Cell最新文献

{"title":"Fronto-insular circuit mechanisms of accelerated intermittent theta burst stimulation.","authors":"Shane B Johnson, Devin Rocks, Laura Chalençon, Kenneth Johnson, Umair Hassan, Anisul Arefin, Gülcan Akgül, Alexander Donatelle, Henry Asher, Immanuel Elbau, David Estrin, Rebecca Zhang, Alexandra Lenz, Rachel Mikofsky, Cory Knox, Rachael Han, Pooja Suganthan, Tahrima Chowdhury, Christine Kuang, Daniel Shaver, Parsa Nilchian, Puja Parekh, Jacob Roshgadol, Natalia DeMarco Garcia, Matthew Wright, Lindsay Victoria, Benjamin Zebley, Joshua Levitz, Corey J Keller, Aaron D Boes, Conor Liston","doi":"10.1016/j.cell.2026.04.030","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.030","url":null,"abstract":"<p><p>Transcranial magnetic stimulation (TMS) is a widely used neuromodulation treatment for depression, but its mechanisms are poorly understood. Indirect clinical evidence suggests that TMS enhances plasticity within the prefrontal cortical target site and engages downstream networks. However, establishing causal mechanisms to help optimize the large stimulation parameter space has been challenging. Using an optogenetic model of accelerated intermittent theta burst stimulation (prelimbic [PL]-aiTBS) that drives rapid antidepressant-like effects, we examined cell type-specific effects on synapse-related gene expression, increased spine density, and increased excitatory currents in prefrontal intratelencephalic projection neurons. Whole-brain c-Fos immunolabeling, fiber photometry, chemogenetic, and projection-specific optogenetic manipulations revealed that PL-aiTBS activates a fronto-insular network that is necessary and sufficient for its antidepressant-like behavioral effects. Finally, we validate a key role for fronto-insular connectivity and TMS-evoked responses in the human insula using intracortical stereo-electroencephalogram (EEG) and resting-state fMRI. These results establish a fronto-insular circuit as a critical mediator of the antidepressant effects of aiTBS.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855976","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":"A blood-brain barrier-like vascular gate limits immunotherapy efficacy in neuroendocrine cancers.","authors":"Yiyun Wang, Ailing Zhong, Bo Wang, Xiaoqian Zhai, Chang Lei, Zuoyu Liang, Xintong Deng, Jian Zhong, Chaoxin Xiao, Jianan Zheng, Baohong Wu, Lanxin Zhang, Yuying Wang, Xiangmeng Luo, Jian Wang, Mengsha Zhang, Hongyu Liu, Xudong Wan, Siqi Dai, Yucen Yang, Shiyu Zhang, Weiya Wang, Shengyong Yang, Jianxin Xue, Chengjian Zhao, Tuomas Tammela, Zhiming Li, Yan Zhang, Feifei Na, Manli Wang, Yu Liu, Chong Chen","doi":"10.1016/j.cell.2026.04.017","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.017","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, exhibits poor response to immunotherapy, and the underlying mechanisms remain unclear. Here, we identify a blood-brain barrier-like vascular gate (BVG) in SCLC, distinct from non-SCLC (NSCLC) and other cancers, composed of tightly connected endothelial cells, a thickened basement membrane, and dense pericyte coverage. Functionally, this blood-brain barrier-like vascular gate restricts immune cell infiltration, contributing to SCLC's immunotherapy resistance. Mechanistically, achaete-scute family basic-helix-loop-helix (bHLH) transcription factor 1 (ASCL1), the master transcription factor of SCLC, is essential for BVG formation by regulating insulin-like growth factor-binding protein 5 (IGFBP5), which activates the IGF1 signaling in endothelial cells. IGFBP5 knockout or treatment with the IGF1R inhibitor OSI-906 enhances CD8⁺ T cell infiltration and synergizes with anti-PD1 therapy. Furthermore, this ASCL1-IGFBP5-IGF1R axis and the BVG are conserved across multiple neuroendocrine cancers (NECs). Our findings reveal a previously unrecognized vascular gate in NECs and propose novel therapeutic strategies to enhance immunotherapy efficacy in these recalcitrant cancers.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855983","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":"A cell type-specific mechanism driving the rapid antidepressant effects of transcranial magnetic stimulation.","authors":"Michael W Gongwer, Alex Qi, Alexander S Enos, Sophia A Rueda Mora, Sabahaddin Taha Solakoğlu, Russell N Ahmed, Cassandra B Klune, Meelan Shari, Adrienne Q Kashay, Owen H Williams, Aliza Hacking, Jack P Riley, Gary A Wilke, Yihong Yang, Hanbing Lu, Andrew F Leuchter, Laura A DeNardo, Scott A Wilke","doi":"10.1016/j.cell.2025.12.040","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.040","url":null,"abstract":"<p><p>Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for brain disorders, but its therapeutic mechanism is poorly understood. We developed a mouse model of rTMS with superior clinical face validity and investigated the neural mechanism by which accelerated intermittent theta burst stimulation (aiTBS), the first rapid-acting rTMS antidepressant protocol, reversed chronic stress-induced behavioral deficits. Using fiber photometry, we showed that aiTBS drives distinct patterns of neural activity in intratelencephalic (IT) and pyramidal tract (PT) projection neurons in dorsomedial prefrontal cortex (dmPFC). However, only IT neurons exhibited persistently increased activity during both aiTBS and subsequent depression-related behaviors. aiTBS reversed stress-related loss of dendritic spines on IT, but not PT neurons, further demonstrating cell type-specific effects of stimulation. Chemogenetically inhibiting dmPFC IT, but not PT neurons, during rTMS blocked the antidepressant-like behavioral effects of aiTBS. Thus, we demonstrate a prefrontal mechanism linking rapid aiTBS-driven therapeutic effects to cell type-specific circuit plasticity.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855972","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":"Affinity-matured B cell responses neutralizing type-I interferons underlie severe viral infections.","authors":"Morgane Fournier, Matthias Vanderkerken, Karim Dorgham, Paul Bastard, Olivia Ahouzi, Stephane Duquerroy, Ngoc Khanh Nguyen, Manon Broutin, Manon Charlet, Alexis Vandenberghe, Paolo Van Endert, Lucy Bizien, Omaira Da Mata-Jardin, Andrés Ferriño-Iriarte, Ahmed Haouz, Thibaut Belmondo, Sophie Hüe, Alessandro Borghesi, Carlos Rodríguez-Gallego, Donald C Vinh, Evangelos Andreakos, Filomeen Haerynck, Rabih Halwani, Qiang Pan-Hammarström, Niklas K Björkström, Benedikt Strunz, Trine H Mogensen, Antonio Piralla, Stefania Varchetta, Jorge Freixinet, Lucie Roussel, Sophie Trouillet Assant, Bénédicte Neven, Romain Levy, Tom le Voyer, Ottavia M Delmonte, Cliona O'Farrelly, Jacques Rivière, Blanca Amador Borrero, Amélie Servettaz, Roger D Kouyos, Daniel E Kaufmann, Etienne Crickx, Marc Michel, Anne Puel, Laurent Abel, Charles-Edouard Luyt, Alexis Mathian, Kai Kisand, Darragh Duffy, Lluis Quintana-Murci, Zahir Amoura, Benjamin G Hale, Jean-Claude Weill, Jean-Laurent Casanova, Felix A Rey, Guy Gorochov, Pascal Chappert, Matthieu Mahévas","doi":"10.1016/j.cell.2026.04.013","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.013","url":null,"abstract":"<p><p>Autoantibodies neutralizing type-I interferons (AAN-I-IFNs) emerge as global, common, and strong determinants of a growing number of severe viral diseases. We report that AAN-I-IFNs⁺ patients with life-threatening COVID-19 pneumonia harbor circulating type-I IFN-specific B cells indistinguishable from patients bearing T cell tolerance defects of genetic origin. This autoimmune response mobilizes a highly diverse and stable circulating B cell response that is detected prior to severe viral infection and acquires high affinity and neutralization potential to type-I IFNs through extended somatic hypermutation. X-ray crystallography and AlphaFold3 structural analysis of hundreds of patient-derived monoclonal antibodies reveals the extended breadth of this response, targeting three major B cell epitopes covering all facets of type-I IFNs. These findings support a model in which a germinal-center-derived memory B cell response directed against type-I IFNs is established before severe viral infection, providing a core mechanism linking T cell tolerance defect to pathogenic AAN-I-IFNs underlying severe viral diseases.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834291","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":"Virological characteristics of SARS-CoV-2-related coronaviruses dynamically circulating in Southeast Asia.","authors":"Supaporn Wacharapluesadee, Wilaiporn Saikruang, Spyros Lytras, Kanata Matsumoto, Keiya Uriu, Alfredo Hinay, Ziyi Guo, Khwankamon Rattanatumhi, Ananporn Supataragul, Sasiprapa Ninwattana, Nattakarn Thippamom, Tanawut Srisuk, Patarapol Maneeorn, Kirana Noradechanon, Prateep Duengkae, Nutthinee Sirichan, Yusuke Kosugi, Shigeru Fujita, Maximilian Stanley Yo, Ryo Matsunaga, Bingjie Hu, Lianzhao Du, Lei Wang, Masumi Tsuda, Yoshitaka Oda, Hesham Nasser, Kanako Terakado Kimura, Hiroaki Akasaka, Hiroyuki Asakura, Mami Nagashima, Kenji Sadamasu, Kazuhisa Yoshimura, Yuki Yamamoto, Tetsuharu Nagamoto, Takanori Asakura, Wataru Shihoya, Takao Hashiguchi, Terumasa Ikeda, Shinya Tanaka, Hin Chu, Kouhei Tsumoto, Osamu Nureki, Arnon Plianchaisuk, Opass Putcharoen, Kei Sato","doi":"10.1016/j.cell.2026.04.019","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.019","url":null,"abstract":"<p><p>By sampling horseshoe bats-the reservoir hosts of SARS-CoV-2-related coronaviruses (SC2r-CoVs)-in Thailand, we present two clades of SC2r-CoVs co-circulating in the same bat population. Through a comprehensive set of experimental approaches, including cryo-electron microscopy (cryo-EM), pseudovirus and live virus assays, and hamster experiments, we characterize the virological properties of these new viruses. We show that one of the two clades discovered in this study is able to bind the human angiotensin converting enzyme 2 (ACE2) receptor; however, it exhibits reduced fusogenicity and replication in vitro and lower pathogenicity and transmissibility compared with SARS-CoV-2. Phylogeography and recombination analyses reveal a complex evolutionary history for these viruses characterized by extensive, recent geographic movement and recombination with co-circulating virus lineages. Our findings provide new insights into the diversity of SC2r-CoVs dynamically co-circulating in Southeast Asia as well as the virological characteristics of these viruses relative to SARS-CoV-2.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834272","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":"Multi-cohort proteogenomic analyses reveal genetic effects across the proteome and diseasome.","authors":"Mine Koprulu, Karl Smith-Byrne, Brian Richard Ferolito, Erin Macdonald-Dunlop, Jian'an Luan, Åsa K Hedman, Chibuzor Franklin Ogamba, Jurgis Kuliesius, Linda Repetto, Anna Ramisch, Fahim Abbasi, Johan Ärnlöv, Themistocles L Assimes, Hanna M Björck, Sophia Björkander, Morten Böttcher, Adam Stuart Butterworth, Zhengming Chen, Kelly Cho, Robert Joseph Clarke, Simon Riddington Cox, Kamila Czene, John Danesh, George Dedoussis, Sölve Elmståhl, Niclas Eriksson, Per Eriksson, Tõnu Esko, Aida Ferreiro-Iglesias, Paul William Franks, Jingyuan Fu, J Michael Gaziano, Mohsen Ghanbari, Christian Gieger, Arthur Gilly, Harald Grallert, Marc James Gunter, Stefan Gustafsson, Andreas Göteson, Per Frans Leonard Hall, Oskar Hansson, Sarah Elizabeth Harris, Caroline Hayward, Christian Herder, Natalia Hernandez-Pacheco, Ziad Hijazi, Robert F Hillary, Jemma Caroline Hopewell, Shixian Hu, Shih-Jen Hwang, Christina Jern, Åsa Johansson, Lina Jonsson, Anette Kalnapenkis, Nicola Dorothy Kerrison, Pik Fang Kho, Lucija Klaric, Leonhard Kohleick, Julia Kraft, Mikael Landén, Daniel Levy, Liming Li, Lars Lind, Jirong Long, Niklas Mattsson-Carlgren, Erik Melén, Simon Kebede Merid, Philipp Mertins, Karl Michaëlsson, Peter Loof Møller, Federico Murgia, Mette Nyegaard, Young-Chan Park, Ewan Pearson, James Peters, John Ross Petrie, Grace Png, Ozren Polašek, Bram Peter Prins, Stephan Ripke, Michael Roden, Palle Duun Rohde, Saredo Said, Xia Shen, Jochen M Schwenk, Agneta Siegbahn, J Gustav Smith, Tara M Stanne, Karsten Suhre, Johan Sundström, Barbara Thorand, Elsa Valdes-Marquez, Costanza L Vallerga, Joyce B J van Meurs, Ana Viñuela, Urmo Võsa, Lars Wallentin, Robin G Walters, Nicholas John Wareham, Joachim Eduard Weber, Rinse Karel Weersma, James F Wilson, Simon Winther, Summaira Yasmeen, Daniela Zanetti, Eleftheria Zeggini, Jing Hua Zhao, Alexandra Zhernakova, Daria V Zhernakova, Matthias Ziehm, Benedikt Mathias Kessler, Alexandre C Pereira, Anders Mälarstig, Maik Pietzner, Claudia Langenberg","doi":"10.1016/j.cell.2026.03.049","DOIUrl":"10.1016/j.cell.2026.03.049","url":null,"abstract":"<p><p>Understanding the genetic regulation of circulating protein levels can provide new insights into disease mechanisms. Here, we present the largest proteogenomic study to date (n = 78,664 participants across 38 studies), identifying >24,000 protein quantitative trait loci (QTLs) associated with 1,116 proteins, acting near to (n = 5,040) or distant (n = 19,698) from the cognate gene. Using machine learning-guided effector gene assignment, we provide genetic evidence for pathways, cell types, and tissues that modulate circulating protein levels, highlighting N-linked glycosylation as an important regulatory pathway. We demonstrate that genetic instruments of protein production/function (\"cis\") versus modulation (\"trans\") reveal distinct phenotypic insights. We identify proteins as candidates for drug targets and engagement (e.g., plasma furin and cardiovascular diseases) by comparing cis-based genetic evidence with protein-disease associations. Systematic triangulation of trans-protein QTLs (pQTLs) with genetic and protein associations across many diseases highlights potential drug repurposing opportunities, e.g., tyrosine kinase 2 (TYK2) inhibitors for rheumatoid arthritis. Our multi-cohort meta-analyses generate proteogenomic insights into disease mechanisms and new treatment opportunities.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834288","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":"Disrupted molecular glue complex drives RAS inhibitor resistance.","authors":"Ben Sang, Ling Feng Ye, Zheng Fu, Yasin Pourfarjam, Antonio Cuevas-Navarro, Shijie Fan, Feng Hu, Aaliyah Washington, Diego J Rodriguez, Alberto Vides, Sumit Kar, Ethan Ahler, Kevin K Lin, Aparna Hegde, Jacqueline A M Smith, Brian M Wolpin, Salman R Punekar, Alexander I Spira, Ignacio Garrido-Laguna, David S Hong, Arvin C Dar, Rona Yaeger, Kathryn C Arbour, Piro Lito","doi":"10.1016/j.cell.2026.03.031","DOIUrl":"https://doi.org/10.1016/j.cell.2026.03.031","url":null,"abstract":"<p><p>Tri-complex inhibitors (TCIs) are molecular glues that bind the active, guanosine triphosphate (GTP)-bound state of RAS and recruit cyclophilin A (CYPA) to form a synthetic complex that blocks oncogenic signaling. Although these agents have shown clinical activity in RAS mutant cancers, resistance mechanisms remain poorly defined. Here, we analyzed paired baseline and end-of-treatment samples from 40 patients treated with the RAS inhibitor daraxonrasib and identified recurrent alterations in 18 cases. Structural and functional analyses revealed that acquired mutations confer resistance by disrupting interactions essential for daraxonrasib binding to RAS, including RAS Y64 mutations, or by enhancing the RAS-RAF interaction, thereby favoring native RAS-RAF signaling, including RAS Y71 or kinase-dead/hypoactive BRAF mutations. We then identified a TCI that targets RAS Y64 mutants and combination therapies to target resistance driven by kinase-dead BRAF. These findings uncover convergent resistance mechanisms that undermine the molecular glue function and offer a mechanistic blueprint for enhancing therapeutic efficacy in RAS-driven malignancies.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834279","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":"Biodiversity and biogeography of the multi-kingdom cancer microbiome.","authors":"Anders B Dohlman, Robin Mjelle, Henry M Wood, Kevin Jiang, Alaina Shumate, Iris Lee, Gianmarco Piccinno, Garazi Serna, Abdul-Rakeem Yakubu, Paolo Nuciforo, Phil Quirke, Curtis Huttenhower, Nicola Segata, Matthew Meyerson","doi":"10.1016/j.cell.2026.04.015","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.015","url":null,"abstract":"<p><p>Microorganisms represent an important component of the tumor microenvironment, but conflicting reports have left the extent of microbial prevalence across cancer types unclear, necessitating more robust methods for characterizing tumor-associated microbiomes. We built and benchmarked a host-subtraction and classification pipeline to identify microbiota in whole-genome sequencing data and applied it to 16,369 high-depth tumor whole genomes from the UK 100,000 Genomes Project. After decontamination, microbial signatures were indistinguishable from the background in most cancer types. However, in orodigestive tumors, we detected multi-kingdom polymicrobial communities, including bacteria, fungi, viruses, archaea, and, in some cases, Trichomonas, a protozoan parasite. These communities varied by tumor site and subtype, with increased microbial colonization of microsatellite-instable and polymerase ε (POLE)/polymerase δ (POLD1)-mutated tumors, supported by a correlation between microbial load and tumor mutation burden observed across orodigestive cancers. This analysis helps to resolve pan-cancer microbial structure and links the tumor microbiome to host phenotype and tumor genomic context.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834340","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":"Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells.","authors":"Peng Lyu, Gaurav Agarwal, Chun-Jie Guo, Adam Sychla, Wallace Bourgeois, Tianyi Ye, Chen Weng, Mateusz Antoszewski, Samantha Joubran, Alexis Caulier, Michael Poeschla, Scott A Armstrong, Silvi Rouskin, Vijay G Sankaran","doi":"10.1016/j.cell.2026.04.014","DOIUrl":"10.1016/j.cell.2026.04.014","url":null,"abstract":"<p><p>The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We found that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9, which we named HOXA opposite-strand transcript, stem-cell regulator, antisense mid-cluster between loci (HOTSCRAMBL). The HOTSCRAMBL variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, HOTSCRAMBL enables appropriate expression and splicing of HOXA genes in HSCs, most notably HOXA9, in an SRSF2-dependent manner. Given the critical role of HOXA gene expression in some blood cancers, we also demonstrate that HOTSCRAMBL variation or deletion compromises HOXA-dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13138457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811509","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}

{"title":"PLANeT: Understanding and leveraging the genome of land plants for a sustainable future.","authors":"Li Wang, Mohamed Amar, Carlos I Arbizu, John L Bowman, Charles H Cannon, David J Cantrill, Xiaofeng Cao, Shilin Chen, Xiaoya Chen, Xuemei Chen, Kang Chong, Xingwang Deng, Weinan E, Hongwei Guo, Chuan He, Peter Hollingsworth, Qing Hu, Hongzhi Kong, Ilia J Leitch, Dezhu Li, Jiayang Li, Hongtao Liu, William Lucas, Eshchar Mizrachi, Mijoro Rakotoarinivo, Hai Ren, Loren Rieseberg, Jue Ruan, Rosa Scherson, Harald Schneider, Douglas E Soltis, Hang Sun, Marcio C Silva-Filho, Stephen Smith, Alex Twyford, Björn Usadel, Yves Van de Peer, Cássio Van den Berg, Rajeev K Varshney, Lyderson Facio Viccini, Qingfeng Wang, Xiao-Quan Wang, Yadong Wang, Jonathan Wendel, Rod Wing, Gane Ka-Shu Wong, Yaowu Xing, Xun Xu, Nieng Yan, Huanming Yang, Shouzhou Zhang, Yuxian Zhu, Pamela S Soltis, Detlef Weigel, Sanwen Huang","doi":"10.1016/j.cell.2026.01.026","DOIUrl":"https://doi.org/10.1016/j.cell.2026.01.026","url":null,"abstract":"<p><p>Land plants underpin civilization and planetary health, yet their genomic diversity remains largely uncharted. Current resources are unstandardized and scarce, lacking reference genomes for 95% of genera, 70% of families, and 51% of orders, impeding evolutionary and functional insight. We thus propose the PLANeT initiative, an international effort to generate high-quality, standardized genomes across the plant tree of life. Integrating artificial intelligence (AI) with genomics, we will decode conserved principles to advance fundamental plant biology, biodiversity conservation, crop improvement, and natural product discovery. Engaging around 100 labs to train 1,000 scientists, we will tackle pivotal questions for a sustainable future.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":"189 9","pages":"2519-2532"},"PeriodicalIF":42.5,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811421","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}