前沿速递 | NCS 集萃:2024-12-13 期

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『Abstract』Limited flexibility, complex manufacturing processes, high costs, and insufficient performance are major factors restricting the scalability and commercialization of flexible inorganic thermoelectrics for wearable electronics and other high-end cooling applications. We developed an innovative, cost-effective technology that integrates solvothermal, screen-printing, and sintering techniques to produce an inorganic flexible thermoelectric film. Our printable film, comprising Bi2Te3-based nanoplates as highly orientated grains and Te nanorods as “nanobinders,” shows excellent thermoelectric performance for printable films, good flexibility, large-scale manufacturability, and low cost. We constructed a flexible thermoelectric device assembled by printable n-type Bi2Te3-based and p-type Bi0.4Sb1.6Te3 films, which achieved a normalized power density of >3 μW cm-2K-2 , ranking among the highest in screen-printed devices. Moreover, this technology can be extended to other inorganic thermoelectric film systems, such as Ag2Se, showing broad applicability.

『摘要』 有限的灵活性、复杂的制造工艺、高成本以及性能不足是制约柔性无机热电材料在可穿戴电子设备和其他高端冷却应用中规模化和商业化的主要因素。我们开发了一种创新且具有成本效益的技术,该技术集成了溶剂热法、丝网印刷和烧结技术,用以生产无机柔性热电薄膜。这种可打印薄膜由作为高取向晶粒的Bi2Te3基纳米片和作为“纳米粘合剂”的Te纳米棒组成,该薄膜展现出优异的热电性能、良好的柔韧性、大规模制造能力和低成本。我们构建了一种由可打印的n型Bi2Te3基薄膜和p型Bi0.4Sb1.6Te3薄膜组装的柔性热电装置,其归一化功率密度达到>3 μW cm-2K-2,在丝网印刷器件中处于最高水平。此外,该技术还可扩展到其他无机热电薄膜系统,如Ag2Se,显示出广泛的应用潜能。

『总结』 研究团队开发了一种结合溶剂热、丝网印刷和烧结技术的创新方法,成功制备出高性能、低成本、可大规模生产的无机柔性热电薄膜,并展示了其在可穿戴设备等领域的应用潜力。

『Abstract』Marine heatwaves are intensifying under climate change, exposing populations of reef-building corals to mass mortality and intense selective pressure. It remains unknown whether adaptation can keep pace with warming and maintain reef functioning. We have developed an eco-evolutionary metapopulation model for Acropora , an ecologically important yet thermally sensitive coral taxon. We found that, although corals have some adaptation capacity, they will suffer severe heatwave-induced declines over the coming decades. For a future in which emissions lead to ~3°C of global warming, natural selection could allow populations to persist, albeit in severely depleted states with elevated extinction risk and potential loss of ecosystem functioning. Yet, for thermally sensitive coral populations to thrive beyond 2050, there must be rapid reductions of greenhouse gas emissions that limit global warming to 2°C.

『摘要』 随着气候变化的加剧,海洋热浪也在加剧,导致造礁珊瑚种群大量死亡并面临巨大的选择压力。目前尚不清楚珊瑚适应能力能否跟上气候变暖的速度并维持珊瑚礁的功能。我们为生态上重要但对温度敏感的珊瑚分类群——鹿角珊瑚建立了一个生态进化元种群模型。我们发现,尽管珊瑚具有一定的适应能力,但在未来几十年里,它们仍将因热浪而遭受严重衰退。在未来由排放导致全球变暖约3℃的情景下,自然选择或许能让珊瑚种群继续存在,但种群数量将严重减少,灭绝风险增加,且可能丧失生态系统功能。然而,要想让对温度敏感的珊瑚种群在2050年之后继续繁衍生息,就必须迅速减少温室气体排放,将全球变暖控制在2℃以内。

『总结』 研究表明,尽管珊瑚有一定适应能力,但未来热浪将导致其严重衰退;控制全球变暖至2℃以内是保护珊瑚种群的关键。

『Abstract』Emotional experiences often evoke neural plasticity that supports adaptive changes in behavior, including maladaptive plasticity associated with mood and substance use disorders. These adaptations are supported in part by experience-dependent activation of immediate-early response genes, such as Npas4 (neuronal PAS domain protein 4). Here we show that a conserved long noncoding enhancer RNA (lnc-eRNA), transcribed from an activity-sensitive enhancer, produces DNA:RNA hybrid R-loop structures that support three-dimensional chromatin looping between enhancer and proximal promoter and rapid Npas4 gene induction. Furthermore, in mouse models, Npas4 lnc-eRNA and its R-loop are required for the development of behavioral adaptations produced by chronic psychosocial stress or cocaine exposure, revealing a potential role for this regulatory mechanism in the transmission of emotional experiences.

『摘要』 情绪体验通常会引发神经可塑性,从而支持行为的适应性变化,包括与情绪障碍和物质(可能是药物)使用障碍相关的非适应性可塑性。这些适应部分得益于经验依赖性即刻早期反应基因(如Npas4,即神经元PAS域蛋白4)的激活。本研究发现,一个由活性敏感增强子转录产生的保守长链非编码增强子RNA(lnc-eRNA)会产生DNA:RNA杂交R-loop环结构,该结构支持增强子与近端启动子之间的三维染色质环化,以及Npas4基因的快速诱导。此外,在小鼠模型中,Npas4 lnc-eRNA及其R环对于慢性心理社会压力或可卡因暴露引起的行为适应的发展至关重要,揭示了这一调控机制在情感体验传递中的潜在作用。

『总结』 研究揭示了Npas4 lnc-eRNA及其R-loop在情绪体验引发的行为适应中的关键作用,提供了情绪和物质使用障碍调控机制的新视角。

【小编注】 有没有人跟你讲过“要提供情绪价值”?男同胞们别反感,这是有科学道理的。情绪会引发基因活动的,想想也对,咱们情绪上脑的时候是不是瞬间产生大量荷尔蒙或肾上腺素。突然感觉我的 DNA 又动了一下?

『Abstract』Global tuna fisheries are valued at more than $40 billion, with the majority of this value derived from purse seine fisheries. Recently created large-scale marine protected areas are potentially big enough to protect highly migratory species such as tuna, possibly leading to increases in abundance (a conservation benefit) and consequent spillover near protected area boundaries (an economic benefit). Using publicly available data from nine large-scale marine protected areas across the Pacific and Indian oceans, we find that catch-per-unit-effort in tuna purse seine fisheries has increased by an average of 12 to 18% near protected area boundaries, and this increase declines with distance from the boundaries. The increase is larger for bigeye tuna ( Thunnus obesus ) than for skipjack tuna ( Katsuwonus pelamis ), in line with fisheries science simulation models.

『摘要』 全球金枪鱼渔业的产值超过400亿美元,其中大部分产值来自围网渔业。近期建立的大规模海洋保护区面积广阔,足以保护金枪鱼等高度洄游物种,有可能增加其种群数量(生态保护效益),并在保护区边界附近产生外溢效应(经济效益)。通过分析太平洋和印度洋九个大规模海洋保护区的公开数据,我们发现金枪鱼围网渔业的单位努力捕获量在保护区边界附近平均增加了12%至18%,且这种增加随边界距离的增加而减少。大眼金枪鱼(Thunnus obesus)的单位努力捕获量增加幅度高于鲣鱼(Katsuwonus pelamis),这与渔业科学模拟模型的预测结果一致。

『总结』 研究发现,靠近大规模海洋保护区边界的金枪鱼围网渔业单位努力捕获量显著增加,且大眼金枪鱼的增长幅度高于鲣鱼。

『Abstract』Recent marine heatwaves have had pervasive effects on marine ecosystems, from declines in primary production to die-offs of top predators. Seabird mortalities are often observed in association with heatwaves, but population impacts are not well understood. In this work, we report the rapid mortality of approximately half of Alaska’s common murre ( Uria aalge ) population in response to an extreme marine heatwave. Between the 7-year period before (2008–2014) and after (2016–2022) the heatwave, murre numbers plummeted 52 to 78% at 13 colonies across two large marine ecosystems. We calculated a loss of 4.00 million common murres, the largest documented wildlife mortality event in the modern era. No evidence of recovery has yet been observed, suggesting that these ecosystems may no longer support historic numbers of seabird top predators.

『摘要』 近期的海洋热浪对海洋生态系统产生了广泛影响,从初级生产力的下降到顶级捕食者的死亡。海鸟死亡事件常与热浪相伴发生,但热浪对海鸟种群的具体影响尚不清楚。本研究报告了一次极端海洋热浪导致阿拉斯加州约一半厚嘴崖海鸦(Uria aalge)种群迅速死亡的情况。在热浪发生前后的两个7年时期(分别为2008-2014年和2016-2022年),两个大型海洋生态系统中的13个栖息地中的厚嘴崖海鸦数量急剧下降了52%至78%。据我们计算,共有400万只厚嘴崖海鸦死亡,这是现代有记录以来规模最大的野生动物死亡事件。目前尚未观察到种群恢复迹象,这表明这些生态系统可能无法再支撑历史上那么多的顶级海鸟捕食者。

『总结』 极端海洋热浪导致阿拉斯加州厚嘴崖海鸦种群数量急剧下降,且尚未恢复,揭示了热浪对海洋生态系统的深远影响。

『Abstract』The inverse design of tailored organic molecules for specific optoelectronic devices of high complexity holds an enormous potential but has not yet been realized. Current models rely on large data sets that generally do not exist for specialized research fields. We demonstrate a closed-loop workflow that combines high-throughput synthesis of organic semiconductors to create large datasets and Bayesian optimization to discover new hole-transporting materials with tailored properties for solar cell applications. The predictive models were based on molecular descriptors that allowed us to link the structure of these materials to their performance. A series of high-performance molecules were identified from minimal suggestions and achieved up to 26.2% (certified 25.9%) power conversion efficiency in perovskite solar cells.

『摘要』 针对高度复杂的光电器件的定制有机分子的逆向设计具有巨大潜力,但尚未实现。当前的模型依赖于大数据集,而专业领域通常不具备这样的数据集。本文展示了一个闭环工作流程,该流程结合了有机半导体的高通量合成来创建大数据集,以及贝叶斯优化来发现具有太阳能电池应用定制性能的新型空穴传输材料。预测模型基于分子描述符,使我们能够将这些材料的结构与性能联系起来。根据极少的建议,我们确定了一系列高性能分子,并在钙钛矿太阳能电池中实现了高达26.2%(经认证为25.9%)的功率转换效率。

『总结』 本研究通过结合高通量合成和贝叶斯优化,实现了为太阳能电池量身定制高性能有机空穴传输材料的逆向设计。

『Abstract』Severe lung injury causes airway basal stem cells to migrate and outcompete alveolar stem cells, resulting in dysplastic repair. We found that this “stem cell collision” generates an injury-induced tissue niche containing keratin 5 epithelial cells and plastic Pdgfra mesenchymal cells. Single-cell analysis revealed that the injury-induced niche is governed by mesenchymal proliferation and Notch signaling, which suppressed Wnt/Fgf signaling in the injured niche. Conversely, loss of Notch signaling rewired alveolar signaling patterns to promote functional regeneration and gas exchange. Signaling patterns in injury-induced niches can differentiate fibrotic from degenerative human lung diseases through altering the direction of Wnt/Fgf signaling. Thus, we have identified an injury-induced niche in the lung with the ability to discriminate human lung disease phenotypes.

『摘要』 严重肺损伤会导致气道基底干细胞迁移并胜过肺泡干细胞,从而导致发育异常性修复。我们发现,这种“干细胞碰撞”会产生一个由损伤诱导的组织微环境,其中包含角蛋白5上皮细胞和可塑性的Pdgfra间质细胞。单细胞分析显示,损伤诱导的微环境受间质细胞增殖和Notch信号通路调控,该通路可抑制损伤微环境中的Wnt/Fgf信号通路。相反,Notch信号通路缺失会改变肺泡信号通路模式,从而促进功能再生和气体交换。损伤诱导的微环境中的信号通路模式可以通过改变Wnt/Fgf信号通路的方向来区分人类肺纤维化疾病和退行性疾病。因此,我们已在肺部确定了一个可区分人类肺疾病表型的损伤诱导微环境。

『总结』 本研究发现了肺部损伤诱导的微环境能够区分人类肺纤维化与退行性疾病,该微环境由Notch信号通路调控并影响Wnt/Fgf信号通路。

『Abstract』Artificial neural networks provide a powerful paradigm for nonbiological information processing. To understand whether similar principles could enable computation within living cells, we combined de novo–designed protein heterodimers and engineered viral proteases to implement a synthetic protein circuit that performs winner-take-all neural network classification. This “perceptein” circuit combines weighted input summation through reversible binding interactions with self-activation and mutual inhibition through irreversible proteolytic cleavage. These interactions collectively generate a large repertoire of distinct protein species stemming from up to eight coexpressed starting protein species. The complete system achieves multi-output signal classification with tunable decision boundaries in mammalian cells and can be used to conditionally control cell death. These results demonstrate how engineered protein-based networks can enable programmable signal classification in living cells.

『摘要』 人工神经网络为非生物信息处理提供了一种强大的范式。为了探究类似的原理是否能够在活细胞内实现计算,我们结合了从头设计的蛋白质异二聚体和工程化病毒蛋白酶,构建了一个合成蛋白质电路,用于执行赢者通吃神经网络分类。这种“感知蛋白”电路通过可逆结合相互作用实现加权输入求和,并通过不可逆的蛋白水解切割实现自激活和相互抑制。这些相互作用共同产生了源自多达八种共表达起始蛋白质物种的大量不同的蛋白质物种。该系统在哺乳动物细胞中实现了具有可调决策边界的多输出信号分类,并且可用于条件性控制细胞死亡。这些结果展示了工程化蛋白质网络如何在活细胞中实现可编程信号分类。

『总结』 本研究通过结合设计的蛋白质异二聚体和病毒蛋白酶,构建了一种在活细胞内执行神经网络分类的合成蛋白质电路,实现了可编程信号分类和细胞死亡的条件性控制。

『Abstract』The transmission of antibiotic-resistance genes, comprising mobilization and relocation events, orchestrates the dissemination of antimicrobial resistance. Inspired by this evolutionarily successful paradigm, we developed ACTIMOT, a CRISPR-Cas9–based approach to unlock the vast chemical diversity concealed within bacterial genomes. ACTIMOT enables the efficient mobilization and relocation of large DNA fragments from the chromosome to replicative plasmids within the same bacterial cell. ACTIMOT circumvents the limitations of traditional molecular cloning methods involving handling and replicating large pieces of genomic DNA. Using ACTIMOT, we mobilized and activated four cryptic biosynthetic gene clusters from Streptomyces , leading to the discovery of 39 compounds across four distinct classes. This work highlights the potential of ACTIMOT for accelerating the exploration of biosynthetic pathways and the discovery of natural products.

『摘要』 抗生素抗性基因的传播,包括动员和易位事件,是抗菌素抗性扩散的主要机制。受此进化上成功范式的启发,我们开发了ACTIMOT,这是一种基于CRISPR-Cas9的方法,旨在解锁细菌基因组中隐藏的丰富化学多样性。ACTIMOT能够在同一细菌细胞内,高效地将大片段DNA从染色体动员并易位到复制性质粒上。该方法避免了传统分子克隆方法在处理和复制大片段基因组DNA时的局限性。利用ACTIMOT,我们从链霉菌中动员并激活了四个隐秘的生物合成基因簇,从而发现了四类共39种化合物。本研究突显了ACTIMOT在加速生物合成途径探索和天然产物发现方面的潜力。

『总结』 本研究开发了一种基于CRISPR-Cas9的ACTIMOT方法,能够有效解锁细菌基因组中的化学多样性,并通过从链霉菌中激活隐秘基因簇发现了多种新化合物。

【小编注】 隐约感觉这是一个很有想象力和应用前景的工作!

『Abstract』Despite the well-known effects of sexual selection on phenotypes, links between this evolutionary process and reproductive isolation, genomic divergence, and speciation have been difficult to establish. We unravel the genetic basis of sexually selected plumage traits to investigate their effects on reproductive isolation in barn swallows. The genetic architecture of sexual traits is characterized by 12 loci on two autosomes and the Z chromosome. Sexual trait loci exhibit signatures of divergent selection in geographic isolation and barriers to gene flow in secondary contact. Linkage disequilibrium between these genes has been maintained by selection in hybrid zones beyond what would be expected under admixture alone. Our findings reveal that selection on coupled sexual trait loci promotes reproductive isolation, providing key empirical evidence for the role of sexual selection in speciation.

『摘要』 尽管性选择对表型的影响已为人熟知,但这种进化过程与生殖隔离、基因组分化和物种形成之间的联系却难以确定。本研究揭示了性选择羽毛特征的遗传基础,以探究其对家燕生殖隔离的影响。性特征的遗传结构特征为位于两条常染色体和Z染色体上的12个基因座。性特征基因座在地理隔离和二次接触中的基因流障碍中表现出分化选择的特征。这些基因之间的连锁不平衡在混合区因选择而得以维持,超出了仅根据混合预期的水平。本研究结果表明,对偶联性特征基因座的选择促进了生殖隔离,为性选择在物种形成中的作用提供了关键的实证证据。

『总结』 本研究通过揭示性选择羽毛特征的遗传基础,证明了性选择对家燕生殖隔离的促进作用,为性选择在物种形成中的关键作用提供了实证证据。

『Abstract』Bacteriophages are the most abundant and phylogenetically diverse biological entities on Earth, yet the ecological mechanisms that sustain this extraordinary diversity remain unclear. In this study, we discovered that phage diversity consistently outstripped the diversity of their bacterial hosts under simple experimental conditions. We assembled and passaged dozens of diverse phage communities on a single, nonevolving strain of Escherichia coli until the phage communities reached equilibrium. In all cases, we found that two or more phage species coexisted stably, despite competition for a single, clonal host population. Phage coexistence was supported through host phenotypic heterogeneity, whereby bacterial cells adopting different growth phenotypes served as niches for different phage species. Our experiments reveal that a rich community ecology of bacteriophages can emerge on a single bacterial host.

『摘要』 噬菌体是地球上数量最多且系统发育最为多样的生物实体,但维持这种非凡多样性的生态机制尚不清楚。在本研究中,我们发现,在简单的实验条件下,噬菌体的多样性始终超过其细菌宿主的多样性。我们在单一、未进化的大肠杆菌菌株上组装并传代了数十个不同的噬菌体群落,直至噬菌体群落达到平衡。在所有情况下,我们都发现,尽管存在对单一克隆宿主种群的竞争,但两种或两种以上的噬菌体物种仍能稳定共存。噬菌体的共存是通过宿主表型异质性来实现的,即采用不同生长表型的细菌细胞为不同的噬菌体物种提供了生态位。我们的实验表明,在单一的细菌宿主上可以出现丰富的噬菌体群落生态。

『总结』 研究表明,在单一细菌宿主上,噬菌体可以通过利用宿主表型异质性实现多种噬菌体的稳定共存,从而形成丰富的噬菌体群落生态。

『Abstract』Gene flow from Neanderthals has shaped genetic and phenotypic variation in modern humans. We generated a catalog of Neanderthal ancestry segments in more than 300 genomes spanning the past 50,000 years. We examined how Neanderthal ancestry is shared among individuals over time. Our analysis revealed that the vast majority of Neanderthal gene flow is attributable to a single, shared extended period of gene flow that occurred between 50,500 to 43,500 years ago, as evidenced by ancestry correlation, colocalization of Neanderthal segments across individuals, and divergence from the sequenced Neanderthals. Most natural selection—positive and negative—on Neanderthal variants occurred rapidly after the gene flow. Our findings provide new insights into how contact with Neanderthals shaped modern human origins and adaptation.

『摘要』 来自尼安德特人的基因流动塑造了现代人类的遗传和表型变异。我们制作了跨越过去5万年、包含300多个基因组的尼安德特人祖先片段目录。我们研究了尼安德特人祖先血统随时间在不同个体间的共享情况。我们的分析显示,绝大多数的尼安德特人基因流动可归因于一个单一的、共享的、发生在50,500至43,500年前的长期基因流动,祖先相关性、尼安德特人片段在不同个体中的共定位和与已测序尼安德特人的分化情况证明了这一点。自然选择(包括正向选择和负向选择)对尼安德特人变异体的作用大多发生在基因流动之后不久。我们的研究结果为与尼安德特人的接触如何塑造现代人类的起源和适应性提供了新的见解。

『总结』 研究发现,现代人类遗传变异受5万至4.35万年前尼安德特人单一长期基因流动影响,自然选择紧随其后。

【小编注】 “尼安德特人的基因流动塑造了现代人类的遗传和表型变异”——这句话山顶洞人和北京人同意吗?

『Abstract』The global ocean covers 71% of Earth’s surface, yet the seafloor is poorly charted compared with land, the Moon, Mars, and Venus. Traditional ocean mapping uses ship-based soundings and nadir satellite radar altimetry—one limited in spatial coverage and the other in spatial resolution. The joint NASA–CNES (Centre National d’Etudes Spatiales) Surface Water and Ocean Topography (SWOT) mission uses phase-coherent, wide-swath radar altimetry to measure ocean surface heights at high precision. We show that 1 year of SWOT data offers more detailed information than 30 years of satellite nadir altimetry in marine gravity, enabling the detection of intricate seafloor structures at 8-kilometer spatial resolution. With the mission still ongoing, SWOT promises critical insights for bathymetric charting, tectonic plate reconstruction, underwater navigation, and deep ocean mixing.

『摘要』 全球海洋覆盖了地球表面的71%,然而与陆地、月球、火星和金星相比,海底的测绘程度却很低。传统的海洋测绘采用基于船舶的测深和垂直向下的卫星雷达测高技术,前者在空间覆盖范围上受限,后者在空间分辨率上受限。美国国家航空航天局(NASA)与法国国家太空研究中心(CNES)联合开展的表层水与海洋地形(SWOT)任务使用相位相干、宽测幅雷达测高技术来高精度测量海洋表面高度。我们的研究表明,1年的SWOT数据提供的海洋重力信息比30年的垂直向下卫星测高数据更为详细,能够在8公里空间分辨率下探测到复杂的海底结构。随着任务的持续进行,SWOT有望为水深测绘、板块构造重建、水下导航和深海混合提供关键见解。

『总结』 SWOT任务利用先进雷达测高技术,提供更详细的海洋信息,助力海底测绘等多个领域的研究。

『Abstract』Stellar superflares are energetic outbursts of electromagnetic radiation that are similar to solar flares but release more energy, up to 10 erg on main-sequence stars. It is unknown whether the Sun can generate superflares and, if so, how often they might occur. We used photometry from the Kepler space observatory to investigate superflares on other stars with Sun-like fundamental parameters. We identified 2889 superflares on 2527 Sun-like stars, out of 56,450 observed. This detection rate indicates that superflares with energies >10 erg occur roughly once per century on stars with Sun-like temperature and variability. The resulting stellar superflare frequency-energy distribution is consistent with an extrapolation of the Sun’s flare distribution to higher energies, so we suggest that both are generated by the same physical mechanism.

『摘要』 恒星超级耀斑是电磁辐射的剧烈爆发,与太阳耀斑类似,但释放的能量更大,在主序星上可达10尔格(erg)。目前尚不清楚太阳是否能产生超级耀斑,以及如果能产生,其频率如何。我们利用开普勒太空观测站的光度数据,研究了其他具有类似太阳基本参数的恒星上的超级耀斑。在观测到的56,450颗恒星中,我们在2527颗类似太阳的恒星上发现了2889次超级耀斑。这一探测率表明,在温度和变异性与太阳相似的恒星上,能量超过10尔格的超级耀斑大约每世纪发生一次。由此得出的恒星超级耀斑频率-能量分布与太阳耀斑分布向更高能量的外推结果一致,因此我们推测两者是由相同的物理机制产生的。

『总结』 研究表明,类太阳恒星每世纪可能发生一次超级耀斑,其机制与太阳耀斑相似,进一步揭示了太阳极端活动的潜在可能性。

『Abstract』Needle-based injections currently enable the administration of a wide range of biomacromolecule therapies across the body, including the gastrointestinal tract , through recent developments in ingestible robotic devices . However, needles generally require training, sharps management and disposal, and pose challenges for autonomous ingestible systems. Here, inspired by the jetting systems of cephalopods, we have developed and evaluated microjet delivery systems that can deliver jets in axial and radial directions into tissue, making them suitable for tubular and globular segments of the gastrointestinal tract. Furthermore, they are implemented in both tethered and ingestible formats, facilitating endoscopic applications or patient self-dosing. Our study identified suitable pressure and nozzle dimensions for different segments of the gastrointestinal tract and applied microjets in a variety of devices that support delivery across the various anatomic segments of the gastrointestinal tract. We characterized the ability of these systems to administer macromolecules, including insulin, a glucagon-like peptide-1 (GLP1) analogue and a small interfering RNA (siRNA) in large animal models, achieving exposure levels similar to those achieved with subcutaneous delivery. This research provides key insights into jetting design parameters for gastrointestinal administration, substantially broadening the possibilities for future endoscopic and ingestible drug delivery devices.

『摘要』 基于针头的注射目前能够实现全身范围内生物大分子疗法的给药,包括通过近年来发展出的可吞服机器人设备对胃肠道的给药。然而,针头通常需要专业培训、针具管理和废弃处理,并对自主吞服系统构成了挑战。在此,我们受头足类动物喷射系统的启发,开发并评估了一种微喷射递送系统,能够将喷射流以轴向和径向方向递送至组织中,适用于胃肠道的管状和球状区域(给药)。此外,该系统既有系留式也有可摄入式,便于内镜应用或患者自行给药。我们的研究确定了胃肠道不同部位适用的压力和喷嘴尺寸,并将微喷射技术应用于多种设备,以支持在胃肠道各解剖部位的给药。我们在大动物模型中评估了这些系统对包括胰岛素、胰高血糖素样肽-1(GLP1)类似物和小干扰RNA(siRNA)等生物大分子的给药能力,其达到了与皮下给药相似的暴露水平。本研究提供了胃肠道给药的喷射设计参数的关键见解,极大地拓宽了未来开发内镜和可摄入给药装置的可能性。

『总结』 受头足类动物启发,开发了一种的微喷射给药系统,实现了在胃肠道各部位的生物大分子给药,为未来内镜和可摄入给药技术的发展提供了重要依据。

『Abstract』The automated synthesis of small organic molecules from modular building blocks has the potential to transform our capacity to create medicines and materials . Disruptive acceleration of this molecule-building strategy broadly unlocks its functional potential and requires the integration of many new assembly chemistries. Although recent advances in high-throughput chemistry can speed up the development of appropriate synthetic methods, for example, in selecting appropriate chemical reaction conditions from the vast range of potential options, equivalent high-throughput analytical methods are needed. Here we report a streamlined approach for the rapid, quantitative analysis of chemical reactions by mass spectrometry. The intrinsic fragmentation features of chemical building blocks generalize the analyses of chemical reactions, allowing sub-second readouts of reaction outcomes. Central to this advance was identifying that starting material fragmentation patterns function as universal barcodes for downstream product analysis by mass spectrometry. Combining these features with acoustic droplet ejection mass spectrometry we could eliminate slow chromatographic steps and continuously evaluate chemical reactions in multiplexed formats. This enabled the assignment of reaction conditions to molecules derived from ultrahigh-throughput chemical synthesis experiments. More generally, these results indicate that fragmentation features inherent to chemical synthesis can empower rapid data-rich experimentation.

『摘要』 利用模块化构建(业内叫“分子砌块”吧)自动合成小有机分子有望改变我们创造药物和材料的能力。这种分子构建策略的颠覆性加速充分释放了其功能潜力,并需要将许多新的组装化学方法整合其中。尽管高通量化学的最新进展可以加快适当合成方法的开发,例如在广泛的潜在选项中选择适当的化学反应条件,但仍需要等效的高通量分析方法。本文报道了一种通过质谱法进行化学反应快速定量分析的简化方法。化学构建模块的内在碎裂特征使化学反应分析具有通用性,从而可以在亚秒级时间内读取反应结果。这一进展的核心在于,确定了原料碎裂模式可作为质谱法分析下游产物的通用条形码。将这些特征与声波液滴喷射质谱法相结合,我们可以省去耗时的色谱步骤,并持续以多重检测的形式评估化学反应。这使我们能够为超高通量化学合成实验衍生的分子分配反应条件。更广泛地来看,这些结果表明,化学合成固有的碎裂特征能够促进开展快速且数据丰富的实验。

『总结』 该研究报道了一种通过质谱快速定量分析化学反应的简化方法,利用分子砌块的碎裂特征结合声波液滴喷射质谱法,实现了高通量化学合成实验的高效评估。

【小编注】 本文实质上是质谱方法开发,识别分子砌块的特征碎裂模式,从而实现快速解析化学反应产物——快是质谱本身的特征,所以可能其亮点在于收集了大量分子砌块的特征碎裂数据,这种方法又贴合了组合化学、高通量筛选的需求,有应用场景,所以能发 Nature。 模块化、规模化、高通量、模型化或者说信息化……这些都是工业思维,但也逐渐嵌入基础科研中,形成一种“宏大叙事”。

『Abstract』Loading of replicative helicases is obligatory for the assembly of DNA replication machineries. The eukaryotic MCM2–7 replicative helicase motor is deposited onto DNA by the origin recognition complex (ORC) and co-loader proteins as a head-to-head double hexamer to license replication origins. Although extensively studied in budding yeast , the mechanisms of origin licensing in multicellular eukaryotes remain poorly defined. Here we use biochemical reconstitution and electron microscopy to reconstruct the human MCM loading pathway. We find that unlike in yeast, the ORC6 subunit of the ORC is not essential for—but enhances—human MCM loading. Electron microscopy analyses identify several intermediates en route to MCM double hexamer formation in the presence and absence of ORC6, including a DNA-loaded, closed-ring MCM single hexamer intermediate that can mature into a head-to-head double hexamer through multiple mechanisms. ORC6 and ORC3 facilitate the recruitment of the ORC to the dimerization interface of the first hexamer into MCM–ORC (MO) complexes that are distinct from the yeast MO complex and may orient the ORC for second MCM hexamer loading. Additionally, MCM double hexamer formation can proceed through dimerization of independently loaded MCM single hexamers, promoted by a propensity of human MCM2–7 hexamers to self-dimerize. This flexibility in human MCM loading may provide resilience against cellular replication stress, and the reconstitution system will enable studies addressing outstanding questions regarding DNA replication initiation and replication-coupled events in the future.

『摘要』 DNA复制机器的组装必须加载复制性解旋酶。真核生物的MCM2-7复制性解旋酶马达由原点识别复合体(ORC)和共加载蛋白作为头对头双六聚体沉积到DNA上,以授权复制原点。尽管在芽殖酵母中已对其进行了广泛研究,但多细胞真核生物中原点授权的机制仍不明确。在这里,我们使用生化重组和电子显微镜技术重建了人类MCM加载途径。我们发现,与酵母不同,ORC的ORC6亚基对于人类MCM加载不是必需的,但可以起到增强作用。电子显微镜分析鉴定了在存在和不存在ORC6的情况下,MCM双六聚体形成途径中的几种中间体,包括一种加载到DNA上的、闭环的MCM单六聚体中间体,该中间体可通过多种机制成熟为头对头双六聚体。ORC6和ORC3可促进ORC被招募到第一个六聚体的二聚化界面,形成不同于酵母MO复合物的MCM-ORC(MO)复合物,并可能为第二个MCM六聚体的加载定位ORC。此外,MCM双六聚体的形成可通过独立加载的MCM单六聚体的二聚化进行,这一过程由人类MCM2-7六聚体自我二聚化的倾向所促进。人类MCM加载的这种灵活性可能提供了对抗细胞复制压力的适应能力,并且该重组系统未来将能够解决有关DNA复制起始和复制偶联事件悬而未决的问题。

『总结』 本研究揭示了人类MCM加载途径的机制,发现与酵母不同,ORC6亚基非必需但可增强MCM加载,且人类MCM加载具有灵活性,可能有助于应对细胞复制压力。

『Abstract』Rainfall events are globally becoming less frequent but more intense under a changing climate, thereby shifting climatic conditions for terrestrial vegetation independent of annual rainfall totals . However, it remains uncertain how changes in daily rainfall variability are affecting global vegetation photosynthesis and growth . Here we use several satellite-based vegetation indices and field observations indicative of photosynthesis and growth, and find that global annual-scale vegetation indices are sensitive to the daily frequency and intensity of rainfall, independent of the total amount of rainfall per year. Specifically, we find that satellite-based vegetation indices are sensitive to daily rainfall variability across 42 per cent of the vegetated land surfaces. On average, the sensitivity of vegetation to daily rainfall variability is almost as large (95 per cent) as the sensitivity of vegetation to annual rainfall totals. Moreover, we find that wet-day frequency and intensity are projected to change with similar magnitudes and spatial extents as annual rainfall changes. Overall, our findings suggest that daily rainfall variability and its trends are affecting global vegetation photosynthesis, with potential implications for the carbon cycle and food security.

『摘要』 随着气候的变化,全球降雨事件的频率正在降低,但强度却在增加,从而改变了陆地植被的气候条件,而这种改变与年降雨总量无关。然而,日降雨量的变化如何影响全球植被的光合作用和生长,目前仍不确定。本研究使用了多个基于卫星的植被指数以及表明光合作用和生长的实地观测数据,发现全球年度尺度的植被指数对日降雨频率和强度敏感,而与每年的降雨总量无关。具体而言,我们发现,基于卫星的植被指数对42%的植被覆盖地表的日降雨量变化敏感。平均而言,植被对日降雨量变化的敏感度(95%)几乎与对年总降雨量的敏感度相当。此外,我们发现,湿天频率和强度的变化预计将在幅度和空间范围上与年降雨变化相似。总体而言,我们的研究结果表明,日降雨量变化及其趋势正在影响全球植被的光合作用,可能对碳循环和粮食安全产生潜在影响。

『总结』 日降雨量变化及其趋势正对全球植被光合作用产生影响,这可能对碳循环和全球粮食安全构成潜在威胁。

【小编注】 我们不能将年降雨量的影响简单等同为日降雨量影响的累积,尽管年降水量是日降水量的累积,但一天涝十天旱肯定不及每天“和风细雨”对庄稼友好。日降水量跟年降水量影响相当——用非常现代的工具(卫星成像),非常宏大的视野(气候变化),讲了一个近乎常识的“重大发现”。看完好像说了什么,但仔细思考……嗯,全球变暖确实是大事(不是我熟悉的领域,纯粹胡诌几句)。

『Abstract』Eukaryotic DNA replication begins with the loading of the MCM replicative DNA helicase as a head-to-head double hexamer at origins of DNA replication . Our current understanding of how the double hexamer is assembled by the origin recognition complex (ORC), CDC6 and CDT1 comes mostly from budding yeast. Here we characterize human double hexamer (hDH) loading using biochemical reconstitution and cryo-electron microscopy with purified proteins. We show that the human double hexamer engages DNA differently from the yeast double hexamer (yDH), and generates approximately five base pairs of underwound DNA at the interface between hexamers, as seen in hDH isolated from cells . We identify several differences from the yeast double hexamer in the order of factor recruitment and dependencies during hDH assembly. Unlike in yeast , the ORC6 subunit of the ORC is not essential for initial MCM recruitment or hDH loading, but contributes to an alternative hDH assembly pathway that requires an intrinsically disordered region in ORC1, which may work through a MCM–ORC intermediate. Our work presents a detailed view of how double hexamers are assembled in an organism that uses sequence-independent replication origins, provides further evidence for diversity in eukaryotic double hexamer assembly mechanisms , and represents a first step towards reconstitution of DNA replication initiation with purified human proteins.

『摘要』 真核生物DNA复制始于MCM复制性DNA解旋酶以头对头双六聚体的形式装载到DNA复制起点。目前我们对双六聚体如何被起点识别复合体(ORC)、CDC6和CDT1组装起来的认识主要来自芽殖酵母的研究。在此,我们使用生化重组和冷冻电子显微镜技术以及纯化后的蛋白质,对人类双六聚体(hDH)的装载进行了表征。我们的研究表明,人类双六聚体与酵母双六聚体(yDH)结合DNA的方式不同,并在六聚体之间的界面处产生了大约5个碱基对的欠绕DNA,这与从细胞中分离出的hDH中所观察到的一致。我们发现了在hDH组装过程中因子招募顺序和依赖性方面与酵母双六聚体的几处不同。与酵母不同的是,ORC的ORC6亚基对于初始MCM招募或hDH装载并不是必需的,但有助于形成一种替代的hDH组装途径,该途径需要ORC1中一个内在无序区域的参与,这可能通过MCM-ORC中间体发挥作用。我们的研究详细阐述了在使用序列非依赖性复制起点的生物体中双六聚体是如何组装的,为真核生物双六聚体组装机制的多样性提供了进一步证据,并且是利用纯化的人类蛋白质重建DNA复制起始的第一步。

『总结』 该研究揭示了人类双六聚体的装载特性及其与酵母的差异,为真核生物双六聚体组装机制的多样性提供了新见解,并为利用人类蛋白质重建DNA复制起始迈出了第一步。

【小编注】 隔了一篇,又是讲 MCM 的,以为看错了,仔细看标题和作者都不一样,这可巧了不是? 也是在这才知道,人类还不能控制 DNA 复制起始步骤,否则为什么质粒的复制一定要在细胞中进行,而不是无细胞体系(不要与恒温PCR扩增相混淆),这么想意义确实重大,尤其是产业化应用,同主题同发一期 Nature 也就可以理解了。

『Abstract』The early radiation of dinosaurs remains a complex and poorly understood evolutionary event . Here we use hundreds of fossils with direct evidence of feeding to compare trophic dynamics across five vertebrate assemblages that record this event in the Triassic–Jurassic succession of the Polish Basin (central Europe). Bromalites, fossil digestive products, increase in size and diversity across the interval, indicating the emergence of larger dinosaur faunas with new feeding patterns. Well-preserved food residues and bromalite-taxon associations enable broad inferences of trophic interactions. Our results, integrated with climate and plant data, indicate a stepwise increase of dinosaur diversity and ecospace occupancy in the area. This involved (1) a replacement of non-dinosaur guild members by opportunistic and omnivorous dinosaur precursors, followed by (2) the emergence of insect and fish-eating theropods and small omnivorous dinosaurs. Climate change in the latest Triassic resulted in substantial vegetation changes that paved the way for ((3) and (4)) an expansion of herbivore ecospace and the replacement of pseudosuchian and therapsid herbivores by large sauropodomorphs and early ornithischians that ingested food of a broader range, even including burnt plants. Finally, (5) theropods rapidly evolved and developed enormous sizes in response to the appearance of the new herbivore guild. We suggest that the processes shown by the Polish data may explain global patterns, shedding new light on the environmentally governed emergence of dinosaur dominance and gigantism that endured until the end-Cretaceous mass extinction.

『摘要』 恐龙早期的辐射演化仍然是一个复杂且鲜为人知的进化事件。在这里,我们使用了数百块有直接觅食证据的化石,比较了波兰盆地(中欧)三叠纪-侏罗纪连续地层中记录这一事件的五个脊椎动物群落的营养动态变化。化石化的消化产物(即“食粪石”)在该区间内大小和多样性均有所增加,表明出现了体型更大且具有新觅食模式的恐龙动物群。保存完好的食物残渣和食粪石-分类群关联使我们能够广泛推断营养相互作用。我们的研究结果结合气候和植物数据表明,该地区恐龙的多样性和生态空间占有率呈逐步阶梯式增长。这一过程包括(1)通过机会主义和杂食性恐龙先驱取代了非恐龙类群体成员,随后(2)出现了食虫和食鱼的兽脚亚目恐龙和小型杂食性恐龙。三叠纪最晚期的气候变化导致植被发生显著变化,为(3)和(4)草食动物生态空间的扩张铺平了道路,且伪鳄类和兽孔类草食动物被取食范围更广(甚至包括烧焦的植物)的大型蜥脚形类和早期鸟臀类恐龙所取代。最后,(5)为了应对新出现的草食动物类群,兽脚类恐龙迅速进化并发展到巨大的体型。我们认为,波兰的数据所显示的过程可以解释全球模式,为环境驱动下的恐龙的主导地位和巨型化现象(该现象一直持续到白垩纪末大灭绝)提供了新的见解。

『总结』 波兰盆地的研究揭示了恐龙早期辐射演化的复杂过程,包括生态位替代、营养级变化及体型巨型化,这些过程可能具有全球性的解释意义。

【小编注】 差点再次被坑,“食粪食”被译成“溴化物”,我以为消化产物的化石中含有大量溴化物……BTW,“大鱼吃小鱼,小鱼吃虾米”,这种食物链上的竞争让顶端的个体越来越大,但个头最大的恐龙已经灭绝了。人类被一个新冠病毒折腾了整4年,至今仍未走出其出阴影……新冠病毒小到看不见摸不着,但这阴影却大到让人心生恐惧。

『Abstract』Rising carbon dioxide emissions are provoking ocean warming and acidification , altering plankton habitats and threatening calcifying organisms , such as the planktonic foraminifera (PF). Whether the PF can cope with these unprecedented rates of environmental change, through lateral migrations and vertical displacements, is unresolved. Here we show, using data collected over the course of a century as FORCIS global census counts, that the PF are displaying evident poleward migratory behaviours, increasing their diversity at mid- to high latitudes and, for some species, descending in the water column. Overall foraminiferal abundances have decreased by 24.2 ± 0.1% over the past eight decades. Beyond lateral migrations , our study has uncovered intricate vertical migration patterns among foraminiferal species, presenting a nuanced understanding of their adaptive strategies. In the temperature and calcite saturation states projected for 2050 and 2100, low-latitude foraminiferal species will face physicochemical environments that surpass their current ecological tolerances. These species may replace higher-latitude species through poleward shifts, which would reduce low-latitude foraminiferal diversity. Our insights into the adaptation of foraminifera during the Anthropocene suggest that migration will not be enough to ensure survival. This underscores the urgent need for us to understand how the interplay of climate change, ocean acidification and other stressors will impact the survivability of large parts of the marine realm.

『摘要』 二氧化碳排放量不断上升导致海洋变暖和酸化,改变了浮游生物的栖息地,并威胁到钙化生物(如有孔虫)的生存。有孔虫能否通过水平迁移和垂直位移来应对这种前所未有的环境变化速度,目前尚无定论。本文利用一个世纪以来收集的FORCIS全球普查数据,发现有孔虫表现出明显的向极地迁移的行为,在中高纬度地区的多样性增加,部分物种在水柱中向下迁移。在过去80年里,有孔虫的总丰度下降了24.2±0.1%。除水平迁移外,本研究还发现了有孔虫物种间复杂的垂直迁移模式,从而对其适应策略有了更深入的了解。根据对2050年和2100年温度和方解石饱和状态的预测,低纬度有孔虫物种将面临超出其当前生态耐受范围的物理化学环境。这些物种可能会通过向极地迁移来取代高纬度物种,从而降低低纬度有孔虫的多样性。我们对有孔虫在人类世适应性的研究表明,迁移不足以确保其生存。这凸显了我们迫切需要了解气候变化、海洋酸化和其他压力因素如何相互作用,从而影响海洋领域大部分生物的生存能力。

『总结』 研究表明,尽管有孔虫通过迁移来应对环境变化,但仅靠迁移不足以确保其生存,亟需了解多重压力因素对海洋生物生存能力的影响。

『Abstract』Although rare neurodevelopmental conditions have a large Mendelian component , common genetic variants also contribute to risk . However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents nor its interplay with rare variants. It is also unclear whether polygenic background affects risk directly through alleles transmitted from parents to children, or whether indirect genetic effects mediated through the family environment also play a role. Here we addressed these questions using genetic data from 11,573 patients with rare neurodevelopmental conditions, 9,128 of their parents and 26,869 controls. Common variants explained around 10% of variance in risk. Patients with a monogenic diagnosis had significantly less polygenic risk than those without, supporting a liability threshold model . A polygenic score for neurodevelopmental conditions showed only a direct genetic effect. By contrast, polygenic scores for educational attainment and cognitive performance showed no direct genetic effect, but the non-transmitted alleles in the parents were correlated with the child’s risk, potentially due to indirect genetic effects and/or parental assortment for these traits . Indeed, as expected under parental assortment, we show that common variant predisposition for neurodevelopmental conditions is correlated with the rare variant component of risk. These findings indicate that future studies should investigate the possible role and nature of indirect genetic effects on rare neurodevelopmental conditions, and consider the contribution of common and rare variants simultaneously when studying cognition-related phenotypes.

『摘要』 尽管罕见的神经发育疾病在很大程度上受孟德尔遗传的影响,但常见的遗传变异也会增加患病风险。关于这些常见变异如何在患病个体及其父母中分布,以及它们与罕见变异的相互作用知之甚少。目前尚不清楚多基因背景是直接通过父母传递给子女的等位基因来直接影响风险,还是通过家庭环境介导的间接遗传效应也发挥作用。本研究使用来自11573例罕见神经发育疾病患者、9128名患者父母和26869例对照者的遗传数据来探讨这些问题。常见变异解释了约10%的风险差异。与无单基因(问题)诊断的患者相比,有单基因(问题)诊断的患者的多基因(问题)风险显著降低,这支持了“易感性阈值”模型。神经发育疾病的多基因评分仅显示出直接的遗传效应。相比之下,教育程度和认知表现的多基因评分没有显示出直接的遗传效应,但父母未传递给子女的等位基因与子女的风险相关,这可能是由于间接遗传效应和/或父母对这些性状上的配对效应。的确,正如在父母配对理论所预期的,我们的研究表明,神经发育疾病的常见变异倾向与风险的罕见变异成分存在相关性。这些发现表明,未来的研究应探讨间接遗传效应对罕见神经发育疾病的可能作用和性质,并在研究认知相关表型时同时考虑常见变异和罕见变异的贡献。

『总结』 研究表明,常见和罕见遗传变异均对罕见神经发育疾病风险有贡献,且未来研究需进一步探讨间接遗传效应的作用。

【小编注】 别的可能看不懂,但一句特别扎心的话我相信大家都能懂。。。

『Abstract』The phosphorylation of synaptic proteins is a significant biochemical reaction that controls the sleep–wake cycle in mammals . Protein phosphorylation in vivo is reversibly regulated by kinases and phosphatases. In this study, we investigate a pair of kinases and phosphatases that reciprocally regulate sleep duration. First, we perform a comprehensive screen of protein kinase A (PKA) and phosphoprotein phosphatase (PPP) family genes by generating 40 gene knockout mouse lines using prenatal and postnatal CRISPR targeting. We identify a regulatory subunit of PKA ( Prkar2b ), a regulatory subunit of protein phosphatase 1 (PP1; Pppr1r9b ) and catalytic and regulatory subunits of calcineurin (also known as PP2B) ( Ppp3ca and Ppp3r1 ) as sleep control genes. Using adeno-associated virus (AAV)-mediated stimulation of PKA and PP1–calcineurin activities, we show that PKA is a wake-promoting kinase, whereas PP1 and calcineurin function as sleep-promoting phosphatases. The importance of these phosphatases in sleep regulation is supported by the marked changes in sleep duration associated with their increased and decreased activities, ranging from approximately 17.3 h per day (PP1 expression) to 4.3 h per day (postnatal CRISPR targeting of calcineurin). Localization signals to the excitatory post-synapse are necessary for these phosphatases to exert their sleep-promoting effects. Furthermore, the wake-promoting effect of PKA localized to the excitatory post-synapse negated the sleep-promoting effect of PP1–calcineurin. These findings indicate that PKA and PP1–calcineurin have competing functions in sleep regulation at excitatory post-synapses.

『摘要』 突触蛋白的磷酸化是一种重要的生物化学反应,可控制哺乳动物的睡眠-觉醒周期。体内蛋白质磷酸化受到激酶和磷酸酶的可逆调节。在本研究中,我们研究了一对可相互调节睡眠时长的激酶和磷酸酶。首先,我们通过产前和产后的CRISPR靶向技术构建了40个基因敲除小鼠品系,对蛋白激酶A(PKA)和磷蛋白磷酸酶(PPP)家族基因进行了全面筛选。我们确定了PKA的调节亚基(Prkar2b)、蛋白磷酸酶1(PP1;Pppr1r9b)的调节亚基以及钙调磷酸酶(又称PP2B)的催化亚基和调节亚基(Ppp3ca和Ppp3r1)为睡眠控制基因。通过腺相关病毒(AAV)介导的PKA和PP1-钙调磷酸酶活性刺激,我们发现PKA是一种促醒激酶,而PP1和钙调磷酸酶则起到促眠磷酸酶的作用。与这些磷酸酶活性增强和减弱相关的睡眠时长发生显著变化,从每天约17.3小时(PP1表达)到每天4.3小时(产后钙调磷酸酶的CRISPR靶向),这一发现进一步支持了这些磷酸酶在睡眠调节中的重要性。这些磷酸酶要发挥促眠作用,必须定位到兴奋性突触后。此外,定位于兴奋性突触后的PKA的促醒作用抵消了PP1-钙调磷酸酶的促眠作用。这些发现表明,在兴奋性突触后,PKA和PP1-钙调磷酸酶在睡眠调节中具有相互竞争的功能。

『总结』 研究发现,PKA和PP1-钙调磷酸酶通过相互拮抗的磷酸化和去磷酸化作用,在兴奋性突触后共同调节哺乳动物的睡眠-觉醒周期。

【小编注】 我好像又看到“一键关机”的希望了……

『Abstract』Zeolites are crystalline microporous materials constructed by corner-sharing tetrahedra (SiO4 and AlO4 ), with many industrial applications as ion exchangers, adsorbents and heterogeneous catalysts . However, the presence of micropores impedes the use of zeolites in areas dealing with bulky substrates. Introducing extrinsic mesopores, that is, intercrystal/intracrystal mesopores, in zeolites is a solution to overcome the diffusion barrier . Still, those extrinsic mesopores are generally disordered and non-uniform; moreover, acidity and crystallinity are always, to some extent, impaired. Thus, synthesizing thermally stable zeolites with intrinsic mesopores that are of uniform size and crystallographically connected with micropores, denoted here as intrinsic mesoporous zeolite, is highly desired but still not achieved. Here we report ZMQ-1 (Zeolitic Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, no. 1), an aluminosilicate zeolite with an intersecting intrinsic meso-microporous channel system delimited by 28 × 10 × 10-rings, in which the 28-ring has a free diameter of 22.76 Å × 11.83 Å, which reaches the mesopore domain. ZMQ-1 has high thermal and hydrothermal stability with tunable framework Si/Al molar ratios. ZMQ-1 is the first aluminosilicate zeolite with an intrinsic meso-microporous channel system. The Bronsted acidity of ZMQ-1 imparts high activity and unique selectivity in the catalytic cracking of heavy oil. The position of the organic structure-directing agent (OSDA) used for ZMQ-1 synthesis was determined from three-dimensional electron diffraction (3D ED) data, which shows the unique structure-directing role of the OSDA in the formation of the intrinsic meso-microporous zeolite. This provides an incentive for preparing other stable mesopore-containing zeolites.

『摘要』 沸石是由角共享四面体(SiO4和AlO4 )构成的结晶微孔材料,在离子交换、吸附和非均相催化等领域具有广泛的工业应用。然而,微孔的存在阻碍了沸石在处理大体积底物领域的应用。在沸石中引入外在介孔(即晶间/晶内介孔)是克服扩散障碍的一种解决方案。不过,这些外在介孔通常是无序且不均匀的;同时沸石的酸性和结晶度也会在一定程度上受到损害。因此,合成具有均匀尺寸的内在介孔且与微孔在晶体学上相连的、热稳定的沸石(本文称为固有介孔沸石)是业界的强烈渴望但尚未实现的。在此,我们报道了ZMQ-1(沸石材料,青岛生物能源与生物过程技术研究所,编号1),它是一种硅铝酸盐沸石,具有由28×10×10元环界定的相交固有介孔-微孔通道系统,其中28元环的自由直径为22.76 Å × 11.83 Å,达到了介孔范围。ZMQ-1具有高热稳定性和水热稳定性,且骨架硅铝摩尔比可调。ZMQ-1是第一个具有固有介孔-微孔通道系统的硅铝酸盐沸石。ZMQ-1的布朗斯特酸度使其在重油催化裂解中具有高活性和独特的选择性。用于ZMQ-1合成的有机结构导向剂(OSDA)的位置是通过三维电子衍射(3D ED)数据确定的,该数据表明了OSDA在形成固有介孔-微孔沸石中的独特结构导向作用。这为制备其他稳定的含介孔沸石提供了新的思路。

『总结』 研究人员报道了首例具有内在介孔-微孔通道系统的硅铝酸盐沸石ZMQ-1,该沸石具有高稳定性和独特的催化性能。

【小编注】 沸石?实验室这么常见、这么不起眼的东东还能做出Nature 呢?

『Abstract』Climate change affects marine organisms, causing migrations, biomass reduction and extinctions . However, the abilities of marine species to adapt to these changes remain poorly constrained on both geological and anthropogenic timescales. Here we combine the fossil record and a global trait-based plankton model to study optimal temperatures of marine calcifying zooplankton (foraminifera, Rhizaria) through time. The results show that spinose foraminifera with algal symbionts acclimatized to deglacial warming at the end of the Last Glacial Maximum (LGM, 19–21 thousand years ago, ka), whereas foraminifera without symbionts (non-spinose or spinose) kept the same thermal preference and migrated polewards. However, when forcing the trait-based plankton model with rapid transient warming over the coming century (1.5 ℃, 2 ℃, 3 ℃ and 4 ℃ relative to pre-industrial baseline), the model suggests that the acclimatization capacities of all ecogroups are limited and insufficient to track warming rates. Therefore, foraminifera are projected to migrate polewards and reduce their global carbon biomass by 5.7–15.1% (depending on the warming) by 2100 relative to 1900–1950. Our study highlights the different challenges posed by anthropogenic and geological warming for marine plankton and their ecosystem functions.

『摘要』 气候变化影响着海洋生物,导致它们迁徙、生物量减少甚至灭绝。然而,无论是从地质时间尺度还是人类活动时间尺度来看,海洋物种对这些变化的适应能力仍然知之甚少。本研究结合了化石记录和基于全球特征的浮游生物模型,来研究海洋钙化浮游动物(有孔虫,原生动物界)随时间变化的最适温度。结果表明,在末次冰盛期(LGM,距今1.9~2.1万年)结束时,带有藻类共生体的有刺有孔虫适应了冰消期变暖,而不带共生体(无刺或有刺)的有孔虫则保持了相同的温度偏好并向两极迁徙。然而,当在本世纪内(相对于工业化前基准线,温度上升1.5℃、2℃、3℃和4℃)用快速瞬态变暖来驱动基于特征的浮游生物模型时,模型显示所有生态群的适应能力都有限,不足以跟上变暖速度。因此,预计到2100年,与1900~1950年相比,有孔虫将向两极迁徙,其全球碳生物量将减少5.7%~15.1%(取决于变暖程度)。本研究强调了人为变暖和地质变暖对海洋浮游生物及其生态系统功能造成的不同挑战。

『总结』 本研究表明,尽管部分有孔虫能适应地质时间尺度的气候变化,但所有人为时间尺度的快速变暖都将超出其适应能力,导致其迁徙和生物量减少。

【小编注】 又是一期两篇,主题都是讲气候变暖,都是用的海洋有孔虫。又学习几个新词:地质时间尺度,人为时间尺度,地质变暖,人为变暖。

『Abstract』Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy improve the outcomes of patients with hormone-receptor (HR)-positive, HER2-negative advanced breast cancer and can be used early as first-line treatment or deferred to second-line treatment . Randomized data comparing the use of CDK4/6i in the first- and second-line setting are lacking. The phase 3 SONIA trial (NCT03425838) randomized 1,050 patients who had not received previous therapy for advanced breast cancer to receive CDK4/6i in the first- or second-line setting . All of the patients received the same endocrine therapy, consisting of an aromatase inhibitor for first-line treatment and fulvestrant for second-line treatment. The primary end point was defined as the time from randomization to disease progression after second-line treatment (progression-free survival 2 (PFS2)). We observed no statistically significant benefit for the use of CDK4/6i as a first-line compared with second-line treatment (median, 31.0 versus 26.8 months, respectively; hazard ratio = 0.87; 95% confidence interval = 0.74–1.03; P = 0.10). The health-related quality of life was similar in both groups. First-line CDK4/6i use was associated with a longer CDK4/6i treatment duration compared with second-line use (median CDK4/6i treatment duration of 24.6 versus 8.1 months, respectively) and more grade ≥3 adverse events (2,763 versus 1,591, respectively). These data challenge the need for first-line use of a CDK4/6i in all patients.

『摘要』 细胞周期蛋白依赖性激酶4和6抑制剂(CDK4/6i)联合内分泌治疗可改善激素受体(HR)阳性、HER2阴性晚期乳腺癌患者的结局,既可早期用作一线治疗,也可推迟至二线治疗时使用。目前缺乏比较一线和二线治疗中使用CDK4/6i的随机数据。III期SONIA试验(NCT03425838)将1050例既往未接受过晚期乳腺癌治疗的患者随机分配至一线或二线治疗中使用CDK4/6i。所有患者均接受相同的内分泌治疗,一线治疗使用芳香化酶抑制剂,二线治疗使用氟维司群。本研究的主要终点定义为从随机分组至二线治疗后疾病进展的时间(无进展生存期2(PFS2))。我们发现,与二线治疗相比,CDK4/6i用作一线治疗未表现出具有统计学意义的获益(中位PFS2:31.0个月 vs 26.8个月;风险比:0.87;95%置信区间:0.74~1.03;P=0.10)。两组患者的健康相关生活质量相似。与二线使用相比,一线使用CDK4/6i的治疗持续时间更长(中位CDK4/6i治疗持续时间:24.6个月 vs 8.1个月),且≥3级不良事件更多(2763例 vs 1591例)。这些数据对在所有患者中一线使用CDK4/6i的必要性提出了质疑。

『总结』 研究结果显示,CDK4/6i用作一线治疗与二线治疗相比,并未显著提高患者获益,但一线治疗持续时间更长且不良事件更多,这质疑了所有患者均一线使用CDK4/6i的必要性。

『Abstract』Natural tissues are composed of diverse cells and extracellular materials whose arrangements across several length scales—from subcellular lengths (micrometre) to the organ scale (centimetre)—regulate biological functions. Tissue-fabrication methods have progressed to large constructs, for example, through stereolithography and nozzle-based bioprinting , and subcellular resolution through subtractive photoablation . However, additive bioprinting struggles with sub-nozzle/voxel features and photoablation is restricted to small volumes by prohibitive heat generation and time . Building across several length scales with temperature-sensitive, water-based soft biological matter has emerged as a critical challenge, leaving large classes of biological motifs—such as multiscalar vascular trees with varying calibres—inaccessible with present technologies . Here we use gallium-based engineered sacrificial capillary pumps for evacuation (ESCAPE) during moulding to generate multiscalar structures in soft natural hydrogels, achieving both cellular-scale (<10 µm) and millimetre-scale features. Decoupling the biomaterial of interest from the process of constructing the geometry allows non-biocompatible tools to create the initial geometry. As an exemplar, we fabricated branched, cell-laden vascular trees in collagen, spanning approximately 300-µm arterioles down to the microvasculature (roughly ten times smaller). The same approach can micropattern the inner surface of vascular walls with topographical cues to orient cells in 3D and engineer fine structures such as vascular malformations. ESCAPE moulding enables the fabrication of multiscalar forms in soft biomaterials, paving the way for a wide range of tissue architectures that were previously inaccessible in vitro.

『摘要』 天然组织由多种细胞和细胞外物质组成,这些成分在跨越若干长度尺度(从亚细胞长度(微米)到器官尺度(厘米))的排列中调节着生物功能。组织制作方法已取得进展,例如,通过立体光刻和基于喷嘴的生物打印技术制作出大型结构,通过减法式光消融技术实现亚细胞分辨率。然而,加法式生物打印在喷嘴下方/体素特征方面存在困难,而光消融则因产生大量热量和耗时过长而仅限于小体积应用。使用温度敏感的水基软生物物质跨越多个长度尺度进行构建已成为一项严峻挑战,导致目前的技术无法获得大量生物基元,例如具有不同口径的多尺度血管树。在本文中,我们在模塑过程中使用基于镓的工程化牺牲毛细管泵进行排空(ESCAPE),以在柔软的天然水凝胶中生成多尺度结构,同时实现细胞尺度(<10微米)和毫米尺度的特征。将目标生物材料与构建几何形状的过程分离,便可使用非生物相容性工具来创建初始几何形状。作为示例,我们在胶原中制作了含有细胞的分支状血管树,其范围从大约300微米的细动脉延伸至微血管(大约小十倍)。同样的方法可以用地形线索在血管壁的内表面进行微图案化,使细胞在三维空间中定向,并构建精细结构,如血管畸形。ESCAPE模塑技术能够在软生物材料中制作多尺度形态,为以前无法在体外获得的各种组织结构铺平了道路。

『总结』 本文介绍了一种使用基于镓的牺牲毛细管泵在模塑过程中进行排空的新方法,能够在软生物材料中构建多尺度结构,为以前无法体外获得的组织架构开辟了新途径。

『Abstract』Glioblastoma is incurable and in urgent need of improved therapeutics . Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, replication stress and tumour cell death . Gliocidin is a prodrug that is anabolized into its tumoricidal metabolite, gliocidin–adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) of the NAD salvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NAD pocket . In vivo, gliocidin penetrates the blood–brain barrier and extends the survival of mice with orthotopic glioblastoma. The DNA alkylating agent temozolomide induces Nmnat1 expression, causing synergistic tumour cell killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings gliocidin to light as a prodrug with the potential to improve the survival of patients with glioblastoma.

『摘要』 胶质母细胞瘤无法治愈,迫切需要改进治疗方法。本研究发现了一种小分子化合物——胶质环素,它能杀死胶质母细胞瘤细胞,同时不影响非肿瘤复制细胞。胶质环素通过间接抑制肌苷单磷酸脱氢酶2(IMPDH2)来靶向胶质母细胞瘤中从头嘌呤合成的一个薄弱点。IMPDH2的阻断会降低细胞内鸟苷酸水平,导致核苷酸失衡、复制应激和肿瘤细胞死亡。胶质环素是一种前药,在NAD补救途径中的烟酰胺核苷腺苷酸转移酶1(NMNAT1)的作用下,被代谢为其具有肿瘤杀伤作用的代谢物——胶质环素-腺嘌呤二核苷酸(GAD)。GAD与IMPDH2的冷冻电子显微镜结构显示了GAD进入、变形和阻断NAD结合位点的过程。在体内,胶质环素能穿透血脑屏障,延长原位胶质母细胞瘤小鼠的生存期。DNA烷化剂替莫唑胺可诱导NMNAT1表达,从而在原位患者来源的异种移植模型中实现肿瘤细胞的协同杀伤和额外的生存获益。本研究揭示了胶质环素作为一种前药,具有改善胶质母细胞瘤患者生存期的潜力。

『总结』 本研究发现胶质环素作为一种新前药,能靶向胶质母细胞瘤的薄弱点,有望改善患者的生存期。

『Abstract』Persistent, memorandum-specific neuronal spiking activity has long been hypothesized to underlie working memory . However, emerging evidence suggests a potential role for ‘activity-silent’ synaptic mechanisms . This issue remains controversial because evidence for either view has largely relied either on datasets that fail to capture single-trial population dynamics or on indirect measures of neuronal spiking. We addressed this controversy by examining the dynamics of mnemonic information on single trials obtained from large, local populations of lateral prefrontal neurons recorded simultaneously in monkeys performing a working memory task. Here we show that mnemonic information does not persist in the spiking activity of neuronal populations during memory delays, but instead alternates between coordinated ‘On’ and ‘Off’ states. At the level of single neurons, Off states are driven by both a loss of selectivity for memoranda and a return of firing rates to spontaneous levels. Further exploiting the large-scale recordings used here, we show that mnemonic information is available in the patterns of functional connections among neuronal ensembles during Off states. Our results suggest that intermittent periods of memorandum-specific spiking coexist with synaptic mechanisms to support working memory.

『摘要』 长久以来,人们一直假设持续且针对特定记忆项的神经元棘波活动与工作记忆的基础机制有关。然而,新兴证据表明,“活动沉默”的突触机制可能也发挥着作用。这一问题仍然存在争议,因为支持这两种观点的证据主要依赖于无法捕捉单次试验中群体动态的数据集,或者依赖于对神经元棘波活动的间接测量。我们通过研究猴子在执行工作记忆任务时,同时记录的大量侧前额叶神经元群体中单个试验的记忆信息动态来解决这一争议。我们发现,在记忆延迟期间,记忆信息并未持续存在于神经元群体的棘波活动中,而是在协调的“开启”和“关闭”状态之间交替。在单个神经元层面,关闭状态是由对记忆项选择性的丧失和放电率恢复到自发水平共同驱动的。通过进一步利用这里使用的大规模记录,我们发现,在关闭状态下,神经元群体之间的功能连接模式中包含着记忆信息。我们的结果表明,特定记忆项的间歇性棘波活动与突触机制共同支持着工作记忆。

『总结』 研究发现,工作记忆并非仅由持续的神经元棘波活动维持,还涉及“活动沉默”的突触机制及神经元群体在“开启”和“关闭”状态间的交替。

【小编注】 看不懂,做脑科学的童鞋来科普下。

『Abstract』The most distant galaxies detected were seen when the Universe was a scant 5% of its current age. At these times, progenitors of galaxies such as the Milky Way were about 10,000 times less massive. Using the James Webb Space Telescope (JWST) combined with magnification from gravitational lensing, these low-mass galaxies can not only be detected but also be studied in detail. Here we present JWST observations of a strongly lensed galaxy at z spec = 8.296 ± 0.001, showing massive star clusters (the Firefly Sparkle) cocooned in a diffuse arc in the Canadian Unbiased Cluster Survey (CANUCS) . The Firefly Sparkle exhibits traits of a young, gas-rich galaxy in its early formation stage. The mass of the galaxy is concentrated in 10 star clusters (49–57% of total mass), with individual masses ranging from 105M ⊙ to 106M ⊙. These unresolved clusters have high surface densities (>103 M⊙pc-2 ), exceeding those of Milky Way globular clusters and young star clusters in nearby galaxies. The central cluster shows a nebular-dominated spectrum, low metallicity, high gas density and high electron temperature, hinting at a top-heavy initial mass function. These observations provide our first spectrophotometric view of a typical galaxy in its early stages, in a 600-million-year-old Universe.

『摘要』 发现的最遥远星系是在宇宙年龄仅为现在的5%时被观测到的。在那个时候,像银河系这样的星系的前身其质量约为现在的1万分之一。利用詹姆斯·韦伯空间望远镜(JWST)结合引力透镜的放大作用,不仅可以探测到这些低质量星系,还可以对其进行详细研究。在此,我们展示了JWST对红移z=8.296±0.001的强引力透镜星系的观测结果,该星系在加拿大无偏星系团巡天(CANUCS)中呈现为弥散弧状结构内包裹着大量星团(称为“萤火虫之光”)。萤火虫之光展现出年轻、富含气体的星系在早期形成阶段的特征。该星系的质量集中在10个星团中(占总质量的49%-57%),单个星团的质量范围在105M ⊙(太阳质量)到106M ⊙之间。这些未解析的星团具有高表面密度(>103M⊙pc-2),超过了银河系球状星团和附近星系中的年轻星团的密度。中心恒星团表现出以星云辐射为主的光谱特征,具有低金属丰度、高气体密度和高电子温度,暗示着具有顶端偏重的初始质量函数。这些观测结果为我们首次提供了宇宙诞生6亿年时一个典型星系早期阶段的分光光度视图。

『总结』 通过JWST与引力透镜效应,研究了一颗宇宙早期(红移值8.296)的低质量星系,揭示其星团集中、高密度、低金属丰度等特性,为理解星系早期形成提供了关键洞察。

『Abstract』Tailored light–matter interactions in the strong coupling regime enable the manipulation and control of quantum systems with up to unit efficiency , with applications ranging from quantum information to photochemistry . Although strong light–matter interactions are readily induced at the valence electron level using long-wavelength radiation , comparable phenomena have been only recently observed with short wavelengths, accessing highly excited multi-electron and inner-shell electron states . However, the quantum control of strong-field processes at short wavelengths has not been possible, so far, because of the lack of pulse-shaping technologies in the extreme ultraviolet (XUV) and X-ray domain. Here, exploiting pulse shaping of the seeded free-electron laser (FEL) FERMI, we demonstrate the strong-field quantum control of ultrafast Rabi dynamics in helium atoms with high fidelity. Our approach reveals a strong dressing of the ionization continuum, otherwise elusive to experimental observables. The latter is exploited to achieve control of the total ionization rate, with prospective applications in many XUV and soft X-ray experiments. Leveraging recent advances in intense few-femtosecond to attosecond XUV to soft X-ray light sources, our results open an avenue to the efficient manipulation and selective control of core electron processes and electron correlation phenomena in real time.

『摘要』 在强耦合状态下,量身定制的光-物质相互作用能够以高达100%的效率对量子系统进行操控,其应用范围从量子信息到光化学不等。尽管使用长波长辐射很容易在价电子层面诱导强光-物质相互作用,但直到最近,使用短波长才观察到类似的现象,这使得我们能够接触到高度激发的多电子和内壳层电子态。然而,由于在极紫外(XUV)和X射线领域缺乏脉冲整形技术,迄今为止还无法实现短波长强场过程的量子控制。在此,我们利用种子型自由电子激光器 (FEL) FERMI的脉冲整形技术,高保真地实现了氦原子中超快拉比动力学的强场量子控制。我们的方法揭示了电离连续谱的强修饰作用,而这种作用在以往的实验观测中难以捉摸。利用这一点,我们实现了对总电离速率的控制,有望应用于许多极紫外和软X射线实验。借助近年来在强飞秒至阿秒极紫外至软X射线光源方面取得的进展,我们的研究结果为实时高效操控和选择性控制核心电子过程及电子相关现象开辟了一条新途径。

『总结』 该研究利用脉冲整形技术实现了短波长下对氦原子超快拉比动力学的高保真量子控制,为操控核心电子过程和电子相关现象提供了新方法。

『Abstract』Persister cells, rare phenotypic variants that survive normally lethal levels of antibiotics, present a major barrier to clearing bacterial infections . However, understanding the precise physiological state and genetic basis of persister formation has been a longstanding challenge. Here we generated a high-resolution single-cell RNA atlas of Escherichia coli growth transitions, which revealed that persisters from diverse genetic and physiological models converge to transcriptional states that are distinct from standard growth phases and instead exhibit a dominant signature of translational deficiency. We then used ultra-dense CRISPR interference to determine how every E. coli gene contributes to persister formation across genetic models. Among critical genes with large effects, we found lon , which encodes a highly conserved protease , and yqgE , a poorly characterized gene whose product strongly modulates the duration of post-starvation dormancy and persistence. Our work reveals key physiologic and genetic factors that underlie starvation-triggered persistence, a critical step towards targeting persisters in recalcitrant bacterial infections.

『摘要』 持久细胞是一种罕见的表型变异体,能在通常致命的抗生素浓度下存活,是清除细菌感染的主要障碍。然而,长期以来,人们一直难以理解持久细胞形成的精确生理状态和遗传基础。本研究生成了大肠杆菌生长过渡阶段的高分辨率单细胞RNA图谱,该图谱显示,来自不同遗传和生理模型的持久细胞会汇聚成一种转录状态,这种状态与标准的生长阶段不同,反而表现出翻译缺陷的主要特征。然后,我们使用超高密度CRISPR干扰技术来确定每个大肠杆菌基因在不同遗传模型中如何促进持久细胞的形成。在具有重大影响的关键基因中,我们发现了编码一种高度保守蛋白酶的lon基因以及特征不明显的yqgE基因,yqgE的产物可强烈调节饥饿后休眠和持久性的持续时间。我们的研究揭示了饥饿触发持久性的关键生理和遗传因素,这是针对难治性细菌感染中持久细胞的重要一步。

『总结』 本研究通过单细胞RNA测序和超高密度CRISPR干扰技术,揭示了大肠杆菌通过 yqgE基因调节饥饿后休眠和持久性持续时间以形成持久细胞的生理和遗传机制。

【小编注】 似乎再次说明了:少吃可以活的更久?

『Abstract』The protozoan parasite Trypanosoma brucei evades clearance by the host immune system through antigenic variation of its dense variant surface glycoprotein (VSG) coat, periodically ‘switching’ expression of the VSG using a large genomic repertoire of VSG-encoding genes . Recent studies of antigenic variation in vivo have focused near exclusively on parasites in the bloodstream , but research has shown that many, if not most, parasites reside in the interstitial spaces of tissues . We sought to explore the dynamics of antigenic variation in extravascular parasite populations using VSG-seq , a high-throughput sequencing approach for profiling VSGs expressed in populations of T. brucei . Here we show that tissues, not the blood, are the primary reservoir of antigenic diversity during both needle- and tsetse bite-initiated T. brucei infections, with more than 75% of VSGs found exclusively within extravascular spaces. We found that this increased diversity is correlated with slower parasite clearance in tissue spaces. Together, these data support a model in which the slower immune response in extravascular spaces provides more time to generate the antigenic diversity needed to maintain a chronic infection. Our findings reveal the important role that extravascular spaces can have in pathogen diversification.

『摘要』 原生动物寄生虫布氏锥虫(Trypanosoma brucei)通过其密集变异表面糖蛋白(VSG)外壳的抗原变异来逃避宿主免疫系统的清除,利用一个包含大量VSG编码基因的基因组库周期性地“转换”VSG的表达。近期关于体内抗原变异的研究几乎全部集中在血流中的寄生虫上,但研究表明,许多(如果不是大多数)寄生虫存在于组织间隙中。我们试图利用VSG-seq(一种用于分析布氏锥虫群体中表达的VSG的高通量测序方法)来探索血管外寄生虫群体中抗原变异的动态。本研究表明,在针刺和采采蝇叮咬引发的布氏锥虫感染中,组织而非血液是抗原多样性的主要储存库,超过75%的VSG仅存在于血管外空间。我们发现,这种增加的多样性与组织间隙中寄生虫清除速度的减慢有关。综合这些数据,我们提出了一个模型:血管外空间中较慢的免疫反应为产生维持慢性感染所需的抗原多样性提供了更多时间。我们的研究结果揭示了血管外空间在病原体多样化中的重要作用。

『总结』 本研究表明,在布氏锥虫感染中,组织间隙而非血液是抗原多样性的主要来源,且血管外空间较慢的免疫反应促进了抗原多样性的形成,从而维持慢性感染。

『Abstract』The intestine is characterized by an environment in which host requirements for nutrient and water absorption are consequently paired with the requirements to establish tolerance to the outside environment. To better understand how the intestine functions in health and disease, large efforts have been made to characterize the identity and composition of cells from different intestinal regions . However, the robustness, nature of adaptability and extent of resilience of the transcriptional landscape and cellular underpinning of the intestine in space are still poorly understood. Here we generated an integrated resource of the spatial and cellular landscape of the murine intestine in the steady and perturbed states. Leveraging these data, we demonstrated that the spatial landscape of the intestine was robust to the influence of the microbiota and was adaptable in a spatially restricted manner. Deploying a model of spatiotemporal acute inflammation, we demonstrated that both robust and adaptable features of the landscape were resilient. Moreover, highlighting the physiological relevance and value of our dataset, we identified a region of the middle colon characterized by an immune-driven multicellular spatial adaptation of structural cells to the microbiota. Our results demonstrate that intestinal regionalization is characterized by robust and resilient structural cell states and that the intestine can adapt to environmental stress in a spatially controlled manner through the crosstalk between immunity and structural cell homeostasis.

『摘要』 肠道的特点是其环境既要满足机体对营养和水分吸收的需求,又要建立起对外部环境的耐受性。为了更好地理解肠道在健康和疾病中的功能,人们投入了大量精力来表征不同肠道区域细胞的特性和组成。然而,对于肠道在空间上的转录谱的稳健性、适应性特质、韧性程度以及细胞基础,人们仍然知之甚少。在此我们构建了一个综合资源,用于展示稳态和扰动状态下小鼠肠道的空间和细胞图谱。利用这些数据,我们证明了肠道的空间图谱对微生物群的影响具有稳健性,并且能以空间限制的方式适应变化。通过构建时空急性炎症模型,我们证明了肠道图谱的稳健性和适应性特征都具有韧性。此外,我们鉴定出中结肠的一个区域,其特征是结构细胞通过疫驱动实现对微生物群体多细胞空间的适应性,凸显我们数据集的生理相关性和价值。我们的研究结果表明,肠道区域化的特征在于稳健且具有韧性的结构细胞状态,并且肠道能够通过免疫与结构细胞稳态之间的相互作用,以空间控制的方式适应环境压力。

『总结』 本研究揭示了肠道在空间和细胞层面的稳健性、适应性和韧性特征,并通过免疫与结构细胞稳态相互作用,在空间受控下适应环境压力。

『Abstract』Nanoscale detection and control of the magnetic order underpins a spectrum of condensed-matter research and device functionalities involving magnetism. The key principle involved is the breaking of time-reversal symmetry, which in ferromagnets is generated by an internal magnetization. However, the presence of a net magnetization limits device scalability and compatibility with phases, such as superconductors and topological insulators. Recently, altermagnetism has been proposed as a solution to these restrictions, as it shares the enabling time-reversal-symmetry-breaking characteristic of ferromagnetism, combined with the antiferromagnetic-like vanishing net magnetization . So far, altermagnetic ordering has been inferred from spatially averaged probes . Here we demonstrate nanoscale imaging of altermagnetic states from 100-nanometre-scale vortices and domain walls to 10-micrometre - scale single-domain states in manganese telluride (MnTe) . We combine the time-reversal-symmetry-breaking sensitivity of X-ray magnetic circular dichroism with magnetic linear dichroism and photoemission electron microscopy to achieve maps of the local altermagnetic ordering vector. A variety of spin configurations are imposed using microstructure patterning and thermal cycling in magnetic fields. The demonstrated detection and controlled formation of altermagnetic spin configurations paves the way for future experimental studies across the theoretically predicted research landscape of altermagnetism, including unconventional spin-polarization phenomena, the interplay of altermagnetism with superconducting and topological phases, and highly scalable digital and neuromorphic spintronic devices .

『摘要』 对磁序进行纳米级检测和控制是涉及磁性的凝聚态研究和器件功能研究的基础。其中涉及的关键原理是打破时间反演对称性,而时间反演对称性在铁磁体中是由内部磁化产生的。然而,净磁化的存在限制了器件的可扩展性和与超导体和拓扑绝缘体等相位的兼容性。最近,交替磁学被提出作为解决这些限制的方法,因为它兼具铁磁体打破时间反演对称性的特征以及类似反铁磁体的净磁化消失特性。迄今为止,交替磁性有序是通过空间平均探头推断出来的。这里我们展示了锰碲化物(MnTe)中交替磁态的纳米级成像,涵盖了从100纳米尺度的涡旋和磁畴壁到10微米尺度的单磁畴状态。我们结合X射线磁圆二色性对时间反演对称性破缺的敏度性、磁线性二色性和光电子显微镜技术,绘制了局部交替磁序矢量成像图。通过微结构图案化和在磁场中的热循环,我们实现了多种自旋结构的引入。对交替磁自旋配置的检测和受控形成为未来实验研究铺平了道路,涵盖理论预测的交替磁性研究领域,包括非常规自旋极化现象、交替磁性与超导和拓扑相的相互作用,以及高度可扩展的数字和神经形态自旋电子学器件。

『总结』 本研究实现了锰碲化物中交替磁自旋的纳米级成像和受控形成,为探索交替磁学的未来研究奠定了实验基础。

『Abstract』Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity . However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes . Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic ‘yo-yo’ effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.

『摘要』 减重以改善代谢健康和相关并发症是治疗肥胖的一个主要目标。然而,维持减重效果是一项相当大的挑战,特别是当机体似乎保留了一种“肥胖记忆”来抵抗体重变化时。由于这一现象的分子机制在很大程度上仍不明确,因此克服这一障碍以实现长期治疗成功(长期保持减重状态)非常困难。在此,我们通过单细胞核RNA测序发现,人类和小鼠的脂肪组织在显著减重后都保留了细胞转录水平的改变。此外,我们还发现小鼠脂肪细胞中因肥胖诱导的表观基因组改变会持续存在,并对脂肪细胞的功能和代谢刺激产生负面影响。携带这种致肥记忆的小鼠表现出体重反弹加速,这种表观遗传记忆可以解释在进一步高脂饮食喂养下脂肪细胞转录失调现象。综上所述,我们的研究结果表明,小鼠脂肪细胞以及可能的其他细胞类型中存在基于稳定表观遗传变化的肥胖记忆。这些变化似乎使细胞在致肥环境中容易发生病理反应,从而导致了节食过程中常见的“溜溜球效应”。未来针对这些变化的干预可能有助于改善长期的体重管理和健康状况。

『总结』 研究表明,小鼠脂肪细胞等可能存在基于稳定表观遗传变化的肥胖记忆,这种记忆促进体重反弹并影响代谢健康,未来针对这些变化的干预或有助于改善体重管理和健康状况。

【小编注】 所以,我已经回不去120斤了是吗? 那我得赶紧把刹车踩到底。

『Abstract』The functionality of materials is determined by their composition and microstructure, that is, the distribution and orientation of crystalline grains, grain boundaries and the defects within them . Until now, characterization techniques that map the distribution of grains, their orientation and the presence of defects have been limited to surface investigations, to spatial resolutions of a few hundred nanometres or to systems of thickness around 100 nm, thus requiring destructive sample preparation for measurements and preventing the study of system-representative volumes or the investigation of materials under operational conditions . Here we present X-ray linear dichroic orientation tomography (XL-DOT), a quantitative, non-invasive technique that allows for an intragranular and intergranular characterization of extended polycrystalline and non-crystalline materials in three dimensions. We present the detailed characterization of a polycrystalline sample of vanadium pentoxide (V2O5 ), a key catalyst in the production of sulfuric acid . We determine the nanoscale composition, microstructure and crystal orientation throughout the polycrystalline sample with 73 nm spatial resolution. We identify and characterize grains, as well as twist, tilt and twin grain boundaries. We further observe the creation and annihilation of topological defects promoted by the presence of volume crystallographic defects. The non-destructive and spectroscopic nature of our method opens the door to operando combined chemical and microstructural investigations of functional materials, including energy, mechanical and quantum materials.

『摘要』 材料的功能由其成分和微观结构决定,即晶粒的分布和取向、晶界以及其中的缺陷。迄今为止,绘制晶粒分布、晶粒取向和缺陷存在的表征技术一直局限于样品表面、几百纳米的空间分辨率或厚度约为100纳米的系统,因此需要在表征时破坏性制样;无法研究其在代表性体积或实际运行条件下的情况。在此,我们提出了一种X射线线性二向色性取向断层成像技术(XL-DOT),这是一种定量、无创技术,能够对扩展的多晶和非晶材料进行三维的晶内和晶间表征。我们对一个五氧化二钒(V2O5)多晶样品(硫酸生产中的关键催化剂)进行了详细表征。我们以73纳米的空间分辨率确定了整个多晶样品的纳米尺度的组成、微观结构和晶体取向。我们识别并表征了晶粒,以及扭转、倾斜和孪晶界面。我们还观察到了由体积晶体学缺陷引起的拓扑缺陷的产生和湮灭。我们方法的非破坏性和光谱学特性为功能材料(包括能源材料、机械材料和量子材料)的原位化学和微观结构联合研究打开了大门。

『总结』 研究团队开发了X射线线性二向色性取向断层成像技术,实现了对多晶和非晶材料的无创三维表征,为功能材料的综合研究提供了新方法。

『Abstract』The unusual properties of superconductivity in magic-angle twisted bilayer graphene (MATBG) have sparked considerable research interest . However, despite the dedication of intensive experimental efforts and the proposal of several possible pairing mechanisms , the origin of its superconductivity remains elusive. Here, by utilizing angle-resolved photoemission spectroscopy with micrometre spatial resolution, we reveal flat-band replicas in superconducting MATBG, where MATBG is unaligned with its hexagonal boron nitride substrate . These replicas show uniform energy spacing, approximately 150 ± 15 meV apart, indicative of strong electron–boson coupling. Strikingly, these replicas are absent in non-superconducting twisted bilayer graphene (TBG) systems, either when MATBG is aligned to hexagonal boron nitride or when TBG deviates from the magic angle. Calculations suggest that the formation of these flat-band replicas in superconducting MATBG are attributed to the strong coupling between flat-band electrons and an optical phonon mode at the graphene K point, facilitated by intervalley scattering. These findings, although they do not necessarily put electron–phonon coupling as the main driving force for the superconductivity in MATBG, unravel the electronic structure inherent in superconducting MATBG, thereby providing crucial information for understanding the unusual electronic landscape from which its superconductivity is derived.

『摘要』 魔角扭曲双层石墨烯(MATBG)中非常规超导特性引发了人们的广泛的研究兴趣。然而,尽管人们开展了大量的实验探索并提出了多种可能的配对机制,但其超导性的起源仍然扑朔迷离。在此,我们利用具有微米空间分辨率的角分辨光电子能谱,揭示了超导MATBG中的平带复制(副本)现象,其中MATBG与其六方氮化硼基底未对齐。这些副本显示出均匀的能量间隔,大约相隔150±15 meV,表明存在强电子-玻色子耦合。令人惊讶的是,这些复制在非超导的扭曲双层石墨烯(TBG)系统中不存在,无论是MATBG与hBN对齐,还是TBG偏离魔角。计算结果表明,超导MATBG中这些平带副本的形成归因于平带电子与石墨烯K点处的光学声子模式之间的强耦合,这种耦合是由谷间散射促进的。这些发现虽然并未明确将电子-声子耦合作为MATBG超导性的主要驱动力,但揭示了超导MATBG中固有的电子结构,从而为理解其超导性所来源的非常规电子态提供了关键信息。

『总结』 研究人员发现了超导魔角扭曲双层石墨烯中因强电子-声子强耦合产生的平带复制现象,为理解其超导性提供了关键电子结构线索。

『Abstract』In transcription-coupled nucleotide excision repair (TC-NER), stalled RNA polymerase II (RNA Pol II) binds CSB and CRL4 , which cooperate with UVSSA and ELOF1 to recruit TFIIH. To explore the mechanism of TC-NER, we recapitulated this reaction in vitro . When a plasmid containing a site-specific lesion is transcribed in frog egg extract, error-free repair is observed that depends on CSB, CRL4 , UVSSA, and ELOF1. Repair also requires STK19, a factor previously implicated in transcription recovery after UV exposure. A 1.9-Å cryo-electron microscopy structure shows that STK19 binds the TC-NER complex through CSA and the RPB1 subunit of RNA Pol II. Furthermore, AlphaFold predicts that STK19 interacts with the XPD subunit of TFIIH, and disrupting this interface impairs cell-free repair. Molecular modeling suggests that STK19 positions TFIIH ahead of RNA Pol II for lesion verification. Our analysis of cell-free TC-NER suggests that STK19 couples RNA Pol II stalling to downstream repair events.

『摘要』 在转录偶联核苷酸切除修复(TC-NER)过程中,停滞的RNA聚合酶II(RNA Pol II)与CSB和CRL4结合,然后再与UVSSA和ELOF1配合,共同招募TFIIH。为了探究TC-NER的作用机制,我们在体外重建了这一反应。当含有特定位点损伤的质粒在蛙卵提取物中进行转录时,可观察到一种无错误修复,该修复依赖于CSB、CRL4、UVSSA和ELOF1。此修复过程还需要STK19,这是一种先前已知与紫外线照射后转录恢复相关的因子。1.9埃(分辨率)的冷冻电子显微镜结构显示,STK19通过CSA和RNA Pol II的RPB1亚基与TC-NER复合物结合。此外,AlphaFold预测STK19与TFIIH的XPD亚基相互作用,破坏这一界面会损害无细胞体系中的修复。分子模拟表明,STK19将TFIIH定位于RNA Pol II的前方,以便进行损伤验证。我们对无细胞TC-NER过程的分析表明,STK19将RNA Pol II的停滞与下游修复事件偶联起来。

『总结』 研究表明,STK19在转录偶联核苷酸切除修复过程中起到关键作用,它通过与转录偶联核苷酸切除修复的复合物TC-NER相结合,将RNA Pol II的停滞与后续的修复过程偶联起来。

『Abstract』Cellular senescence plays critical roles in aging, regeneration, and disease; yet, the ability to discern its contributions across various cell types to these biological processes remains limited. In this study, we generated an in vivo genetic toolbox consisting of three p16-related intersectional genetic systems, enabling pulse-chase tracing (Sn-pTracer), Cre-based tracing and ablation (Sn-cTracer), and gene manipulation combined with tracing (Sn-gTracer) of defined p16 cell types. Using liver injury and repair as an example, we found that macrophages and endothelial cells (ECs) represent distinct senescent cell populations with different fates and functions during liver fibrosis and repair. Notably, clearance of p16 macrophages significantly mitigates hepatocellular damage, whereas eliminating p16 ECs aggravates liver injury. Additionally, targeted reprogramming of p16 ECs through Kdr overexpression markedly reduces liver fibrosis. This study illuminates the functional diversity of p16 cells and offers insights for developing cell-type-specific senolytic therapies in the future.

『摘要』 细胞衰老在机体衰老、再生和疾病过程中发挥着关键作用;然而,不同细胞类型的衰老对这些生物过程的贡献大小,目前依然知之甚少。在本研究中,我们构建了一个由三个p16相关交叉遗传系统组成的体内遗传工具箱,实现了对特定p16细胞类型的脉冲追踪(Sn-pTracer)、基于Cre的追踪和消融(Sn-cTracer)以及结合追踪的基因操作(Sn-gTracer)。以肝损伤和修复为例,我们发现巨噬细胞和内皮细胞(ECs)在肝纤维化和修复过程中代表着不同的衰老细胞群体,具有不同的命运和功能。值得注意的是,清除p16巨噬细胞显著减轻了肝细胞损伤,而清除p16内皮细胞则加重了肝损伤。此外,通过Kdr过表达对p16内皮细胞进行靶向重编程可显著降低肝纤维化程度。本研究揭示了不同p16细胞的功能多样性,并为未来开发细胞类型特异性的抗衰老疗法提供了见解。

『总结』 本研究通过构建遗传工具箱揭示了不同p16细胞在肝损伤修复中的功能多样性,为开发针对细胞特异性抗衰老疗法提供了新视角。

『Abstract』The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here, we show that the immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of major histocompatibility complex class I (MHC class I) molecules. IRGQ directs misfolded MHC class I toward lysosomal degradation through its binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC class I heavy chains do not only accumulate in the cell but are also transported to the cell surface, thereby promoting an immune response. Mice and human patients suffering from hepatocellular carcinoma show improved survival rates with reduced IRGQ levels due to increased reactivity of CD8+ T cells toward IRGQ knockout tumor cells. Thus, we reveal IRGQ as a regulator of MHC class I quality control, mediating tumor immune evasion.

『摘要』 自噬-溶酶体系统负责多种胞内降解,并参与肿瘤进展。本研究发现,迄今尚未清楚表征的免疫相关GTP酶家族Q蛋白(IRGQ)在主要组织相容性复合体I类(MHC I类)分子的质量控制中发挥作用。IRGQ通过与GABARAPL2和LC3B的结合模式,将错误折叠的MHC I类分子引导至溶酶体进行降解。在缺乏IRGQ的情况下,游离的MHC I类(应该特指“错误折叠的 MHC I类”)重链不仅在细胞内积累,而且还会被运输到细胞表面,从而促进免疫反应。患有肝细胞癌的小鼠和人类患者在IRGQ水平降低时,由于CD8+ T细胞对IRGQ敲除肿瘤细胞的反应性增强,其生存率有所提高。因此,本研究揭示IRGQ是MHC I类分子质量控制的调节因子,介导肿瘤免疫逃避。

『总结』 研究发现IRGQ通过调节MHC I类分子的质量控制介导肿瘤免疫逃避,降低IRGQ水平可提高肝细胞癌患者的生存率。

『Abstract』Epithelial tumors are characterized by abundant inter- and intra-tumor heterogeneity, which complicates diagnostics and treatment. The contribution of cancer-stroma interactions to this heterogeneity is poorly understood. Here, we report a paradigm to quantify phenotypic diversity in head and neck squamous cell carcinoma (HNSCC) with single-cell resolution. By combining cell-state markers with morphological features, we identify phenotypic signatures that correlate with clinical features, including metastasis and recurrence. Integration of tumor and stromal signatures reveals that partial epithelial-mesenchymal transition (pEMT) renders disease outcome highly sensitive to stromal composition, generating a strong prognostic and predictive signature. Spatial transcriptomics and subsequent analyses of cancer spheroid dynamics identify the cancer-associated fibroblast-pEMT axis as a nexus for intercompartmental signaling that reprograms pEMT cells into an invasive phenotype. Taken together, we establish a paradigm to identify clinically relevant tumor phenotypes and discover a cell-state-dependent interplay between stromal and epithelial compartments that drives cancer aggression.

『摘要』 上皮性肿瘤的特征是肿瘤间和肿瘤内具有高度异质性,这使诊断和治疗变得复杂。目前,癌症与基质之间的相互作用对这种异质性的贡献尚不清楚。本文报道了一种范式,可在单细胞分辨率下量化头颈部鳞状细胞癌(HNSCC)的表型多样性。通过结合细胞状态标志物和形态学特征,我们发现了与临床特征(包括转移和复发)相关的表型特征。整合肿瘤和基质特征后发现,部分上皮-间质转化(pEMT)使疾病结局对基质成分高度敏感,从而产生强有力的预后和预测特征。空间转录组学和后续癌症类器官动态分析发现,癌症相关成纤维细胞-pEMT轴是介导跨隔室信号传导的关键通路,可将pEMT细胞重编程为具有侵袭性的表型。综上所述,我们建立了一种识别临床相关肿瘤表型的范式,并发现基质与上皮间依赖细胞状态的相互作用驱动癌症侵袭性

『总结』 本研究建立了一种范式,用于在单细胞水平识别头颈部鳞状细胞癌的表型多样性,并发现了基质与上皮区间细胞状态依赖性的相互作用可促进癌症侵袭。

『Abstract』Chemotherapy is often combined with immune checkpoint inhibitor (ICIs) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1α as a critical checkpoint that restricts the immunostimulatory effects of taxane chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1α RNase silences taxane-induced double-stranded RNA (dsRNA) through regulated IRE1-dependent decay (RIDD) to prevent NLRP3 inflammasome-dependent pyroptosis. Inhibition of IRE1α in Trp53 TNBC allows taxane to induce extensive dsRNAs that are sensed by ZBP1, which in turn activates NLRP3-GSDMD-mediated pyroptosis. Consequently, IRE1α RNase inhibitor plus taxane converts PD-L1-negative, ICI-unresponsive TNBC tumors into PD-L1 immunogenic tumors that are hyper-sensitive to ICI. We reveal IRE1α as a cancer cell defense mechanism that prevents taxane-induced danger signal accumulation and pyroptotic cell death.

『摘要』 化疗通常与免疫检查点抑制剂(ICI)联合使用,以增强免疫治疗效果。尽管化疗-免疫疗法已获批用于多种人类癌症的治疗,但许多免疫学上的冷肿瘤(对免疫治疗不敏感的肿瘤)对其仍无应答。决定化疗免疫原性的机制尚不清楚。本研究发现,内质网应激传感器IRE1α是一个关键检查点,可限制紫杉烷化疗的免疫刺激作用,并阻止先天免疫对免疫学上冷的三阴性乳腺癌(TNBC)的识别。IRE1α核糖核酸酶(RNase)通过调节IRE1依赖性衰减(RIDD)沉默紫杉烷诱导的双链RNA(dsRNA),以防止NLRP3炎症小体依赖性的焦亡。在Trp53 TNBC中抑制IRE1α后,紫杉烷可诱导产生大量被ZBP1识别的dsRNA,进而激活NLRP3-GSDMD介导的焦亡。因此,IRE1α核糖核酸酶抑制剂联合紫杉烷可将PD-L1阴性、对ICI无应答的TNBC肿瘤转化为对PD-L1有免疫原性且对ICI超敏感的肿瘤。本研究揭示了IRE1α是一种癌细胞防御机制,可防止紫杉烷诱导的危险信号积聚和焦亡性细胞死亡。

『总结』 本研究发现IRE1α是限制紫杉烷化疗免疫刺激效果的关键检查点,通过抑制紫杉烷诱导的双链RNA和细胞焦亡,限制TNBC的免疫反应;抑制IRE1α可将对免疫检查点抑制剂无应答的冷肿瘤转化为敏感肿瘤。

【小编注】 所以 PD-1,PD-L1也不总是有效。

『Abstract』Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.

『摘要』 胰腺导管腺癌(PDAC)中重复RNA的异常表达模拟了病毒样反应,对肿瘤细胞状态和周围微环境的反应产生影响。为更好地理解重复RNA在人类PDAC中的关系,我们对46例原发性肿瘤进行了单细胞分辨率的空间分子成像,揭示了重复RNA高表达与PDAC细胞上皮状态改变和癌症相关成纤维细胞(CAF)中肌成纤维细胞表型之间的相关性。在胰腺导管腺癌和CAF细胞培养模型中,给予细胞外囊泡(EV)和个体重复RNA后,也观察到了细胞特性(身份)丧失的现象,这表明这些病毒样元件在细胞间存在通讯(应该是指这些病毒样元件本身在细胞间存在交换,大家斟酌一下)。PDAC和CAF反应的差异是由干扰素调节因子3(IRF3)介导的不同先天免疫信号驱动的。重复 RNA 引发的细胞背景特异性的病毒样反应,为PDAC微环境中不同细胞类型的细胞可塑性调节提供了一种机制。

『总结』 研究表明,PDAC中重复RNA的异常表达通过模拟病毒样反应和细胞间通讯影响肿瘤细胞和微环境,为PDAC微环境中不同细胞类型的细胞可塑性调节提供了一种机制。

『Abstract』An antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the fusion-peptide site of vulnerability with infection by simian-human immunodeficiency virus (SHIV). In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45%–77% breadth (geometric mean 50% inhibitory dilution [ID 50 ] ∼100) on a 208-strain panel. Molecular dissection of these responses by antibody isolation and cryo-electron microscopy (cryo-EM) structure determination revealed 15 of 16 antibody lineages with cross-clade neutralization to be directed toward the fusion-peptide site of vulnerability. In each macaque, isolated antibodies from memory B cells recapitulated the plasma-neutralizing response, with fusion-peptide-binding antibodies reaching breadths of 40%–60% (50% inhibitory concentration [IC 50 ] < 50 μg/mL) and total lineage-concentrations estimates of 50–200 μg/mL. Longitudinal mapping indicated that these responses arose prior to SHIV infection. Collectively, these results provide in vivo molecular examples for one to a few B cell lineages affording potent, broadly neutralizing plasma responses.

『摘要』 基于抗体的HIV-1疫苗需要诱导产生强烈的交叉反应性HIV-1中和反应。为了证明这一目标的可行性,我们将靶向易感位点融合肽的疫苗接种与猿-人免疫缺陷病毒(SHIV)感染相结合。在四只产生疫苗诱导中和反应的猕猴中,SHIV感染使包含208株病毒株面板上的血浆中和反应广度提高至45%~77%(几何平均50%抑制稀释度[ID50]≈100)。通过抗体分离和冷冻电子显微镜(Cryo-EM)结构测定对这些反应进行分子剖析,发现16个抗体谱系中有15个具有跨亚型中和作用,靶向融合肽易感位点。在每只猕猴中,从记忆B细胞中分离的抗体再现了血浆中和反应,其中融合肽结合抗体的中和广度达到40%~60%(50%抑制浓度[IC50]<50微克/毫升),估计的总谱系浓度为50~200微克/毫升。纵向追踪表明,这些反应在SHIV感染前就已产生。总的来说,这些结果为体内一个或少数几个B细胞谱系产生强烈、广泛的中和血浆反应提供了分子层面的实例。

『总结』 研究表明,针对HIV-1易感位点融合肽的疫苗接种与SHIV感染相结合,可在猕猴体内诱导产生强烈且广泛的交叉反应性中和抗体反应。

『Abstract』Brain recordings collected at different resolutions support distinct signatures of neural coding, leading to scale-dependent theories of brain function. Here, we show that these disparate signatures emerge from a heavy-tailed, multiscale functional organization of neuronal activity observed across calcium-imaging recordings collected from the whole brains of zebrafish and C. elegans as well as from sensory regions in Drosophila , mice, and macaques. Network simulations demonstrate that this conserved hierarchical structure enhances information processing. Finally, we find that this organization is maintained despite significant cross-scale reconfiguration of cellular coordination during behavior. Our findings suggest that this nonlinear organization of neuronal activity is a universal principle conserved for its ability to adaptively link behavior to neural dynamics across multiple spatiotemporal scales while balancing functional resiliency and information processing efficiency.

『摘要』 以不同分辨率采集的脑记录支持不同的神经编码特征,进而产生了依赖于尺度的脑功能理论。在本研究中,我们展示了这些不同的特征源自源自神经活动的重尾、多尺度功能结构,该结构在斑马鱼、秀丽隐杆线虫全脑,以及果蝇、小鼠和猕猴感觉区域通过钙成像记录中观察到。网络模拟表明,这种保守的层次结构增强了信息处理能力。最后,我们发现,尽管在行为过程中细胞间的协调发生了显著的跨尺度重构,但这种组织仍然得以维持。我们的研究结果表明,这种神经元活动的非线性组织是一个普遍原则,因其能够在多个时空尺度上将行为与神经动力学自适应地联系起来,同时平衡功能韧性和信息处理效率。

『总结』 神经元活动的多尺度、重尾功能结构是保守且通用的,能跨时空尺度自适应关联行为与神经活动,并平衡信息处理的高效性和功能的稳定性。

『Abstract』Type III CRISPR systems provide immunity against genetic invaders through the production of cyclic oligo-adenylate (cA n ) molecules that activate effector proteins that contain CRISPR-associated Rossman fold (CARF) domains. Here, we characterized the function and structure of an effector in which the CARF domain is fused to an adenosine deaminase domain, CRISPR-associated adenosine deaminase 1 (Cad1). We show that upon binding of cA 4 or cA 6 to its CARF domain, Cad1 converts ATP to ITP, both in vivo and in vitro . Cryoelectron microscopy (cryo-EM) structural studies on full-length Cad1 reveal an hexameric assembly composed of a trimer of dimers, with bound ATP at inter-domain sites required for activity and ATP/ITP within deaminase active sites. Upon synthesis of cA n during phage infection, Cad1 activation leads to a growth arrest of the host that prevents viral propagation. Our findings reveal that CRISPR-Cas systems employ a wide range of molecular mechanisms beyond nucleic acid degradation to provide adaptive immunity in prokaryotes.

『摘要』 III型CRISPR系统通过产生环状寡腺苷酸(cAn)分子来激活含有CRISPR相关Rossmann折叠(CARF)结构域的效应蛋白,从而为生物体提供抵御基因入侵者的免疫力。本研究表征了一个效应蛋白的功能和结构,该效应蛋白中的CARF结构域与腺苷脱氨酶结构域(CRISPR相关腺苷脱氨酶1,Cad1)相融合。研究表明,无论是体内还是体外,当cA4或cA6与其CARF结构域结合时,Cad1会将ATP转化为ITP。对全长Cad1的冷冻电子显微镜(cryo-EM)结构研究表明,Cad1形成一个由二聚体组成的三聚六聚体组装体(三组二聚体组成一个六聚体),其中活性所需的跨结构域位点结合有ATP,脱氨酶活性位点内则含有ATP/ITP。在噬菌体感染期间,cAn的合成激活Cad1,导致宿主生长停滞,从而阻止病毒传播。本研究结果表明,CRISPR-Cas系统除了核酸降解外,还采用多种分子机制为原核生物提供适应性免疫。

『总结』 本研究发现III型CRISPR系统通过产生环状寡腺苷酸分子来激活融合效应蛋白后,将ATP转化为ITP,让宿主生长停滞以阻止病毒传播,揭示了CRISPR-Cas系统采用多种分子机制为原核生物提供适应性免疫。

【小编注】 “要么你死,要么我活(反正都是我活)”,就要拼个“鱼死网破”——连我们原核低维生命都这么倔强和顽强,人类有何理由苟活?当然,你们人类也是有狠人的,比如,“要想成功,必先自宫”,OMG!

『Abstract』Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects.

『摘要』 慢性瘙痒是一种严重影响胆汁淤积等肝病患者生活质量的衰弱症状。胆汁酸(BAs)激活人类G蛋白偶联受体MRGPRX4(hX4)可促进胆汁淤积性瘙痒。然而,其详细的潜在机制仍不清楚。本研究发现,在有瘙痒症状的胆汁淤积患者体内,3-硫酸化胆汁酸有所升高。我们解析了hX4-Gq与3-磷酸脱氧胆酸(DCA-3P)(内源性3-硫酸脱氧胆酸(DCA-3S)的模拟物)复合物的冷冻电镜结构。该结构揭示了MRGPR家族蛋白中一个前所未有的配体结合口袋,突出了胆汁酸上的3-羟基(3-OH)在激活hX4中的关键作用。基于这一结构信息,我们设计并开发了化合物7(C7),这是一种缺乏3-OH的胆汁酸衍生物。值得注意的是,C7在肝病模型中有效减轻肝损伤和纤维化,同时显著缓解了瘙痒副作用。

『总结』 研究发现3-硫酸化胆汁酸在胆汁淤积瘙痒患者中的升高,并基于胆汁酸受体hX4的结构设计出新化合物C7,其既能减轻肝病又能缓解瘙痒。

【小编注】 尼玛,原来译成“慢性瘙痒是一种衰弱性症状,对胆汁淤积等肝病患者的生活质量有严重影响”,吓得我立马挠遍了全身,感觉自己弱爆了,根本停不下来,突然意识到今晚洗完澡就坐在电脑前,忘了抹身体乳(冬天、湿度45%)。乱说话真的吓死人!完全相同的字词,但不一样的组合表达截然不同的意思——AI 在处理自然语言这块儿,目前还是差等生,不管土洋。

『Abstract』Cardiac fibrosis impairs cardiac function, but no effective clinical therapies exist. To address this unmet need, we employed a high-throughput screening for antifibrotic compounds using human induced pluripotent stem cell (iPSC)-derived cardiac fibroblasts (CFs). Counter-screening of the initial candidates using iPSC-derived cardiomyocytes and iPSC-derived endothelial cells excluded hits with cardiotoxicity. This screening process identified artesunate as the lead compound. Following profibrotic stimuli, artesunate inhibited proliferation, migration, and contraction in human primary CFs, reduced collagen deposition, and improved contractile function in 3D-engineered heart tissues. Artesunate also attenuated cardiac fibrosis and improved cardiac function in heart failure mouse models. Mechanistically, artesunate targeted myeloid differentiation factor 2 (MD2) and inhibited MD2/Toll-like receptor 4 (TLR4) signaling pathway, alleviating fibrotic gene expression in CFs. Our study leverages multiscale drug screening that integrates a human iPSC platform, tissue engineering, animal models, in silico simulations, and multiomics to identify MD2 as a therapeutic target for cardiac fibrosis.

『摘要』 心脏纤维化会损害心脏功能,但目前缺乏有效的临床治疗方法。为满足这一未竟需求,我们采用高通量筛选方法,利用人诱导多能干细胞(iPSC)衍生的心脏成纤维细胞(CF)筛选抗纤维化化合物。利用iPSC衍生的心肌细胞和内皮细胞对初步候选药物进行反向筛选,排除了具有心脏毒性的候选药物。通过这一筛选过程,我们确定了青蒿琥酯为先导化合物。在促纤维化刺激后,青蒿琥酯可抑制人原代CF的增殖、迁移和收缩,减少胶原沉积,并改善3D工程(制备的)心脏组织的收缩功能。青蒿琥酯还可减轻心力衰竭小鼠模型的心脏纤维化并改善其心脏功能。在机制上,青蒿琥酯靶向髓样分化因子2(MD2)并抑制MD2/Toll样受体4(TLR4)信号通路,从而减少(抑制基因表达更准确,但原文用的就是alleviating)CF中的纤维化基因表达。本研究利用融合了人iPSC平台、组织工程、动物模型、计算机模拟和多组学的多尺度药物筛选方法,确定MD2为心脏纤维化的治疗靶点。

『总结』 本研究通过多尺度药物筛选确定MD2为心脏纤维化的治疗靶点,并揭示青蒿琥酯通过抑制MD2/TLR4信号通路减轻心脏纤维化。

【小编注】 调侃一下,现代药物筛选不都是从体外到体内么?路径相同方法不同,算不算创新?如果方法上的重大改进,大大缩短了开发路径,提高筛选效率等算是创新,简单的工具堆砌我认为不算。好在本篇落点在 MD2靶点,筛出了靶点做出了效果(结果导向),并发了Cell,否则国内常讲的一句话叫什么来着?

『Abstract』Targeted protein degradation (TPD) utilizes molecular glues or proteolysis-targeting chimeras (PROTACs) to eliminate disease-causing proteins by promoting their interaction with E3 ubiquitin ligases. Current TPD approaches are limited by reliance on a small number of constitutively active E3 ubiquitin ligases. Here, we report that ( S )-ACE-OH, a metabolite of the antipsychotic drug acepromazine, acts as a molecular glue to induce an interaction between the E3 ubiquitin ligase TRIM21 and the nucleoporin NUP98, leading to the degradation of nuclear pore proteins and disruption of nucleocytoplasmic trafficking. Functionalization of acepromazine into PROTACs enabled selective degradation of multimeric proteins, such as those within biomolecular condensates, while sparing monomeric proteins. This selectivity is consistent with the requirement of substrate-induced clustering for TRIM21 activation. As aberrant protein assemblies cause diseases such as autoimmunity, neurodegeneration, and cancer, our findings highlight the potential of TRIM21-based multimer-selective degraders as a strategy to tackle the direct causes of these diseases.

『摘要』 靶向蛋白质降解(TPD)技术利用分子胶或蛋白水解靶向嵌合体(PROTACs)促进致病蛋白与E3泛素连接酶的相互作用,从而消除致病蛋白。目前的TPD方法受限于对少数组成型活性E3泛素连接酶的依赖。本研究报道,我们发现抗精神病药物氯丙嗪的代谢物(S)-ACE-OH可以作为一种分子胶,诱导E3泛素连接酶TRIM21与核孔蛋白NUP98发生相互作用,从而导致核孔蛋白降解,破坏核质运输。将乙酰丙嗪功能化为PROTACs后,可选择性地降解多聚体蛋白(如生物分子凝聚物中的蛋白),而单体蛋白则不受影响。这种选择性与TRIM21活化所需的底物诱导聚集一致。由于蛋白质异常聚集会导致自身免疫性疾病、神经退行性疾病和癌症等,我们的研究表明,以TRIM21为基础的多聚体选择性降解剂,有潜力成为直接针对疾病成因的一种治疗策略。

『总结』 本研究发现TRIM21可通过(S)-ACE-OH靶向多聚体蛋白实现选择性降解,为治疗由蛋白质异常聚集引起的疾病提供了新策略。

【小编注】 胶原蛋白、角蛋白、血红蛋白、低密度脂蛋白等,多种大家耳熟能详的正常功能性蛋白都是蛋白多聚体,靶向蛋白多聚体有没有风险?另:蛋白质异常是疾病的“果”还是“因”,这是思维角度或层次问题,不同看法所采取的策略也不一样,治疗效果也不一样。 另:靶向致病蛋白与靶向致病基因,是不同的竞争策略;单纯从减少致病蛋白的角度上进,siRNA一类可能成药性更高;抑制功能错误的蛋白,但功能正常的蛋白哪里来,这会导致另一个问题,所以真正从根源解决问题还是得基因水平,但这又涉及成本、风险获益问题。

『Abstract』Transcription-coupled DNA repair (TCR) removes bulky DNA lesions impeding RNA polymerase II (RNAPII) transcription. Recent studies have outlined the stepwise assembly of TCR factors CSB, CSA, UVSSA, and transcription factor IIH (TFIIH) around lesion-stalled RNAPII. However, the mechanism and factors required for the transition to downstream repair steps, including RNAPII removal to provide repair proteins access to the DNA lesion, remain unclear. Here, we identify STK19 as a TCR factor facilitating this transition. Loss of STK19 does not impact initial TCR complex assembly or RNAPII ubiquitylation but delays lesion-stalled RNAPII clearance, thereby interfering with the downstream repair reaction. Cryoelectron microscopy (cryo-EM) and mutational analysis reveal that STK19 associates with the TCR complex, positioning itself between RNAPII, UVSSA, and CSA. The structural insights and molecular modeling suggest that STK19 positions the ATPase subunits of TFIIH onto DNA in front of RNAPII. Together, these findings provide new insights into the factors and mechanisms required for TCR.

『摘要』 转录偶联DNA修复(TCR)能够去除阻碍RNA聚合酶II(RNAPII)转录的大块(bulky lesion)DNA损伤。近期研究表明,TCR因子CSB、CSA、UVSSA和转录因子IIH(TFIIH)会在RNAPII停滞的损伤位点周围逐步组装。然而,向下游修复步骤(包括移除RNAPII以便修复蛋白接触DNA损伤位点)转变的机制和所需因子仍不明确。本研究发现STK19是促进这一转变的TCR因子。STK19缺失不会影响初始TCR复合物的组装或RNAPII的泛素化,但会延迟因 DNA损伤导致转录停滞的RNAPII的清除,从而干扰下游修复反应。冷冻电子显微镜技术(Cryo-EM)和突变分析显示,STK19与TCR复合物结合,定位于RNAPII、UVSSA和CSA之间。结构分析和分子模拟表明,STK19将TFIIH的ATP酶亚基定位于RNAPII前方的DNA上。综上,这些研究结果为TCR所需的因子和机制提供了新的见解。

『总结』 本研究发现STK19是促进转录偶联DNA修复中,协助受损位点RNAPII清除的关键因子,为理解TCR的机制提供了新的视角。

【小编注】 如果能够人为定点制造一些 DNA 损伤,让转录过程在特定位点停下来或慢下来,是否会影响 RNA 产物的高级结构?

『Abstract』Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, receptor molecular mimicry, and interactions with RBM backbone atoms. Consequently, VIR-7229 features a high barrier for selection of escape mutants, which are rare and associated with reduced viral fitness, underscoring its potential to be resilient to future viral evolution. VIR-7229 is a strong candidate to become a next-generation medicine.

『摘要』 严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的进化导致病毒能够逃逸临床批准的单克隆抗体(mAb)治疗(失效),因此,需要开发能够抵御表位多样化的单克隆抗体。能够广泛中和冠状病毒、即使病毒变异也能保持活性且足够强效以满足临床开发需求的单克隆抗体仍难以获得(这句没有让我满意的翻译结果)。我们鉴定出一种人源单克隆抗体VIR-7229,该抗体靶向病毒受体结合结构域(RBM),表现出对所有亚属冠状病毒(包括非ACE2依赖的蝙蝠亚属冠状病毒)都具有前所未有的交叉反应性,同时对2019年以来出现的SARS-CoV-2变异株(包括最近的EG.5、BA.2.86和JN.1)具有强大的中和作用。VIR-7229可耐受异常的表位变异,这部分归因于其高结合亲和力、受体分子模拟特性以及与RBM骨架原子的相互作用。因此,VIR-7229在选择逃逸突变体方面具有高壁垒(这句话可能原文表达就有问题,应该是要表达“这个抗体为病毒选择逃逸突变体建立了高壁垒”,而不是抗体本身选择突变体),这些逃逸突变体十分罕见,且会降低病毒的适应性,这突显了VIR-7229 为应对未来病毒进化具有 强大抵抗潜力。VIR-7229是下一代药物的强有力候选。

『总结』 研究发现了一种人源单克隆抗体VIR-7229,能够强效中和多种冠状病毒变异株,且对病毒表位变异(应对病毒进化)具有高度耐受性,有望成为下一代抗病毒药物。

【小编注】 应对不确定性(变化中)的事物总是充满不确定且很被动;“以不变应万变”是上策,本文有这个意思……