Science Advances最新文献_第6页

Thr4 phosphorylation on RNA Pol II occurs at early transcription regulating 3′-end processing RNA Pol II 上的 Thr4 磷酸化发生在调节 3'-end 处理的转录早期。

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2024-09-06 DOI: 10.1126/sciadv.adq0350

Rosamaria Y. Moreno, Svetlana B. Panina, Seema Irani, Haley A. Hardtke, Renee Stephenson, Brendan M. Floyd, Edward M. Marcotte, Qian Zhang, Y. Jessie Zhang

RNA polymerase II relies on a repetitive sequence domain (YSPTSPS) within its largest subunit to orchestrate transcription. While phosphorylation on serine-2/serine-5 of the carboxyl-terminal heptad repeats is well established, threonine-4’s role remains enigmatic. Paradoxically, threonine-4 phosphorylation was only detected after transcription end sites despite functionally implicated in pausing, elongation, termination, and messenger RNA processing. Our investigation revealed that threonine-4 phosphorylation detection was obstructed by flanking serine-5 phosphorylation at the onset of transcription, which can be removed selectively. Subsequent proteomic analyses identified many proteins recruited to transcription via threonine-4 phosphorylation, which previously were attributed to serine-2. Loss of threonine-4 phosphorylation greatly reduces serine-2 phosphorylation, revealing a cross-talk between the two marks. Last, the function analysis of the threonine-4 phosphorylation highlighted its role in alternative 3′-end processing within pro-proliferative genes. Our findings unveil the true genomic location of this evolutionarily conserved phosphorylation mark and prompt a reassessment of functional assignments of the carboxyl-terminal domain.

RNA 聚合酶 II 依靠其最大亚基中的重复序列结构域（YSPTSPS）来协调转录。虽然羧基末端七联重复序列的丝氨酸-2/丝氨酸-5的磷酸化作用已被证实，但苏氨酸-4的作用仍是个谜。奇怪的是，尽管苏氨酸-4 在功能上与转录暂停、延长、终止和信使 RNA 处理有关，但只有在转录终止位点后才检测到苏氨酸-4 磷酸化。我们的研究发现，苏氨酸-4 磷酸化的检测受到转录开始时侧翼丝氨酸-5 磷酸化的阻碍，而丝氨酸-5 磷酸化可以被选择性地去除。随后的蛋白质组分析发现了许多通过苏氨酸-4 磷酸化被转录所招募的蛋白质，而这些蛋白质之前被归因于丝氨酸-2。苏氨酸-4 磷酸化的缺失大大降低了丝氨酸-2 磷酸化，揭示了这两种标记之间的交叉作用。最后，苏氨酸-4 磷酸化的功能分析强调了它在促增殖基因的替代 3'- 末端处理中的作用。我们的发现揭示了这一进化保守的磷酸化标记的真正基因组位置，并促使我们重新评估羧基末端结构域的功能分配。

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引用次数: 0

Water deficit and storm disturbances co-regulate Amazon rainforest seasonality 缺水和风暴干扰共同调节亚马逊雨林的季节性。

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2024-09-06 DOI: 10.1126/sciadv.adk5861

Xu Lian, Catherine Morfopoulos, Pierre Gentine

Canopy leaf abundance of Amazon rainforests increases in the dry season but decreases in the wet season, contrary to earlier expectations of water stress adversely affecting plant functions. Drivers of this seasonality, particularly the role of water availability, remain debated. We introduce satellite-based ecophysiological indicators to demonstrate that Amazon rainforests are constrained by water during dry seasons despite light-driven canopy greening. Evidence includes a shifted partitioning of photosynthetically active radiation toward more isoprene emissions and synchronized declines in leaf and xylem water potentials. In addition, we find that convective storms attenuate light-driven ecosystem greening in the late dry season and then reverse to net leaf loss in the wet season, improving rainforest leaf area predictability by 24 to 31%. These findings highlight the susceptibility of Amazon rainforests to increasing risks of drought and windthrow disturbances under warming.

亚马逊雨林的树冠叶片丰度在旱季会增加，但在雨季会减少，这与早先关于水压力会对植物功能产生不利影响的预期相反。这种季节性的驱动因素，尤其是水供应的作用，仍然存在争议。我们引入了基于卫星的生态生理学指标，以证明亚马逊雨林在旱季受到水的限制，尽管光照驱动了树冠绿化。证据包括：光合有效辐射的分配发生了变化，转向更多的异戊二烯排放，以及叶片和木质部水势的同步下降。此外，我们还发现，对流风暴在旱季后期会减弱光驱动的生态系统绿化，然后在雨季逆转为净叶片损失，从而将雨林叶面积的可预测性提高了 24% 到 31%。这些发现突出表明，在气候变暖的情况下，亚马逊雨林易受干旱和风卷干扰的影响。

引用次数: 0

Excitable Rho dynamics control cell shape and motility by sequentially activating ERM proteins and actomyosin contractility 可兴奋的 Rho 动力通过依次激活 ERM 蛋白和肌动蛋白收缩力来控制细胞的形状和运动。

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2024-09-06 DOI: 10.1126/sciadv.adn6858

Seph Marshall-Burghardt, Rodrigo A. Migueles-Ramírez, Qiyao Lin, Nada El Baba, Rayan Saada, Mustakim Umar, Kian Mavalwala, Arnold Hayer

Migration of endothelial and many other cells requires spatiotemporal regulation of protrusive and contractile cytoskeletal rearrangements that drive local cell shape changes. Unexpectedly, the small GTPase Rho, a crucial regulator of cell movement, has been reported to be active in both local cell protrusions and retractions, raising the question of how Rho activity can coordinate cell migration. Here, we show that Rho activity is absent in local protrusions and active during retractions. During retractions, Rho rapidly activated ezrin-radixin-moesin proteins (ERMs) to increase actin-membrane attachment, and, with a delay, nonmuscle myosin 2 (NM2). Rho activity was excitable, with NM2 acting as a slow negative feedback regulator. Strikingly, inhibition of SLK/LOK kinases, through which Rho activates ERMs, caused elongated cell morphologies, impaired Rho-induced cell contractions, and reverted Rho-induced blebbing. Together, our study demonstrates that Rho activity drives retractions by sequentially enhancing ERM-mediated actin-membrane attachment for force transmission and NM2-dependent contractility.

内皮细胞和许多其他细胞的迁移需要时空调控推动局部细胞形状变化的突起和收缩细胞骨架重排。意外的是，小 GTP 酶 Rho 是细胞运动的关键调控因子，据报道它在局部细胞突起和回缩中都有活性，这就提出了 Rho 活性如何协调细胞迁移的问题。在这里，我们发现 Rho 活性在局部突起中缺失，而在回缩过程中活跃。在回缩过程中，Rho迅速激活ezrin-radixin-moesin蛋白（ERMs）以增加肌动蛋白膜附着，并延迟激活非肌肉肌球蛋白2（NM2）。Rho 活性是可兴奋的，而 NM2 则是一个缓慢的负反馈调节器。令人震惊的是，抑制 SLK/LOK 激酶（Rho 通过该激酶激活 ERMs）会导致细胞形态拉长、Rho 诱导的细胞收缩受阻，并逆转 Rho- 诱导的出血。总之，我们的研究表明，Rho活性通过连续增强ERM介导的肌动蛋白膜附着力传递和NM2依赖性收缩力来驱动回缩。

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引用次数: 0

Ion transport and ultra-efficient osmotic power generation in boron nitride nanotube porins 氮化硼纳米管孔隙中的离子传输和超高效渗透发电。

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2024-09-06 DOI: 10.1126/sciadv.ado8081

Zhongwu Li, Alex T. Hall, Yaqing Wang, Yuhao Li, Dana O. Byrne, Lyndsey R. Scammell, R. Roy Whitney, Frances I. Allen, John Cumings, Aleksandr Noy

Nanotube porins form transmembrane nanomaterial-derived scaffolds that mimic the geometry and functionality of biological membrane channels. We report synthesis, transport properties, and osmotic energy harvesting performance of another member of the nanotube porin family: boron nitride nanotube porins (BNNTPs). Cryo–transmission electron microscopy imaging, liposome transport assays, and DNA translocation experiments show that BNNTPs reconstitute into lipid membranes to form functional channels of ~2-nm diameter. Ion transport studies reveal ion conductance characteristics of individual BNNTPs, which show an unusual C^1/4 scaling with ion concentration and pronounced pH sensitivity. Reversal potential measurements indicate that BNNTPs have strong cation selectivity at neutral pH, attributable to the high negative charge on the channel. BNNTPs also deliver very large power density up to 12 kW/m² in the osmotic gradient transport experiments at neutral pH, surpassing that of other BNNT-based devices by two orders of magnitude under similar conditions. Our results suggest that BNNTPs are a promising platform for mass transport and osmotic power generation.

纳米管孔蛋白形成了跨膜纳米材料支架，可模仿生物膜通道的几何形状和功能。我们报告了纳米管孔蛋白家族另一成员：氮化硼纳米管孔蛋白（BNNTPs）的合成、传输特性和渗透能量收集性能。低温透射电子显微镜成像、脂质体运输测定和 DNA 转位实验表明，BNNTPs 能重组到脂质膜中，形成直径约为 2 纳米的功能通道。离子传输研究揭示了单个 BNNTPs 的离子传导特性，这些特性显示出不同寻常的 C1/4 离子浓度比例和明显的 pH 敏感性。反转电位测量结果表明，BNNTPs 在中性 pH 值下具有很强的阳离子选择性，这归因于通道上的高负电荷。在中性 pH 值的渗透梯度传输实验中，BNNTP 还能提供高达 12 kW/m2 的超大功率密度，比其他基于 BNNT 的器件在类似条件下的功率密度高出两个数量级。我们的研究结果表明，BNNTPs 是一种很有前途的质量传输和渗透发电平台。

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引用次数: 0

Oscillatory-Quality of sleep spindles links brain state with sleep regulation and function 睡眠棘波的振荡-质量将大脑状态与睡眠调节和功能联系起来。

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2024-09-06 DOI: 10.1126/sciadv.adn6247

Cristina Blanco-Duque, Suraya A. Bond, Lukas B. Krone, Jean-Phillipe Dufour, Edward C. P. Gillen, Ross J. Purple, Martin C. Kahn, David M. Bannerman, Edward O. Mann, Peter Achermann, Eckehard Olbrich, Vladyslav V. Vyazovskiy

Here, we characterized the dynamics of sleep spindles, focusing on their damping, which we estimated using a metric called oscillatory-Quality (o-Quality), derived by fitting an autoregressive model to electrophysiological signals, recorded from the cortex in mice. The o-Quality of sleep spindles correlates weakly with their amplitude, shows marked laminar differences and regional topography across cortical regions, reflects the level of synchrony within and between cortical networks, is strongly modulated by sleep-wake history, reflects the degree of sensory disconnection, and correlates with the strength of coupling between spindles and slow waves. As most spindle events are highly localized and not detectable with conventional low-density recording approaches, o-Quality thus emerges as a valuable metric that allows us to infer the spread and dynamics of spindle activity across the brain and directly links their spatiotemporal dynamics with local and global regulation of brain states, sleep regulation, and function.

在这里，我们描述了睡眠棘波的动力学特征，重点是其阻尼，我们使用一种称为振荡质量（o-Quality）的指标来估算睡眠棘波的阻尼，该指标是通过对小鼠大脑皮层记录的电生理信号拟合自回归模型得出的。睡眠纺锤体的 o-质量与其振幅的相关性很弱，在不同皮层区域表现出明显的层状差异和区域拓扑，反映了皮层网络内部和之间的同步水平，受到睡眠-觉醒历史的强烈调节，反映了感觉断开的程度，并与纺锤体和慢波之间的耦合强度相关。由于大多数纺锤体事件都是高度局部化的，无法用传统的低密度记录方法检测到，因此o-Quality 成为了一种有价值的指标，它能让我们推断纺锤体活动在大脑中的扩散和动态，并将其时空动态与大脑状态的局部和全局调节、睡眠调节和功能直接联系起来。

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引用次数: 0

Crucial role of interfacial thermal dissipation in the operational stability of organic field-effect transistors 界面热耗散在有机场效应晶体管运行稳定性中的关键作用。

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2024-09-06 DOI: 10.1126/sciadv.adn5964

Kai Tie, Jiannan Qi, Yongxu Hu, Yao Fu, Shougang Sun, Yanpeng Wang, Yinan Huang, Zhongwu Wang, Liqian Yuan, Liqiang Li, Dacheng Wei, Xiaosong Chen, Wenping Hu

The operational stability becomes a key issue affecting the commercialization for organic field-effect transistors (OFETs). It is widely recognized to be closely related to the defects and traps at the interface between dielectric and organic semiconductors, but this understanding does not always effectively address operational instability, implying that the factors influencing the operational stability have not been fully understood. Here, we reveal that the self-heating effect is another crucial factor in operational stability. By using hexagonal boron nitride (hBN) to assist interfacial thermal dissipation, the dinaphtho[2,3-b:2′,3′-f]thieno[3,2-b]thiophene (DNTT) FETs exhibit high mobility of 14.18 cm² V⁻¹ s⁻¹ and saturated power density up to 1.8 × 10⁴ W cm⁻². The OFET can operate at a power density of 1.06 × 10⁴ W cm⁻² for 30,000 s with negligible performance degradation, showing excellent operational stability under high power density. This work deepens the understanding on operational stability and develops an effective way for ultrahigh stable devices.

工作稳定性是影响有机场效应晶体管（OFET）商业化的一个关键问题。人们普遍认为这与介电质和有机半导体界面上的缺陷和陷阱密切相关，但这种认识并不总能有效地解决工作不稳定性问题，这意味着影响工作稳定性的因素尚未被完全理解。在这里，我们揭示了自热效应是影响运行稳定性的另一个关键因素。通过使用六方氮化硼（hBN）来帮助界面散热，二萘并[2,3-b:2',3'-f]噻吩并[3,2-b]噻吩（DNTT）场效应晶体管表现出 14.18 cm2 V-1 s-1 的高迁移率和高达 1.8 × 104 W cm-2 的饱和功率密度。该场效应晶体管可在 1.06 × 104 W cm-2 的功率密度下工作 30,000 秒，性能下降几乎可以忽略不计，显示出在高功率密度下出色的工作稳定性。这项工作加深了人们对工作稳定性的理解，并为超高稳定器件开发了一条有效途径。

{"title":"Crucial role of interfacial thermal dissipation in the operational stability of organic field-effect transistors","authors":"Kai Tie, Jiannan Qi, Yongxu Hu, Yao Fu, Shougang Sun, Yanpeng Wang, Yinan Huang, Zhongwu Wang, Liqian Yuan, Liqiang Li, Dacheng Wei, Xiaosong Chen, Wenping Hu","doi":"10.1126/sciadv.adn5964","DOIUrl":"10.1126/sciadv.adn5964","url":null,"abstract":"<div >The operational stability becomes a key issue affecting the commercialization for organic field-effect transistors (OFETs). It is widely recognized to be closely related to the defects and traps at the interface between dielectric and organic semiconductors, but this understanding does not always effectively address operational instability, implying that the factors influencing the operational stability have not been fully understood. Here, we reveal that the self-heating effect is another crucial factor in operational stability. By using hexagonal boron nitride (hBN) to assist interfacial thermal dissipation, the dinaphtho[2,3-b:2′,3′-f]thieno[3,2-b]thiophene (DNTT) FETs exhibit high mobility of 14.18 cm<sup>2</sup> V<sup>−1</sup> s<sup>−1</sup> and saturated power density up to 1.8 × 10<sup>4</sup> W cm<sup>−2</sup>. The OFET can operate at a power density of 1.06 × 10<sup>4</sup> W cm<sup>−2</sup> for 30,000 s with negligible performance degradation, showing excellent operational stability under high power density. This work deepens the understanding on operational stability and develops an effective way for ultrahigh stable devices.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adn5964","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sub–180-nanometer-thick ultraconformable high-performance carbon nanotube–based dual-gate transistors and differential amplifiers 厚度低于 180 纳米的超可变高性能碳纳米管双栅晶体管和差分放大器。

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2024-09-06 DOI: 10.1126/sciadv.adq6022

Yuru Wang, Tingzhi Wang, Li Xiang, Ruyi Huang, Guanhua Long, Wanyi Wang, Meiqi Xi, Jiamin Tian, Wangchang Li, Xiaosong Deng, Qibei Gong, Tianshun Bai, Yufan Chen, Hong Liu, Yu Xia, Xuelei Liang, Qing Chen, Lian-Mao Peng, Youfan Hu

There is increased interest in ultrathin flexible devices with thicknesses of <1 micrometers due to excellent conformability toward advanced laminated bioelectronics. However, because of limitations in materials, device structure, and fabrication methodology, the performance of these ultrathin devices and circuits is insufficient to support higher-level applications. Here, we report high-performance carbon nanotube–based thin-film transistors (TFTs) and differential amplifiers on ultrathin polyimide films with a total thickness of <180 nanometers. A dual-gate structure is introduced to guarantee excellent gate control efficiency and mechanical stability of the ultrathin TFTs, which exhibit high transconductance (8.96 microsiemens per micrometer), high mobility (127 square centimeters per volt per second), and steep subthreshold swing (84 millivolts per decade), and can sustain a bending radius of curvature of <10 micrometers. The differential amplifier achieves the highest gain-bandwidth product (1.83 megahertz) among flexible differential amplifiers, enabling higher-gain amplification of weak signals over an extended frequency spectrum that is demonstrated by amplification of electromyography signals in situ.

人们对超薄柔性设备的兴趣日益浓厚。

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引用次数: 0

Ultralow voltage–driven efficient and stable perovskite light-emitting diodes 超低电压驱动高效稳定的过氧化物发光二极管。

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2024-09-06 DOI: 10.1126/sciadv.adp8473

Song Zheng, Zhibin Wang, Naizhong Jiang, Hailiang Huang, Ximing Wu, Dan Li, Qian Teng, Jinyang Li, Chenhao Li, Jinsui Li, Tao Pang, Lingwei Zeng, Ruidan Zhang, Feng Huang, Lei Lei, Tianmin Wu, Fanglong Yuan, Daqin Chen

The poor operational stability of perovskite light-emitting diodes (PeLEDs) remains a major obstacle to their commercial application. Achieving high brightness and quantum efficiency at low driving voltages, thus effectively reducing heat accumulation, is key to enhancing the operational lifetime of PeLEDs. Here, we present a breakthrough, attaining a record-low driving voltage while maintaining high brightness and efficiency. By thoroughly suppressing interface recombination and ensuring excellent charge transport, our PeLEDs, with an emission peak at 515 nanometers, achieve a maximum brightness of 90,295 candelas per square meter and a peak external quantum efficiency of 27.8% with an ultralow turn-on voltage of 1.7 volts (~70% bandgap voltage). Notably, Joule heat is nearly negligible at these low driving voltages, substantially extending the operational lifetime to 7691.1 hours. Our optimized strategies effectively tackle stability issue through thermal management, paving the way for highly stable PeLEDs.

过氧化物发光二极管（PeLED）的工作稳定性较差，这仍然是其商业应用的主要障碍。在低驱动电压下实现高亮度和量子效率，从而有效减少热量积累，是提高 PeLED 工作寿命的关键。在此，我们取得了突破性进展，在保持高亮度和高效率的同时，实现了创纪录的低驱动电压。通过彻底抑制界面重组并确保出色的电荷传输，我们的珀尔LED 的发射峰值为 515 纳米，在 1.7 伏特的超低开启电压（约 70% 带隙电压）下，最大亮度可达每平方米 90,295 烛光，外部量子效率峰值为 27.8%。值得注意的是，在这些低驱动电压下，焦耳热几乎可以忽略不计，从而将工作寿命大幅延长至 7691.1 小时。我们的优化策略通过热管理有效地解决了稳定性问题，为实现高度稳定的 PeLED 铺平了道路。

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引用次数: 0

Label-free, real-time monitoring of cytochrome C drug responses in microdissected tumor biopsies with a multi-well aptasensor platform 利用多孔式传感器平台对微观解剖肿瘤活检组织中的细胞色素 C 药物反应进行无标记实时监测。

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2024-09-06 DOI: 10.1126/sciadv.adn5875

Tran N. H. Nguyen, Lisa F. Horowitz, Timothy Krilov, Ethan Lockhart, Heidi L. Kenerson, Taranjit S. Gujral, Raymond S. Yeung, Netzahualcóyotl Arroyo-Currás, Albert Folch

Functional assays on intact tumor biopsies can complement genomics-based approaches for precision oncology, drug testing, and organs-on-chips cancer disease models by capturing key therapeutic response determinants, such as tissue architecture, tumor heterogeneity, and the tumor microenvironment. Most of these assays rely on fluorescent labeling, a semiquantitative method best suited for single-time-point assays or labor-intensive immunostaining analysis. Here, we report integrated aptamer electrochemical sensors for on-chip, real-time monitoring of cytochrome C, a cell death indicator, from intact microdissected tissues with high affinity and specificity. The platform features a multi-well sensor layout and a multiplexed electronic setup. The aptasensors measure increases in cytochrome C in the supernatant of mouse or human microdissected tumors after exposure to various drug treatments. Because of the sensor’s high affinity, it primarily tracks rising concentrations of cytochrome C, capturing dynamic changes during apoptosis. This approach could help develop more advanced cancer disease models and apply to other complex in vitro disease models, such as organs-on-chips and organoids.

对完整肿瘤活检组织进行功能测定，可以捕捉组织结构、肿瘤异质性和肿瘤微环境等关键治疗反应决定因素，从而补充基于基因组学的精准肿瘤学、药物测试和芯片上器官癌症疾病模型方法。这些检测方法大多依赖荧光标记，这种半定量方法最适合单时间点检测或劳动密集型免疫染色分析。在此，我们报告了用于芯片上实时监测细胞色素 C（一种细胞死亡指示剂）的集成适配体电化学传感器，该传感器来自完整的显微解剖组织，具有高亲和力和特异性。该平台采用多孔传感器布局和多路复用电子装置。该灵敏传感器可测量小鼠或人类显微解剖肿瘤暴露于各种药物治疗后上清液中细胞色素 C 的增加量。由于传感器的高亲和力，它主要跟踪细胞色素C浓度的上升，捕捉细胞凋亡过程中的动态变化。这种方法有助于开发更先进的癌症疾病模型，并适用于其他复杂的体外疾病模型，如片上器官和有机体。

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引用次数: 0

Lung-innervating nociceptor sensory neurons promote pneumonic sepsis during carbapenem-resistant Klebsiella pneumoniae lung infection 在耐碳青霉烯类肺炎克雷伯氏菌肺部感染过程中，肺部神经感受器感觉神经元促进了肺炎性败血症的发生。

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2024-09-06 DOI: 10.1126/sciadv.adl6162

Prabhu Raj Joshi, Sandeep Adhikari, Chinemerem Onah, Camille Carrier, Abigail Judd, Matthias Mack, Pankaj Baral

Carbapenem-resistant Klebsiella pneumoniae (CRKP) causes Gram-negative lung infections and fatal pneumonic sepsis for which limited therapeutic options are available. The lungs are densely innervated by nociceptor sensory neurons that mediate breathing, cough, and bronchoconstriction. The role of nociceptors in defense against Gram-negative lung pathogens is unknown. Here, we found that lung-innervating nociceptors promote CRKP pneumonia and pneumonic sepsis. Ablation of nociceptors in mice increased lung CRKP clearance, suppressed trans-alveolar dissemination of CRKP, and protected mice from hypothermia and death. Furthermore, ablation of nociceptors enhanced the recruitment of neutrophils and Ly6C^hi monocytes and cytokine induction. Depletion of Ly6C^hi monocytes, but not of neutrophils, abrogated lung and extrapulmonary CRKP clearance in ablated mice, suggesting that Ly6C^hi monocytes are a critical cellular population to regulate pneumonic sepsis. Further, neuropeptide calcitonin gene–related peptide suppressed the induction of reactive oxygen species in Ly6C^hi monocytes and their CRKP-killing abilities. Targeting nociceptor signaling could be a therapeutic approach for treating multidrug-resistant Gram-negative infection and pneumonic sepsis.

耐碳青霉烯类肺炎克雷伯氏菌（CRKP）可导致革兰氏阴性肺部感染和致命的肺炎败血症，但目前的治疗方法有限。肺部有密集的痛觉神经元，它们介导呼吸、咳嗽和支气管收缩。痛觉神经元在防御革兰氏阴性肺部病原体中的作用尚不清楚。在这里，我们发现肺神经感受器能促进 CRKP 肺炎和肺炎败血症。消融小鼠的神经感受器可增加肺部CRKP的清除率，抑制CRKP的跨肺泡扩散，并保护小鼠免于低体温和死亡。此外，痛觉感受器的消融增强了中性粒细胞和 Ly6Chi 单核细胞的募集以及细胞因子的诱导。Ly6Chi单核细胞（而非嗜中性粒细胞）的耗竭会降低消融小鼠肺部和肺外CRKP的清除率，这表明Ly6Chi单核细胞是调节肺炎败血症的关键细胞群。此外，神经肽降钙素基因相关肽抑制了 Ly6Chi 单核细胞中活性氧的诱导及其杀伤 CRKP 的能力。以神经肽信号为靶点可能是治疗耐多药革兰氏阴性菌感染和肺炎败血症的一种治疗方法。

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引用次数: 0