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Table of Contents
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CLIM-TIME links genetic cancer drivers to immune landscapes
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Lili Zhu, Chen Yang, René Bernards, Cun Wang
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Immunotherapy resistance is associated with immune-privileged microenvironments, yet the interacting role of tumor-intrinsic genetics remains unclear. In this issue of Cell, Wang et al. introduce CLIM-TIME, a spatially resolved in vivo CRISPR screening platform linking loss of tumor suppressor genes to distinct metastatic immune architectures and divergent responses to immunotherapy.
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Harnessing skull immunity for brain drug delivery
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Samuel J.C. McCullough, Taylor J. Stevenson, Justin Rustenhoven
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Therapeutic delivery to the brain after stroke is limited by the blood-brain barrier. In this issue of Cell, Gao et al. bypass this obstacle by harnessing skull bone marrow immune cells to deliver drug-loaded nanoparticles to injured brain regions, improving outcomes and revealing a feasible translational strategy for targeted CNS therapy.
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Somatic genomics as a discovery engine for biomedicine
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Simon F. Brunner, Iñigo Martincorena, Gregory Mannino, Caroline S. Fox, Michael R. Stratton, Jacob R. Rubens, Peter J. Campbell, Hao Zhu
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Open Access
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Somatic genetics uses tissue mutations to understand aging, reveal disease mechanisms, and guide new therapies.
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Persistent T cell activation and cytotoxicity against glioblastoma following single oncolytic virus treatment in a clinical trial
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Maxime Meylan, Ye Tian, Lijian Wu, Alexander L. Ling, Daniel Kovarsky, Graham L. Barlow, Linh D. Nguyen, Jason Pyrdol, Sascha Marx, Lucas Westphal, Julius Michel, L. Nicolas Gonzalez Castro, Sydney Dumont, Andres Santos, Itay Tirosh, Mario L. Suvà, E. Antonio Chiocca, Kai W. Wucherpfennig
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Single oncolytic virus treatment in patients with glioblastoma induces deep and persistent T cell activation against tumor cells. Direct and sustained T cell engagement with tumor cells upon treatment correlates with survival outcome.
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Meningeal blood vessel blockage enhances anti-glioblastoma immunity
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Yixin Gao, Yushan Peng, Jiying Cheng, Xinyu Zhang, Jian Zhong, Chenfei Lu, Xudong Xing, Yanxing Lai, Huixin Sun, Xuechao Zeng, Zhiying Liu, Kejun He, Xinman Liu, Feizhe Xiao, Xiuxing Wang, Fan Bai, Nu Zhang
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Meningeal blood vessel blockage enhances anti-tumor immunity against GBM in preclinical models by expanding dural resident border-associated macrophages, which are equipped with an elevated antigen-presentation function and are poised for effective T cell activation, suggesting a surgical strategy for potentiating GBM immunotherapy.
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Nanoparticles hijack calvarial immune cells for CNS drug delivery and stroke therapy
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Xize Gao, Xiangrong Liu, Nanxing Wang, Chengqian Cui, Weiming Liu, Mo Yang, Qin Li, Yunwei Ou, Aiyi Ning, Xinyue Wei, Meiyang Zhang, Shuowen Qiu, Yang Lei, Dongjie Fu, Huimin Li, Leming Sun, Meng Lu, Mingjun Zhang, Yilong Wang
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Open Access
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Drug-loaded albumin NPs hijack calvarial immune cells to bypass the BBB via skull-meninges microchannels for CNS drug delivery and stroke therapy, establishing skull-based delivery and immune-assisted transport as a clinically translatable strategy for neurological therapeutics.
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Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity
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Jason S. Rush, Joshua D. Wertheimer, Steven D. Goldberg, Donald Raymond, Mateusz Szuchnicki, Andrew J. Baltus, Jeff Branson, Christopher F. Stratton, Aaron N. Patrick, Ruth Steele, Suraj Adhikary, Amanda Del Rosario, Annie Liu, Noah J. Gomersall, Michael Chung, Matthew J. Ranaghan, Xiebin Gu, Marta Brandt, Zhifang Cao, Adrian Bebenek, Blayne A. Oliver, Kasper Hoebe, Lawrence M. Szewczuk, Jennifer D. Venable, Daniel B. Graham, Jennifer Towne, Ramnik J. Xavier
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A binder-first approach enables the identification of a druggable pocket and compound for the immune protein CARD9 that dampens its inflammatory signaling. This compound reduces cytokine production in immune cells and in a mouse model, demonstrating how therapeutic modulation can mimic effects of a CARD9 variant protective against Crohn’s disease.
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MYC binding to nascent RNA suppresses innate immune signaling by R-loop-derived RNA-DNA hybrids
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Leonie Uhl, Amel Aziba, Sinah Löbbert, Timothy Russell, Bastian Krenz, Francisco Montesinos, Toshitha Kannan, Omkar R. Valanju, Christina Schülein-Völk, Tim de Martines, Michael Bolz, Daniel Fleischhauer, Giacomo Cossa, Theresa Endres, Daniel Solvie, Peter Gallant, Andreas Rosenwald, Hans M. Maric, Dimitrios Papadopoulos, Seychelle M. Vos, Martin Eilers
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Open Access
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RNA-binding-mediated multimerization of MYC concentrates RNA-degrading factors around double-stranded RNAs and R-loops. This prevents aberrant RNAs from accumulating and leaking into the cytosol. Through RNA binding, MYC suppresses innate immune signaling and promotes tumor growth.
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A regulatory network promotes apoplastic alkalinization to prime plant immunity in tissues distal to site of infection
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Hongze Wang, Xiuming Li, Keran Zhai, Jack Rhodes, Tian Sang, Jiwen Zhao, Yong Gao, Shengwei Ma, Beibei Song, Qing Pan, Meijuan Hu, Peiyong Xin, Jinfang Chu, Pengcheng Wang, Cyril Zipfel, Jian-Min Zhou
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Open Access
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Pathogen-exposed plant cells communicate with neighboring cells through apoplastic alkalinization and phytocytokines, which jointly propagate from the pathogen-exposed local tissue to distal tissues, providing a warning system for robust defenses and disease resistance.
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An uORF-encoded mobile peptide sparks systemic stomatal immunity
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Changzhen Liu, Qiangsheng Yu, Yunfan Jin, Wei Ma, Jing Li, Tianxue Song, Meng Han, Yi Qian, Qi Xue, Leyi Ke, Yuxin Dong, Congcong Hou, Xuna Wu, Yule Liu, Jizong Wang, Liwen Jiang, Zhizhong Gong, Haiteng Deng, Daoxin Xie, Shengyang He, Zhi John Lu, Susheng Song, Tiancong Qi
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In Arabidopsis, the uORF-encoded long-distance mobile peptide USIC in pathogen-infected local leaves activates systemic stomatal immunity, leading to stomatal closure in uninfected distal leaves.
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Giant DNA viruses encode a hallmark translation initiation complex of eukaryotic life
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J. Maximilian Fels, Aidan B. Hill, Richard Han, Jasmine M. Garcia, Hugo Bisio, Chantal Abergel, Philip J. Kranzusch, Amy S.Y. Lee
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Open Access
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Giant DNA viruses encode a cap-binding complex homologous to eIF4F, the defining translation-initiation complex of eukaryotes. The viral cap-binding complex is required for viral protein synthesis and enables an unusual degree of replication plasticity under altered host conditions.
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A GPCR-G protein-β-arrestin megacomplex enabled by a versatile allosteric modulator
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Guodong He, Qinxin Sun, Xinyu Xu, Fang Kong, Shuhao Zhang, Kexin Ye, Xiaoou Sun, Bin Lin, Xin Chen, Chuangye Yan, Xiangyu Liu
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Identification of atazanavir as a pan-positive allosteric modulator for family A GPCRs that stabilizes a unique GPCR-G protein-β-arrestin megacomplex and mediates sustained signaling.
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Structural decoding of reversible covalent linkage of odorants in human olfactory receptor OR6A2
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Tian Wang, Yiran Wu, Ling Wang, Shanshan Li, Fei Zhao, Lijie Wu, Yue Liu, Jingzi Qin, Qiwen Tan, Junlin Liu, Liting Zeng, Yilin Chen, Shenyuan Gao, Wenqing Shui, Suwen Zhao, Tian Hua, Zhi-Jie Liu
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The human olfactory receptor OR6A2, re-engineered to be functional, demonstrates the mechanism by which it detects aldehydes. Using this approach, Wang, Wu, et al. uncovered a broadly conserved activation switch in class II odorant receptors. This work also outlines a practical approach to decode smell, with potential uses in fragrance design and inflammation therapy.
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Mechanistic insights into fatty acid odor detection mediated by class II olfactory receptors
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Xiang Han, Ming-Hui Zhang, Nai-Kang Rong, Kong-Kai Zhu, Yuan Pei, Xiao-Yan Ge, Qi Liu, Huan Lu, Jing Liu, Li-Jun Zhang, Hong-Qiang Bao, Jia-Hao Pi, Lei Fan, Yu Fu, Xu-Hang Shao, Wen-Qi Yan, Xi-He Gao, Ming-Yue Zhang, Lu-Lu Guo, Yan Lu, Shang-Lei Ning, Hua Zhang, Yun-Fei Xu, Xiao-Ya Feng, Jie Cheng, Ming Xia, Qian Li, Xiao Yu, Fan Yang, Jin-Peng Sun
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Cryo-EM structures reveal how Olfr110, a class II odorant receptor, binds hydrophobic odorants such as unsaturated fatty acid metabolites in a large polar pocket with an unconventional activation mechanism, defining the structural basis of odor recognition and guiding drug targeting.
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Identification of Or5v1/Olfr110 as an oxylipin receptor and anti-obesity target
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Xiao-Yan Ge, Jie Cheng, Li-Jun Zhang, Lu-Lu Guo, Rui Xiang, Yan Lu, Shang-Lei Ning, Kai-Yu Wang, Kong-Kai Zhu, Ming-Xin Gao, Yue Li, Yu-Song Zhang, Nai-Kang Rong, Xiang Han, Ming-Hui Zhang, Le Fang, Yun-Fei Xu, Su-Wen Zhao, Qian Li, Fan Yang, Yong Hao, Ren-Jie Chai, Xiao Yu, Ji-Chun Yang, Jin-Peng Sun
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Or5v1/Olfr110, a high-affinity odor receptor, detects an oxylipin signal to boost liver fat burning and glucose control, and a synthetic agonist can amplify this metabolic benefit.
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Liver exerkine reverses aging- and Alzheimer’s-related memory loss via vasculature
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Gregor Bieri, Karishma J.B. Pratt, Yasuhiro Fuseya, Turan Aghayev, Juliana Sucharov, Alana M. Horowitz, Amber R. Philp, Karla Fonseca-Valencia, Rebecca Chu, Mason Phan, Laura Remesal, Shih-Hsiu J. Wang, Andrew C. Yang, Kaitlin B. Casaletto, Saul A. Villeda
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Open Access
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Liver exercise factor GPLD1 rejuvenates blood-brain barrier integrity and reverses cognitive impairments in aging and Alzheimer’s disease models by targeting GPI-anchored proteins on brain endothelial cells.
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CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis
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Avi J. Samelson, Nabeela Ariqat, Justin McKetney, Gita Rohanitazangi, Celeste Parra Bravo, Rudra S. Bose, Kyle J. Travaglini, Victor L. Lam, Darrin Goodness, Thomas Ta, Gary Dixon, Emily Marzette, Julianne Jin, Ruilin Tian, Eric Tse, Romany Abskharon, Henry S. Pan, Emma C. Carroll, Rosalie E. Lawrence, Jason E. Gestwicki, Jessica E. Rexach, David S. Eisenberg, Nicholas M. Kanaan, Daniel R. Southworth, John D. Gross, Li Gan, Danielle L. Swaney, Martin Kampmann
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Open Access
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CRISPR screens in iPSC-derived neurons reveal that the E3 ubiquitin ligase CRL5SOCS4 ubiquitinates tau, that CUL5 expression is correlated with resilience in human Alzheimer’s disease, and that electron transport chain dysfunction alters tau degradation by the proteasome.
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Brain-wide mapping of oligodendrocyte organization, oligodendrogenesis, and myelin injury
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Yu Kang T. Xu, Abigail Bush, Ephraim Musheyev, Jacob Umans, Lingzi Zhang, Anya A. Kim, Sen Zhang, Jaime Eugenin von Bernhardi, Yuqing Yan, Jeremias Sulam, Dwight E. Bergles
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Open Access
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Generation of brain-wide oligodendrocyte atlases across aging, disease, sex, and strain reveals striking regional differences in myelin abundance, resilience, and vulnerability. Integration with transcriptomic and ultrastructural data identifies factors that may shape this diverse oligodendrocyte patterning.
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CLIM-TIME identifies metastatic microenvironment modulators for T cell therapy response
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Yinghua Wang, Weiwei Hu, Rui Xia, Xianfa Yang, Yange Gu, Zihan Ning, Tiange Yang, Chune Yu, Lulu Zhang, Dun Li, Yitian Jin, Jianhua Li, Feifei Zhang, Yaochen Xu, Chenqi Xu, Zhengxin Wang, Naihe Jing, Luonan Chen, Guangchuan Wang
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CLIM-TIME provides a high-throughput perturbation-mapping platform that links tumor suppressor gene loss to spatially defined metastatic niches and immune responses, identifying LOXL2 as a key modulator of suppressive metastatic environments. Inhibition of LOXL2 restores T cell infiltration into tumors and improves the efficacy of therapy.
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A single-cell time-series atlas of endothelial cell embryonic development
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Lihui Lin, Jing Zhong, Fuqing Jiang, Yu-xiang Wang, Lan-yue Ma, Jia-xin Yang, Yu-yan Li, Rong-Rong Gao, Huijian Feng, Baomei Cai, Ziyu Feng, Xin Zhou, Ya-hai Shu, Pan Chen, Xue Wu, Chen-Leng Cai, Qiang Wang, Guangming Wu, Duanqing Pei, Shangtao Cao, Yang Liu, Guangdun Peng, Jiekai Chen, Qi Chen
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Open Access
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The STED-EC atlas enables inter-organ and multi-time-point comparisons of gene expression in endothelial cells, revealing substantial transcriptomic variations across endothelial cells from different embryonic organs and facilitating investigation of previously unknown molecular mechanisms that govern organ-specific vascular development.
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