Iris Titos, Alen Juginović, Alexandra Vaccaro, Keishi Nambara, Pavel Gorelik, Ofer Mazor, Dragana Rogulja
Suppressing sensory arousal is critical for sleep, with deeper sleep requiring stronger sensory suppression. The mechanisms that enable sleeping animals to largely ignore their surroundings are not well understood. We show that the responsiveness of sleeping flies and mice to mechanical vibrations is better suppressed when the diet is protein rich. In flies, we describe a signaling pathway through which information about ingested proteins is conveyed from the gut to the brain to help suppress arousability. Higher protein concentration in the gut leads to increased activity of enteroendocrine cells that release the peptide CCHa1...
March 17, 2023: Cell
Grace E McAuley, Gloria Yiu, Patrick C Chang, Gregory A Newby, Beatriz Campo-Fernandez, Sorel T Fitz-Gibbon, Xiaomeng Wu, Sung-Hae L Kang, Amber Garibay, Jeffrey Butler, Valentina Christian, Ryan L Wong, Kelcee A Everette, Anthony Azzun, Hila Gelfer, Christopher S Seet, Aru Narendran, Luis Murguia-Favela, Zulema Romero, Nicola Wright, David R Liu, Gay M Crooks, Donald B Kohn
CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3δ SCID patient's HSPCs resulted in a 71.2% ± 7.85% (n = 3) correction of the pathogenic mutation...
March 15, 2023: Cell
Daan J Kloosterman, Leila Akkari
Macrophages are versatile and heterogeneous innate immune cells undertaking central functions in balancing immune responses and tissue repair to maintain homeostasis. This plasticity, once co-opted by malignant outgrowth, orchestrates manifold reciprocal interactions within the tumor microenvironment, fueling the evolution of the cancer ecosystem. Here, we review the multilayered sources of influence that jointly underpin and longitudinally shape tumor-associated macrophage (TAM) phenotypic states in solid neoplasms...
March 14, 2023: Cell
Emma Nolan, Geoffrey J Lindeman, Jane E Visvader
Breast cancer remains a leading cause of cancer-related mortality in women, reflecting profound disease heterogeneity, metastasis, and therapeutic resistance. Over the last decade, genomic and transcriptomic data have been integrated on an unprecedented scale and revealed distinct cancer subtypes, critical molecular drivers, clonal evolutionary trajectories, and prognostic signatures. Furthermore, multi-dimensional integration of high-resolution single-cell and spatial technologies has highlighted the importance of the entire breast cancer ecosystem and the presence of distinct cellular "neighborhoods...
March 13, 2023: Cell
Kyle Swanson, Eric Wu, Angela Zhang, Ash A Alizadeh, James Zou
Machine learning (ML) is increasingly used in clinical oncology to diagnose cancers, predict patient outcomes, and inform treatment planning. Here, we review recent applications of ML across the clinical oncology workflow. We review how these techniques are applied to medical imaging and to molecular data obtained from liquid and solid tumor biopsies for cancer diagnosis, prognosis, and treatment design. We discuss key considerations in developing ML for the distinct challenges posed by imaging and molecular data...
March 7, 2023: Cell
Abigail K Grootveld, Wunna Kyaw, Veera Panova, Angelica W Y Lau, Emily Ashwin, Guillaume Seuzaret, Rama Dhenni, Nayan Deger Bhattacharyya, Weng Hua Khoo, Maté Biro, Tanmay Mitra, Michael Meyer-Hermann, Patrick Bertolino, Masato Tanaka, David A Hume, Peter I Croucher, Robert Brink, Akira Nguyen, Oliver Bannard, Tri Giang Phan
Germinal centers (GCs) that form within lymphoid follicles during antibody responses are sites of massive cell death. Tingible body macrophages (TBMs) are tasked with apoptotic cell clearance to prevent secondary necrosis and autoimmune activation by intracellular self antigens. We show by multiple redundant and complementary methods that TBMs derive from a lymph node-resident, CD169-lineage, CSF1R-blockade-resistant precursor that is prepositioned in the follicle. Non-migratory TBMs use cytoplasmic processes to chase and capture migrating dead cell fragments using a "lazy" search strategy...
March 1, 2023: Cell
Yong-Qiang Gao, Pedro Jimenez-Sandoval, Satyam Tiwari, Stéphanie Stolz, Jing Wang, Gaëtan Glauser, Julia Santiago, Edward E Farmer
Leaf-feeding insects trigger high-amplitude, defense-inducing electrical signals called slow wave potentials (SWPs). These signals are thought to be triggered by the long-distance transport of low molecular mass elicitors termed Ricca's factors. We sought mediators of leaf-to-leaf electrical signaling in Arabidopsis thaliana and identified them as β-THIOGLUCOSIDE GLUCOHYDROLASE 1 and 2 (TGG1 and TGG2). SWP propagation from insect feeding sites was strongly attenuated in tgg1 tgg2 mutants and wound-response cytosolic Ca2+ increases were reduced in these plants...
February 25, 2023: Cell
Changwei Shao, Shuai Sun, Kaiqiang Liu, Jiahao Wang, Shuo Li, Qun Liu, Bruce E Deagle, Inge Seim, Alberto Biscontin, Qian Wang, Xin Liu, So Kawaguchi, Yalin Liu, Simon Jarman, Yue Wang, Hong-Yan Wang, Guodong Huang, Jiang Hu, Bo Feng, Cristiano De Pittà, Shanshan Liu, Rui Wang, Kailong Ma, Yiping Ying, Gabrielle Sales, Tao Sun, Xinliang Wang, Yaolei Zhang, Yunxia Zhao, Shanshan Pan, Xiancai Hao, Yang Wang, Jiakun Xu, Bowen Yue, Yanxu Sun, He Zhang, Mengyang Xu, Yuyan Liu, Xiaodong Jia, Jiancheng Zhu, Shufang Liu, Jue Ruan, Guojie Zhang, Huanming Yang, Xun Xu, Jun Wang, Xianyong Zhao, Bettina Meyer, Guangyi Fan
Antarctic krill (Euphausia superba) is Earth's most abundant wild animal, and its enormous biomass is vital to the Southern Ocean ecosystem. Here, we report a 48.01-Gb chromosome-level Antarctic krill genome, whose large genome size appears to have resulted from inter-genic transposable element expansions. Our assembly reveals the molecular architecture of the Antarctic krill circadian clock and uncovers expanded gene families associated with molting and energy metabolism, providing insights into adaptations to the cold and highly seasonal Antarctic environment...
February 24, 2023: Cell
Kazushige Shiraishi, Parisha P Shah, Michael P Morley, Claudia Loebel, Garrett T Santini, Jeremy Katzen, Maria C Basil, Susan M Lin, Joseph D Planer, Edward Cantu, Dakota L Jones, Ana N Nottingham, Shanru Li, Fabian L Cardenas-Diaz, Su Zhou, Jason A Burdick, Rajan Jain, Edward E Morrisey
Lungs undergo mechanical strain during breathing, but how these biophysical forces affect cell fate and tissue homeostasis are unclear. We show that biophysical forces through normal respiratory motion actively maintain alveolar type 1 (AT1) cell identity and restrict these cells from reprogramming into AT2 cells in the adult lung. AT1 cell fate is maintained at homeostasis by Cdc42- and Ptk2-mediated actin remodeling and cytoskeletal strain, and inactivation of these pathways causes a rapid reprogramming into the AT2 cell fate...
February 23, 2023: Cell
Dayu Lin
Fighting is an intense experience not only for the executors but also for the observers. In the current issue of Cell, Yang et al. identified hypothalamic aggression mirror neurons, activated during both physical fighting and witnessing a fight, possibly representing a neural mechanism for understanding social experiences in other minds.
February 22, 2023: Cell
Lydia W S Finley
The uptake and metabolism of nutrients support fundamental cellular process from bioenergetics to biomass production and cell fate regulation. While many studies of cell metabolism focus on cancer cells, the principles of metabolism elucidated in cancer cells apply to a wide range of mammalian cells. The goal of this review is to discuss how the field of cancer metabolism provides a framework for revealing principles of cell metabolism and for dissecting the metabolic networks that allow cells to meet their specific demands...
February 22, 2023: Cell
Jidong Zhang, Christine Lair, Christine Roubert, Kwame Amaning, María Belén Barrio, Yannick Benedetti, Zhicheng Cui, Zhongliang Xing, Xiaojun Li, Scott G Franzblau, Nicolas Baurin, Florence Bordon-Pallier, Cathy Cantalloube, Stephanie Sans, Sandra Silve, Isabelle Blanc, Laurent Fraisse, Alexey Rak, Lasse B Jenner, Gulnara Yusupova, Marat Yusupov, Junjie Zhang, Takushi Kaneko, T J Yang, Nader Fotouhi, Eric Nuermberger, Sandeep Tyagi, Fabrice Betoudji, Anna Upton, James C Sacchettini, Sophie Lagrange
The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb...
February 20, 2023: Cell
Stephen P Burr, Florian Klimm, Angelos Glynos, Malwina Prater, Pamella Sendon, Pavel Nash, Christopher A Powell, Marie-Lune Simard, Nina A Bonekamp, Julia Charl, Hector Diaz, Lyuba V Bozhilova, Yu Nie, Haixin Zhang, Michele Frison, Maria Falkenberg, Nick Jones, Michal Minczuk, James B Stewart, Patrick F Chinnery
Mitochondrial activity differs markedly between organs, but it is not known how and when this arises. Here we show that cell lineage-specific expression profiles involving essential mitochondrial genes emerge at an early stage in mouse development, including tissue-specific isoforms present before organ formation. However, the nuclear transcriptional signatures were not independent of organelle function. Genetically disrupting intra-mitochondrial protein synthesis with two different mtDNA mutations induced cell lineage-specific compensatory responses, including molecular pathways not previously implicated in organellar maintenance...
February 17, 2023: Cell
Marion Déjosez, Arturo Marin, Graham M Hughes, Ariadna E Morales, Carlos Godoy-Parejo, Jonathan L Gray, Yiren Qin, Arun A Singh, Hui Xu, Javier Juste, Carlos Ibáñez, Kris M White, Romel Rosales, Nancy J Francoeur, Robert P Sebra, Dominic Alcock, Thomas L Volkert, Sébastien J Puechmaille, Andrzej Pastusiak, Simon D W Frost, Michael Hiller, Richard A Young, Emma C Teeling, Adolfo García-Sastre, Thomas P Zwaka
Bats are distinctive among mammals due to their ability to fly, use laryngeal echolocation, and tolerate viruses. However, there are currently no reliable cellular models for studying bat biology or their response to viral infections. Here, we created induced pluripotent stem cells (iPSCs) from two species of bats: the wild greater horseshoe bat (Rhinolophus ferrumequinum) and the greater mouse-eared bat (Myotis myotis). The iPSCs from both bat species showed similar characteristics and had a gene expression profile resembling that of cells attacked by viruses...
February 15, 2023: Cell
Bernadeta Dadonaite, Katharine H D Crawford, Caelan E Radford, Ariana G Farrell, Timothy C Yu, William W Hannon, Panpan Zhou, Raiees Andrabi, Dennis R Burton, Lihong Liu, David D Ho, Helen Y Chu, Richard A Neher, Jesse D Bloom
A major challenge in understanding SARS-CoV-2 evolution is interpreting the antigenic and functional effects of emerging mutations in the viral spike protein. Here, we describe a deep mutational scanning platform based on non-replicative pseudotyped lentiviruses that directly quantifies how large numbers of spike mutations impact antibody neutralization and pseudovirus infection. We apply this platform to produce libraries of the Omicron BA.1 and Delta spikes. These libraries each contain ∼7,000 distinct amino acid mutations in the context of up to ∼135,000 unique mutation combinations...
February 13, 2023: Cell
Taehong Yang, Daniel W Bayless, Yichao Wei, Dan Landayan, Ivo M Marcelo, Yangpeng Wang, Laura A DeNardo, Liqun Luo, Shaul Druckmann, Nirao M Shah
Social interactions require awareness and understanding of the behavior of others. Mirror neurons, cells representing an action by self and others, have been proposed to be integral to the cognitive substrates that enable such awareness and understanding. Mirror neurons of the primate neocortex represent skilled motor tasks, but it is unclear if they are critical for the actions they embody, enable social behaviors, or exist in non-cortical regions. We demonstrate that the activity of individual VMHvlPR neurons in the mouse hypothalamus represents aggression performed by self and others...
February 7, 2023: Cell
Yina Gao, Xiu Luo, Peipei Li, Zhaolong Li, Feng Ye, Songqing Liu, Pu Gao
Adenosine-to-inosine RNA editing has been proposed to be involved in a bacterial anti-phage defense system called RADAR. RADAR contains an adenosine triphosphatase (RdrA) and an adenosine deaminase (RdrB). Here, we report cryo-EM structures of RdrA, RdrB, and currently identified RdrA-RdrB complexes in the presence or absence of RNA and ATP. RdrB assembles into a dodecameric cage with catalytic pockets facing outward, while RdrA adopts both autoinhibited tetradecameric and activation-competent heptameric rings...
February 7, 2023: Cell
Brianna Duncan-Lowey, Nitzan Tal, Alex G Johnson, Shaun Rawson, Megan L Mayer, Shany Doron, Adi Millman, Sarah Melamed, Taya Fedorenko, Assaf Kacen, Alexander Brandis, Tevie Mehlman, Gil Amitai, Rotem Sorek, Philip J Kranzusch
RADAR is a two-protein bacterial defense system that was reported to defend against phage by "editing" messenger RNA. Here, we determine cryo-EM structures of the RADAR defense complex, revealing RdrA as a heptameric, two-layered AAA+ ATPase and RdrB as a dodecameric, hollow complex with twelve surface-exposed deaminase active sites. RdrA and RdrB join to form a giant assembly up to 10 MDa, with RdrA docked as a funnel over the RdrB active site. Surprisingly, our structures reveal an RdrB active site that targets mononucleotides...
February 3, 2023: Cell
Gavin Y Oudit, Kaiming Wang, Anissa Viveiros, Max J Kellner, Josef M Penninger
ACE2 is the indispensable entry receptor for SARS-CoV and SARS-CoV-2. Because of the COVID-19 pandemic, it has become one of the most therapeutically targeted human molecules in biomedicine. ACE2 serves two fundamental physiological roles: as an enzyme, it alters peptide cascade balance; as a chaperone, it controls intestinal amino acid uptake. ACE2's tissue distribution, affected by co-morbidities and sex, explains the broad tropism of coronaviruses and the clinical manifestations of SARS and COVID-19. ACE2-based therapeutics provide a universal strategy to prevent and treat SARS-CoV-2 infections, applicable to all SARS-CoV-2 variants and other emerging zoonotic coronaviruses exploiting ACE2 as their cellular receptor...
February 2, 2023: Cell
Shu-Ting Hung, Gabriel R Linares, Wen-Hsuan Chang, Yunsun Eoh, Gopinath Krishnan, Stacee Mendonca, Sarah Hong, Yingxiao Shi, Manuel Santana, Chuol Kueth, Samantha Macklin-Isquierdo, Sarah Perry, Sarah Duhaime, Claudia Maios, Jonathan Chang, Joscany Perez, Alexander Couto, Jesse Lai, Yichen Li, Samuel V Alworth, Eric Hendricks, Yaoming Wang, Berislav V Zlokovic, Dion K Dickman, J Alex Parker, Daniela C Zarnescu, Fen-Biao Gao, Justin K Ichida
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results from many diverse genetic causes. Although therapeutics specifically targeting known causal mutations may rescue individual types of ALS, these approaches cannot treat most cases since they have unknown genetic etiology. Thus, there is a pressing need for therapeutic strategies that rescue multiple forms of ALS. Here, we show that pharmacological inhibition of PIKFYVE kinase activates an unconventional protein clearance mechanism involving exocytosis of aggregation-prone proteins...
February 2, 2023: Cell
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