CellPub Date : 2025-07-11DOI: 10.1016/j.cell.2025.06.024
Felix Wong, Alicia Li, Satotaka Omori, Ryan S. Lach, Jose Nunez, Yunke Ren, Sean P. Brown, Vipul Singhal, Brent R. Lyda, Taivan Batjargal, Ethan Dickson, Jose Roberto Rodrigues Reyes, Juan Manual Uruena Vargas, Shalaka Wahane, Hahn Kim, James J. Collins, Maxwell Z. Wilson
{"title":"Optogenetics-enabled discovery of integrated stress response modulators","authors":"Felix Wong, Alicia Li, Satotaka Omori, Ryan S. Lach, Jose Nunez, Yunke Ren, Sean P. Brown, Vipul Singhal, Brent R. Lyda, Taivan Batjargal, Ethan Dickson, Jose Roberto Rodrigues Reyes, Juan Manual Uruena Vargas, Shalaka Wahane, Hahn Kim, James J. Collins, Maxwell Z. Wilson","doi":"10.1016/j.cell.2025.06.024","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.024","url":null,"abstract":"The integrated stress response (ISR) is a conserved stress response that maintains homeostasis in eukaryotic cells. Modulating the ISR holds therapeutic potential for diseases including viral infection, cancer, and neurodegeneration, but few known compounds can do so without toxicity. Here, we present an optogenetic platform for the discovery of compounds that selectively modulate the ISR. Optogenetic clustering of PKR induces ISR-mediated cell death, enabling the high-throughput screening of 370,830 compounds. We identify compounds that potentiate cell death without cytotoxicity across diverse cell types and stressors. Mechanistic studies reveal that these compounds upregulate activating transcription factor 4 (ATF4), sensitizing cells to stress and apoptosis, and identify GCN2 as a molecular target. Additionally, these compounds exhibit antiviral activity, and one compound reduced viral titers in a mouse model of herpesvirus infection. Structure-activity and toxicology studies highlight opportunities to optimize therapeutic efficacy. This work demonstrates an optogenetic approach to drug discovery and introduces ISR potentiators with therapeutic potential.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"697 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602978","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 : 2025-07-11DOI: 10.1016/j.cell.2025.06.025
Fankang Meng, William M. Shaw, Yui Kei Keith Kam, Tom Ellis
{"title":"Engineering yeast multicellular behaviors via synthetic adhesion and contact signaling","authors":"Fankang Meng, William M. Shaw, Yui Kei Keith Kam, Tom Ellis","doi":"10.1016/j.cell.2025.06.025","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.025","url":null,"abstract":"Multicellular coordination enhances biological complexity, yet the widely used yeast <em>Saccharomyces cerevisiae</em> possesses limited multicellular capabilities. Here, we expand the possibilities for engineering multicellular behaviors in yeast by developing modular toolkits for two key mechanisms in multicellularity, contact-dependent signaling and specific cell-cell adhesion. MARS (mating-peptide anchored response system) enables contact-dependent signaling via surface-displayed peptides and G protein-coupled receptors, mimicking juxtacrine communication, while <em>Saccharomyces</em> SATURN (adhesion toolkit for multicellular patterning) uses adhesion-protein pairs for the creation of programmable cell aggregation patterns. Combining these allows the construction of multicellular logic circuits, equivalent to developmental programs that lead to cell differentiation based on local population. We further created JUPITER (juxtacrine sensor for protein-protein interaction), a genetic sensor based on MARS and SATURN, for assaying protein-protein interactions and selecting high-affinity nanobody binders. Collectively, these toolkits present versatile building blocks for constructing complex, user-defined multicellular yeast systems and expand the scope of its biotechnological applications.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"7 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602976","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 : 2025-07-10DOI: 10.1016/j.cell.2025.06.005
Lingfeng Gou, Yanzhi Wang, Le Gao, Sang Liu, Mingli Wang, Qinwen Chai, Jiao Fang, Lijie Zhan, Xiaowen Shen, Tao Jiang, Wenqiang Ren, Miao Ren, Xueyan Jia, Chi Xiao, Anan Li, Xiangning Li, Qingming Luo, Gouki Okazawa, Tianming Yang, Zhen Liu, Jun Yan
{"title":"Single-neuron projectomes of macaque prefrontal cortex reveal refined axon targeting and arborization","authors":"Lingfeng Gou, Yanzhi Wang, Le Gao, Sang Liu, Mingli Wang, Qinwen Chai, Jiao Fang, Lijie Zhan, Xiaowen Shen, Tao Jiang, Wenqiang Ren, Miao Ren, Xueyan Jia, Chi Xiao, Anan Li, Xiangning Li, Qingming Luo, Gouki Okazawa, Tianming Yang, Zhen Liu, Jun Yan","doi":"10.1016/j.cell.2025.06.005","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.005","url":null,"abstract":"Cortical expansion endows advanced cognitive functions in primates, and whole-brain single-neuron projection analysis helps to elucidate underlying neural circuit mechanisms. Here, we reconstructed 2,231 single-neuron projectomes for the macaque prefrontal cortex (PFC) and identified 32 projectome-based subtypes of intra-telencephalic, pyramidal-tract, and cortico-thalamic neurons. Each subtype exhibited distinct topography in their soma distribution within the PFC, a characteristic pattern of axon targeting, and subregion-specific patchy terminal arborization in the targeted area, with putative functions annotated. Furthermore, we identified a subdomain connectivity network and extensive local axons within the PFC. Compared with those in mice, macaque PFC projectomes exhibited a similar topographic gradient of terminal arborization at the targeted regions but much higher target specificity, fewer collaterals, and smaller brain size-normalized arbors. Thus, whole-brain single-axon macaque projectomes revealed highly refined axon targeting and arborization, providing key insights into the structural basis for complex brain functions in primates.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"710 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594759","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 : 2025-07-10DOI: 10.1016/j.cell.2025.05.018
L. John Fahrner, Emma Chen, Eric Topol, Pranav Rajpurkar
{"title":"The generative era of medical AI","authors":"L. John Fahrner, Emma Chen, Eric Topol, Pranav Rajpurkar","doi":"10.1016/j.cell.2025.05.018","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.018","url":null,"abstract":"Rapid advancements in artificial intelligence (AI), particularly large language models (LLMs) and multimodal AI, are transforming medicine through enhancements in diagnostics, patient interaction, and medical forecasting. LLMs enable conversational interfaces, simplify medical reports, and assist clinicians with decision making. Multimodal AI integrates diverse data like images and genetic data for superior performance in pathology and medical screening. AI-driven tools promise proactive, personalized healthcare through continuous monitoring and multiscale forecasting. However, challenges like bias, privacy, regulatory hurdles, and integration into healthcare systems must be addressed for widespread clinical adoption.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"14 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594758","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":"Identification and application of cell-type-specific enhancers for the macaque brain","authors":"Ling Li, Yiming Huang, Dengyu Lu, Jiqiang Fu, Luyan Wu, Zheyuan Chen, Haiou Liao, Jiaqi Zhang, Li Li, Tianyue Gu, Fang He, Hean Liu, Xiangqing Leng, Jing Tang, Jiaqi Yan, Cirong Liu, Chao Li, Huapin Huang, Lina Wang, Longqi Liu, Zhen Liu","doi":"10.1016/j.cell.2025.06.040","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.040","url":null,"abstract":"Genetic targeting methods for monitoring and manipulating neuronal activity are not widely used for studying the primate brain, largely owing to the lack of a cell-type-specific targeting method. Using single-cell RNA and ATAC sequencing of macaque brains combined with <em>in vivo</em> screening, we identified a large set of enhancers capable of driving targeted gene expression in specific cell types. AAV vectors driven by these enhancers successfully targeted layer-specific glutamatergic neurons, GABAergic interneuron subtypes, astrocytes, and oligodendrocytes with high specificity. Cross-species comparison revealed that some macaque enhancers are conserved and functional across species, but enhancers with layer-specific targeting in macaques did not label neurons in mice, highlighting evolutionary differences in cortical CREs. Targeting precision was further improved using a FLPo-dependent intersectional approach with two enhancers. These enhancer-AAVs were validated by monitoring and manipulating activity in macaque visual cortex, providing valuable tools to dissect primate neural circuit functions.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"279 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602979","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 : 2025-07-10DOI: 10.1016/j.cell.2025.06.012
Michael D. Gershon
{"title":"Targeting serotonin transporter boosts tumor-fighting T cells","authors":"Michael D. Gershon","doi":"10.1016/j.cell.2025.06.012","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.012","url":null,"abstract":"In this issue of <em>Cell</em>, Yang and colleagues demonstrate that autocrine activation of serotonin receptors on tumor-infiltrating CD8<sup>+</sup> T cells enhances antitumor immunity. Modulating serotonin signaling may provide a new approach to therapy for cancer. Serotonin-targeting drugs such as SSRIs and others, developed to fight depression, may thus be repurposed for cancer immunotherapy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"11 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594691","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 : 2025-07-10DOI: 10.1016/j.cell.2025.06.013
Yan-Gang Sun, Qingming Luo, Mu-Ming Poo
{"title":"Mesoscopic mapping of the brain: From rodents to primates","authors":"Yan-Gang Sun, Qingming Luo, Mu-Ming Poo","doi":"10.1016/j.cell.2025.06.013","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.013","url":null,"abstract":"Advances in brain mapping technologies have made substantial progress in identifying diverse cell types and their connectivity. Focusing on papers recently contributed by the Mesoscopic Brain Mapping Consortium to <em>Cell</em>, <em>Neuron</em>, and <em>Developmental Cell</em>, this commentary discusses insights into brain organization, development, evolution, and diseases, as well as future research directions.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"191 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594757","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 : 2025-07-10DOI: 10.1016/j.cell.2025.06.023
James P. Cooney, Ashley Hirons, Natasha Jansz, Cody C. Allison, Peter Hickey, Charis E. Teh, Tania Tan, Laura F. Dagley, Jumana Yousef, David Yurick, Georges Khoury, Simon P. Preston, Philip Arandjelovic, Kathryn C. Davidson, Lewis J. Williams, Stefanie M. Bader, Le Wang, Reet Bhandari, Liana Mackiewicz, Merle Dayton, Marc Pellegrini
{"title":"Combination antiretroviral therapy and MCL-1 inhibition mitigate HTLV-1 infection in vivo","authors":"James P. Cooney, Ashley Hirons, Natasha Jansz, Cody C. Allison, Peter Hickey, Charis E. Teh, Tania Tan, Laura F. Dagley, Jumana Yousef, David Yurick, Georges Khoury, Simon P. Preston, Philip Arandjelovic, Kathryn C. Davidson, Lewis J. Williams, Stefanie M. Bader, Le Wang, Reet Bhandari, Liana Mackiewicz, Merle Dayton, Marc Pellegrini","doi":"10.1016/j.cell.2025.06.023","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.023","url":null,"abstract":"This study investigated preventative and therapeutic agents against human T cell lymphotropic virus type-1 subtype-C (HTLV-1c) infection. We established and characterized a humanized mouse model of HTLV-1c infection and identified that HTLV-1c disease appears slightly more aggressive than the prevalent HTLV-1 subtype-A (HTLV-1a), which may underpin increased risk for infection-associated pulmonary complications in HTLV-1c. Combination antiretroviral therapy with tenofovir and dolutegravir at clinically relevant doses significantly reduced HTLV-1c transmission and disease progression <em>in vivo</em>. Single-cell RNA sequencing (scRNA-seq) and intracellular flow cytometry identified that HTLV-1c infection leads to dysregulated intrinsic apoptosis in infected cells <em>in vivo</em>. Pharmacological inhibition using BH3 mimetic compounds against MCL-1, but not BCL-2, BCL-XL, or BCL-w, killed HTLV-1c-infected cells <em>in vitro</em> and <em>in vivo</em> and significantly delayed disease progression when combined with tenofovir and dolutegravir in mice. Our data suggest that combination antiretroviral therapy with MCL-1 antagonism may represent an effective, clinically relevant, and potentially curative strategy against HTLV-1c.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"23 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594799","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 : 2025-07-10DOI: 10.1016/j.cell.2025.06.016
Luísa V. Lopes, Paula A. Pousinha
{"title":"Burst firing in Alzheimer’s disease: A shift beyond amyloid?","authors":"Luísa V. Lopes, Paula A. Pousinha","doi":"10.1016/j.cell.2025.06.016","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.016","url":null,"abstract":"In this issue of <em>Cell</em>, Harris et al. reveal that high-molecular-weight soluble tau—rather than amyloid-beta—impairs burst firing in hippocampal neurons, providing a mechanistic link to cognitive decline in Alzheimer’s disease. This disruption, linked to CaV2.3 downregulation, highlights soluble tau as a key driver of neuronal dysfunction and a promising therapeutic target.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"13 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594690","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":"High-speed mapping of whole-mouse peripheral nerves at subcellular resolution","authors":"Mei-Yu Shi, Yuchen Yao, Miao Wang, Qi Yang, Lufeng Ding, Rui Li, Yuanyuan Li, Haimeng Huang, Chao-Yu Yang, Zhao Zhou, Zhenxiang Zhu, Pengjie Wen, Fangling Dai, Xiaohui Zeng, Ke-Ming Zhang, Yuhong Guo, Zi-An Sun, Huanhuan Xia, Zhenhua Ren, Yusuf Ozgur Cakmak, Guo-Qiang Bi","doi":"10.1016/j.cell.2025.06.011","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.011","url":null,"abstract":"In contrast to the rapid advancements in mesoscale connectomic mapping of the mammalian brain, similar mapping of the peripheral nervous system has remained challenging due to the body size and complexity. Here, we present a high-speed blockface volumetric imaging system with an optimized workflow of whole-body clearing, capable of imaging the entire adult mouse at micrometer resolution within 40 h. Three-dimensional reconstruction of individual spinal fibers in Thy1-EGFP mice reveals distinct morphological features of sensory and motor projections along the ventral and dorsal rami. Immunostaining facilitates body-wide mapping of sympathetic nerves and their branches, highlighting their perivascular patterns in limb muscles, bones, and most visceral organs. Viral tracing elucidates the fine architecture of vagus nerves and individual vagal fibers, revealing unexpected projection routes to various organs. Our approach offers an effective means to achieve a holistic understanding of cellular-level interactions among different systems that underlie body physiology and disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"7 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594800","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}