| Table of Contents |
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| Multi-adjuvant personalized neoantigen vaccines: Fine-tuning anti-cancer T cells |
| Hejia Henry Wang, Neeha Zaidi |
| Personalized cancer vaccines aim to broaden the anti-tumor T cell repertoire by targeting neoantigens unique to each patient’s tumor, but immunogenicity has been inconsistent. In this issue of Cell, Blass, Keskin, Tu et al. evaluate NeoVaxMI, a multi-adjuvant personalized synthetic long-peptide vaccine administered with nivolumab in patients with melanoma. NeoVaxMI elicited stronger CD4+ and CD8+ responses than earlier iterations, and vaccine-induced T cells trafficked to regressing metastatic lesions. |
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| Hybrid genome spawns tuber development and potato diversity |
| James H. Leebens-Mack |
| In this issue of Cell, Huang and colleagues reveal how ancient hybridization between ancestors of tomato and a related wild species, Solanum etuberosum, enabled the origin of tuber formation and the diversification of potato species. Their genomic analyses highlight how interactions between genes derived from distinct progenitors can drive development of novel traits in hybrids. |
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| A multi-adjuvant personal neoantigen vaccine generates potent immunity in melanoma |
| Eryn Blass, Derin B. Keskin, Chloe R. Tu, Cleo Forman, Allison Vanasse, Haley E. Sax, Bohoon Shim, Vipheaviny Chea, Nawoo Kim, Isabel Carulli, Jackson Southard, Haoxiang Lyu, Wesley Lu, Micah Rickles-Young, Alexander B. Afeyan, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Keerthi Shetty, Joanna Baginska, Ilana Gomez Diaz, Allison Nau, Kathleen L. Pfaff, Andrew Gans, Srinika Ranasinghe, Elizabeth I. Buchbinder, Tamara A. Sussman, Megan L. Insco, Charles H. Yoon, Scott J. Rodig, Sachet A. Shukla, Shuqiang Li, Jon C. Aster, David A. Braun, Carrie Cibulskis, Nir Hacohen, Donna S. Neuberg, Anita Giobbie-Hurder, Kenneth J. Livak, Edward F. Fritsch, Giacomo Oliveira, Jeremy M. Simon, Catherine J. Wu, Patrick A. Ott |
| A personalized neoantigen peptide vaccine formulated with Montanide plus poly-ICLC and administered with local ipilimumab plus systemic nivolumab induces robust neoepitope-specific T cell responses and reshapes the T cell repertoire in blood and tumor. |
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| GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity |
| Aikaterini Motso, Benjamin Pelcman, Anastasia Kalinovich, Nour Aldin Kahlous, Muhammad Hamza Bokhari, Nodi Dehvari, Carina Halleskog, Erik Waara, Jasper de Jong, Elizabeth Cheesman, Christine Kallenberg, Gopala Krishna Yakala, Praerona Murad, Erika Wetterdal, Pia Andersson, Sten van Beek, Anna Sandström, Diane Natacha Alleluia, Emanuela Talamonti, Sonia Youhanna, Pierre Sabatier, Claire Koenig, Sabine Willems, Aurino M. Kemas, Dana S. Hutchinson, Seungmin Ham, Lukas Grätz, Jan Voss, Jose G. Marchan-Alvarez, Martins Priede, Krista Jaunsleine, Jana Spura, Vadims Kovada, Linda Supe, Leigh A. Stoddart, Nicholas D. Holliday, Phillip T. Newton, Nicolas J. Pillon, Gunnar Schulte, Roger J. Summers, Ilga Mutule, Edgars Suna, Jesper V. Olsen, Peter Molenaar, Jens Carlsson, Volker M. Lauschke, Shane C. Wright, Tore Bengtsson |
| Open Access |
| Design of compounds with divergent signaling reveals GRK2-biased β2AR agonists that demonstrate efficacy and safety in preclinical models of metabolic disease and are well tolerated in a phase 1 clinical trial. |
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| Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications |
| Min Tian, Riki Kawaguchi, Yang Shen, Michal Machnicki, Nikole G. Villegas, Delaney R. Cooper, Natalia Montgomery, Ying Cai, Jacqueline Haring, Ruirui Lan, Angelina H. Yuan, Christopher K. Williams, Shino Magaki, Harry V. Vinters, Ye Zhang, Lindsay M. De Biase, Alcino J. Silva, S. Thomas Carmichael |
| Open Access |
| Analysis of the conserved intercellular interactome in human vascular dementia and in a mouse model reveals the Serpine2-Lrp1 and CD39-A3AR signaling axes as potential therapeutic targets. |
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| Fibroblast bioelectric signaling drives hair growth |
| Daoming Chen, Zhou Yu, Wenbo Wu, Yingxue Du, Qianqian Du, Huanwei Huang, Yaqi Li, Ting Xuan, Ya-Chen Liang, Yang Liu, Zijuan Wang, Rina Su, Yi Zhao, Qi Li, Minmin Luo, Fengchao Wang, Ji Li, Cheng-Ming Chuong, Zhimiao Lin, Ting Chen |
| Chen et al. reveal that bioelectric changes in dermal fibroblasts regulate hair growth. By activating the potassium channel KCNJ2, fibroblast hyperpolarization enhances regenerative Wnt signaling and promotes hair growth, offering a potential therapeutic strategy for treating hair loss through modulation of membrane potential. |
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| Procr+ chondroprogenitors sense mechanical stimuli to govern articular cartilage maintenance and regeneration |
| Qiaoling Zhu, Feng Yin, Jiachen Qin, Wanyu Shi, Yaojia Liu, Yuanyuan Zhao, Jianfang Wang, Lei Zhang, Aoyuan Fan, Dandan Cao, Qiqi Peng, Bin Zhou, Lijun Wang, Weiguo Zou, Rui Yue |
| Zhu et al. identified Procr+ chondroprogenitors in the superficial layer of articular cartilage and meniscus, which are sensitive to mechanical stimulation and regenerate articular chondrocytes in a Piezo1-dependent manner, highlighting their therapeutic potential in treating cartilage defects and osteoarthritis. |
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| Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling |
| Travis E. Faust, Yi-Han Lee, Ciara D. O’Connor, Margaret A. Boyle, Georgia Gunner, Violeta Durán-Laforet, Loris L. Ferrari, Robert E. Murphy, Ana Badimon, Kristina Sakers, Cagla Eroglu, Pinar Ayata, Anne Schaefer, Dorothy P. Schafer |
| Open Access |
| In the postnatal mouse cortex, microglia use Wnts to direct astrocytes to reduce their contact with synapses prior to synapse engulfment by microglia. This mechanism allows microglia to instruct astrocyte-synapse interactions to facilitate synapse removal and remodeling. |
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| NRT1.1B acts as an abscisic acid receptor in integrating compound environmental cues for plants |
| Xiaojun Ma, Wei Wang, Jingyi Zhang, Zhimin Jiang, Chengyuan Xu, Wenjun Zhu, Bihai Shi, Wanling Yang, Haiwei Su, Xiaohan Wang, Da Chen, Yanfei Wang, Juntao Wang, Jingchi Wang, Xiujie Liu, Xiaotian Wang, Xiahe Huang, Wenjun Xie, Yanting Cai, Ke Xu, Peiyong Xin, Linchuan Liu, Peitao Lü, Yingchun Wang, Jinfang Chu, Xin Gong, Chengcai Chu, Bin Hu |
| NRT1.1B, a traditionally recognized nitrate receptor, can directly perceive the extracellular ABA signal to form a complex with the repressor protein SPX4, thereby releasing the SPX4-sequestered transcription factor NLP4 and initiating the ABA transcriptional response, while the competitive binding of nitrate and ABA to NRT1.1B generates a flexible ABA response to fluctuating nutrient conditions for compound environmental cues integration. |
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| Ancient hybridization underlies tuberization and radiation of the potato lineage |
| Zhiyang Zhang, Pingxian Zhang, Yiyuan Ding, Zefu Wang, Zhaoxu Ma, Edeline Gagnon, Yuxin Jia, Lin Cheng, Zhigui Bao, Zinan Liu, Yaoyao Wu, Yong Hu, Qun Lian, Weichao Lin, Nan Wang, Keyi Ye, Hongru Wang, Jinzhe Zhang, Yongfeng Zhou, Liang Liu, Suhua Li, William J. Lucas, Tiina Särkinen, Sandra Knapp, Loren H. Rieseberg, Jianquan Liu, Sanwen Huang |
| Open Access |
| Genomic and functional analyses reveal that the potato lineage originated from a homoploid interspecific hybridization event between the Tomato and Etuberosum lineages 8–9 million years ago. The alternate inheritance of highly divergent parental alleles drove the origin of tubers and explosive species diversification and niche expansion into the high Andes. |
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| A host organelle integrates stolen chloroplasts for animal photosynthesis |
| Corey A.H. Allard, Angus B. Thies, Rishav Mitra, Patric M. Vaelli, Olivia D. Leto, Brittany L. Walsh, Elise M.J. Laetz, Martin Tresguerres, Amy S.Y. Lee, Nicholas W. Bellono |
| Sea slugs steal foreign chloroplasts and store them in specialized organelles that facilitate photosynthesis and eventual digestion to mediate starvation resistance. |
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| The genetic history of the Southern Caucasus from the Bronze Age to the Early Middle Ages: 5,000 years of genetic continuity despite high mobility |
| Eirini Skourtanioti, Xiaowen Jia, Nino Tavartkiladze, Liana Bitadze, Ramaz Shengelia, Nikoloz Tushabramishvili, Vladimer Aslanishvili, Boris Gasparyan, Andrew W. Kandel, David Naumann, Gunnar U. Neumann, Raffaela Angelina Bianco, Angela Mötsch, Kay Prüfer, Thiseas C. Lamnidis, Luca Traverso, Ayshin Ghalichi, Sturla Ellingvåg, Philipp W. Stockhammer, Johannes Krause, Harald Ringbauer |
| Open Access |
| Ancient DNA from the Southern Caucasus reveals remarkable genetic continuity, with some mixing from Anatolia/Iran and the Eurasian Steppe, and shows that even periods of urbanization and increased mobility—including the spread of cranial deformation in the Middle Ages—had minimal impact on the region’s core gene pool. |
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| Structure of gut microbial glycolipid modulates host inflammatory response |
| Hyoung-Soo Cho, Ji-Sun Yoo, Xinyang Song, Byoungsook Goh, Alos Diallo, Jesang Lee, Sumin Son, Yoon Soo Hwang, Seung Bum Park, Sungwhan F. Oh, Dennis L. Kasper |
| Structural variations in the number of acyl chains and phosphate groups of gram-negative microbial lipid A differentially modulate DC-derived IFN-β responses, which are mechanistically regulated by TLR4 endocytosis and lipid droplet formation. This lipid A-structure-driven immunomodulation via IFN-β contributes to the maintenance of colonic RORγt+ Tregs during homeostasis and helps mitigate colonic inflammation. |
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| Uncovering phenotypic inheritance from single cells with Microcolony-seq |
| Raya Faigenbaum-Romm, Noam Yedidi, Orit Gefen, Naama Katsowich-Nagar, Lior Aroeti, Irine Ronin, Maskit Bar-Meir, Ilan Rosenshine, Nathalie Q. Balaban |
| Open Access |
| Microcolony-seq systematically uncovers inherited phenotypic diversity directly from infected human samples, revealing that bacteria can retain long-term genetic and nongenetic memory from the host environment. These findings suggest that bacterial memory is widespread and may inform the development of strategies to target the multiple coexisting subpopulations within infections that can evade treatment. |
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| Quantifying the varying harvest of fermentation products from the human gut microbiota |
| Markus Arnoldini, Richa Sharma, Claudia Moresi, Griffin Chure, Julien Chabbey, Emma Slack, Jonas Cremer |
| Open Access |
| Fermentation products are the most abundant gut microbial metabolites absorbed by the host, with important dose-dependent consequences for health. In this study, we present a systems-level analysis integrating bacterial metabolism and host physiology to quantify this exchange and its dependence on microbiota composition and diet in humans. |
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| Modeling the vertebrate regulatory sequence landscape by UUATAC-seq and deep learning |
| Xiaoping Han, Hanyu Wu, Xueyi Wang, Daiyuan Liu, Yuting Fu, Lei Yang, Renying Wang, Peijing Zhang, Jingjing Wang, Lifeng Ma, Jizhong Mao, Lina Zhou, Siqi Wang, Xinlian Zhang, Mengmeng Jiang, Xinru Wang, Guoxia Wen, Danmei Jia, Guoji Guo |
| Open Access |
| Regulatory sequence landscapes from five vertebrate species were mapped using high-resolution single-nucleus ATAC-seq. This comprehensive dataset enables a systematic interpretation of vertebrate regulatory sequence grammar through deep learning. |
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| Human-specific gene expansions contribute to brain evolution |
| Daniela C. Soto, José M. Uribe-Salazar, Gulhan Kaya, Ricardo Valdarrago, Aarthi Sekar, Nicholas K. Haghani, Keiko Hino, Gabriana La, Natasha Ann F. Mariano, Cole Ingamells, Aidan Baraban, Zoeb Jamal, Tychele N. Turner, Eric D. Green, Sergi Simó, Gerald Quon, Aida M. Andrés, Megan Y. Dennis |
| A complete human genome and functional modeling in zebrafish pinpoint gene expansions that may underlie the evolutionary innovations of the human brain. |
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| SPIDR enables multiplexed mapping of RNA-protein interactions and uncovers a mechanism for selective translational suppression upon cell stress |
| Erica Wolin, Jimmy K. Guo, Mario R. Blanco, Isabel N. Goronzy, Darvesh Gorhe, Wenzhao Dong, Andrew A. Perez, Abdurrahman Keskin, Elizabeth Valenzuela, Ahmed A. Abdou, Carl R. Urbinati, Ross Kaufhold, H. Tomas Rube, Jailson Brito Querido, Mitchell Guttman, Marko Jovanovic |
| Open Access |
| SPIDR, a massively multiplexed method that simultaneously maps dozens of RNA-binding proteins to their RNA targets at single-nucleotide resolution, uncovers new RNA-protein interactions and provides comprehensive insights into RNA regulation throughout the mRNA life cycle. |
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| Systematic profiling reveals betaine as an exercise mimetic for geroprotection |
| Lingling Geng, Jiale Ping, Ruochen Wu, Haoteng Yan, Hui Zhang, Yuan Zhuang, Taixin Ning, Jun Wang, Chuqian Liang, Jiachen Zhang, Qingqing Chu, Jing Zhang, Yifan Wen, Yaobin Jing, Shuhui Sun, Qin Qiao, Qian Zhao, Qianzhao Ji, Shuai Ma, Yusheng Cai, Yandong Zheng, Zhiran Zou, Zhiqing Diao, Mingheng Li, Hao Zhang, Jianli Hu, Liangzheng Fu, Wang Kang, Ruijun Bai, Hongkai Zhao, Sheng Zhang, Yingjie Ding, Jinghui Lei, Wei Wang, Yun Ji, Bo Gou, Guoqiang Sun, Jian Yin, Pengze Yan, Hao Li, Zehua Wang, Shikun Ma, Zunpeng Liu, Hezhen Shan, Qiaoran Wang, Tianling Cao, Shanshan Yang, Cui Wang, Ping Yang, Yanling Fan, Yanxia Ye, Jinghao Hu, Mengmeng Jiang, Ye Wang, Kan Liu, Yujing Li, Yuanxiang Li, Jingyi Li, Weimin Ci, Zi-Bing Jin, Xiaobing Fu, Xu Zhang, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Si Wang, Moshi Song, Weiqi Zhang, Jing Qu, Guang-Hui Liu |
| Elucidating the multi-faceted health effects of exercise in humans identifies kidney-derived betaine as an exercise mimetic acting as a TBK1 inhibitor with anti-inflammatory and geroprotective activities. |
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| Systematic profiling reveals betaine as an exercise mimetic for geroprotection |
| Lingling Geng, Jiale Ping, Ruochen Wu, Haoteng Yan, Hui Zhang, Yuan Zhuang, Taixin Ning, Jun Wang, Chuqian Liang, Jiachen Zhang, Qingqing Chu, Jing Zhang, Yifan Wen, Yaobin Jing, Shuhui Sun, Qin Qiao, Qian Zhao, Qianzhao Ji, Shuai Ma, Yusheng Cai, Yandong Zheng, Zhiran Zou, Zhiqing Diao, Mingheng Li, Hao Zhang, Jianli Hu, Liangzheng Fu, Wang Kang, Ruijun Bai, Hongkai Zhao, Sheng Zhang, Yingjie Ding, Jinghui Lei, Wei Wang, Yun Ji, Bo Gou, Guoqiang Sun, Jian Yin, Pengze Yan, Hao Li, Zehua Wang, Shikun Ma, Zunpeng Liu, Hezhen Shan, Qiaoran Wang, Tianling Cao, Shanshan Yang, Cui Wang, Ping Yang, Yanling Fan, Yanxia Ye, Jinghao Hu, Mengmeng Jiang, Ye Wang, Kan Liu, Yujing Li, Yuanxiang Li, Jingyi Li, Weimin Ci, Zi-Bing Jin, Xiaobing Fu, Xu Zhang, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Si Wang, Moshi Song, Weiqi Zhang, Jing Qu, Guang-Hui Liu |
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| GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity |
| Aikaterini Motso, Benjamin Pelcman, Anastasia Kalinovich, Nour Aldin Kahlous, Muhammad Hamza Bokhari, Nodi Dehvari, Carina Halleskog, Erik Waara, Jasper de Jong, Elizabeth Cheesman, Christine Kallenberg, Gopala Krishna Yakala, Praerona Murad, Erika Wetterdal, Pia Andersson, Sten van Beek, Anna Sandström, Diane Natacha Alleluia, Emanuela Talamonti, Sonia Youhanna, Pierre Sabatier, Claire Koenig, Sabine Willems, Aurino M. Kemas, Dana S. Hutchinson, Seungmin Ham, Lukas Grätz, Jan Voss, Jose G. Marchan-Alvarez, Martins Priede, Krista Jaunsleine, Jana Spura, Vadims Kovada, Linda Supe, Leigh A. Stoddart, Nicholas D. Holliday, Phillip T. Newton, Nicolas J. Pillon, Gunnar Schulte, Roger J. Summers, Ilga Mutule, Edgars Suna, Jesper V. Olsen, Peter Molenaar, Jens Carlsson, Volker M. Lauschke, Shane C. Wright, Tore Bengtsson |
| Open Access |
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