CellPub Date : 2024-10-17DOI: 10.1016/j.cell.2024.09.031
Ilana Witten, Daniel L.K. Yamins, Claudia Clopath, Matthias Bethge, Yi Zeng, Ann Kennedy, Abeba Birhane, Doris Tsao, Been Kim, Ila Fiete
{"title":"Future views on neuroscience and AI","authors":"Ilana Witten, Daniel L.K. Yamins, Claudia Clopath, Matthias Bethge, Yi Zeng, Ann Kennedy, Abeba Birhane, Doris Tsao, Been Kim, Ila Fiete","doi":"10.1016/j.cell.2024.09.031","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.031","url":null,"abstract":"The relationship between neuroscience and artificial intelligence (AI) has evolved rapidly over the past decade. These two areas of study influence and stimulate each other. We invited experts to share their perspectives on this exciting intersection, focusing on current achievements, unsolved questions, and future directions.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"25 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444194","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 : 2024-10-16DOI: 10.1016/j.cell.2024.09.032
Longyong Xu, Fanglue Peng, Qin Luo, Yao Ding, Fei Yuan, Liting Zheng, Wei He, Sophie S. Zhang, Xin Fu, Jin Liu, Ayse Sena Mutlu, Shuyue Wang, Ralf Bernd Nehring, Xingyu Li, Qianzi Tang, Catherine Li, Xiangdong Lv, Lacey E. Dobrolecki, Weijie Zhang, Dong Han, Xi Chen
{"title":"IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer","authors":"Longyong Xu, Fanglue Peng, Qin Luo, Yao Ding, Fei Yuan, Liting Zheng, Wei He, Sophie S. Zhang, Xin Fu, Jin Liu, Ayse Sena Mutlu, Shuyue Wang, Ralf Bernd Nehring, Xingyu Li, Qianzi Tang, Catherine Li, Xiangdong Lv, Lacey E. Dobrolecki, Weijie Zhang, Dong Han, Xi Chen","doi":"10.1016/j.cell.2024.09.032","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.032","url":null,"abstract":"Chemotherapy is often combined with immune checkpoint inhibitor (ICIs) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1α as a critical checkpoint that restricts the immunostimulatory effects of taxane chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1α RNase silences taxane-induced double-stranded RNA (dsRNA) through regulated IRE1-dependent decay (RIDD) to prevent NLRP3 inflammasome-dependent pyroptosis. Inhibition of IRE1α in <em>Trp53</em><sup><em>−/</em><em>−</em></sup> TNBC allows taxane to induce extensive dsRNAs that are sensed by ZBP1, which in turn activates NLRP3-GSDMD-mediated pyroptosis. Consequently, IRE1α RNase inhibitor plus taxane converts PD-L1-negative, ICI-unresponsive TNBC tumors into PD-L1<sup>high</sup> immunogenic tumors that are hyper-sensitive to ICI. We reveal IRE1α as a cancer cell defense mechanism that prevents taxane-induced danger signal accumulation and pyroptotic cell death.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439743","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 : 2024-10-15DOI: 10.1016/j.cell.2024.09.034
Hao Zhang, Phung N. Thai, Rabindra V. Shivnaraine, Lu Ren, Xuekun Wu, Dirk H. Siepe, Yu Liu, Chengyi Tu, Hye Sook Shin, Arianne Caudal, Souhrid Mukherjee, Jeremy Leitz, Wilson Tan Lek Wen, Wenqiang Liu, Wenjuan Zhu, Nipavan Chiamvimonvat, Joseph C. Wu
{"title":"Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target","authors":"Hao Zhang, Phung N. Thai, Rabindra V. Shivnaraine, Lu Ren, Xuekun Wu, Dirk H. Siepe, Yu Liu, Chengyi Tu, Hye Sook Shin, Arianne Caudal, Souhrid Mukherjee, Jeremy Leitz, Wilson Tan Lek Wen, Wenqiang Liu, Wenjuan Zhu, Nipavan Chiamvimonvat, Joseph C. Wu","doi":"10.1016/j.cell.2024.09.034","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.034","url":null,"abstract":"Cardiac fibrosis impairs cardiac function, but no effective clinical therapies exist. To address this unmet need, we employed a high-throughput screening for antifibrotic compounds using human induced pluripotent stem cell (iPSC)-derived cardiac fibroblasts (CFs). Counter-screening of the initial candidates using iPSC-derived cardiomyocytes and iPSC-derived endothelial cells excluded hits with cardiotoxicity. This screening process identified artesunate as the lead compound. Following profibrotic stimuli, artesunate inhibited proliferation, migration, and contraction in human primary CFs, reduced collagen deposition, and improved contractile function in 3D-engineered heart tissues. Artesunate also attenuated cardiac fibrosis and improved cardiac function in heart failure mouse models. Mechanistically, artesunate targeted myeloid differentiation factor 2 (MD2) and inhibited MD2/Toll-like receptor 4 (TLR4) signaling pathway, alleviating fibrotic gene expression in CFs. Our study leverages multiscale drug screening that integrates a human iPSC platform, tissue engineering, animal models, <em>in silico</em> simulations, and multiomics to identify MD2 as a therapeutic target for cardiac fibrosis.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"83 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436342","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 : 2024-10-14DOI: 10.1016/j.cell.2024.09.030
Rongzhen Yan, Dongyu Wei, Avni Varshneya, Lynn Shan, Bing Dai, Hector J. Asencio, Aishwarya Gollamudi, Dayu Lin
{"title":"The multi-stage plasticity in the aggression circuit underlying the winner effect","authors":"Rongzhen Yan, Dongyu Wei, Avni Varshneya, Lynn Shan, Bing Dai, Hector J. Asencio, Aishwarya Gollamudi, Dayu Lin","doi":"10.1016/j.cell.2024.09.030","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.030","url":null,"abstract":"Winning increases the readiness to attack and the probability of winning, a widespread phenomenon known as the “winner effect.” Here, we reveal a transition from target-specific to generalized aggression enhancement over 10 days of winning in male mice. This behavioral change is supported by three causally linked plasticity events in the ventrolateral part of the ventromedial hypothalamus (VMHvl), a critical node for aggression. Over 10 days of winning, VMHvl cells experience monotonic potentiation of long-range excitatory inputs, transient local connectivity strengthening, and a delayed excitability increase. Optogenetically coactivating the posterior amygdala (PA) terminals and VMHvl cells potentiates the PA-VMHvl pathway and triggers the same cascade of plasticity events observed during repeated winning. Optogenetically blocking PA-VMHvl synaptic potentiation eliminates all winning-induced plasticity. These results reveal the complex Hebbian synaptic and excitability plasticity in the aggression circuit during winning, ultimately leading to increased “aggressiveness” in repeated winners.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"207 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431227","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 : 2024-10-11DOI: 10.1016/j.cell.2024.09.029
Young-Cheul Shin, Pedro Latorre-Muro, Amina Djurabekova, Oleksii Zdorevskyi, Christopher F. Bennett, Nils Burger, Kangkang Song, Chen Xu, Joao A. Paulo, Steven P. Gygi, Vivek Sharma, Maofu Liao, Pere Puigserver
{"title":"Structural basis of respiratory complex adaptation to cold temperatures","authors":"Young-Cheul Shin, Pedro Latorre-Muro, Amina Djurabekova, Oleksii Zdorevskyi, Christopher F. Bennett, Nils Burger, Kangkang Song, Chen Xu, Joao A. Paulo, Steven P. Gygi, Vivek Sharma, Maofu Liao, Pere Puigserver","doi":"10.1016/j.cell.2024.09.029","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.029","url":null,"abstract":"In response to cold, mammals activate brown fat for respiratory-dependent thermogenesis reliant on the electron transport chain. Yet, the structural basis of respiratory complex adaptation upon cold exposure remains elusive. Herein, we combined thermoregulatory physiology and cryoelectron microscopy (cryo-EM) to study endogenous respiratory supercomplexes from mice exposed to different temperatures. A cold-induced conformation of CI:III<sub>2</sub> (termed type 2) supercomplex was identified with a ∼25° rotation of CIII<sub>2</sub> around its inter-dimer axis, shortening inter-complex Q exchange space, and exhibiting catalytic states that favor electron transfer. Large-scale supercomplex simulations in mitochondrial membranes reveal how lipid-protein arrangements stabilize type 2 complexes to enhance catalytic activity. Together, our cryo-EM studies, multiscale simulations, and biochemical analyses unveil the thermoregulatory mechanisms and dynamics of increased respiratory capacity in brown fat at the structural and energetic level.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"6 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405137","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 : 2024-10-11DOI: 10.1016/j.cell.2024.09.020
Owen T. Tuck, Benjamin A. Adler, Emily G. Armbruster, Arushi Lahiri, Jason J. Hu, Julia Zhou, Joe Pogliano, Jennifer A. Doudna
{"title":"Genome integrity sensing by the broad-spectrum Hachiman antiphage defense complex","authors":"Owen T. Tuck, Benjamin A. Adler, Emily G. Armbruster, Arushi Lahiri, Jason J. Hu, Julia Zhou, Joe Pogliano, Jennifer A. Doudna","doi":"10.1016/j.cell.2024.09.020","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.020","url":null,"abstract":"Hachiman is a broad-spectrum antiphage defense system of unknown function. We show here that Hachiman is a heterodimeric nuclease-helicase complex, HamAB. HamA, previously a protein of unknown function, is the effector nuclease. HamB is the sensor helicase. HamB constrains HamA activity during surveillance of intact double-stranded DNA (dsDNA). When the HamAB complex detects DNA damage, HamB helicase activity activates HamA, unleashing nuclease activity. Hachiman activation degrades all DNA in the cell, creating “phantom” cells devoid of both phage and host DNA. We demonstrate Hachiman activation in the absence of phage by treatment with DNA-damaging agents, suggesting that Hachiman responds to aberrant DNA states. Phylogenetic similarities between the Hachiman helicase and enzymes from eukaryotes and archaea suggest deep functional symmetries with other important helicases across domains of life.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"193 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405136","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":"Using artificial intelligence to document the hidden RNA virosphere","authors":"Xin Hou, Yong He, Pan Fang, Shi-Qiang Mei, Zan Xu, Wei-Chen Wu, Jun-Hua Tian, Shun Zhang, Zhen-Yu Zeng, Qin-Yu Gou, Gen-Yang Xin, Shi-Jia Le, Yin-Yue Xia, Yu-Lan Zhou, Feng-Ming Hui, Yuan-Fei Pan, John-Sebastian Eden, Zhao-Hui Yang, Chong Han, Yue-Long Shu, Mang Shi","doi":"10.1016/j.cell.2024.09.027","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.027","url":null,"abstract":"Current metagenomic tools can fail to identify highly divergent RNA viruses. We developed a deep learning algorithm, termed LucaProt, to discover highly divergent RNA-dependent RNA polymerase (RdRP) sequences in 10,487 metatranscriptomes generated from diverse global ecosystems. LucaProt integrates both sequence and predicted structural information, enabling the accurate detection of RdRP sequences. Using this approach, we identified 161,979 potential RNA virus species and 180 RNA virus supergroups, including many previously poorly studied groups, as well as RNA virus genomes of exceptional length (up to 47,250 nucleotides) and genomic complexity. A subset of these novel RNA viruses was confirmed by RT-PCR and RNA/DNA sequencing. Newly discovered RNA viruses were present in diverse environments, including air, hot springs, and hydrothermal vents, with virus diversity and abundance varying substantially among ecosystems. This study advances virus discovery, highlights the scale of the virosphere, and provides computational tools to better document the global RNA virome.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"69 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385779","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 : 2024-10-09DOI: 10.1016/j.cell.2024.10.008
Abdeladim Moumen, Philip Masterson, Mark J. O’Connor, Stephen P. Jackson
{"title":"Retraction notice to: hnRNP K: An HDM2 Target and Transcriptional Coactivator of p53 in Response to DNA Damage","authors":"Abdeladim Moumen, Philip Masterson, Mark J. O’Connor, Stephen P. Jackson","doi":"10.1016/j.cell.2024.10.008","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.008","url":null,"abstract":"(Cell <em>123</em>, 1065–1078; December 16, 2005)","PeriodicalId":9656,"journal":{"name":"Cell","volume":"56 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385927","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 : 2024-10-08DOI: 10.1016/j.cell.2024.09.023
Shukun Wang, Romana Siddique, Mark C. Hall, Phoebe A. Rice, Leifu Chang
{"title":"Structure of TnsABCD transpososome reveals mechanisms of targeted DNA transposition","authors":"Shukun Wang, Romana Siddique, Mark C. Hall, Phoebe A. Rice, Leifu Chang","doi":"10.1016/j.cell.2024.09.023","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.023","url":null,"abstract":"Tn7-like transposons are characterized by their ability to insert specifically into host chromosomes. Recognition of the attachment (<em>att</em>) site by TnsD recruits the TnsABC proteins to form the transpososome and facilitate transposition. Although this pathway is well established, atomic-level structural insights of this process remain largely elusive. Here, we present the cryo-electron microscopy (cryo-EM) structures of the TnsC-TnsD-<em>att</em> DNA complex and the TnsABCD transpososome from the Tn7-like transposon in <em>Peltigera membranacea cyanobiont</em> 210A, a type I-B CRISPR-associated transposon. Our structures reveal a striking bending of the <em>att</em> DNA, featured by the intercalation of an arginine side chain of TnsD into a CC/GG dinucleotide step. The TnsABCD transpososome structure reveals TnsA-TnsB interactions and demonstrates that TnsC not only recruits TnsAB but also directly participates in the transpososome assembly. These findings provide mechanistic insights into targeted DNA insertion by Tn7-like transposons, with implications for improving the precision and efficiency of their genome-editing applications.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"3 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384342","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 : 2024-10-08DOI: 10.1016/j.cell.2024.09.024
Eunae You, Patrick Danaher, Chenyue Lu, Siyu Sun, Luli Zou, Ildiko E. Phillips, Alexandra S. Rojas, Natalie I. Ho, Yuhui Song, Michael J. Raabe, Katherine H. Xu, Peter M. Richieri, Hao Li, Natalie Aston, Rebecca L. Porter, Bidish K. Patel, Linda T. Nieman, Nathan Schurman, Briana M. Hudson, Khrystyna North, David T. Ting
{"title":"Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer","authors":"Eunae You, Patrick Danaher, Chenyue Lu, Siyu Sun, Luli Zou, Ildiko E. Phillips, Alexandra S. Rojas, Natalie I. Ho, Yuhui Song, Michael J. Raabe, Katherine H. Xu, Peter M. Richieri, Hao Li, Natalie Aston, Rebecca L. Porter, Bidish K. Patel, Linda T. Nieman, Nathan Schurman, Briana M. Hudson, Khrystyna North, David T. Ting","doi":"10.1016/j.cell.2024.09.024","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.024","url":null,"abstract":"Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"19 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384347","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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