CellPub Date : 2025-08-14DOI: 10.1016/j.cell.2025.07.033
Aarti Krishnan, Melis N. Anahtar, Jacqueline A. Valeri, Wengong Jin, Nina M. Donghia, Leif Sieben, Andreas Luttens, Yu Zhang, Seyed Majed Modaresi, Andrew Hennes, Jenna Fromer, Parijat Bandyopadhyay, Jonathan C. Chen, Danyal Rehman, Ronak Desai, Paige Edwards, Ryan S. Lach, Marie-Stéphanie Aschtgen, Margaux Gaborieau, Massimiliano Gaetani, James J. Collins
{"title":"A generative deep learning approach to de novo antibiotic design","authors":"Aarti Krishnan, Melis N. Anahtar, Jacqueline A. Valeri, Wengong Jin, Nina M. Donghia, Leif Sieben, Andreas Luttens, Yu Zhang, Seyed Majed Modaresi, Andrew Hennes, Jenna Fromer, Parijat Bandyopadhyay, Jonathan C. Chen, Danyal Rehman, Ronak Desai, Paige Edwards, Ryan S. Lach, Marie-Stéphanie Aschtgen, Margaux Gaborieau, Massimiliano Gaetani, James J. Collins","doi":"10.1016/j.cell.2025.07.033","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.033","url":null,"abstract":"The antimicrobial resistance crisis necessitates structurally distinct antibiotics. While deep learning approaches can identify antibacterial compounds from existing libraries, structural novelty remains limited. Here, we developed a generative artificial intelligence framework for designing <em>de novo</em> antibiotics through two approaches: a fragment-based method to comprehensively screen >10<sup>7</sup> chemical fragments <em>in silico</em> against <em>Neisseria gonorrhoeae</em> or <em>Staphylococcus aureus</em>, subsequently expanding promising fragments, and an unconstrained <em>de novo</em> compound generation, each using genetic algorithms and variational autoencoders. Of 24 synthesized compounds, seven demonstrated selective antibacterial activity. Two lead compounds exhibited bactericidal efficacy against multidrug-resistant isolates with distinct mechanisms of action and reduced bacterial burden <em>in vivo</em> in mouse models of <em>N. gonorrhoeae</em> vaginal infection and methicillin-resistant <em>S. aureus</em> skin infection. We further validated structural analogs for both compound classes as antibacterial. Our approach enables the generative deep-learning-guided design of <em>de novo</em> antibiotics, providing a platform for mapping uncharted regions of chemical space.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"24 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-08-13DOI: 10.1016/j.cell.2025.07.038
Ryan Mahling, Bence Hegyi, Erin R Cullen, Timothy M Cho, Aaron R Rodriques, Lucile Fossier, Marc Yehya, Lin Yang, Bi-Xing Chen, Alexander N Katchman, Nourdine Chakouri, Ruiping Ji, Elaine Y Wan, Jared Kushner, Steven O Marx, Sergey Ovchinnikov, Christopher D Makinson, Donald M Bers, Manu Ben-Johny
{"title":"De novo design of a peptide modulator to reverse sodium channel dysfunction linked to cardiac arrhythmias and epilepsy.","authors":"Ryan Mahling, Bence Hegyi, Erin R Cullen, Timothy M Cho, Aaron R Rodriques, Lucile Fossier, Marc Yehya, Lin Yang, Bi-Xing Chen, Alexander N Katchman, Nourdine Chakouri, Ruiping Ji, Elaine Y Wan, Jared Kushner, Steven O Marx, Sergey Ovchinnikov, Christopher D Makinson, Donald M Bers, Manu Ben-Johny","doi":"10.1016/j.cell.2025.07.038","DOIUrl":"10.1016/j.cell.2025.07.038","url":null,"abstract":"<p><p>Ion channels orchestrate electrical signaling in excitable cells. In nature, ion channel function is customized by modulatory proteins that have evolved to fulfill distinct physiological needs. Yet, engineering synthetic modulators that precisely tune ion channel function is challenging. One example involves the voltage-gated sodium (Na<sub>V</sub>) channel that initiates the action potential and whose dysfunction amplifies the late/persistent sodium current (I<sub>NaL</sub>), a commonality that underlies various human diseases, including cardiac arrhythmias and epilepsy. Here, using a computational protein design platform, we engineered a de novo peptide modulator, engineered late-current inhibitor X by inactivation-gate release (ELIXIR), that binds Na<sub>V</sub> channels with submicromolar affinity. Functional analysis revealed unexpected selectivity in inhibiting \"pathogenic\" I<sub>NaL</sub> and confirmed its effectiveness in reversing Na<sub>V</sub> dysfunction linked to both cardiac arrhythmias and epilepsy in cellular and murine models. These findings exemplify the efficacy of de novo protein design for engineering synthetic ion channel modulators and set the stage for the rational design of future therapeutic approaches.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-08-13DOI: 10.1016/j.cell.2025.07.041
Akiko Ogawa, Satoshi Watanabe, Iuliia Ozerova, Allen Yi-Lun Tsai, Yoshihiko Kuchitsu, Harrison Byron Chong, Tomoyoshi Kawakami, Jirio Fuse, Wei Han, Ryuhei Kudo, Tomoki Naito, Kota Sato, Toru Nakazawa, Yasunori Saheki, Akiyoshi Hirayama, Peter F Stadler, Mieko Arisawa, Kimi Araki, Liron Bar-Peled, Tomohiko Taguchi, Shinichiro Sawa, Kenji Inaba, Fan-Yan Wei
{"title":"Adenosine kinase and ADAL coordinate detoxification of modified adenosines to safeguard metabolism.","authors":"Akiko Ogawa, Satoshi Watanabe, Iuliia Ozerova, Allen Yi-Lun Tsai, Yoshihiko Kuchitsu, Harrison Byron Chong, Tomoyoshi Kawakami, Jirio Fuse, Wei Han, Ryuhei Kudo, Tomoki Naito, Kota Sato, Toru Nakazawa, Yasunori Saheki, Akiyoshi Hirayama, Peter F Stadler, Mieko Arisawa, Kimi Araki, Liron Bar-Peled, Tomohiko Taguchi, Shinichiro Sawa, Kenji Inaba, Fan-Yan Wei","doi":"10.1016/j.cell.2025.07.041","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.041","url":null,"abstract":"<p><p>RNA contains diverse post-transcriptional modifications, and its catabolic breakdown yields numerous modified nucleosides requiring correct processing, but the mechanisms remain unknown. Here, we demonstrate that three RNA-derived modified adenosines, N<sup>6</sup>-methyladenosine (m<sup>6</sup>A), N<sup>6</sup>,N<sup>6</sup>-dimethyladenosine (m<sup>6,6</sup>A), and N<sup>6</sup>-isopentenyladenosine (i<sup>6</sup>A), are sequentially metabolized into inosine monophosphate (IMP) to mitigate their intrinsic cytotoxicity. After phosphorylation by adenosine kinase (ADK), they undergo deamination by adenosine deaminase-like (ADAL). In Adal knockout mice, N<sup>6</sup>-modified adenosine monophosphates (AMPs) accumulate and allosterically inhibit AMP-activated protein kinase (AMPK), dysregulating glucose metabolism. Furthermore, ADK deficiency, linked to human inherited disorders of purine metabolism, elevates levels of the three modified adenosines, resulting in early lethality in mice. Mechanistically, excessive m<sup>6</sup>A, m<sup>6,6</sup>A, and i<sup>6</sup>A impair lysosomal function by interfering with lysosomal membrane proteins, thereby disrupting lipid metabolism and causing cellular toxicity. Through this nucleotide metabolism pathway and mechanism, cells detoxify modified adenosines, linking modified RNA metabolism to human disease.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-08-12DOI: 10.1016/j.cell.2025.07.044
Lei Wang, Louis-Philippe Maier, Nga Pham, Yan L Wang, Xu Wang, Andreas Schaller, Judith Fliegmann, Matthias Erb, Thomas Boller, Georg Felix
{"title":"A receptor antagonist counterbalances multiple systemin phytocytokines in tomato.","authors":"Lei Wang, Louis-Philippe Maier, Nga Pham, Yan L Wang, Xu Wang, Andreas Schaller, Judith Fliegmann, Matthias Erb, Thomas Boller, Georg Felix","doi":"10.1016/j.cell.2025.07.044","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.044","url":null,"abstract":"<p><p>Tight regulation of immune activation is crucial for plant health. How plants control the actions of their immunostimulatory phytocytokines is largely unknown. Here, we identify antiSYS as a natural inhibitor of the tomato cytokine systemin. AntiSYS is a systemin-like peptide encoded in a gene cluster with four additional paralogs, three of which comprise newly identified agonistic systemins. AntiSYS is a potent and specific antagonist of the systemin receptor. Tomato mutants lacking antiSYS show aberrant growth and reduced reproductive fitness. These symptoms of antiSYS deficiency are not observed in plants lacking functional systemin receptors, suggesting a role of antiSYS in counterbalancing agonistic systemins. Thus, reminiscent of antagonistic interleukins controlling immune homeostasis in animals, antiSYS serves a crucial role in the regulation of phytocytokine activity in tomato plants.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"VIVIT: Resolving trans-scale volumetric biological architectures via ionic glassy tissue","authors":"Yixiao Gao, Fengyuan Xin, Tao Wang, Chengjun Shao, Ying Hu, Zhuoya Chen, Yiwei Wang, Fenghua Xie, Tianyu Li, Sijie Li, Liqun Ren, Caiqin Li, Xian Yang, Zhongjun Yang, Meijie Li, KaMun Tan, Tao Bai, Changwei Wei, Hanchuan Peng, Kun Li, Kexin Yuan","doi":"10.1016/j.cell.2025.07.023","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.023","url":null,"abstract":"Biological structures across scales integrate seamlessly to perform essential functions. While various histological methods have been developed to reveal these intricate structures, preserving the integrity of large-volume architectures while revealing microstructures with high resolution remains a major challenge. Here, we introduce vitreous ionic-liquid-solvent-based volumetric inspection of trans-scale biostructure (VIVIT), a 3D histological method leveraging the chemical properties of ionic liquids. VIVIT transforms biological tissue into an ionic glassy state, which enables optical clearing with minimal distortion and high transparency, preserves tissue from low-temperature crystal damage, and amplifies fluorescent signals from both genetically encoded and immunostained labels, thus yielding precise and reliable mapping of fluorescent signals within intact 3D architectures. Using VIVIT, we demonstrate the link between the modality of synaptic inputs to multisensory thalamic neurons and the targets of their brain-wide outputs and identified aspects of inhibitory control in the human cortex. VIVIT thus offers opportunities to elucidate the organizational principles underlying trans-scale biostructures.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"165 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-08-11DOI: 10.1016/j.cell.2025.07.021
Zikun Zhu, Saurav Mallik, Taylor A. Stevens, Riming Huang, Emmanuel D. Levy, Shu-ou Shan
{"title":"Principles of cotranslational mitochondrial protein import","authors":"Zikun Zhu, Saurav Mallik, Taylor A. Stevens, Riming Huang, Emmanuel D. Levy, Shu-ou Shan","doi":"10.1016/j.cell.2025.07.021","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.021","url":null,"abstract":"Nearly all mitochondrial proteins are translated on cytosolic ribosomes. How these proteins are subsequently delivered to mitochondria remains poorly understood. Using selective ribosome profiling, we show that nearly 20% of mitochondrial proteins can be imported cotranslationally in human cells. Cotranslational import requires an N-terminal presequence on the nascent protein and contributes to localized translation at the mitochondrial surface. This pathway does not favor membrane proteins but instead prioritizes large, multi-domain, topologically complex proteins, whose import efficiency is enhanced when targeted cotranslationally. In contrast to the early onset of cotranslational protein targeting to the endoplasmic reticulum (ER), the presequence on mitochondrial proteins is inhibited from initiating targeting early during translation until a large globular domain emerges from the ribosome. Our findings reveal a multi-layered protein sorting strategy that controls the timing and specificity of mitochondrial protein targeting.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"24 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-08-11DOI: 10.1016/j.cell.2025.07.029
Ian Light-Maka, Taylor R. Hermes, Raffaela Angelina Bianco, Lena Semerau, Pavel Kosintsev, Valeriia Alekseeva, Donghee Kim, William P. Hanage, Alexander Herbig, Choongwon Jeong, Christina Warinner, Felix M. Key
{"title":"Bronze Age Yersinia pestis genome from sheep sheds light on hosts and evolution of a prehistoric plague lineage","authors":"Ian Light-Maka, Taylor R. Hermes, Raffaela Angelina Bianco, Lena Semerau, Pavel Kosintsev, Valeriia Alekseeva, Donghee Kim, William P. Hanage, Alexander Herbig, Choongwon Jeong, Christina Warinner, Felix M. Key","doi":"10.1016/j.cell.2025.07.029","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.029","url":null,"abstract":"Most human pathogens are of zoonotic origin. Many emerged during prehistory, coinciding with domestication providing more opportunities for spillover into human populations. However, we lack direct DNA evidence linking animal and human infections during prehistory. Here, we present a <em>Yersinia pestis</em> genome recovered from a 3rd-millennium BCE domesticated sheep from the Eurasian Steppe belonging to the Late Neolithic Bronze Age (LNBA) lineage, until now exclusively identified in ancient humans across Eurasia. We show that this ancient lineage underwent ancestral gene decay paralleling extant lineages, but evolved under distinct selective pressures, contributing to its lack of geographic differentiation. We collect evidence supporting a scenario where the LNBA lineage, unable to efficiently transmit via fleas, spread from an unidentified reservoir to sheep and likely other domesticates, elevating human infection risk. Collectively, our results connect prehistoric livestock with infectious disease in humans and showcase the power of moving paleomicrobiology into the zooarchaeological record.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"36 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-08-11DOI: 10.1016/j.cell.2025.07.036
Hao-Chen Xue, Zhou-Geng Xu, Yu-Jie Liu, Long Wang, Xin Ming, Ze-Yu Wu, Heng Lian, Yu-Wei Han, Jie Xu, Zheng-Da Zhang, Qiao-Lin Shao, Ke Liu, Fu-Xiang Wang, Ai-Hua Wang, Jian Zhao, Jinfeng Zhang, Jianghua Chen, Yanfei Mao, Jia-Wei Wang
{"title":"A unified cell atlas of vascular plants reveals cell-type foundational genes and accelerates gene discovery.","authors":"Hao-Chen Xue, Zhou-Geng Xu, Yu-Jie Liu, Long Wang, Xin Ming, Ze-Yu Wu, Heng Lian, Yu-Wei Han, Jie Xu, Zheng-Da Zhang, Qiao-Lin Shao, Ke Liu, Fu-Xiang Wang, Ai-Hua Wang, Jian Zhao, Jinfeng Zhang, Jianghua Chen, Yanfei Mao, Jia-Wei Wang","doi":"10.1016/j.cell.2025.07.036","DOIUrl":"10.1016/j.cell.2025.07.036","url":null,"abstract":"<p><p>The pace of gene discovery in plants has slowed as forward genetic screens reach saturation. To address this, we built a unified single-cell atlas of shoot apices from six vascular plant species spanning major evolutionary groups. This cross-species resource allowed us to identify a core set of cell-type foundational genes linked to key tissues such as the epidermis, xylem, and phloem, streamlining gene discovery with greater accuracy. Among these, we uncovered a previously unrecognized clade of X8 domain proteins and JULGI-LIKE as regulators of phloem development. We also identified companion-cell-like cells in ferns and gymnosperms that cannot be distinguished by conventional histological methods and developed an automated cell-type annotation tool for vascular plant cell types, expanding the utility of our approach. Our findings establish a high-resolution framework for identifying key regulators of plant cell types and set an innovative paradigm for studying plant cell-type evolution.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-08-11DOI: 10.1016/j.cell.2025.07.024
Adam C. Nelson, Vikrant Kapoor, Eric Vaughn, Jeshurun A. Gnanasegaram, Nimrod D. Rubinstein, Mustafa Talay, Venkatesh N. Murthy, Catherine Dulac
{"title":"Molecular and neural control of social hierarchy by a forebrain-thalamocortical circuit","authors":"Adam C. Nelson, Vikrant Kapoor, Eric Vaughn, Jeshurun A. Gnanasegaram, Nimrod D. Rubinstein, Mustafa Talay, Venkatesh N. Murthy, Catherine Dulac","doi":"10.1016/j.cell.2025.07.024","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.024","url":null,"abstract":"Many animal groups are organized hierarchically, which generates behavioral states that facilitate social interactions. Although generally stable, social status can change, underscoring the plasticity of underlying neural circuits. We examined competition among unfamiliar male mice and uncovered how the molecular and biophysical characteristics of a forebrain-thalamocortical circuit affect hierarchy. We identify the mediodorsal thalamus (MDT) as a hub receiving inputs from the orbitofrontal cortex and basal forebrain and projecting to the caudal anterior cingulate cortex (cACC) to regulate competitive performance. This circuit becomes potentiated or depressed in high- and low-rank males, respectively, in part through altered expression of the voltage-gated ion channel <em>Trpm3</em> and synaptic plasticity. In high-rank mice, MDT projections drive inhibition of cACC pyramidal cells, promoting winning, in a pattern strikingly opposite to the dorsomedial prefrontal cortex, where winners display increased pyramidal cell activity. Our data suggest a model in which hierarchy modulation relies on coordinated remodeling of multiple forebrain-thalamocortical circuits.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"30 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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