【Science】2024年3月9日-2024年4月29日刊论文导读

期刊介绍：

《Science》（科学杂志）是一份由美国科学促进会（American Association for the Advancement of Science，简称AAAS）出版的著名科学杂志。该杂志创建于1880年，是全球最具影响力和知名度的跨学科科学期刊之一。该杂志以发表高质量、原创性的科学研究论文和评论而闻名，涵盖了各个科学领域，包括生命科学、物理学、化学、地球与环境科学、工程技术等。它是科学领域内同行评议制度的支持者，通过评审和编辑确保所发表的研究具有学术水平和可靠性。除了研究论文外，该杂志还经常刊发关于科学前沿、科学政策、科学教育和科学社会问题的评论文章。《Science》还定期发布一些专题特刊，深入探讨特定主题或领域的最新进展。因其在科学界的声望和影响力，《Science》成为科学家们追求学术卓越和科学创新的重要平台之一。最新影响因子为56.9。

VOLUME 383|ISSUE 6688|15 MAR 2024

在2024年03月15日，《Science》共发表文章34篇：7篇NEWS,11篇INSIGHTS,其中1篇EXPERT VOICES，4篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK，3篇LETTERS,15篇RESEARCH,其中1篇REVIEWS，14篇RESEARCH ARTICLES,1篇EDITORIAL

1.Cryptic diversity of cellulose-degrading gut bacteria in industrialized humans

工业化人类纤维素降解肠道细菌的隐秘多样性

以色列本·古里安大学内盖夫国家生物技术研究所和生命科学系

Abstract

Humans, like all mammals, depend on the gut microbiome for digestion of cellulose, the main component of plant fiber. However, evidence for cellulose fermentation in the human gut is scarce. We have identified ruminococcal species in the gut microbiota of human populations that assemble functional multienzymatic cellulosome structures capable of degrading plant cell wall polysaccharides. One of these species, which is strongly associated with humans, likely originated in the ruminant gut and was subsequently transferred to the human gut, potentially during domestication where it underwent diversification and diet-related adaptation through the acquisition of genes from other gut microbes. Collectively, these species are abundant and widespread among ancient humans, hunter-gatherers, and rural populations but are rare in populations from industrialized societies thus indicating potential disappearance in response to the westernized lifestyle.

摘要：

像所有哺乳动物一样，人类依靠肠道微生物群来消化植物纤维的主要成分——纤维素。然而，纤维素在人体肠道发酵的证据很少。我们在人类肠道微生物菌群中确定了瘤胃球菌物种，它们组装了能够降解植物细胞壁多糖的功能性多酶纤维素结构。其中与人类密切相关的一个物种可能起源于反刍动物肠道，随后转移到人类肠道，可能是由于在驯化过程中通过获取其他肠道微生物的基因，经历了多样化和饮食适应。总之，这些菌种在古人类、狩猎采集者和农村人群中数量丰富并且广泛分布，但在工业化社会人口中却很少见，表明这类菌种可能会因为西化的生活方式而消失。

2. Oral administration of obeldesivir protects nonhuman primates against Sudan ebolavirus

口服奥贝德西韦可保护非人类灵长类动物免受苏丹埃博拉病毒的侵害

美国得克萨斯大学加尔维斯顿国家实验室和微生物与免疫学学系

Abstract

Obeldesivir (ODV, GS-5245) is an orally administered prodrug of the parent nucleoside of remdesivir (RDV) and is presently in phase 3 trials for COVID-19 treatment. In this work, we show that ODV and its circulating parent nucleoside metabolite, GS-441524, have similar in vitro antiviral activity against filoviruses, including Marburg virus, Ebola virus, and Sudan virus (SUDV). We also report that once-daily oral ODV treatment of cynomolgus monkeys for 10 days beginning 24 hours after SUDV exposure confers 100% protection against lethal infection. Transcriptomics data show that ODV treatment delayed the onset of inflammation and correlated with antigen presentation and lymphocyte activation. Our results offer promise for the further development of ODV to control outbreaks of filovirus disease more rapidly.

摘要

奥贝德西韦(Obeldesivir, ODV, GS-5245)是瑞德西韦(remdesivir, RDV)母体核苷的口服前体药，目前正在进行COVID-19治疗的3期试验。在这项工作中，研究人员发现ODV及其循环母体核苷代谢物GS-441524对丝状病毒具有相似的体外抗病毒活性，包括马尔堡病毒、埃博拉病毒和苏丹埃博拉病毒(Sudan virus，SUDV)。研究人员还报道，在SUDV暴露后24小时内食蟹猴每天一次口服ODV治疗10天，可100%预防致命感染。转录组学数据显示，ODV治疗延迟了炎症发展，并与抗原呈递和淋巴细胞活化相关。研究人员的结果为进一步发展ODV以更快地控制丝状病毒病的爆发提供了希望。

3. Structural basis of U12-type intron engagement by the fully assembled human minor spliceosome

完全组装的人类次要剪接体与U12型内含子结合的结构基础

中国西湖大学生命科学学院浙江结构生物学重点实验室未来产业研究中心和生命科学与生物医学实验室

Abstract

The minor spliceosome, which is responsible for the splicing of U12-type introns, comprises five small nuclear RNAs (snRNAs), of which only one is shared with the major spliceosome. In this work, we report the 3.3-angstrom cryo–electron microscopy structure of the fully assembled human minor spliceosome pre-B complex. The atomic model includes U11 small nuclear ribonucleoprotein (snRNP), U12 snRNP, and U4atac/U6atac.U5 tri-snRNP. U11 snRNA is recognized by five U11-specific proteins (20K, 25K, 35K, 48K, and 59K) and the heptameric Sm ring. The 3′ half of the 5′-splice site forms a duplex with U11 snRNA; the 5′ half is recognized by U11-35K, U11-48K, and U11 snRNA. Two proteins, CENATAC and DIM2/TXNL4B, specifically associate with the minor tri-snRNP. A structural analysis uncovered how two conformationally similar tri-snRNPs are differentiated by the minor and major prespliceosomes for assembly.

摘要

负责U12型内含子剪接的次要剪接体由5个小核RNA (snRNAs)组成，其中只有一个与主要剪接体共享。在这项工作中，研究人员报道了完全组装的人类次要剪接体pre-B复合体的3.3埃米冷冻电镜结构。原子模型包括U11小核核糖核蛋白(snRNP)、U12 snRNP和U4atac/U6atac.U5 tri-snRNP。U11 snRNA由5种U11特异性蛋白(20K、25K、35K、48K和59K)和七聚体Sm环识别。5'剪接位点的3 '半与U11 snRNA形成双链；5'半部分被U11- 35k、U11- 48k和U11 snRNA识别。两个蛋白，CENATAC和DIM2/TXNL4B，与次要tri-snRNP特异性结合。结构分析揭示了两种结构类似的tri-snRNPs是如何被主要和次要的剪接前体区分和组装的。

4. Generalized fear after acute stress is caused by change in neuronal cotransmitter identity

急性应激后的泛化恐惧由神经元共递质同一性的改变引起

美国加利福尼亚大学圣迭戈分校生物科学学院和神经回路与行为研究中心神经生物学部和卡维利大脑与心智研究所

Abstract

Overgeneralization of fear to harmless situations is a core feature of anxiety disorders resulting from acute stress, yet the mechanisms by which fear becomes generalized are poorly understood. In this study, we show that generalized fear in mice results from a transmitter switch from glutamate to γ-aminobutyric acid (GABA) in serotonergic neurons of the lateral wings of the dorsal raphe. Similar change in transmitter identity was found in the postmortem brains of individuals with posttraumatic stress disorder (PTSD). Overriding the transmitter switch in mice prevented the acquisition of generalized fear. Corticosterone release and activation of glucocorticoid receptors mediated the switch, and prompt antidepressant treatment blocked the cotransmitter switch and generalized fear. Our results provide important insight into the mechanisms involved in fear generalization.

摘要

对无害情境的过度泛化恐惧是急性应激引起焦虑障碍的核心特征，但人们对恐惧泛化的机制知之甚少。在这项研究中，研究人员发现小鼠的泛化恐惧是由背侧中缝侧翼的5-羟色胺能神经元中的兴奋性谷氨酸神经递质向抑制性GABA神经递质的转换引起的。在创伤后应激障碍(PTSD)患者死后的大脑中也发现了类似的递质转化。在小鼠中抑制这种神经递质转换可以防止泛化恐惧的产生。皮质醇的释放和糖皮质激素受体的激活介导了这种神经递质的转换，及时接受抗抑郁药物治疗能够阻止这种神经递质的转换和泛化恐惧。我们的研究结果为恐惧泛化的机制提供了重要的见解。

VOLUME 383|ISSUE 6689|22 MAR 2024

在2024年03月22日，《Science》共发表文章37篇：8篇NEWS，12篇INSIGHTS，其中1篇EXPERT VOICES，5篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK，3篇LETTERS，15篇RESEARCH，2篇EDITORIAL

1. Evolution-inspired engineering of nonribosomal peptide synthetases

受进化启发的非核糖体肽合成酶工程

德国马克斯-普朗克陆地微生物研究所和法兰克福大学分子生物科学系

Abstract

Many clinically used drugs are derived from or inspired by bacterial natural products that often are produced through nonribosomal peptide synthetases (NRPSs), megasynthetases that activate and join individual amino acids in an assembly line fashion. In this work, we describe a detailed phylogenetic analysis of several bacterial NRPSs that led to the identification of yet undescribed recombination sites within the thiolation (T) domain that can be used for NRPS engineering. We then developed an evolution-inspired “eXchange Unit between T domains” (XUT) approach, which allows the assembly of NRPS fragments over a broad range of GC contents, protein similarities, and extender unit specificities, as demonstrated for the specific production of a proteasome inhibitor designed and assembled from five different NRPS fragments.

摘要

许多临床使用的药物来源于或受到细菌天然产物的启发，这些天然产物通常通过非核糖体肽合成酶(NRPSs)产生，大合成酶以流水线方式激活并连接单个氨基酸。在这项工作中，研究人员描述了几种细菌NRPS的详细系统发育分析，进而识别出硫基化(T)结构域内尚未描述的重组位点，这些位点可用于NRPS工程。然后，研究人员开发了一种受进化启发的“T结构域之间的交换单元”(XUT)方法，该方法允许在广泛的GC含量、蛋白质相似性和扩展单元特异性范围内组装NRPS片段，正如由五种不同的NRPS片段设计并组装的蛋白酶体抑制剂的特异性生产中所证明的那样。

2. Adaptive introgression of a visual preference gene

视觉偏好基因的适应性渗入

德国慕尼黑大学生物学系和史密森热带森林研究中心

Abstract

Visual preferences are important drivers of mate choice and sexual selection, but little is known of how they evolve at the genetic level. In this study, we took advantage of the diversity of bright warning patterns displayed by Heliconius butterflies, which are also used during mate choice. Combining behavioral, population genomic, and expression analyses, we show that two Heliconius species have evolved the same preferences for red patterns by exchanging genetic material through hybridization. Neural expression of regucalcin1 correlates with visual preference across populations, and disruption of regucalcin1 with CRISPR-Cas9 impairs courtship toward conspecific females, providing a direct link between gene and behavior. Our results support a role for hybridization during behavioral evolution and show how visually guided behaviors contributing to adaptation and speciation are encoded within the genome.

摘要

视觉偏好是择偶和性选择的重要驱动因素，但关于其如何在基因水平上进化知之甚少。在这项研究中，研究人员利用了袖蝶属蝴蝶所展示的亮色警告图案的多样性，这些图案也被用于择偶过程。结合行为、群体基因组和表达分析，研究人员发现两个袖蝶属物种通过杂交交换遗传物质，进化出了对红色图案的相同偏好。regucalcin1的神经表达与种群中的视觉偏好相关，而利用CRISPR-Cas9破坏regucalcin1会损害袖蝶属蝴蝶对同种雌性的求偶，从而证明了基因与行为之间的直接联系。我们的研究结果支持了杂交在行为进化中的作用，并揭示了视觉引导下的行为如何在基因组中编码，从而促进了适应和物种形成。

VOLUME 383|ISSUE 6690|29 MAR 2024

在2024年03月29日，《Science》共发表文章37篇：9篇NEWS，12篇INSIGHTS，其中1篇EXPERT VOICES，5篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK，3篇LETTERS，14篇RESEARCH，1篇EDITORIAL

1. Vocal learning–associated convergent evolution in mammalian proteins and regulatory elements

哺乳动物蛋白质和调节元件中与发声学习相关的趋同进化

美国卡耐基梅隆大学计算生物系和神经科学研究所、加州大学伯克利分校Helen Wills 神经科学研究所

Abstract

Vocal production learning (“vocal learning”) is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (Rousettus aegyptiacus) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.

摘要

发声学习(“声学习”)是脊椎动物的一种趋同进化特征。为了确定与哺乳动物发声学习相关的大脑基因组元件，研究人员整合了埃及果蝠(Rousettus aegyptiacus)的基因组、解剖学和神经生理学数据及215种胎生哺乳动物的基因组数据。首先，研究人员确定了一组在发声学习者中进化缓慢的蛋白质。然后，研究人员发现了埃及果蝠(一种新兴的声音学习者)的一个声音运动皮层区域，在此发现基础上识别声音学习者运动皮层中的活性顺式调节元件。应用于运动皮质开放染色质的机器学习方法揭示了50个与声乐学习密切相关但活性较低的增强子。研究人员的研究揭示了在哺乳动物声乐学习进化中运动皮质调节元件的趋同损失。

2. BCG vaccination reduces bovine tuberculosis transmission, improving prospects for elimination

卡介苗接种减少牛结核病的传播，改善了消除结核病的前景

埃塞俄比亚亚的斯亚贝巴大学Aklilu Lemma病理学研究所、英国剑桥大学动物医学系和美国宾夕法尼亚州立大学Huck生命科学研究所

Abstract

Bacillus Calmette-Guérin (BCG) is a routinely used vaccine for protecting children against Mycobacterium tuberculosis that comprises attenuated Mycobacterium bovis. BCG can also be used to protect livestock against M. bovis; however, its effectiveness has not been quantified for this use. We performed a natural transmission experiment to directly estimate the rate of transmission to and from vaccinated and unvaccinated calves over a 1-year exposure period. The results show a higher indirect efficacy of BCG to reduce transmission from vaccinated animals that subsequently become infected [74%; 95% credible interval (CrI): 46 to 98%] compared with direct protection against infection (58%; 95% CrI: 34 to 73%) and an estimated total efficacy of 89% (95% CrI: 74 to 96%). A mechanistic transmission model of bovine tuberculosis (bTB) spread within the Ethiopian dairy sector was developed and showed how the prospects for elimination may be enabled by routine BCG vaccination of cattle.

摘要

卡介苗(BCG)是一种用于保护儿童免受结核分枝杆菌包括减毒牛分枝杆菌感染的常用疫苗。卡介苗还可用于保护牲畜免受牛分枝杆菌感染。然而，这种治疗的有效性还没有得到量化。研究人员进行了一项自然传播实验以直接估计1年暴露期内接种疫苗和未接种疫苗小牛之间的传播率。结果显示，相比于直接预防感染 (58%，95% CI：34 ~ 73%)，卡介苗对减少已接种但随后感染的动物的传播间接效力较高[74%，95%CI：46 - 98%]，总有效率估计为89% (95% CI：74 ~ 96%)。我们开发了一个牛结核病(bTB)在埃塞俄比亚乳业部门传播的机械传播模型，这个模型展示了通过给牛常规接种卡介苗，如何实现消除牛结核病的前景。

3. Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model

小鼠模型中具有抗病毒效力的SARS-CoV-2木瓜蛋白酶样蛋白酶抑制剂的设计

美国罗格斯大学Ernest Mario药学院药物化学系和化学与化学生物系、俄克拉何马州立大学动物医学院生理科学系

Abstract

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PLpro) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PLpro inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PLpro with the inhibitory constant Ki values from 13.2 to 88.2 nanomolar. The co-crystal structures of PLpro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC50 from 0.44 to 2.02 micromolar. Oral treatment with Jun12682 improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting that PLpro inhibitors are promising oral SARS-CoV-2 antiviral candidates.

摘要

严重急性呼吸综合征冠状病毒（SARS-CoV-2）变体和耐药突变体的出现需要更多的口服抗病毒药物。SARS-CoV-2木瓜蛋白酶样蛋白酶(PLpro)是一个有前景但同时有挑战性的药物靶点。我们设计并合成了85种结合至新发现的泛素结合位点和已知的S4亚基位点附近的BL2凹槽袋的非共价PLpro抑制剂。先导PLpro的抑制常数Ki值在13.2 ~ 88.2nmol。PLpro和8个先导抑制剂的共晶结构揭示了它们的相互作用模式。体内首选药物Jun12682抑制SARS-CoV-2及其变体，包括耐尼马特瑞韦菌株（EC50 0.44~2.02 mmol）。口服Jun12682可改善SARS-CoV-2感染小鼠的生存率并减少肺部病毒载量和病变范围，表明PLpro抑制剂是具有前景的口服SARS-CoV-2抗病毒候选药物。

4.Mechanism for feature learning in neural networks and backpropagation-free machine learning models

神经网络中的特征学习机制与无反向传播的机器学习模型

美国哈佛大学工程与应用科学学院、Broad研究所和加州大学圣地亚哥分校计算机科学与工程学院

Abstract

Understanding how neural networks learn features, or relevant patterns in data, for prediction is necessary for their reliable use in technological and scientific applications. In this work, we presented a unifying mathematical mechanism, known as average gradient outer product (AGOP), that characterized feature learning in neural networks. We provided empirical evidence that AGOP captured features learned by various neural network architectures, including transformer-based language models, convolutional networks, multilayer perceptrons, and recurrent neural networks. Moreover, we demonstrated that AGOP, which is backpropagation-free, enabled feature learning in machine learning models, such as kernel machines, that a priori could not identify task-specific features. Overall, we established a fundamental mechanism that captured feature learning in neural networks and enabled feature learning in general machine learning models.

摘要

了解神经网络如何学习数据特征或相关模式以进行预测，这对于其在技术和科学应用中的可靠使用至关重要。在这项工作中，我们提出了一种统一的数学机制，称为平均梯度外积(AGOP)，用于表征神经网络中的特征学习。我们提供了证明AGOP捕获各种神经网络架构学习特征的经验证据，包括基于变压器的语言模型、卷积网络、多层感知器和循环神经网络。此外，我们证明了无反向传播的AGOP能够在无法先验识别任务特定特征的机器学习模型(如内核机器)中实现特征学习。总之，研究人员建立了一个可在神经网络中捕获特征学习并在一般机器学习模型中实现特征学习的基本机制。

5. Oxygen imaging of hypoxic pockets in the mouse cerebral cortex

小鼠大脑皮层缺氧袋的氧成像

丹麦哥本哈根大学健康与医学科学学院转化神经医学中心

Abstract

Consciousness is lost within seconds upon cessation of cerebral blood flow. The brain cannot store oxygen, and interruption of oxidative phosphorylation is fatal within minutes. Yet only rudimentary knowledge exists regarding cortical partial oxygen tension (Po2) dynamics under physiological conditions. Here we introduce Green enhanced Nano-lantern (GeNL), a genetically encoded bioluminescent oxygen indicator for Po2 imaging. In awake behaving mice, we uncover the existence of spontaneous, spatially defined "hypoxic pockets" and demonstrate their linkage to the abrogation of local capillary flow. Exercise reduced the burden of hypoxic pockets by 52% compared with rest. The study provides insight into cortical oxygen dynamics in awake behaving animals and concurrently establishes a tool to delineate the importance of oxygen tension in physiological processes and neurological diseases.

摘要

意识在脑血流中断后几秒内消失。大脑不能储存氧气，中断氧化磷酸化反应数分钟对大脑是致命的打击。然而，关于生理条件下皮质部分氧压(Po2)动力学的知识还在初步阶段。在这里，我们提出了绿色增强纳米灯(Green enhanced Nano-lantern，GeNL)，一种用于PO2成像的基因编码的生物发光氧指示器。研究人员在清醒行为的小鼠中发现了天然存在且空间上定义的“缺氧口袋”，并证明了它们与局部毛细血管流动的消失有关。与休息行为相比，运动使“缺氧口袋”的负担减轻了52%。该研究深入了解了清醒行为动物的皮质氧动力学，同时也建立了一种工具用来说明氧压在生理过程和神经系统疾病中的重要性。

6. Selection of experience for memory by hippocampal sharp wave ripples

海马尖波涟漪对记忆经验的选择

美国纽约大学格罗斯曼医学院神经科学研究所及神经内科和加拿大Mila人工智能研究院

Abstract

Experiences need to be tagged during learning for further consolidation. However, neurophysiological mechanisms that select experiences for lasting memory are not known. By combining large-scale neural recordings in mice with dimensionality reduction techniques, we observed that successive maze traversals were tracked by continuously drifting populations of neurons, providing neuronal signatures of both places visited and events encountered. When the brain state changed during reward consumption, sharp wave ripples (SPW-Rs) occurred on some trials, and their specific spike content decoded the trial blocks that surrounded them. During postexperience sleep, SPW-Rs continued to replay those trial blocks that were reactivated most frequently during waking SPW-Rs. Replay content of awake SPW-Rs may thus provide a neurophysiological tagging mechanism to select aspects of experience that are preserved and consolidated for future use.

摘要

为了进一步巩固记忆，在学习过程中需要标记经验。然而，选择经验以形成持久记忆的神经生理机制尚不清楚。通过将大规模小鼠神经记录与降维技术相结合，我们观察到连续的迷宫穿越被不断漂移的神经元群跟踪，提供了所访问的地方和遇到的事件的神经元特征。当大脑状态在奖励摄入过程中发生变化时，在一些试验中出现了尖波涟漪(SPW-Rs)，其特定的尖峰内容解码了围绕它们的试验块。在经验后睡眠期间，SPW-R继续重播那些在醒着的SPW-R期间最频繁被重新激活的试验块。因此，清醒时SPW-R的重放内容可能提供了一种神经生理标记机制，以选择那些被保存和巩固的经历方面以备将来使用。

VOLUME 384|ISSUE 6691|5 APR 2024

在2024年04月05日，《Science》共发表文章37篇：8篇NEWS，10篇INSIGHTS，其中1篇EXPERT VOICES，5篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK，1篇LETTERS，3篇ESSAYS，15篇RESEARCH，1篇EDITORIAL

1. Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages

凋亡细胞类型诱导巨噬细胞对IL-4的不同功能应答

德国汉堡-埃彭多夫大学医学中心医学部和Bernhard Nocht热带医学研究所

Abstract

Macrophages are functionally heterogeneous cells essential for apoptotic cell clearance. Apoptotic cells are defined by homogeneous characteristics, ignoring their original cell lineage identity. We found that in an interleukin-4 (IL-4)-enriched environment, the sensing of apoptotic neutrophils by macrophages triggered their tissue remodeling signature. Engulfment of apoptotic hepatocytes promoted a tolerogenic phenotype, whereas phagocytosis of T cells had little effect on IL-4-induced gene expression. In a mouse model of parasite-induced pathology, the transfer of macrophages conditioned with IL-4 and apoptotic neutrophils promoted parasitic egg clearance. Knockout of phagocytic receptors required for the uptake of apoptotic neutrophils and partially T cells, but not hepatocytes, exacerbated helminth infection. These findings suggest that the identity of apoptotic cells may contribute to the development of distinct IL-4-driven immune programs in macrophages.

摘要

巨噬细胞是对于清除凋亡细胞至关重要的功能异质性细胞。凋亡细胞是由同质特征定义的，忽略了其原始细胞谱系特征。我们发现，在白细胞介素-4（IL-4）富集环境中，巨噬细胞对凋亡中性粒细胞的感知激发了其组织重塑特征。凋亡肝细胞的吞噬促进了耐受表型，而T细胞的吞噬作用对IL-4诱导的基因表达几乎没有影响。在寄生虫诱导的病理小鼠模型中，IL-4和凋亡中性粒细胞调节的巨噬细胞转移促进了寄生虫卵的清除。敲除用于吞噬凋亡的中性粒细胞和部分T细胞（而非肝细胞）的吞噬细胞受体加剧了蠕虫感染。这些发现表明凋亡细胞类型可能有助于巨噬细胞中不同的由IL-4驱动的免疫程序的发展。

美国德州农工大学生物化学与生物物理系和噬菌体技术研究中心

Abstract

The retractile type IV pilus (T4P) is important for virulence of the opportunistic human pathogen Pseudomonas aeruginosa. The single-stranded RNA (ssRNA) phage PP7 binds to T4P and is brought to the cell surface through pilus retraction. Using fluorescence microscopy, we discovered that PP7 detaches T4P, which impairs cell motility and restricts the pathogen's virulence. Using cryo-electron microscopy, mutagenesis, optical trapping, and Langevin dynamics simulation, we resolved the structure of PP7, T4P, and the PP7/T4P complex and showed that T4P detachment is driven by the affinity between the phage maturation protein and its bound pilin, plus the pilus retraction force and speed, and pilus bending. Pilus detachment may be widespread among other ssRNA phages and their retractile pilus systems and offers new prospects for antibacterial prophylaxis and therapeutics.

摘要

可收缩的IV型菌毛(T4P)对机会性人类病原体铜绿假单胞菌的毒力至关重要。与T4P结合的单链RNA (ssRNA)噬菌体PP7通过菌毛回缩带至细胞表面。通过荧光显微镜，我们发现PP7与T4P分离，从而损害了细胞运动并限制病原体毒力。通过低温电子显微镜、诱变、光学捕获和郎之万动力学模拟，我们解析了PP7、T4P和PP7/T4P复合物的结构，发现T4P的分离是由噬菌体成熟蛋白与其结合的菌毛蛋白之间的亲和力、菌毛的收缩力和速度以及菌毛的弯曲驱动的。菌毛脱落在其他ssRNA噬菌体及其可收缩的菌毛脱落系统中广泛存在，为抗菌预防和治疗提供了新的前景。

3.Bronchoconstriction damages airway epithelia by crowding-induced excess cell extrusion

支气管收缩通过拥挤诱导的过度细胞挤压损害气道上皮

英国伦敦国王学院基础与医学生物科学学院Randall细胞与分子生物物理中心和西班牙巴伦西亚大学生物化学与分子生物系

Abstract

Asthma is deemed an inflammatory disease, yet the defining diagnostic feature is mechanical bronchoconstriction. We previously discovered a conserved process called cell extrusion that drives homeostatic epithelial cell death when cells become too crowded. In this work, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion in both mice and humans. Although relaxing the airways with the rescue treatment albuterol did not affect these responses, inhibiting live cell extrusion signaling during bronchoconstriction prevented all these features. Our findings show that bronchoconstriction causes epithelial damage and inflammation by excess crowding-induced cell extrusion and suggest that blocking epithelial extrusion, instead of the ensuing downstream inflammation, could prevent the feed-forward asthma inflammatory cycle.

摘要

哮喘被认为是一种炎症性疾病，然而其定义的诊断指征为机械性支气管收缩。我们既往发现了一种命名为细胞挤压作用的保守过程，当细胞过于拥挤时，它会驱动稳态上皮细胞的死亡。在这项工作中，研究人员表明，支气管收缩产生的病理性拥挤导致许多上皮细胞受到挤压，从而损害气道，进而导致小鼠和人类的炎症产生和粘液分泌。尽管使用缓解治疗药物沙丁胺醇舒张气道不会影响这类反应，但在支气管收缩过程中抑制细胞挤压信号可阻止上述所有特征。研究结果表明，支气管收缩通过过度挤压诱导了细胞挤压作用，导致了上皮损伤和炎症，并表明阻断上皮挤压作用而不是阻断下游炎症反应可以阻止前馈哮喘炎症循环。

4.Antibacterial activity of nonantibiotics is orthogonal to standard antibiotics

非抗生素的抑菌活性与标准抗生素呈正交关系

美国马萨诸塞大学医学院系统生物系

Abstract

Numerous nonantibiotic drugs have potent antibacterial activity and can adversely affect the human microbiome. The mechanistic underpinning of this toxicity remains largely unknown. We investigated the antibacterial activity of 200 drugs using genetic screens with thousands of barcoded Escherichia coli knockouts. We analyzed 2 million gene-drug interactions underlying drug-specific toxicity. Network-based analysis of drug-drug similarities revealed that antibiotics clustered into modules that are consistent with the mode of action of their established classes, whereas nonantibiotics remained unconnected. Half of the nonantibiotics clustered into separate modules, potentially revealing shared and unexploited targets for new antimicrobials. Analysis of efflux systems revealed that they widely affect antibiotics and nonantibiotics alike, suggesting that the impact of nonantibiotics on antibiotic cross-resistance should be investigated closely in vivo.

摘要

许多非抗生素药物具有强大的抗菌活性，可能对人体微生物群产生不利影响。这种毒性机制原理大部分仍然未知。我们通过使用数千个带有条形码的大肠杆菌敲除株进行基因筛选，测试了200种药物的抗菌活性，我们分析了构成特异性药物毒性的200万个基因-药物相互作用。基于网络的药物-药物相似性分析显示，抗生素聚集成与其既定类别作用模式一致的模块，而非抗生素保持未联系状态。一半的非抗生素聚集成了单独模块，可能揭示了新抗菌素的共享和未利用的目标。外排系统分析表明，它们广泛影响抗生素和非抗生素，这表明应在体内密切研究非抗生素对抗生素交叉耐药性的影响。

5.De novo design of drug-binding proteins with predictable binding energy and specificity

可预测结合能量和特异性的药物结合蛋白的从头设计

美国加州大学药物化学系与心血管研究所

Abstract

The de novo design of small molecule-binding proteins has seen exciting recent progress; however, high-affinity binding and tunable specificity typically require laborious screening and optimization after computational design. We developed a computational procedure to design a protein that recognizes a common pharmacophore in a series of poly (ADP-ribose) polymerase-1 inhibitors. One of three designed proteins bound different inhibitors with affinities ranging from <5 nM to low micromolar. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free energy calculations performed directly on the designed models were in excellent agreement with the experimentally measured affinities. We conclude that de novo design of high-affinity small molecule-binding proteins with tuned interaction energies is feasible entirely from computation.

摘要

最近，小分子结合蛋白的从头设计取得了令人兴奋的进展。但是高亲和力结合和可调特异性通常需要经过计算设计后进行费心力的筛选和优化。我们开发了一种计算程序，用于设计在一系列聚（ADP核糖）聚合酶-1抑制剂中识别共同的药效团的蛋白质。三种设计的蛋白质中的一种与不同抑制剂结合，其亲和力范围从较高的5 nM到较低的微摩尔不等。X-射线晶体结构证实了设计的蛋白质-药物相互作用的准确性。分子动力学模拟揭示了水在结合中的作用。直接在设计模型上进行的结合自由能计算与实验测量的亲和力非常吻合。我们得出结论，完全通过计算来实现具有调节作用的高亲和力小分子结合蛋白的从头设计是可行的。

VOLUME 384|ISSUE 6692|12 APR 2024

在2024年04月12日，《Science》共发表文章35篇：7篇NEWS，12篇INSIGHTS，其中1篇EXPERT VOICES，5篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK，3篇LETTERS，15篇RESEARCH，其中1篇REVIEWS，14篇RESEARCH ARTICLES，1篇EDITORIAL

1.Sexual dimorphism in skin immunity is mediated by an androgen-ILC2-dendritic cell axis

皮肤免疫中的两性二态性是由雄激素- ILC2-树突状细胞轴介导的

美国国立卫生研究院国立过敏和传染病研究所宿主免疫和微生物组实验室

Abstract

Males and females exhibit profound differences in immune responses and disease susceptibility. However, the factors responsible for sex differences in tissue immunity remain poorly understood. Here, we uncovered a dominant role for type 2 innate lymphoid cells (ILC2s) in shaping sexual immune dimorphism within the skin. Mechanistically, negative regulation of ILC2s by androgens leads to a reduction in dendritic cell accumulation and activation in males, along with reduced tissue immunity. Collectively, our results reveal a role for the androgen-ILC2-dendritic cell axis in controlling sexual immune dimorphism. Moreover, this work proposes that tissue immune set points are defined by the dual action of sex hormones and the microbiota, with sex hormones controlling the strength of local immunity and microbiota calibrating its tone.

摘要

男性和女性在免疫反应和疾病易感性方面表现出深刻的差异。然而，导致组织免疫中性别差异的因素仍然知之甚少。在这里，我们揭示了2型先天性淋巴细胞（ILC2s）在形成皮肤内两性免疫二态性中的主导作用。从机制上讲，雄激素对ILC2的负调控导致男性树突状细胞的聚集和活化减少，并伴有组织免疫力降低。总之，这些研究结果揭示了雄激素-ILC2-树突状细胞轴在控制性免疫二态性中的作用。此外，这项工作提出组织免疫设定点是由性激素和微生物群的双重作用决定的，性激素控制局部免疫强度而微生物群则校准基调。

2. Two inhibitory neuronal classes govern acquisition and recall of spinal sensorimotor adaptation

两类抑制性神经元支配着脊髓感觉运动适应的习得和回忆

比利时VIB-神经电子研究弗兰德斯(NERF)和荷语鲁汶大学神经科学系和鲁汶脑研究所

Abstract

Spinal circuits are central to movement adaptation, yet the mechanisms within the spinal cord responsible for acquiring and retaining behavior upon experience remain unclear. Using a simple conditioning paradigm, we found that dorsal inhibitory neurons are indispensable for adapting protective limb-withdrawal behavior by regulating the transmission of a specific set of somatosensory information to enhance the saliency of conditioning cues associated with limb position. By contrast, maintaining previously acquired motor adaptation required the ventral inhibitory Renshaw cells. Manipulating Renshaw cells does not affect the adaptation itself but flexibly alters the expression of adaptive behavior. These findings identify a circuit basis involving two distinct populations of spinal inhibitory neurons, which enables lasting sensorimotor adaptation independently from the brain.

摘要

脊髓回路是运动适应的核心，但脊髓内负责根据经验获得和保持行为的机制尚不清楚。通过一个基础条件反射，我们发现背侧抑制性神经元通过调节特殊躯体感觉信息的传递来增强与肢体位置相关的条件反射信号，从而在适应保护性肢体回缩行为的过程中起到至关重要的作用。相反，需要腹侧抑制性闰绍细胞来维持先前获得的运动适应。调节闰绍细胞不会影响适应本身，但会灵活改变适应行为的表达。这些发现揭示了涉及两种不同脊髓抑制性神经元群回路基础，该回路可独立于大脑实现持续的感觉运动适应。