SPAC-seq和TARDIS工具，揭示了基因扰动与空间表型和通路的关系，为研究空间分辨的功能基因组和通路提供有效框架。
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