| Table of Contents |
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| A gut-to-brain pathway that limits protein intake |
| Marito Hayashi |
| In this issue of Cell, Jaschke and Luchsinger et al. uncover a gut-to-brain signaling mechanism that dynamically shapes protein intake. During recovery from extreme fasting, ammonia derived from the metabolism of specific dietary amino acids is detected by Trpa1-expressing intestinal epithelial cells, leading to the activation of a protein aversion pathway. |
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| Stimulants as agents of arousal in whole-brain functional connectivity |
| Elizabeth V. Goldfarb |
| In this issue of Cell, Kay and colleagues show robust and reproducible differences in human brain networks associated with stimulants. Individuals taking stimulants had distinct functional connectivity of a set of brain networks linked to better sleep and higher physical arousal but no significant changes in connectivity with networks canonically involved in attention. This multi-dataset investigation suggests an arousal-based pathway linking stimulants to improved cognition. |
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| The evolving landscape of Alzheimer’s disease therapy: From Aβ to tau |
| Jean-Philippe Courade, Henrik Zetterberg, Günter U. Höglinger, Ilse Dewachter |
| Open Access |
| Emerging tau-targeting approaches show promise in slowing Alzheimer’s disease progression, complementing recent advances in FDA-approved anti-Aβ therapies. This perspective outlines the progress in Alzheimer’s disease therapeutic development, highlighting how tau trial outcomes are providing insights into tau pathobiology and paving the way for next-generation disease-modifying interventions. |
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| Bacterial tubular networks channel carbohydrates in insect endosymbiosis |
| Séverine Balmand, Camille Rivard, Sergio Peignier, Rachel Santarella-Mellwig, Meriem Ghanem-Debbache, Justin Maire, Tobias Engl, Mariana Galvão Ferrarini, Elisa Dell’Aglio, Blanca Soriano-Saiz, Charline Dalverny, Veronica La Padula, Petri Turunen, Isabelle Rahioui, Agnès Vallier, Carole Vincent-Monégat, Baptiste Vierne, Nicolas Parisot, Guy Condemine, Pedro Da Silva, Xavier Jaurand, Yannick Schwab, Martin Kaltenpoth, Abdelaziz Heddi, Anna Zaidman-Rémy |
| Open Access |
| Bacteria with an intracellular lifestyle need to feed from inside their host cells. This study shows an adaptation of certain symbiotic bacteria, allowing them to actively retrieve nutrients from the host. High-pressure cryofixation has been combined with volume electron microscopy and in situ high spatial resolution chemical analysis. It reveals a complex bacterial membranous network that increases the exchange interface between the bacteria and host cytosol and maximizes carbohydrate acquisition. |
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| An archaeal transcription factor bridges prokaryotic and eukaryotic regulatory paradigms |
| Fernando Medina Ferrer, Dipti D. Nayak |
| Open Access |
| Methanogenic archaea use the one-component system AmzR to sense methylamines and regulate the expression of methylamine-metabolizing genes. Unlike other prokaryotic one-component systems, the DNA-binding motif of AmzR resembles a structural fold typically found in eukaryotic transcription factors. This discovery narrows the gap between prokaryotic and eukaryotic regulatory proteins. |
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| A stepwise decoding mechanism for heat sensing in plants connects lipid remodeling to a nuclear signaling cascade |
| Yi Kan, Xiao-Rui Mu, Fangfang Qu, Zhi-An Dai, Jin Gao, Ning-Jing Liu, Siqi Li, Jun-Xiang Shan, Wang-Wei Ye, Nai-Qian Dong, Xiaolan Huang, Yi-Bing Yang, Shuang-Qin Guo, Jie-Jie Lei, Ying-Jie Cao, Ji-Fu Zhou, Pengcheng Li, Jianchuan Wang, Yixue Li, Hong-Xuan Lin, Youshun Lin |
| A complete hierarchical thermo-decoding mechanism in plants connects cell membrane lipid remodeling during heat stress to the downstream signaling cascade in the nucleus. Field trials demonstrate the potential application of this mechanism in customized heat-tolerant crop design in rice. |
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| Inhibition of oligomeric BAX by an anti-apoptotic dimer |
| Catherine E. Newman, Micah A. Gygi, Haleh Alimohamadi, Thomas M. DeAngelo, Christina M. Camara, Julian Mintseris, Ezra Yu, Edward P. Harvey, Zachary J. Hauseman, Lixin Fan, Yun-Xing Wang, Elizabeth W.-C. Luo, Marina Godes, Jacob Gehtman, Ann M. Cathcart, Steven P. Gygi, John R. Engen, Gregory H. Bird, Gerard C.L. Wong, Thomas E. Wales, Loren D. Walensky |
| A full-length dimeric form of the anti-apoptotic protein BCL-w can block oligomeric BAX-driven mitochondrial permeabilization and apoptosis, revealing a new layer of cell-death control. |
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| Phase separation to buffer growth-mediated dilution in synthetic circuits |
| Rong Zhang, Wangfei Yang, Rixin Zhang, Amanda Godar, Sadikshya Rijal, Abdelrahaman Youssef, David R. Nielsen, Wenwei Zheng, Xiao-Jun Tian |
| Phase separation stabilizes synthetic gene circuits and boosts production under dynamic growth conditions. By locally concentrating transcription factors at promoters, it protects gene expression from growth-driven dilution and provides a broadly applicable strategy for gene circuit engineering. |
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| Fertilization triggers early proteomic symmetry breaking in mammalian embryos |
| Lisa K. Iwamoto-Stohl, Aleksandra A. Petelski, Baiyi Quan, Maciej Meglicki, Audrey Fu, Shoma Nakagawa, Breanna McMahon, Ting-Yu Wang, Saad Khan, Harrison Specht, Gray Huffman, Jason Derks, Sergi Junyent, Bailey A.T. Weatherbee, Antonia Weberling, Carlos W. Gantner, Rachel S. Mandelbaum, Richard J. Paulson, Lisa Lam, Tsui-Fen Chou, Nikolai Slavov, Magdalena Zernicka-Goetz |
| Open Access |
| Single-cell proteomics finds asymmetries between sister blastomeres from the 2-cell stage in human and mouse embryos, defining two states: alpha and beta. Alpha-beta asymmetry can be traced back to the zygote, is triggered by fertilization, and is linked to differential developmental potential, with beta blastomeres having a higher potential. |
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| Adrenergic signaling coordinates distant and local responses to amputation in axolotl |
| Duygu Payzin-Dogru, Tim Froitzheim, Steven J. Blair, Siddhartha G. Jena, Hani Singer, Julia C. Paoli, Ryan T. Kim, Emil Kriukov, Sarah E. Wilson, Renzhi Hou, Aaron M. Savage, Victor Cat, Louis V. Cammarata, S.Y. Celeste Wu, Vivien Bothe, Burcu Erdogan, Shifa Hossain, Noah Lopez, Julia Losner, Juan Velazquez Matos, Sangwon Min, Sebastian Böhm, Anthony E. Striker, Kelly E. Dooling, Adam H. Freedman, Bobby Groves, Benjamin Tajer, Glory Kalu, Eric Wynn, Alan Y.L. Wong, Nadia Fröbisch, Petr Baranov, Maksim V. Plikus, Jason D. Buenrostro, Brian J. Haas, Isaac M. Chiu, Timothy B. Sackton, Jessica L. Whited |
| Open Access |
| The nervous system regulates a systemic response following amputation that primes distant appendages for faster regeneration upon a second injury, a scenario relevant to salamanders in the wild who experience repeated limb loss. |
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| Distinct components of mRNA vaccines cooperate to instruct efficient germinal center responses |
| Diana Castaño, Emily Bettini, Binod Kumar, Aleksey Chudnovskiy, Anna Siv, Giulia Protti, Sandra Nakadakari-Higa, Simona Ceglia, Nina De Luna, Joy E. Chiu, Katlyn Lederer, Shuk Hang Li, Hassaan Ibrahim, Hiromi Muramatsu, Thandiswa Mdluli, Edit Abraham, Sinem E. Sahingur, Ivan Maillard, Ying K. Tam, Sunny Shin, Scott E. Hensley, Jonathan J. Miner, Zoltan Lipinszki, Andrea Reboldi, Norbert Pardi, Roberto Spreafico, Gabriel D. Victora, Michela Locci |
| Open Access |
| This study dissects the individual contributions of the different components of mRNA vaccines to immune responses. Nucleoside-modified mRNA promotes the production of type I interferons that act on dendritic cells, while lipid nanoparticles instruct discrete Tfh-cell-inducing properties in dendritic cells. Both components are required for optimal germinal center responses. |
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| Gut-to-brain signaling restricts dietary protein intake during recovery from catabolic states |
| Nikolai P. Jaschke, Joseph R. Luchsinger, Zuojia Chen, Vera C. Wulfmeyer, Xavier de la Rosa, Oliver Hahn, Cuiling Zhang, Nathaniel D. Bachtel, Jaime L. Cullen, Tilman D. Rachner, Ruslan Medzhitov, Markus M. Rinschen, Chuan Wu, Andrew Wang |
| Gut sensing of dietary amino-acid-derived ammoniagenesis restricts dietary protein intake during recovery from catabolic states. |
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| De novo designed voltage-gated anion channels suppress neuron firing |
| Chen Zhou, Huican Li, Jiaxing Wang, Cheng Qian, Hui Xiong, Zhilin Chu, Qiming Shao, Xuan Li, Shijin Sun, Ke Sun, Aiqin Zhu, Jiawei Wang, Xueqin Jin, Fan Yang, Tamer M. Gamal El-Din, Bo Li, Jing Huang, Kun Wu, Peilong Lu |
| This study reports the successful de novo design of voltage-gated anion channels that are distinct from native channels. They exhibit voltage-dependent ion conductance and are capable of being tuned for biological applications such as neuronal suppression. |
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| Zebrafish use spectral information to suppress the visual background |
| Chiara Fornetto, Thomas Euler, Tom Baden |
| Open Access |
| Vertebrate eyes first evolved in water, where spectral content rapidly fades with distance. Zebrafish exploit this loss by antagonizing cone signals to suppress the background, pointing to distance estimation—rather than color—as an ancestral cone function. |
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| Stimulant medications affect arousal and reward, not attention networks |
| Benjamin P. Kay, Muriah D. Wheelock, Joshua S. Siegel, Ryan V. Raut, Roselyne J. Chauvin, Athanasia Metoki, Aishwarya Rajesh, Andrew Eck, Jim Pollaro, Anxu Wang, Vahdeta Suljic, Babatunde Adeyemo, Noah J. Baden, Kristen M. Scheidter, Julia S. Monk, Forrest I. Whiting, Nadeshka Ramirez-Perez, Samuel R. Krimmel, Russell T. Shinohara, Brenden Tervo-Clemmens, Robert J.M. Hermosillo, Steven M. Nelson, Timothy J. Hendrickson, Thomas Madison, Lucille A. Moore, Óscar Miranda-Domínguez, Anita Randolph, Eric Feczko, Jarod L. Roland, Ginger E. Nicol, Timothy O. Laumann, Scott Marek, Evan M. Gordon, Marcus E. Raichle, Deanna M. Barch, Damien A. Fair, Nico U.F. Dosenbach |
| Open Access |
| Stimulant medications (e.g., methylphenidate) were thought to improve attention by acting on the brain's attention networks. Functional connectivity data now reveal that stimulants are associated with changes in arousal and reward, but not attention systems, suggesting that they enhance performance by increasing vigilance and perceived task value, not attentional capabilities. |
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| In vivo transcriptomic, functional, circuit-based, and translational analyses of enteric neurons |
| Claire J. Millett, James J. Shaver, Bernadette Bracken, Sunny J. Jones, Robert J. Lovelett, Dave A. Rubinow, Rijul Singhal, Celia Charlton, Nadine Piazza, Quinn Hauck, Nikhil Sharma, Paul A. Muller |
| A comprehensive neuronal molecular map spanning the entire murine gastrointestinal tract enables selective, in vivo investigation of the roles that genetically defined enteric neuron subtypes play in motility, secretions, satiety, and inflammation. Comparison of this murine map with its human counterpart reveals both conserved and unique circuitry, positioning enteric neurons as tractable therapeutic targets for multiple indications. |
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| Properties and functions of transcriptionally distinct enteric neurons |
| David Shi, Pranav Reddy, McKayla Marrin, Christopher Walker, Catherine Siu, Paul A. Muller, Ee-Lynn Yap, Nikhil Sharma |
| Developing genetic access to transcriptionally distinct enteric neurons in vivo enables the examination of morphological heterogeneity across cell types as well as cell-type-specific influences on GI function. |
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| StealTHY: An immunogen-free CRISPR platform to expose concealed metastasis regulators in immunocompetent models |
| Massimo Saini, Francesc Castro-Giner, Adriana Hotz, Magdalena K. Sznurkowska, Manuel Nüesch, François M. Cuenot, Selina Budinjas, Gilles Bilfeld, Ece Su Ildız, Karin Strittmatter, Ilona Krol, Zoi Diamantopoulou, Aino Paasinen-Sohns, Maria Waldmeier, Rafaela Cássio, Susanne Kreutzer, Zacharias Kontarakis, Ana Gvozdenovic, Nicola Aceto |
| Open Access |
| By sidestepping Cas9 immunogenicity, the StealTHY CRISPR platform enables immune-compatible in vivo genetic screens, directly translatable to humanized cancer models. Using this immune-stealth strategy allows for the discovery of metastatic drivers and reveals the AMH-AMHR2 axis as a clinically actionable pathway for dampening carcinoma metastasis. |
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| Charting the landscape of cytoskeletal diversity in microbial eukaryotes |
| Felix Mikus, Armando Rubio Ramos, Hiral Shah, Jonas Hellgoth, Marine Olivetta, Susanne Borgers, Clémence Saint-Donat, Margarida Araújo, Chandni Bhickta, Paulina Cherek, Jone Bilbao, Estibalitz Txurruka, Yana Eglit, Nikolaus Leisch, Yannick Schwab, Filip Husnik, Sergio Seoane, Ian Probert, Paul Guichard, Virginie Hamel, Gautam Dey, Omaya Dudin |
| Open Access |
| An imaging resource of over 200 microbial eukaryotic species provides a glimpse into the remarkable universe of cytoskeletal diversity. |
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| Retraction notice to: Transcriptome-scale RNA-targeting CRISPR screens reveal essential lncRNAs in human cells |
| Wen-Wei Liang, Simon Müller, Sydney K. Hart, Hans-Hermann Wessels, Alejandro Méndez-Mancilla, Akash Sookdeo, Olivia Choi, Christina M. Caragine, Alba Corman, Lu Lu, Olena Kolumba, Breanna Williams, Neville E. Sanjana |
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