前沿速递 | NCS 集萃:2025-01-24 期
总结
1. 人类胶质母细胞瘤中不同的髓系来源的抑制性细胞群
Distinct myeloid-derived suppressor cell populations in human glioblastoma
『Abstract』 The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood. We performed single-cell RNA sequencing of immune and tumor cells from 33 gliomas, identifying two distinct myeloid-derived suppressor cell (MDSC) populations in isocitrate dehydrogenase–wild-type (IDT-WT) glioblastoma: an early progenitor MDSC (E-MDSC) population with up-regulation of metabolic and hypoxia pathways and a monocytic MDSC (M-MDSC) population. Spatial transcriptomics demonstrated that E-MDSCs geographically colocalize with metabolic stem-like tumor cells in the pseudopalisading region. Ligand-receptor analysis revealed cross-talk between these cells, where glioma stem-like cells produce chemokines attracting E-MDSCs, which in turn produce growth factors for the tumor cells. This interaction is absent in IDH-mutant gliomas, associated with hypermethylation and repressed gene expression of MDSC-attracting chemokines. Our study elucidates specific MDSCs that may facilitate glioblastoma progression and mediate tumor immunosuppression.
『摘要』 胶质瘤相关髓系细胞在肿瘤生长和免疫逃逸中的作用尚不完全清楚。我们对33例胶质瘤中的免疫细胞和肿瘤细胞进行了单细胞RNA测序,在异柠檬酸脱氢酶野生型(IDT-WT)胶质母细胞瘤中发现了两种不同的髓系衍生抑制性细胞(MDSC)群体:一种是代谢和缺氧通路上调的早期祖细胞MDSC(E-MDSC)群体,另一种是单核细胞MDSC(M-MDSC)群体。空间转录组学研究表明,E-MDSC在地理上与假栅栏区域的代谢干细胞样肿瘤细胞共定位。配体-受体分析揭示了这些细胞之间的交叉对话,其中胶质瘤干细胞样细胞产生吸引E-MDSC的趋化因子,而E-MDSC又产生促进肿瘤细胞生长的生长因子。这种相互作用在IDH突变型胶质瘤中不存在,后者与MDSC吸引趋化因子的基因高甲基化和表达抑制相关。我们的研究阐明了可能促进胶质母细胞瘤进展并介导肿瘤免疫抑制的特定MDSC。
『总结』 研究发现IDT-WT胶质母细胞瘤中存在两种MDSC群体,它们与代谢干细胞样肿瘤细胞相互作用,促进肿瘤进展和免疫抑制,而IDH突变型胶质瘤中则无此相互作用。
2. 斯特克方丹的南方古猿并未食用大量的哺乳动物肉类
Australopithecus at Sterkfontein did not consume substantial mammalian meat
『Abstract』 Incorporation of animal-based foods into early hominin diets has been hypothesized to be a major catalyst of many important evolutionary events, including brain expansion. However, direct evidence of the onset and evolution of animal resource consumption in hominins remains elusive. The nitrogen-15 to nitrogen-14 ratio of collagen provides trophic information about individuals in modern and geologically recent ecosystems (<200,000 years ago), but diagenetic loss of this organic matter precludes studies of greater age. By contrast, nitrogen in tooth enamel is preserved for millions of years. We report enamel-bound organic nitrogen and carbonate carbon isotope measurements of Sterkfontein Member 4 mammalian fauna, including seven Australopithecus specimens. Our results suggest a variable but plant-based diet (largely C 3 ) for these hominins. Therefore, we argue that Australopithecus at Sterkfontein did not engage in regular mammalian meat consumption.
『摘要』 将动物性食物纳入早期人类饮食中被认为是包括大脑扩张在内的许多重要进化事件的主要催化剂。然而,关于人类祖先开始食用动物资源及其演变的直接证据仍然难以捉摸。在现代和近期地质时代(<20万年前)的生态系统中,胶原蛋白的氮-15与氮-14比值提供了关于个体营养级的信息,但这种有机物质的成岩损失阻碍了对更古老时期的研究。相比之下,牙釉质中的氮可以保存数百万年。我们报告了对斯泰克方丹第4层哺乳动物群(包括7个南方古猿样本)牙釉质结合有机氮和碳酸盐碳同位素的测量结果。我们的研究结果表明,这些人类祖先的饮食以植物为主(主要是C3植物),但有所变化。因此,我们认为斯泰克方丹的南方古猿并没有定期食用哺乳动物肉。
『总结』 研究表明斯泰克方丹的南方古猿饮食以植物为主,并未定期食用哺乳动物肉。
【小编注】 看来还是要多吃肉——不过话说回来,人类这么弱小,想要站在食物链顶端可不得向优进化吗,不然哪能有肉吃?所以,我是“吃了肉才进化到现在”,还是“为了吃肉进化到现在”状态的?
3. 在气候变暖、二氧化碳浓度升高的条件下,干旱限制了草原的水分利用和土壤水分混合
Drought in a warmer, CO2-rich climate restricts grassland water use and soil water mixing
『Abstract』 Soil water sustains terrestrial life, yet its fate is uncertain under a changing climate. We conducted a deuterium labeling experiment to determine whether elevated atmospheric carbon dioxide (CO2 ), warming, and drought impact soil water storage and transport in a temperate grassland. Elevated CO2 created a wetter rootzone compared with ambient conditions, whereas warming decreased soil moisture. Soil water remained well mixed in all global change treatments except for summer drought combined with warming and elevated CO2 . These combined treatments caused the grassland to conserve water and restricted soil water flow to large, rapidly draining pores without mixing with small, slowly draining pores. Our results suggest that drought in a warmer, more CO 2 -rich climate can severely alter grassland ecohydrology by constraining postdrought soil water flow and grassland water use.
『摘要』 土壤水分维持着陆地生命,但在气候变化下,其命运却充满了不确定性。我们进行了一项氘标记实验,以确定大气中二氧化碳(CO2)浓度升高、气温升高和干旱是否会影响温带草原的土壤水分储存和运输。与环境条件相比,CO2 浓度升高使根区土壤变得更湿润,而气温升高则使土壤水分减少。在所有全球变化处理中,土壤水分均保持充分混合状态,但夏季干旱与气温升高和CO2 浓度升高相结合的情况除外。这些综合处理条件使草原保存了水分,并限制了土壤水分流向快速排水的大孔隙,而使其无法与缓慢排水的小孔隙混合。我们的结果表明,在气候更暖、CO2 浓度更高的条件下发生干旱,可能会通过限制干旱后的土壤水分流动和草原水分利用,从而严重改变草原生态水文状况。
『总结』 研究表明,在温暖且CO2 浓度更高的气候条件下,干旱会严重影响草原的生态水文,改变土壤水分的流动和利用。
4. 全球多年生干旱的发生和影响增加
Global increase in the occurrence and impact of multiyear droughts
『Abstract』 Persistent multiyear drought (MYD) events pose a growing threat to nature and humans in a changing climate. We identified and inventoried global MYDs by detecting spatiotemporally contiguous climatic anomalies, showing that MYDs have become drier, hotter, and led to increasingly diminished vegetation greenness. The global terrestrial land affected by MYDs has increased at a rate of 49,279 ± 14,771 square kilometers per year from 1980 to 2018. Temperate grasslands have exhibited the greatest declines in vegetation greenness during MYDs, whereas boreal and tropical forests have had comparably minor responses. With MYDs becoming more common, this global quantitative inventory of the occurrence, severity, trend, and impact of MYDs provides an important benchmark for facilitating more effective and collaborative preparedness toward mitigation of and adaptation to such extreme events.
『摘要』 随着气候的变化,持续多年的干旱(MYD)事件对自然和人类构成了日益严重的威胁。我们通过检测时空连续的气候异常现象,识别并统计了全球的多年干旱事件,结果表明这些事件已变得愈发干燥、炎热,并导致植被绿度持续下降。从1980年至2018年,受多年干旱影响的全球陆地面积以每年49,279 ± 14,771平方公里的速度增加。在多年干旱期间,温带草原的植被绿度下降最为严重,而北方森林和热带森林的反应相对较小。随着多年干旱事件愈发频繁,这份关于其发生频率、严重程度、趋势及影响的全球定量统计报告,为更有效地协作准备、减轻和适应此类极端事件提供了一个重要的基准。
『总结』 全球持续多年的干旱事件愈发严重,对植被造成显著影响,此报告为应对此类极端事件提供了重要基准。
5. 机械互锁二维聚合物
Mechanically interlocked two-dimensional polymers
『Abstract』 Mechanical bonds arise between molecules that contain interlocked subunits, such as one macrocycle threaded through another. Within polymers, these linkages will confer distinctive mechanical properties and other emergent behaviors, but polymerizations that form mechanical bonds efficiently and use simple monomeric building blocks are rare. In this work, we introduce a solid-state polymerization in which one monomer infiltrates crystals of another to form a macrocycle and mechanical bond at each repeat unit of a two-dimensional (2D) polymer. This mechanically interlocked 2D polymer is formed as a layered solid that is readily exfoliated in common organic solvents, enabling spectroscopic characterization and atomic-resolution imaging using advanced electron microscopy techniques. The 2D mechanically interlocked polymer is easily prepared on multigram scales, which, along with its solution processibility, enables the facile fabrication of composite fibers with Ultem that exhibit enhanced stiffness and strength.
『摘要』 机械键产生于含有相互锁定亚单位的分子之间,例如一个大环穿过另一个大环。在高分子中,这些键合将赋予其独特的机械性能和其他衍生特性,但能够高效形成机械键且使用简单单体结构单元的聚合反应很少见。在本文中,我们介绍了一种固相聚合方法,在这种方法中,一种单体渗入另一种单体的晶体中,在二维(2D)聚合物的每个重复单元处形成一个大环和机械键。这种机械互锁的二维聚合物形成一种层状固体,易溶于普通有机溶剂,从而能够使用先进的电子显微技术对其进行光谱表征和原子分辨率成像。这种二维机械互锁聚合物很容易以克级规模(更符合国人表达习惯)制备,再加上其溶液可加工性,使得能够轻松地与Ultem一起制备出具有增强刚度和强度的复合纤维。
『总结』 本研究开发了一种固相聚合方法,制备出易于表征和成像的机械互锁二维聚合物,且该聚合物可大规模制备并用于制造增强型复合纤维。
【小编注】 “机械键”,这是新概念,共价和非共价键之外的一种键;浏览了下全文,通过多环芳酚羟基化合物晶体与氯硅烷进行硅烷化反应形成互锁结构——【思路很巧妙】。晶体结构提供了形成互锁结构的绝对证据www.ccdc.cam.ac.uk/data_request/cif.
6. 气候变化对沙漠蜥蜴生活成本的影响
Climate change and the cost-of-living squeeze in desert lizards
『Abstract』 Climate warming can induce a cost-of-living “squeeze” in ectotherms by increasing energetic expenditures while reducing foraging gains. We used biophysical models (validated by 2685 field observations) to test this hypothesis for 10 ecologically diverse lizards in African and Australian deserts. Historical warming (1950–2020) has been more intense in Africa than in Australia, translating to an energetic squeeze for African diurnal species. Although no net impact on Australian diurnal species was observed, warming generated an energetic “relief” (by increasing foraging time) for nocturnal species. Future warming impacts will be more severe in Africa than in Australia, requiring increased rates of food intake (+10% per hour active for diurnal species). The effects of climate warming on desert lizard energy budgets will thus be species-specific but potentially predictable.
『摘要』 气候变暖会增加变温动物的能量消耗,同时减少其觅食收获,从而给它们的生活成本带来“压力”。我们通过生物物理模型(该模型已通过2685次实地观测验证)对非洲和澳大利亚沙漠中的10种生态多样化的蜥蜴进行了假设验证。1950年至2020年,非洲的历史变暖程度比澳大利亚更为剧烈,这给非洲的日行性物种带来了能量压力。虽然澳大利亚日行性物种没有受到净影响,但变暖却为夜行性物种带来了能量“缓解”(通过增加觅食时间)。未来,非洲受变暖的影响将比澳大利亚更为严重,非洲日行性物种的食物摄入量需要增加(每小时活动增加10%)。因此,气候变暖对沙漠蜥蜴能量预算的影响会因物种而异,但可能具有可预测性。
『总结』 气候变暖对沙漠蜥蜴的能量预算有物种特异性的影响,非洲日行性物种受负面影响更大,而澳大利亚夜行性物种则可能受益。
7. 种子植物间独脚金内酯生物合成的演化
Evolution of interorganismal strigolactone biosynthesis in seed plants
『Abstract』 Strigolactones (SLs) are methylbutenolide molecules derived from β-carotene through an intermediate carlactonoic acid (CLA). Canonical SLs act as signals to microbes and plants, whereas noncanonical SLs are primarily plant hormones. The cytochrome P450 CYP722C catalyzes a critical step, converting CLA to canonical SLs in most angiosperms. Using synthetic biology, we investigated the function of CYP722A , an evolutionary predecessor of CYP722C . CYP722A converts CLA into 16-hydroxy-CLA (16-OH-CLA), a noncanonical SL detected exclusively in the shoots of various flowering plants. 16-OH-CLA application restores control of shoot branching to SL-deficient mutants in Arabidopsis thaliana and is perceived by the SL signaling pathway. We hypothesize that biosynthesis of 16-OH-CLA by CYP722A was a metabolic stepping stone in the evolution of canonical SLs that mediate rhizospheric signaling in many flowering plants.
『摘要』 独脚金内酯(SLs, 真是这么叫的,这名字有点可爱)是由β-胡萝卜素通过中间产物卡拉克酮酸(CLA)衍生而来的甲基丁烯内酯分子。典型SLs是微生物和植物的信号分子,而非典型SLs主要是植物激素。细胞色素P450酶CYP722C催化了一个关键步骤,即将CLA转化为大多数被子植物中的典型SLs。本研究利用合成生物学方法,探究了CYP722C的进化前身CYP722A的功能。CYP722A将CLA转化为16-羟基-CLA(16-OH-CLA),这是一种仅在多种开花植物的茎中检测到的非典型SL。外源施加16-OH-CLA可恢复拟南芥SL缺陷型突变体的分枝控制能力,并且该过程受SL信号通路调控。本研究假设,CYP722A催化生成16-OH-CLA的生物合成过程,是典型SLs进化中的一个代谢垫脚石(基石),这些典型SLs在许多开花植物中介导根际信号传导。
『总结』 本研究发现CYP722A催化CLA生成非典型SL 16-OH-CLA,这一过程可能是典型SLs进化中的关键步骤。
8. 通过碘插层法制备非合金α相甲脒铅三碘化物太阳能电池
Nonalloyed α-phase formamidinium lead triiodide solar cells through iodine intercalation
『Abstract』 Formamidinium lead triiodide (FAPbI3 ) is considered the most promising composition for high-performing single-junction solar cells. However, nonalloyed α-FAPbI3 is metastable with respect to the photoinactive δ-phase. We have developed a kinetic modulation strategy to fabricate high-quality and stable nonalloyed α-FAPbI3 films, assisted by cogenetic volatile iodine intercalation and decalation. The intercalation of iodine facilitated the formation of corner-sharing Pb-I framework building blocks and reduced the kinetic barrier for α-FAPbI3 formation, whereas the iodine decalation improved the final perovskite film quality in terms of composition purity and overall homogeneity. Solar cells based on this nonalloyed α-FAPbI3 (free of other extrinsic composition ions) achieved a power conversion efficiency of >24%. The devices also exhibited excellent durability, retaining 99% of their original power conversion efficiency after operating for more than 1100 hours at 85° ± 5°C under illumination.
『摘要』 甲脒铅碘(FAPbI3, 应该是碘甲胺,按命名习惯应为:碘甲胺化碘化铅)被认为是制造高性能单结太阳能电池最具前景的材料。然而,非合金化α-FAPbI3相对于无光学活性的δ相而言处于亚稳状态。我们开发了一种动力学调制策略,在共生的挥发性碘插层和去插层的辅助下,制备出高质量且稳定的非合金化α-FAPbI3薄膜。碘的插层促进了角共享Pb-I框架构建块的形成,并降低了α-FAPbI3形成的动力学壁垒,而碘的去插层则提高了最终钙钛矿(这里翻译可能不对)薄膜在成分纯度和整体均匀性方面的质量。基于这种非合金化α-FAPbI3(不含其他外源性成分离子)的太阳能电池实现了超过24%的功率转换效率。器件还表现出优异的耐久性,在85°±5°C的光照条件下连续工作1100多小时后,仍保持了99%的原始功率转换效率。
『总结』 研究人员通过动力学调制策略及碘插层和去插层技术,成功制备了高质量稳定的非合金化α-FAPbI3薄膜,并基于此制造出功率转换效率超过24%且耐久性优异的太阳能电池。
【小编注】 看了下补充材料, perovskite应该是指“光电转换”材料,而不是钙钛矿。
9. 由teneurin-latrophilin复合物协调的突触连接重建
Reconstitution of synaptic junctions orchestrated by teneurin-latrophilin complexes
『Abstract』 Synapses are organized by trans-synaptic adhesion molecules that coordinate assembly of pre- and postsynaptic specializations, which, in turn, are composed of scaffolding proteins forming liquid-liquid phase-separated condensates. Presynaptic teneurins mediate excitatory synapse organization by binding to postsynaptic latrophilins; however, the mechanism of action of teneurins, driven by extracellular domains evolutionarily derived from bacterial toxins, remains unclear. In this work, we show that only the intracellular sequence, a dimerization sequence, and extracellular bacterial toxin–derived latrophilin-binding domains of Teneurin-3 are required for synapse organization, suggesting that teneurin-induced latrophilin clustering mediates synaptogenesis. Intracellular Teneurin-3 sequences capture liquid-liquid phase-separated presynaptic active zone scaffolds, enabling us to reconstitute an entire synaptic junction from purified proteins in which trans-synaptic teneurin-latrophilin complexes recruit phase-separated pre- and postsynaptic specializations.
『摘要』 神经元突触的形成是由跨突触粘附分子协调突触前和突触后的特化组装实现的,而这些特化又由形成液-液相分离凝聚体的支架蛋白组成。突触前的Teneurins通过与突触后的Latrophilins结合来介导兴奋性突触的形成( 这里 organization 我就意译了);然而,这种由细菌毒素进化而来的胞外结构域所驱动的Teneurins的作用机制尚不清楚。在本研究中,我们发现仅有Teneurin-3的胞内序列、二聚化序列和胞外细菌毒素衍生的Latrophilin结合结构域是突触组织所需要的,这表明Teneurin诱导的Latrophilin聚集介导了突触形成。Teneurin-3的胞内序列能够捕获“液-液相分离”的突触前活性区支架,使我们能够从纯化蛋白中重建整个突触连接,其中跨突触的Teneurin-Latrophilin复合物招募了相分离的突触前和突触后特化。
『总结』 Teneurin-3诱导Latrophilin的聚集,并通过捕获支架蛋白形成的液-液相分离凝聚体的活性区,进而协调突触的形成。这种机制的理解让我们可以从纯化蛋白中重建整个突触连接。
【小编注】 不懂,但隐约感觉——重建突触连接是很有意义的:比如,让此时此刻我短路的神经“啪嗒”一声接上,让我快速完成这篇集萃的校对,小编想过年了……
10. 通过人类体感皮层的模式化微刺激实现触觉边缘和运动感知
Tactile edges and motion via patterned microstimulation of the human somatosensory cortex
『Abstract』 Intracortical microstimulation (ICMS) of somatosensory cortex evokes tactile sensations whose properties can be systematically manipulated by varying stimulation parameters. However, ICMS currently provides an imperfect sense of touch, limiting manual dexterity and tactile experience. Leveraging our understanding of how tactile features are encoded in the primary somatosensory cortex (S1), we sought to inform individuals with paralysis about local geometry and apparent motion of objects on their skin. We simultaneously delivered ICMS through electrodes with spatially patterned projected fields (PFs), evoking sensations of edges. We then created complex PFs that encode arbitrary tactile shapes and skin indentation patterns. By delivering spatiotemporally patterned ICMS, we evoked sensation of motion across the skin, the speed and direction of which could be controlled. Thus, we improved individuals’ tactile experience and use of brain-controlled bionic hands.
『摘要』 通过在体微刺激(ICMS)躯体感觉皮层可产生触觉,且通过改变刺激参数可以系统地控制触觉的特性。然而,目前的ICMS提供的触觉并不完美,限制了手部灵活性和触觉体验。利用我们对触觉特征如何在初级躯体感觉皮层(S1)中编码的理解,我们试图向瘫痪患者传达其皮肤上物体的局部几何形状和表观运动信息。我们通过具有空间图案投射场(PF)的电极同时传递ICMS,从而产生边缘感觉。然后,我们创建了能够编码任意触觉形状和皮肤凹陷图案的复杂PF。通过传递时空模式的ICMS,我们在皮肤上产生了运动感觉,并且可以控制其速度和方向。因此,我们改善了瘫痪患者的触觉体验和脑控仿生手的使用。
『总结』 研究通过具有空间图案投射场的电极传递时空模式的在体微刺激,改善了瘫痪患者的触觉体验和脑控仿生手的使用。
【小编注】 模拟触觉感受——这事是可以大开脑洞的,比如人形机器人的应用,虚拟世界中的应用——比如吵架吵不过视频那边的人,猛扇一巴掌过去,那边的人不疼我还很爽了,想想就解气……
11. 肌肉来源的肌抑素是促进卵泡刺激素合成的主要内分泌驱动因素
Muscle-derived myostatin is a major endocrine driver of follicle-stimulating hormone synthesis
『Abstract』 Myostatin is a paracrine myokine that regulates muscle mass in a variety of species, including humans. In this work, we report a functional role for myostatin as an endocrine hormone that directly promotes pituitary follicle-stimulating hormone (FSH) synthesis and thereby ovarian function in mice. Previously, this FSH-stimulating role was attributed to other members of the transforming growth factor–β family, the activins. Our results both challenge activin’s eponymous role in FSH synthesis and establish an unexpected endocrine axis between skeletal muscle and the pituitary gland. Our data also suggest that efforts to antagonize myostatin to increase muscle mass may have unintended consequences on fertility.
『摘要』 肌抑素是一种旁分泌肌动蛋白,可调节包括人类在内的多种物种的肌肉量。在本研究中,我们报告了肌抑素作为一种内分泌激素的功能性作用,它能直接促进小鼠垂体卵泡刺激素(FSH)的合成,从而促进卵巢功能。此前,卵泡刺激素的刺激作用一直归因于转化生长因子-β家族的其他成员——激活素。我们的研究结果既挑战了激活素在卵泡刺激素合成中的专有作用,也建立了骨骼肌和垂体之间一个意料之外的内分泌轴。我们的数据还表明,为增加肌肉量而拮抗肌抑素的尝试可能会对生育能力产生意外后果。
『总结』 研究发现肌抑素可直接促进小鼠垂体卵泡刺激素合成和卵巢功能,建立了骨骼肌与垂体之间的新内分泌轴,同时提示拮抗肌抑素增加肌肉量可能影响生育能力。
【小编注】 拮抗肌抑素增加肌肉量:仿佛看到了健身捷径了——八块腹肌马上就来……
12. 立体微观结构调控的生物降解粘合剂
Stereomicrostructure-regulated biodegradable adhesives
『Abstract』 Commercial adhesives are petroleum-based thermoset networks or nonbiodegradable thermoplastic hot melts, making them ideal targets for replacement by biodegradable alternatives. Poly(3-hydroxybutyrate) (P3HB) is a biorenewable and biodegradable alternative to conventional plastics, but microbial P3HB, which has a stereoperfect stereomicrostructure, exhibits no adhesion. In this study, by elucidating the fundamental relationship between chemocatalytically engineered P3HB stereomicrostructures and adhesion properties, we found that biodegradable syndio-rich P3HB exhibits high adhesion strength and outperforms common commercial adhesives, whereas syndiotactic, isotactic, or iso-rich P3HB shows no measurable adhesion. The syndio-rich stereomicrostructure brings about desired thermomechanical and viscoelastic properties of P3HB that enable strong adhesion to a range of substrates tested, including aluminum, steel, glass, and wood, and its performance is insensitive to molar mass and reprocessing or reuse.
『摘要』 商业粘合剂是基于石油的热固性网络或不可生物降解的热塑性热熔胶,因此成为生物可降解替代品的理想目标。聚(3-羟基丁酸酯)(P3HB)是传统塑料的一种可再生且可生物降解的替代品,但具有立体完美立体微观结构的微生物P3HB不具有粘性。本研究通过阐明化学催化工程P3HB立体微观结构与粘附性能之间的基本关系,我们发现可生物降解的富含间同立构(间同立体异构)的P3HB表现出较高的粘附强度,优于常见的商业粘合剂,而间同立构、全同立构或富含全同立构的P3HB则未表现出可测量的粘附性。富含间同立构的立体微观结构赋予了P3HB理想的热机械性能和粘弹性,使其能够牢固粘附于一系列受试基材,包括铝、钢、玻璃和木材,且其性能对摩尔质量以及再加工或再利用不敏感。 *注:全同立构——由A、B 两种手性分子组成全左(右)手性的化合物,间同立构:左右左——这样讲大家就好理解了。
『总结』 富含间同立构的P3HB表现出高粘附强度,优于常见商业粘合剂,且对多种基材均有良好粘附性。
【小编注】 没想到手性结构的排列对胶的性能影响这么大!所以本文讲的是分子水平的构象异构,“立体微观结构”描述是不准确的,后者更像是聚集材料的物理结构而非分子结构。
13. 神经元-ILC2细胞相互作用调节胰腺胰高血糖素和葡萄糖稳态
Neuronal-ILC2 interactions regulate pancreatic glucagon and glucose homeostasis
『Abstract』 The immune system shapes body metabolism, while interactions between peripheral neurons and immune cells control tissue homeostasis and immunity. However, whether peripheral neuroimmune interactions orchestrate endocrine system functions remains unexplored. After fasting, mice lacking type 2 innate lymphoid cells (ILC2s) displayed disrupted glucose homeostasis, impaired pancreatic glucagon secretion, and inefficient hepatic gluconeogenesis. Additionally, intestinal ILC2s were found in the pancreas, which was dependent on their expression of the adrenergic beta 2 receptor. Targeted activation of catecholaminergic intestinal neurons promoted the accumulation of ILC2s in the pancreas. Our work provides evidence that immune cells can be regulated by neuronal signals in response to fasting, activating an inter-organ communication route that promotes pancreatic endocrine function and regulation of blood glucose levels.
『摘要』 免疫系统塑造着身体的新陈代谢,而外周神经元与免疫细胞之间的相互作用则控制着组织稳态和免疫功能。然而,外周神经免疫相互作用是否协调内分泌系统功能仍尚待研究。禁食后,缺乏2型先天性淋巴样细胞(ILC2)的小鼠表现出葡萄糖稳态失衡、胰腺胰高血糖素分泌受损以及肝糖异生作用减弱。此外,研究人员在胰腺中发现了肠道ILC2,这依赖于其表达的肾上腺素能β2受体。靶向激活儿茶酚胺能肠道神经元可促进ILC2在胰腺中的聚集。本研究提供证据表明,免疫细胞可受神经元信号的调节以响应禁食,从而激活一种促进胰腺内分泌功能和调节血糖水平的器官间通讯途径。
『总结』 本研究发现禁食可通过神经免疫相互作用促进肠道免疫细胞向胰腺聚集,进而调节胰腺内分泌功能和血糖水平。
【小编注】 神经-免疫系统可发生相互作用,还可以影响内分泌,所以身体健康与精神健康相关联也就不难理解了。
14. 3D 多重链接构筑材料
3D polycatenated architected materials
『Abstract』 Architected materials derive their properties from the geometric arrangement of their internal structural elements. Their designs rely on continuous networks of members to control the global mechanical behavior of the bulk. In this study, we introduce a class of materials that consist of discrete concatenated rings or cage particles interlocked in three-dimensional networks, forming polycatenated architected materials (PAMs). We propose a general design framework that translates arbitrary crystalline networks into particle concatenations and geometries. In response to small external loads, PAMs behave like non-Newtonian fluids, showing both shear-thinning and shear-thickening responses, which can be controlled by their catenation topologies. At larger strains, PAMs behave like lattices and foams, with a nonlinear stress-strain relation. At microscale, we demonstrate that PAMs can change their shapes in response to applied electrostatic charges. The distinctive properties of PAMs pave the path for developing stimuli-responsive materials, energy-absorbing systems, and morphing architectures.
『摘要』 架构化材料的特性源自其内部结构元素的几何排列。它们的设计依赖于连续的网络成员来控制整体的机械性能。在本研究中,我们介绍了一类由三维网络中相互锁定的离散连接环或笼状颗粒组成的材料,形成了多连接架构化材料(PAMs)。我们提出了一个通用的设计框架,可将任意晶体网络转换为颗粒连接和几何形状。在受到较小的外部载荷时,PAMs表现出非牛顿流体的特性,既具有剪切稀化响应,又具有剪切稠化响应,这可通过其连接拓扑结构来控制。在较大的应变下,PAMs表现出类似晶格和泡沫的行为,具有非线性的应力-应变关系。在微观尺度上,我们证明了PAMs能够响应施加的静电荷而改变其形状。PAMs的独特特性为开发刺激响应材料、吸能系统和变形结构铺平了道路。
『总结』 本研究介绍了多连接架构化材料(PAMs)及其设计框架,PAMs在受到不同大小和类型的外部作用时可表现出非牛顿流体、晶格、泡沫等特性,为新材料开发提供了新思路。
【小编注】 类似前面讲“机械互锁”,看上去更复杂。
15. 哺乳动物衰老过程中细胞群体动态的全面视图
A panoramic view of cell population dynamics in mammalian aging
『Abstract』 To elucidate aging-associated cellular population dynamics, we present PanSci, a single-cell transcriptome atlas profiling >20 million cells from 623 mouse tissues across different life stages, sexes, and genotypes. This comprehensive dataset reveals >3000 different cellular states and >200 aging-associated cell populations. Our panoramic analysis uncovered organ-, lineage-, and sex-specific shifts in cellular dynamics during life-span progression. Moreover, we identify both systematic and organ-specific alterations in immune cell populations associated with aging. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte dependent. Our “cell-omics” strategy enhances comprehension of cellular aging and lays the groundwork for exploring the complex cellular regulatory networks in aging and aging-associated diseases.
『摘要』 为了阐明与衰老相关的细胞群体动态,我们推出了PanSci,这是一个单细胞转录组图谱,描绘了来自不同生命阶段、性别和基因型的623只小鼠组织中的超过2000万个细胞。这一综合数据集揭示了超过3000种不同的细胞状态和超过200个与衰老相关的细胞群体。我们的全景分析发现了在生命周期进程中细胞动态在器官、谱系和性别方面的特异性变化。此外,我们还确定了与衰老相关的免疫细胞群体中的系统性和器官特异性改变。我们进一步探讨了免疫系统对衰老的调节作用,并确定了淋巴细胞依赖的特定年龄相关性细胞群体扩张。我们的“细胞组学”策略增强了对细胞衰老的理解,并为探索衰老和衰老相关疾病中复杂的细胞调控网络奠定了基础。
『总结』 PanSci图谱通过分析623只小鼠的超过2000万个细胞,揭示了衰老过程中免疫细胞群体的动态变化及其与免疫系统的关系,为衰老及相关疾病的研究提供了重要基础。
【小编注】 大家注意到没有,现在搞科研也朝着大数据化方向发展……
16. 超冷费米气体中的二维非厄米趋肤效应
Two-dimensional non-Hermitian skin effect in an ultracold Fermi gas
『Abstract』The concept of non-Hermiticity has expanded the understanding of band topology, leading to the emergence of counter-intuitive phenomena. An example is the non-Hermitian skin effect (NHSE) , which involves the concentration of eigenstates at the boundary. However, despite the potential insights that can be gained from high-dimensional non-Hermitian quantum systems in areas such as curved space , high-order topological phases and black holes , the realization of this effect in high dimensions remains unexplored. Here we create a two-dimensional (2D) non-Hermitian topological band for ultracold fermions in spin–orbit-coupled optical lattices with tunable dissipation, which exhibits the NHSE. We first experimentally demonstrate pronounced nonzero spectral winding numbers in the complex energy plane with nonzero dissipation, which establishes the existence of 2D skin effect. Furthermore, we observe the real-space dynamical signature of NHSE in real space by monitoring the centre of mass motion of atoms. Finally, we also demonstrate that a pair of exceptional points are created in the momentum space, connected by an open-ended bulk Fermi arc, in contrast to closed loops found in Hermitian systems. The associated exceptional points emerge and shift with increasing dissipation, leading to the formation of the Fermi arc. Our work sets the stage for further investigation into simulating non-Hermitian physics in high dimensions and paves the way for understanding the interplay of quantum statistics with NHSE.
『摘要』 非厄米性概念拓宽了对能带拓扑的理解,催生了诸多有悖直觉的现象。非厄米趋肤效应(NHSE)便是其中一例,涉及本征态在边界的集中。然而,尽管在高维非厄米量子系统中可能获得关于弯曲空间、高阶拓扑相和黑洞等领域的深刻见解,但高维空间中该效应的实现尚未得到探索。在此,我们在具有可调耗散的自旋轨道耦合光学晶格中,为超冷费米子创建了一个表现出非厄米趋肤效应的二维(2D)非厄米拓扑能带。首先,我们在实验上证明了在非零耗散的情况下,复能量平面上存在明显的非零谱绕组数,从而证实了二维趋肤效应的存在。此外,我们通过监测原子的质心运动,在实空间中观察到了非厄米趋肤效应的动力学特征。最后,我们还证明了在动量空间中产生了一对由开放式费米弧连接的特殊点,这与厄米系统中发现的闭环截然不同。随着耗散的增加,相关的特殊点出现并发生移动,从而形成费米弧。我们的工作为进一步探索高维空间中非厄米物理的模拟奠定了基础,并为理解量子统计与非厄米趋肤效应的相互作用开辟了道路。
『总结』 本研究在自旋轨道耦合光学晶格中实现了二维非厄米拓扑能带,并观察到了非厄米趋肤效应及其动力学特征,为探索高维非厄米物理和量子统计与非厄米趋肤效应的相互作用提供了基础。
17. 针对H3K27M+弥漫性中线胶质瘤的静脉和颅内GD2-CAR T细胞
Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas
『Abstract』H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. ). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models . Arm A of Phase I trial no. NCT04196413 (ref. ) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 10 kg ; DL2, 3 × 10 kg ) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 10 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study ( n = 3 DL1 (3 DIPG); n = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG.
『摘要』 H3K27M突变型弥漫性中线胶质瘤(DMG)高表达二唾液酸神经节苷脂GD2。靶向GD2的嵌合抗原受体修饰T细胞(GD2-CART)在临床前模型中消灭了DMG。I期试验(编号:NCT04196413)A组在进行淋巴细胞减少性化疗后,给予H3K27M突变型脑干胶质瘤(DIPG)或脊髓DMG(sDMG)患者两个剂量水平(DL1,1×10^6细胞/kg;DL2,3×10^6细胞/kg)的自体GD2-CART静脉(IV)注射一次。临床或影像学检查显示获益的患者可接受后续的脑室内(ICV)颅内输注(10-30×10^6 GD2-CART)。主要目标为评估制造的可行性、耐受性,以及确定静脉注射的最大耐受剂量。次要目标包括对获益的初步评估。共纳入13例患者,其中11例在研究期间接受了静脉GD2-CART治疗(DL1组3例(均为DIPG);DL2组8例(6例DIPG,2例sDMG))。所有患者均成功制备了GD2-CART。DL1组未发生剂量限制性毒性,但DL2组有3例患者出现剂量限制性细胞因子释放综合征,因此确定DL1为静脉注射的最大耐受剂量。9例患者接受了ICV输注,未发生剂量限制性毒性。所有患者均出现肿瘤炎症相关的神经毒性,通过密切监测和护理后安全缓解。4例患者的肿瘤体积显著缩小(分别为52%、54%、91%和100%),另有3例患者的肿瘤体积有较小程度的缩小。1例患者达到完全缓解,且自入组以来已持续30个多月。根据方案指导的临床改善评分,9例患者的神经功能得到改善。序贯静脉注射和脑室内输注GD2-CART可使DIPG患者和sDMG患者的肿瘤消退,神经功能改善。
『总结』 靶向GD2的CAR-T细胞疗法在H3K27M突变型弥漫性中线胶质瘤患者中显示出良好的制造可行性、耐受性和初步疗效。
【小编注】 胶质瘤确实恐怖,不过本文细胞治疗效果明显,但自体,颅内注射都是比较麻烦的过程。
18. 果蝇社交状态会通过三种环路机制通过改变其视觉(注意)
Social state alters vision using three circuit mechanisms in Drosophila
『Abstract』Animals are often bombarded with visual information and must prioritize specific visual features based on their current needs. The neuronal circuits that detect and relay visual features have been well studied . Much less is known about how an animal adjusts its visual attention as its goals or environmental conditions change. During social behaviours, flies need to focus on nearby flies . Here we study how the flow of visual information is altered when female Drosophila enter an aggressive state. From the connectome, we identify three state-dependent circuit motifs poised to modify the response of an aggressive female to fly-sized visual objects: convergence of excitatory inputs from neurons conveying select visual features and internal state; dendritic disinhibition of select visual feature detectors; and a switch that toggles between two visual feature detectors. Using cell-type-specific genetic tools, together with behavioural and neurophysiological analyses, we show that each of these circuit motifs is used during female aggression. We reveal that features of this same switch operate in male Drosophila during courtship pursuit, suggesting that disparate social behaviours may share circuit mechanisms. Our study provides a compelling example of using the connectome to infer circuit mechanisms that underlie dynamic processing of sensory signals.
『摘要』 动物经常会接收到大量视觉信息,必须根据当前需求划分特定视觉特征的优先级。检测和传递视觉特征的神经回路已经被充分研究。然而,对于动物如何根据目标或环境条件的变化调整其视觉注意力,人们知之甚少。在社交行为中,果蝇需要关注附近的果蝇。本研究探讨了雌性果蝇进入攻击状态时视觉信息流的变化。根据连接组,我们确定了三种状态依赖性回路基序,这些基序能够改变攻击性雌性对蝇大小视觉对象的反应:传递选定视觉特征和内部状态的神经元兴奋性输入的汇聚;选定视觉特征检测器的树突去抑制;以及在两个视觉特征检测器之间切换的开关。我们使用细胞类型特异性遗传工具,结合行为学和神经生理学分析,证明了这些回路基序在雌性攻击行为中均有使用。我们发现,相同开关的特征在雄性果蝇求偶追逐过程中也有体现,这表明不同的社交行为可能共享相同的回路机制。本研究提供了一个利用连接组推断感官信号动态处理底层回路机制的有力示例。
『总结』 本研究发现果蝇在攻击和求偶行为中会调整视觉注意力,揭示了其视觉信息处理的动态回路机制,并指出不同社交行为可能共享相同的神经回路。
【小编注】 见到红包和心仪的人“两眼放光”——原来,眼睛不止是人类心灵的窗户。
19. 具有单锯齿形边缘局域态的Janus石墨烯纳米带
Janus graphene nanoribbons with localized states on a single zigzag edge
『Abstract』Topological design of π electrons in zigzag-edged graphene nanoribbons (ZGNRs) leads to a wealth of magnetic quantum phenomena and exotic quantum phases . Symmetric ZGNRs typically show antiferromagnetically coupled spin-ordered edge states . Eliminating cross-edge magnetic coupling in ZGNRs not only enables the realization of a class of ferromagnetic quantum spin chains , enabling the exploration of quantum spin physics and entanglement of multiple qubits in the one-dimensional limit , but also establishes a long-sought-after carbon-based ferromagnetic transport channel, pivotal for ultimate scaling of GNR-based quantum electronics . Here we report a general approach for designing and fabricating such ferromagnetic GNRs in the form of Janus GNRs (JGNRs) with two distinct edge configurations. Guided by Lieb’s theorem and topological classification theory , we devised two JGNRs by asymmetrically introducing a topological defect array of benzene motifs to one zigzag edge, while keeping the opposing zigzag edge unchanged. This breaks the structural symmetry and creates a sublattice imbalance within each unit cell, initiating a spin-symmetry breaking. Three Z-shaped precursors are designed to fabricate one parent ZGNR and two JGNRs with an optimal lattice spacing of the defect array for a complete quench of the magnetic edge states at the ‘defective’ edge. Characterization by scanning probe microscopy and spectroscopy and first-principles density functional theory confirms the successful fabrication of JGNRs with a ferromagnetic ground-state localized along the pristine zigzag edge.
『摘要』 锯齿形边缘石墨烯纳米带(ZGNRs)中π电子的拓扑设计催生了一系列磁性量子现象和奇异量子相。对称的ZGNRs通常表现出反铁磁耦合的自旋有序边缘态。消除ZGNRs中的跨边缘磁耦合,不仅能实现一类铁磁量子自旋链,从而能够在一维极限下探索量子自旋物理和多个量子比特的纠缠,而且建立了长期以来一直寻求的基于碳的铁磁传输通道,这对基于GNR的量子电子器件的最终缩放至关重要。在此,我们报告了一种设计和制造这种铁磁性GNRs的通用方法,即采用两种不同边缘配置的Janus GNRs(JGNRs)。受Lieb定理和拓扑分类理论的指导,我们通过不对称地在一条锯齿形边缘引入苯基拓扑缺陷阵列,同时保持对侧锯齿形边缘不变,从而设计出了两种JGNRs。这破坏了结构对称性,并在每个晶胞内产生了子晶格失衡,从而引发了自旋对称性破缺。我们设计了三种Z形前体,用于制造一个母本ZGNR和两个JGNRs,其中缺陷阵列的晶格间距最优,以完全猝灭“缺陷”边缘的磁性边缘态。扫描探针显微镜和光谱学以及第一性原理密度泛函理论的表征结果证实了具有沿原始锯齿形边缘局域的铁磁基态的JGNRs的成功制备。
『总结』 本研究通过不对称引入拓扑缺陷阵列,成功设计出铁磁性Janus石墨烯纳米带,并实验验证了其铁磁基态的存在。
【小编注】 让石墨烯具有铁磁性——这至少是颠覆我目前认知的。C 元素真是地球上最神奇的元素。
20. 小分子和多氟烷基物质中的光催化C-F键活化
Photocatalytic C–F bond activation in small molecules and polyfluoroalkyl substances
『Abstract』Organic halides are highly useful compounds in chemical synthesis, in which the halide serves as a versatile functional group for elimination, substitution and cross-coupling reactions with transition metals or photocatalysis . However, the activation of carbon–fluorine (C–F) bonds—the most commercially abundant organohalide and found in polyfluoroalkyl substances (PFAS), or ‘forever chemicals’—is much rarer. Current approaches based on photoredox chemistry for the activation of small-molecule C–F bonds are limited by the substrates and transition metal catalysts needed . A general method for the direct activation of organofluorines would have considerable value in organic and environmental chemistry. Here we report an organic photoredox catalyst system that can efficiently reduce C–F bonds to generate carbon-centred radicals, which can then be intercepted for hydrodefluorination (swapping F for H) and cross-coupling reactions. This system enables the general use of organofluorines as synthons under mild reaction conditions. We extend this method to the defluorination of PFAS and fluorinated polymers, a critical challenge in the breakdown of persistent and environmentally damaging forever chemicals.
『摘要』 有机卤化物是化学合成中非常有用的化合物,其中的卤素是作为消除、取代以及与过渡金属或光催化进行交叉偶联反应的多功能基团。然而,碳–氟(C-F)键的活化却十分罕见,尽管碳–氟键是商业上最丰富的有机卤化物,并存在于多氟烷基物质(PFAS)或“永恒化学品”中。目前基于光氧化还原化学来活化小分子C-F键的方法受限于所需的底物和过渡金属催化剂。一种直接活化有机氟化物的通用方法对有机化学和环境化学都具有重要意义。本研究报告了一种有机光氧化还原催化剂体系,可有效还原C-F键以生成碳中心自由基,然后可通过拦截这些自由基来进行氢脱氟(将F替换为H)和交叉偶联反应。该体系使得有机氟化物能够在温和的反应条件下作为合成子得到广泛应用。本研究还将这种方法扩展到PFAS和氟化聚合物的脱氟过程,这是分解持久且对环境有害的永恒化学品所面临的一项关键挑战。
『总结』 本研究开发了一种有机光氧化还原催化剂体系,实现了C-F键的有效活化,并展示了其在温和条件下对有机氟化物进行多样化转化以及在处理环境有害PFAS方面的潜力。
【小编注】 在我看来,C-F 键是有机化学里最稳定的化学键之一,C-F 居然能被活化 C 自由基。
21. 巨噬细胞通过谷氨酸刺激肌梭以促进运动
Macrophages excite muscle spindles with glutamate to bolster locomotion
『Abstract』The stretch reflex is a fundamental component of the motor system that orchestrates the coordinated muscle contractions underlying movement. At the heart of this process lie the muscle spindles (MS), specialized receptors finely attuned to fluctuations in tension within intrafusal muscle fibres. The tension variation in the MS triggers a series of neuronal events including an initial depolarization of sensory type Ia afferents that subsequently causes the activation of motoneurons within the spinal cord . This neuronal cascade culminates in the execution of muscle contraction, underscoring a presumed closed-loop mechanism between the musculoskeletal and nervous systems. By contrast, here we report the discovery of a new population of macrophages with exclusive molecular and functional signatures within the MS that express the machinery for synthesizing and releasing glutamate. Using mouse intersectional genetics with optogenetics and electrophysiology, we show that activation of MS macrophages (MSMP) drives proprioceptive sensory neuron firing on a millisecond timescale. MSMP activate spinal circuits, motor neurons and muscles by means of a glutamate-dependent mechanism that excites the MS. Furthermore, MSMP respond to neural and muscle activation by increasing the expression of glutaminase, enabling them to convert the uptaken glutamine released by myocytes during muscle contraction into glutamate. Selective silencing or depletion of MSMP in hindlimb muscles disrupted the modulation of the stretch reflex for force generation and sensory feedback correction, impairing locomotor strategies in mice. Our results have identified a new cellular component, the MSMP, that directly regulates neural activity and muscle contraction. The glutamate-mediated signalling of MSMP and their dynamic response to sensory cues introduce a new dimension to our understanding of sensation and motor action, potentially offering innovative therapeutic approaches in conditions that affect sensorimotor function.
『摘要』 牵张反射是运动系统的基本组成部分,负责协调运动所需的肌肉收缩。这一过程的核心是肌梭(MS),这是一种专门感受肌原纤维内部张力变化的感受器。肌梭中的张力变化会引发一系列神经事件,包括感觉型Ia传入纤维的初始去极化,进而激活脊髓内的运动神经元。这一神经级联反应最终导致肌肉收缩,突显了肌肉骨骼系统和神经系统之间存在的假定闭环机制。相比之下,本文报道了在肌梭内发现了一群具有独特分子和功能特征的新巨噬细胞群体,这些细胞表达合成和释放谷氨酸的机器(场所?机翻译成机制肯定不对)。我们通过小鼠交叉遗传学结合光遗传学和电生理学方法,证明肌梭巨噬细胞(MSMP)的激活可在毫秒级时间尺度上驱动本体感觉神经元放电。MSMP通过谷氨酸依赖性机制激活肌梭,进而激活脊髓回路、运动神经元和肌肉。此外,MSMP通过增加谷氨酰胺酶的表达来响应神经和肌肉的激活,使它们能够将肌肉收缩期间肌细胞释放的谷氨酰胺摄取并转化为谷氨酸。在后肢肌肉中选择性沉默或耗竭MSMP会破坏牵张反射对力量产生和感觉反馈校正的调节,从而损害小鼠的运动策略。我们的研究结果确定了一种新的细胞成分——MSMP,它直接调节神经活动和肌肉收缩。MSMP的谷氨酸介导信号传导及其对感觉线索的动态反应为我们的感觉和运动行为理解引入了新的维度,可能为影响感觉运动功能的疾病提供创新的治疗方法。
『总结』 本研究发现了一种新的肌梭巨噬细胞,它通过谷氨酸介导的信号传导直接调节神经活动和肌肉收缩,为理解感觉和运动行为提供了新的视角,并为治疗感觉运动功能障碍提供了新的潜在方法。
22. 胰腺癌细胞间信号传导的临床功能蛋白质组学
Clinical functional proteomics of intercellular signalling in pancreatic cancer
『Abstract』Pancreatic ductal adenocarcinoma (PDAC) has an atypical, highly stromal tumour microenvironment (TME) that profoundly contributes to its poor prognosis . Here, to better understand the intercellular signalling between cancer and stromal cells directly in PDAC tumours, we developed a multidimensional proteomic strategy called TMEPro. We applied TMEPro to profile the glycosylated secreted and plasma membrane proteome of 100 human pancreatic tissue samples to a great depth, define cell type origins and identify potential paracrine cross-talk, especially that mediated through tyrosine phosphorylation. Temporal dynamics during pancreatic tumour progression were investigated in a genetically engineered PDAC mouse model. Functionally, we revealed reciprocal signalling between stromal cells and cancer cells mediated by the stromal PDGFR–PTPN11–FOS signalling axis. Furthermore, we examined the generic shedding mechanism of plasma membrane proteins in PDAC tumours and revealed that matrix-metalloprotease-mediated shedding of the AXL receptor tyrosine kinase ectodomain provides an additional dimension of intercellular signalling regulation in the PDAC TME. Importantly, the level of shed AXL has a potential correlation with lymph node metastasis, and inhibition of AXL shedding and its kinase activity showed a substantial synergistic effect in inhibiting cancer cell growth. In summary, we provide TMEPro, a generically applicable clinical functional proteomic strategy, and a comprehensive resource for better understanding the PDAC TME and facilitating the discovery of new diagnostic and therapeutic targets.
『摘要』 胰腺导管腺癌(PDAC)具有非典型的、高度基质化的肿瘤微环境(TME),这是导致其预后不良的重要原因。为了更深入地直接了解PDAC肿瘤中癌细胞与基质细胞之间的细胞间信号传导,我们开发了一种名为TMEPro的多维度蛋白质组学策略。我们利用TMEPro对100例人类胰腺组织样本的糖基化分泌蛋白和质膜蛋白组进行了深入剖析,确定了细胞类型来源,并鉴定了潜在的旁分泌交叉串扰,特别是通过酪氨酸磷酸化介导的串扰。我们还在基因工程化的PDAC小鼠模型中研究了胰腺肿瘤进展过程中的时间动态变化。在功能方面,我们揭示了基质细胞与癌细胞之间通过基质PDGFR-PTPN11-FOS信号轴介导的相互信号传导。此外,我们还研究了PDAC肿瘤中质膜蛋白的普遍脱落机制,并发现基质金属蛋白酶介导的AXL受体酪氨酸激酶胞外域的脱落为PDAC TME中的细胞间信号调节提供了额外的维度。重要的是,脱落AXL的水平与淋巴结转移存在潜在相关性,抑制AXL的脱落及其激酶活性在抑制癌细胞生长方面显示出显著的协同作用。总之,我们提供了TMEPro这一普遍适用的临床功能蛋白质组学策略,以及一个综合资源,以更好地理解PDAC的TME,并促进新诊断和治疗靶点的发现。
『总结』 本研究开发了一种多维度蛋白质组学策略TMEPro,用于深入分析PDAC的肿瘤微环境,揭示了癌细胞与基质细胞间信号传导机制,并为发现新的诊断和治疗靶点提供了有力支持。
【小编注】 看成了 PDCA,紧张了一下。
23. 克拉通边缘由碳酸盐熔体形成的富含硫化物的大陆根
Sulfide-rich continental roots at cratonic margins formed by carbonated melts
『Abstract』The cratonic crust contains abundant mineral deposits of metals such as gold, copper and rare earths and is underlain by a thick mantle lithosphere rich in the volatiles carbon, sulfur and water. Although volatiles are known to be key components in metallogenesis , how and where they are distributed in the cratonic lithosphere mantle and their role in the initial enrichment of metals have not been sufficiently explored. Here we compile sulfur and copper contents of global cratonic peridotites, identifying sulfide-rich and copper-rich continental roots at depths of 160–190 km at cratonic margins. Our new high-pressure experiments show that carbonated silicate melts originating from the asthenosphere lose silicate components during reaction with lithospheric peridotite, evolving to carbonatite melts that become concentrated at cratonic margins. Sulfur solubility in melts substantially decreases as the SiO2 content of melts decreases during this process, forcing sulfide precipitation and the formation of sulfide-rich continental roots at the base of the mantle lithosphere. The migration of carbonated melts towards cratonic margins replenishes the continental roots there with sulfur, explaining the co-location of magmatic metal deposits with carbonatites close to cratonic margins. These findings highlight the notable role of carbonated melts in metallogenesis and provide a potential platform for metal ore exploration.
『摘要』 克拉通地壳含有丰富的金、铜和稀土等金属矿床,其下伏为富含挥发性碳、硫和水厚层地幔岩石圈。众所周知,挥发性物质是成矿作用的关键组成部分,但它们在克拉通岩石圈地幔中的分布方式及位置,以及它们在金属初始富集中的作用尚未得到充分研究。本文汇编了全球克拉通橄榄岩的硫和铜含量,在克拉通边缘160–190公里深度处发现了富硫化物和富铜的大陆根。我们最新的高压实验表明,源自软流圈的碳酸盐硅酸盐熔体在与岩石圈橄榄岩反应过程中会失去硅酸盐组分,逐渐演变为碳酸岩熔体并集中在克拉通边缘。在此过程中,随着熔体中SiO2含量的减少,硫在熔体中的溶解度大幅降低,从而迫使硫化物沉淀并在地幔岩石圈底部形成富硫化物的大陆根。碳酸盐熔体向克拉通边缘迁移,为那里的大陆根补充了硫,这解释了岩浆金属矿床与克拉通边缘附近的碳酸岩共存的现象。这些发现突出了碳酸盐熔体在成矿作用中的重要作用,并为金属矿产勘探提供了潜在平台。
『总结』 研究发现碳酸盐熔体在克拉通成矿中扮演关键角色,为金属矿产勘探提供了新方向。
24. 冰川融水流中细菌微生物组的多样性及生物地理学
Diversity and biogeography of the bacterial microbiome in glacier-fed streams
『Abstract』The rapid melting of mountain glaciers and the vanishing of their streams is emblematic of climate change . Glacier-fed streams (GFSs) are cold, oligotrophic and unstable ecosystems in which life is dominated by microbial biofilms . However, current knowledge on the GFS microbiome is scarce , precluding an understanding of its response to glacier shrinkage. Here, by leveraging metabarcoding and metagenomics, we provide a comprehensive survey of bacteria in the benthic microbiome across 152 GFSs draining the Earth’s major mountain ranges. We find that the GFS bacterial microbiome is taxonomically and functionally distinct from other cryospheric microbiomes. GFS bacteria are diverse, with more than half being specific to a given mountain range, some unique to single GFSs and a few cosmopolitan and abundant. We show how geographic isolation and environmental selection shape their biogeography, which is characterized by distinct compositional patterns between mountain ranges and hemispheres. Phylogenetic analyses furthermore uncovered microdiverse clades resulting from environmental selection, probably promoting functional resilience and contributing to GFS bacterial biodiversity and biogeography. Climate-induced glacier shrinkage puts this unique microbiome at risk. Our study provides a global reference for future climate-change microbiology studies on the vanishing GFS ecosystem.
『摘要』 山地冰川的快速融化和其河流的消失是气候变化的象征。冰川流(Glacier-fed streams,GFS,冰川形成的河流)是寒冷、寡营养且不稳定的生态系统,其中的生命以微生物生物膜为主。然而,目前关于GFS微生物群的研究知之甚少,无法了解其如何应对冰川萎缩。在本文中,我们通过利用宏条形码技术和宏基因组学,对来自地球主要山脉的152条GFS的底栖微生物群中的细菌进行了全面调查。我们发现,GFS细菌微生物群在分类和功能上与其他冰冻圈微生物群截然不同。GFS中的细菌种类繁多,其中一半以上特定存在于某一山脉中,有些仅存在于单一的GFS中,而少数则是广泛存在且数量丰富的。我们展示了地理隔离和环境选择如何塑造其生物地理分布,这种分布以山脉和半球之间不同的组成模式为特征。此外,系统发育分析还发现了由环境选择产生的微多样化分支,这可能促进了功能韧性,并有助于GFS细菌的生物多样性和生物地理分布。气候导致的冰川萎缩使这一独特的微生物群面临风险。我们的研究为未来关于正在消失的GFS生态系统的气候变化微生物学研究提供了全球参考。
『总结』 本研究通过宏条形码和宏基因组学揭示了GFS独特细菌微生物群的分类、功能、多样性和生物地理分布特征,强调了气候导致的冰川萎缩对其构成的潜在威胁。
【小编注】 本篇研究的是 GFS 微生物群的自然特征,并未展示出气候的直接影响(只是其推测)——不由怀疑,不提气候变化是不是就发不了 NCS?
25. 通过拟南芥中的CENH3染色质实现的着丝粒亲和性逆转座子整合
Centrophilic retrotransposon integration via CENH3 chromatin in Arabidopsis
『Abstract』In organisms ranging from vertebrates to plants, major components of centromeres are rapidly evolving repeat sequences, such as tandem repeats (TRs) and transposable elements (TEs), which harbour centromere-specific histone H3 (CENH3) . Complete centromere structures recently determined in human and Arabidopsis suggest frequent integration and purging of retrotransposons within the TR regions of centromeres . Despite the high impact of ‘centrophilic’ retrotransposons on the paradox of rapid centromere evolution, the mechanisms involved in centromere targeting remain poorly understood in any organism. Here we show that both Ty3 and Ty1 long terminal repeat retrotransposons rapidly turnover within the centromeric TRs of Arabidopsis species. We demonstrate that the Ty1/Copia element Tal1 ( Transposon of Arabidopsis lyrata 1 ) integrates de novo into regions occupied by CENH3 in Arabidopsis thaliana , and that ectopic expansion of the CENH3 region results in spread of Tal1 integration regions. The integration spectra of chimeric TEs reveal the key structural variations responsible for contrasting chromatin-targeting specificities to centromeres versus gene-rich regions, which have recurrently converted during the evolution of these TEs. Our findings show the impact of centromeric chromatin on TE-mediated rapid centromere evolution, with relevance across eukaryotic genomes.
『摘要』 从脊椎动物到植物,各类生物体中的着丝粒主要成分是快速进化的重复序列,如串联重复序列(TRs)和转座子元件(TEs),这些序列中包含着丝粒特异性组蛋白H3(CENH3)。最近在人类和拟南芥中确定的完整着丝粒结构表明,着丝粒的TR区域内逆转录转座子频繁整合与清除。尽管“着丝粒亲和性”逆转录转座子对着丝粒快速进化的悖论有很大影响,但在任何生物体中,着丝粒靶向的机制仍知之甚少。本研究发现,Ty3和Ty1长末端重复逆转录转座子在拟南芥物种的着丝粒TR区域内快速周转。研究证明,Ty1/Copia元件Tal1(阿拉伯芥Transposon of Arabidopsis lyrata 1)在拟南芥中可从头整合至CENH3占据的区域,且CENH3区域的异位扩张会导致Tal1整合区域扩散。嵌合体TEs的整合谱揭示了导致着丝粒与基因富集区域染色质靶向特异性差异的关键结构变异,这些变异在TEs进化过程中反复转化。研究结果着重表明了着丝粒染色质对TE介导的着丝粒快速进化的影响,这与真核生物基因组的研究密切相关。
『总结』 研究发现拟南芥着丝粒中的逆转录转座子快速周转,并揭示了着丝粒染色质对逆转录转座子介导的着丝粒快速进化的重要作用。
26. 阳离子钯络合物对酮和酯的β-C−H键官能化
β-C−H bond functionalization of ketones and esters by cationic Pd complexes
『Abstract』C–H activation is the most direct way of functionalizing organic molecules. Many advances in this field still require specific directing groups to achieve the necessary activity and selectivity. Developing C–H activation reactions directed by native functional groups is essential for their broad application in synthesis . Over the past decade, several generations of bifunctional ligands developed have enabled C( sp )–H activation reactions of free carboxylic acids , free aliphatic amines , native amides and alcohols . However, an effective catalyst for ketones and carboxylic esters remains to be realized. Here we report diverse methyl β-C−H functionalizations, including intermolecular arylation, hydroxylation and intramolecular C( sp )–H/C( sp )–H coupling of ketones and carboxylic esters with a monoprotected amino neutral amide (MPANA) ligand. The in situ generation of cationic Pd(II) complexes by the combination MPANA ligand and HBF 4 is crucial for achieving the reactivity. The compatibility of these reactions with cyclic ketones and lactams provides a method to access spirocyclic and fused ring systems. Mechanistic experiments and density functional theory studies support the role of cationic Pd complexes with MPANA ligands in enhancing catalyst–substrate affinity and facilitating the C−H cleavage step.
『摘要』 C–H活化是使有机分子官能化的最直接方法。该领域的许多进展仍然需要特定的导向基团来实现所需的活性和选择性。开发由原生官能团导向的C–H活化反应对于其在合成中的广泛应用至关重要。在过去十年中,已开发的几代双功能配体已实现了游离羧酸、游离脂肪族胺、原生酰胺和醇的C(sp)–H活化反应。然而,针对酮和羧酸酯的有效催化剂仍有待开发。本文报告了多种甲基β-C−H官能化反应,包括酮和羧酸酯与单保护氨基中性酰胺(MPANA)配体的分子间芳基化、羟基化和分子内C(sp)–H/C(sp)–H偶联反应。MPANA配体与HBF4结合原位生成阳离子Pd(II)配合物,对实现该反应性至关重要。这些反应与环酮和内酰胺的相容性为获取螺环和稠环系统提供了一种方法。机理实验和密度泛函理论研究表明,MPANA配体的阳离子Pd配合物可提高催化剂-底物亲和力并促进C−H裂解步骤。
『总结』 本研究开发了一种由单保护氨基中性酰胺配体导向的酮和羧酸酯甲基β-C−H官能化反应,并阐明了阳离子Pd(II)配合物在实现该反应中的关键作用。
27. 长期运动记忆的组合神经编码
A combinatorial neural code for long-term motor memory
『Abstract』Motor skill repertoire can be stably retained over long periods, but the neural mechanism that underlies stable memory storage remains poorly understood . Moreover, it is unknown how existing motor memories are maintained as new motor skills are continuously acquired. Here we tracked neural representation of learned actions throughout a significant portion of the lifespan of a mouse and show that learned actions are stably retained in combination with context, which protects existing memories from erasure during new motor learning. We established a continual learning paradigm in which mice learned to perform directional licking in different task contexts while we tracked motor cortex activity for up to six months using two-photon imaging. Within the same task context, activity driving directional licking was stable over time with little representational drift. When learning new task contexts, new preparatory activity emerged to drive the same licking actions. Learning created parallel new motor memories instead of modifying existing representations. Re-learning to make the same actions in the previous task context re-activated the previous preparatory activity, even months later. Continual learning of new task contexts kept creating new preparatory activity patterns. Context-specific memories, as we observed in the motor system, may provide a solution for stable memory storage throughout continual learning.
『摘要』 运动技能库可以在很长一段时间内保持稳定,但支撑稳定记忆存储的神经机制仍不清楚。此外,目前尚不清楚在持续获得新运动技能的过程中,现有的运动记忆是如何得到保持的。在本文中,我们追踪了小鼠一生中大部分时间所学动作的神经表征,并表明所学动作可与情境相结合从而得到稳定保留,这能够在新运动技能学习过程中保护现有记忆不被清除。我们建立了一种持续学习范式,让小鼠在不同的任务情境中学习进行定向舔舐,同时我们使用双光子成像技术追踪了长达六个月的运动皮层活动。在相同的任务情境中,驱动定向舔舐的活动随时间推移保持稳定,表征漂移很少。当学习新的任务情境时,新的准备活动出现以驱动相同的舔舐动作。学习过程会创建新的并行运动记忆,而不是修改现有的表征。在之前的任务情境中重新学习相同的动作会重新激活之前的准备活动,即使在数月之后也是如此。持续学习新的任务情境会不断产生新的准备活动模式。正如我们在运动系统中观察到的,情境特异性记忆或许可以为持续学习过程中的稳定记忆存储提供一种解决方案。
『总结』 研究发现小鼠运动记忆可与情境结合稳定保留,持续学习会创建新记忆而非修改旧记忆,为稳定记忆存储提供了可能机制。
【小编注】 解释了新运动技能的学习是写入新的“内存”而不是改写原有“内存”,但并未解释清楚为什么运动记忆能够长期持久,比如骑车、游泳学会了终身不忘,但读书就不行——希望早日找到答案,我还想“回炉再造”。我觉得运动的感觉很重要,比如记住掌握平衡的感觉了骑车不会倒。
28. 癌细胞损害单核细胞介导的T细胞刺激以逃避免疫
Cancer cells impair monocyte-mediated T cell stimulation to evade immunity
『Abstract』The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses . Within the tumour microenvironment, CD8 T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches . Although interactions with type 1 conventional dendritic cells have been implicated in this process , the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express Cxcl9 , Cxcl10 and Il15 , but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide–major histocompatibility complex class I complexes from tumour cells through ‘cross-dressing’. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E 2 (PGE 2 ), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE 2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE 2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.
『摘要』 肿瘤微环境是由癌细胞编程形成,并对抗肿瘤免疫反应有重要影响。在肿瘤微环境中,CD8 T细胞在特定生态位中完全分化为效应细胞,并获得细胞毒性抗肿瘤功能。尽管已知1型传统树突状细胞参与这一过程,但潜在的细胞角色和分子机制仍不完全清楚。本研究表明,炎性单核细胞在肿瘤内T细胞刺激中起关键作用。这些细胞表达Cxcl9、Cxcl10和Il15,但与交叉呈递抗原的1型传统树突状细胞不同,炎性单核细胞通过“交叉着装”从肿瘤细胞中获取并呈递肽-主要组织相容性复合体I类复合物。癌细胞中MAPK信号的超活化通过协同抑制I型干扰素(IFN-I)细胞因子的产生并诱导前列腺素E 2(PGE 2)的分泌来阻碍这一过程,这损害了炎性单核细胞状态和肿瘤内T细胞刺激。增强IFN-I细胞因子产生和阻断PGE 2分泌可恢复这一过程,并使肿瘤重新对T细胞介导的免疫产生敏感。总体而言,本研究揭示了炎性单核细胞在肿瘤内T细胞刺激中的核心作用,阐明了致癌信号如何通过PGE 2和IFN-I的反向调节来破坏T细胞反应,并提出了增强免疫疗法的合理联合疗法。
『总结』 本研究发现炎性单核细胞在促进肿瘤内T细胞活化中扮演关键角色,并揭示了癌细胞通过MAPK信号通路干扰T细胞反应的机制,提出了增强免疫治疗效果的新策略。
29. 纤锌矿型异质结构中的邻近铁电性
Proximity ferroelectricity in wurtzite heterostructures
『Abstract』Proximity ferroelectricity is an interface-associated phenomenon in electric-field-driven polarization reversal in a non-ferroelectric polar material induced by one or more adjacent ferroelectric materials. Here we report proximity ferroelectricity in wurtzite ferroelectric heterostructures. In the present case, the non-ferroelectric layers are AlN and ZnO, whereas the ferroelectric layers are Al 1 − x B x N, Al 1 − x Sc x N and Zn 1 − x Mg x O. The layered structures include nitride–nitride, oxide–oxide and nitride–oxide stacks that feature two-layer (asymmetric) and three-layer (symmetric) configurations . Ferroelectric switching in both layers is validated by multimodal characterization methods, including polarization hysteresis, anisotropic chemical etching, second harmonic generation, piezo response force microscopy, electromechanical testing and atomic resolution polarization orientation imaging in real space by scanning transmission electron microscopy. We present a physical switching model in which antipolar nuclei originate in the ferroelectric layer and propagate towards the internal non-ferroelectric interface. The domain wall leading edge produces elastic and electric fields that extend beyond the interface at close proximity, reducing the switching barrier in the non-ferroelectric layer, and allowing complete domain propagation without breakdown. Density functional theory calculations of polymorph energies, reversal barriers and domain wall energies support this model. Proximity ferroelectricity enables polarization reversal in wurtzites without the chemical or structural disorder that accompanies elemental substitution, opening new questions and opportunities regarding interface-based ferroelectricity.
『摘要』 邻近铁电性是一种与界面相关的现象,指的是一种或多种相邻铁电材料诱导非铁电极性材料在电场驱动下发生极化反转。本文报道了纤锌矿铁电异质结构中的邻近铁电性。在本例中,非铁电层为氮化铝(AlN)和氧化锌(ZnO),而铁电层为Al1−xBxN、Al 1−xScxN和Zn1−xMgxO。层状结构包括氮化物-氮化物、氧化物-氧化物和氮化物-氧化物堆叠,具有两层(非对称)和三层(对称)配置。包括极化滞回线、各向异性化学蚀刻、二次谐波产生、压电响应力显微镜、机电测试以及通过扫描透射电子显微镜在实空间中进行原子分辨率极化方向成像在内的多模式表征方法,均验证了双层中的铁电开关特性。本文提出了一个物理开关模型,即反极核在铁电层中形成并向内部非铁电界面传播。畴壁前沿产生弹性和电场,在靠近界面处扩展到界面之外,降低了非铁电层中的开关势垒,从而允许畴壁完全传播而不发生击穿。多态能量、反转势垒和畴壁能量的密度泛函理论计算支持了这一模型。邻近铁电性使纤锌矿材料能够在没有元素替代所带来的化学或结构无序的情况下发生极化反转,这为基于界面的铁电性提出了新的问题和机遇。
『总结』 本研究发现了纤锌矿铁电异质结构中的邻近铁电性,提出了物理开关模型,并通过多模式表征方法和密度泛函理论计算进行了验证,为基于界面的铁电性开辟了新的研究方向。
30. 从系统发育树中学习病原体的适应动力学
Learning the fitness dynamics of pathogens from phylogenies
『Abstract』The dynamics of the genetic diversity of pathogens, including the emergence of lineages with increased fitness, is a foundational concept of disease ecology with key public-health implications. However, the identification of such lineages and estimation of associated fitness remain challenging, and is rarely done outside densely sampled systems . Here we present phylowave, a scalable approach that summarizes changes in population composition in phylogenetic trees, enabling the automatic detection of lineages based on shared fitness and evolutionary relationships. We use our approach on a broad set of viruses and bacteria (SARS-CoV-2, influenza A subtype H3N2, Bordetella pertussis and Mycobacterium tuberculosis ), which include both well-studied and understudied threats to human health. We show that phylowave recovers the main known circulating lineages for each pathogen and that it can detect specific amino acid changes linked to fitness changes. Furthermore, phylowave identifies previously undetected lineages with increased fitness, including three co-circulating B. pertussis lineages. Inference using phylowave is robust to uneven and limited observations. This widely applicable approach provides an avenue to monitor evolution in real time to support public-health action and explore fundamental drivers of pathogen fitness.
『摘要』 病原体遗传多样性的动态变化,包括适应性增强谱系的出现,是疾病生态学的基础概念,对公共卫生具有重要意义。然而,识别此类谱系并估算其相关适应性仍然具有挑战性,并且在采样密集的系统之外很少进行。在此,我们提出了phylowave,这是一种可扩展的方法,可总结系统发育树中种群组成的变化,从而能够基于共同的适应性和进化关系自动检测谱系。我们在多种病毒和细菌(包括SARS-CoV-2、甲型H3N2亚型流感病毒、百日咳博德特氏菌和结核分枝杆菌)上使用了该方法,这些病原体既包括对人类健康已得到充分研究的威胁,也包括研究不足的威胁。结果表明,phylowave能够恢复每种病原体的主要已知流行谱系,并且能够检测到与适应性变化相关的特定氨基酸变化。此外,phylowave还发现了以前未检测到的适应性增强的谱系,包括三种共同流行的百日咳博德特氏菌谱系。使用phylowave进行的推断对于不均匀和有限的观察具有稳健性。这种广泛适用的方法为实时监测进化提供了途径,以支持公共卫生行动并探索病原体适应性的基本驱动因素。
『总结』 phylowave是一种新方法,能自动检测病原体谱系并监测其进化,有助于公共卫生行动和病原体适应性研究。
31. 理解应激的神经编码以控制快感缺失
Understanding the neural code of stress to control anhedonia
『Abstract』Anhedonia, the diminished drive to seek, value, and learn about rewards, is a core feature of major depressive disorder . The neural underpinnings of anhedonia and how this emotional state drives behaviour remain unclear. Here we investigated the neural code of anhedonia by taking advantage of the fact that when mice are exposed to traumatic social stress, susceptible animals become socially withdrawn and anhedonic, whereas others remain resilient. By performing high-density electrophysiology to record neural activity patterns in the basolateral amygdala (BLA) and ventral CA1 (vCA1), we identified neural signatures of susceptibility and resilience. When mice actively sought rewards, BLA activity in resilient mice showed robust discrimination between reward choices. By contrast, susceptible mice exhibited a rumination-like signature, in which BLA neurons encoded the intention to switch or stay on a previously chosen reward. Manipulation of vCA1 inputs to the BLA in susceptible mice rescued dysfunctional neural dynamics, amplified dynamics associated with resilience, and reversed anhedonic behaviour. Finally, when animals were at rest, the spontaneous BLA activity of susceptible mice showed a greater number of distinct neural population states. This spontaneous activity allowed us to decode group identity and to infer whether a mouse had a history of stress better than behavioural outcomes alone. This work reveals population-level neural dynamics that explain individual differences in responses to traumatic stress, and suggests that modulating vCA1–BLA inputs can enhance resilience by regulating these dynamics.
『摘要』 无快感症,即寻求、珍视和了解奖励的动力减弱,是重度抑郁症的核心特征。然而,无快感症的神经基础以及这种情绪状态如何驱动行为仍然不明确。本研究利用了这样一个事实:当小鼠暴露于创伤性社交压力时,易感动物会变得社交退缩和无快感,而其他动物则表现出适应性。我们通过高密度电生理技术记录基外侧杏仁核(BLA)和腹侧CA1(vCA1)的神经活动模式,确定了易感性和适应性的神经特征。当小鼠积极寻求奖励时,有适应性小鼠的BLA活动在奖励选择之间表现出明显的区分。相比之下,易感小鼠则表现出一种类似反复思索的特征,其BLA神经元编码了转换或坚持之前选择奖励的意图。通过调节易感小鼠vCA1至BLA的输入,可以挽救功能障碍的神经动力学,增强与适应性相关的动力学,并逆转无快感行为。最后,当动物处于静息状态时,易感小鼠的BLA自发活动表现出更多不同的神经群体状态。这种自发活动使我们能够解码群体身份,并且比仅凭行为结果更能推断出小鼠是否有过应激史。本研究揭示了群体层面的神经动力学,解释了个体对创伤性应激反应的差异,并表明通过调节vCA1-BLA输入可以通过调控这些动力学来增强适应性。
『总结』 本研究通过小鼠模型揭示了无快感症的神经机制,发现调节vCA1-BLA神经回路可以增强个体对创伤性应激的适应性。
32. 硅藻植物色素整合水下光谱以感知深度
Diatom phytochromes integrate the underwater light spectrum to sense depth
『Abstract』Aquatic life is strongly structured by the distribution of light, which, besides attenuation in intensity, exhibits a continuous change in the spectrum with depth . The extent to which these light changes are perceived by phytoplankton through photoreceptors is still inadequately known. We addressed this issue by integrating functional studies of diatom phytochrome (DPH) photoreceptors in model species with environmental surveys of their distribution and activity. Here, by developing an in vivo dose–response assay to light spectral variations mediated by DPH, we show that DPH can trigger photoreversible responses across the entire light spectrum, resulting in a change in DPH photoequilibrium with depth. By generating dph mutants in the diatom Thalassiosira pseudonana , we also demonstrate that under simulated low-blue-light conditions of ocean depth, DPH regulates photosynthesis acclimation, thus linking optical depth detection with a functional response. The latitudinal distribution of DPH -containing diatoms from permanently stratified regions to seasonally mixed regions suggests an adaptive value of DPH functions in coping with vertical displacements in the water column. By establishing DPH as a detector of optical depth, this study provides a new view of how information embedded in the underwater light field can be exploited by diatoms to modulate their physiology throughout the photic zone.
『摘要』 水生生物的分布受光分布的强烈影响,光强会随着深度的增加而衰减,光谱也会随深度发生持续变化。目前尚不清楚浮游植物通过光感受器感知这些光变化的程度。我们通过将模式生物中硅藻植物色素(DPH)光感受器的功能研究与其分布和活性的环境调查相结合来解决这一问题。在本研究中,我们通过开发一种体内剂量-反应测定法来检测DPH介导的光谱变化,结果表明DPH可在整个光谱范围内触发光可逆反应,导致DPH光平衡随深度发生变化。通过在硅藻假微型海链藻中生成dph突变体,我们还证明了在模拟海洋深度的低蓝光条件下,DPH可调节光合作用适应,从而将光学深度检测与功能反应联系起来。从永久分层区域到季节性混合区域,含有DPH的硅藻的纬度分布表明,DPH功能在应对水柱中的垂直位移方面具有适应价值。本研究通过确定DPH是一种光学深度检测器,提供了一种新视角,即硅藻如何利用水下光场中的信息来调节其在整个光照区的生理机能(这句话译成中文怎么译怎么别扭,但看英文好像习以为常了)。
『总结』 本研究表明硅藻能利用DPH光感受器感知光谱变化并调节生理机能,揭示了硅藻如何应对水柱中的垂直位移。
33. 适时抑制TGFβ信号传导可诱导脊索形成
Timely TGFβ signalling inhibition induces notochord
『Abstract』The formation of the vertebrate body involves the coordinated production of trunk tissues from progenitors located in the posterior of the embryo. Although in vitro models using pluripotent stem cells replicate aspects of this process , they lack crucial components, most notably the notochord—a defining feature of chordates that patterns surrounding tissues . Consequently, cell types dependent on notochord signals are absent from current models of human trunk formation. Here we performed single-cell transcriptomic analysis of chick embryos to map molecularly distinct progenitor populations and their spatial organization. Guided by this map, we investigated how differentiating human pluripotent stem cells develop a stereotypical spatial organization of trunk cell types. We found that YAP inactivation in conjunction with FGF-mediated MAPK signalling facilitated WNT pathway activation and induced expression of TBXT (also known as BRA). In addition, timely inhibition of WNT-induced NODAL and BMP signalling regulated the proportions of different tissue types, including notochordal cells. This enabled us to create a three-dimensional model of human trunk development that undergoes morphogenetic movements, producing elongated structures with a notochord and ventral neural and mesodermal tissues. Our findings provide insights into the mechanisms underlying vertebrate notochord formation and establish a more comprehensive in vitro model of human trunk development. This paves the way for future studies of tissue patterning in a physiologically relevant environment.
『摘要』 脊椎动物体的形成涉及胚胎后部的祖细胞协调产生躯干组织。虽然使用多能干细胞的体外模型复制了该过程的某些方面,但它们缺乏关键组成部分,尤其是脊索——这是决定周围组织模式的脊索动物的一个定义特征。因此,依赖脊索信号的细胞类型在当前的人类躯干形成模型中缺失。在这里,我们对鸡胚进行了单细胞转录组分析,以绘制分子上不同的祖细胞群体及其空间组织。在该图谱的指导下,我们研究了分化中的人类多能干细胞如何发育成躯干细胞类型的典型空间组织。我们发现,YAP失活与FGF介导的MAPK信号传导共同促进了WNT通路的激活并诱导了TBXT(也称为BRA)的表达。此外,及时抑制WNT诱导的NODAL和BMP信号传导可调节不同组织类型的比例,包括脊索细胞。这使我们能够创建一个经历形态发生运动的人类躯干发育三维模型,该模型产生了带有脊索以及腹侧神经和中胚层组织的细长结构。我们的研究结果为脊椎动物脊索形成的机制提供了见解,并建立了一个更全面的人类躯干发育体外模型。这为未来在生理相关环境中研究组织模式奠定了基础。
『总结』 研究揭示了脊椎动物脊索形成的机制,并通过单细胞转录组分析和信号通路调控,建立了更全面的人类躯干发育体外模型。
34. 通过人工分子马达催化传递化学能
Transducing chemical energy through catalysis by an artificial molecular motor
『Abstract』Cells display a range of mechanical activities generated by motor proteins powered through catalysis . This raises the fundamental question of how the acceleration of a chemical reaction can enable the energy released from that reaction to be transduced (and, consequently, work to be done) by a molecular catalyst . Here we demonstrate the molecular-level transduction of chemical energy to mechanical force in the form of the powered contraction and powered re-expansion of a cross-linked polymer gel driven by the directional rotation of artificial catalysis-driven molecular motors. Continuous 360° rotation of the rotor about the stator of the catalysis-driven motor-molecules incorporated in the polymeric framework of the gel twists the polymer chains of the cross-linked network around one another. This progressively increases writhe and tightens entanglements, causing a macroscopic contraction of the gel to approximately 70% of its original volume. The subsequent addition of the opposite enantiomer fuelling system powers the rotation of the motor-molecules in the reverse direction, unwinding the entanglements and causing the gel to re-expand. Continued powered twisting of the strands in the new direction causes the gel to re-contract. In addition to actuation, motor-molecule rotation in the gel produces other chemical and physical outcomes, including changes in the Young modulus and storage modulus—the latter is proportional to the increase in strand crossings resulting from motor rotation. The experimental demonstration of work against a load by a synthetic organocatalyst, and its mechanism of energy transduction , informs both the debate surrounding the mechanism of force generation by biological motors and the design principles for artificial molecular nanotechnology.
『摘要』 细胞表现出由催化驱动的马达蛋白产生的一系列机械活动。这就引出了一个根本性问题:化学反应的加速如何使反应释放的能量通过分子催化剂进行转导(并因此做功)。在此,我们以人工催化驱动的分子马达驱动交联聚合物凝胶的动力收缩和再膨胀的形式,展示了化学能向机械力的分子水平转导。在凝胶聚合物框架中嵌入的催化驱动马达分子中,转子相对于定子进行连续的360°旋转,使交联网络中聚合物链相互缠绕。这逐渐增加了扭曲程度和缠结紧密度,导致凝胶宏观收缩至原始体积的约70%。随后加入相反的对映体供能系统,驱动马达分子反向旋转,解开缠结,使凝胶重新膨胀。继续沿新方向对链进行动力扭转会使凝胶再次收缩。除了驱动作用外,凝胶中马达分子的旋转还会产生其他化学和物理结果,包括杨氏模量和储能模量的变化——后者与马达旋转导致的链交叉点增加成正比。合成有机催化剂对负载做功的实验演示及其能量转导机制,既为生物马达的力生成机制的相关辩论提供了依据,也为人工分子纳米技术的设计原则提供了信息。
『总结』 本研究展示了人工催化驱动的分子马达如何将化学能转化为机械力,实现了凝胶的动力收缩和再膨胀,并揭示了马达分子旋转对凝胶物理化学性质的影响。
【小编注】 化学家搞了这么些年的分子马达,原来是受生物启发的。
35. 支持多达100种语言的语音和文本联合机器翻译
Joint speech and text machine translation for up to 100 languages
『Abstract』Creating the Babel Fish, a tool that helps individuals translate speech between any two languages, requires advanced technological innovation and linguistic expertise. Although conventional speech-to-speech translation systems composed of multiple subsystems performing translation in a cascaded fashion exist , scalable and high-performing unified systems remain underexplored. To address this gap, here we introduce SEAMLESSM4T–Massively Multilingual and Multimodal Machine Translation–a single model that supports speech-to-speech translation (101 to 36 languages), speech-to-text translation (from 101 to 96 languages), text-to-speech translation (from 96 to 36 languages), text-to-text translation (96 languages) and automatic speech recognition (96 languages). Built using a new multimodal corpus of automatically aligned speech translations and other publicly available data, SEAMLESSM4T is one of the first multilingual systems that can translate from and into English for both speech and text. Moreover, it outperforms the existing state-of-the-art cascaded systems, achieving up to 8% and 23% higher BLEU (Bilingual Evaluation Understudy) scores in speech-to-text and speech-to-speech tasks, respectively. Beyond quality, when tested for robustness, our system is, on average, approximately 50% more resilient against background noise and speaker variations in speech-to-text tasks than the previous state-of-the-art systems. We evaluated SEAMLESSM4T on added toxicity and gender bias to assess translation safety. For the former, we included two strategies for added toxicity mitigation working at either training or inference time. Finally, all contributions in this work are publicly available for non-commercial use to propel further research on inclusive speech translation technologies.
『摘要』 开发巴别鱼(Babel Fish)这一能够帮助个人在任意两种语言之间进行语音翻译的工具,需要先进的技术创新和语言专业知识。尽管目前存在由多个子系统以级联方式进行翻译的传统语音到语音翻译系统,但可扩展且高性能的统一系统仍有待深入探索。为弥补这一空白,我们在此推出了SEAMLESSM4T(大规模多语种和多模态机器翻译)——这是一个支持语音到语音翻译(101种语言至36种语言)、语音到文本翻译(101种语言至96种语言)、文本到语音翻译(96种语言至36种语言)、文本到文本翻译(96种语言)以及自动语音识别(96种语言)的单一模型。SEAMLESSM4T是使用一个新的多模态语料库(包含自动对齐的语音翻译和其他公开可用的数据)构建的,是首批能够实现英语与另一种语言之间语音和文本互译的多语言系统之一。此外,它的表现优于现有的最先进的级联系统,在语音到文本和语音到语音任务中,分别取得了高出8%和23%的BLEU(双语评估替补)分数。除了质量上的提升,在鲁棒性测试方面,我们的系统在语音到文本任务中,相比之前的系统平均提高了约50%的抗背景噪声和语音变化能力。我们还评估了SEAMLESSM4T在附加毒性内容和性别偏见方面的表现,以评估翻译的安全性。对于前者,我们采用了两种策略来减轻附加毒性内容,这两种策略分别在训练或推理时起作用。最后,本工作的所有成果均公开供非商业使用,以推动对包容性语音翻译技术的进一步研究。
『总结』 研究推出了SEAMLESSM4T,这是一款多功能机器翻译模型,支持多种语言和模态的翻译,且表现优于现有系统,同时更具鲁棒性,并已公开供非商业使用。
【小编注】 AI 现在做复杂、系统的事情确实有难度,但在自然语言的处理方面确实有优势,大胆预测一下:以后外语的学习可能没那么重要了。
36. mRNA帽结构识别机制
The mechanism of mRNA cap recognition
『Abstract』During translation initiation, mRNA molecules must be identified and activated for loading into a ribosome . In this rate-limiting step, the heterotrimeric protein eukaryotic initiation factor eIF4F must recognize and productively interact with the 7-methylguanosine cap at the 5′ end of the mRNA and subsequently activate the message . Despite its fundamental, regulatory role in gene expression, the molecular events underlying cap recognition and mRNA activation remain unclear . Here we generate a single-molecule fluorescence imaging system to examine the dynamics with which eIF4F discriminates productive and non-productive locations on full-length, native mRNA molecules. At the single-molecule level, we observe stochastic sampling of eIF4F along the length of the mRNA and identify allosteric communication between the eIF4F subunits that ultimately drive cap-recognition and subsequent activation of the message. Our experiments uncover functions for each subunit of eIF4F and we conclude by presenting a model for mRNA activation that precisely defines the composition of the activated message. This model provides a general framework for understanding how mRNA molecules may be discriminated from one another and how other RNA-binding proteins may control the efficiency of translation initiation.
『摘要』 在翻译起始阶段,mRNA分子必须被识别并激活以装载到核糖体上。在这一限速步骤中,异三聚体蛋白真核起始因子eIF4F必须识别mRNA 5'端的7-甲基鸟嘌呤帽结构并与之有效结合,随后激活mRNA。尽管eIF4F在基因表达的调控中发挥着根本性作用,但帽结构识别和mRNA激活的潜在分子机制仍不明确。本研究构建了一个单分子荧光成像系统,用以探究eIF4F在全长天然mRNA分子上区分有效和非有效结合位点的动态过程。在单分子水平上,我们观察到了eIF4F沿mRNA长度的随机取样,并确定了eIF4F亚基之间的变构通信,这种通信最终驱动了帽结构的识别和随后的mRNA激活。我们的实验揭示了eIF4F每个亚基的功能,最后我们提出了一个mRNA激活模型,该模型精确定义了激活态mRNA的组成。该模型为了解mRNA分子如何被区分以及其他RNA结合蛋白如何控制翻译起始效率提供了一个通用框架。
『总结』 本研究通过单分子荧光成像技术揭示了eIF4F在mRNA激活过程中的动态行为和亚基间的相互作用,并提出了一个描述激活态mRNA组成的模型。
【小编注】 mRNA翻译起始不止是限速、还是限价步骤,人工生产 mRNA,帽子结构占大部分成本,这是值得研究的。 BTW,当年读书的时候单分子荧光或吸收还是一条一条的线状图谱,现在都可用于单分子成像了,科技发展真是迅猛!
37. 新西鲁里安棘皮动物化石揭示了软体动物复杂的早期历史
New Silurian aculiferan fossils reveal complex early history of Mollusca
『Abstract』Mollusca is the second most species-rich animal phylum, but the pathways of early molluscan evolution have long been controversial . Modern faunas retain only a fraction of the past forms in this hyperdiverse and long-lived group. Recent analyses have consistently recovered a fundamental split into two sister clades, Conchifera (including gastropods, bivalves and cephalopods) and Aculifera , comprising Polyplacophora (‘chitons’) and Aplacophora. Molluscan evolution in toto is characterized by plasticity in body-plan characters , but historically aculiferans have been interpreted as more conservative . The few completely preserved aculiferan or aculiferan-like fossils from the early Palaeozoic have been largely regarded as transitional forms that inform questions of character polarity between the extant polyplacophoran and aplacophoran body forms . The history of early aculiferans, and the morphological and ecological range that they occupied, remain inadequately sampled. Here we describe two new three-dimensionally preserved aculiferan species from the Silurian Herefordshire Lagerstatte , which substantially extend the morphological and ecological range of the clade. Phylogenetic analyses indicate positions within a complex nexus of taxa and suggest reversals in the states of fundamental characters such as the presence of valves and the nature of the foot. In contrast to previous hypotheses of morphological conservatism, evolution in early aculiferans generated a profusion of unusual forms comparable to the diversification of other crown-group molluscs.
『摘要』 软体动物是物种丰富度第二高的动物门,但早期软体动物的演化路径一直备受争议。在现代动物群中,这个超多样化和历史悠久的类群中只保留了过去形态的一小部分。最新分析始终发现软体动物门存在两个基本分支:有壳类(包括腹足类、双壳类和头足类)和无壳类,后者包括多板纲(石鳖)和无板纲。软体动物的整体演化以身体结构特征的多样性为特点,但从历史上看,无壳类被认为更为保守。早古生代极少数保存完好的无壳类或类似无壳类的化石大多被视为过渡形态,为了解现存多板纲和无板纲之间形态极性的问题提供了信息。然而,早期无壳类的历史以及它们所占据的形态和生态范围仍然采样不足。本文描述了来自西尔里安赫里福德郡特异埋藏化石库的两个新发现的三维保存的无壳类物种,它们极大地扩展了该类群的形态和生态范围。系统发育分析表明了它们在一个复杂的分类群连接点中的位置,并揭示了基本特征(如瓣膜的存在和足的性质)的状态逆转。与之前关于形态保守性的假设相反,早期无壳类的演化产生了大量不同寻常的形态,与其他冠群软体动物的多样化程度相当。
『总结』 本研究发现了两种早期无壳类软体动物新物种,其形态和生态范围的扩展挑战了关于无壳类形态保守性的传统观点,揭示了早期软体动物演化的多样性和复杂性。