CellPub Date : 2024-12-18DOI: 10.1016/j.cell.2024.11.014
Erica L. Huey, Josef Turecek, Michelle M. Delisle, Ofer Mazor, Gabriel E. Romero, Malvika Dua, Zoe K. Sarafis, Alexis Hobble, Kevin T. Booth, Lisa V. Goodrich, David P. Corey, David D. Ginty
{"title":"The auditory midbrain mediates tactile vibration sensing","authors":"Erica L. Huey, Josef Turecek, Michelle M. Delisle, Ofer Mazor, Gabriel E. Romero, Malvika Dua, Zoe K. Sarafis, Alexis Hobble, Kevin T. Booth, Lisa V. Goodrich, David P. Corey, David D. Ginty","doi":"10.1016/j.cell.2024.11.014","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.014","url":null,"abstract":"Vibrations are ubiquitous in nature, shaping behavior across the animal kingdom. For mammals, mechanical vibrations acting on the body are detected by mechanoreceptors of the skin and deep tissues and processed by the somatosensory system, while sound waves traveling through air are captured by the cochlea and encoded in the auditory system. Here, we report that mechanical vibrations detected by the body’s Pacinian corpuscle neurons, which are distinguished by their ability to entrain to high-frequency (40–1,000 Hz) environmental vibrations, are prominently encoded by neurons in the lateral cortex of the inferior colliculus (LCIC) of the midbrain. Remarkably, most LCIC neurons receive convergent Pacinian and auditory input and respond more strongly to coincident tactile-auditory stimulation than to either modality alone. Moreover, the LCIC is required for behavioral responses to high-frequency mechanical vibrations. Thus, environmental vibrations captured by Pacinian corpuscles are encoded in the auditory midbrain to mediate behavior.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"48 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841457","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":"YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies","authors":"Zhenhua Chen, Chengwu Zeng, Lu Yang, Yuan Che, Meiling Chen, Lillian Sau, Bintao Wang, Keren Zhou, Yu Chen, Ying Qing, Chao Shen, Tingjian Zhang, Mark Wunderlich, Dong Wu, Wei Li, Kitty Wang, Keith Leung, Miao Sun, Tingting Tang, Xin He, Jianjun Chen","doi":"10.1016/j.cell.2024.11.007","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.007","url":null,"abstract":"Long-term durable remission in patients with B cell malignancies following chimeric antigen receptor (CAR)-T cell immunotherapy remains unsatisfactory, often due to antigen escape. Malignant B cell transformation and oncogenic growth relies on efficient ATP synthesis, although the underlying mechanisms remain unclear. Here, we report that YTHDF2 facilitates energy supply and antigen escape in B cell malignancies, and its overexpression alone is sufficient to cause B cell transformation and tumorigenesis. Mechanistically, YTHDF2 functions as a dual reader where it stabilizes mRNAs as a 5-methylcytosine (m<sup>5</sup>C) reader via recruiting PABPC1, thereby enhancing their expression and ATP synthesis. Concomitantly, YTHDF2 also promotes immune evasion by destabilizing other mRNAs as an <em>N</em><sup>6</sup>-methyladenosine (m<sup>6</sup>A) reader. Small-molecule-mediated targeting of YTHDF2 suppresses aggressive B cell malignancies and sensitizes them to CAR-T cell therapy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"101 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832850","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":"Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration","authors":"Han Chen, Chao Liu, Shiyao Cui, Yingqian Xia, Ke Zhang, Hanxiao Cheng, Jingyu Peng, Xiaoling Yu, Luyang Li, Hualin Yu, Jufang Zhang, Ju-Sheng Zheng, Bing Zhang","doi":"10.1016/j.cell.2024.11.004","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.004","url":null,"abstract":"Intermittent fasting has gained global popularity for its potential health benefits, although its impact on somatic stem cells and tissue biology remains elusive. Here, we report that commonly used intermittent fasting regimens inhibit hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). This effect is independent of calorie reduction, circadian rhythm alterations, or the mTORC1 cellular nutrient-sensing mechanism. Instead, fasting activates crosstalk between adrenal glands and dermal adipocytes in the skin, triggering the rapid release of free fatty acids into the niche, which in turn disrupts the normal metabolism of HFSCs and elevates their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. A randomized clinical trial (NCT05800730) indicates that intermittent fasting inhibits human hair growth. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration and identifies interorgan communication that eliminates activated HFSCs and halts tissue regeneration during periods of unstable nutrient supply.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"16 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816154","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":"Engineering source-sink relations by prime editing confers heat-stress resilience in tomato and rice","authors":"Huanchang Lou, Shujia Li, Zihang Shi, Yupan Zou, Yueqin Zhang, Xiaozhen Huang, Dandan Yang, Yongfang Yang, Zuoyao Li, Cao Xu","doi":"10.1016/j.cell.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.005","url":null,"abstract":"A 2°C climate-warming scenario is expected to further exacerbate average crop losses by 3%–13%, yet few heat-tolerant staple-crop varieties are available toward meeting future food demands. Here, we develop high-efficiency prime-editing tools to precisely knockin a 10-bp heat-shock element (HSE) into promoters of cell-wall-invertase genes (<em>CWINs</em>) in elite rice and tomato cultivars. HSE insertion endows <em>CWINs</em> with heat-responsive upregulation in both controlled and field environments to enhance carbon partitioning to grain and fruits, resulting in per-plot yield increases of 25% in rice cultivar Zhonghua11 and 33% in tomato cultivar Ailsa Craig over heat-stressed controls, without fruit quality penalties. Up to 41% of heat-induced grain losses were rescued in rice. Beyond a prime-editing system for tweaking gene expression by efficiently delivering bespoke changes into crop genomes, we demonstrate broad and robust utility for targeted knockin of <em>cis</em>-regulatory elements to optimize source-sink relations and boost crop climate resilience.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"41 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816155","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 : 2024-12-12DOI: 10.1016/j.cell.2024.11.016
Giulia Irene Maria Pasquesi, Holly Allen, Atma Ivancevic, Arturo Barbachano-Guerrero, Olivia Joyner, Kejun Guo, David M. Simpson, Keala Gapin, Isabella Horton, Lily L. Nguyen, Qing Yang, Cody J. Warren, Liliana D. Florea, Benjamin G. Bitler, Mario L. Santiago, Sara L. Sawyer, Edward B. Chuong
{"title":"Regulation of human interferon signaling by transposon exonization","authors":"Giulia Irene Maria Pasquesi, Holly Allen, Atma Ivancevic, Arturo Barbachano-Guerrero, Olivia Joyner, Kejun Guo, David M. Simpson, Keala Gapin, Isabella Horton, Lily L. Nguyen, Qing Yang, Cody J. Warren, Liliana D. Florea, Benjamin G. Bitler, Mario L. Santiago, Sara L. Sawyer, Edward B. Chuong","doi":"10.1016/j.cell.2024.11.016","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.016","url":null,"abstract":"Innate immune signaling is essential for clearing pathogens and damaged cells and must be tightly regulated to avoid excessive inflammation or autoimmunity. Here, we found that the alternative splicing of exons derived from transposable elements is a key mechanism controlling immune signaling in human cells. By analyzing long-read transcriptome datasets, we identified numerous transposon exonization events predicted to generate functional protein variants of immune genes, including the type I interferon receptor IFNAR2. We demonstrated that the transposon-derived isoform of IFNAR2 is more highly expressed than the canonical isoform in almost all tissues and functions as a decoy receptor that potently inhibits interferon signaling, including in cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our findings uncover a primate-specific axis controlling interferon signaling and show how a transposon exonization event can be co-opted for immune regulation.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"29 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809590","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 : 2024-12-12DOI: 10.1016/j.cell.2024.11.015
Charlotte Bunne, Yusuf Roohani, Yanay Rosen, Ankit Gupta, Xikun Zhang, Marcel Roed, Theo Alexandrov, Mohammed AlQuraishi, Patricia Brennan, Daniel B. Burkhardt, Andrea Califano, Jonah Cool, Abby F. Dernburg, Kirsty Ewing, Emily B. Fox, Matthias Haury, Amy E. Herr, Eric Horvitz, Patrick D. Hsu, Viren Jain, Stephen R. Quake
{"title":"How to build the virtual cell with artificial intelligence: Priorities and opportunities","authors":"Charlotte Bunne, Yusuf Roohani, Yanay Rosen, Ankit Gupta, Xikun Zhang, Marcel Roed, Theo Alexandrov, Mohammed AlQuraishi, Patricia Brennan, Daniel B. Burkhardt, Andrea Califano, Jonah Cool, Abby F. Dernburg, Kirsty Ewing, Emily B. Fox, Matthias Haury, Amy E. Herr, Eric Horvitz, Patrick D. Hsu, Viren Jain, Stephen R. Quake","doi":"10.1016/j.cell.2024.11.015","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.015","url":null,"abstract":"Cells are essential to understanding health and disease, yet traditional models fall short of modeling and simulating their function and behavior. Advances in AI and omics offer groundbreaking opportunities to create an AI virtual cell (AIVC), a multi-scale, multi-modal large-neural-network-based model that can represent and simulate the behavior of molecules, cells, and tissues across diverse states. This Perspective provides a vision on their design and how collaborative efforts to build AIVCs will transform biological research by allowing high-fidelity simulations, accelerating discoveries, and guiding experimental studies, offering new opportunities for understanding cellular functions and fostering interdisciplinary collaborations in open science.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"88 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809970","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 : 2024-12-11DOI: 10.1016/j.cell.2024.11.022
Jake F. Watson, Victor Vargas-Barroso, Rebecca J. Morse-Mora, Andrea Navas-Olive, Mojtaba R. Tavakoli, Johann G. Danzl, Matthias Tomschik, Karl Rössler, Peter Jonas
{"title":"Human hippocampal CA3 uses specific functional connectivity rules for efficient associative memory","authors":"Jake F. Watson, Victor Vargas-Barroso, Rebecca J. Morse-Mora, Andrea Navas-Olive, Mojtaba R. Tavakoli, Johann G. Danzl, Matthias Tomschik, Karl Rössler, Peter Jonas","doi":"10.1016/j.cell.2024.11.022","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.022","url":null,"abstract":"Our brain has remarkable computational power, generating sophisticated behaviors, storing memories over an individual’s lifetime, and producing higher cognitive functions. However, little of our neuroscience knowledge covers the human brain. Is this organ truly unique, or is it a scaled version of the extensively studied rodent brain? Combining multicellular patch-clamp recording with expansion-based superresolution microscopy and full-scale modeling, we determined the cellular and microcircuit properties of the human hippocampal CA3 region, a fundamental circuit for memory storage. In contrast to neocortical networks, human hippocampal CA3 displayed sparse connectivity, providing a circuit architecture that maximizes associational power. Human synapses showed unique reliability, high precision, and long integration times, exhibiting both species- and circuit-specific properties. Together with expanded neuronal numbers, these circuit characteristics greatly enhanced the memory storage capacity of CA3. Our results reveal distinct microcircuit properties of the human hippocampus and begin to unravel the inner workings of our most complex organ.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"200 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804861","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 : 2024-12-11DOI: 10.1016/j.cell.2024.11.011
Yago A. Arribas, Blandine Baudon, Maxime Rotival, Guadalupe Suárez, Pierre-Emmanuel Bonté, Vanessa Casas, Apollinaire Roubert, Paul Klein, Elisa Bonnin, Basma Mchich, Patricia Legoix, Sylvain Baulande, Benjamin Sadacca, Julien Diharce, Joshua J. Waterfall, Catherine Etchebest, Montserrat Carrascal, Christel Goudot, Lluís Quintana-Murci, Marianne Burbage, Sebastian Amigorena
{"title":"Transposable element exonization generates a reservoir of evolving and functional protein isoforms","authors":"Yago A. Arribas, Blandine Baudon, Maxime Rotival, Guadalupe Suárez, Pierre-Emmanuel Bonté, Vanessa Casas, Apollinaire Roubert, Paul Klein, Elisa Bonnin, Basma Mchich, Patricia Legoix, Sylvain Baulande, Benjamin Sadacca, Julien Diharce, Joshua J. Waterfall, Catherine Etchebest, Montserrat Carrascal, Christel Goudot, Lluís Quintana-Murci, Marianne Burbage, Sebastian Amigorena","doi":"10.1016/j.cell.2024.11.011","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.011","url":null,"abstract":"Alternative splicing enhances protein diversity in different ways, including through exonization of transposable elements (TEs). Recent transcriptomic analyses identified thousands of unannotated spliced transcripts with exonizing TEs, but their contribution to the proteome and biological relevance remains unclear. Here, we use transcriptome assembly, ribosome profiling, and proteomics to describe a population of 1,227 unannotated TE exonizing isoforms generated by mRNA splicing and recurrent in human populations. Despite being shorter and lowly expressed, these isoforms are shared between individuals and efficiently translated. Functional analyses show stable expression, specific cellular localization, and, in some cases, modified functions. Exonized TEs are rich in ancient genes, whereas the involved splice sites are recent and can be evolutionarily conserved. In addition, exonized TEs contribute to the secondary structure of the emerging isoforms, supporting their functional relevance. We conclude that TE-spliced isoforms represent a diversity reservoir of functional proteins on which natural selection can act.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"2 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804864","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 : 2024-12-11DOI: 10.1016/j.cell.2024.11.021
Bibekananda Sahoo, Zongjun Mou, Wei Liu, George Dubyak, Xinghong Dai
{"title":"How NINJ1 mediates plasma membrane rupture and why NINJ2 cannot","authors":"Bibekananda Sahoo, Zongjun Mou, Wei Liu, George Dubyak, Xinghong Dai","doi":"10.1016/j.cell.2024.11.021","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.021","url":null,"abstract":"Ninjurin-1 (NINJ1) is an active executioner of plasma membrane rupture (PMR), a process previously thought to be a passive osmotic lysis event in lytic cell death. Ninjurin-2 (NINJ2) is a close paralog of NINJ1 but cannot mediate PMR. Using cryogenic electron microscopy (cryo-EM), we show that NINJ1 and NINJ2 both assemble into linear filaments that are hydrophobic on one side but hydrophilic on the other. This structural feature and other evidence point to a PMR mechanism by which NINJ1 filaments wrap around and solubilize membrane fragments and, less frequently, form pores in the plasma membrane. In contrast to the straight NINJ1 filament, the NINJ2 filament is curved toward the intracellular space, preventing its circularization or even assembly on a relatively flat membrane to mediate PMR. Mutagenesis studies further demonstrate that the NINJ2 filament curvature is induced by strong association with lipids, particularly a cholesterol molecule, at the cytoplasmic leaflet of the lipid bilayer.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"10 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804868","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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