Cell-mediated drug-delivery systems have garnered significant attention for their potential to boost therapeutic efficacy in cancer treatment. Here, we engineered immunoglobulin E (IgE)-sensitized mast cells (IgE-MCs) to achieve antigen-guided delivery of oncolytic adenoviruses (OVs) and local immune activation. By harnessing tumor-specific antigens as allergens, IgE-MCs accumulated at antigen-positive tumors, enabling targeted OV delivery and releasing chemokines and inflammatory mediators that remodeled the tumor microenvironment. IgE-MCs encapsulating OVs induced robust anticancer immune responses and inhibited tumor growth in several murine models. Of note, in a humanized human epidermal growth factor receptor-2 (HER2)-positive patient-derived xenograft model, human MCs armed with anti-HER2 IgE and loaded with OVs increased intratumoral T cell responses and reduced tumor growth, demonstrating feasibility in a clinically relevant setting and supporting patient-specific IgE selection. Together, our study highlights the translational promise of IgE-MCs as an antigen-specific delivery platform for cancer immunotherapy.
{"title":"Sensitized mast cells for targeted drug delivery and augmented cancer immunotherapy","authors":"Yan Xu, Xiaoge Zhang, Xiao Han, Hanwei Huang, Chaoyang Meng, Yinxian Yang, Tao Sheng, En Ren, Jiaqi Shi, Kaixin He, Dong Cen, Peng Zhao, Weijia Fang, Hongjun Li, Yuqi Zhang, Xiujun Cai, Funan Liu, Jicheng Yu, Zhen Gu","doi":"10.1016/j.cell.2025.11.015","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.015","url":null,"abstract":"Cell-mediated drug-delivery systems have garnered significant attention for their potential to boost therapeutic efficacy in cancer treatment. Here, we engineered immunoglobulin E (IgE)-sensitized mast cells (IgE-MCs) to achieve antigen-guided delivery of oncolytic adenoviruses (OVs) and local immune activation. By harnessing tumor-specific antigens as allergens, IgE-MCs accumulated at antigen-positive tumors, enabling targeted OV delivery and releasing chemokines and inflammatory mediators that remodeled the tumor microenvironment. IgE-MCs encapsulating OVs induced robust anticancer immune responses and inhibited tumor growth in several murine models. Of note, in a humanized human epidermal growth factor receptor-2 (HER2)-positive patient-derived xenograft model, human MCs armed with anti-HER2 IgE and loaded with OVs increased intratumoral T cell responses and reduced tumor growth, demonstrating feasibility in a clinically relevant setting and supporting patient-specific IgE selection. Together, our study highlights the translational promise of IgE-MCs as an antigen-specific delivery platform for cancer immunotherapy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"6 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704285","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}
Pub Date : 2025-12-09DOI: 10.1016/j.cell.2025.11.016
Jeya Maria Jose Valanarasu, Hanwen Xu, Naoto Usuyama, Chanwoo Kim, Cliff Wong, Peniel Argaw, Racheli Ben Shimol, Angela Crabtree, Kevin Matlock, Alexandra Q. Bartlett, Jaspreet Bagga, Yu Gu, Sheng Zhang, Tristan Naumann, Bernard A. Fox, Bill Wright, Ari Robicsek, Brian Piening, Carlo Bifulco, Sheng Wang, Hoifung Poon
The tumor immune microenvironment (TIME) critically impacts cancer progression and immunotherapy response. Multiplex immunofluorescence (mIF) is a powerful imaging modality for deciphering TIME, but its applicability is limited by high cost and low throughput. We propose GigaTIME, a multimodal AI framework for population-scale TIME modeling by bridging cell morphology and states. GigaTIME learns a cross-modal translator to generate virtual mIF images from hematoxylin and eosin (H&E) slides by training on 40 million cells with paired H&E and mIF data across 21 proteins. We applied GigaTIME to 14,256 patients from 51 hospitals and over 1,000 clinics across seven US states in Providence Health, generating 299,376 virtual mIF slides spanning 24 cancer types and 306 subtypes. This virtual population uncovered 1,234 statistically significant associations linking proteins, biomarkers, staging, and survival. Such analyses were previously infeasible due to the scarcity of mIF data. Independent validation on 10,200 TCGA patients further corroborated our findings.
{"title":"Multimodal AI generates virtual population for tumor microenvironment modeling","authors":"Jeya Maria Jose Valanarasu, Hanwen Xu, Naoto Usuyama, Chanwoo Kim, Cliff Wong, Peniel Argaw, Racheli Ben Shimol, Angela Crabtree, Kevin Matlock, Alexandra Q. Bartlett, Jaspreet Bagga, Yu Gu, Sheng Zhang, Tristan Naumann, Bernard A. Fox, Bill Wright, Ari Robicsek, Brian Piening, Carlo Bifulco, Sheng Wang, Hoifung Poon","doi":"10.1016/j.cell.2025.11.016","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.016","url":null,"abstract":"The tumor immune microenvironment (TIME) critically impacts cancer progression and immunotherapy response. Multiplex immunofluorescence (mIF) is a powerful imaging modality for deciphering TIME, but its applicability is limited by high cost and low throughput. We propose <em>GigaTIME</em>, a multimodal AI framework for population-scale TIME modeling by bridging cell morphology and states. <em>GigaTIME</em> learns a cross-modal translator to generate virtual mIF images from hematoxylin and eosin (H&E) slides by training on 40 million cells with paired H&E and mIF data across 21 proteins. We applied <em>GigaTIME</em> to 14,256 patients from 51 hospitals and over 1,000 clinics across seven US states in Providence Health, generating 299,376 virtual mIF slides spanning 24 cancer types and 306 subtypes. This virtual population uncovered 1,234 statistically significant associations linking proteins, biomarkers, staging, and survival. Such analyses were previously infeasible due to the scarcity of mIF data. Independent validation on 10,200 TCGA patients further corroborated our findings.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"2 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711128","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}
Pub Date : 2025-12-08DOI: 10.1016/j.cell.2025.11.011
Sung Ryul Choi, Thorsten B. Blum, Matteo Giono, Bibhas Roy, Ioannis Vakonakis, Dominic Schmid, Nicole Oelgarth, Apisha Ranganathan, Alvar D. Gossert, G.V. Shivashankar, Alfred Zippelius, Michel O. Steinmetz
Microtubules have long been recognized as upstream mediators of intracellular signaling, but the mechanisms underlying this fundamental function remain elusive. Here, we identify the structural basis by which microtubules regulate the guanine nucleotide exchange factor H1 (GEFH1), a key activator of the Ras homolog family member A (RhoA) pathway. We show that specific features of the microtubule lattice bind the C1 domain of GEFH1, leading to the sequestration and inactivation of this signaling protein. Targeted mutations in C1 residues disrupt this interaction, triggering GEFH1 release and activation of RhoA-dependent immune responses. Building on this sequestration-and-release mechanism, we identify microtubule-binding C1 domains in additional signaling proteins, including other guanine nucleotide exchange factors (GEFs), kinases, a GTPase-activating protein (GAP), and a tumor suppressor, and show that microtubule-mediated regulation via C1 domains is conserved in the Ras association domain-containing protein 1A (RASSF1A). Our findings establish a structural framework for understanding how microtubules can function as spatiotemporal signal sensors, integrating and processing diverse signaling pathways to control important cellular processes.
{"title":"Structural basis of microtubule-mediated signal transduction","authors":"Sung Ryul Choi, Thorsten B. Blum, Matteo Giono, Bibhas Roy, Ioannis Vakonakis, Dominic Schmid, Nicole Oelgarth, Apisha Ranganathan, Alvar D. Gossert, G.V. Shivashankar, Alfred Zippelius, Michel O. Steinmetz","doi":"10.1016/j.cell.2025.11.011","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.011","url":null,"abstract":"Microtubules have long been recognized as upstream mediators of intracellular signaling, but the mechanisms underlying this fundamental function remain elusive. Here, we identify the structural basis by which microtubules regulate the guanine nucleotide exchange factor H1 (GEFH1), a key activator of the Ras homolog family member A (RhoA) pathway. We show that specific features of the microtubule lattice bind the C1 domain of GEFH1, leading to the sequestration and inactivation of this signaling protein. Targeted mutations in C1 residues disrupt this interaction, triggering GEFH1 release and activation of RhoA-dependent immune responses. Building on this sequestration-and-release mechanism, we identify microtubule-binding C1 domains in additional signaling proteins, including other guanine nucleotide exchange factors (GEFs), kinases, a GTPase-activating protein (GAP), and a tumor suppressor, and show that microtubule-mediated regulation via C1 domains is conserved in the Ras association domain-containing protein 1A (RASSF1A). Our findings establish a structural framework for understanding how microtubules can function as spatiotemporal signal sensors, integrating and processing diverse signaling pathways to control important cellular processes.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"138 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704286","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}
Pub Date : 2025-12-05DOI: 10.1016/j.cell.2025.11.009
Quan Jiang, Ling-Xiao Shao, Shenqin Yao, Neil K. Savalia, Amelia D. Gilbert, Pasha A. Davoudian, Jack D. Nothnagel, Guilian Tian, Tin Shing Hung, Hei Ming Lai, Kevin T. Beier, Hongkui Zeng, Alex C. Kwan
Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal cortical pyramidal neurons. We discover that psilocybin's effect on connectivity is network specific, strengthening the routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on the drug-evoked spiking activity because silencing a presynaptic region during psilocybin administration disrupts the rewiring. Collectively, the results reveal the impact of psilocybin on the connectivity of large-scale cortical networks and demonstrate neural activity modulation as an approach to sculpt the psychedelic-evoked neural plasticity.
{"title":"Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks","authors":"Quan Jiang, Ling-Xiao Shao, Shenqin Yao, Neil K. Savalia, Amelia D. Gilbert, Pasha A. Davoudian, Jack D. Nothnagel, Guilian Tian, Tin Shing Hung, Hei Ming Lai, Kevin T. Beier, Hongkui Zeng, Alex C. Kwan","doi":"10.1016/j.cell.2025.11.009","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.009","url":null,"abstract":"Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal cortical pyramidal neurons. We discover that psilocybin's effect on connectivity is network specific, strengthening the routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on the drug-evoked spiking activity because silencing a presynaptic region during psilocybin administration disrupts the rewiring. Collectively, the results reveal the impact of psilocybin on the connectivity of large-scale cortical networks and demonstrate neural activity modulation as an approach to sculpt the psychedelic-evoked neural plasticity.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"2 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689948","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}
Pub Date : 2025-12-04DOI: 10.1016/j.cell.2025.11.014
Svenja M. Lorenz, Adam Wahida, Mark J. Bostock, Tobias Seibt, André Santos Dias Mourão, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S. Woo, Jana K. Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F. Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Cheng, Marcus Conrad
Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer’s-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.
{"title":"A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis","authors":"Svenja M. Lorenz, Adam Wahida, Mark J. Bostock, Tobias Seibt, André Santos Dias Mourão, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S. Woo, Jana K. Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F. Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Cheng, Marcus Conrad","doi":"10.1016/j.cell.2025.11.014","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.014","url":null,"abstract":"Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal <em>Gpx4</em> deletion or neuron-specific GPX4<sup>R152H</sup> expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer’s-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673657","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}
Pub Date : 2025-12-04DOI: 10.1016/j.cell.2025.11.013
Rose Z. Hill, Jonathan W. Nelson, Georgina Gyarmati, Silvia Medrano, Sepenta Shirvan, James A. McCormick, Sebastian Burquez, Jeanine Ahmed, Diana G. Eng, Jan Wysocki, Adrienne E. Dubin, M. Rocio Servin-Vences, Arjun Lakshmanan, R. Ariel Gomez, Maria Luisa S. Sequeira-Lopez, Stuart J. Shankland, Daniel Batlle, Jeffrey H. Miner, Janos Peti-Peterdi, Ardem Patapoutian
Renin synthesis and release is the rate-limiting step of the renin-angiotensin-aldosterone system (RAAS) that controls fluid homeostasis. A major activator of the RAAS is a decrease in perfusion pressure within the kidneys, suggesting a link between renal mechanotransduction and renin. However, the identity of the mechanosensor(s) in the kidneys and their physiological significance to the RAAS remain unclear. We find that loss of the force-gated nonselective cation channel PIEZO2 in cells of renin lineage dysregulates the RAAS by elevating renin. We observe that PIEZO2 is expressed in renin-producing juxtaglomerular granular cells and is required for their calcium dynamics in vivo. PIEZO2 deficiency in cells of renin lineage drives renin-dependent and MAS-receptor-dependent glomerular hyperfiltration and regulates the RAAS during acute and chronic blood volume challenges. Collectively, our study identifies PIEZO2 as an essential regulator of juxtaglomerular granular cell calcium activity and renin in vivo.
{"title":"Renal PIEZO2 is an essential regulator of renin","authors":"Rose Z. Hill, Jonathan W. Nelson, Georgina Gyarmati, Silvia Medrano, Sepenta Shirvan, James A. McCormick, Sebastian Burquez, Jeanine Ahmed, Diana G. Eng, Jan Wysocki, Adrienne E. Dubin, M. Rocio Servin-Vences, Arjun Lakshmanan, R. Ariel Gomez, Maria Luisa S. Sequeira-Lopez, Stuart J. Shankland, Daniel Batlle, Jeffrey H. Miner, Janos Peti-Peterdi, Ardem Patapoutian","doi":"10.1016/j.cell.2025.11.013","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.013","url":null,"abstract":"Renin synthesis and release is the rate-limiting step of the renin-angiotensin-aldosterone system (RAAS) that controls fluid homeostasis. A major activator of the RAAS is a decrease in perfusion pressure within the kidneys, suggesting a link between renal mechanotransduction and renin. However, the identity of the mechanosensor(s) in the kidneys and their physiological significance to the RAAS remain unclear. We find that loss of the force-gated nonselective cation channel PIEZO2 in cells of renin lineage dysregulates the RAAS by elevating renin. We observe that PIEZO2 is expressed in renin-producing juxtaglomerular granular cells and is required for their calcium dynamics <em>in vivo</em>. PIEZO2 deficiency in cells of renin lineage drives renin-dependent and MAS-receptor-dependent glomerular hyperfiltration and regulates the RAAS during acute and chronic blood volume challenges. Collectively, our study identifies PIEZO2 as an essential regulator of juxtaglomerular granular cell calcium activity and renin <em>in vivo</em>.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"28 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673658","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}
Pub Date : 2025-12-03DOI: 10.1016/j.cell.2025.11.006
Lisa K. Iwamoto-Stohl, Aleksandra A. Petelski, Baiyi Quan, Maciej Meglicki, Audrey Fu, Shoma Nakagawa, Breanna McMahon, Ting-Yu Wang, Saad Khan, Harrison Specht, Gray Huffman, Jason Derks, Sergi Junyent, Bailey A.T. Weatherbee, Antonia Weberling, Carlos W. Gantner, Rachel S. Mandelbaum, Richard J. Paulson, Lisa Lam, Tsui-Fen Chou, Magdalena Zernicka-Goetz
While non-mammalian embryos often rely on spatial pre-patterning, mammalian development has long been thought to begin with equivalent blastomeres. However, emerging evidence challenges this. Here, using multiplexed and label-free single-cell proteomics, we identify over 300 asymmetrically abundant proteins—many involved in protein degradation and transport—dividing mouse 2-cell-stage blastomeres into two distinct clusters, which we term alpha and beta. These proteomic asymmetries are detectable as early as the zygote stage, intensify by the 4-cell stage, and correlate with the sperm entry site, implicating fertilization as a symmetry-breaking event. Splitting 2-cell-stage embryos into halves reveals that beta blastomeres possess greater developmental potential than alpha blastomeres. Similar clustering and protein enrichment patterns found in human 2-cell embryos suggest this early asymmetry might be conserved. These findings uncover a previously unrecognized proteomic pre-patterning triggered by fertilization in mammalian embryos, with important implications for understanding totipotency and early lineage bias.
{"title":"Fertilization triggers early proteomic symmetry breaking in mammalian embryos","authors":"Lisa K. Iwamoto-Stohl, Aleksandra A. Petelski, Baiyi Quan, Maciej Meglicki, Audrey Fu, Shoma Nakagawa, Breanna McMahon, Ting-Yu Wang, Saad Khan, Harrison Specht, Gray Huffman, Jason Derks, Sergi Junyent, Bailey A.T. Weatherbee, Antonia Weberling, Carlos W. Gantner, Rachel S. Mandelbaum, Richard J. Paulson, Lisa Lam, Tsui-Fen Chou, Magdalena Zernicka-Goetz","doi":"10.1016/j.cell.2025.11.006","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.006","url":null,"abstract":"While non-mammalian embryos often rely on spatial pre-patterning, mammalian development has long been thought to begin with equivalent blastomeres. However, emerging evidence challenges this. Here, using multiplexed and label-free single-cell proteomics, we identify over 300 asymmetrically abundant proteins—many involved in protein degradation and transport—dividing mouse 2-cell-stage blastomeres into two distinct clusters, which we term alpha and beta. These proteomic asymmetries are detectable as early as the zygote stage, intensify by the 4-cell stage, and correlate with the sperm entry site, implicating fertilization as a symmetry-breaking event. Splitting 2-cell-stage embryos into halves reveals that beta blastomeres possess greater developmental potential than alpha blastomeres. Similar clustering and protein enrichment patterns found in human 2-cell embryos suggest this early asymmetry might be conserved. These findings uncover a previously unrecognized proteomic pre-patterning triggered by fertilization in mammalian embryos, with important implications for understanding totipotency and early lineage bias.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657144","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}
Pub Date : 2025-12-03DOI: 10.1016/j.cell.2025.11.032
Wen-Wei Liang, Simon Müller, Sydney K. Hart, Hans-Hermann Wessels, Alejandro Méndez-Mancilla, Akash Sookdeo, Olivia Choi, Christina M. Caragine, Alba Corman, Lu Lu, Olena Kolumba, Breanna Williams, Neville E. Sanjana
(Cell 187, 7637–7654.e1–e29; December 26, 2024)
（187,7637 - 7654.e1 - e29； 2024年12月26日）
{"title":"Retraction notice to: Transcriptome-scale RNA-targeting CRISPR screens reveal essential lncRNAs in human cells","authors":"Wen-Wei Liang, Simon Müller, Sydney K. Hart, Hans-Hermann Wessels, Alejandro Méndez-Mancilla, Akash Sookdeo, Olivia Choi, Christina M. Caragine, Alba Corman, Lu Lu, Olena Kolumba, Breanna Williams, Neville E. Sanjana","doi":"10.1016/j.cell.2025.11.032","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.032","url":null,"abstract":"(Cell <em>187</em>, 7637–7654.e1–e29; December 26, 2024)","PeriodicalId":9656,"journal":{"name":"Cell","volume":"117 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657142","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}
Pub Date : 2025-12-02DOI: 10.1016/j.cell.2025.11.007
Min Xie, Markus Eyting, Christian Bommer, Haroon Ahmed, Pascal Geldsetzer
Using natural experiments, we have previously reported that live-attenuated herpes zoster (HZ) vaccination appears to have prevented or delayed dementia diagnoses in both Wales and Australia. Here, we find that HZ vaccination also reduces mild cognitive impairment diagnoses and, among patients living with dementia, deaths due to dementia. Exploratory analyses suggest that the effects are not driven by a specific dementia type. Our approach takes advantage of the fact that individuals who had their eightieth birthday just after the start date of the HZ vaccination program in Wales were eligible for the vaccine for 1 year, whereas those who had their eightieth birthday just before were ineligible and remained ineligible for life. The key strength of our natural experiments is that these comparison groups should be similar in all characteristics except for a minute difference in age. Our findings suggest that live-attenuated HZ vaccination prevents or delays mild cognitive impairment and dementia and slows the disease course among those already living with dementia.
{"title":"The effect of shingles vaccination at different stages of the dementia disease course","authors":"Min Xie, Markus Eyting, Christian Bommer, Haroon Ahmed, Pascal Geldsetzer","doi":"10.1016/j.cell.2025.11.007","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.007","url":null,"abstract":"Using natural experiments, we have previously reported that live-attenuated herpes zoster (HZ) vaccination appears to have prevented or delayed dementia diagnoses in both Wales and Australia. Here, we find that HZ vaccination also reduces mild cognitive impairment diagnoses and, among patients living with dementia, deaths due to dementia. Exploratory analyses suggest that the effects are not driven by a specific dementia type. Our approach takes advantage of the fact that individuals who had their eightieth birthday just after the start date of the HZ vaccination program in Wales were eligible for the vaccine for 1 year, whereas those who had their eightieth birthday just before were ineligible and remained ineligible for life. The key strength of our natural experiments is that these comparison groups should be similar in all characteristics except for a minute difference in age. Our findings suggest that live-attenuated HZ vaccination prevents or delays mild cognitive impairment and dementia and slows the disease course among those already living with dementia.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"158 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651425","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}
Heat stress triggers cell membrane lipid remodeling, yet whether this signals plants to perceive high temperatures and how such physical signals are decoded into biological signals remains unclear. Here, we demonstrate that diacylglycerol kinase 7 (DGK7) responds to heat stress at the plasma membrane, converting diacylglycerol into the second messenger, phosphatidic acid (PA). Subsequently, metal-dependent phosphodiesterase (MdPDE1) senses PA, acquires its activity by binding to PA, and translocates to the nucleus to degrade another second messenger, cyclic adenosine monophosphate (cAMP). MdPDE1 then elicits transcriptional landscape changes via altering cAMP signaling. Furthermore, G protein subunit thermotolerance 2 (TT2) inhibits DGK7 activity by Ser477 dephosphorylation, blocking MdPDE1 activity and nuclear translocation. Notably, field trials demonstrated the promising applications of this mechanism that confers varying degrees of rice thermotolerance as needed. This study establishes a complete hierarchical thermo-decoding mechanism that opens opportunities for creating customized heat-tolerant crops, aiding in mitigating yield losses from global warming.
{"title":"A stepwise decoding mechanism for heat sensing in plants connects lipid remodeling to a nuclear signaling cascade","authors":"Yi Kan, Xiao-Rui Mu, Fangfang Qu, Zhi-An Dai, Jin Gao, Ning-Jing Liu, Siqi Li, Jun-Xiang Shan, Wang-Wei Ye, Nai-Qian Dong, Xiaolan Huang, Yi-Bing Yang, Shuang-Qin Guo, Jie-Jie Lei, Ying-Jie Cao, Ji-Fu Zhou, Pengcheng Li, Jianchuan Wang, Yixue Li, Hong-Xuan Lin, Youshun Lin","doi":"10.1016/j.cell.2025.11.003","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.003","url":null,"abstract":"Heat stress triggers cell membrane lipid remodeling, yet whether this signals plants to perceive high temperatures and how such physical signals are decoded into biological signals remains unclear. Here, we demonstrate that diacylglycerol kinase 7 (DGK7) responds to heat stress at the plasma membrane, converting diacylglycerol into the second messenger, phosphatidic acid (PA). Subsequently, metal-dependent phosphodiesterase (MdPDE1) senses PA, acquires its activity by binding to PA, and translocates to the nucleus to degrade another second messenger, cyclic adenosine monophosphate (cAMP). MdPDE1 then elicits transcriptional landscape changes via altering cAMP signaling. Furthermore, G protein subunit thermotolerance 2 (TT2) inhibits DGK7 activity by Ser<sup>477</sup> dephosphorylation, blocking MdPDE1 activity and nuclear translocation. Notably, field trials demonstrated the promising applications of this mechanism that confers varying degrees of rice thermotolerance as needed. This study establishes a complete hierarchical thermo-decoding mechanism that opens opportunities for creating customized heat-tolerant crops, aiding in mitigating yield losses from global warming.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657146","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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