| Table of Contents |
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| Atomic unification in molecular AI |
| Xiaozhi Fu |
| Artificial intelligence has rapidly advanced molecular science, yet progress has largely unfolded through specialized models tailored to specific tasks. In this issue of Cell, Peng et al. introduce PocketXMol, a unified 3D generative framework that reframes molecular design problems as conditional reconstruction of atomic interactions. Demonstrations across design scenarios highlight its potential in molecular engineering. |
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| New approach methodologies for drug discovery |
| Wenqiang Liu, Paul D. Pang, Catherine A. Wu, Danilo Tagle, Joseph C. Wu |
| New approach methodologies that are human-centered, such as stem cells, organoids, and in silico models, can span the full drug discovery pipeline—from disease modeling to efficacy testing—and hold promise as both tools for drug discovery and potential therapies. |
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| Unified modeling of 3D molecular generation via atomic interactions with PocketXMol |
| Xingang Peng, Ruihan Guo, Fenglin Guo, Ziyi Wang, Jiayu Sun, Jiaqi Guan, Yinjun Jia, Yan Xu, Yanwen Huang, Muhan Zhang, Jian Peng, Xinquan Wang, Chuanhui Han, Zihua Wang, Jianzhu Ma |
| Open Access |
| A versatile, atom-level generative AI model enables unified pocket-interacting tasks, from docking to de novo design, and demonstrates robust experimental validation for both small-molecule and peptide therapeutics. |
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| Efficient amyloid-β degradation in Alzheimer’s disease using SPYTACs |
| Fei Teng, Jing Liu, Tongtong Cui, Xiangtian Tan, Kailun Liu, Zongren Hou, Li Zhou, Yuanzhi Xie, Rongqi Li, Da Li, Bojin Li, Dongmei Wang, Qi Zhou, Baoyang Hu, Wei Li |
| Open Access |
| SPYTAC is a synthetic peptide-programmed targeted protein degradation platform harnessing LRP1 to drive lysosomal degradation of extracellular amyloid-β in the brain and periphery. In 5×FAD mice, SPYTAC treatment efficiently degrades amyloid-β, preserves neurons, and improves cognition with reduced neuroinflammation and microhemorrhage when compared with antibody therapy. |
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| Ferritin aggregation cell engager for CAR T avidity engineering against refractory leukemias |
| Feng Li, Yuxing Hu, Yan Wang, Xiao Zhang, Shaowei Qiu, Xiaoming Hu, Wenjing Wang, Shuang Wang, Peilin Guo, Cui Song, Huaiji Wang, Changhao He, Jie Sun, Di Yu, Shuhua Yi, Jun Wei, Feifan Liu, Caopei Zheng, Jianxiang Wang, Yuhua Li, Guanghui Ma, Wei Wei |
| Li et al. developed a ferritin aggregation cell engager that helps CAR T cells better recognize and attack leukemia cells without re-engineering the CAR itself. This versatile platform overcomes antigen modulation and enables combination with chemotherapy. |
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| A GPX1-OSBPL8 axis mediates noncanonical in vivo ferroptosis and cancer growth suppression |
| Zhangchuan Xia, Xin Yang, Sviatlana N. Samovich, Yulia Y. Tyurina, Vladimir A. Tyurin, Ning Kon, Jiankang Zhang, Xuejun Jiang, Brent R. Stockwell, Jian Jin, Hülya Bayir, Valerian E. Kagan, Wei Gu |
| An in vivo, noncanonical ferroptosis pathway, critical for tumor supression, is driven by reactive oxygen species-induced phosphatidic acid peroxidation at the ER under the control of the GPX1-OSBPL8 signaling axis. |
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| Pyruvate is a natural suppressor of interferon signaling by inducing STAT1 protein pyruvylation |
| Yibo Zuo, Qin Wang, Wanying Tian, Xinhe Wang, Zhijin Zheng, Wei He, Renxia Zhang, Qian Zhao, Ying Miao, Yukang Yuan, Tingting Zhang, Qun Cui, Yuerong Zhang, Chunyan Liu, Haiyan Zhou, Hui Zheng |
| Open Access |
| Yibo et al. identify protein pyruvylation as a post-translational modification that can modulate immune signaling and host antiviral response. |
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| Metabolite-gated vascular contractility switch: OXGR1 activation mechanism enables agonist therapy for rosacea erythema |
| Wenqin Xiao, Yan Zhu, Xinjie Tang, Kongkai Zhu, Weifeng Zhang, Mengting Chen, Kui Cai, San Xu, Zheng Wu, Mei Wang, Jiayi Liu, Linglong Long, Zixin Tan, Aike Wu, Songqi Zhou, Zhixiang Zhao, Yan Tang, Yingxue Huang, Ben Wang, Fangfen Liu, Qian Wang, Fan Yang, Dan Jian, Wei Shi, Hongfu Xie, Xiang Chen, Lulu Guo, Zhili Deng, Jinpeng Sun, Ji Li |
| Xiao et al. identify α-KG as a rosacea-associated metabolite that activates the OXGR1-Gq-MYL9 axis in the vascular smooth muscle cells to boost contractility and suppress pathological vasodilation underlying erythema. Cryo-EM reveals a bipartite-acid pocket of OXGR1 that enables structure-guided development of A-1, a selective agonist that alleviates erythema in rosacea-like models. |
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| Restoring circadian rhythms in the hypothalamic paraventricular nucleus reverses aging biomarkers and extends lifespan in male mice |
| Haijiao Zhao, Meimei Liao, Ran Huo, Ting He, Hongni Tian, Zeqi Li, Chen Chen, Ziqing Yu, Juan Chai, Xiaocui Song, Ruichao Shao, Shuhua Ying, Wen Gao, Ling Liu, Di Sang, Qi Li, Haohong Li, Fengchao Wang, Dapeng Ju, Eric Erquan Zhang |
| Enhancing circadian amplitude in mouse hypothalamic paraventricular nucleus neurons by 3′-deoxyadenosine treatment alleviates age-related pathologies and extends lifespan. |
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| Nuclear speckles enable processing of RNA from GC-rich isochores |
| Michał Małszycki, Lisa Martina, İbrahim Avşar Ilık, Daniela Salgado Figueroa, Nirmalya Dasgupta, Menşura Feray Çoşar, Keun-Tae Kim, Gil Carraco, Beatrix Fauler, David Meierhofer, Thorsten Mielke, Hiroo Imai, Cantaş Alev, Ferhat Ay, Tuğçe Aktaş |
| Open Access |
| Nuclear speckles are key subnuclear structures that regulate gene expression in GC-rich regions. This work shows that the evolution and expansion of core speckle proteins were crucial for the increased GC content seen in amniote genomes. |
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| Four centuries of commercial whaling eroded 11,000 years of population stability in bowhead whales |
| Michael V. Westbury, Stuart C. Brown, Andrea A. Cabrera, Hernán E. Morales, Bárbara Parreira, Jilong Ma, Moisès Coll Macià, Alba Rey-Iglesia, Arthur Dyke, Camilla Hjorth Scharff-Olsen, Michael B. Scott, Øystein Wiig, Lutz Bachmann, Kit M. Kovacs, Christian Lydersen, Steven H. Ferguson, Paul Szpak, Damien A. Fordham, Eline D. Lorenzen |
| Open Access |
| Although bowhead whales remained genetically stable through 11,000 years of Holocene environmental change, commercial whaling upended this long-term stability, driving population subdivision and genomic erosion that are still unfolding today. |
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| Editing strigolactone hormone receptor for robust antiviral silencing in rice |
| Guoyi Yang, Ming Wu, Shuai Zhang, Yucen Huang, Yixiao Liu, Xiyuan Yu, Jiayang Hu, Le Mi, Peng Gan, Yuansheng Wu, Jing Zou, Baogang Zhang, Qun Hu, Jie Hu, Ruifeng Yao, Bojian Zhong, Xianbo Huang, Huiting Xie, Yinghua Ji, Yi Li, Jie Zhang, Liming Yan, Shou-wei Ding, Shanshan Zhao, Jianguo Wu |
| Open Access |
| Precise genome editing of the rice strigolactone receptor DWARF14 confers robust, transgene-free antiviral resistance by blocking viral suppression of endogenous RNA silencing, offering a promising strategy for durable disease protection without a yield penalty. |
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| Planetary microbiome structure and generalist-driven gene flow across disparate habitats |
| Chan Yeong Kim, Daniel Podlesny, Jonas Schiller, Supriya Khedkar, Anthony Fullam, Askarbek Orakov, Christian Schudoma, Shahriyar Mahdi Robbani, Anastasiia Grekova, Michael Kuhn, Peer Bork |
| Open Access |
| A planetary-scale analysis of over 85,000 metagenomes establishes a framework for exploring the structure and drivers of global microbial habitats, revealing that generalist species bridge ecological boundaries to mediate gene flow across disparate habitats, including the dissemination of antimicrobial resistance. |
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| The MicrobeAtlas database: Global trends and insights into Earth’s microbial ecosystems |
| João Frederico Matias Rodrigues, Janko Tackmann, Lukas Malfertheiner, David Patsch, Eugenio Perez-Molphe-Montoya, Nicolas Näpflin, Daniela Gaio, Gregor Rot, Mihai Danaila, Matteo Eustachio Peluso, Marija Dmitrijeva, Thomas Sebastian Benedikt Schmidt, Christian von Mering |
| Open Access |
| MicrobeAtlas ( www.microbeatlas.org ) is an integrated, reference-based resource for truly planet-wide microbiomics, analyzing hundreds of thousands of microbial lineages across diverse environments, conditions, and technologies. |
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| Genetically encoded fluorescent reporters to visualize α-synuclein pathology in live brain |
| Li Zhang, Minhui Yu, Guoqing Chen, Siyuan Ge, Mengdi Wang, Xianying Zhang, Miao Zhao, Huating Gu, Meizhu Huang, Aixue Liu, Gengxin Ran, Zeyuan Liu, Tiepeng Liao, Qi Chen, Chenjian Miao, Yao Lu, Yibing Wang, Fengchao Wang, Zhihui Liu, Hongying Zhu, Qian Wu, Zhuan Zhou, Wei Xiong, Xiaoqun Wang, Peng Cao |
| Open Access |
| The development of genetically encoded fluorescent reporters, along with their corresponding knock-in mouse lines for labeling α-Syn inclusions, enables diverse applications in studying the propagation and pathological effects of α-Syn inclusions in the live brain. |
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| Large-scale proteomics across neurological disorders uncovers biomarker panel and targets in multiple sclerosis |
| Jakob Maximilian Bader, Christine Makarov, Sabrina Richter, Maximilian Thomas Strauss, Friederike Held, Maria Wahle, Michael Baggio Lorenz, Lara Pöschl, Patricia Skowronek, Marvin Thielert, Achim Berthele, Wen-Feng Zeng, Constantin Ammar, Isabell Bludau, Benjamin Schubert, Fabian J. Theis, Christiane Gasperi, Bernhard Hemmer, Matthias Mann |
| Open Access |
| Deep proteome profiling of over 5,000 cerebrospinal fluid samples by mass spectrometry maps protein alterations across major neurological disorders, resolving key sources of variation as well as shared and disease-specific signatures. This framework yields a 22-protein assay that improves the differential diagnosis of multiple sclerosis from other inflammatory conditions, particularly in diagnostically challenging oligoclonal band-negative individuals. |
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| Cell-type-specific transposon demethylation and TAD remodeling in aging mouse brain |
| Qiurui Zeng, Wenliang Wang, Wei Tian, Amit Klein, Anna Bartlett, Hanqing Liu, Joseph R. Nery, Rosa G. Castanon, Julia Osteen, Nicholas D. Johnson, Wubin Ding, Huaming Chen, Jordan Altshul, Mia Kenworthy, Cynthia Valadon, William Owens, Zhanghao Wu, Maria Luisa Amaral, Nathan R. Zemke, Yuru Song, Cindy Tatiana Báez-Becerra, Silvia Cho, Chumo Chen, Jackson Willier, Stella Cao, Jonathan Rink, Jasper Lee, Ariana Barcoma, Jessica Arzavala, Nora Emerson, Yuancheng Ryan Lu, Bing Ren, M. Margarita Behrens, Joseph R. Ecker |
| Open Access |
| A multi-omic single-cell atlas of the aging mouse brain reveals cell-type-specific transposon methylation changes, strengthening of 3D genome boundaries, and regionally heterogeneous aging signatures. These findings offer a resource to understand the molecular mechanisms of brain aging and guide future research on neurodegeneration. |
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| The E3-ome gene-centric compendium reveals the human E3 ligase landscape |
| Ngee Kiat Chua, Tania J. González-Robles, Cameron J. Reddington, Jane Dudley-Fraser, Richard W. Birkinshaw, Jiru Han, Ashleigh Solano, Soon Wei Wong, Tomasz Kochańczyk, Joshua J. Peter, Mark A. Nakasone, Florian Aust, Jacob Munro, Yeh Huei Tong, Julie Iskander, Waruni Abeysekera, Alex Garnham, Hannah Huckstep, Matthew E. Ritchie, Ingrid Wertz, Sarah Hymowitz, Sharad Kumar, Ron C. Conaway, Gilbert G. Privé, Alex N. Bullock, Jeffrey J. Babon, Rachel E. Klevit, Sonja Lorenz, Alessio Ciulli, Eric S. Fischer, Nicolas H. Thomä, Radosław P. Nowak, Brenda A. Schulman, Michael Rapé, Katrin Rittinger, Julia K. Pagan, Melanie Bahlo, Joel P. Mackay, Peter D. Mace, Christopher D. Lima, Ronald T. Hay, David Komander, Bernhard C. Lechtenberg, Claudio A.P. Joazeiro, Michele Pagano, Kay Hofmann, Rebecca Feltham |
| Open Access |
| The E3-ome defines the human repertoire of ubiquitin E3 ligases, creating a unified resource that maps their diversity across the ubiquitin and ubiquitin-like systems. By consolidating fragmented knowledge, this framework provides a foundation for studying ubiquitin signaling and accelerating discovery. |
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| Functional RNA splitting drove the evolutionary emergence of type V CRISPR-Cas systems from transposons |
| Shuai Jin, Zixu Zhu, Yunjia Li, Shouyue Zhang, Yijing Liu, Danyuan Li, Yuanqing Li, Yingfeng Luo, Zhiheng Cheng, Kevin Tianmeng Zhao, Qiang Gao, Guanglei Yang, Hongchao Li, Ronghong Liang, Rui Zhang, Jin-Long Qiu, Yong E. Zhang, Jun-Jie Gogo Liu, Caixia Gao |
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