前沿速递 | NCS 集萃:2025-01-13 期 [Up]
总结
1. 野生黑猩猩对栖息地的本地遗传适应
Local genetic adaptation to habitat in wild chimpanzees
『Abstract』Abstract How populations adapt to their environment is a fundamental question in biology. Yet, we know surprisingly little about this process, especially for endangered species, such as nonhuman great apes. Chimpanzees, our closest living relatives, are particularly notable because they inhabit diverse habitats, from rainforest to woodland-savannah. Whether genetic adaptation facilitates such habitat diversity remains unknown, despite it having wide implications for evolutionary biology and conservation. By using newly sequenced exomes from 828 wild chimpanzees (388 postfiltering), we found evidence of fine-scale genetic adaptation to habitat, with signatures of positive selection in forest chimpanzees in the same genes underlying adaptation to malaria in humans. This work demonstrates the power of noninvasive samples to reveal genetic adaptations in endangered populations and highlights the importance of adaptive genetic diversity for chimpanzees.
『摘要』 了解种群如何适应其环境是生物学中的一个根本问题。然而,我们对这一过程知之甚少,尤其是对于濒危物种,如非人类大型类人猿。黑猩猩是与我们亲缘关系最近的现存物种,尤其值得关注,因为它们栖息于从雨林到林地-稀树草原等多种多样的栖息地。尽管遗传适应对进化生物学和保护生物学具有广泛意义,但遗传适应是否促进了这种栖息地的多样性仍然未知。通过对828只野生黑猩猩(过滤后为388只)新测序的外显子组进行研究,我们发现了黑猩猩对栖息地精细遗传适应的证据,在森林黑猩猩中发现了与人类适应疟疾相同的基因中存在正选择的特征。这项工作证明了非侵入性样本在揭示濒危种群遗传适应方面的作用,并强调了适应性遗传多样性对黑猩猩的重要性。
『总结』 研究发现黑猩猩对栖息地具有精细的遗传适应性,强调了遗传多样性对黑猩猩保护的重要性,并展示了非侵入性样本在相关研究中的应用潜力。
2. 四频带协同作用使地球上丰富的硫化锡晶体实现高热电效率
Quadruple-band synglisis enables high thermoelectric efficiency in earth-abundant tin sulfide crystals
『Abstract』Abstract Thermoelectrics have been limited by the scarcity of their constituent elements, especially telluride. The earth-abundant, wide-bandgap ( E g ≈ 46 k B T ) tin sulfide (SnS) has shown promising performance in its crystal form. We improved the thermoelectric efficiency in SnS crystals by promoting the convergence of energy and momentum of four valance bands, termed quadruple-band synglisis. We introduced more Sn vacancies to activate quadruple-band synglisis and facilitate carrier transport by inducing SnS 2 in selenium (Se)–alloyed SnS, leading to a high dimensionless figure of merit ( ZT ) of ~1.0 at 300 kelvin and an average ZT of ~1.3 at 300 to 773 kelvin in p-type SnS crystals. We further obtained an experimental efficiency of ~6.5%, and our fabricated cooler demonstrated a maximum cooling temperature difference of ~48.4 kelvin at 353 kelvin. Our observations should draw interest to earth-abundant SnS crystals for applications of waste-heat recovery and thermoelectric cooling.
『摘要』 热电材料一直受其组成元素稀缺性的限制,尤其是碲化物。地球上储量丰富且带隙较宽(E g ≈ 46 k B T)的硫化锡(SnS)晶体已展现出良好性能。我们通过促进四个价带的能量和动量聚合(称为四带聚合),提高了硫化锡晶体的热电效率。我们通过在硒(Se)合金化的硫化锡中引入更多锡空位来激活四带聚合,并通过诱导产生硫化锡二(SnS2)来促进载流子传输,从而在300开尔文时获得了约1.0的高无量纲优值(ZT),在300至773开尔文范围内,p型硫化锡晶体的平均ZT约为1.3。我们进一步获得了约6.5%的实验效率,并且所制造的冷却器在353开尔文时表现出约48.4开尔文的最大冷却温差。我们的研究结果应能引起人们对地球上储量丰富的硫化锡晶体在余热回收和热电制冷方面应用的关注。
『总结』 研究通过促进四带聚合提高了硫化锡晶体的热电效率,为余热回收和热电制冷提供了新的应用前景。
3. 砍伐热带森林会影响生物多样性和功能,而伐木则会改变其结构
Tropical forest clearance impacts biodiversity and function, whereas logging changes structure
『Abstract』Abstract The impacts of degradation and deforestation on tropical forests are poorly understood, particularly at landscape scales. We present an extensive ecosystem analysis of the impacts of logging and conversion of tropical forest to oil palm from a large-scale study in Borneo, synthesizing responses from 82 variables categorized into four ecological levels spanning a broad suite of ecosystem properties: (i) structure and environment, (ii) species traits, (iii) biodiversity, and (iv) ecosystem functions. Responses were highly heterogeneous and often complex and nonlinear. Variables that were directly impacted by the physical process of timber extraction, such as soil structure, were sensitive to even moderate amounts of logging, whereas measures of biodiversity and ecosystem functioning were generally resilient to logging but more affected by conversion to oil palm plantation.
『摘要』 人们对森林退化和砍伐对热带雨林的影响知之甚少,尤其是在景观尺度上。本研究通过对婆罗洲的一项大规模研究,综合了82个变量的反应,这些变量分为涵盖一系列生态系统特性的四个生态层次:(i)结构和环境,(ii)物种特征,(iii)生物多样性,以及(iv)生态系统功能,对热带森林砍伐和转化为油棕榈林的影响进行了广泛的生态系统分析。反应具有高度异质性,且通常是复杂和非线性的。直接受到木材采伐物理过程影响的变量(如土壤结构)即使对中等程度的采伐也很敏感,而生物多样性和生态系统功能的衡量指标通常对采伐具有抵抗力,但更易受到转化为油棕榈种植园的影响。
『总结』 热带森林砍伐和油棕榈转化对其生态系统有多方面影响,土壤结构对采伐敏感,而生物多样性和生态系统功能更易受种植园转化的影响。
4. 光子轴子绝缘体
Photonic axion insulator
『Abstract』Abstract Axions, hypothetical elementary particles that remain undetectable in nature, can arise as quasiparticles in three-dimensional crystals known as axion insulators. Previous implementations of axion insulators have largely been limited to two-dimensional systems, leaving their topological properties in three dimensions unexplored in experiment. Here, we realize an axion insulator in a three-dimensional photonic crystal and probe its topological properties. Demonstrated features include half-quantized Chern numbers on each surface that resembles a fractional Chern insulator, unidirectional chiral hinge states forming topological transport in three dimensions, and arithmetic operations between fractional and integer Chern numbers. Our work experimentally establishes the axion insulator as a three-dimensional topological phase of matter and enables chiral states to form complex, unidirectional three-dimensional networks through braiding.
『摘要』 轴子是自然界中尚未探测到的假设基本粒子,它可以在被称为轴子绝缘体的三维晶体中作为准粒子出现。以往的轴子绝缘体实现大多局限于二维系统,其在三维空间中的拓扑特性尚未得到实验探索。在此,我们在三维光子晶体中实现了轴子绝缘体,并探究了其拓扑特性。所展示的特性包括:每个表面上类似分数切尔恩绝缘体的半量子化切尔恩数、在三维空间中形成拓扑传输的单向手性铰链态,以及分数切尔恩数与整数切尔恩数之间的算术运算。我们的工作通过实验证实了轴子绝缘体是一种三维拓扑物态,并使手性态能够通过编织形成复杂、单向的三维网络。
『总结』 该研究在三维光子晶体中首次实现了轴子绝缘体,并验证了其独特的三维拓扑特性。
5. 建筑材料每年可储存超过160亿吨二氧化碳
Building materials could store more than 16 billion tonnes of CO2 annually
『Abstract』Abstract Achieving net-zero greenhouse gas emissions likely entails not only lowering emissions but also deploying carbon dioxide (CO 2 ) removal technologies. We explored the annual potential to store CO 2 in building materials. We found that fully replacing conventional building materials with CO 2 -storing alternatives in new infrastructure could store as much as 16.6 ± 2.8 billion tonnes of CO 2 each year—roughly 50% of anthropogenic CO 2 emissions in 2021. The total storage potential is far more sensitive to the scale of materials used than the quantity of carbon stored per unit mass of materials. Moreover, the carbon storage reservoir of building materials will grow in proportion to demand for such materials, which could reduce demand for more costly or environmentally risky geological, terrestrial, or ocean storage.
『摘要』 实现温室气体净零排放可能不仅需要减少排放,还需要部署二氧化碳(CO 2)清除技术。我们探讨了建筑材料中储存CO 2的年度潜力。我们发现,在新基础设施中完全用CO 2储存型替代材料取代传统建筑材料,每年可储存多达166±28亿吨CO 2,大约是2021年人类活动产生的CO 2排放量的50%。总储存潜力对所用材料规模的敏感度远高于每单位质量材料所储存的碳量。此外,随着对此类材料需求的增长,建筑材料的碳储存库也将相应增加,这可能会减少对成本更高或环境风险更大的地质、陆地或海洋储存的需求。
『总结』 用CO 2储存型材料替代传统建筑材料,每年可储存大量CO 2,其储存潜力与材料使用规模密切相关,并可能降低对其他储存方式的需求。
6. 温冰的线性黏性流动
Linear-viscous flow of temperate ice
『Abstract』Abstract Accurately modeling the deformation of temperate glacier ice, which is at its pressure-melting temperature and contains liquid water at grain boundaries, is essential for predicting ice sheet discharge to the ocean and associated sea-level rise. Central to such modeling is Glen’s flow law, in which strain rate depends on stress raised to a power of n = 3 to 4. In sharp contrast to this nonlinearity, we found by conducting large-scale, shear-deformation experiments that temperate ice is linear-viscous ( n ≈ 1.0) over common ranges of liquid water content and stress expected near glacier beds and in ice-stream margins. This linearity is likely caused by diffusive pressure melting and refreezing at grain boundaries and could help to stabilize modeled responses of ice sheets to shrinkage-induced stress increases.
『摘要』 准确模拟处于压融温度且晶界含有液态水的温性冰川冰的变形,对于预测冰盖向海洋的排放以及相关的海平面上升至关重要。此类建模的核心是格伦流动定律,其中应变率取决于应力,且应力的幂次方n为3到4。我们通过大规模剪切变形实验发现,与这种非线性截然不同,在冰川底部和冰流边缘常见的液态水含量和应力范围内,温性冰表现出线性黏性(n≈1.0)。这种线性特征很可能是由于晶界的扩散压融和再冻结造成的,可能有助于使模型中冰盖对收缩引起的应力增加的响应趋于稳定。
『总结』 研究发现,在常见应力与液态水含量范围内,温性冰川冰表现出线性黏性特征,与格伦流动定律的非线性特征不同,该发现或有助于稳定冰盖模型的响应。
7. 平行基因扩张推动草食木鼠快速适应饮食
Parallel gene expansions drive rapid dietary adaptation in herbivorous woodrats
『Abstract』Abstract How mammalian herbivores evolve to feed on chemically defended plants remains poorly understood. In this study, we investigated the adaptation of two species of woodrats ( Neotoma lepida and N. bryanti ) to creosote bush ( Larrea tridentata ), a toxic shrub that expanded across the southwestern United States after the Last Glacial Maximum. We found that creosote-adapted woodrats have elevated gene dosage across multiple biotransformation enzyme families. These duplication events occurred independently across species and substantially increase expression of biotransformation genes, especially within the glucuronidation pathway. We propose that increased gene dosage resulting from duplication is an important mechanism by which animals initially adapt to novel environmental pressures.
『摘要』 对哺乳动物食草动物如何进化出食用具有化学防御机制的植物的能力,目前仍知之甚少。在本研究中,我们调查了两种林鼠(Neotoma lepida和N. bryanti)对克雷欧树(Larrea tridentata)的适应情况。克雷欧树是一种有毒灌木,在末次冰盛期后在美国西南部广泛扩散。我们发现,适应克雷欧树的林鼠在多个生物转化酶家族中的基因剂量有所增加。这些重复事件在不同物种中独立发生,并显著增加了生物转化基因的表达,尤其是在葡糖醛酸化途径中。我们认为,由重复导致的基因剂量增加是动物初步适应新环境压力的一种重要机制。
『总结』 研究发现,适应有毒灌木克雷欧树的林鼠通过基因重复增加了生物转化酶的表达,这是动物初步适应新环境压力的重要机制。
8. 用于稳定高效钙钛矿太阳能电池的晶圆级单层二硫化钼薄膜集成
Wafer-scale monolayer MoS2 film integration for stable, efficient perovskite solar cells
『Abstract』Abstract One of the primary challenges in commercializing perovskite solar cells (PSCs) is achieving both high power conversion efficiency (PCE) and sufficient stability. We integrate wafer-scale continuous monolayer MoS 2 buffers at the top and bottom of a perovskite layer through a transfer process. These films physically block ion migration of perovskite into carrier transport layers and chemically stabilize the formamidinium lead iodide phase through strong coordination interaction. Effective chemical passivation results from the formation of Pb-S bonds, and minority carriers are blocked through a type-I band alignment. Planar p-i-n PSCs (0.074 square centimeters) and modules (9.6 square centimeters) with MoS 2 /perovskite/MoS 2 configuration achieve PCEs up to 26.2% (certified steady-state PCE of 25.9%) and 22.8%, respectively. Moreover, the devices show excellent damp heat (85°C and 85% relative humidity) stability with <5% PCE loss after 1200 hours and notable high temperature (85°C) operational stability with <4% PCE loss after 1200 hours.
『摘要』 将钙钛矿太阳能电池(PSC)商业化面临的主要挑战之一是同时实现高功率转换效率(PCE)和足够的稳定性。我们通过转移工艺在钙钛矿层的顶部和底部集成了晶片级连续单层二硫化钼(MoS2)缓冲层。这些薄膜物理上阻断了钙钛矿中的离子向载流子传输层的迁移,并通过强配位作用使甲脒碘化铅相在化学上保持稳定。二硫化钼与铅形成Pb-S键,实现了有效的化学钝化,并通过I型能带排列阻挡了少数载流子。具有MoS2/钙钛矿/MoS2结构的平面p-i-n型PSC(0.074平方厘米)和组件(9.6平方厘米)分别实现了高达26.2%(经认证的稳定态PCE为25.9%)和22.8%的PCE。此外,这些器件表现出优异的抗湿热(85°C,相对湿度85%)稳定性,在1200小时后PCE损失<5%,并且具有显著的高温(85°C)运行稳定性,在1200小时后PCE损失<4%。
『总结』 研究通过在钙钛矿层上下集成单层二硫化钼缓冲层,实现了钙钛矿太阳能电池的高功率转换效率和长期稳定性。
9. 胆汁酸合成阻碍肝癌中肿瘤特异性T细胞反应
Bile acid synthesis impedes tumor-specific T cell responses during liver cancer
『Abstract』Abstract The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid–CoA:amino acid N -acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy. Furthermore, different BAs regulated CD8 T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.
『摘要』 肿瘤的代谢状态对抗肿瘤免疫有巨大影响,但肿瘤微环境中特定器官的代谢产物如何影响免疫监视仍不清楚。我们发现,初级结合胆汁酸和次级胆汁酸(BAs)的累积是人类肝细胞癌和实验性肝癌模型的代谢特征。通过敲除胆汁酸结合酶胆汁酸-辅酶A:氨基酸N-酰基转移酶(BAAT)抑制肝细胞中的结合胆汁酸合成,可增强肿瘤特异性T细胞反应,减少肿瘤生长,并使肿瘤对抗程序性细胞死亡蛋白1(抗PD-1)免疫治疗敏感。此外,不同的胆汁酸对CD8 T细胞的调节作用不同;初级胆汁酸可诱导氧化应激,而次级胆汁酸石胆酸则通过内质网应激抑制T细胞功能,熊去氧胆酸可抵消这一作用。本研究结果表明,改变胆汁酸合成或饮食中熊去氧胆酸的摄入量可改善肝癌模型系统中的肿瘤免疫治疗。
『总结』 研究发现调控胆汁酸合成或增加熊去氧胆酸的摄入有助于改善肝癌的免疫治疗效果。
10. 超稳定的脂质液泡赋予软骨形状和生物力学特性
Superstable lipid vacuoles endow cartilage with its shape and biomechanics
『Abstract』Abstract Conventionally, the size, shape, and biomechanics of cartilages are determined by their voluminous extracellular matrix. By contrast, we found that multiple murine cartilages consist of lipid-filled cells called lipochondrocytes. Despite resembling adipocytes, lipochondrocytes were molecularly distinct and produced lipids exclusively through de novo lipogenesis. Consequently, lipochondrocytes grew uniform lipid droplets that resisted systemic lipid surges and did not enlarge upon obesity. Lipochondrocytes also lacked lipid mobilization factors, which enabled exceptional vacuole stability and protected cartilage from shrinking upon starvation. Lipid droplets modulated lipocartilage biomechanics by decreasing the tissue’s stiffness, strength, and resilience. Lipochondrocytes were found in multiple mammals, including humans, but not in nonmammalian tetrapods. Thus, analogous to bubble wrap, superstable lipid vacuoles confer skeletal tissue with cartilage-like properties without “packing foam–like” extracellular matrix.
『摘要』 传统上,软骨的大小、形状和生物力学特性由其大量的细胞外基质决定。相比之下,我们发现多种小鼠软骨由充满脂质的细胞组成,这些细胞被称为脂质软骨细胞。尽管脂质软骨细胞与脂肪细胞相似,但它们在分子层面上存在差异,并且仅通过从头脂肪生成途径产生脂质。因此,脂质软骨细胞生长出均匀的脂滴,这些脂滴能够抵抗全身性脂质激增,并且在肥胖情况下不会增大。脂质软骨细胞还缺乏脂质动员因子,这使得其液泡具有异常的稳定性,并能在饥饿状态下防止软骨收缩。脂滴通过降低组织的硬度、强度和弹性来调节脂质软骨的生物力学特性。研究发现,包括人类在内的多种哺乳动物中都存在脂质软骨细胞,但在非哺乳类四足动物中并不存在。因此,类似于气泡膜,超稳定的脂质液泡使骨骼组织具有类似软骨的特性,而无需“包装泡沫状”的细胞外基质。
『总结』 研究发现脂质软骨细胞通过其独特的脂质生成和储存机制,调节软骨的生物力学特性,并首次在哺乳动物中发现该细胞的存在。
11. 性二态多巴胺能回路决定性别偏好
Sexually dimorphic dopaminergic circuits determine sex preference
『Abstract』Abstract Sociosexual preference is critical for reproduction and survival. However, neural mechanisms encoding social decisions on sex preference remain unclear. In this study, we show that both male and female mice exhibit female preference but shift to male preference when facing survival threats; their preference is mediated by the dimorphic changes in the excitability of ventral tegmental area dopaminergic (VTA ) neurons. In males, VTA projections to the nucleus accumbens (NAc) mediate female preference, and those to the medial preoptic area mediate male preference. In females, firing-pattern (phasic-like versus tonic-like) alteration of the VTA -NAc projection determines sociosexual preferences. These findings define VTA neurons as a key node for social decision-making and reveal the sexually dimorphic DA circuit mechanisms underlying sociosexual preference.
『摘要』 社会性行为偏好对繁殖和生存至关重要。然而,编码性偏好社会决策的神经机制尚不清楚。本研究表明,雄性和雌性小鼠均表现出对雌性的偏好,但在面临生存威胁时会转变为对雄性的偏好;这种偏好转变是由腹侧被盖区(VTA)多巴胺能神经元兴奋性的双态变化介导的。在雄性小鼠中,VTA至伏隔核(NAc)的投射介导对雌性的偏好,而VTA至内侧视前区的投射介导对雄性的偏好。在雌性小鼠中,VTA-NAc投射的放电模式(类似阵发与类似紧张性放电)改变决定了其社会性行为偏好。这些发现确定了VTA神经元是社会决策的关键节点,并揭示了社会性行为偏好潜在的性别二态多巴胺(DA)环路机制。
『总结』 研究揭示了小鼠社会性行为偏好受VTA神经元及其投射模式影响,并存在性别差异。
12. 用于分离液态脂肪族化合物的富氟聚(芳亚胺)膜
Fluorine-rich poly(arylene amine) membranes for the separation of liquid aliphatic compounds
『Abstract』Abstract We explored the potential for membrane materials to reduce energy and carbon requirements for the separation of aliphatic hydrocarbon feedstocks and products. We developed a series of fluorine-rich poly(arylene amine) polymer membranes that feature rigid polymer backbones with segregated perfluoroalkyl side chains. This combination imbues the polymers with resistance to dilation induced by hydrocarbon immersion without the loss of solution-based membrane fabrication techniques. These materials exhibit good separation of liquid-phase alkane isomers at ambient temperatures. The integration of these polymeric membranes into fuel and chemical feedstock separation processes was investigated in a series of experiments. Technoeconomic analyses based on these experiments indicate that the best-performing membrane materials can substantially reduce the energy costs and associated carbon emissions of hydrocarbon separations (two to 10 times, depending on product specifications).
『摘要』 我们探索了膜材料在减少脂肪烃原料和产品分离过程中的能源和碳需求的潜力。我们开发了一系列富含氟的聚(芳基胺)聚合物膜,这些膜具有刚性聚合物主链和分离的全氟烷基侧链。这种组合使聚合物具有抵抗烃类浸泡引起的膨胀的能力,同时不会损失基于溶液的膜制备技术。这些材料在环境温度下对液相烷烃异构体表现出良好的分离效果。在一系列实验中,我们研究了将这些聚合物膜整合到燃料和化工原料分离过程中的效果。基于这些实验的技术经济分析表明,性能最佳的膜材料可以显著降低烃类分离的能源成本和相关的碳排放(根据产品规格,降低幅度为2至10倍)。
『总结』 富含氟的聚(芳基胺)聚合物膜能显著降低烃类分离的能源成本和碳排放。
13. 利用快速体积纳米显微镜解码CD20与治疗性抗体之间的分子相互作用
Decoding the molecular interplay of CD20 and therapeutic antibodies with fast volumetric nanoscopy
『Abstract』Abstract Elucidating the interaction between membrane proteins and antibodies requires whole-cell imaging at high spatiotemporal resolution. Lattice light-sheet (LLS) microscopy offers fast volumetric imaging but suffers from limited spatial resolution. DNA-based point accumulation for imaging in nanoscale topography (DNA-PAINT) achieves molecular resolution but is restricted to two-dimensional imaging owing to long acquisition times. We have developed two-dye imager (TDI) probes that enable ~15-fold faster imaging. Combining TDI-DNA-PAINT and LLS microscopy on immunological B cells revealed the oligomeric states and interaction of endogenous CD20 with the therapeutic monoclonal antibodies (mAbs) rituximab, ofatumumab, and obinutuzumab. Our results demonstrate that CD20 is abundantly expressed on microvilli that bind mAbs, which leads to an antibody concentration–dependent B cell polarization and stabilization of microvilli protrusions. These findings could aid rational design of improved immunotherapies targeting tumor-associated antigens.
『摘要』 阐明膜蛋白与抗体的相互作用需要在高时空分辨率下进行全细胞成像。光栅光片(LLS)显微镜可提供快速的体积成像,但空间分辨率有限。基于DNA的纳米尺度地形成像的点积累技术(DNA-PAINT)虽然达到了分子分辨率,但由于采集时间长,仅限于二维成像。我们开发了两染料成像(TDI)探针,能够使成像速度提高约15倍。将TDI-DNA-PAINT与LLS显微镜结合,对免疫B细胞进行成像,揭示了内源性CD20与治疗性单克隆抗体(mAbs)利妥昔单抗、奥法木单抗和奥布替尼单抗的寡聚状态及其相互作用。研究结果表明,CD20在微绒毛上大量表达并与mAbs结合,从而导致抗体浓度依赖性B细胞极化和微绒毛突起的稳定。这些发现有助于合理设计针对肿瘤相关抗原的改进免疫疗法。
『总结』 本研究通过结合TDI-DNA-PAINT和LLS显微镜揭示了B细胞上CD20与治疗性mAbs的相互作用,为改进肿瘤免疫疗法提供了新思路。
14. 自由活动猴子自然行为的神经生态学
Neuroethology of natural actions in freely moving monkeys
『Abstract』Abstract The current understanding of primate natural action organization derives from laboratory experiments in restrained contexts (RCs) under the assumption that this knowledge generalizes to freely moving contexts (FMCs). In this work, we developed a neurobehavioral platform to enable wireless recording of the same premotor neurons in both RCs and FMCs. Neurons often encoded the same hand and mouth actions differently in RCs and FMCs. Furthermore, in FMCs, we identified cells that selectively encoded actions untestable during RCs and others that displayed mixed selectivity for multiple actions, which is compatible with an organization based on cortical motor synergies at different levels of complexity. Cross-context decoding demonstrated that neural activity in FMCs is richer and more generalizable than in RCs, which suggests that neuroethological approaches are better suited to unveil the neural bases of behavior.
『摘要』 当前对灵长类动物自然动作组织的理解基于受限环境(RCs)下的实验室实验,并假设这些知识同样适用于自由活动环境(FMCs)。在本研究中,我们开发了一个神经行为平台,能够无线记录同一组前运动神经元在RCs和FMCs中的活动。研究发现,这些神经元在RCs和FMCs中经常以不同的方式编码相同的手部和口腔动作。此外,在FMCs中,我们还发现了某些专门编码在RCs中无法测试的动作的神经元,以及其他对多种动作表现出混合选择性的神经元,这与基于不同复杂程度皮层运动协同作用的组织方式相符。跨环境解码表明,FMCs中的神经活动比RCs中的更丰富且更具泛化性,这表明神经行为学方法更适合揭示行为的神经基础。
『总结』 研究通过无线记录发现,灵长类动物在自由活动环境中神经元的编码方式比受限环境下更丰富、泛化性更强,强调神经行为学方法更适合探索行为的神经机制。
15. 袋鼠的食物广度使其能够适应第四纪的气候变化
Dietary breadth in kangaroos facilitated resilience to Quaternary climatic variations
『Abstract』Abstract Identifying what drove the late Pleistocene megafaunal extinctions on the continents remains one of the most contested topics in historical science. This is especially so in Australia, which lost 90% of its large species by 40,000 years ago, more than half of them kangaroos. Determining causation has been obstructed by a poor understanding of their ecology. Using dental microwear texture analysis, we show that most members of Australia’s richest Pleistocene kangaroo assemblage had diets that were much more generalized than their craniodental anatomy implies. Mixed feeding across most kangaroos pinpoints dietary breadth as a key behavioral adaptation to climate-driven fluctuations in vegetation structure, dispelling the likelihood that late Pleistocene climatic variation was a primary driver of their disappearance.
『摘要』 确定是什么导致了大陆上的更新世末期大型动物灭绝,仍然是历史科学中最有争议的话题之一。这一点在澳大利亚尤其如此,该国在4万年前就失去了90%的大型物种,其中一半以上是袋鼠。由于对这些物种的生态了解不足,确定灭绝原因一直受阻。我们通过牙齿微磨损纹理分析表明,澳大利亚最丰富的更新世袋鼠群落中的大多数成员的饮食比其颅牙解剖学所显示的要更为广泛。大多数袋鼠的混合食性表明,饮食广泛性是对气候驱动的植被结构变化的一种关键行为适应,这排除了更新世末期气候变化是其消失主要原因的可能性。
『总结』 通过分析牙齿微磨损,研究发现澳大利亚更新世袋鼠的饮食比预想更广泛,这表明气候驱动的植被变化不是导致其灭绝的主因。
16. 非线性感受野引发自然场景视网膜编码的冗余
Nonlinear receptive fields evoke redundant retinal coding of natural scenes
『Abstract』The role of the vertebrate retina in early vision is generally described by the efficient coding hypothesis , which predicts that the retina reduces the redundancy inherent in natural scenes by discarding spatiotemporal correlations while preserving stimulus information . It is unclear, however, whether the predicted decorrelation and redundancy reduction in the activity of ganglion cells, the retina’s output neurons, hold under gaze shifts, which dominate the dynamics of the natural visual input . We show here that species-specific gaze patterns in natural stimuli can drive correlated spiking responses both in and across distinct types of ganglion cells in marmoset as well as mouse retina. These concerted responses disrupt redundancy reduction to signal fixation periods with locally high spatial contrast. Model-based analyses of ganglion cell responses to natural stimuli show that the observed response correlations follow from nonlinear pooling of ganglion cell inputs. Our results indicate cell-type-specific deviations from efficient coding in retinal processing of natural gaze shifts.
『摘要』 高效编码假说通常用来描述脊椎动物视网膜在早期视觉中的作用,该假说预测视网膜通过丢弃时空相关性同时保留刺激信息来减少自然场景中固有的冗余。然而,目前尚不清楚在主导自然视觉输入动态的眼球运动下,视网膜输出神经元即神经节细胞的活动中,预测的去相关和冗余减少是否仍然成立。本研究表明,自然刺激中的物种特异性注视模式可以驱动恒河猴和小鼠视网膜中不同类型神经节细胞内和细胞间的相关脉冲反应。这些协同反应破坏了局部高空间对比度下信号固定时期的冗余减少。基于模型分析神经节细胞对自然刺激的反应表明,观察到的反应相关性源于神经节细胞输入的非线性整合。我们的研究结果表明,在处理自然眼球运动的视网膜过程中,存在偏离高效编码的细胞类型特异性。
『总结』 研究发现自然刺激下的物种特异性注视模式会影响神经节细胞的活动,导致视网膜处理偏离高效编码。
17. 用于快速、无标记检测胶质瘤浸润的基础模型
Foundation models for fast, label-free detection of glioma infiltration
『Abstract』A critical challenge in glioma treatment is detecting tumour infiltration during surgery to achieve safe maximal resection . Unfortunately, safely resectable residual tumour is found in the majority of patients with glioma after surgery, causing early recurrence and decreased survival . Here we present FastGlioma, a visual foundation model for fast (<10 s) and accurate detection of glioma infiltration in fresh, unprocessed surgical tissue. FastGlioma was pretrained using large-scale self-supervision (around 4 million images) on rapid, label-free optical microscopy, and fine-tuned to output a normalized score that indicates the degree of tumour infiltration within whole-slide optical images. In a prospective, multicentre, international testing cohort of patients with diffuse glioma ( n = 220), FastGlioma was able to detect and quantify the degree of tumour infiltration with an average area under the receiver operating characteristic curve of 92.1 ± 0.9%. FastGlioma outperformed image-guided and fluorescence-guided adjuncts for detecting tumour infiltration during surgery by a wide margin in a head-to-head, prospective study ( n = 129). The performance of FastGlioma remained high across diverse patient demographics, medical centres and diffuse glioma molecular subtypes as defined by the World Health Organization. FastGlioma shows zero-shot generalization to other adult and paediatric brain tumour diagnoses, demonstrating the potential for our foundation model to be used as a general-purpose adjunct for guiding brain tumour surgeries. These findings represent the transformative potential of medical foundation models to unlock the role of artificial intelligence in the care of patients with cancer.
『摘要』 在胶质瘤治疗中,一项关键挑战是在手术中检测肿瘤浸润情况,以实现安全最大限度的切除。不幸的是,大多数胶质瘤患者在手术后仍会发现可安全切除的残留肿瘤,这会导致早期复发和存活率降低。本文介绍了一种名为FastGlioma的视觉基础模型,该模型可以快速(<10秒)且准确地检测新鲜、未处理的手术组织中的胶质瘤浸润情况。FastGlioma使用大规模自监督(约400万张图像)在快速、无标记的光学显微镜上进行预训练,并经过微调以输出一个标准化评分,该评分指示全切片光学图像中的肿瘤浸润程度。在一项前瞻性、多中心、国际性的弥漫性胶质瘤患者测试队列(n=220)中,FastGlioma能够检测和量化肿瘤浸润程度,平均受试者工作特征曲线下面积为92.1±0.9%。在一项前瞻性、头对头研究(n=129)中,FastGlioma在检测术中肿瘤浸润方面,以较大优势超过了图像引导和荧光引导的辅助手段。FastGlioma在不同患者人口统计学特征、医疗中心和世界卫生组织定义的弥漫性胶质瘤分子亚型中均表现出高水平的性能。FastGlioma对其他成人和儿童脑肿瘤诊断表现出零样本泛化能力,证明了我们的基础模型作为通用辅助手段用于指导脑肿瘤手术的潜力。这些研究结果展示了医学基础模型在释放人工智能在癌症患者护理中的作用方面具有变革性潜力。
『总结』 FastGlioma是一种可快速准确检测胶质瘤浸润的视觉基础模型,在前瞻性测试中表现出色,具有指导脑肿瘤手术的潜力。
18. 泛基因组将小麦的结构变异与生态环境和育种联系起来
Pan-genome bridges wheat structural variations with habitat and breeding
『Abstract』Wheat is the second largest food crop with a very good breeding system and pedigree record in China. Investigating the genomic footprints of wheat cultivars will unveil potential avenues for future breeding efforts . Here we report chromosome-level genome assemblies of 17 wheat cultivars that chronicle the breeding history of China. Comparative genomic analysis uncovered a wealth of structural rearrangements, identifying 249,976 structural variations with 49.03% (122,567) longer than 5 kb. Cultivars developed in 1980s displayed significant accumulations of structural variations, a pattern linked to the extensive incorporation of European and American varieties into breeding programmes of that era. We further proved that structural variations in the centromere-proximal regions are associated with a reduction of crossover events. We showed that common wheat evolved from spring to winter types via mutations and duplications of the VRN-A1 gene as an adaptation strategy to a changing environment. We confirmed shifts in wheat cultivars linked to dietary preferences, migration and cultural integration in Northwest China. We identified large presence or absence variations of pSc200 tandem repeats on the 1RS terminal, suggesting its own rapid evolution in the wheat genome. The high-quality genome assemblies of 17 representatives developed and their good complementarity to the 10+ pan-genomes offer a robust platform for future genomics-assisted breeding in wheat.
『摘要』 中国拥有非常完善的育种体系和系谱记录,小麦是中国的第二大粮食作物。研究小麦品种的基因组特征将为未来的育种工作开辟潜在途径。本文报告了17个中国小麦品种的染色体级基因组组装结果,这些品种记录了中国的小麦育种历史。比较基因组分析发现了大量的结构重排,鉴定出249976个结构变异,其中49.03%(122567个)的长度大于5千碱基对。20世纪80年代培育的品种显示出结构变异显著累积,这一模式与该时期育种计划中广泛引入欧美品种有关。本研究进一步证明,着丝粒近端区域的结构变异与交叉事件的减少有关。研究还表明,普通小麦通过VRN-A1基因的突变和重复,从春性类型进化为冬性类型,以适应不断变化的环境。本文证实了小麦品种与西北地区饮食偏好、人口迁移和文化融合之间的联系。研究发现1RS末端存在大量的pSc200串联重复序列的有无变异,表明其在小麦基因组中快速进化。17个代表性小麦品种的高质量基因组组装结果,以及与10+泛基因组的良好互补性,为小麦未来的基因组辅助育种提供了坚实平台。
『总结』 本研究通过对17个中国小麦品种进行染色体级基因组组装和比较分析,揭示了小麦育种历史和基因组特征,为小麦未来的基因组辅助育种提供了重要资源。
19. 胎肝细胞通过胎球蛋白A保护造血干细胞和祖细胞(HSPC)基因组
Fetal hepatocytes protect the HSPC genome via fetuin-A
『Abstract』The maintenance of genomic integrity in rapidly proliferating cells is a substantial challenge during embryonic development . Although numerous cell-intrinsic mechanisms have been revealed , little is known about genome-protective effects and influences of developmental tissue microenvironments on tissue-forming cells. Here we show that fetal liver hepatocytes provide protection to haematopoietic stem and progenitor cell (HSPC) genomes. Lineage tracing and depletion in mice demonstrated that delayed hepatocyte development in early fetal livers increased the chromosomal instability of newly colonizing HSPCs. In addition, HSPCs developed tolerance to genotoxins in hepatocyte-conditioned medium, suggesting that hepatocytes protect the HSPC genome in a paracrine manner. Proteomic analyses demonstrated the enrichment of fetuin-A in hepatocyte-conditioned medium but not in early fetal livers. Fetuin-A activates a Toll-like receptor pathway to prevent pathogenic R-loop accumulation in HSPCs undergoing DNA replication and gene transcription in the fetal liver. Numerous haematopoietic regulatory genes frequently involved in leukaemogenic mutations are associated with R-loop-enriched regions. In Fetua -knockout mice, HSPCs showed increased genome instability and susceptibility to malignancy induction. Moreover, low concentrations of fetuin-A correlated with the oncogenesis of childhood leukaemia. Therefore, we uncover a mechanism operating in developmental tissues that offers tissue-forming cell genome protection and is implicated in developmental-related diseases.
『摘要』 在胚胎发育过程中,维持快速增殖细胞的基因组完整性是一项艰巨的挑战。尽管已经揭示了许多细胞内在机制,但对于发育组织微环境对组织形成细胞的基因组保护作用和影响却知之甚少。本研究发现,胎肝肝细胞可为造血干细胞和祖细胞(HSPC)的基因组提供保护。小鼠的谱系追踪和耗竭实验表明,早期胎肝中肝细胞发育延迟会增加新定植HSPC的染色体不稳定性。此外,HSPC在肝细胞条件培养基中对基因毒素产生耐受性,表明肝细胞以旁分泌方式保护HSPC基因组。蛋白质组学分析表明,肝细胞条件培养基中富含胎球蛋白A,但在早期胎肝中并不富含。胎球蛋白A可激活Toll样受体通路,防止胎肝中正在进行DNA复制和基因转录的HSPC中致病性R环积累。许多经常参与白血病突变的造血调节基因与R环富集区相关。在Fetua基因敲除小鼠中,HSPC表现出基因组不稳定性增加和易诱发恶性肿瘤。此外,胎球蛋白A低浓度与儿童白血病的发生相关。因此,本研究发现了一种在发育组织中运作的机制,该机制为组织形成细胞提供基因组保护,并与发育相关疾病有关。
『总结』 本研究揭示了胎肝肝细胞通过旁分泌胎球蛋白A保护造血干细胞和祖细胞基因组的新机制,这一发现与发育相关疾病有密切联系。
20. 通过压缩折叠实现鳄鱼头部鳞片的自组织图案化
Self-organized patterning of crocodile head scales by compressive folding
『Abstract』Amniote integumentary appendages constitute a diverse group of micro-organs, including feathers, hair and scales. These structures typically develop as genetically controlled units , the spatial patterning of which emerges from a self-organized chemical Turing system with integrated mechanical feedback . The seemingly purely mechanical patterning of polygonal crocodile head scales provides an exception to this paradigm . However, the nature and origin of the mechanical stress field driving this patterning remain unclear. Here, using precise in ovo intravenous injections of epidermal growth factor protein, we generate Nile crocodile embryos with substantially convoluted head skin, as well as hatchlings with smaller polygonal head scales resembling those of caimans. We then use light-sheet fluorescence microscopy to quantify embryonic tissue-layer geometry, collagen architecture and the spatial distribution of proliferating cells. Using these data, we build a phenomenological three-dimensional mechanical growth model that recapitulates both normal and experimentally modified patterning of crocodile head scales. Our experiments and numerical simulations demonstrate that crocodile head scales self-organize through compressive folding, originating from near-homogeneous skin growth with differential stiffness of the dermis versus the epidermis. Our experiments and theoretical morphospace analyses indicate that variation in embryonic growth and material properties of skin layers provides a simple evolutionary mechanism that produces a diversity of head-scale patterns among crocodilian species.
『摘要』 羊膜动物外皮附属物是由多种微器官组成的群体,包括羽毛、毛发和鳞片。这些结构通常是作为基因控制的单元而发育的,其空间图案源自一个具有综合机械反馈的自组织化学图灵系统。多边形鳄鱼头部鳞片看似仅由机械作用形成的图案,则成为了这一范式的例外。然而,驱动这一图案形成的机械应力场的性质和起源仍不清楚。在本文中,我们通过向鳄鱼卵内静脉注射表皮生长因子蛋白,培育出了头部皮肤高度褶皱的尼罗河鳄鱼胚胎,以及头部鳞片更小、呈多边形、类似凯门鳄的幼鳄。随后,我们使用光片荧光显微镜量化了胚胎组织层的几何形状、胶原蛋白结构和增殖细胞的空间分布。基于这些数据,我们建立了一个现象学的三维机械生长模型,该模型能够重现鳄鱼头部鳞片的正常和实验性修饰图案。我们的实验和数值模拟表明,鳄鱼头部鳞片是通过压缩折叠实现自组织的,这种折叠起源于真皮与表皮刚度不同的近乎均匀的皮肤生长。我们的实验和理论形态空间分析表明,胚胎生长的变化和皮肤层的材料特性为鳄鱼物种间头部鳞片图案的多样性提供了一种简单的进化机制。
『总结』 研究发现鳄鱼头部鳞片通过压缩折叠实现自组织,其图案多样性源自胚胎生长变化和皮肤层材料特性的差异。
21. 胎盘靶向VEGF mRNA脂质纳米粒改善小鼠先兆子痫
Placenta-tropic VEGF mRNA lipid nanoparticles ameliorate murine pre-eclampsia
『Abstract』Pre-eclampsia is a placental disorder that affects 3–5% of all pregnancies and is a leading cause of maternal and fetal morbidity worldwide . With no drug available to slow disease progression, engineering ionizable lipid nanoparticles (LNPs) for extrahepatic messenger RNA (mRNA) delivery to the placenta is an attractive therapeutic option for pre-eclampsia. Here we use high-throughput screening to evaluate a library of 98 LNP formulations in vivo and identify a placenta-tropic LNP (LNP 55) that mediates more than 100-fold greater mRNA delivery to the placenta in pregnant mice than a formulation based on the Food and Drug Administration-approved Onpattro LNP (DLin-MC3-DMA) . We propose an endogenous targeting mechanism based on β 2 -glycoprotein I adsorption that enables LNP delivery to the placenta. In both inflammation- and hypoxia-induced models of pre-eclampsia, a single administration of LNP 55 encapsulating vascular endothelial growth factor (VEGF) mRNA resolves maternal hypertension until the end of gestation. In addition, with our VEGF mRNA LNP 55 therapeutic, we demonstrate improvements in fetal health and partially restore placental vasculature, the local and systemic immune landscape and serum levels of soluble Fms-like tyrosine kinase-1, a clinical biomarker of pre-eclampsia . Together, these results demonstrate the potential of this mRNA LNP platform for treating placental disorders such as pre-eclampsia.
『摘要』 子痫前期是一种胎盘疾病,影响着3~5%的妊娠,也是全球孕产妇和胎儿发病的主要原因。目前尚无药物可延缓该疾病的进展,因此,设计可电离脂质纳米粒(LNPs)用于将细胞外信使核糖核酸(mRNA)递送至胎盘,是子痫前期的一个有吸引力的治疗方案。本研究利用高通量筛选技术在体内评估了98种LNP配方,并确定了一种胎盘嗜向性LNP(LNP 55),在妊娠小鼠中,其向胎盘递送mRNA的效率是基于美国食品药品监督管理局(Food and Drug Administration,FDA)批准的Onpattro LNP(DLin-MC3-DMA)配方的100倍以上。本研究提出了一种基于β2-糖蛋白I吸附的内源性靶向机制,该机制使LNP能够递送至胎盘。在炎症和缺氧诱导的子痫前期模型中,单次注射包裹有血管内皮生长因子(VEGF)mRNA的LNP 55可使孕产妇高血压缓解至妊娠结束。此外,通过VEGF mRNA LNP 55治疗方案,我们还观察到胎儿的健康状况有所改善,并且胎盘血管、局部和全身免疫以及血清中可溶性Fms样酪氨酸激酶-1(子痫前期的临床生物标志物)的水平均得到部分恢复。这些结果共同表明,该mRNA LNP平台在治疗子痫前期等胎盘疾病方面具有潜力。
『总结』 本研究开发了一种胎盘嗜向性LNP用于mRNA递送,并在子痫前期模型中验证了其治疗潜力。
22. 摩擦断裂和地震是如何孕育和演化的
How frictional ruptures and earthquakes nucleate and evolve
『Abstract』Frictional motion is mediated by rapidly propagating ruptures that detach the ensemble of contacts forming the frictional interface between contacting bodies . These ruptures are similar to shear cracks. When this process takes place in natural faults, these rapid ruptures are essentially earthquakes . Although fracture mechanics describe the rapid motion of these singular objects, the nucleation process that creates them is not understood . Here we fully describe the nucleation process by extending fracture mechanics to explicitly incorporate finite interface widths (which are generally ignored ). We show, experimentally and theoretically, that slow steady creep ensues at a well-defined stress threshold. Moreover, as slowly creeping patches approach the interface width, a topological transition takes place in which these creeping patches smoothly transition to the rapid fracture that is described by classical fracture mechanics . Apart from its relevance to fracture and material strength, this new picture of rupture nucleation dynamics is directly relevant to earthquake nucleation dynamics; slow, aseismic rupture must always precede rapid seismic rupture (so long as the initial defect in the interface is localized in both spatial dimensions). The theory may provide a new framework for understanding how and when earthquakes nucleate.
『摘要』 摩擦运动是通过快速传播的破裂来实现的,这些破裂会使接触体之间形成摩擦界面的接触集合体分离。这些破裂与剪切裂纹相似。当这一过程发生在天然断层中时,这些快速破裂实质上就是地震。虽然断裂力学描述了这些独特物体的快速运动,但产生这些物体的成核过程尚不清楚。在这里,我们通过扩展断裂力学以明确纳入通常被忽略的有限界面宽度,从而充分描述了成核过程。我们通过实验和理论证明,在一个明确的应力阈值下,会发生缓慢的稳定蠕变。此外,随着缓慢蠕变区域接近界面宽度,会发生拓扑转变,即这些蠕变区域会平稳过渡到经典断裂力学所描述的快速断裂。除了与断裂和材料强度相关之外,这种关于破裂成核动力学的新观点还直接与地震成核动力学相关;慢速、无震破裂必然总是先于快速地震破裂发生(只要界面上的初始缺陷在空间维度上是局部的)。该理论可能为理解地震何时以及如何成核提供了新的框架。
『总结』 研究发现摩擦运动中的快速破裂与地震相似,通过扩展断裂力学描述了破裂成核过程,这一新观点不仅与材料断裂强度相关,还为理解地震成核动力学提供了新框架。
23. 光酶中C-N键形成独特机制的出现
Emergence of a distinct mechanism of C–N bond formation in photoenzymes
『Abstract』C–N bond formation is integral to modern chemical synthesis owing to the ubiquity of nitrogen heterocycles in small-molecule pharmaceuticals and agrochemicals. Alkene hydroamination with unactivated alkenes is an atom-economical strategy for constructing these bonds. However, these reactions are challenging to render asymmetric when preparing fully substituted carbon stereocentres. Here we report a photoenzymatic alkene hydroamination to prepare 2,2-disubstituted pyrrolidines by a Baeyer–Villiger mono-oxygenase. Five rounds of protein engineering afforded a mutant, providing excellent product yield and stereoselectivity. Unlike related photochemical hydroaminations, which rely on the oxidation of the amine or alkene for C–N bond formation, this work exploits a through-space interaction of a reductively generated benzylic radical and the nitrogen lone pair. This antibonding interaction lowers the oxidation potential of the radical, enabling electron transfer to the flavin cofactor. Experiments indicate that the enzyme microenvironment is essential in enabling a innovative C–N bond formation mechanism with no parallel in small-molecule catalysis. Molecular dynamics simulations were performed to investigate the substrate in the enzyme active site, which further support this hypothesis. This work is a rare example of an emerging mechanism in non-natural biocatalysis in which an enzyme has access to a mechanism that its individual components do not. Our study showcases the potential of enhancing emergent mechanisms using protein engineering to provide unique mechanistic solutions to unanswered challenges in chemical synthesis.
『摘要』 C–N键的形成是现代化学合成不可或缺的一部分,因为含氮杂环广泛存在于小分子药物和农药中。利用未活化烯烃进行烯烃氢化胺化是构建这些键的一种原子经济策略。然而,在制备全取代碳立体中心时,这些反应很难实现不对称性。本文报道了一种利用Baeyer–Villiger单加氧酶进行的光酶促烯烃氢化胺化反应,用于制备2,2-二取代吡咯烷。经过五轮蛋白质工程,我们获得了一个突变体,可提供优异的产品产率和立体选择性。与依赖于胺或烯烃氧化形成C-N键的相关光化学氢化胺化不同,本研究利用了还原生成的苄基自由基和氮孤对电子之间的空间相互作用。这种反键相互作用降低了自由基的氧化电位,从而实现了向黄素辅因子的电子转移。实验表明,酶的微环境对于实现这种创新的C–N键形成机制至关重要,该机制在小分子催化中没有相似之处。为了进一步研究底物在酶活性位点的情况,我们进行了分子动力学模拟,进一步支持了这一假设。本研究是非天然生物催化领域中出现的一种新机制的罕见例子,在这种机制中,酶可以获得其单个组分所不具备的机制。我们的研究展示了利用蛋白质工程增强新出现机制的潜力,为化学合成中悬而未决的挑战提供了独特的机制解决方案。
『总结』 本研究报道了一种利用光酶促烯烃氢化胺化反应制备2,2-二取代吡咯烷的方法,并通过蛋白质工程提高了反应的产率和立体选择性,揭示了一种创新的C–N键形成机制。
24. 神经元微外显子错误剪接促进自闭症谱系障碍(ASD)中CPEB4的聚集
Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD
『Abstract』The inclusion of microexons by alternative splicing occurs frequently in neuronal proteins. The roles of these sequences are largely unknown, and changes in their degree of inclusion are associated with neurodevelopmental disorders . We have previously shown that decreased inclusion of a 24-nucleotide neuron-specific microexon in CPEB4, a RNA-binding protein that regulates translation through cytoplasmic changes in poly(A) tail length, is linked to idiopathic autism spectrum disorder (ASD) . Why this microexon is required and how small changes in its degree of inclusion have a dominant-negative effect on the expression of ASD-linked genes is unclear. Here we show that neuronal CPEB4 forms condensates that dissolve after depolarization, a transition associated with a switch from translational repression to activation. Heterotypic interactions between the microexon and a cluster of histidine residues prevent the irreversible aggregation of CPEB4 by competing with homotypic interactions between histidine clusters. We conclude that the microexon is required in neuronal CPEB4 to preserve the reversible regulation of CPEB4-mediated gene expression in response to neuronal stimulation.
『摘要』 可变剪接中微外显子的纳入在神经元蛋白中经常发生。这些序列的作用在很大程度上尚不清楚,其纳入程度的变化与神经发育障碍有关。我们此前已证明,CPEB4(一种通过胞质中多聚(A)尾长度变化来调节翻译的RNA结合蛋白)中一个24核苷酸的神经元特异性微外显子纳入减少与特发性自闭症谱系障碍(ASD)有关。目前尚不清楚为什么需要这个微外显子,也不清楚其纳入程度的微小变化如何对ASD相关基因的表达产生显性负效应。本研究表明,神经元CPEB4可形成凝聚体,在去极化后溶解,这一转变与翻译抑制到翻译激活的转换有关。微外显子与一组组氨酸残基之间的异型相互作用通过与组氨酸簇之间的同型相互作用竞争,阻止了CPEB4的不可逆聚集。我们得出的结论是,神经元CPEB4需要微外显子来保持对神经元刺激反应的CPEB4介导的基因表达的可逆调节。
『总结』 研究发现神经元CPEB4中的微外显子对于维持其在神经元刺激下基因表达的可逆调节至关重要。
25. 肠道微生物菌群丰富度具有物种特异性并影响定植
Gut microbiota strain richness is species specific and affects engraftment
『Abstract』Despite the fundamental role of bacterial strain variation in gut microbiota function , the number of unique strains of a species that can stably colonize the human intestine is still unknown for almost all species. Here we determine the strain richness (SR) of common gut species using thousands of sequenced bacterial isolates with paired metagenomes. We show that SR varies across species, is transferable by faecal microbiota transplantation, and is uniquely low in the gut compared with soil and lake environments. Active therapeutic administration of supraphysiologic numbers of strains per species increases recipient SR, which then converges back to the population average after dosing is ceased. Stratifying engraftment outcomes by high or low SR shows that SR predicts microbial addition or replacement in faecal transplants. Together, these results indicate that properties of the gut ecosystem govern the number of strains of each species colonizing the gut and thereby influence strain addition and replacement in faecal microbiota transplantation and defined live biotherapeutic products.
『摘要』 尽管细菌菌株变异在肠道微生物组功能中发挥着基础性作用,但几乎对于所有物种而言,能够稳定定植于人类肠道的独特菌株数量仍不得而知。本研究利用数千个已测序的细菌分离株与配对的宏基因组,确定了常见肠道物种的菌株丰富度(SR)。研究结果显示,SR因物种而异,可通过粪便微生物群移植进行转移,并且与土壤和湖泊环境相比,肠道中的SR独特地处于较低水平。对每种物种给予超过生理数量的菌株进行积极治疗可增加受体的SR,但在停止给药后,SR会恢复至群体平均水平。根据SR的高低对定植结果进行分层显示,SR可预测粪便移植中的微生物添加或替代情况。总体而言,这些结果表明,肠道生态系统的特性决定了定植于肠道的每种物种的菌株数量,从而影响了粪便微生物群移植和定义的活菌生物治疗药物中的菌株添加和替代。
『总结』 本研究表明肠道生态系统的特性决定了肠道中每种物种的菌株数量,并影响粪便微生物群移植中的菌株动态变化。
26. 用于无线电合成的捕光微电子器件
Light-harvesting microelectronic devices for wireless electrosynthesis
『Abstract』High-throughput experimentation (HTE) has accelerated academic and industrial chemical research in reaction development and drug discovery and has been broadly applied in many domains of organic chemistry . However, application of HTE in electrosynthesis—an enabling tool for chemical synthesis—has been limited by a dearth of suitable standardized reactors . Here we report the development of microelectronic devices, which are produced using standard nanofabrication techniques, to enable wireless electrosynthesis on the microlitre scale. These robust and inexpensive devices are powered by visible light and convert any traditional 96-well or 384-well plate into an electrochemical reactor. We validate the devices in oxidative, reductive and paired electrolysis and further apply them to achieve the library synthesis of biologically active compounds and accelerate the development of two electrosynthetic methodologies. We anticipate that, by simplifying the way electrochemical reactions are set up, this user-friendly solution will not only enhance the experience and efficiency of current practitioners but also substantially reduce the barrier for nonspecialists to enter the field of electrosynthesis, thus allowing the broader community of synthetic chemists to explore and benefit from new reactivities and synthetic strategies enabled by electrochemistry .
『摘要』 高通量实验(HTE)加速了学术界和工业界的化学反应开发和药物发现研究,并已在有机化学的许多领域得到广泛应用。然而,高通量实验在电合成(一种化学合成的工具)中的应用一直受到缺乏合适标准化反应器这一问题的限制。本文报告了我们利用标准纳米制造技术开发出的微电子器件,这些器件能够实现微升级别的无线电合成。这些坚固且廉价的器件由可见光供电,并能将任何传统的96孔板或384孔板转化为电化学反应器。我们在氧化、还原和配对电解中对这些器件进行了验证,并进一步应用它们实现了生物活性化合物的库合成,同时加速了两种电合成方法的开发。我们预计,这种用户友好的解决方案通过简化电化学反应的设置方式,不仅能够提高当前从业人员的体验和效率,还能大幅降低非专业人员进入电合成领域的门槛,从而让更广泛的合成化学家群体能够探索电化学所带来的新反应性和合成策略,并从中受益。
『总结』 本文介绍了一种利用标准纳米制造技术开发的微电子器件,能够实现微升级无线电合成,有望提高电化学反应的效率并促进电合成领域的发展。
27. FBP1控制从衰老MASH肝细胞发展而来的肝癌进程
FBP1 controls liver cancer evolution from senescent MASH hepatocytes
『Abstract』Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or metabolic-dysfunction-associated steatohepatitis (MASH) . While increasing HCC risk , MASH triggers p53-dependent hepatocyte senescence , which we found to parallel hypernutrition-induced DNA breaks. How this tumour-suppressive response is bypassed to license oncogenic mutagenesis and enable HCC evolution was previously unclear. Here we identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a p53 target that is elevated in senescent-like MASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically stressed premalignant disease-associated hepatocytes and HCC progenitor cells , paralleling the protumorigenic activation of AKT and NRF2. By accelerating FBP1 and p53 degradation, AKT and NRF2 enhance the proliferation and metabolic activity of previously senescent HCC progenitors. The senescence-reversing and proliferation-supportive NRF2–FBP1–AKT–p53 metabolic switch, operative in mice and humans, also enhances the accumulation of DNA-damage-induced somatic mutations needed for MASH-to-HCC progression.
『摘要』 肝细胞癌(Hepatocellular Carcinoma,HCC)起源于因病毒或代谢功能障碍相关脂肪性肝炎(Metabolic-Dysfunction-Associated Steatohepatitis,MASH)而受损的肝脏中发生代偿性增殖的分化肝细胞。MASH在增加HCC风险的同时,还会触发p53依赖性肝细胞衰老,我们发现这一过程与营养过剩诱导的DNA断裂平行发生。此前尚不清楚这种肿瘤抑制反应是如何被绕过从而促成癌症突变、推动HCC演进的。在本研究中,我们发现糖异生酶果糖-1,6-二磷酸酶1(Fructose-1,6-Bisphosphatase 1,FBP1)是p53的靶标,其在类似衰老的MASH肝细胞中表达升高,但在大多数人类HCC中却因启动子高甲基化和蛋白酶体降解而受到抑制。FBP1在代谢压力下的癌前病变相关肝细胞和HCC祖细胞中首先下降,这与AKT和NRF2的促肿瘤激活平行发生。AKT和NRF2通过加速FBP1和p53的降解,增强了先前处于衰老状态的HCC祖细胞的增殖和代谢活性。这种在小鼠和人类中都存在的、可逆转衰老并支持增殖的NRF2–FBP1–AKT–p53代谢开关,也促进了MASH向HCC进展过程中所需的DNA损伤诱导的体细胞突变的累积。
『总结』 研究发现FBP1是p53靶标,其在MASH肝细胞中升高但在HCC中受抑制,NRF2–FBP1–AKT–p53代谢开关促进了HCC的演进。
28. 癌症中缺氧诱导的炎性细胞死亡机制
A mechanism for hypoxia-induced inflammatory cell death in cancer
『Abstract』Hypoxic cancer cells resist many antineoplastic therapies and can seed recurrence . We previously found that either deficiency or inhibition of protein-tyrosine phosphatase (PTP1B) promotes human epidermal growth factor receptor 2-positive breast cancer cell death in hypoxia by activation of RNF213 (ref. ), a large protein with multiple AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) implicated in Moyamoya disease, lipotoxicity and innate immunity . Here we report that PTP1B and ABL1/2 reciprocally control RNF213 tyrosine phosphorylation and, consequently, its oligomerization and RZ domain activation. The RZ domain ubiquitylates and induces the degradation of the major NF-κB regulator CYLD/SPATA2. Decreased CYLD/SPATA2 levels lead to NF-κB activation and induction of the NLRP3 inflammasome which, together with hypoxia-induced endoplasmic reticulum stress, triggers pyroptotic cell death. Consistent with this model, CYLD deletion phenocopies, whereas NLRP3 deletion blocks, the effects of PTP1B deficiency on human epidermal growth factor receptor 2-positive breast cancer xenograft growth. Reconstitution studies with RNF213 mutants confirm that the RZ domain mediates tumour cell death. In concert, our results identify a unique, potentially targetable PTP1B–RNF213–CYLD–SPATA2 pathway critical for the control of inflammatory cell death in hypoxic tumours, provide new insights into RNF213 regulation and have potential implications for the pathogenesis of Moyamoya disease, inflammatory disorders and autoimmune disease.
『摘要』 缺氧的癌细胞对许多抗肿瘤治疗都有耐药性,并能引起癌症复发。我们之前发现,蛋白酪氨酸磷酸酶(PTP1B)缺乏或抑制可通过激活RNF213(一种与烟雾病、脂质毒性和先天免疫有关,含多个AAA-ATPase结构域和两个泛素连接酶结构域(RING和RZ)的大型蛋白)来促进人表皮生长因子受体2(HER2)阳性乳腺癌细胞在缺氧条件下的死亡。本研究发现PTP1B与ABL1/2相互调控RNF213酪氨酸磷酸化,进而调控其寡聚化和RZ结构域活化。RZ结构域可促进NF-κB的主要调控因子CYLD/SPATA2发生泛素化并诱导其降解。CYLD/SPATA2水平降低导致NF-κB活化并诱导NLRP3炎性小体产生,NLRP3炎性小体与缺氧诱导的内质网应激一起触发细胞焦亡。与该模型一致的是,CYLD缺失可模拟PTP1B缺乏对人表皮生长因子受体2阳性乳腺癌异种移植瘤生长的影响,而NLRP3缺失则可阻断这一影响。利用RNF213突变体的重构研究证实,RZ结构域可介导肿瘤细胞死亡。综上,我们的研究结果确定了一条独特的、潜在可靶向的PTP1B–RNF213–CYLD–SPATA2通路,该通路对控制缺氧肿瘤中的炎性细胞死亡至关重要,为RNF213的调控提供了新的见解,并对烟雾病、炎症性疾病和自身免疫性疾病的发病机制具有潜在意义。
『总结』 研究发现PTP1B–RNF213–CYLD–SPATA2通路对控制缺氧肿瘤中的炎性细胞死亡至关重要,为抗肿瘤治疗和疾病研究提供新视角。
29. 超越费米子和玻色子的粒子交换统计
Particle exchange statistics beyond fermions and bosons
『Abstract』It is commonly believed that there are only two types of particle exchange statistics in quantum mechanics, fermions and bosons, with the exception of anyons in two dimensions . In principle, a second exception known as parastatistics, which extends outside two dimensions, has been considered but was believed to be physically equivalent to fermions and bosons . Here we show that non-trivial parastatistics inequivalent to either fermions or bosons can exist in physical systems. These new types of identical particle obey generalized exclusion principles, leading to exotic free-particle thermodynamics distinct from any system of free fermions and bosons. We formulate our theory by developing a second quantization of paraparticles that naturally includes exactly solvable non-interacting theories and incorporates physical constraints such as locality. We then construct a family of exactly solvable quantum spin models in one and two dimensions, in which free paraparticles emerge as quasiparticle excitations, and their exchange statistics can be physically observed and are notably distinct from fermions and bosons. This demonstrates the possibility of a new type of quasiparticle in condensed matter systems and—more speculatively—the potential for previously unconsidered types of elementary particle.
『摘要』 人们普遍认为,量子力学中只存在两种粒子交换统计类型:费米子和玻色子,二维空间中的任意子除外。原则上,人们考虑过第二种例外情况,即超出二维空间的仲旋量子统计,但人们认为它在物理上等价于费米子和玻色子。本文表明,不同于费米子和玻色子的非平凡仲旋量子统计可存在于物理系统中。这类新型的全同粒子遵循广义排除原理,从而产生不同于任何自由费米子和玻色子系统的奇异自由粒子热力学。我们通过开发仲粒子的二次量子化来构建理论,该理论自然包括可精确求解的非相互作用理论,并纳入局域性等物理约束。然后,我们在一维和二维空间中构建了一系列可精确求解的量子自旋模型,其中自由仲粒子作为准粒子激发态出现,其交换统计特性可通过物理观察得到,并且明显不同于费米子和玻色子。这证明了凝聚态系统中存在新型准粒子的可能性,并且更具推测性地表明了存在以前未曾考虑过的基本粒子类型的潜力。
『总结』 研究发现了一种不同于费米子和玻色子的新型粒子交换统计——仲旋量子统计,它遵循广义排除原理,可存在于物理系统中,为凝聚态系统和基本粒子物理领域带来了新的可能性。
30. 二聚体NINJ1的自抑制可防止质膜破裂
Autoinhibition of dimeric NINJ1 prevents plasma membrane rupture
『Abstract』Lytic cell death culminates in plasma membrane rupture, which releases large intracellular molecules to augment the inflammatory response. Plasma membrane rupture is mediated by the effector membrane protein ninjurin-1 (NINJ1) , which polymerizes and ruptures the membrane via its hydrophilic face . How NINJ1 is restrained under steady-state conditions to ensure cell survival remains unknown. Here we describe the molecular underpinnings of NINJ1 inhibition. Using cryogenic electron microscopy, we determined the structure of inactive-state mouse NINJ1 bound to the newly developed nanobody Nb538. Inactive NINJ1 forms a face-to-face homodimer by adopting a three-helix conformation with unkinked transmembrane helix 1 (TM1), in contrast to the four-helix TM1-kinked active conformation . Accordingly, endogenous NINJ1 from primary macrophages is a dimer under steady-state conditions. Inactive dimers sequester the membrane rupture-inducing hydrophilic face of NINJ1 and occlude the binding site for kinked TM1 from neighbouring activated NINJ1 molecules. Mutagenesis studies in cells show that destabilization of inactive face-to-face dimers leads to NINJ1-mediated cell death, whereas stabilization of face-to-face dimers inhibits NINJ1 activity. Moreover, destabilizing mutations prompt spontaneous TM1 kink formation, a hallmark of NINJ1 activation. Collectively, our data demonstrate that dimeric NINJ1 is autoinhibited in trans to prevent unprovoked plasma membrane rupture and cell death.
『摘要』 细胞溶解性死亡最终导致质膜破裂,会释放大量细胞内分子以增强炎症反应。质膜破裂由效应膜蛋白Ninjurin-1(NINJ1)介导,它通过其亲水面聚合并破裂膜。稳态条件下如何抑制NINJ1以确保细胞存活尚不清楚。本文阐述了NINJ1抑制的分子基础。我们通过冷冻电子显微镜确定了与新开发的纳米抗体Nb538结合的非活化态小鼠NINJ1的结构。非活化态NINJ1采用具有未扭曲跨膜螺旋1(TM1)的三螺旋构象,形成面对面同源二聚体,而活化态构象则是具有四螺旋的TM1扭曲结构。因此,原代巨噬细胞中的内源性NINJ1在稳态条件下也是二聚体。非活化二聚体隔离了NINJ1的诱导膜破裂的亲水面,并阻塞了来自邻近活化NINJ1分子的扭曲TM1结合位点。细胞突变研究表明,非活化面对面二聚体的不稳定导致NINJ1介导的细胞死亡,而面对面二聚体的稳定则抑制NINJ1活性。此外,去稳定突变促使自发形成TM1扭曲,这是NINJ1活化的标志。综上所述,本研究数据表明,二聚体NINJ1以反式自身抑制的方式存在,以防止无故的质膜破裂和细胞死亡。
『总结』 本研究揭示了NINJ1通过形成非活化面对面二聚体实现自身抑制,从而防止细胞无故死亡的新机制。
31. 基于表格基础模型对小数据进行准确预测
Accurate predictions on small data with a tabular foundation model
『Abstract』Tabular data, spreadsheets organized in rows and columns, are ubiquitous across scientific fields, from biomedicine to particle physics to economics and climate science . The fundamental prediction task of filling in missing values of a label column based on the rest of the columns is essential for various applications as diverse as biomedical risk models, drug discovery and materials science. Although deep learning has revolutionized learning from raw data and led to numerous high-profile success stories , gradient-boosted decision trees have dominated tabular data for the past 20 years. Here we present the Tabular Prior-data Fitted Network (TabPFN), a tabular foundation model that outperforms all previous methods on datasets with up to 10,000 samples by a wide margin, using substantially less training time. In 2.8 s, TabPFN outperforms an ensemble of the strongest baselines tuned for 4 h in a classification setting. As a generative transformer-based foundation model, this model also allows fine-tuning, data generation, density estimation and learning reusable embeddings. TabPFN is a learning algorithm that is itself learned across millions of synthetic datasets, demonstrating the power of this approach for algorithm development. By improving modelling abilities across diverse fields, TabPFN has the potential to accelerate scientific discovery and enhance important decision-making in various domains.
『摘要』 表格数据是以行和列形式组织的电子表格,在生物医学、粒子物理、经济学和气候科学等科学领域无处不在。根据其他列来填补标签列中缺失值的基本预测任务,对于生物医学风险模型、药物发现和材料科学等多种应用至关重要。虽然深度学习已经从根本上改变了从原始数据中学习的方式,并带来了众多引人注目的成功案例,但在过去20年里,梯度提升决策树一直在表格数据领域占据主导地位。本文提出了表格先验数据拟合网络(TabPFN),这是一个表格基础模型,在最多包含10000个样本的数据集上,其表现远超以往所有方法,且训练时间大大缩短。在分类设置中,TabPFN在2.8秒内就超过了调优4小时的最强基线集成模型。作为一个基于生成式变换器的基础模型,该模型还支持微调、数据生成、密度估计和可重用嵌入的学习。TabPFN是一种学习算法,它本身是通过数百万个合成数据集学习而来的,展现了这种方法在算法开发方面的强大能力。通过提高不同领域的建模能力,TabPFN有可能加速科学发现,并改进各个领域的重要决策。
『总结』 表格先验数据拟合网络(TabPFN)作为新提出的表格基础模型,在预测任务上表现优异且训练时间短,具有微调、数据生成等多功能,有望提升跨领域的建模能力。
32. IgE介导的FcεRI活化的分子机制
Molecular mechanism of IgE-mediated FcεRI activation
『Abstract』Allergic diseases affect more than a quarter of individuals in industrialized countries, and are a major public health concern . The high-affinity Fc receptor for immunoglobulin E (FcεRI), which is mainly present on mast cells and basophils, has a crucial role in allergic diseases . Monomeric immunoglobulin E (IgE) binding to FcεRI regulates mast cell survival, differentiation and maturation . However, the underlying molecular mechanism remains unclear. Here we demonstrate that prior to IgE binding, FcεRI exists mostly as a homodimer on human mast cell membranes. The structure of human FcεRI confirms the dimeric organization, with each promoter comprising one α subunit, one β subunit and two γ subunits. The transmembrane helices of the α subunits form a layered arrangement with those of the γ and β subunits. The dimeric interface is mediated by a four-helix bundle of the α and γ subunits at the intracellular juxtamembrane region. Cholesterol-like molecules embedded within the transmembrane domain may stabilize the dimeric assembly. Upon IgE binding, the dimeric FcεRI dissociates into two protomers, each of which binds to an IgE molecule. This process elicits transcriptional activation of Egr1 , Egr3 and Ccl2 in rat basophils, which can be attenuated by inhibiting the FcεRI dimer-to-monomer transition. Collectively, our study reveals the mechanism of antigen-independent, IgE-mediated FcεRI activation.
『摘要』 在工业化国家,过敏性疾病影响着超过四分之一的人群,是一个主要的公共卫生问题。高亲和力免疫球蛋白E(FcεRI)受体主要存在于肥大细胞和嗜碱性粒细胞上,在过敏性疾病中发挥着关键作用。单体免疫球蛋白E(IgE)与FcεRI的结合可调节肥大细胞的存活、分化和成熟。然而,其潜在的分子机制尚不清楚。本研究发现,在IgE结合之前,FcεRI主要以同源二聚体的形式存在于人肥大细胞膜上。人FcεRI的结构证实了其二聚体的组成,每个原聚体由一个α亚基、一个β亚基和两个γ亚基组成。α亚基的跨膜螺旋与γ和β亚基的跨膜螺旋形成分层排列。二聚体界面由细胞内近膜区的α和γ亚基的四螺旋束介导。嵌入跨膜结构域内的胆固醇样分子可能稳定二聚体组装。IgE结合后,二聚体FcεRI解离成两个原聚体,每个原聚体与一个IgE分子结合。这一过程可诱导大鼠嗜碱性粒细胞中Egr1、Egr3和Ccl2的转录激活,而抑制FcεRI二聚体向单体的转变可减弱这种激活。综上所述,我们的研究揭示了抗原非依赖性、IgE介导的FcεRI激活机制。
『总结』 本研究揭示了FcεRI在IgE结合前以二聚体形式存在,IgE结合后解离为单体并激活相关基因转录的分子机制。
33. 分数量子霍尔效应中的激子
Excitons in the fractional quantum Hall effect
『Abstract』Excitons, Coulomb-driven bound states of electrons and holes, are typically composed of integer charges . However, in bilayer systems influenced by charge fractionalization , a more interesting form of interlayer exciton can emerge, in which pairing occurs between constituents that carry fractional charges. Despite numerous theoretical predictions for these fractional excitons , their experimental observation has remained unexplored. Here we report transport signatures of excitonic pairing in fractional quantum Hall effect states. By probing the composition of these excitons and their impact on the underlying wavefunction, we discover two new types of quantum phases of matter. One of these can be viewed as the fractional counterpart of the exciton condensate at a total filling of 1, whereas the other involves a more unusual type of exciton that obeys non-bosonic quantum statistics, challenging the standard model of bosonic excitons.
『摘要』 激子是由电子和空穴通过库仑相互作用形成的束缚态,通常带有整数电荷。然而,在受电荷分馏影响的双层系统中,可以产生一种更有趣的层间激子形式,其中携带分数电荷的成分之间会发生配对。尽管这些分数激子已有很多理论预测,但其实验观测一直未曾实现。在此,我们报告了分数量子霍尔效应态中激子配对的传输特征。通过研究这些激子的组成及其对底层波函数的影响,我们发现了两种新的物质量子相。其中一种可被视为总填充为1时的激子凝聚体的分数对应物,而另一种则涉及一种更不寻常的激子,它服从非玻色子量子统计,对玻色子激子的标准模型提出了挑战。
『总结』 本研究在分数量子霍尔效应态中发现了激子配对的传输特征,揭示了两种新的物质量子相,其中一种为非玻色子激子。
34. 实时追踪转录-翻译偶联
Tracking transcription–translation coupling in real time
『Abstract』A central question in biology is how macromolecular machines function cooperatively. In bacteria, transcription and translation occur in the same cellular compartment, and can be physically and functionally coupled . Although high-resolution structures of the ribosome–RNA polymerase (RNAP) complex have provided initial mechanistic insights into the coupling process , we lack knowledge of how these structural snapshots are placed along a dynamic reaction trajectory. Here we reconstitute a complete and active transcription–translation system and develop multi-colour single-molecule fluorescence microscopy experiments to directly and simultaneously track transcription elongation, translation elongation and the physical and functional coupling between the ribosome and the RNAP in real time. Our data show that physical coupling between ribosome and RNAP can occur over hundreds of nucleotides of intervening mRNA by mRNA looping, a process facilitated by NusG. We detect active transcription elongation during mRNA looping and show that NusA-paused RNAPs can be activated by the ribosome by long-range physical coupling. Conversely, the ribosome slows down while colliding with the RNAP. We hereby provide an alternative explanation for how the ribosome can efficiently rescue RNAP from frequent pausing without requiring collisions by a closely trailing ribosome. Overall, our dynamic data mechanistically highlight an example of how two central macromolecular machineries, the ribosome and RNAP, can physically and functionally cooperate to optimize gene expression.
『摘要』 生物学中的一个核心问题是大分子机器如何协同工作。在细菌中,转录和翻译发生在同一个细胞区室内,可以在物理和功能上相互偶联。虽然核糖体-RNA聚合酶(RNAP)复合物的高分辨率结构为理解这一偶联过程的机制提供了初步见解,但我们尚不清楚这些结构快照是如何沿着动态反应轨迹分布的。在这里,我们重构了一个完整且活跃的转录-翻译系统,并开发了多色单分子荧光显微镜实验,以实时、直接地同时追踪转录延伸、翻译延伸以及核糖体和RNAP之间的物理和功能偶联。我们的数据表明,在NusG的协助下,通过mRNA成环,核糖体与RNAP之间的物理偶联可以跨越数百个核苷酸长度的mRNA间隔区发生。我们检测到了mRNA成环过程中的活跃转录延伸,并表明NusA暂停的RNAP可以通过核糖体的长距离物理偶联被激活。相反,核糖体在与RNAP碰撞时会减速。我们据此为核糖体如何无需紧密跟随的核糖体碰撞即可有效拯救频繁暂停的RNAP提供了另一种解释。总体而言,我们的动态数据从机制上突出了一个例子,即两个核心的大分子机器——核糖体和RNAP——如何通过物理和功能上的协同作用来优化基因表达。
『总结』 本研究揭示了核糖体和RNAP在细菌中转录和翻译过程中的物理和功能协同机制,为理解大分子机器如何优化基因表达提供了新的见解。
35. 压电陶瓷中的纵向应变增强和弯曲变形
Longitudinal strain enhancement and bending deformations in piezoceramics
『Abstract』Piezoelectric materials directly convert between electrical and mechanical energies. They are used as transducers in applications such as nano-positioning and ultrasound imaging. Improving the properties of these devices requires piezoelectric materials capable of delivering a large longitudinal strain on the application of an electric field. A large longitudinal strain of more than 1% is generally anticipated in suitably oriented single crystals of specific compositions of ferroelectric materials . Polycrystalline piezoceramics typically show a longitudinal strain of approximately 0.2–0.4%. We demonstrate that when the thickness of a polycrystalline piezoceramic is reduced to such an extent that a large fraction of the grains are in the triaxial–biaxal crossover regime, the domain-switching fraction increases considerably. If the positive and the negative surfaces of the piezoceramic respond to electric fields symmetrically, as in the classical PbZr x Ti x O 3 , a longitudinal strain of approximately 1% can be achieved in a 0.2 mm disc of the morphotropic phase boundary composition (a 300% increase from a thickness of 0.7 mm). We show that oxygen vacancies in piezoceramics cause asymmetrical switching at the positive and negative surfaces, which causes thin piezoceramics to bend. We expect these findings will encourage further engineering of these mechanisms across different piezoelectric material systems, opening new applications for electromechanical actuation.
『摘要』 压电材料可以直接实现电能和机械能之间的转换。它们被用作纳米定位和超声成像等应用中的换能器。改善这些器件的性能需要压电材料能够在施加电场时产生较大的纵向应变。在特定组成的铁电材料适当定向的单晶中,通常预期会产生超过1%的较大纵向应变。多晶压电陶瓷通常显示出约0.2-0.4%的纵向应变。本研究证明,当多晶压电陶瓷的厚度减小到使大部分晶粒处于三轴-双轴交叉区域时,畴转换比例会显著增加。如果压电陶瓷的正负表面对电场的响应是对称的,如经典的PbZr x Ti x O 3,则在形态相界组成的0.2毫米圆盘中可以实现约1%的纵向应变(与0.7毫米厚度相比增加了300%)。本研究表明,压电陶瓷中的氧空位会导致正负表面的不对称转换,从而使薄压电陶瓷弯曲。预计这些发现将促进不同压电材料系统中这些机制的进一步研究,为电机械驱动开辟新的应用领域。
『总结』 研究发现,减小多晶压电陶瓷的厚度可显著增加畴转换比例,实现约1%的纵向应变,但氧空位会导致其弯曲,这些发现有望促进压电材料系统的进一步研究和应用。
36. 血液学设定点是一种稳定且患者特异性的深度表型
Haematological setpoints are a stable and patient-specific deep phenotype
『Abstract』The complete blood count (CBC) is an important screening tool for healthy adults and a common test at periodic exams. However, results are usually interpreted relative to one-size-fits-all reference intervals , undermining the precision medicine goal to tailor care for patients on the basis of their unique characteristics . Here we study thousands of diverse patients at an academic medical centre and show that routine CBC indices fluctuate around stable values or setpoints , and setpoints are patient-specific, with the typical healthy adult’s nine CBC setpoints distinguishable as a group from those of 98% of other healthy adults, and setpoint differences persist for at least 20 years. Haematological setpoints reflect a deep physiologic phenotype enabling investigation of acquired and genetic determinants of haematological regulation and its variation among healthy adults. Setpoints in apparently healthy adults were associated with significant variation in clinical risk: absolute risk of some common diseases and morbidities varied by more than 2% (heart attack and stroke, diabetes, kidney disease, osteoporosis), and absolute risk of all-cause 10 year mortality varied by more than 5%. Setpoints also define patient-specific reference intervals and personalize the interpretation of subsequent test results. In retrospective analysis, setpoints improved sensitivity and specificity for evaluation of some common conditions including diabetes, kidney disease, thyroid dysfunction, iron deficiency and myeloproliferative neoplasms. This study shows CBC setpoints are sufficiently stable and patient-specific to help realize the promise of precision medicine for healthy adults.
『摘要』 全血细胞计数(CBC)是健康成年人的重要筛查工具,也是常规体检中的常见检测项目。然而,其结果通常是根据一刀切的参考区间来解释的,这破坏了根据患者的独特特征定制治疗的精准医疗目标。本研究在一家学术医疗中心研究了数千名不同的患者,结果表明,常规CBC指标在稳定值或设定值附近波动,且设定值具有患者特异性,典型健康成年人的九项CBC设定值作为一组可与其他98%的健康成年人的设定值相区分,并且设定值差异至少持续20年。血液学设定值反映了一种深入的生理学表型,使我们能够研究血液学调节及其在健康成年人中的差异的获得性和遗传决定因素。表面健康的成年人的设定值与临床风险的显著差异相关:一些常见疾病和发病率的绝对风险差异超过2%(心脏病发作和中风、糖尿病、肾病、骨质疏松症),而全因10年死亡率的绝对风险差异超过5%。设定值还可以确定患者特异性的参考区间,并使后续检测结果的解释个性化。在回顾性分析中,设定值提高了对某些常见疾病(包括糖尿病、肾病、甲状腺功能障碍、缺铁和骨髓增殖性肿瘤)评估的灵敏度和特异性。本研究表明,CBC设定值足够稳定且具有患者特异性,有助于实现对健康成年人的精准医疗承诺。
『总结』 研究发现CBC设定值具有患者特异性且足够稳定,可用于提高疾病评估的灵敏度和特异性,并助力实现对健康成年人的精准医疗。
37. 用于持久型锂金属电池的Li2ZrF6基电解质
Li2ZrF6-based electrolytes for durable lithium metal batteries
『Abstract』Lithium (Li) metal batteries (LMBs) are promising for high-energy-density rechargeable batteries . However, Li dendrites formed by the reaction between highly active Li and non-aqueous electrolytes lead to safety concerns and rapid capacity decay . Developing a reliable solid–electrolyte interphase is critical for realizing high-rate and long-life LMBs, but remains technically challenging . Here we demonstrate that adding excess m -Li 2 ZrF 6 (monoclinic) nanoparticles to a commercial LiPF 6 -containing carbonate electrolyte of LMBs facilitates the release of abundant ZrF 6 ions into the electrolyte driven by the applied voltage, converting to t -Li 2 ZrF 6 (trigonal) and creating a stable solid–electrolyte interphase in situ with high Li-ion conductivity. Computational and cryogenic transmission electron microscopy studies revealed that the in situ formation of the t -Li 2 ZrF 6 -rich solid–electrolyte interphase markedly enhanced Li-ion transfer and suppressed the growth of Li dendrites. As a result, LMBs assembled with LiFePO 4 cathodes (areal loading, 1.8/2.2 mAh cm ), three-dimensional Li–carbon anodes (50-µm-thick Li) and Li 2 ZrF 6 -based electrolyte displayed greatly improved cycling stability with high capacity retention (>80.0%) after 3,000 cycles (1C/2C rate). This achievement represents leading performance and, thus, delivers a reliable Li 2 ZrF 6 -based electrolyte for durable LMBs under practical high-rate conditions.
『摘要』 锂(Li)金属电池(LMB)是高能量密度充电电池的有力竞争者。然而,高活性锂与非水电解质反应形成的锂枝晶会带来安全隐患,并导致电池容量迅速衰减。开发可靠的固体电解质中间相(SEI)对于实现高倍率和长寿命的锂金属电池至关重要,但这在技术上仍然具有挑战性。本研究表明,在商用含LiPF6的锂金属电池碳酸盐电解质中加入过量的单斜晶系Li2ZrF6纳米颗粒,可促进在施加电压的驱动下向电解质中释放大量的ZrF6离子,这些离子会转化为三角晶系Li2ZrF6,并原位形成具有高锂离子电导率的稳定固体电解质中间相。计算研究和冷冻透射电子显微镜研究表明,原位形成的富含三角晶系Li2ZrF6的固体电解质中间相显著增强了锂离子的传输,并抑制了锂枝晶的生长。因此,使用磷酸铁锂正极(面载量1.8/2.2 mAh cm)、三维锂碳负极(50微米厚的锂)和基于Li2ZrF6的电解质组装的锂金属电池在3000次循环(1C/2C充放电速率)后,循环稳定性显著提高,容量保持率超过80.0%。这一成果代表了领先的性能,因而为实际高倍率条件下的耐用锂金属电池提供了一种可靠的基于Li2ZrF6的电解质。
『总结』 研究表明,在锂金属电池电解质中加入过量的单斜晶系Li2ZrF6纳米颗粒,可显著提高电池的循环稳定性和容量保持率,为高性能锂金属电池的开发提供了新策略。
38. 动态超分子链环立方体
Dynamic supramolecular snub cubes
『Abstract』Mimicking the superstructures and properties of spherical biological encapsulants such as viral capsids and ferritin offers viable pathways to understand their chiral assemblies and functional roles in living systems. However, stereospecific assembly of artificial polyhedra with mechanical properties and guest-binding attributes akin to biological encapsulants remains a formidable challenge. Here we report the stereospecific assembly of dynamic supramolecular snub cubes from 12 helical macrocycles, which are held together by 144 weak C–H hydrogen bonds . The enantiomerically pure snub cubes, which have external diameters of 5.1 nm, contain 2,712 atoms and chiral cavities with volumes of 6,215 Å . The stereospecific assembly of left- and right-handed snub cubes was achieved by means of a hierarchical chirality transfer protocol , which was streamlined by diastereoselective crystallization. In addition to their reversible photochromic behaviour, the snub cubes exhibit photocontrollable elasticity and hardness in their crystalline states. The snub cubes can accommodate numerous small guest molecules simultaneously and encapsulate two different guest molecules separately inside the uniquely distinct compartments in their frameworks. This research expands the scope of artificial supramolecular assemblies to imitate the chiral superstructures, dynamic features and binding properties of spherical biomacromolecules and also establishes a protocol for construction of crystalline materials with photocontrollable mechanical properties.
『摘要』 模仿病毒衣壳和铁蛋白等球形生物封装物的超结构和特性,为了解它们在生物系统中的手性组装和功能作用提供了可行的途径。然而,构建具有与生物封装物相似的机械性能和客体结合特性的人工多面体,仍是一项艰巨的挑战。本文报告了由12个螺旋大环通过144个弱C-H氢键组合而成的动态超分子扭立方体的立体特异性组装。这些对映体纯的扭立方体外部直径为5.1纳米,包含2712个原子和手性空腔,体积为6215 ų。左旋和右旋扭立方体的立体特异性组装是通过分级手性转移协议实现的,该协议通过非对映选择性结晶得到简化。除了具有可逆的光致变色行为外,扭立方体在其结晶状态下还表现出光可控的弹性和硬度。扭立方体可以同时容纳众多小型客体分子,并在其框架内独特且不同的空间内分别封装两种不同的客体分子。本研究拓展了人工超分子组装的应用范围,以模仿球形生物大分子的手性超结构、动态特性和结合特性,并建立了一种构建具有光可控机械性能的晶体材料的协议。
『总结』 本研究通过12个螺旋大环组装出动态超分子扭立方体,模仿生物封装物特性,并实现了光可控机械性能和客体分子封装。
39. 与学习相关的星形胶质细胞群调节记忆回忆
Learning-associated astrocyte ensembles regulate memory recall
『Abstract』The physical manifestations of memory formation and recall are fundamental questions that remain unresolved . At the cellular level, ensembles of neurons called engrams are activated by learning events and control memory recall . Astrocytes are found in close proximity to neurons and engage in a range of activities that support neurotransmission and circuit plasticity . Moreover, astrocytes exhibit experience-dependent plasticity , although whether specific ensembles of astrocytes participate in memory recall remains obscure. Here we show that learning events induce c-Fos expression in a subset of hippocampal astrocytes, and that this subsequently regulates the function of the hippocampal circuit in mice. Intersectional labelling of astrocyte ensembles with c-Fos after learning events shows that they are closely affiliated with engram neurons, and reactivation of these astrocyte ensembles stimulates memory recall. At the molecular level, learning-associated astrocyte (LAA) ensembles exhibit elevated expression of nuclear factor I-A, and its selective deletion from this population suppresses memory recall. Taken together, our data identify LAA ensembles as a form of plasticity that is sufficient to provoke memory recall and indicate that astrocytes are an active component of the engram.
『摘要』 记忆形成和回忆的生理表现是仍未解决的基本问题。在细胞层面,被称为记忆印迹的神经元集合会被学习活动激活,并控制记忆的回忆。星形胶质细胞与神经元紧密相邻,参与一系列支持神经传递和回路可塑性的活动。此外,星形胶质细胞表现出经验依赖性可塑性,尽管特定星形胶质细胞集合是否参与记忆回忆仍不明确。本研究表明,学习活动会诱导小鼠海马体中部分星形胶质细胞表达c-Fos,这随后会调节海马体回路的功能。学习活动后对星形胶质细胞集合与c-Fos进行交叉标记显示,它们与记忆印迹神经元密切相关,且这些星形胶质细胞集合的重新激活会刺激记忆回忆。在分子层面,与学习相关的星形胶质细胞(learning-associated astrocyte,LAA)集合表现出核因子I-A表达升高,若从该群体中选择性删除核因子I-A,则会抑制记忆回忆。综上,本研究数据确定了LAA集合是一种足以引发记忆回忆的可塑性形式,并表明星形胶质细胞是记忆印迹的活跃组成部分。
『总结』 研究发现学习活动可诱导星形胶质细胞特定集合参与记忆回忆,表明星形胶质细胞是记忆印迹的重要组成部分。
40. 胶质样味觉细胞介导外周甜味适应的细胞间模式
Glia-like taste cells mediate an intercellular mode of peripheral sweet adaptation
『Abstract』The sense of taste generally shows diminishing sensitivity to prolonged sweet stimuli, referred to as sweet adaptation. Yet, its mechanistic landscape remains incomplete. Here, we report that glia-like type I cells provide a distinct mode of sweet adaptation via intercellular crosstalk with chemosensory type II cells. Using the microfluidic-based intravital tongue imaging system, we found that sweet adaptation is facilitated along the synaptic transduction from type II cells to gustatory afferent nerves, while type I cells display temporally delayed and prolonged activities. We identified that type I cells receive purinergic input from adjacent type II cells via P2RY2 and provide inhibitory feedback to the synaptic transduction of sweet taste. Aligning with our cellular-level findings, purinergic activation of type I cells attenuated sweet licking behavior, and P2RY2 knockout mice showed decelerated adaptation behavior. Our study highlights a veiled intercellular mode of sweet adaptation, potentially contributing to the efficient encoding of prolonged sweetness.
『摘要』 味觉通常会对持续的甜味刺激表现出敏感度降低,这被称为甜味适应。然而,其机制尚不完全清楚。在本研究中,我们发现类似神经胶质的I型细胞通过与化学感觉II型细胞之间的细胞间通讯,提供了一种独特的甜味适应模式。使用基于微流体的活体舌成像系统,我们发现从II型细胞到味觉传入神经的突触传导促进了甜味适应,而I型细胞则表现出时间上延迟且延长的活动。我们确定I型细胞通过P2RY2受体接收来自邻近II型细胞的嘌呤能输入,并对甜味的突触传导提供抑制性反馈。与我们的细胞水平研究结果一致,I型细胞的嘌呤能激活减弱了舔食甜味的行为,而P2RY2敲除小鼠则表现出适应行为减缓。我们的研究揭示了一种隐藏的细胞间甜味适应模式,可能有助于高效编码持续的甜味。
『总结』 研究发现类似神经胶质的I型细胞通过与II型细胞通讯,提供了一种新的甜味适应机制,即通过P2RY2受体接收嘌呤能输入并抑制甜味传导,从而调节甜味感知和舔食行为。
41. 人类骨骼发育的功能基因组学与身高遗传性的模式研究
Functional genomics of human skeletal development and the patterning of height heritability
『Abstract』Underlying variation in height are regulatory changes to chondrocytes, cartilage cells comprising long-bone growth plates. Currently, we lack knowledge on epigenetic regulation and gene expression of chondrocytes sampled across the human skeleton, and therefore we cannot understand basic regulatory mechanisms controlling height biology. We first rectify this issue by generating extensive epigenetic and transcriptomic maps from chondrocytes sampled from different growth plates across developing human skeletons, discovering novel regulatory networks shaping human bone/joint development. Next, using these maps in tandem with height genome-wide association study (GWAS) signals, we disentangle the regulatory impacts that skeletal element-specific versus global-acting variants have on skeletal growth, revealing the prime importance of regulatory pleiotropy in controlling height variation. Finally, as height is highly heritable, and thus often the test case for complex-trait genetics, we leverage these datasets within a testable omnigenic model framework to discover novel chondrocyte developmental modules and peripheral-acting factors shaping height biology and skeletal growth.
『摘要』 身高差异的根源在于软骨细胞(构成长骨生长板的软骨细胞)的调控变化。目前,我们对从人体骨骼不同部位取样的软骨细胞的表观遗传调控和基因表达缺乏了解,因此无法理解控制身高生物学特征的基本调控机制。我们首先通过从发育中的人类骨骼不同生长板取样的软骨细胞生成广泛的表观遗传和转录组图谱,发现了塑造人类骨骼/关节发育的新型调控网络,从而解决了这一问题。接下来,我们将这些图谱与身高全基因组关联研究(GWAS)信号结合使用,厘清了骨骼元素特异性与全局作用变异对骨骼生长的不同调控影响,揭示了调控多效性在控制身高变异中的首要作用。最后,由于身高具有高度遗传性,因此经常作为复杂特征遗传学的测试用例,我们在可测试的泛基因模型框架内利用这些数据集,发现了塑造身高生物学特征和骨骼生长的新型软骨细胞发育模块和外围作用因子。
『总结』 本研究通过生成软骨细胞的表观遗传和转录组图谱,结合GWAS信号,揭示了身高差异的调控机制,并发现了影响身高和骨骼生长的新型发育模块和因素。
42. 新复制的哺乳动物染色质的单分子可及性景观
The single-molecule accessibility landscape of newly replicated mammalian chromatin
『Abstract』We present replication-aware single-molecule accessibility mapping (RASAM), a method to nondestructively measure replication status and protein-DNA interactions on chromatin genome-wide. Using RASAM, we uncover a genome-wide state of single-molecule “hyperaccessibility” post-replication that resolves over several hours. Combining RASAM with cellular models for rapid protein degradation, we demonstrate that histone chaperone CAF-1 reduces nascent chromatin accessibility by filling single-molecular “gaps” and generating closely spaced dinucleosomes on replicated DNA. At cis -regulatory elements, we observe unique modes by which nascent chromatin hyperaccessibility resolves: at CCCTC-binding factor (CTCF)-binding sites, CTCF and nucleosomes compete, reducing CTCF occupancy and motif accessibility post-replication; at active transcription start sites, high chromatin accessibility is maintained, implying rapid re-establishment of nucleosome-free regions. Our study introduces a new paradigm for studying replicated chromatin fiber organization. More broadly, we uncover a unique organization of newly replicated chromatin that must be reset by active processes, providing a substrate for epigenetic reprogramming.
『摘要』 我们提出了一种复制感知单分子可及性测绘(RASAM)方法,用于在全染色质基因组范围内非破坏性地测量复制状态和蛋白质-DNA相互作用。利用RASAM,我们发现了复制后持续数小时的单分子“超可及性”的全基因组状态。将RASAM与细胞快速蛋白质降解模型相结合,我们证明组蛋白伴侣CAF-1通过填补单分子“缺口”并在复制的DNA上生成紧密间隔的二核小体,从而降低了新生染色质的可及性。在顺式调控元件中,我们观察到了新生染色质超可及性消解的独特模式:在CCCTC结合因子(CTCF)结合位点,CTCF和核小体相互竞争,降低了复制后CTCF的占据率和基序的可及性;在活性转录起始位点,染色质的高可及性得以保持,暗示着无核小体区域的快速重建。我们的研究为研究复制的染色质纤维组织引入了一种新范式。从更广泛的角度来看,我们发现了新生复制染色质的一种独特组织方式,这种组织方式必须通过主动过程进行重置,为表观遗传重编程提供了基础。
『总结』 本研究提出RASAM方法用于测量染色质状态,并揭示了新生复制染色质的独特组织及其主动重置过程,为表观遗传学研究提供新视角。
43. 2018年至2024年刚果民主共和国I型猴痘病毒基因组多样性:人畜共患传播占主导
Clade I mpox virus genomic diversity in the Democratic Republic of the Congo, 2018–2024: Predominance of zoonotic transmission
『Abstract』Recent reports raise concerns on the changing epidemiology of mpox in the Democratic Republic of the Congo (DRC). High-quality genomes were generated for 337 patients from 14/26 provinces to document whether the increase in number of cases is due to zoonotic spillover events or viral evolution, with enrichment of APOBEC3 mutations linked to human adaptation. Our study highlights two patterns of transmission contributing to the source of human cases. All new sequences from the eastern South Kivu province ( n = 17; 4.8%) corresponded to the recently described clade Ib, associated with sexual contact and sustained human-to-human transmission. By contrast, all other genomes are clade Ia, which exhibits high genetic diversity with low numbers of APOBEC3 mutations compared with clade Ib, suggesting multiple zoonotic introductions. The presence of multiple clade I variants in urban areas highlights the need for coordinated international response efforts and more studies on the transmission and the reservoir of mpox.
『摘要』 近期报告引发了人们对刚果民主共和国(DRC)猴痘流行病学变化的担忧。研究从该国26个省中的14个省收集了337名患者的高质量基因组,以记录病例数量的增加是由于人畜共患溢出事件还是病毒进化,并关注与人类适应相关的APOBEC3突变富集情况。本研究强调了两种导致人类感染的传播途径。来自南基伍省东部的所有新序列(n=17;4.8%)均对应最近描述的Ib支系,该支系与性接触和持续的人传人传播相关。相比之下,所有其他基因组均为Ia支系,与Ib支系相比,Ia支系遗传多样性高,但APOBEC3突变数量少,表明发生了多次人畜共患传入。城市中存在多种I支系变体,凸显了协调国际应对工作和深入研究猴痘传播及宿主的必要性。
『总结』 研究表明刚果民主共和国猴痘病例增加或由性接触传播和高遗传多样性的多次人畜共患传入共同导致,强调需加强国际协调研究和应对。
44. 粪便微生物载量是肠道微生物组变异的主要决定因素,也是疾病相关性的混杂因素
Fecal microbial load is a major determinant of gut microbiome variation and a confounder for disease associations
『Abstract』The microbiota in individual habitats differ in both relative composition and absolute abundance. While sequencing approaches determine the relative abundances of taxa and genes, they do not provide information on their absolute abundances. Here, we developed a machine-learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applying our prediction model to a large-scale metagenomic dataset ( n = 34,539), we demonstrated that microbial load is the major determinant of gut microbiome variation and is associated with numerous host factors, including age, diet, and medication. We further found that for several diseases, changes in microbial load, rather than the disease condition itself, more strongly explained alterations in patients’ gut microbiome. Adjusting for this effect substantially reduced the statistical significance of the majority of disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease.
『摘要』 不同栖息地的微生物群落在相对组成和绝对丰度上均存在差异。虽然测序方法可以确定分类群和基因的相对丰度,但它们并不提供关于其绝对丰度的信息。本研究开发了一种仅根据相对丰度数据预测粪便微生物载量(每克中的微生物细胞数)的机器学习方法。我们将预测模型应用于一个大规模宏基因组数据集(n=34539),结果表明,微生物载量是肠道微生物组变异的主要决定因素,并且与包括年龄、饮食和药物在内的许多宿主因素相关。我们还发现,对于几种疾病而言,患者肠道微生物组的变化更多地是由微生物载量的变化而非疾病状态本身来解释的。对这一效应进行校正后,大多数与疾病相关的物种的统计学意义大幅降低。我们的分析显示,粪便微生物载量是微生物组研究中的一个主要混杂因素,强调了其在理解健康和疾病中微生物组变异方面的重要性。
『总结』 研究发现粪便微生物载量是肠道微生物组变异的主要决定因素,且是与多种宿主因素相关的关键指标,对理解健康和疾病中的微生物组变化具有重要意义。
45. 钾离子通道中电场刺激离子传导的直接可视化
Direct visualization of electric-field-stimulated ion conduction in a potassium channel
『Abstract』Understanding protein function would be facilitated by direct, real-time observation of chemical kinetics in the atomic structure. The selectivity filter (SF) of the K channel provides an ideal model, catalyzing the dehydration and transport of K ions across the cell membrane through a narrow pore. We used a “pump-probe” method called electric-field-stimulated time-resolved X-ray crystallography (EFX) to initiate and observe K conduction in the NaK2K channel in both directions on the timescale of the transport process. We observe both known and potentially new features in the high-energy conformations visited along the conduction pathway, including the associated dynamics of protein residues that control selectivity and conduction rate. A single time series of one channel in action shows the orderly appearance of features observed in diverse homologs with diverse methods, arguing for deep conservation of the dynamics underlying the reaction coordinate in this protein family.
『摘要』 对原子结构中化学动力学的直接实时观察将有助于理解蛋白质功能。钾离子通道的选择性过滤器(SF)提供了一个理想模型,它通过一个狭窄的孔隙催化钾离子跨细胞膜的脱水和运输。我们使用了一种称为电场刺激时间分辨X射线晶体学(EFX)的“泵浦-探测”方法,在传输过程的时间尺度上启动并观察NaK2K通道中钾离子双向传导的情况。我们在传导途径中观察到的高能构象中既包含了已知特征,也可能包含新特征,包括控制选择性和传导速率的蛋白质残基的相关动力学。一个单独的作用中通道的时间序列显示了用不同方法在不同同源物中观察到的特征有序出现,这表明在这个蛋白质家族中,反应坐标所依据的动力学具有深度保守性。
『总结』 研究人员通过实时观测原子结构中的化学动力学,揭示了钾离子通道中钾离子传导的新特征及其动力学机制。
46. 蛋白质能量营养不良是慢性疾病的发病机制之一
Proteolethargy is a pathogenic mechanism in chronic disease
『Abstract』The pathogenic mechanisms of many diseases are well understood at the molecular level, but there are prevalent syndromes associated with pathogenic signaling, such as diabetes and chronic inflammation, where our understanding is more limited. Here, we report that pathogenic signaling suppresses the mobility of a spectrum of proteins that play essential roles in cellular functions known to be dysregulated in these chronic diseases. The reduced protein mobility, which we call proteolethargy, was linked to cysteine residues in the affected proteins and signaling-related increases in excess reactive oxygen species. Diverse pathogenic stimuli, including hyperglycemia, dyslipidemia, and inflammation, produce similar reduced protein mobility phenotypes. We propose that proteolethargy is an overlooked cellular mechanism that may account for various pathogenic features of diverse chronic diseases.
『摘要』 在分子层面,许多疾病的发病机制已经得到了充分的理解,但也有一些与致病信号相关的常见综合征,如糖尿病和慢性炎症,我们对它们的理解仍然有限。本研究报告指出,致病信号会抑制一系列在细胞功能中发挥重要作用且已知在这些慢性疾病中失调的蛋白质的流动性。这种降低的蛋白质流动性(我们称之为蛋白质活力下降)与受影响蛋白质中的半胱氨酸残基以及信号传导相关活性氧物种的过度增加有关。包括高血糖、血脂异常和炎症在内的多种致病刺激都会产生类似的蛋白质流动性降低的表型。我们认为,蛋白质活力下降是一种被忽视的细胞机制,可能是多种慢性疾病表现出各种致病特征的原因。
『总结』 本研究发现致病信号会抑制关键蛋白质的流动性,导致蛋白质活力下降,这或是多种慢性疾病呈现不同致病特征的原因。
47. 脂质化ApoE受体相互作用减少可保护溶酶体免受ApoE及其脂质货物的致病性影响
Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes
『Abstract』While apolipoprotein E ( APOE ) is the strongest genetic modifier for late-onset Alzheimer’s disease (LOAD), the molecular mechanisms underlying isoform-dependent risk and the relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding of lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 and decreases the uptake of cholesteryl esters (CEs), which are lipids linked to neurodegeneration. In human neurons, the addition of ApoE carrying polyunsaturated fatty acids (PUFAs)-CE revealed an allelic series (ApoE4 > ApoE3 > ApoE2) associated with lipofuscinosis, an age-related lysosomal pathology resulting from lipid peroxidation. Lipofuscin increased lysosomal accumulation of tau fibrils and was elevated in the APOE4 mouse brain with exacerbation by tau pathology. Intrahippocampal injection of PUFA-CE-lipApoE4 was sufficient to induce lipofuscinosis in wild-type mice. Finally, the protective Christchurch mutation also reduced LDLR binding and phenocopied ApoE2. Collectively, our data strongly suggest decreased lipApoE-LDLR interactions minimize LOAD risk by reducing the deleterious effects of endolysosomal targeting of ApoE and associated pathogenic lipids.
『摘要』 载脂蛋白E(APOE)是迟发性阿尔茨海默病(LOAD)最强的遗传修饰因子,但依赖其异构体的风险机制以及与载脂蛋白E相关脂质的相关性仍不明确。本研究报告指出,脂质化载脂蛋白E2(lipApoE2)与低密度脂蛋白(LDL)受体(LDLR)的结合受损,避免了lipApoE3/E4出现的LDLR循环缺陷,并减少了与神经退行性病变相关的胆固醇酯(CEs)的摄入。在人神经元中,加入携带多不饱和脂肪酸(PUFAs)胆固醇酯的载脂蛋白E后,显示出一种与脂褐素沉着症相关的等位基因系列(ApoE4 > ApoE3 > ApoE2),脂褐素沉着症是一种由脂质过氧化引起的与年龄相关的溶酶体病变。脂褐素会增加溶酶体内tau原纤维的积聚,并且在APOE4小鼠大脑中升高,且tau病变会加剧这一现象。向野生型小鼠的海马内注射PUFA-CE-lipApoE4足以诱导脂褐素沉着症。最后,研究发现,具有保护作用的克赖斯特彻奇(Christchurch)突变也减少了LDLR的结合,并表现出与ApoE2相似的表型。总的来说,本研究数据强烈表明,减少lipApoE与LDLR的相互作用可通过减轻载脂蛋白E及其相关致病脂质的内溶酶体靶向的有害影响来降低迟发性阿尔茨海默病的风险。
『总结』 研究发现减少lipApoE与LDLR的相互作用可降低载脂蛋白E及其相关致病脂质的有害影响,从而减小迟发性阿尔茨海默病的风险。
48. 听觉中脑介导触觉振动感知
The auditory midbrain mediates tactile vibration sensing
『Abstract』Vibrations are ubiquitous in nature, shaping behavior across the animal kingdom. For mammals, mechanical vibrations acting on the body are detected by mechanoreceptors of the skin and deep tissues and processed by the somatosensory system, while sound waves traveling through air are captured by the cochlea and encoded in the auditory system. Here, we report that mechanical vibrations detected by the body’s Pacinian corpuscle neurons, which are distinguished by their ability to entrain to high-frequency (40–1,000 Hz) environmental vibrations, are prominently encoded by neurons in the lateral cortex of the inferior colliculus (LCIC) of the midbrain. Remarkably, most LCIC neurons receive convergent Pacinian and auditory input and respond more strongly to coincident tactile-auditory stimulation than to either modality alone. Moreover, the LCIC is required for behavioral responses to high-frequency mechanical vibrations. Thus, environmental vibrations captured by Pacinian corpuscles are encoded in the auditory midbrain to mediate behavior.
『摘要』 振动在自然界中无处不在,影响着整个动物界的行为。对于哺乳动物而言,作用于身体的机械振动由皮肤和深层组织的机械感受器检测,并由躯体感觉系统处理;而通过空气传播的声音则被耳蜗捕获,并在听觉系统中进行编码。本研究发现,身体中的帕西尼小体神经元检测到的机械振动能被中脑下丘外侧皮质(LCIC)的神经元显著编码,这些神经元能够对高频(40~1000赫兹)环境振动产生适应。值得注意的是,大多数LCIC神经元会同时接收帕西尼小体和听觉的输入信号,并且对触觉-听觉同时刺激的反应比单独任一模态的刺激更为强烈。此外,高频机械振动引起的行为反应需要LCIC的参与。因此,帕西尼小体捕获的环境振动在听觉中脑中被编码,以介导行为反应。
『总结』 研究发现哺乳动物中脑的下丘外侧皮质能编码由帕西尼小体检测到的高频环境振动,并介导相应的行为反应。
49. 拟南芥蓝光光受体CRY2在黑暗条件下活跃以抑制根系生长
The Arabidopsis blue-light photoreceptor CRY2 is active in darkness to inhibit root growth
『Abstract』Cryptochromes (CRYs) are blue-light receptors that regulate diverse aspects of plant growth. However, whether and how non-photoexcited CRYs function in darkness or non-blue-light conditions is unknown. Here, we show that CRY2 affects the Arabidopsis transcriptome even in darkness, revealing a non-canonical function. CRY2 suppresses cell division in the root apical meristem to downregulate root elongation in darkness. Blue-light oligomerizes CRY2 to de-repress root elongation. CRY2 physically interacts with FORKED-LIKE 1 (FL1) and FL3, and these interactions are inhibited by blue light, with only monomeric but not dimeric CRY2 able to interact. FL1 and FL3 associate with the chromatin of cell division genes to facilitate their transcription. This pro-growth activity is inhibited by CRY2’s physical interaction with FLs in darkness. Plants have evolved to perceive both blue-light and dark cues to coordinate activation and repression of competing developmental processes in above- and below-ground organs through economical and dichotomous use of ancient light receptors.
『摘要』 隐花色素(CRYs)是蓝光受体,可调节植物生长的多个方面。然而,非光激发的CRYs在黑暗或非蓝光条件下是否发挥作用以及如何发挥作用尚不清楚。本研究发现,即使在黑暗中,CRY2也会影响拟南芥的转录组,揭示了一种非经典功能。CRY2抑制根尖分生组织中的细胞分裂,从而在黑暗中下调根的伸长。蓝光使CRY2寡聚化,从而解除对根伸长的抑制。CRY2与FORKED-LIKE 1(FL1)和FL3发生物理相互作用,并且这些相互作用会被蓝光抑制,因为只有单体而非二聚体形式的CRY2能够进行相互作用。FL1和FL3与细胞分裂基因的染色质结合,以促进其转录。这种促生长活性在黑暗中会被CRY2与FLs的物理相互作用所抑制。植物已经进化出感知蓝光和黑暗信号的能力,通过对古老光感受器的经济和二分法使用,来协调地上和地下器官中竞争发育过程的激活和抑制。
『总结』 研究发现CRY2在黑暗中也能影响植物生长,通过与FL1和FL3的相互作用抑制细胞分裂和根伸长,揭示了植物利用光感受器协调不同发育过程的新机制。
50. 北美东部早期玉米的基因组起源
The genomic origin of early maize in eastern North America
『Abstract』Indigenous maize varieties from eastern North America have played an outsized role in breeding programs, yet their early origins are not fully understood. We generated paleogenomic data to reconstruct how maize first reached this region and how it was selected during the process. Genomic ancestry analyses reveal recurrent movements northward from different parts of Mexico, likely culminating in at least two dispersals from the US Southwest across the Great Plains to the Ozarks and beyond. We find that 1,000-year-old Ozark specimens carry a highly differentiated wx1 gene, which is involved in the synthesis of amylose, highlighting repeated selective pressures on the starch metabolic pathway throughout maize’s domestication. This population shows a close affinity with the lineage that ultimately became the Northern Flints, a major contributor to modern commercial maize.
『摘要』 来自北美东部的本土玉米品种在育种计划中发挥了巨大作用,但其早期起源尚不完全清楚。我们生成了古基因组数据,以重建玉米最初是如何到达该地区以及在此过程中是如何被选择的。基因组祖先分析揭示了从墨西哥不同地区反复向北的迁移,最终可能至少有两次是从美国西南部横跨大平原分散到奥扎克地区及其他更远的地方。我们发现,有1000年历史的奥扎克标本携带了一种高度分化的wx1基因,该基因参与直链淀粉的合成,突显了在玉米驯化过程中淀粉代谢途径上反复的选择压力。该群体与最终成为北方燧石种(现代商业玉米的主要贡献者)的谱系有着密切的亲缘关系。
『总结』 研究通过古基因组数据揭示了北美东部本土玉米的起源和驯化过程中的选择压力,并发现其与现代商业玉米主要贡献者北方燧石种有密切亲缘关系。
51. β-羟丁酸分流途径产生抗肥胖酮代谢产物
A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites
『Abstract』β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.
『摘要』 β-羟基丁酸(BHB)是一种丰富的酮体。迄今为止,所有已知的BHB代谢途径都涉及BHB与主要能量中间体的相互转化。本研究发现了一种以前未描述的BHB次生代谢途径,即通过CNDP2依赖的酶促偶联反应将BHB与游离氨基酸结合。这种BHB分流途径产生了一系列抗肥胖酮代谢物,即BHB-氨基酸。小鼠CNDP2基因的遗传消融消除了组织氨基酸BHB化活性,并降低了BHB-氨基酸水平。最丰富的BHB-氨基酸,BHB-Phe,是Lac-Phe的一种酮症诱导同源物,可激活下丘脑和脑干神经元并抑制进食。相反,CNDP2基因敲除(CNDP2-KO)小鼠在外源性酮酯补充或生酮饮食后,食物摄入量和体重增加。CNDP2依赖的氨基酸BHB化和BHB-氨基酸代谢物在人类中也存在。因此,酶促氨基酸BHB化定义了一种与能量平衡相关的酮分流途径和生物活性酮代谢物。
『总结』 研究发现了一种新的BHB次生代谢途径,通过CNDP2酶将BHB与氨基酸结合,生成具有抗肥胖作用的BHB-氨基酸,该途径在人类中也保守,并与能量平衡相关。
52. 压力扰乱小鼠外侧杏仁核中的记忆印迹集合,导致威胁记忆泛化
Stress disrupts engram ensembles in lateral amygdala to generalize threat memory in mice
『Abstract』Stress induces aversive memory overgeneralization, a hallmark of many psychiatric disorders. Memories are encoded by a sparse ensemble of neurons active during an event (an engram ensemble). We examined the molecular and circuit processes mediating stress-induced threat memory overgeneralization in mice. Stress, acting via corticosterone, increased the density of engram ensembles supporting a threat memory in lateral amygdala, and this engram ensemble was reactivated by both specific and non-specific retrieval cues (generalized threat memory). Furthermore, we identified a critical role for endocannabinoids, acting retrogradely on parvalbumin-positive (PV+) lateral amygdala interneurons in the formation of a less-sparse engram and memory generalization induced by stress. Glucocorticoid receptor antagonists, endocannabinoid synthesis inhibitors, increasing PV+ neuronal activity, and knocking down cannabinoid receptors in lateral amygdala PV+ neurons restored threat memory specificity and a sparse engram in stressed mice. These findings offer insights into stress-induced memory alterations, providing potential therapeutic avenues for stress-related disorders.
『摘要』 压力会导致厌恶记忆过度泛化,这是许多精神障碍的一个标志。记忆由事件发生时活跃的稀疏神经元集群(印记神经元集群)进行编码。我们研究了小鼠压力诱导的威胁记忆过度泛化的分子和回路过程。压力通过皮质酮的作用,增加了支持外侧杏仁核中威胁记忆的印记神经元集群的密度,并且该印记神经元集群可被特异性和非特异性检索线索重新激活(泛化威胁记忆)。此外,我们发现了内源性大麻素在形成稀疏度较低的印记和压力诱导的记忆泛化中的关键作用,其可逆向作用于外侧杏仁核中小清蛋白阳性(PV+)中间神经元。糖皮质激素受体拮抗剂、内源性大麻素合成抑制剂、增加PV+神经元活性以及敲除外侧杏仁核PV+神经元中的大麻素受体可恢复压力小鼠的威胁记忆特异性和稀疏印记。这些发现为了解压力导致的记忆改变提供了见解,并为应激相关障碍提供了潜在的治疗途径。
『总结』 研究揭示了压力通过特定分子和神经回路机制导致记忆泛化的过程,并指出了潜在的治疗靶点。
53. 间歇性禁食引发器官间通讯以抑制毛囊再生
Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration
『Abstract』Intermittent fasting has gained global popularity for its potential health benefits, although its impact on somatic stem cells and tissue biology remains elusive. Here, we report that commonly used intermittent fasting regimens inhibit hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). This effect is independent of calorie reduction, circadian rhythm alterations, or the mTORC1 cellular nutrient-sensing mechanism. Instead, fasting activates crosstalk between adrenal glands and dermal adipocytes in the skin, triggering the rapid release of free fatty acids into the niche, which in turn disrupts the normal metabolism of HFSCs and elevates their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. A randomized clinical trial (NCT05800730) indicates that intermittent fasting inhibits human hair growth. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration and identifies interorgan communication that eliminates activated HFSCs and halts tissue regeneration during periods of unstable nutrient supply.
『摘要』 间歇性禁食因其潜在的健康益处而风靡全球,但其对体干细胞和组织生物学的影响仍不明确。本研究发现,常用的间歇性禁食方案会选择性地诱导活化的毛囊干细胞(HFSCs)凋亡,从而抑制毛囊再生。这一效应与热量减少、昼夜节律改变或mTORC1细胞营养感知机制无关。相反,禁食会激活皮肤中肾上腺和真皮脂肪细胞之间的串扰,触发游离脂肪酸快速释放到微环境中,进而扰乱毛囊干细胞的正常代谢,提高其细胞活性氧水平,导致氧化损伤和凋亡。一项随机临床试验(NCT05800730)表明,间歇性禁食会抑制人的头发生长。本研究揭示了间歇性禁食对组织再生的抑制作用,并发现了一种在营养供应不稳定期间消除活化的毛囊干细胞并阻止组织再生的器官间通信机制。
『总结』 研究发现间歇性禁食通过诱导毛囊干细胞凋亡抑制毛囊再生及头发生长,其机制与器官间通信导致细胞代谢紊乱和氧化损伤有关。
54. 玉米属特异性微肽控制玉米籽粒脱水
A Zea genus-specific micropeptide controls kernel dehydration in maize
『Abstract』Kernel dehydration rate (KDR) is a crucial production trait that affects mechanized harvesting and kernel quality in maize; however, the underlying mechanisms remain unclear. Here, we identified a quantitative trait locus (QTL), qKDR1 , as a non-coding sequence that regulates the expression of qKDR1 REGULATED PEPTIDE GENE ( RPG ). RPG encodes a 31 amino acid micropeptide, microRPG1, which controls KDR by precisely modulating the expression of two genes, ZmETHYLENE-INSENSITIVE3-like 1 and 3 , in the ethylene signaling pathway in the kernels after filling. microRPG1 is a Zea genus-specific micropeptide and originated de novo from a non-coding sequence. Knockouts of microRPG1 result in faster KDR in maize. By contrast, overexpression or exogenous application of the micropeptide shows the opposite effect both in maize and Arabidopsis . Our findings reveal the molecular mechanism of microRPG1 in kernel dehydration and provide an important tool for future crop breeding.
『摘要』 玉米籽粒脱水率(KDR)是影响机械化收获和籽粒品质的关键生产性状,但其潜在机制尚不清楚。本研究鉴定到一个数量性状位点(QTL),即qKDR1,它是一个非编码序列,可调节qKDR1调控肽基因(RPG)的表达。RPG编码一个由31个氨基酸组成的微肽,即microRPG1,通过精确调控灌浆后籽粒中乙烯信号通路中的两个基因ZmETHYLENE-INSENSITIVE3-like 1和3的表达来控制KDR。microRPG1是玉米属特有的微肽,由非编码序列从头起源而来。敲除microRPG1会导致玉米KDR加快。相反,在玉米和拟南芥中过表达或外源施加该微肽则会产生相反的效果。本研究揭示了microRPG1在籽粒脱水过程中的分子机制,为未来作物育种提供了重要工具。
『总结』 本研究发现了一个新的微肽microRPG1,并阐明了其通过调控乙烯信号通路相关基因表达来控制玉米籽粒脱水率的分子机制。
55. 电突触配置过滤感觉信息以驱动行为选择
Configuration of electrical synapses filters sensory information to drive behavioral choices
『Abstract』Synaptic configurations underpin how the nervous system processes sensory information to produce a behavioral response. This is best understood for chemical synapses, and we know far less about how electrical synaptic configurations modulate sensory information processing and context-specific behaviors. We discovered that innexin 1 (INX-1), a gap junction protein that forms electrical synapses, is required to deploy context-specific behavioral strategies underlying thermotaxis behavior in C. elegans . Within this well-defined circuit, INX-1 couples two bilaterally symmetric interneurons to integrate sensory information during migratory behavior across temperature gradients. In inx-1 mutants, uncoupled interneurons display increased excitability and responses to subthreshold sensory stimuli due to increased membrane resistance and reduced membrane capacitance, resulting in abnormal responses that extend run durations and trap the animals in context-irrelevant tracking of isotherms. Thus, a conserved configuration of electrical synapses enables differential processing of sensory information to deploy context-specific behavioral strategies.
『摘要』 突触配置支撑着神经系统如何处理感觉信息以产生行为反应。这一点在化学突触中得到了最好的理解,而关于电突触配置如何调节感觉信息处理和情境特异性行为,我们知之甚少。本研究发现,形成电突触的间隙连接蛋白innexin 1(INX-1)是秀丽隐杆线虫(C. elegans)在热趋性行为中采取情境特异性行为策略所必需的。在这一明确的神经回路中,INX-1将两个双侧对称的中间神经元偶联起来,以在跨越温度梯度的迁移行为过程中整合感觉信息。在inx-1突变体中,由于膜电阻增加和膜电容减少,未偶联的中间神经元表现出兴奋性增强和对阈下感觉刺激的反应增强,从而导致异常反应,即延长奔跑持续时间并使动物陷入与情境无关的等温线追踪。因此,电突触的保守配置能够对感觉信息进行差异处理,从而采取情境特异性的行为策略。
『总结』 研究发现INX-1蛋白通过电突触配置在秀丽隐杆线虫热趋性行为中整合感觉信息,进而实现情境特异性的行为策略。