前沿速递 | NCS 集萃:2025-01-31 期 [Up]
总结
1. 通过设计重复元件间的重组实现人类基因组的随机化[静]
Randomizing the human genome by engineering recombination between repeat elements
『Abstract』Abstract We lack tools to edit DNA sequences at scales necessary to study 99% of the human genome that is noncoding. To address this gap, we applied CRISPR prime editing to insert recombination handles into repetitive sequences, up to 1697 per cell line, which enables generating large-scale deletions, inversions, translocations, and circular DNA. Recombinase induction produced more than 100 stochastic megabase-sized rearrangements in each cell. We tracked these rearrangements over time to measure selection pressures, finding a preference for shorter variants that avoided essential genes. We characterized 29 clones with multiple rearrangements, finding an impact of deletions on expression of genes in the variant but not on nearby genes. This genome-scrambling strategy enables large deletions, sequence relocations, and the insertion of regulatory elements to explore genome dispensability and organization.
『摘要』 我们缺乏在必要规模上编辑DNA序列的工具来研究占人类基因组99%的非编码区。为弥补这一空白,我们应用CRISPR首位编辑技术将重组把手插入重复序列中,每个细胞系最多可插入1697个,从而实现大规模缺失、倒位、易位和环形DNA的生成。重组酶的诱导使每个细胞产生超过100个随机性的百万碱基大小的重组。我们随时间跟踪这些重组以测量选择压力,发现较短的、能避开必需基因的变异体更受青睐。我们对29个具有多重重组的克隆进行了特征分析,发现缺失会影响变异体中基因的表达,但不会影响附近基因的表达。这种基因组混排策略可实现大片段缺失、序列易位和调控元件的插入,用于探索基因组的可弃性和组织结构。
『总结』 研究应用CRISPR首位编辑技术开发了一种新的基因组混排策略,能够实现在非编码区进行大规模DNA序列编辑,为探索基因组结构和功能提供了新工具。
2. 暴露前抗体预防可保护猕猴免受严重流感侵袭
Pre-exposure antibody prophylaxis protects macaques from severe influenza
『Abstract』Abstract Influenza virus pandemics and seasonal epidemics have claimed countless lives. Recurrent zoonotic spillovers of influenza viruses with pandemic potential underscore the need for effective countermeasures. In this study, we show that pre-exposure prophylaxis with broadly neutralizing antibody (bnAb) MEDI8852 is highly effective in protecting cynomolgus macaques from severe disease caused by aerosolized highly pathogenic avian influenza H5N1 virus infection. Protection was antibody dose–dependent yet independent of Fc-mediated effector functions at the dose tested. Macaques receiving MEDI8852 at 10 milligrams per kilogram or higher had negligible impairment of respiratory function after infection, whereas control animals were not protected from severe disease and fatality. Given the breadth of MEDI8852 and other bnAbs, we anticipate that protection from unforeseen pandemic influenza A viruses is achievable.
『摘要』 流感病毒的大流行和季节性流行已夺去无数生命。具有大流行潜力的流感病毒反复发生跨物种传播,凸显了采取有效对策的必要性。本研究表明,预先暴露于广谱中和抗体(bnAb)MEDI8852可有效保护食蟹猴免受气溶胶传播的高致病性禽流感H5N1病毒感染引起的严重疾病。研究发现,这种保护作用依赖于抗体剂量,但在所测试的剂量下并不依赖于Fc介导的效应功能。接受每公斤10毫克或以上MEDI8852的食蟹猴在感染后呼吸功能几乎未受损,而对照组动物则未能免受严重疾病和死亡的威胁。鉴于MEDI8852和其他广谱中和抗体的广谱性,我们预计可以实现对未知大流行性甲型流感病毒的防护。
『总结』 研究表明,预先使用广谱中和抗体MEDI8852可有效保护食蟹猴免受高致病性禽流感H5N1病毒感染,这为预防未知大流行性流感病毒提供了可能。
3. 野生果蝠社会群体中身份、性别、等级和归属的海马体编码
Hippocampal coding of identity, sex, hierarchy, and affiliation in a social group of wild fruit bats
『Abstract』Abstract Social animals live in groups and interact volitionally in complex ways. However, little is known about neural responses under such natural conditions. Here, we investigated hippocampal CA1 neurons in a mixed-sex group of five to 10 freely behaving wild Egyptian fruit bats that lived continuously in a laboratory-based cave and formed a stable social network. In-flight, most hippocampal place cells were socially modulated and represented the identity and sex of conspecifics. Upon social interactions, neurons represented specific interaction types. During active observation, neurons encoded the bat’s own position and head direction, together with the position, direction, and identity of multiple conspecifics. Identity-coding neurons encoded the same bat across contexts. The strength of identity coding was modulated by sex, hierarchy, and social affiliation. Thus, hippocampal neurons form a multidimensional sociospatial representation of the natural world.
『摘要』 社会动物群体而居,以复杂的方式进行自愿互动。然而,在这种自然条件下神经反应的相关情况仍知之甚少。本研究调查了持续生活在实验室洞穴中并形成稳定社交网络的5至10只自由活动的野生埃及果蝠(雌雄混合)的海马体CA1神经元。在飞行中,大多数海马体位置细胞受社交影响,表征同种动物的身份和性别。在社交互动时,神经元表征特定的互动类型。在主动观察期间,神经元编码蝙蝠自身的位置和头部方向,以及多个同种动物的位置、方向和身份。身份编码神经元在不同情境下对同一只蝙蝠进行编码。身份编码的强度受性别、等级和社会归属关系的调节。因此,海马体神经元构成了自然界的多维社交空间表征。
『总结』 研究发现,在自由活动的野生埃及果蝠中,海马体神经元能形成包含社交信息和空间信息的多维表征。
4. 能量限制导致北极熊哨兵种群数量下降
Energetic constraints drive the decline of a sentinel polar bear population
『Abstract』Abstract Human-driven Arctic warming and resulting sea ice loss have been associated with declines in several polar bear populations. However, quantifying how individual responses to environmental change integrate and scale to influence population dynamics in polar bears has yet to be achieved. We developed an individual-based bioenergetic model and hindcast population dynamics across 42 years of observed sea ice conditions in Western Hudson Bay, a region undergoing rapid environmental change. The model successfully captured trends in individual morphometrics, reproduction, and population abundance observed over four decades of empirical monitoring data. Our study provides evidence for the interplay between individual energetics and environmental constraints in shaping population dynamics and for the fundamental role of a single limiting mechanism—energy—underpinning the decline of an apex Arctic predator.
『摘要』 人类活动导致的北极变暖以及由此造成的海冰流失与北极熊种群数量的减少有关。然而,量化北极熊对环境变化的个体反应如何整合并影响种群动态,目前尚未实现。我们开发了一个基于个体的生物能量模型,并根据西哈德逊湾42年来观测到的海冰状况对种群动态进行了反演。该模型成功地捕捉到了40年实证监测数据中观察到的个体形态特征、繁殖和种群丰度的变化趋势。我们的研究证明了个体能量与环境限制之间的相互作用对种群动态的影响,以及单一限制机制——能量——在导致这种顶级北极掠食者数量下降中的根本作用。
『总结』 本研究表明,北极熊的种群动态受到个体能量状态与环境因素相互作用的共同影响,能量是这一北极顶级掠食者数量下降的根本原因。
5. 将非手性半导体转化为具有卓越圆二色性的手性区域
Transforming achiral semiconductors into chiral domains with exceptional circular dichroism
『Abstract』Abstract Highly concentrated solutions of asymmetric semiconductor magic-sized clusters (MSCs) of cadmium sulfide, cadmium selenide, and cadmium telluride were directed through a controlled drying meniscus front, resulting in the formation of chiral MSC assemblies. This process aligned their transition dipole moments and produced chiroptic films with exceptionally strong circular dichroism. G -factors reached magnitudes as high as 1.30 for drop-cast films and 1.06 for patterned films, approaching theoretical limits. By controlling the evaporation geometry, various domain shapes and sizes were achieved, with homochiral domains exceeding 6 square millimeters that transition smoothly between left- and right-handed chirality. Our results uncovered fundamental relationships between meniscus deposition processes, the alignment of supramolecular filaments and their MSC constituents, and their connection to emergent chiral properties.
『摘要』 将高浓度的不对称半导体魔尺簇(MSCs)溶液——包括硫化镉、硒化镉和碲化镉——通过受控干燥的弯月面前缘,从而形成了手性MSC组装体。这一过程使它们的跃迁偶极矩排列一致,并产生了具有极强圆二色性的手性光学薄膜。滴涂薄膜的G因子高达1.30,图案化薄膜的G因子达到1.06,接近理论极限。通过控制蒸发几何形状,获得了各种形状和尺寸的畴区,其中同手性畴区超过6平方毫米,并且在左旋和右旋手性之间平滑过渡。我们的研究结果揭示了弯月面沉积过程、超分子丝及其MSC成分的排列与它们所产生的手性特性之间的基本关系。
『总结』 研究通过控制干燥过程制备了手性MSC组装体,揭示了弯月面沉积与手性特性之间的基本关系,并获得了具有极强圆二色性的手性光学薄膜。
6. SETD2在染色质转录过程中催化H3K36三甲基化的结构基础
Structural basis of H3K36 trimethylation by SETD2 during chromatin transcription
『Abstract』Abstract During transcription, RNA polymerase II traverses through chromatin, and posttranslational modifications including histone methylations mark regions of active transcription. Histone protein H3 lysine 36 trimethylation (H3K36me3), which is established by the histone methyltransferase SET domain containing 2 (SETD2), suppresses cryptic transcription, regulates splicing, and serves as a binding site for transcription elongation factors. The mechanism by which the transcription machinery coordinates the deposition of H3K36me3 is not well understood. Here we provide cryo–electron microscopy structures of mammalian RNA polymerase II–DSIF-SPT6-PAF1c-TFIIS-IWS1-SETD2-nucleosome elongation complexes, revealing that the transcription machinery regulates H3K36me3 deposition by SETD2 on downstream and upstream nucleosomes. SPT6 binds the exposed H2A-H2B dimer during transcription, and the SPT6 death-like domain mediates an interaction with SETD2 bound to a nucleosome upstream of RNA polymerase II.
『摘要』 在转录过程中,RNA聚合酶II穿过染色质,包括组蛋白甲基化在内的翻译后修饰标记了活跃转录的区域。由含有SET结构域的组蛋白甲基转移酶2(SETD2)催化的组蛋白H3第36位赖氨酸三甲基化(H3K36me3)可以抑制隐秘转录,调节剪接,并为转录延伸因子提供结合位点。然而,转录机制如何协调H3K36me3的沉积尚不清楚。本研究提供了哺乳动物RNA聚合酶II-DSIF-SPT6-PAF1c-TFIIS-IWS1-SETD2-核小体延长复合物的冷冻电子显微镜结构,揭示了转录机制通过SETD2调节下游和上游核小体上H3K36me3的沉积。在转录过程中,SPT6与暴露的H2A-H2B二聚体结合,其死亡结构域与结合在RNA聚合酶II上游核小体上的SETD2发生相互作用。
『总结』 本研究揭示了哺乳动物转录机制中SETD2如何通过与SPT6的相互作用,在核小体上调节H3K36me3的沉积。
7. TIR信号传导激活了细菌中的类胱天蛋白酶免疫
TIR signaling activates caspase-like immunity in bacteria
『Abstract』Abstract Caspase family proteases and Toll/interleukin-1 receptor (TIR)-domain proteins have central roles in innate immunity and regulated cell death in humans. We describe a bacterial immune system comprising both a caspase-like protease and a TIR-domain protein. We found that the TIR protein, once it recognizes phage invasion, produces the previously unknown immune signaling molecule adenosine 5′-diphosphate-cyclo[N7:1′′]-ribose (N7-cADPR). This molecule specifically activates the bacterial caspase-like protease, which then indiscriminately degrades cellular proteins to halt phage replication. The TIR-caspase defense system, which we denote as type IV Thoeris, is abundant in bacteria and efficiently protects against phage propagation. Our study highlights the diversity of TIR-produced immune signaling molecules and demonstrates that cell death regulated by proteases of the caspase family is an ancient mechanism of innate immunity.
『摘要』 人体中的胱天蛋白酶家族蛋白酶和Toll样/白介素-1受体(TIR)结构域蛋白在先天免疫和调节性细胞死亡中发挥核心作用。本研究描述了一种包含胱天蛋白酶样蛋白酶和TIR结构域蛋白的细菌免疫系统。研究发现,TIR蛋白在识别噬菌体入侵后,会产生一种先前未知的免疫信号分子——腺苷5′-二磷酸-环[N7:1′′]-核糖(N7-cADPR)。该分子特异性激活细菌中的胱天蛋白酶样蛋白酶,后者随即无差别地降解细胞蛋白,从而阻止噬菌体复制。本研究将这种TIR-胱天蛋白酶防御系统命名为IV型Thoeris,该系统在细菌中普遍存在,可有效防止噬菌体传播。本研究强调了TIR产生的免疫信号分子的多样性,并证明胱天蛋白酶家族蛋白酶调节的细胞死亡是一种古老的先天免疫机制。
『总结』 研究发现细菌中存在一种包含胱天蛋白酶样蛋白酶和TIR结构域蛋白的IV型Thoeris免疫系统,可有效防止噬菌体传播,揭示了先天免疫和调节性细胞死亡的新机制。
8. 海马重放的时序与组织
The time course and organization of hippocampal replay
『Abstract』Abstract The mechanisms by which the brain replays neural activity sequences remain unknown. Recording from large ensembles of hippocampal place cells in freely behaving rats, we observed that replay content is strictly organized over multiple timescales and governed by self-avoidance. After movement cessation, replays avoided the animal’s previous path for 3 seconds. Chains of replays avoided self-repetition over a shorter timescale. We used a continuous attractor model of neural activity to demonstrate that neuronal fatigue both generates replay sequences and produces self-avoidance over the observed timescales. In addition, replay of past experience became predominant later into the stopping period, in a manner requiring cortical input. These results indicate a mechanism for replay generation that unexpectedly constrains which sequences can be produced across time.
『摘要』 大脑重放神经活动序列的机制尚不清楚。通过记录自由活动大鼠海马体中大量位置细胞的活动,我们观察到重放内容在多个时间尺度上受到严格组织,并遵循自我避免的原则。在运动停止后的3秒内,重放会避开动物之前的路径。在更短的时间尺度上,重放链会避免自我重复。我们使用神经活动的连续吸引子模型证明,神经元疲劳既会产生重放序列,又会在观察到的时间尺度上产生自我避免。此外,在停止期的后期,过去经验的重放变得更为主要,这一过程需要皮层的输入。这些结果表明了一种重放产生机制,该机制出乎意料地限制了随时间推移可能产生的序列。
『总结』 研究发现大脑通过神经元疲劳和自我避免原则在多个时间尺度上组织和约束神经活动重放序列。
9. 古代基因组学与家畜羊的起源、扩散及发展
Ancient genomics and the origin, dispersal, and development of domestic sheep
『Abstract』Abstract The origins and prehistory of domestic sheep ( Ovis aries ) are incompletely understood; to address this, we generated data from 118 ancient genomes spanning 12,000 years sampled from across Eurasia. Genomes from Central Turkiye ~8000 BCE are genetically proximal to the domestic origins of sheep but do not fully explain the ancestry of later populations, suggesting a mosaic of wild ancestries. Genomic signatures indicate selection by ancient herders for pigmentation patterns, hornedness, and growth rate. Although the first European sheep flocks derive from Turkiye, in a notable parallel with ancient human genome discoveries, we detected a major influx of Western steppe–related ancestry in the Bronze Age.
『摘要』 家羊(Ovis aries)的起源和史前历史尚不完全清楚;为了解决这个问题,我们从欧亚大陆各地采集了跨越12000年的118个古代基因组数据。来自公元前8000年左右土耳其中部的基因组与家羊的起源在遗传上较为接近,但并不能完全解释后来种群的祖先情况,这表明其祖先具有多种野生血统。基因组特征表明,古代牧民对家羊的色素沉着模式、有无角和生长速度进行了选择。尽管最早的欧洲羊群来自土耳其,但与古代人类基因组的发现显著相似的是,我们在青铜时代检测到了大量来自西方草原的相关血统涌入。
『总结』 通过研究118个跨越12000年的古代家羊基因组,揭示了家羊起源的复杂性及古代牧民对家羊性状的选择,同时发现了青铜时代西方草原血统的大量涌入。
10. 氧化铝纳米粒子中η到θ相变的非确定性动力学
Nondeterministic dynamics in the η-to-θ phase transition of alumina nanoparticles
『Abstract』Abstract Phase diagrams and crystallography are standard tools for studying structural phase transitions, whereas acquiring kinetic information at the atomistic level has been considered essential but challenging. The η-to-θ phase transition of alumina is unidirectional in bulk and retains the crystal lattice orientation. We report a rare example of a statistical kinetics study showing that for nanoparticles on a bulk Al(OH) 3 surface, this phase transition occurs nondeterministically through an ergodic equilibrium through the molten state, and the memory of the lattice orientation is lost in this process. The rate of the interconversion was found to be insensitive to the electron dose rate, and this process had a small Gibbs free energy of activation. These nondeterministic kinetics should be a key feature of crystal nucleation occurring in high-surface-energy regions of bulk crystals.
『摘要』 相图和晶体学是研究结构相变的标准工具,然而在原子层面上获取动力学信息虽至关重要,却也充满挑战。氧化铝的η相到θ相转变在块体中是单向的,且保持晶格取向。我们报告了一个统计动力学研究的罕见案例,研究表明,对于块体Al(OH) 3表面的纳米颗粒而言,该相变通过熔融态的非遍历平衡非确定性地发生,并且在此过程中失去了晶格取向的记忆。发现相互转换的速率对电子剂量率不敏感,且该过程的吉布斯自由活化能较小。这种非确定性动力学应是块体晶体高表面能区域中晶体成核的关键特征。
『总结』 研究发现氧化铝纳米颗粒在块体Al(OH) 3表面发生的η到θ相变具有非确定性动力学特征,且此过程中会失去晶格取向记忆。
11. 通过神经源性肥大细胞活化,搔抓可促进过敏性炎症和宿主防御反应
Scratching promotes allergic inflammation and host defense via neurogenic mast cell activation
『Abstract』Abstract Itch is a dominant symptom in dermatitis, and scratching promotes cutaneous inflammation, thereby worsening disease. However, the mechanisms through which scratching exacerbates inflammation and whether scratching provides benefit to the host are largely unknown. We found that scratching was required for skin inflammation in mouse models dependent on FcεRI-mediated mast cell activation. Scratching-induced inflammation required pain-sensing nociceptors, the neuropeptide substance P, and the mast cell receptor MrgprB2. Scratching also increased cutaneous inflammation and augmented host defense to superficial Staphylococcus aureus infection. Thus, through the activation of nociceptor-driven neuroinflammation, scratching both exacerbated allergic skin disease and provided protection from S. aureus , reconciling the seemingly paradoxical role of scratching as a pathological process and evolutionary adaptation.
『摘要』 瘙痒是皮炎的主要症状,抓挠会促进皮肤炎症,从而加重病情。然而,抓挠加剧炎症的机制以及抓挠是否对机体有益,在很大程度上仍不清楚。我们发现,在小鼠模型中,依赖于FcεRI介导的肥大细胞活化的皮肤炎症需要抓挠行为。抓挠诱导的炎症需要疼痛感知的伤害感受器、神经肽P物质和肥大细胞受体MrgprB2。抓挠还会加剧皮肤炎症并增强机体对表皮金黄色葡萄球菌感染的防御能力。因此,通过激活伤害感受器驱动的神经炎症,抓挠既加剧了过敏性皮肤病,又为机体提供了对金黄色葡萄球菌的保护,从而调和了抓挠作为一种病理过程和进化适应看似矛盾的作用。
『总结』 研究发现抓挠行为通过激活伤害感受器驱动的神经炎症,既加剧了皮肤炎症,又增强了机体对金黄色葡萄球菌的防御。
12. 哺乳动物基因组中结构变异的多重生成和单细胞分析
Multiplex generation and single-cell analysis of structural variants in mammalian genomes
『Abstract』Abstract Studying the functional consequences of structural variants (SVs) in mammalian genomes is challenging because (i) SVs arise much less commonly than single-nucleotide variants or small indels and (ii) methods to generate, map, and characterize SVs in model systems are underdeveloped. To address these challenges, we developed Genome-Shuffle-seq, a method that enables the multiplex generation and mapping of thousands of SVs (deletions, inversions, translocations, and extrachromosomal circles) throughout mammalian genomes. We also demonstrate the co-capture of SV identity with single-cell transcriptomes, facilitating the measurement of SV impact on gene expression. We anticipate that Genome-Shuffle-seq will be broadly useful for the systematic exploration of the functional consequences of SVs on gene expression, the chromatin landscape, and three-dimensional nuclear architecture, while also initiating a path toward a minimal mammalian genome.
『摘要』 研究哺乳动物基因组中结构变异(SV)的功能性后果具有挑战性,原因在于:(i)结构变异的出现频率远低于单核苷酸变异或小片段插入/缺失;(ii)在模型系统中生成、定位和表征结构变异的方法尚不成熟。为了应对这些挑战,我们开发了Genome-Shuffle-seq方法,该方法能够在哺乳动物基因组中多路复用地生成和定位数千个结构变异(包括缺失、倒位、易位和染色体外环状DNA)。我们还展示了结构变异特征与单细胞转录组的共同捕获,从而能够评估结构变异对基因表达的影响。我们预计,Genome-Shuffle-seq将广泛用于系统探索结构变异对基因表达、染色质景观和三维核结构的功能性后果,同时为构建最小哺乳动物基因组开辟道路。
『总结』 我们开发了Genome-Shuffle-seq方法,能够高效生成和定位哺乳动物基因组中的多种结构变异,并评估其对基因表达等的影响,为深入研究结构变异的功能性后果和构建最小基因组提供了有力工具。
13. 人与贫困中的老虎恢复
Tiger recovery amid people and poverty
『Abstract』Abstract Recovery of large yet ecologically important carnivores poses a formidable global challenge. Tiger ( Panthera tigris ) recovery in India, the world’s most populated region, offers a distinct opportunity to evaluate the socio-ecological drivers of megafauna recovery. Tiger occupancy increased by 30% (at 2929 square kilometers per year) over the past two decades, leading to the largest global population occupying ~138,200 square kilometers. Tigers persistently occupied human-free, prey-rich protected areas (35,255 square kilometers) but also colonized proximal connected habitats that were shared with ~60 million people. Tiger absence and extinction were characterized by armed conflict, poverty, and extensive land-use changes. Sparing land for tigers enabled land sharing, provided that socioeconomic prosperity and political stability prevailed. India’s tiger recovery offers cautious optimism for megafauna recovery, particularly in the Global South.
『摘要』 在过去二十年中,大型但生态上重要的食肉动物的恢复是一个艰巨的全球挑战。印度是世界上人口最多的地区,其老虎(Panthera tigris)的恢复为评估大型动物恢复的社会生态驱动因素提供了一个独特的机会。过去二十年里,老虎的栖息地增加了30%(每年增加2929平方公里),使全球老虎栖息地总面积达到约138200平方公里,成为最大老虎栖息地。老虎一直占据着没有人类居住且猎物丰富的保护区(35255平方公里),同时也栖息在与约6000万人共享的附近连通栖息地中。老虎的消失和灭绝与武装冲突、贫困和大规模的土地利用变化有关。在社会经济繁荣和政治稳定的前提下,为老虎保留土地可以实现土地共享。印度老虎的恢复让我们对大型动物的恢复持谨慎乐观态度,特别是在全球南方地区。
『总结』 印度老虎栖息地的显著增加为全球大型动物恢复提供了谨慎乐观的前景,特别是在社会经济繁荣和政治稳定的条件下。
14. 厌氧固碳过程中多酶复合体的构象动力学
Conformational dynamics of a multienzyme complex in anaerobic carbon fixation
『Abstract』Abstract In the ancient microbial Wood-Ljungdahl pathway, carbon dioxide (CO 2 ) is fixed in a multistep process that ends with acetyl–coenzyme A (acetyl-CoA) synthesis at the bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase complex (CODH/ACS). In this work, we present structural snapshots of the CODH/ACS from the gas-converting acetogen Clostridium autoethanogenum , characterizing the molecular choreography of the overall reaction, including electron transfer to the CODH for CO 2 reduction, methyl transfer from the corrinoid iron-sulfur protein (CoFeSP) partner to the ACS active site, and acetyl-CoA production. Unlike CODH, the multidomain ACS undergoes large conformational changes to form an internal connection to the CODH active site, accommodate the CoFeSP for methyl transfer, and protect the reaction intermediates. Altogether, the structures allow us to draw a detailed reaction mechanism of this enzyme, which is crucial for CO 2 fixation in anaerobic organisms.
『摘要』 在古老的微生物伍德-朗达尔(Wood-Ljungdahl)途径中,二氧化碳(CO 2)通过一个多步过程被固定,该过程最终在一氧化碳脱氢酶/乙酰辅酶A(乙酰-CoA)合酶复合体(CODH/ACS)处合成乙酰-CoA。本研究展示了来自产气乙酸菌Clostridium autoethanogenum的CODH/ACS的结构快照,描述了整个反应的分子动态过程,包括向CODH的电子转移以促进CO 2还原、从钴胺铁硫蛋白(CoFeSP)配偶体到ACS活性位点的甲基转移以及乙酰-CoA的生成。与CODH不同,多结构域的ACS会发生较大的构象变化,以便与CODH活性位点形成内部连接,容纳CoFeSP以实现甲基转移,并保护反应中间体。总体而言,这些结构使我们能够绘制出这种酶的详细反应机制,该机制对厌氧生物中的CO 2固定至关重要。
『总结』 本研究揭示了产气乙酸菌中CODH/ACS复合体的结构特征和反应机制,为理解厌氧生物中CO 2固定的关键步骤提供了重要信息。
15. 耐用全无机钙钛矿串联光伏器件
Durable all-inorganic perovskite tandem photovoltaics
『Abstract』All-inorganic perovskites prepared by substituting the organic cations (for example, methylammonium and formamidinium) with inorganic cations (for example, Cs ) are effective concepts to enhance the long-term photostability and thermal stability of perovskite solar cells (PSCs) . Hence, inorganic perovskite tandem solar cells (IPTSCs) are promising candidates for breaking the efficiency bottleneck and addressing the stability issue, too . However, challenges remain in fabricating two-terminal (2T) IPTSCs due to the inferior film formation and deep trap states induced by tin cations . Here a ligand evolution (LE) strategy with p -toluenesulfonyl hydrazide (PTSH) is used to regulate film formation and eliminate deep traps in inorganic narrow-bandgap (NBG) perovskites, enabling the successful development of 2T IPTSCs. Accordingly, the 1.31 eV CsPb 0.4 Sn 0.6 I 3 :LE device delivers a record efficiency of 17.41%. Combined with the 1.92 eV CsPbI 2 Br top cell, 2T IPTSCs exhibit a champion efficiency of 22.57% (certified, 21.92%). Moreover, IPTSCs are engineered to deliver remarkable durability under maximum power point (MPP) tracking, maintaining 80% of their initial efficiency at 65 °C for 1,510 h and at 85 °C for 800 h. We elucidate that LE deliberately leverages multiple roles for inorganic NBG perovskite growth and anticipate that our study provides an insightful guideline for developing high-efficiency and stable IPTSCs.
『摘要』 用无机阳离子(例如铯)取代有机阳离子(例如甲胺和甲脒)制备的全无机钙钛矿,是提高钙钛矿太阳能电池(PSCs)长期光稳定性和热稳定性的有效方法。因此,无机钙钛矿叠层太阳能电池(IPTSCs)也有望成为打破效率瓶颈和解决稳定性问题的候选方案。然而,由于锡阳离子导致的成膜质量差和深陷阱态,在制备两端(2T)IPTSCs时仍存在挑战。本研究采用对甲苯磺酰肼(PTSH)的配体演化(LE)策略来调节无机窄带隙(NBG)钙钛矿的成膜过程并消除深陷阱,从而成功开发出2T IPTSCs。因此,1.31电子伏特(eV)的CsPb0.4Sn0.6I3:LE器件实现了17.41%的创纪录效率。与1.92 eV的CsPbI2Br顶电池结合,2T IPTSCs表现出22.57%的冠军效率(经认证为21.92%)。此外,IPTSCs还被设计为在最大功率点(MPP)跟踪下具有卓越的耐久性,在65°C下保持1510小时和在85°C下保持800小时后,仍能维持80%的初始效率。本研究阐明,LE策略在无机NBG钙钛矿的生长中发挥了多重作用,并期望本研究能为开发高效稳定的IPTSCs提供有见地的指导。
『总结』 本研究通过配体演化策略成功开发出高效且稳定的两端无机钙钛矿叠层太阳能电池,为解决钙钛矿太阳能电池的效率和稳定性问题提供了新思路。
16. 利用原子力显微镜和深度神经网络确定RNA构象体的结构
Determining structures of RNA conformers using AFM and deep neural networks
『Abstract』Much of the human genome is transcribed into RNAs , many of which contain structural elements that are important for their function. Such RNA molecules—including those that are structured and well-folded —are conformationally heterogeneous and flexible, which is a prerequisite for function , but this limits the applicability of methods such as NMR, crystallography and cryo-electron microscopy for structure elucidation. Moreover, owing to the lack of a large RNA structure database, and no clear correlation between sequence and structure, approaches such as AlphaFold for protein structure prediction do not apply to RNA. Therefore, determining the structures of heterogeneous RNAs remains an unmet challenge. Here we report holistic RNA structure determination method using atomic force microscopy, unsupervised machine learning and deep neural networks (HORNET), a novel method for determining three-dimensional topological structures of RNA using atomic force microscopy images of individual molecules in solution. Owing to the high signal-to-noise ratio of atomic force microscopy, this method is ideal for capturing structures of large RNA molecules in distinct conformations. In addition to six benchmark cases, we demonstrate the utility of HORNET by determining multiple heterogeneous structures of RNase P RNA and the HIV-1 Rev response element (RRE) RNA. Thus, our method addresses one of the major challenges in determining heterogeneous structures of large and flexible RNA molecules, and contributes to the fundamental understanding of RNA structural biology.
『摘要』 人类基因组的大部分会转录成RNA,其中许多RNA包含对其功能至关重要的结构元素。这些RNA分子(包括那些结构良好且折叠良好的分子)在构象上是异质且灵活的,这是其功能发挥的前提条件,但也限制了核磁共振、晶体学和冷冻电子显微镜等方法在结构阐明中的应用。此外,由于缺乏大型的RNA结构数据库,以及序列与结构之间缺乏明确的相关性,诸如用于蛋白质结构预测的AlphaFold等方法并不适用于RNA。因此,确定异质RNA的结构仍然是一个未解决的挑战。本研究报告了一种使用原子力显微镜、无监督机器学习和深度神经网络的整体RNA结构测定方法(HORNET),这是一种利用原子力显微镜拍摄溶液中单个分子的图像来确定RNA三维拓扑结构的新方法。由于原子力显微镜具有高信噪比,这种方法非常适合捕捉不同构象的大型RNA分子的结构。除了六个基准案例外,本研究还通过确定RNase P RNA和HIV-1 Rev反应元件(RRE)RNA的多个异质结构,证明了HORNET的实用性。因此,我们的方法解决了在确定大型和灵活RNA分子的异质结构方面存在的主要挑战之一,并为RNA结构生物学的基本理解做出了贡献。
『总结』 本研究开发了一种名为HORNET的新方法,结合原子力显微镜、无监督机器学习和深度神经网络,成功解决了大型灵活RNA分子异质结构测定的重大挑战。
17. 肝X受体解除肠道再生与肿瘤生成的关联
Liver X receptor unlinks intestinal regeneration and tumorigenesis
『Abstract』Uncontrolled regeneration leads to neoplastic transformation . The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin ( Areg ), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1 , LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis.
『摘要』 未受控制的再生会导致肿瘤转化。肠道上皮在持续稳态和损伤诱导的组织更新过程中需要精确的调控,以防止肿瘤转化,这表明一定存在将肿瘤生长与再生过程分离开来的途径。本研究通过挖掘两个肠道损伤模型的RNA测序数据集,并利用药理学、转录组学和遗传学工具,确定了肝X受体(LXR)通路激活是一种损伤后的组织适应反应,可相互调节肠道再生和肿瘤发生。通过单细胞RNA测序、肠道类器官以及功能增强和丧失实验,我们发现肠道上皮细胞中的LXR激活可诱导双调蛋白(Areg)的产生,从而增强再生反应。这一反应由LXR配体产生酶CYP27A1协调,该酶在受损的肠道隐窝微环境中上调。敲除Cyp27a1会损害肠道再生,而外源性LXR激动剂可以挽救这一现象。值得注意的是,在肿瘤模型中,Cyp27a1缺乏会导致肿瘤生长增加,而LXR激活则引发依赖于适应性免疫的抗肿瘤反应。同样,人类结直肠癌标本中的CYP27A1、LXR靶基因以及B细胞和CD8 T细胞基因特征均表达降低。因此,我们发现了一种上皮适应损伤的机制,其中LXR作为变阻器,在促进组织修复的同时限制肿瘤发生。
『总结』 研究表明,肝X受体(LXR)通路在肠道损伤后被激活,可协调组织再生并抑制肿瘤发生,为肠道上皮提供了一种适应损伤的机制。
18. 具有点状费米面的半金属外尔铁磁体的合成
Synthesis of a semimetallic Weyl ferromagnet with point Fermi surface
『Abstract』Quantum materials governed by emergent topological fermions have become a cornerstone of physics. Dirac fermions in graphene form the basis for moire quantum matter and Dirac fermions in magnetic topological insulators enabled the discovery of the quantum anomalous Hall (QAH) effect . By contrast, there are few materials whose electromagnetic response is dominated by emergent Weyl fermions . Nearly all known Weyl materials are overwhelmingly metallic and are largely governed by irrelevant, conventional electrons. Here we theoretically predict and experimentally observe a semimetallic Weyl ferromagnet in van der Waals (Cr,Bi) 2 Te 3 . In transport, we find a record bulk anomalous Hall angle of greater than 0.5 along with non-metallic conductivity, a regime that is strongly distinct from conventional ferromagnets. Together with symmetry analysis, our data suggest a semimetallic Fermi surface composed of two Weyl points, with a giant separation of more than 75% of the linear dimension of the bulk Brillouin zone, and no other electronic states. Using state-of-the-art crystal-synthesis techniques, we widely tune the electronic structure, allowing us to annihilate the Weyl state and visualize a unique topological phase diagram exhibiting broad Chern insulating, Weyl semimetallic and magnetic semiconducting regions. Our observation of a semimetallic Weyl ferromagnet offers an avenue towards new correlated states and nonlinear phenomena, as well as zero-magnetic-field Weyl spintronic and optical devices.
『摘要』 由新兴拓扑费米子支配的量子材料已成为物理学的基石。石墨烯中的狄拉克费米子构成了摩尔量子物质的基础,而磁性拓扑绝缘体中的狄拉克费米子促成了量子反常霍尔(QAH)效应的发现。相比之下,几乎没有哪种材料的电磁响应是由新兴外尔费米子主导的。几乎所有已知的外尔材料都主要呈现出金属性,并且主要受无关的传统电子支配。本文从理论上预测并在实验中观察到范德华(Cr,Bi)2Te3中的一种半金属外尔铁磁体。在传输实验中,我们发现其体态反常霍尔角大于0.5,且具有非金属导电性,这种特性与传统铁磁体截然不同。结合对称性分析,我们的数据表明,该材料有一个由两个外尔点组成的半金属费米面,这两个外尔点之间的距离巨大,超过了体态布里渊区线性尺寸的75%,且没有其他电子态。我们采用最先进的晶体合成技术,广泛调整其电子结构,使我们能够湮灭外尔态,并直观地看到一个独特的拓扑相图,该相图显示出广泛的陈绝缘区、外尔半金属区和磁性半导体区。我们对半金属外尔铁磁体的观察为探索新的相关态和非线性现象,以及开发零磁场外尔自旋电子和光学器件提供了一条途径。
『总结』 本研究发现并证实了范德华(Cr,Bi)2Te3中的半金属外尔铁磁体,其独特的电磁响应和拓扑相图为探索新的物理现象和应用提供了可能。
19. 石墨烯/六方氮化硼摩尔超晶格中的扩展量子反常霍尔态
Extended quantum anomalous Hall states in graphene/hBN moire superlattices
『Abstract』Electrons in topological flat bands can form new topological states driven by correlation effects. The pentalayer rhombohedral graphene/hexagonal boron nitride (hBN) moire superlattice was shown to host fractional quantum anomalous Hall effect (FQAHE) at approximately 400 mK (ref. ), triggering discussions around the underlying mechanism and role of moire effects . In particular, new electron crystal states with non-trivial topology have been proposed . Here we report electrical transport measurements in rhombohedral pentalayer and tetralayer graphene/hBN moire superlattices at electronic temperatures down to below 40 mK. We observed two more fractional quantum anomalous Hall (FQAH) states and smaller R xx values in pentalayer devices than those previously reported. In the new tetralayer device, we observed FQAHE at moire filling factors v = 3/5 and 2/3. With a small current at the base temperature, we observed a new extended quantum anomalous Hall (EQAH) state and magnetic hysteresis, where R xy = h / e and vanishing R xx spans a wide range of v from 0.5 to 1.3. At increased temperature or current, EQAH states disappear and partially transition into the FQAH liquid . Furthermore, we observed displacement field-induced quantum phase transitions from the EQAH states to the Fermi liquid, FQAH liquid and the likely composite Fermi liquid. Our observations established a new topological phase of electrons with quantized Hall resistance at zero magnetic field and enriched the emergent quantum phenomena in materials with topological flat bands.
『摘要』 拓扑平带中的电子可以受相关效应驱动而形成新的拓扑态。研究表明,五层菱形石墨烯/六方氮化硼(hBN)摩尔超晶格在约400 mK时表现出分数量子反常霍尔效应(FQAHE),引发了关于潜在机制及摩尔效应作用的讨论。特别地,有人提出了具有非平庸拓扑特性的新型电子晶体态。本文报道了在电子温度低至40 mK以下时,对菱形五层和四层石墨烯/hBN摩尔超晶格进行的电输运测量结果。我们在五层器件中观察到了另外两个分数量子反常霍尔(FQAH)态,且R xx值比之前报道的更小。在新的四层器件中,我们在摩尔填充因子v = 3/5和2/3时观察到了FQAHE。在基础温度下通以小电流,我们观察到了一个新的扩展量子反常霍尔(EQAH)态和磁滞现象,其中R xy = h / e,且R xx在v从0.5到1.3的宽范围内均消失。随着温度升高或电流增大,EQAH态消失,并部分转变为FQAH液体。此外,我们还观察到了由位移场诱导的从EQAH态到费米液体、FQAH液体以及可能的复合费米液体的量子相变。我们的研究发现了一种新的电子拓扑相,该相在无磁场时具有量子化的霍尔电阻,并丰富了具有拓扑平带的材料中出现的量子现象。
『总结』 本研究在极低温下对石墨烯/hBN摩尔超晶格进行了电输运测量,发现了新的分数量子反常霍尔态和扩展量子反常霍尔态,以及多种量子相变,为理解拓扑平带中的电子行为提供了新的视角。
20. 单等位基因表达可控制免疫先天错误的显性度
Monoallelic expression can govern penetrance of inborn errors of immunity
『Abstract』Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy . Incomplete penetrance is common among IEIs despite their monogenic basis . Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele , to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters allele expression commitment, in support of two proposed mechanisms for the regulation of aRMAE. We tested peripheral blood mononuclear cells from individuals with IEIs with shared genetic lesions but discordant clinical phenotypes for aRMAE. Among two relatives who were heterozygous for a mutation in PLCG2 (delEx19), an antibody deficiency phenotype corresponds to selective mutant allele expression in B cells. By contrast, among relatives who were heterozygous for a mutation in JAK1 (c.2099G>A; p.S700N), the unaffected carrier T cells predominantly expressed the wild-type JAK1 allele, whereas the affected carrier T cells exhibited biallelic expression. Allelic expression bias was also documented in phenotypically discordant family members with mutations in STAT1 and CARD11 . This study highlights the importance of considering both the genotype and the ‘transcriptotype’ in analyses of the penetrance and expressivity of monogenic disorders.
『摘要』 原发性免疫缺陷病(IEIs)是一种遗传性疾病,可导致易感感染、自身免疫、自身炎症、过敏和/或恶性肿瘤。尽管原发性免疫缺陷病具有单基因基础,但不完全外显率却很常见。本研究探讨了常染色体随机单等位基因表达(aRMAE,即一种体细胞对单等位基因表达的承诺)对原发性免疫缺陷病患者家族中观察到的表型变异的影响。研究者利用克隆性原代T细胞系统评估健康个体中基因的aRMAE状态,发现4.30%的原发性免疫缺陷病相关基因和5.20%的全部基因存在aRMAE。H3K27me3和DNA甲基化的改变会影响等位基因表达承诺,这支持了aRMAE调控的两种机制。研究者对有相同基因病变但临床表型不一致的原发性免疫缺陷病患者的外周血单核细胞进行了aRMAE检测。在两名PLCG2基因(delEx19)杂合突变携带者中,B细胞选择性突变等位基因表达的患者表现出抗体缺陷表型。相比之下,在JAK1基因(c.2099G>A;p.S700N)杂合突变携带者中,未受影响的携带者T细胞主要表达野生型JAK1等位基因,而受影响的携带者T细胞则表现出双等位基因表达。在具有STAT1和CARD11突变的表型不一致的家族成员中,也记录到了等位基因表达偏倚。本研究强调了在分析单基因疾病的外显率和表现度时,需同时考虑基因型和“转录型”的重要性。
『总结』 本研究发现常染色体随机单等位基因表达影响原发性免疫缺陷病的表型变异,强调了基因型和转录型在分析单基因疾病时的重要性。
21. 扭曲石墨烯中的莫尔驱动拓扑电子晶体
Moire-driven topological electronic crystals in twisted graphene
『Abstract』In a dilute two-dimensional electron gas, Coulomb interactions can stabilize the formation of a Wigner crystal . Although Wigner crystals are topologically trivial, it has been predicted that electrons in a partially filled band can break continuous translational symmetry and time-reversal symmetry spontaneously, resulting in a type of topological electron crystal known as an anomalous Hall crystal . Here we report signatures of a generalized version of the anomalous Hall crystal in twisted bilayer–trilayer graphene, whose formation is driven by the moire potential. The crystal forms at a band filling of one electron per four moire unit cells ( ν = 1/4) and quadruples the unit-cell area, coinciding with an integer quantum anomalous Hall effect. The Chern number of the state is exceptionally tunable, and it can be switched reversibly between +1 and −1 by electric and magnetic fields. Several other topological electronic crystals arise in a modest magnetic field, originating from ν = 1/3, 1/2, 2/3 and 3/2. The quantum geometry of the interaction-modified bands is likely to be very different from that of the original parent band, which enables possible future discoveries of correlation-driven topological phenomena.
『摘要』 在稀释的二维电子气中,库仑相互作用可以稳定维格纳晶体的形成。尽管维格纳晶体在拓扑上是平庸的,但据预测,部分填充能带中的电子可以自发地打破连续的平移对称性和时间反演对称性,从而产生一种被称为反常霍尔晶体的拓扑电子晶体。在此,我们报告了在扭曲的双层-三层石墨烯中发现了一种广义反常霍尔晶体的特征,其形成是由摩尔势驱动的。该晶体在每四个摩尔单元格填充一个电子(ν=1/4)时形成,并使单元格面积增大四倍,同时伴随着整数量子反常霍尔效应的出现。该状态下的陈数具有异常的可调性,并且可以通过电场和磁场在+1和-1之间可逆切换。在适度的磁场中,还出现了其他几种拓扑电子晶体,它们分别源自ν=1/3、1/2、2/3和3/2。相互作用修饰能带的量子几何形状可能与原始母带的量子几何形状截然不同,这有望在未来发现由相关性驱动的拓扑现象。
『总结』 研究发现扭曲双层-三层石墨烯中可形成由摩尔势驱动的广义反常霍尔晶体,其展现出可调的陈数和整数量子反常霍尔效应。
22. 元素冷冻成像揭示依赖于SOS1的液泡钠积累
Elemental cryo-imaging reveals SOS1-dependent vacuolar sodium accumulation
『Abstract』Increasing soil salinity causes significant crop losses globally; therefore, understanding plant responses to salt (sodium) stress is of high importance. Plants avoid sodium toxicity through subcellular compartmentation by intricate processes involving a high level of elemental interdependence. Current technologies to visualize sodium, in particular, together with other elements, are either indirect or lack in resolution. Here we used the newly developed cryo nanoscale secondary ion mass spectrometry ion microprobe , which allows high-resolution elemental imaging of cryo-preserved samples and reveals the subcellular distributions of key macronutrients and micronutrients in root meristem cells of Arabidopsis and rice. We found an unexpected, concentration-dependent change in sodium distribution, switching from sodium accumulation in the cell walls at low external sodium concentrations to vacuolar accumulation at stressful concentrations. We conclude that, in root meristems, a key function of the NHX family sodium/proton antiporter SALT OVERLY SENSITIVE 1 (also known as Na /H exchanger 7; SOS1/NHX7) is to sequester sodium into vacuoles, rather than extrusion of sodium into the extracellular space. This is corroborated by the use of new genomic, complementing fluorescently tagged SOS1 variants. We show that, in addition to the plasma membrane, SOS1 strongly accumulates at late endosome/prevacuoles as well as vacuoles, supporting a role of SOS1 in vacuolar sodium sequestration.
『摘要』 全球范围内,土壤盐度增加导致农作物产量大幅损失;因此,了解植物对盐(钠)胁迫的响应至关重要。植物通过涉及高度元素相互依赖的复杂过程,实现亚细胞区室化,从而避免钠毒性。目前,可视化钠的技术,尤其是与其他元素同时可视化的技术,或是具有间接性,或是分辨率不足。本研究使用了新开发的冷冻纳米次级离子质谱离子显微探针,该技术可对冷冻保存的样品进行高分辨率元素成像,并揭示拟南芥和水稻根分生组织细胞中关键常量元素和微量元素的亚细胞分布。我们发现了钠分布随浓度变化的意外现象:在低外部钠浓度下,钠在细胞壁中积累;而在高胁迫浓度下,钠则在液泡中积累。我们得出结论,在根分生组织中,NHX家族钠/氢逆向转运蛋白SALT OVERLY SENSITIVE 1(也称为Na+/H+交换体7;SOS1/NHX7)的关键功能是将钠隔离到液泡中,而不是将钠排出到细胞外空间。这一结论通过使用新的基因组学和互补的荧光标记SOS1变体得到了证实。我们的研究表明,SOS1不仅大量存在于质膜上,还强烈积累在晚期核内体/前液泡以及液泡中,这支持了SOS1在液泡钠隔离中的作用。
『总结』 本研究利用新技术揭示了植物根分生组织细胞中钠的亚细胞分布变化,发现SOS1蛋白在液泡钠隔离中发挥关键作用。
23. 用于触觉引导舌头控制的丘状图
A collicular map for touch-guided tongue control
『Abstract』Accurate goal-directed behaviour requires the sense of touch to be integrated with information about body position and ongoing motion . Behaviours such as chewing, swallowing and speech critically depend on precise tactile events on a rapidly moving tongue , but neural circuits for dynamic touch-guided tongue control are unknown. Here, using high-speed videography, we examined three-dimensional lingual kinematics as mice drank from a water spout that unexpectedly changed position during licking, requiring re-aiming in response to subtle contact events on the left, centre or right surface of the tongue. Mice integrated information about both precise touch events and tongue position to re-aim ensuing licks. Touch-guided re-aiming was unaffected by photoinactivation of tongue sensory, premotor and motor cortices, but was impaired by photoinactivation of the lateral superior colliculus (latSC). Electrophysiological recordings identified latSC neurons with mechanosensory receptive fields for precise touch events that were anchored in tongue-centred, head-centred or conjunctive reference frames. Notably, latSC neurons also encoded tongue position before contact, information that is important for tongue-to-head-based coordinate transformations underlying accurate touch-guided aiming. Viral tracing revealed tongue sensory inputs to the latSC from the lingual trigeminal nucleus, and optical microstimulation in the latSC revealed a topographic map for aiming licks. These findings demonstrate that touch-guided tongue control relies on a collicular mechanosensorimotor map, analogous to collicular visuomotor maps associated with visually guided orienting across many species.
『摘要』 精确的目标导向行为需要将触觉信息与身体位置和持续运动的信息相结合。咀嚼、吞咽和说话等行为严重依赖于快速移动的舌头上精确的触觉事件,但动态触觉引导舌头控制的神经回路尚不清楚。在本研究中,我们使用高速摄像技术,观察了小鼠在从水嘴喝水时的三维舌部运动学特征,水嘴会在舔舐过程中意外改变位置,这就需要小鼠根据舌头左侧、中间或右侧表面的轻微触觉事件重新调整舔舐目标。小鼠会整合关于精确触觉事件和舌头位置的信息,以重新调整后续的舔舐方向。光失活舌感觉皮层、运动前皮层和运动皮层并不影响触觉引导的重新定位,但光失活外侧上丘(latSC)则会损害这一过程。电生理记录发现了latSC神经元具有机械感觉感受野,这些感受野以舌头为中心、以头部为中心或结合两种参考系,对精确的触觉事件作出反应。值得注意的是,latSC神经元还编码接触前的舌头位置信息,这一信息对于基于舌头到头部的坐标转换至关重要,是实现精确触觉引导定位的基础。病毒追踪显示,舌三叉神经核向latSC传递舌感觉输入,而在latSC的光微刺激则揭示了一个用于定位舔舐的地形图。这些发现表明,触觉引导的舌头控制依赖于上丘的机械感觉运动图,类似于许多物种中与视觉引导定位相关的上丘视觉运动图。
『总结』 研究表明,触觉引导的舌头控制依赖于一个类似于视觉引导定位中的上丘视觉运动图的上丘机械感觉运动图。
24. 铁器时代英国的大陆人口涌入与普遍的母系居住制度
Continental influx and pervasive matrilocality in Iron Age Britain
『Abstract』Roman writers found the relative empowerment of Celtic women remarkable . In southern Britain, the Late Iron Age Durotriges tribe often buried women with substantial grave goods . Here we analyse 57 ancient genomes from Durotrigian burial sites and find an extended kin group centred around a single maternal lineage, with unrelated (presumably inward migrating) burials being predominantly male. Such a matrilocal pattern is undescribed in European prehistory, but when we compare mitochondrial haplotype variation among European archaeological sites spanning six millennia, British Iron Age cemeteries stand out as having marked reductions in diversity driven by the presence of dominant matrilines. Patterns of haplotype sharing reveal that British Iron Age populations form fine-grained geographical clusters with southern links extending across the channel to the continent. Indeed, whereas most of Britain shows majority genomic continuity from the Early Bronze Age to the Iron Age, this is markedly reduced in a southern coastal core region with persistent cross-channel cultural exchange . This southern core has evidence of population influx in the Middle Bronze Age but also during the Iron Age. This is asynchronous with the rest of the island and points towards a staged, geographically granular absorption of continental influence, possibly including the acquisition of Celtic languages.
『摘要』 罗马作家发现凯尔特女性相对较高的社会地位十分引人注目。在英国南部,铁器时代晚期的杜罗特里奇斯部落经常为女性陪葬大量的随葬品。我们分析了来自杜罗特里奇斯人墓葬地的57个古代基因组,并发现了一个以单一母系血统为中心的庞大的亲属群体,而与之无关(推测为迁入)的墓葬主要为男性。这种母系模式在欧洲史前时期从未被描述过,但是当我们比较跨越六千年的欧洲考古遗址的线粒体单倍型变异时,英国铁器时代的墓地因其主导母系血统的存在而表现出显著的多样性减少。单倍型共享模式揭示,英国铁器时代的人口形成了精细的地理集群,南部的联系跨越英吉利海峡延伸至欧洲大陆。事实上,虽然英国大部分地区从青铜时代早期到铁器时代都表现出主要的基因组连续性,但在南部沿海核心地区,这种连续性因持续不断的跨海峡文化交流而显著减少。这个南部核心地区在中青铜时代和铁器时代都有人口涌入的证据。这与岛上其他地区不同步,表明大陆影响是分阶段、地理上逐步吸收的,可能包括凯尔特语的习得。
『总结』 英国铁器时代墓地显示出母系主导和减少的遗传多样性,揭示出与欧洲大陆不同步的文化交流和可能的凯尔特语言习得。
25. 肌营养不良蛋白糖蛋白复合物的结构和组装
Structure and assembly of the dystrophin glycoprotein complex
『Abstract』The dystrophin glycoprotein complex (DGC) has a crucial role in maintaining cell membrane stability and integrity by connecting the intracellular cytoskeleton with the surrounding extracellular matrix . Dysfunction of dystrophin and its associated proteins results in muscular dystrophy, a disorder characterized by progressive muscle weakness and degeneration . Despite the important roles of the DGC in physiology and pathology, its structural details remain largely unknown, hindering a comprehensive understanding of its assembly and function. Here we isolated the native DGC from mouse skeletal muscle and obtained its high-resolution structure. Our findings unveil a markedly divergent structure from the previous model of DGC assembly. Specifically, on the extracellular side, β-, γ- and δ-sarcoglycans co-fold to form a specialized, extracellular tower-like structure, which has a central role in complex assembly by providing binding sites for α-sarcoglycan and dystroglycan. In the transmembrane region, sarcoglycans and sarcospan flank and stabilize the single transmembrane helix of dystroglycan, rather than forming a subcomplex as previously proposed . On the intracellular side, sarcoglycans and dystroglycan engage in assembly with the dystrophin–dystrobrevin subcomplex through extensive interaction with the ZZ domain of dystrophin. Collectively, these findings enhance our understanding of the structural linkage across the cell membrane and provide a foundation for the molecular interpretation of many muscular dystrophy-related mutations.
『摘要』 抗肌萎缩蛋白糖蛋白复合物(DGC)在将细胞内骨架与周围细胞外基质连接方面对于维持细胞膜的稳定性和完整性至关重要。抗肌萎缩蛋白及其相关蛋白的功能障碍会导致肌肉营养不良,这是一种以进行性肌肉无力和退化为特征的疾病。尽管DGC在生理学和病理学中具有重要作用,但其结构细节仍知之甚少,这阻碍了对其组装和功能的全面理解。在这里,我们从小鼠骨骼肌中分离出了天然DGC,并获得了其高分辨率结构。我们的研究结果揭示了与先前DGC组装模型明显不同的结构。具体而言,在细胞外侧,β-、γ-和δ-肌聚糖共同折叠形成一个专门化的、细胞外塔状结构,该结构通过为α-肌聚糖和抗肌萎缩蛋白聚糖提供结合位点,在复合物组装中发挥核心作用。在跨膜区,肌聚糖和肌聚糖跨膜蛋白在抗肌萎缩蛋白聚糖的单跨膜螺旋两侧排列并使其稳定,而不是像先前提出的那样形成一个亚复合物。在细胞内侧,肌聚糖和抗肌萎缩蛋白聚糖通过与抗肌萎缩蛋白的ZZ结构域广泛相互作用,与抗肌萎缩蛋白-抗肌萎缩蛋白相关蛋白亚复合物结合。总体而言,这些研究结果增强了我们对细胞膜跨膜结构联系的理解,并为许多肌肉营养不良相关突变的分子解释提供了基础。
『总结』 本研究揭示了抗肌萎缩蛋白糖蛋白复合物的高分辨率结构,为理解细胞膜跨膜结构联系和肌肉营养不良相关突变提供了重要基础。
26. 原生DGC结构阐释了导致肌肉萎缩症的突变
Native DGC structure rationalizes muscular dystrophy-causing mutations
『Abstract』Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder marked by progressive muscle wasting leading to premature mortality . Discovery of the DMD gene encoding dystrophin both revealed the cause of DMD and helped identify a family of at least ten dystrophin-associated proteins at the muscle cell membrane, collectively forming the dystrophin–glycoprotein complex (DGC) . The DGC links the extracellular matrix to the cytoskeleton, but, despite its importance, its molecular architecture has remained elusive. Here we determined the native cryo-electron microscopy structure of rabbit DGC and conducted biochemical analyses to reveal its intricate molecular configuration. An unexpected β-helix comprising β-, γ- and δ-sarcoglycan forms an extracellular platform that interacts with α-dystroglycan, β-dystroglycan and α-sarcoglycan, allowing α-dystroglycan to contact the extracellular matrix. In the membrane, sarcospan anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, while in the cytoplasm, β-dystroglycan’s juxtamembrane fragment binds dystrophin’s ZZ domain. Through these interactions, the DGC links laminin 2 to intracellular actin. Additionally, dystrophin’s WW domain, along with its EF-hand 1 domain, interacts with α-dystrobrevin. A disease-causing mutation mapping to the WW domain weakens this interaction, as confirmed by deletion of the WW domain in biochemical assays. Our findings rationalize more than 110 mutations affecting single residues associated with various muscular dystrophy subtypes and contribute to ongoing therapeutic developments, including protein restoration, upregulation of compensatory genes and gene replacement.
『摘要』 Duchenne肌营养不良(DMD)是一种严重的X连锁隐性遗传病,以进行性肌肉消瘦为特征,最终导致早逝。DMD基因(编码肌营养不良蛋白)的发现不仅揭示了DMD的病因,还帮助确定了肌肉细胞膜上至少由十种肌营养不良蛋白相关蛋白组成的家族,这些蛋白共同构成了肌营养不良蛋白-糖蛋白复合体(DGC)。DGC将细胞外基质与细胞骨架连接起来,但尽管其很重要,其分子结构却一直难以捉摸。在此,我们确定了兔DGC的原生冷冻电子显微镜结构,并进行了生化分析,以揭示其复杂的分子构型。一个由β-、γ-和δ-肌聚糖组成的意外β-螺旋形成了一个细胞外平台,该平台与α-肌营养不良蛋白聚糖、β-肌营养不良蛋白聚糖和α-肌聚糖相互作用,使α-肌营养不良蛋白聚糖能够与细胞外基质接触。在膜中,sarcospan将β-肌营养不良蛋白聚糖锚定到β-、γ-和δ-肌聚糖三聚体上,而在细胞质中,β-肌营养不良蛋白聚糖的近膜片段与肌营养不良蛋白的ZZ结构域结合。通过这些相互作用,DGC将层粘连蛋白2与细胞内肌动蛋白连接起来。此外,肌营养不良蛋白的WW结构域与其EF-hand 1结构域一起与α-肌营养不良相关蛋白相互作用。生化分析中的WW结构域缺失证实,映射到WW结构域上的致病突变会削弱这种相互作用。我们的研究结果合理解释了影响与各种肌营养不良亚型相关的单个残基的110多个突变,并为正在进行的治疗方法开发(包括蛋白质恢复、补偿性基因上调和基因替换)做出了贡献。
『总结』 本研究揭示了DGC的复杂分子结构,解释了多种致病突变,并为DMD的治疗提供了重要依据。
27. 中和GDF-15可以克服固体肿瘤对PD-1抑制剂和PD-L1抑制剂的耐药性
Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours
『Abstract』Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment . Yet, response rates are still limited, and tumour progression commonly occurs . Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition . In a first-in-human phase 1–2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.
『摘要』 阻断免疫检查点分子的抗体癌症免疫疗法在多种癌症中均表现出临床疗效,并显著改善了癌症治疗。然而,该疗法的应答率仍然有限,肿瘤进展仍时有发生。肿瘤微环境中的可溶性因子和细胞结合因子对癌症免疫产生负面影响。近期研究发现,生长分化因子15(GDF-15)是一种由多种癌症大量产生的细胞因子,会干扰抗肿瘤免疫反应。在临床前癌症模型中,阻断GDF-15可协同增强抗程序性死亡受体-1(anti-PD-1)介导的检查点抑制的疗效。在一项首次人体1~2a期研究(GDFATHER-1/2a试验,NCT04725474)中,对抗PD-1或抗PD-L1治疗(统称为抗PD-1/PD-L1治疗耐药)难治性的晚期癌症患者,采用了中和性抗GDF-15抗体visugromab(CTL-002)联合抗PD-1抗体纳武利尤单抗的治疗方案。本研究显示,部分非鳞状非小细胞肺癌和尿路上皮癌患者获得了持久且深度的应答,这两种癌症实体在癌症基因组图谱数据库中约10000个肿瘤样本的计算机筛选中被确定为常受到GDF-15免疫抑制的癌症。治疗后观察到肿瘤浸润、增殖增加,细胞毒性T细胞的干扰素-γ相关信号传导和颗粒酶B表达增强。中和GDF-15有望克服癌症对免疫检查点抑制治疗的耐药性。
『总结』 研究发现中和生长分化因子15(GDF-15)或可增强部分晚期癌症患者对免疫检查点抑制剂治疗的应答,为克服治疗耐药性提供新策略。
28. 北溪海底管道泄漏的甲烷排放
Methane emissions from the Nord Stream subsea pipeline leaks
『Abstract』The amount of methane released to the atmosphere from the Nord Stream subsea pipeline leaks remains uncertain, as reflected in a wide range of estimates . A lack of information regarding the temporal variation in atmospheric emissions has made it challenging to reconcile pipeline volumetric (bottom-up) estimates with measurement-based (top-down) estimates
『摘要』 对北溪海底管道泄漏向大气中释放的甲烷量,人们仍无法确定,这体现在各种估算结果存在巨大差异上。由于缺乏有关大气排放时间变化的信息,因此难以将基于管道体积(自下而上)的估算结果与基于测量(自上而下)的估算结果统一起来。
『总结』 北溪海底管道泄漏的甲烷量仍不确定,估算差异大,且因缺乏时间变化信息而难以调和不同估算方法的结果。
29. 前列腺癌中髓系介导的免疫治疗耐药的演变
Evolution of myeloid-mediated immunotherapy resistance in prostate cancer
『Abstract』Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs) , partly because there are immunosuppressive myeloid cells in tumours . However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts ( SPP1 -TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8 T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1 -TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1 -TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1 -TAM-mediated immunosuppression in CD8 T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1 -TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1 -TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.
『摘要』 转移性去势抵抗性前列腺癌(mCRPC)晚期患者对免疫检查点抑制剂(ICI)产生耐药性,部分原因是肿瘤中存在免疫抑制性髓系细胞。然而,髓系细胞的异质性导致它们难以成为靶标,从而使集落刺激因子-1受体(CSF1R)阻断剂在临床上无效。本研究对处于疾病连续谱的患者活检样本进行了单细胞分析,发现一群转录水平上调的分泌型磷蛋白1(SPP1)转录本的肿瘤相关巨噬细胞(SPP1-TAM)随着前列腺癌进展至mCRPC而逐渐增多。在同基因小鼠模型中,类似的巨噬细胞群可在体外抑制CD8 T细胞活性,并在体内促进ICI耐药。此外,SPP1-TAM对抗CSF1R抗体治疗无反应。通路分析确定,腺苷信号传导是SPP1-TAM介导免疫治疗耐药的潜在机制。的确,药理抑制腺苷A2A受体(A2AR)可显著逆转SPP1-TAM在体外介导的CD8 T细胞免疫抑制,并在体内增强去势抵抗性前列腺癌(CRPC)对程序性细胞死亡蛋白1(PD-1)阻断治疗的反应性。与临床前研究结果一致,使用ciforadenant抑制A2AR联合使用atezolizumab阻断程序性死亡配体1(PD-L1),可使mCRPC患者产生临床应答。此外,抑制A2AR可显著降低CRPC中SPP1-TAM的数量,表明该通路参与耐药性的诱导和下游免疫抑制。综上,这些研究结果表明,SPP1-TAM通过腺苷信号传导成为mCRPC中ICI耐药性的关键介质,强调了其作为治疗靶点和预测治疗疗效的潜在生物标志物的重要性。
『总结』 研究发现SPP1-TAM通过腺苷信号导致mCRPC患者产生免疫检查点抑制剂耐药性,为治疗该疾病提供了新靶点和潜在疗效预测标志物。
30. 贝努样本中记录的来自古代盐水的蒸发岩序列
An evaporite sequence from ancient brine recorded in Bennu samples
『Abstract』Evaporation or freezing of water-rich fluids with dilute concentrations of dissolved salts can produce brines, as observed in closed basins on Earth and detected by remote sensing on icy bodies in the outer Solar System . The mineralogical evolution of these brines is well understood in regard to terrestrial environments , but poorly constrained for extraterrestrial systems owing to a lack of direct sampling. Here we report the occurrence of salt minerals in samples of the asteroid (101955) Bennu returned by the OSIRIS-REx mission . These include sodium-bearing phosphates and sodium-rich carbonates, sulfates, chlorides and fluorides formed during evaporation of a late-stage brine that existed early in the history of Bennu’s parent body. Discovery of diverse salts would not be possible without mission sample return and careful curation and storage, because these decompose with prolonged exposure to Earth’s atmosphere. Similar brines probably still occur in the interior of icy bodies Ceres and Enceladus, as indicated by spectra or measurement of sodium carbonate on the surface or in plumes .
『摘要』 在地球上的封闭盆地中可以观察到,在外太阳系冰冻天体上也已通过遥感检测到,富含水且溶解盐浓度较低的流体蒸发或冻结会产生盐水。关于这些盐水在地球环境中的矿物学演化已研究得相当透彻,但由于缺乏直接取样,对于其在外星系统中的演化尚不明确。在此,我们报告了在“奥西里斯-雷克斯”(OSIRIS-REx)任务返回的(101955)贝努小行星样本中发现了盐类矿物。这些矿物包括含钠磷酸盐以及富含钠的碳酸盐、硫酸盐、氯化物和氟化物,它们是在贝努小行星母体早期存在的一个晚期盐水蒸发过程中形成的。如果没有任务样本的返回以及精心的管理和储存,就不可能发现这些多种多样的盐类,因为这些盐类在长时间暴露于地球大气中后会分解。光谱分析或在表面或羽流中对碳酸钠的测量结果表明,类似的盐水可能仍然存在于谷神星和土卫二的内部。
『总结』 研究发现贝努小行星样本中含多种盐矿物,表明类似盐水可能也存在于外星冰冻天体中,且该发现依赖于样本的成功返回与妥善保存。
31. 通过反极化阻挫增强反铁电体中的能量存储
Enhanced energy storage in antiferroelectrics via antipolar frustration
『Abstract』Dielectric-based energy storage capacitors characterized with fast charging and discharging speed and reliability play a vital role in cutting-edge electrical and electronic equipment. In pursuit of capacitor miniaturization and integration, dielectrics must offer high energy density and efficiency . Antiferroelectrics with antiparallel dipole configurations have been of significant interest for high-performance energy storage due to their negligible remanent polarization and high maximum polarization in the field-induced ferroelectric state . However, the low antiferroelectric–ferroelectric phase-transition field and accompanying large hysteresis loss deteriorate energy density and reliability. Here, guided by phase-field simulations, we propose a new strategy to frustrate antipolar ordering in antiferroelectrics by incorporating non-polar or polar components. Our experiments demonstrate that this approach effectively tunes the antiferroelectric–ferroelectric phase-transition fields and simultaneously reduces hysteresis loss. In PbZrO 3 -based films, we hence realized a record high energy density among all antiferroelectrics of 189 J cm along with a high efficiency of 81% at an electric field of 5.51 MV cm , which rivals the most state-of-the-art energy storage dielectrics . Atomic-scale characterization by scanning transmission electron microscopy directly revealed that the dispersed non-polar regions frustrate the long-range antipolar ordering, which contributes to the improved performance. This strategy presents new opportunities to manipulate polarization profiles and enhance energy storage performances in antiferroelectrics.
『摘要』 基于电介质的储能电容器具有充放电速度快、可靠性高的特点,在尖端电气和电子设备中发挥着重要作用。为了实现电容器的小型化和集成化,电介质必须具备高能量密度和高效率。具有反平行偶极子构型的反铁电体因其在场致铁电状态下可忽略不计的剩余极化和高最大极化而成为高性能储能领域的研究热点。然而,低反铁电-铁电相变场以及伴随的大滞后损耗会降低能量密度和可靠性。在此,我们在相场模拟的指导下,提出了一种通过引入非极性或极性组分来破坏反铁电体中反极性有序的新策略。我们的实验表明,这种方法可以有效地调节反铁电-铁电相变场,同时降低滞后损耗。在PbZrO3基薄膜中,我们在5.51 MV/cm的电场下实现了189 J/cm3的能量密度,这是所有反铁电体中的最高纪录,同时效率也高达81%,可与最先进的储能电介质相媲美。扫描透射电子显微镜的原子尺度表征直接显示,分散的非极性区域破坏了长程反极性有序,从而提高了性能。这一策略为调控极化分布和提高反铁电体的储能性能提供了新机遇。
『总结』 研究提出通过添加非极性或极性成分来破坏反铁电体的反极性有序,从而提高其储能性能的新策略,并在实验中实现了创纪录的能量密度和效率。
32. 溶液中RNase P RNA的构象空间
The conformational space of RNase P RNA in solution
『Abstract』RNA conformational diversity has fundamental biological roles , but direct visualization of its full conformational space in solution has not been possible using traditional biophysical techniques. Using solution atomic force microscopy, a deep neural network and statistical analyses, we show that the ribonuclease P (RNase P) RNA adopts heterogeneous conformations consisting of a conformationally invariant core and highly flexible peripheral structural elements that sample a broad conformational space, with amplitudes as large as 20–60 Å in a multitude of directions, with very low net energy cost. Increasing Mg drives compaction and enhances enzymatic activity, probably by narrowing the conformational space. Moreover, analyses of the correlations and anticorrelations between spatial flexibility and sequence conservation suggest that the functional roles of both the structure and dynamics of key regions are embedded in the primary sequence. These findings reveal the structure–dynamics basis for the embodiment of both enzymatic precision and substrate promiscuity in the RNA component of the RNase P. Mapping the conformational space of the RNase P RNA demonstrates a new general approach to studying RNA structure and dynamics.
『摘要』 RNA构象多样性在生物学中具有基本作用,但使用传统的生物物理技术无法直接观察到其在溶液中的完整构象空间。本研究利用溶液原子力显微镜、深度神经网络和统计分析,发现核糖核酸酶P(RNase P)RNA呈现出由构象不变核心和高度灵活的外周结构元件组成的异质构象,这些外周结构元件以非常低的净能量成本在多个方向上采样了高达20-60Å的广泛构象空间。Mg浓度的增加会驱动RNA结构紧缩并提高其酶活性,这可能是通过缩小构象空间来实现的。此外,对空间灵活性与序列保守性之间的相关性和负相关性的分析表明,关键区域的结构和功能作用以及动力学特性都嵌入在其一级序列中。这些研究结果揭示了RNase P的RNA组分中酶精确性和底物多样性的结构和动力学基础。对RNase P RNA构象空间的绘制为研究RNA结构和动力学提供了一种新的通用方法。
『总结』 本研究利用新技术揭示了RNase P RNA的异质构象特性,及其与酶活性和底物多样性的关联,为RNA结构和动力学研究提供了新方法。
33. 睡眠微观结构组织记忆重放
Sleep microstructure organizes memory replay
『Abstract』Recently acquired memories are reactivated in the hippocampus during sleep, an initial step for their consolidation . This process is concomitant with the hippocampal reactivation of previous memories , posing the problem of how to prevent interference between older and recent, initially labile, memory traces. Theoretical work has suggested that consolidating multiple memories while minimizing interference can be achieved by randomly interleaving their reactivation . An alternative is that a temporal microstructure of sleep can promote the reactivation of different types of memories during specific substates. Here, to test these two hypotheses, we developed a method to simultaneously record large hippocampal ensembles and monitor sleep dynamics through pupillometry in naturally sleeping mice. Oscillatory pupil fluctuations revealed a previously unknown microstructure of non-REM sleep-associated memory processes. We found that memory replay of recent experiences dominated in sharp-wave ripples during contracted pupil substates of non-REM sleep, whereas replay of previous memories preferentially occurred during dilated pupil substates. Selective closed-loop disruption of sharp-wave ripples during contracted pupil non-REM sleep impaired the recall of recent memories, whereas the same manipulation during dilated pupil substates had no behavioural effect. Stronger extrinsic excitatory inputs characterized the contracted pupil substate, whereas higher recruitment of local inhibition was prominent during dilated pupil substates. Thus, the microstructure of non-REM sleep organizes memory replay, with previous versus new memories being temporally segregated in different substates and supported by local and input-driven mechanisms, respectively. Our results suggest that the brain can multiplex distinct cognitive processes during sleep to facilitate continuous learning without interference.
『摘要』 在睡眠期间,最近获得的记忆会在海马体中重新激活,这是其巩固的第一步。这一过程与海马体对先前记忆的重新激活同时发生,这就带来了如何防止新旧记忆(新记忆最初是不稳定的)之间产生干扰的问题。理论研究表明,通过随机交错激活多个记忆可以减少干扰,从而实现记忆的巩固。另一种观点是,睡眠的微观时间结构可以促进在特定子状态下重新激活不同类型的记忆。在本研究中,为了验证这两种假设,我们开发了一种方法,能够在自然睡眠的小鼠中同时记录大量的海马体神经元活动,并通过瞳孔测量法监测睡眠动态。瞳孔振荡的波动揭示了与非快速眼动(non-rapid eye movement, non-REM)睡眠相关的记忆过程的先前未知的微观结构。我们发现在非快速眼动睡眠的瞳孔收缩子状态下,最近经历的记忆在尖波涟漪中占主导地位,而先前记忆的重放则更倾向于发生在瞳孔扩张子状态下。在非快速眼动睡眠的瞳孔收缩子状态下选择性闭环破坏尖波涟漪会损害对最近记忆的回忆,而在瞳孔扩张子状态下进行同样的操作则不会对行为产生影响。瞳孔收缩子状态的特征是外在兴奋性输入更强,而瞳孔扩张子状态则表现为局部抑制性募集更高。因此,非快速眼动睡眠的微观结构会组织记忆的重放,使先前记忆与新记忆在不同的子状态下实现时间上的分离,并分别由局部机制和输入驱动机制支持。我们的研究结果表明,大脑可以在睡眠期间进行多重不同的认知过程,从而促进持续学习而不产生干扰。
『总结』 研究表明,睡眠中的非快速眼动阶段具有微观结构,能够分别重新激活并巩固新旧记忆,防止干扰,促进持续学习。
34. 海马神经元中特征选择性的突触基础
Synaptic basis of feature selectivity in hippocampal neurons
『Abstract』A central question in neuroscience is how synaptic plasticity shapes the feature selectivity of neurons in behaving animals . Hippocampal CA1 pyramidal neurons display one of the most striking forms of feature selectivity by forming spatially and contextually selective receptive fields called place fields, which serve as a model for studying the synaptic basis of learning and memory. Various forms of synaptic plasticity have been proposed as cellular substrates for the emergence of place fields. However, despite decades of work, our understanding of how synaptic plasticity underlies place-field formation and memory encoding remains limited, largely due to a shortage of tools and technical challenges associated with the visualization of synaptic plasticity at the single-neuron resolution in awake behaving animals. To address this, we developed an all-optical approach to monitor the spatiotemporal tuning and synaptic weight changes of dendritic spines before and after the induction of a place field in single CA1 pyramidal neurons during spatial navigation. We identified a temporally asymmetric synaptic plasticity kernel resulting from bidirectional modifications of synaptic weights around the induction of a place field. Our work identified compartment-specific differences in the magnitude and temporal expression of synaptic plasticity between basal dendrites and oblique dendrites. Our results provide experimental evidence linking synaptic plasticity to the rapid emergence of spatial selectivity in hippocampal neurons, a critical prerequisite for episodic memory.
『摘要』 神经科学中的一个核心问题是突触可塑性如何塑造行为动物中神经元的特征选择性。海马体CA1锥体神经元通过形成空间和情境选择性的感受野(称为位置野)表现出最显著的特征选择性形式之一,这为研究学习与记忆的突触基础提供了一个模型。已有研究提出了多种形式的突触可塑性,作为位置野产生的细胞基础。然而,尽管已经研究了数十年,但我们对突触可塑性如何参与位置野的形成和记忆编码的了解仍然有限,这主要是因为缺乏工具以及在清醒行为动物中以单神经元分辨率可视化突触可塑性时面临的技术挑战。为了解决这一问题,我们开发了一种全光学方法,以监测空间导航期间单个CA1锥体神经元在位置野诱导前后树突棘的时空调谐和突触权重变化。我们发现了在位置野诱导前后由突触权重的双向修饰产生的时间不对称突触可塑性核。我们的工作发现了基础树突和斜树突在突触可塑性的幅度和时间表达上存在区室特异性差异。我们的研究结果为突触可塑性与海马神经元中空间选择性的快速出现之间的联系提供了实验证据,这是情景记忆的关键先决条件。
『总结』 本研究通过全光学方法揭示了突触可塑性在清醒行为动物海马体CA1锥体神经元位置野形成及空间选择性快速出现中的重要作用。
35. 协同光生物催化用于对映体选择性三自由基分类
Synergistic photobiocatalysis for enantioselective triple-radical sorting
『Abstract』Multicomponent reactions—those where three or more substrates combine into a product—have been highly useful in rapidly building chemical building blocks of increased complexity , but achieving this enzymatically has remained rare . This limitation primarily arises because an enzyme’s active site is not typically set up to address multiple substrates, especially in cases involving multiple radical intermediates . Recently, chemical catalytic radical sorting has emerged as an enabling strategy for a variety of useful reactions . However, making such processes enantioselective is highly challenging owing to the inherent difficulty in the stereochemical control of radicals . Here we repurpose a thiamine-dependent enzyme through directed evolution and combine it with photoredox catalysis to achieve a photobiocatalytic enantioselective three-component radical cross-coupling. This approach combines three readily available starting materials—aldehydes, α-bromo-carbonyls and alkenes—to give access to enantioenriched ketone products. Mechanistic investigations provide insights into how this dual photocatalyst–enzyme system precisely directs the three distinct radicals involved in the transformation, unlocking enzyme reactivity. Our approach has achieved exceptional stereoselectivity, with 24 out of 33 examples achieving ≥97% enantiomeric excess.
『摘要』 多组分反应,即三种或更多种底物结合生成产物的反应,对于快速构建复杂度更高的化学结构单元非常有用,但酶促实现这一过程仍然罕见。这一局限主要是因为酶的活性位点通常不适合处理多种底物,特别是在涉及多种自由基中间体的情况下。最近,化学催化自由基分类已成为实现多种有用反应的有效策略。然而,由于自由基的立体化学控制本身具有难度,因此使这些过程具有对映选择性极具挑战性。在本研究中,我们通过定向进化对一种依赖硫胺素的酶进行改造,并将其与光氧化还原催化相结合,实现了光生物催化对映选择性三组分自由基交叉偶联。这种方法结合了三种容易获得的起始原料——醛、α-溴羰基化合物和烯烃,从而获得了对映体过量的酮类产品。对反应机制的研究表明,这种光催化剂-酶双系统如何精确指导参与转化中三种不同的自由基,从而释放酶的活性。我们的方法实现了极佳的立体选择性,在33个实例中有24个实现了≥97%的对映体过量。
『总结』 本研究通过定向进化改造酶并与光氧化还原催化结合,成功实现了高立体选择性的光生物催化对映选择性三组分自由基交叉偶联反应。
36. 钽酸锂中的超宽带集成电光频率梳
Ultrabroadband integrated electro-optic frequency comb in lithium tantalate
『Abstract』The integrated frequency comb generator based on Kerr parametric oscillation has led to chip-scale, gigahertz-spaced combs with new applications spanning hyperscale telecommunications, low-noise microwave synthesis, light detection and ranging, and astrophysical spectrometer calibration . Recent progress in lithium niobate (LiNbO 3 ) photonic integrated circuits (PICs) has resulted in chip-scale, electro-optic (EO) frequency combs , offering precise comb-line positioning and simple operation without relying on the formation of dissipative Kerr solitons. However, current integrated EO combs face limited spectral coverage due to the large microwave power required to drive the non-resonant capacitive electrodes and the strong intrinsic birefringence of LiNbO 3 . Here we overcome both challenges with an integrated triply resonant architecture, combining monolithic microwave integrated circuits with PICs based on the recently emerged thin-film lithium tantalate (LiTaO 3 ) . With resonantly enhanced EO interaction and reduced birefringence in LiTaO 3 , we achieve a fourfold comb span extension and a 16-fold power reduction compared to the conventional, non-resonant microwave design. Driven by a hybrid integrated laser diode, the comb spans over 450 nm (more than 60 THz) with more than 2,000 lines, and the generator fits within a compact 1-cm footprint. We additionally observe that the strong EO coupling leads to an increased comb existence range approaching the full free spectral range of the optical microresonator. The ultra-broadband comb generator, combined with detuning-agnostic operation, could advance chip-scale spectrometry and ultra-low-noise millimetre wave synthesis and unlock octave-spanning EO combs. The methodology of co-designing microwave and photonics can be extended to a wide range of integrated EOs applications .
『摘要』 基于克尔参数振荡的综合频率梳状发生器催生了芯片级、吉赫兹间隔的梳状谱,在超大规模电信、低噪声微波合成、激光雷达探测和天体物理光谱仪校准等领域开拓了新的应用。近期,铌酸锂(LiNbO3)光子集成电路(PIC)取得了进展,产生了芯片级、电光(EO)频率梳,实现了精确的梳状谱线定位和简化操作,且无需依赖耗散克尔孤子的形成。然而,当前的集成EO梳状谱由于驱动非共振电容电极所需的大微波功率和铌酸锂较强的固有双折射,面临着光谱覆盖范围受限的问题。在此,我们通过集成的三重共振架构克服了这两个挑战,该架构将单片微波集成电路与基于新兴薄膜钽酸锂(LiTaO3)的PIC相结合。凭借LiTaO3中共振增强的EO相互作用和减小的双折射,我们实现了梳状谱跨度扩展四倍、功率降低16倍,相比传统的非共振微波设计有了显著提升。在混合集成激光二极管的驱动下,梳状谱覆盖了超过450纳米(超过60太赫兹)的范围,包含2000多条谱线,且发生器尺寸紧凑,仅占1平方厘米。我们还观察到,强EO耦合导致梳状谱存在范围增加,接近光学微谐振器的全自由光谱范围。这种超宽带梳状谱发生器与无需调谐的操作相结合,可推动芯片级光谱学和超低噪声毫米波合成的进步,并解锁跨八度EO梳状谱。微波与光子学的协同设计方法可推广应用于广泛的集成EO领域。
『总结』 研究通过集成的三重共振架构,克服了当前集成EO梳状谱面临的挑战,实现了超宽带梳状谱生成,为芯片级光谱学和毫米波合成等领域带来进步。
37. 哺乳动物运动纤毛中轴丝的结构多样性
Structural diversity of axonemes across mammalian motile cilia
『Abstract』Reproduction, development and homeostasis depend on motile cilia, whose rhythmic beating is powered by a microtubule-based molecular machine called the axoneme. Although an atomic model of the axoneme is available for the alga Chlamydomonas reinhardtii , structures of mammalian axonemes are incomplete . Furthermore, we do not fully understand how molecular structures of axonemes vary across motile-ciliated cell types in the body. Here we use cryoelectron microscopy, cryoelectron tomography and proteomics to resolve the 96-nm modular repeat of axonemal doublet microtubules (DMTs) from both sperm flagella and epithelial cilia of the oviduct, brain ventricles and respiratory tract. We find that sperm DMTs are the most specialized, with epithelial cilia having only minor differences across tissues. We build a model of the mammalian sperm DMT, defining the positions and interactions of 181 proteins including 34 newly identified proteins. We elucidate the composition of radial spoke 3 and uncover binding sites of kinases associated with regeneration of ATP and regulation of ciliary motility. We discover a sperm-specific, axoneme-tethered T-complex protein ring complex (TRiC) chaperone that may contribute to construction or maintenance of the long flagella of mammalian sperm. We resolve axonemal dyneins in their prestroke states, illuminating conformational changes that occur during ciliary movement. Our results illustrate how elements of chemical and mechanical regulation are embedded within the axoneme, providing valuable resources for understanding the aetiology of ciliopathy and infertility, and exemplifying the discovery power of modern structural biology.
『摘要』 生殖、发育和稳态依赖于运动纤毛,纤毛的节奏性摆动是由一种基于微管的分子机器——轴丝所驱动的。虽然已有藻类莱茵衣藻轴丝的原子模型,但哺乳动物轴丝的结构尚不完整。此外,我们还不完全了解体内运动纤毛细胞类型间轴丝的分子结构是如何变化的。在这里,我们使用冷冻电子显微镜、冷冻电子断层扫描和蛋白质组学技术,解析了精子鞭毛和输卵管、脑室、呼吸道上皮纤毛中轴丝二联微管(DMTs)的96纳米模块化重复单元。我们发现精子DMT最具特殊性,而不同组织的上皮纤毛只有微小差异。我们构建了哺乳动物精子DMT的模型,定义了包括34种新鉴定蛋白在内的181种蛋白的位置和相互作用。我们阐明了径向辐条3的组成,并发现了与ATP再生和纤毛运动调节相关的激酶结合位点。我们发现了一种精子特异性的、与轴丝相连的T-复合物蛋白环复合体(TRiC)伴侣蛋白,可能有助于构建或维持哺乳动物精子的长鞭毛。我们解析了处于预 stroke 状态的轴丝动力蛋白,揭示了纤毛运动过程中发生的构象变化。我们的研究结果阐明了化学和机械调节元件是如何嵌入轴丝中的,为理解纤毛病和不孕症的病因提供了宝贵资源,并展示了现代结构生物学的发现能力。
『总结』 本研究通过冷冻电子显微镜等技术解析了哺乳动物不同细胞类型中轴丝的结构特征,并构建了精子DMT模型,为理解纤毛病和不孕症提供了重要资源和见解。
38. 利用地震正则模态建立全球地幔衰减三维模型
Global 3D model of mantle attenuation using seismic normal modes
『Abstract』Seismic tomographic models based only on wave velocities have limited ability to distinguish between a thermal or compositional origin for Earth’s 3D structure . Complementing wave velocities with attenuation observations can make that distinction, which is fundamental for understanding mantle convection evolution. However, global 3D attenuation models are only available for the upper mantle at present . Here we present a 3D global model of attenuation for the whole mantle made using whole-Earth oscillations, constraining even spherical harmonics up to degree four. In the upper mantle, we find that high attenuation correlates with low velocity, indicating a thermal origin, in agreement with previous studies . In the lower mantle, we find the opposite and observe the highest attenuation in the ‘ring around the Pacific’, which is seismically fast, and the lowest attenuation in the large low-seismic-velocity provinces (LLSVPs). Comparing our model with wave speeds and attenuation predicted by a laboratory-based viscoelastic model suggests that the circum-Pacific is a colder and small-grain-size region , surrounding the warmer and large-grain-size LLSVPs. Viscosities calculated for the inferred variations in grain size and temperature confirm LLSVPs as long-lived, stable features .
『摘要』 仅基于波速的地震层析成像模型在区分地球三维结构的热源或成分起源方面能力有限。用衰减观测来补充波速可以实现这种区分,这对于理解地幔对流演化至关重要。然而,目前全球三维衰减模型仅适用于上地幔。本文利用整个地球振荡数据,构建了一个涵盖整个地幔的三维全球衰减模型,该模型甚至对高达四阶的球谐函数也进行了约束。在上地幔中,我们发现高衰减与低速度相关,表明其热源起源,这与先前的研究结果一致。在下地幔中,情况则相反,我们在“环太平洋地震带”观察到最高衰减,该区域地震波速较快,而在大地震波低速区(LLSVPs)观察到最低衰减。将我们的模型与基于实验室的粘弹性模型预测的波速和衰减进行对比后表明,环太平洋地震带是一个温度较低且晶粒尺寸较小的区域,环绕着温度较高且晶粒尺寸较大的大地震波低速区。根据推断的晶粒尺寸和温度变化计算出的粘度证实,大地震波低速区是长期存在的稳定特征。
『总结』 本研究通过结合波速和衰减观测,构建了全球首个涵盖整个地幔的三维衰减模型,并揭示了上、下地幔在衰减特性上的差异及其与热源或成分起源的关系。
39. SARS-CoV-2 NSP14 RNA帽结构甲基转移酶的小分子抑制
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase
『Abstract』Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . The rapid development of highly effective vaccines against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity . Here we report the discovery and development of a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14. High-throughput screening identified RU-0415529, which inhibited SARS-CoV-2 NSP14 by forming a unique ternary S -adenosylhomocysteine (SAH)-bound complex. Hit-to-lead optimization of RU-0415529 resulted in TDI-015051 with a dissociation constant ( K d ) of 61 pM and a half-maximal effective concentration (EC 50 ) of 11 nM, inhibiting virus infection in a cell-based system. TDI-015051 also inhibited viral replication in primary small airway epithelial cells and in a transgenic mouse model of SARS CoV-2 infection with an efficacy comparable with the FDA-approved reversible covalent protease inhibitor nirmatrelvir . The inhibition of viral cap methylases as an antiviral strategy is also adaptable to other pandemic viruses.
『摘要』 2019冠状病毒病(COVID-19)由严重急性呼吸综合征冠状病毒2(SARS-CoV-2)引起。针对SARS-CoV-2的高效疫苗的快速研发改变了疫情的发展轨迹,抗病毒治疗方法也进一步降低了COVID-19的住院率和死亡率。冠状病毒是一种包膜病毒,属于正链单链RNA病毒,编码多种结构和非结构蛋白,其中包括对病毒RNA复制和逃避先天免疫至关重要的蛋白。本文报道了病毒鸟嘌呤-N7甲基转移酶(MTase)NSP14这一首创非共价小分子抑制剂的发现与开发过程。高通量筛选发现了RU-0415529,它通过形成一种独特的S-腺苷高半胱氨酸(SAH)结合的三元复合物来抑制SARS-CoV-2 NSP14。对RU-0415529进行先导化合物优化后得到了TDI-015051,其解离常数(Kd)为61 pM,半最大效应浓度(EC50)为11 nM,可在细胞系统中抑制病毒感染。TDI-015051还能抑制原代小气道上皮细胞和SARS-CoV-2感染转基因小鼠模型中的病毒复制,疗效与美国食品药品监督管理局(FDA)批准的可逆共价蛋白酶抑制剂奈玛特韦(nirmatrelvir)相当。抑制病毒帽甲基化酶作为一种抗病毒策略也适用于其他大流行病毒。
『总结』 研究人员发现了SARS-CoV-2 NSP14的非共价小分子抑制剂TDI-015051,其可有效抑制细胞、原代细胞和动物模型中的病毒感染,且对其他大流行病毒也适用。
40. 克里米亚-刚果出血热病毒糖蛋白复合物的工程与结构
Engineering and structures of Crimean-Congo hemorrhagic fever virus glycoprotein complexes
『Abstract』Crimean-Congo hemorrhagic fever virus (CCHFV) is a tickborne virus that can cause severe disease in humans with case fatality rates of 10%–40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we use structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-Gn -Gc). A cryo-electron microscopy (cryo-EM) structure of this complex provides the molecular basis for GP38’s association on the viral surface, reveals the structure of Gn, and demonstrates that GP38-Gn restrains the Gc fusion loops in the prefusion conformation, facilitated by an N-linked glycan attached to Gn. Immunization with GP38-Gn -Gc conferred 40% protection against lethal IbAr10200 challenge in mice. These data define the architecture of a GP38-Gn-Gc protomer and provide a template for structure-guided vaccine antigen development.
『摘要』 克里米亚-刚果出血热病毒(CCHFV)是一种蜱传病毒,可引起人类严重疾病,病死率为10%~40%。尽管CCHFV糖蛋白GP38和Gc的结构为了解病毒入侵和确定中和抗体及保护性抗体的表位提供了依据,但糖蛋白Gn的结构及其与GP38和Gc的相互作用仍不清楚。本研究利用结构指导的蛋白质工程技术,制备了稳定的GP38-Gn-Gc异三聚体糖蛋白复合物(GP38-Gn -Gc)。该复合物的冷冻电子显微镜(Cryo-EM)结构为GP38在病毒表面的结合提供了分子基础,揭示了Gn的结构,并证明GP38-Gn通过将N连接聚糖附着在Gn上,将Gc融合环固定在融合前构象。用GP38-Gn -Gc免疫可为小鼠提供40%的针对致死性IbAr10200攻击的保护。这些数据定义了GP38-Gn-Gc原聚体的结构,并为结构指导的疫苗抗原开发提供了模板。
『总结』 本研究揭示了CCHFV的GP38-Gn-Gc异三聚体糖蛋白复合物结构,为疫苗抗原开发提供了新模板,并展示了该复合物在动物模型中的保护效果。
41. 利用人工智能从可穿戴设备中获取数字表型特征以表征精神障碍并识别遗传关联
Digital phenotyping from wearables using AI characterizes psychiatric disorders and identifies genetic associations
『Abstract』Psychiatric disorders are influenced by genetic and environmental factors. However, their study is hindered by limitations on precisely characterizing human behavior. New technologies such as wearable sensors show promise in surmounting these limitations in that they measure heterogeneous behavior in a quantitative and unbiased fashion. Here, we analyze wearable and genetic data from the Adolescent Brain Cognitive Development (ABCD) study. Leveraging >250 wearable-derived features as digital phenotypes, we show that an interpretable AI framework can objectively classify adolescents with psychiatric disorders more accurately than previously possible. To relate digital phenotypes to the underlying genetics, we show how they can be employed in univariate and multivariate genome-wide association studies (GWASs). Doing so, we identify 16 significant genetic loci and 37 psychiatric-associated genes, including ELFN1 and ADORA3 , demonstrating that continuous, wearable-derived features give greater detection power than traditional case-control GWASs. Overall, we show how wearable technology can help uncover new linkages between behavior and genetics.
『摘要』 精神障碍受遗传和环境因素的影响。然而,精确描述人类行为的局限性阻碍了相关研究。可穿戴传感器等新技术有望克服这些局限,因为它们能够以定量和无偏见的方式测量异质行为。在本文中,我们分析了青少年大脑认知发展(ABCD)研究中的可穿戴设备数据和基因数据。我们利用250多个由可穿戴设备衍生的特征作为数字表型,表明一个可解释的人工智能框架可以比以往更准确地客观分类患有精神障碍的青少年。为了将数字表型与潜在的遗传学联系起来,我们展示了如何将它们用于单变量和多变量全基因组关联研究(GWAS)。通过这种方式,我们确定了16个重要的遗传基因座和37个与精神障碍相关的基因,包括ELFN1和ADORA3,这表明由可穿戴设备持续监测得到的特征比传统的病例对照全基因组关联研究具有更强的检测能力。总的来说,我们展示了可穿戴技术如何帮助发现行为与遗传学之间的新联系。
『总结』 本研究利用可穿戴设备数据和基因数据,通过可解释的人工智能框架提高了精神障碍分类的准确性,并发现了新的遗传与精神障碍之间的联系。
42. 一种常见的人类PCSK9遗传变异通过LRP1受体促进乳腺癌转移
A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor
『Abstract』Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18 . Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival—uncovering a hereditary basis underlying breast cancer metastasis.
『摘要』 确定有转移性复发风险的患者是一项关键的医疗需求。我们发现前蛋白转化酶枯草溶菌素9(PCSK9)基因(rs562556,V474I)中的一个常见错义生殖系变异与多个乳腺癌患者队列的存活率降低相关。该功能获得性单核苷酸变异的小鼠遗传模型显示,它可在因果上促进乳腺癌转移。相反,宿主PCSK9缺失可减少多个乳腺癌模型中的转移性定植。宿主PCSK9通过靶向肿瘤低密度脂蛋白受体相关蛋白1(LRP1)受体,促进肺部转移性起始事件,并增强转移性增殖能力,而LRP1受体可抑制促转移基因XAF1和USP18。在多个模型中,抗体介导的PCSK9治疗性抑制可抑制乳腺癌转移。在瑞典一个大规模早期乳腺癌队列中,rs562556纯合子在15年时的远处转移性复发风险为22%,而非纯合子为2%。我们的研究结果表明,一种常见的遗传变异可控制乳腺癌转移并预测存活率,从而揭示了乳腺癌转移的遗传基础。
『总结』 研究发现PCSK9基因中的常见错义生殖系变异与乳腺癌转移和存活率降低相关,为乳腺癌转移提供了潜在的遗传标记和治疗靶点。
43. 机械力依赖性的山梨醇积累支持生物分子凝聚
Mechano-dependent sorbitol accumulation supports biomolecular condensate
『Abstract』Condensed droplets of protein regulate many cellular functions, yet the physiological conditions regulating their formation remain largely unexplored. Increasing our understanding of these mechanisms is paramount, as failure to control condensate formation and dynamics can lead to many diseases. Here, we provide evidence that matrix stiffening promotes biomolecular condensation in vivo . We demonstrate that the extracellular matrix links mechanical cues with the control of glucose metabolism to sorbitol. In turn, sorbitol acts as a natural crowding agent to promote biomolecular condensation. Using in silico simulations and in vitro assays, we establish that variations in the physiological range of sorbitol concentrations, but not glucose concentrations, are sufficient to regulate biomolecular condensates. Accordingly, pharmacological and genetic manipulation of intracellular sorbitol concentration modulates biomolecular condensates in breast cancer—a mechano-dependent disease. We propose that sorbitol is a mechanosensitive metabolite enabling protein condensation to control mechano-regulated cellular functions.
『摘要』 蛋白质凝聚液滴调节着许多细胞功能,然而调节其形成的生理条件在很大程度上仍不清楚。深入了解这些机制至关重要,因为无法控制凝聚物的形成和动态变化会导致多种疾病。本研究提供了证据,表明基质硬化可促进体内生物分子凝聚。本研究证明,细胞外基质将机械信号与葡萄糖代谢为山梨醇的控制联系起来。而山梨醇作为一种天然的拥挤剂,可促进生物分子凝聚。通过计算机模拟和体外试验,本研究证实,在山梨醇浓度的生理范围内变化(而非葡萄糖浓度变化)便足以调节生物分子凝聚物。相应地,通过药物和基因手段改变乳腺癌(一种机械依赖性疾病)细胞内的山梨醇浓度可调节生物分子凝聚物。本研究提出,山梨醇是一种机械敏感性代谢物,可通过促进蛋白质凝聚来控制机械调节的细胞功能。
『总结』 本研究发现基质硬化通过促进山梨醇的产生,作为天然拥挤剂调节生物分子凝聚,从而影响细胞功能,这在乳腺癌等机械依赖性疾病中具有重要作用。
44. 一种肠道共生原生动物通过塑造肺部免疫力来决定呼吸系统疾病的转归
A gut commensal protozoan determines respiratory disease outcomes by shaping pulmonary immunity
『Abstract』The underlying mechanisms used by the intestinal microbiota to shape disease outcomes of the host are poorly understood. Here, we show that the gut commensal protozoan, Tritrichomonas musculis ( T.mu ), remotely shapes the lung immune landscape to facilitate perivascular shielding of the airways by eosinophils. Lung-specific eosinophilia requires a tripartite immune network between gut-derived inflammatory group 2 innate lymphoid cells and lung-resident T cells and B cells. This network exacerbates the severity of allergic airway inflammation while hindering the systemic dissemination of pulmonary Mycobacterium tuberculosis . The identification of protozoan DNA sequences in the sputum of patients with severe allergic asthma further emphasizes the relevance of commensal protozoa in human disease. Collectively, these findings demonstrate that a commensal protozoan tunes pulmonary immunity via a gut-operated lung immune network, promoting both beneficial and detrimental disease outcomes in response to environmental airway allergens and pulmonary infections.
『摘要』 肠道微生物群影响宿主疾病结果的潜在机制尚不清楚。本研究表明,肠道共生原生动物鼠三毛滴虫(Tritrichomonas musculis,T.mu)可远程塑造肺部免疫环境,从而促进嗜酸性粒细胞对气道周围血管的保护。肺特异性嗜酸性粒细胞增多需要肠道来源的炎症性2型固有淋巴样细胞与肺常驻T细胞和B细胞之间的三方免疫网络。该网络会加剧过敏性气道炎症的严重程度,同时阻碍肺结核分枝杆菌的系统性传播。在重度过敏性哮喘患者的痰液中发现原生动物DNA序列,这进一步强调了共生原生动物在人类疾病中的相关性。综上所述,这些研究结果表明,一种共生原生动物通过肠道调控的肺部免疫网络来调节肺部免疫,从而在应对环境气道过敏原和肺部感染时,既可促进有利结果,也会产生不利结果。
『总结』 研究发现肠道共生原生动物鼠三毛滴虫可影响肺部免疫,加重过敏性气道炎症,同时阻碍肺结核传播,显示了其对肺部疾病结果的双重作用。
45. YTHDF2促进B细胞恶性肿瘤中的ATP合成和免疫逃逸
YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies
『Abstract』Long-term durable remission in patients with B cell malignancies following chimeric antigen receptor (CAR)-T cell immunotherapy remains unsatisfactory, often due to antigen escape. Malignant B cell transformation and oncogenic growth relies on efficient ATP synthesis, although the underlying mechanisms remain unclear. Here, we report that YTHDF2 facilitates energy supply and antigen escape in B cell malignancies, and its overexpression alone is sufficient to cause B cell transformation and tumorigenesis. Mechanistically, YTHDF2 functions as a dual reader where it stabilizes mRNAs as a 5-methylcytosine (m C) reader via recruiting PABPC1, thereby enhancing their expression and ATP synthesis. Concomitantly, YTHDF2 also promotes immune evasion by destabilizing other mRNAs as an N -methyladenosine (m A) reader. Small-molecule-mediated targeting of YTHDF2 suppresses aggressive B cell malignancies and sensitizes them to CAR-T cell therapy.
『摘要』 研究发现,B细胞恶性肿瘤患者在接受嵌合抗原受体(CAR)-T细胞免疫治疗后,长期持续缓解的情况仍不理想,这往往是由于抗原逃逸所致。尽管恶性B细胞转化和致癌生长的机制尚不完全清楚,但其依赖于高效的ATP合成。本研究发现,YTHDF2可促进B细胞恶性肿瘤的能量供应和抗原逃逸,其单独过表达就足以导致B细胞转化和肿瘤发生。从机制上讲,YTHDF2作为一种双重读取蛋白,通过招募PABPC1作为5-甲基胞嘧啶(mC)读取蛋白来稳定mRNA,从而增强它们的表达和ATP合成。同时,YTHDF2还作为N-甲基腺苷(mA)读取蛋白,通过使其他mRNA不稳定来促进免疫逃逸。通过小分子介导靶向YTHDF2,可以抑制侵袭性B细胞恶性肿瘤,并使其对CAR-T细胞治疗敏感。
『总结』 研究揭示了YTHDF2在B细胞恶性肿瘤中的作用机制,其过表达可促进肿瘤发生和抗原逃逸,而通过小分子靶向YTHDF2可增强B细胞恶性肿瘤对CAR-T细胞治疗的敏感性。
46. 通过碱基编辑技术构建源库关系赋予番茄和水稻耐热性
Engineering source-sink relations by prime editing confers heat-stress resilience in tomato and rice
『Abstract』A 2°C climate-warming scenario is expected to further exacerbate average crop losses by 3%–13%, yet few heat-tolerant staple-crop varieties are available toward meeting future food demands. Here, we develop high-efficiency prime-editing tools to precisely knockin a 10-bp heat-shock element (HSE) into promoters of cell-wall-invertase genes ( CWINs ) in elite rice and tomato cultivars. HSE insertion endows CWINs with heat-responsive upregulation in both controlled and field environments to enhance carbon partitioning to grain and fruits, resulting in per-plot yield increases of 25% in rice cultivar Zhonghua11 and 33% in tomato cultivar Ailsa Craig over heat-stressed controls, without fruit quality penalties. Up to 41% of heat-induced grain losses were rescued in rice. Beyond a prime-editing system for tweaking gene expression by efficiently delivering bespoke changes into crop genomes, we demonstrate broad and robust utility for targeted knockin of cis -regulatory elements to optimize source-sink relations and boost crop climate resilience.
『摘要』 预计全球气候变暖2°C将使平均作物损失进一步加剧3%–13%,但目前耐热的主粮作物品种很少,无法满足未来的粮食需求。本研究开发了高效的精准编辑工具,可精确地将一个10碱基对的热激元件(HSE)敲入优质水稻和番茄品种中细胞壁转化酶基因(CWINs)的启动子中。HSE的插入使CWINs在可控环境和田间环境下均具有热响应上调特性,促进了碳向籽粒和果实的分配,从而使水稻品种“中华11”的单产提高了25%,番茄品种“艾尔莎克雷格”的单产提高了33%,且果实品质未受影响。水稻中多达41%的热害导致的减产得到了挽救。除开发了一种可通过高效地将定制变化引入作物基因组来调整基因表达的精准编辑系统外,本研究还证明了靶向敲入顺式调控元件在优化源库关系和增强作物气候适应性方面具有广泛而强大的作用。
『总结』 研究开发了高效的精准编辑工具,通过敲入热激元件提高了水稻和番茄的耐热性和产量,为优化作物源库关系和增强气候适应性提供了新方法。
47. 成纤维网状细胞在肺癌中产生保护性的肿瘤内T细胞环境
Fibroblastic reticular cells generate protective intratumoral T cell environments in lung cancer
『Abstract』Stringent control of T cell activity in the tumor microenvironment is essential for the generation of protective antitumor immunity. However, the identity, differentiation, and functions of the cells that create critical fibroblastic niches promoting tumor-infiltrating T cells remain elusive. Here, we show that CCL19-expressing fibroblastic reticular cells (FRCs) generate interconnected T cell environments (TEs) in human non-small cell lung cancer, including tertiary lymphoid structures and T cell tracks. Analysis of the FRC-T cell interactome in TEs indicated molecular networks regulating niche-specific differentiation of CCL19-expressing fibroblasts and T cell activation pathways. Single-cell transcriptomics and cell fate-mapping analyses in mice confirmed that FRCs in TEs originate from mural and adventitial progenitors. Ablation of intratumoral FRC precursors decreased antitumor T cell activity, resulting in reduced tumor control during coronavirus vector-based immunotherapy. In summary, specialized FRC niches in the tumor microenvironment govern the quality and extent of antitumor T cell immunity.
『摘要』 在肿瘤微环境中严格控制T细胞活性对于产生保护性抗肿瘤免疫至关重要。然而,构建促进肿瘤浸润T细胞的关键纤维细胞生态位的细胞的身份、分化和功能仍不明确。本研究发现,表达CCL19的纤维性网织细胞(FRCs)在人类非小细胞肺癌中形成了相互连接的T细胞环境(TEs),包括三级淋巴结构和T细胞轨迹。对TEs中FRC-T细胞相互作用组的分析揭示了调控表达CCL19的成纤维细胞生态位特异性分化和T细胞活化途径的分子网络。小鼠的单细胞转录组学和细胞命运图谱分析证实,TEs中的FRCs来源于壁细胞和外膜祖细胞。清除肿瘤内FRC前体细胞会降低抗肿瘤T细胞活性,导致在基于冠状病毒载体的免疫治疗期间肿瘤控制减弱。总之,肿瘤微环境中的特化FRC生态位决定着抗肿瘤T细胞免疫的质量和范围。
『总结』 研究指出,肿瘤微环境中特化的纤维性网织细胞生态位对T细胞的抗肿瘤免疫应答具有关键调控作用。
48. 大豆发育的空间解析多组学单细胞图谱
A spatially resolved multi-omic single-cell atlas of soybean development
『Abstract』Cis -regulatory elements (CREs) precisely control spatiotemporal gene expression in cells. Using a spatially resolved single-cell atlas of gene expression with chromatin accessibility across ten soybean tissues, we identified 103 distinct cell types and 303,199 accessible chromatin regions (ACRs). Nearly 40% of the ACRs showed cell-type-specific patterns and were enriched for transcription factor (TF) motifs defining diverse cell identities. We identified de novo enriched TF motifs and explored the conservation of gene regulatory networks underpinning legume symbiotic nitrogen fixation. With comprehensive developmental trajectories for endosperm and embryo, we uncovered the functional transition of the three sub-cell types of endosperm, identified 13 sucrose transporters sharing the DNA binding with one finger 11 (DOF11) motif that were co-upregulated in late peripheral endosperm, and identified key embryo cell-type specification regulators during embryogenesis, including a homeobox TF that promotes cotyledon parenchyma identity. This resource provides a valuable foundation for analyzing gene regulatory programs in soybean cell types across tissues and life stages.
『摘要』 顺式调控元件(CREs)精准控制着细胞中的时空基因表达。我们利用跨越十个大豆组织、具有染色质可及性的空间分辨单细胞基因表达图谱,鉴定出103种不同的细胞类型和303199个可及染色质区域(ACRs)。近40%的ACR显示出细胞类型特异性模式,并富集了定义各种细胞特性的转录因子(TF)基序。我们鉴定了从头富集的TF基序,并探索了支撑豆科植物共生固氮的基因调控网络的保守性。通过胚乳和胚胎的全面发育轨迹,我们揭示了胚乳三种亚细胞类型的功能转变,鉴定了13个蔗糖转运蛋白(与单指11(DOF11)基序结合)在晚期周边胚乳中共同上调,并确定了胚胎发育过程中关键的胚胎细胞类型特异性调控因子,包括一个促进子叶薄壁细胞特性的同源异型盒转录因子。本资源为分析大豆不同组织和生命阶段细胞类型中的基因调控程序提供了宝贵基础。
『总结』 本研究利用空间分辨单细胞图谱鉴定了大豆中的多种细胞类型和可及染色质区域,揭示了基因调控网络及关键调控因子,为大豆基因调控程序分析提供了重要资源。
49. 持续存在的染色体粉碎现象奠定了骨肉瘤基因组复杂性和克隆进化的基础
Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution
『Abstract』Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, clonal diversification, and intra-tumor heterogeneity across diverse sarcomas and carcinomas. In addition, we characterize a new mechanism, termed loss-translocation-amplification (LTA) chromothripsis, which mediates punctuated evolution in about half of pediatric and adult high-grade osteosarcomas. LTA chromothripsis occurs when a single double-strand break triggers concomitant TP53 inactivation and oncogene amplification through breakage-fusion-bridge cycles. It is particularly prevalent in osteosarcoma and is not detected in other cancers driven by TP53 mutation. Finally, we identify the level of genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.
『摘要』 骨肉瘤是最常见的原发性骨癌,儿童和年轻人的发病率最高。我们通过多区域全基因组测序发现,染色体粉碎是一个持续发生的突变过程,在74%的骨肉瘤中以亚克隆方式发生。染色体粉碎会产生高度不稳定的衍生染色体,其持续进化会促使致癌突变、克隆多样化和多种肉瘤及癌瘤的瘤内异质性产生。此外,我们还发现了一种新机制,即缺失-易位-扩增(LTA)染色体粉碎,该机制在约半数的儿童和成人高级别骨肉瘤中介导了突变进化。当单个双链断裂通过断裂-融合-桥接周期引发TP53并发失活和癌基因扩增时,就会发生LTA染色体粉碎。该现象在骨肉瘤中尤为普遍,而在其他由TP53突变驱动的癌症中则未检测到。最后,我们确定全基因组杂合性缺失水平是高级别骨肉瘤的一个强预后指标。
『总结』 研究发现染色体粉碎是骨肉瘤中持续发生的突变过程,并发现了一种新机制LTA染色体粉碎,同时确定了全基因组杂合性缺失水平是高级别骨肉瘤的强预后指标。
50. 周期性内质网-质膜连接支持树突中的长距离Ca2+信号整合
Periodic ER-plasma membrane junctions support long-range Ca2+ signal integration in dendrites
『Abstract』Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. Here, we discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at ∼1 μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca channels and ER Ca -release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca homeostasis, and local activation of the Ca /calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca modulatory machinery, facilitating signal transmission and ryanodine-receptor-dependent Ca release at ER-PM junctions over 20 μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations.
『摘要』 神经元的树突必须远距离传递突触输入,但活动诱发的细胞内信号在宏观距离上传播的机制仍不清楚。本研究发现,内质网-质膜(ER-PM)连接系统以约1微米的间隔周期性地排列在树突的质膜上,并通过呈梯子状排列的内质网管状网络相互连接。内质网-质膜连接处富集了由连接蛋白连接的质膜电压门控钙通道和内质网钙释放通道(Ryanodine受体),是内质网-质膜相互作用、钙稳态精细调节和钙/钙调蛋白依赖性蛋白激酶II局部活化的枢纽。局部树突棘刺激会激活钙调节机制,促进信号传输和距离超过20微米的内质网-质膜连接处的Ryanodine受体依赖性钙释放。因此,相互连接的内质网-质膜连接支持信号传播和来自棘附近内质网的钙释放。这种亚细胞结构能够改变局部和远距离膜邻近的生物化学特性,可能对树突的计算有所贡献。
『总结』 研究发现了神经元树突中周期性排列的内质网-质膜连接系统,支持信号传播和钙释放,可能对树突的计算发挥作用。
51. ACSL4和多不饱和脂质支持转移性外渗和定植
ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization
『Abstract』Metastatic dissemination to distant organs demands that cancer cells possess high morphological and metabolic adaptability. However, contributions of the cellular lipidome to metastasis remain elusive. Here, we uncover a correlation between metastasis potential and ferroptosis susceptibility in multiple cancers. Metastases-derived cancer cells exhibited higher ferroptosis sensitivity and polyunsaturated fatty acyl (PUFA)-lipid contents than primary-tumor-derived cells from ovarian cancer patients. Metabolism-focused CRISPR screens in a mouse model for ovarian cancer distant metastasis established via two rounds of in vivo selection revealed the PUFA-lipid biosynthesis enzyme acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) as a pro-hematogenous metastasis factor. ACSL4 promotes metastatic extravasation by enhancing membrane fluidity and cellular invasiveness. While promoting metastasis, the high PUFA-lipid state creates dependencies on abhydrolase-domain-containing 6, acylglycerol lipase (ABHD6), enoyl-CoA delta isomerase 1 (ECI1), and enoyl-CoA hydratase 1 (ECH1)—rate-limiting enzymes preparing unsaturated fatty acids (UFAs) for β-oxidation. ACSL4/ECH1 co-inhibition achieved potent suppression of metastasis. Our work establishes the dual functions of PUFA-lipids in tumor progression and metastasis that may be exploitable for therapeutic development.
『摘要』 研究发现,癌细胞向远处器官转移需要具备高度的形态和代谢适应能力。然而,细胞脂质组在转移过程中的作用仍不明确。本研究揭示了多种癌症中转移潜能与铁死亡敏感性之间的相关性。与来自卵巢癌患者的原发肿瘤相比,转移衍生的癌细胞表现出更高的铁死亡敏感性和多不饱和脂肪酸(PUFA)脂质含量。通过两轮体内筛选建立的卵巢癌远处转移小鼠模型中进行了以代谢为重点的CRISPR筛选,结果显示PUFA脂质生物合成酶酰基辅酶A(CoA)合成酶长链家族成员4(ACSL4)是促进血源性转移的因素。ACSL4通过增强膜流动性和细胞侵袭性来促进转移过程中的细胞外渗。在促进转移的同时,高PUFA脂质状态使细胞依赖于含有abhydrolase结构域的酰基甘油酯酶(ABHD6)、烯醇辅酶Aδ异构酶1(ECI1)和烯醇辅酶A水合酶1(ECH1),这些酶是限制不饱和脂肪酸(UFA)进入β-氧化的关键酶。联合抑制ACSL4/ECH1可强效抑制转移。本研究确立了PUFA脂质在肿瘤进展和转移中的双重功能,这些功能或许可用于开发治疗方法。
『总结』 本研究揭示了PUFA脂质通过影响铁死亡敏感性和细胞代谢,在癌症转移中发挥关键作用,为癌症治疗提供了新的潜在靶点。
52. 通过转录组范围内snoRNA靶点鉴定揭示snoRNA促进的蛋白质分泌
snoRNA-facilitated protein secretion revealed by transcriptome-wide snoRNA target identification
『Abstract』Small nucleolar RNAs (snoRNAs) are non-coding RNAs known for guiding RNA modifications, including 2′- O -methylation (N m ) and pseudouridine (Ψ). While snoRNAs may also interact with other RNAs, such as mRNA, the full repertoire of RNAs targeted by snoRNA remains elusive due to the lack of effective technologies that identify snoRNA targets transcriptome wide. Here, we develop a chemical crosslinking-based approach that comprehensively detects cellular RNA targets of snoRNAs, yielding thousands of previously unrecognized snoRNA-mRNA interactions in human cells and mouse brain tissues. Many interactions occur outside of snoRNA-guided RNA modification sites, hinting at non-canonical functions beyond RNA modification. We find that one of these snoRNAs, SNORA73 , targets mRNAs that encode secretory proteins and membrane proteins. SNORA73 also interacts with 7SL RNA, part of the signal recognition particle (SRP) required for protein secretion. The mRNA- SNORA73 - 7SL RNA interactions enhance the association of the SNORA73 -target mRNAs with SRP, thereby facilitating the secretion of encoded proteins.
『摘要』 小核仁小RNA(snoRNA)是非编码RNA,以指导RNA修饰而闻名,包括2′-O-甲基化(Nm)和假尿嘧啶(Ψ)。虽然snoRNA也可能与其他RNA(如mRNA)相互作用,但由于缺乏在转录组范围内鉴定snoRNA靶标的有效技术,snoRNA靶标的全部范围仍然难以确定。本研究开发了一种基于化学交联的方法,可全面检测snoRNA的细胞RNA靶标,在人类细胞和小鼠脑组织中发现了数千种先前未知的snoRNA-mRNA相互作用。许多相互作用发生在snoRNA引导的RNA修饰位点之外,这暗示了除RNA修饰之外的非经典功能。研究发现,这些snoRNA中的一种,即SNORA73,靶向编码分泌蛋白和膜蛋白的mRNA。SNORA73还与7SL RNA相互作用,7SL RNA是蛋白质分泌所需的信号识别颗粒(SRP)的一部分。mRNA-SNORA73-7SL RNA的相互作用增强了SNORA73靶mRNA与SRP的结合,从而促进了编码蛋白的分泌。
『总结』 本研究发现了一种检测snoRNA细胞RNA靶标的新方法,揭示了snoRNA在RNA修饰之外的新功能,并具体阐述了SNORA73如何通过与7SL RNA的相互作用促进编码蛋白的分泌。
53. NINJ1如何介导质膜破裂以及为什么NINJ2不能
How NINJ1 mediates plasma membrane rupture and why NINJ2 cannot
『Abstract』Ninjurin-1 (NINJ1) is an active executioner of plasma membrane rupture (PMR), a process previously thought to be a passive osmotic lysis event in lytic cell death. Ninjurin-2 (NINJ2) is a close paralog of NINJ1 but cannot mediate PMR. Using cryogenic electron microscopy (cryo-EM), we show that NINJ1 and NINJ2 both assemble into linear filaments that are hydrophobic on one side but hydrophilic on the other. This structural feature and other evidence point to a PMR mechanism by which NINJ1 filaments wrap around and solubilize membrane fragments and, less frequently, form pores in the plasma membrane. In contrast to the straight NINJ1 filament, the NINJ2 filament is curved toward the intracellular space, preventing its circularization or even assembly on a relatively flat membrane to mediate PMR. Mutagenesis studies further demonstrate that the NINJ2 filament curvature is induced by strong association with lipids, particularly a cholesterol molecule, at the cytoplasmic leaflet of the lipid bilayer.
『摘要』 Ninjurin-1(NINJ1)是质膜破裂(PMR)的主动执行者,而质膜破裂以往被认为是裂解性细胞死亡中的被动渗透裂解事件。Ninjurin-2(NINJ2)与NINJ1密切相关,但不能介导质膜破裂。我们使用冷冻电子显微镜(cryo-EM)发现,NINJ1和NINJ2均可组装成线性细丝,这些细丝一侧具有疏水性,而另一侧具有亲水性。这一结构特征以及其他证据表明,NINJ1细丝包裹并溶解膜片段,从而实现质膜破裂机制,同时它们也会(但频率较低地)在质膜上形成孔隙。与笔直的NINJ1细丝不同,NINJ2细丝向细胞内空间弯曲,这阻碍了其在相对平坦的膜上环绕成圈甚至组装,从而无法介导质膜破裂。突变研究进一步证明,NINJ2细丝的弯曲是由其与脂质双层细胞质小叶中的脂质(尤其是胆固醇分子)强烈结合引起的。
『总结』 NINJ1能主动介导质膜破裂,而NINJ2由于细丝结构向细胞内弯曲且与脂质强烈结合,无法实现这一过程。
54. 人类海马体CA3区采用特定的功能连接规则以实现高效联想记忆
Human hippocampal CA3 uses specific functional connectivity rules for efficient associative memory
『Abstract』Our brain has remarkable computational power, generating sophisticated behaviors, storing memories over an individual’s lifetime, and producing higher cognitive functions. However, little of our neuroscience knowledge covers the human brain. Is this organ truly unique, or is it a scaled version of the extensively studied rodent brain? Combining multicellular patch-clamp recording with expansion-based superresolution microscopy and full-scale modeling, we determined the cellular and microcircuit properties of the human hippocampal CA3 region, a fundamental circuit for memory storage. In contrast to neocortical networks, human hippocampal CA3 displayed sparse connectivity, providing a circuit architecture that maximizes associational power. Human synapses showed unique reliability, high precision, and long integration times, exhibiting both species- and circuit-specific properties. Together with expanded neuronal numbers, these circuit characteristics greatly enhanced the memory storage capacity of CA3. Our results reveal distinct microcircuit properties of the human hippocampus and begin to unravel the inner workings of our most complex organ.
『摘要』 人类大脑拥有惊人的计算能力,能够产生复杂的行为,存储个人终身的记忆,并产生高级认知功能。然而,我们对神经科学的了解中,关于人类大脑的部分却寥寥无几。这个器官真的是独一无二的吗,还是只是我们广泛研究过的啮齿类动物大脑的放大版?本研究结合了多细胞膜片钳记录、基于膨胀的超分辨率显微镜和全尺度建模,确定了人类海马体CA3区域的细胞和微电路特性,而该区域是记忆存储的基本回路。与人类新皮层网络相比,人类海马体CA3区域显示出稀疏的连接性,这种电路结构最大化了关联能力。人类的突触表现出独特的可靠性、高精度和长整合时间,显示出物种特异性和电路特异性。这些电路特性与增加的神经元数量一起,极大地增强了CA3的记忆存储能力。我们的研究结果揭示了人类海马体独特的微电路特性,并开始揭示我们这个最复杂器官的内部工作机制。
『总结』 本研究通过综合技术揭示了人类海马体CA3区域的独特微电路特性,这些特性显著增强了记忆存储能力,并初步揭示了人类大脑的复杂工作机制。
55. 利用逆向追踪技术表征并靶向胶质母细胞瘤神经元-肿瘤网络
Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing
『Abstract』Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain, engaging in widespread functional communication, with cholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor-cell-state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasiveness. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.
『摘要』 胶质母细胞瘤是具有高度治疗耐药性的侵袭性脑肿瘤。已有研究表明,神经元-胶质瘤突触可促进胶质母细胞瘤的进展。然而,由于缺乏相关技术,对与肿瘤相连的神经元进行特征分析一直受到阻碍。在本研究中,我们采用狂犬病毒进行逆行追踪,以调查和操控神经元-肿瘤网络。胶质母细胞瘤迅速整合到全脑的神经回路中,并进行广泛的功能性通讯,其中胆碱能神经元驱动胶质母细胞瘤的侵袭。我们发现了与神经元-肿瘤连接和随后侵袭性相关的突触生成基因表达的患者特异性和肿瘤细胞状态依赖性差异。重要的是,放疗通过增加神经元活动增强了神经元-肿瘤的连接。反之,同时抑制神经元活动和进行放疗显示出增强的治疗效果,这表明神经元-胶质瘤突触在治疗耐药性中发挥作用。最后,通过狂犬病毒介导的基因消融技术清除与肿瘤相连的神经元,阻止了胶质母细胞瘤的进展,为治疗胶质母细胞瘤提供了一种病毒策略。总体而言,本研究提供了一个全面特征分析神经元-肿瘤网络并靶向胶质母细胞瘤的框架。
『总结』 本研究利用狂犬病毒逆行追踪技术揭示了神经元-胶质瘤突触在胶质母细胞瘤进展和治疗耐药性中的作用,并提出了一种病毒策略来阻止肿瘤进展。