IF 64.5 1区生物学

Cell Pub Date : 2024-10-24 DOI: 10.1016/j.cell.2024.09.044

Min Cheol Kim, Rachel Gate, David S. Lee, Andrew Tolopko, Andrew Lu, Erin Gordon, Eric Shifrut, Pablo E. Garcia-Nieto, Alexander Marson, Vasilis Ntranos, Chun Jimmie Ye

{"title":"Method of moments framework for differential expression analysis of single-cell RNA sequencing data","authors":"Min Cheol Kim, Rachel Gate, David S. Lee, Andrew Tolopko, Andrew Lu, Erin Gordon, Eric Shifrut, Pablo E. Garcia-Nieto, Alexander Marson, Vasilis Ntranos, Chun Jimmie Ye","doi":"10.1016/j.cell.2024.09.044","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.044","url":null,"abstract":"Differential expression analysis of single-cell RNA sequencing (scRNA-seq) data is central for characterizing how experimental factors affect the distribution of gene expression. However, distinguishing between biological and technical sources of cell-cell variability and assessing the statistical significance of quantitative comparisons between cell groups remain challenging. We introduce Memento, a tool for robust and efficient differential analysis of mean expression, variability, and gene correlation from scRNA-seq data, scalable to millions of cells and thousands of samples. We applied Memento to 70,000 tracheal epithelial cells to identify interferon-responsive genes, 160,000 CRISPR-Cas9 perturbed T cells to reconstruct gene-regulatory networks, 1.2 million peripheral blood mononuclear cells (PBMCs) to map cell-type-specific quantitative trait loci (QTLs), and the 50-million-cell CELLxGENE Discover corpus to compare arbitrary cell groups. In all cases, Memento identified more significant and reproducible differences in mean expression compared with existing methods. It also identified differences in variability and gene correlation that suggest distinct transcriptional regulation mechanisms imparted by perturbations.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"94 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Adaptive multi-epitope targeting and avidity-enhanced nanobody platform for ultrapotent, durable antiviral therapy 用于超强、持久抗病毒治疗的自适应多表位靶向和抗体增强型纳米抗体平台

IF 64.5 1区生物学

Cell Pub Date : 2024-10-23 DOI: 10.1016/j.cell.2024.09.043

Yufei Xiang, Jialu Xu, Briana L. McGovern, Anna Ranzenigo, Wei Huang, Zhe Sang, Juan Shen, Randy Diaz-tapia, Ngoc Dung Pham, Abraham J.P. Teunissen, M. Luis Rodriguez, Jared Benjamin, Derek J. Taylor, Mandy M.T. van Leent, Kris M. White, Adolfo García-Sastre, Peijun Zhang, Yi Shi

{"title":"Adaptive multi-epitope targeting and avidity-enhanced nanobody platform for ultrapotent, durable antiviral therapy","authors":"Yufei Xiang, Jialu Xu, Briana L. McGovern, Anna Ranzenigo, Wei Huang, Zhe Sang, Juan Shen, Randy Diaz-tapia, Ngoc Dung Pham, Abraham J.P. Teunissen, M. Luis Rodriguez, Jared Benjamin, Derek J. Taylor, Mandy M.T. van Leent, Kris M. White, Adolfo García-Sastre, Peijun Zhang, Yi Shi","doi":"10.1016/j.cell.2024.09.043","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.043","url":null,"abstract":"Pathogens constantly evolve and can develop mutations that evade host immunity and treatment. Addressing these escape mechanisms requires targeting evolutionarily conserved vulnerabilities, as mutations in these regions often impose fitness costs. We introduce adaptive multi-epitope targeting with enhanced avidity (AMETA), a modular and multivalent nanobody platform that conjugates potent bispecific nanobodies to a human immunoglobulin M (IgM) scaffold. AMETA can display 20+ nanobodies, enabling superior avidity binding to multiple conserved and neutralizing epitopes. By leveraging multi-epitope SARS-CoV-2 nanobodies and structure-guided design, AMETA constructs exponentially enhance antiviral potency, surpassing monomeric nanobodies by over a million-fold. These constructs demonstrate ultrapotent, broad, and durable efficacy against pathogenic sarbecoviruses, including Omicron sublineages, with robust preclinical results. Structural analysis through cryoelectron microscopy and modeling has uncovered multiple antiviral mechanisms within a single construct. At picomolar to nanomolar concentrations, AMETA efficiently induces inter-spike and inter-virus cross-linking, promoting spike post-fusion and striking viral disarmament. AMETA’s modularity enables rapid, cost-effective production and adaptation to evolving pathogens.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"13 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanistic study of a low-power bacterial maintenance state using high-throughput electrochemistry 利用高通量电化学对低功率细菌维持状态进行机理研究

IF 64.5 1区生物学

Cell Pub Date : 2024-10-23 DOI: 10.1016/j.cell.2024.09.042

John A. Ciemniecki, Chia-Lun Ho, Richard D. Horak, Akihiro Okamoto, Dianne K. Newman

引用次数: 0

P-stalk ribosomes act as master regulators of cytokine-mediated processes P-stalk 核糖体是细胞因子介导过程的主调节器

IF 64.5 1区生物学

Cell Pub Date : 2024-10-21 DOI: 10.1016/j.cell.2024.09.039

Anna Dopler, Ferhat Alkan, Yuval Malka, Rob van der Kammen, Kelly Hoefakker, Daniel Taranto, Naz Kocabay, Iris Mimpen, Christel Ramirez, Elke Malzer, Olga I. Isaeva, Mandy Kerkhoff, Anastasia Gangaev, Joana Silva, Sofia Ramalho, Liesbeth Hoekman, Maarten Altelaar, Roderick Beijersbergen, Leila Akkari, Jonathan Wilson Yewdell, William James Faller

{"title":"P-stalk ribosomes act as master regulators of cytokine-mediated processes","authors":"Anna Dopler, Ferhat Alkan, Yuval Malka, Rob van der Kammen, Kelly Hoefakker, Daniel Taranto, Naz Kocabay, Iris Mimpen, Christel Ramirez, Elke Malzer, Olga I. Isaeva, Mandy Kerkhoff, Anastasia Gangaev, Joana Silva, Sofia Ramalho, Liesbeth Hoekman, Maarten Altelaar, Roderick Beijersbergen, Leila Akkari, Jonathan Wilson Yewdell, William James Faller","doi":"10.1016/j.cell.2024.09.039","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.039","url":null,"abstract":"Inflammatory cytokines are pivotal to immune responses. Upon cytokine exposure, cells enter an “alert state” that enhances their visibility to the immune system. Here, we identified an alert-state subpopulation of ribosomes defined by the presence of the P-stalk. We show that P-stalk ribosomes (PSRs) are formed in response to cytokines linked to tumor immunity, and this is at least partially mediated by P-stalk phosphorylation. PSRs are involved in the preferential translation of mRNAs vital for the cytokine response via the more efficient translation of transmembrane domains of receptor molecules involved in cytokine-mediated processes. Importantly, loss of the PSR inhibits CD8+ T cell recognition and killing, and inhibitory cytokines like transforming growth factor β (TGF-β) hinder PSR formation, suggesting that the PSR is a central regulatory hub upon which multiple signals converge. Thus, the PSR is an essential mediator of the cellular rewiring that occurs following cytokine exposure via the translational regulation of this process.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"209 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Potent efficacy of an IgG-specific endoglycosidase against IgG-mediated pathologies IgG特异性内糖苷酶对IgG介导的病症具有强大疗效

IF 64.5 1区生物学

Cell Pub Date : 2024-10-21 DOI: 10.1016/j.cell.2024.09.038

Diego E. Sastre, Stylianos Bournazos, Jonathan Du, E. Josephine Boder, Julia E. Edgar, Tala Azzam, Nazneen Sultana, Maros Huliciak, Maria Flowers, Lea Yoza, Ting Xu, Tatiana A. Chernova, Jeffrey V. Ravetch, Eric J. Sundberg

{"title":"Potent efficacy of an IgG-specific endoglycosidase against IgG-mediated pathologies","authors":"Diego E. Sastre, Stylianos Bournazos, Jonathan Du, E. Josephine Boder, Julia E. Edgar, Tala Azzam, Nazneen Sultana, Maros Huliciak, Maria Flowers, Lea Yoza, Ting Xu, Tatiana A. Chernova, Jeffrey V. Ravetch, Eric J. Sundberg","doi":"10.1016/j.cell.2024.09.038","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.038","url":null,"abstract":"Endo-β-N-acetylglucosaminidases (ENGases) that specifically hydrolyze the Asn297-linked glycan on immunoglobulin G (IgG) antibodies, the major molecular determinant of fragment crystallizable (Fc) γ receptor (FcγR) binding, are exceedingly rare. All previously characterized IgG-specific ENGases are multi-domain proteins secreted as an immune evasion strategy by Streptococcus pyogenes strains. Here, using in silico analysis and mass spectrometry techniques, we identified a family of single-domain ENGases secreted by pathogenic corynebacterial species that exhibit strict specificity for IgG antibodies. By X-ray crystallographic and surface plasmon resonance analyses, we found that the most catalytically efficient IgG-specific ENGase family member recognizes both protein and glycan components of IgG. Employing in vivo models, we demonstrated the remarkable efficacy of this IgG-specific ENGase in mitigating numerous pathologies that rely on FcγR-mediated effector functions, including T and B lymphocyte depletion, autoimmune hemolytic anemia, and antibody-dependent enhancement of dengue disease, revealing its potential for treating and/or preventing a wide range of IgG-mediated diseases in humans.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense 双线营养供应环境通过对营养吸收和宿主防御的不同调控促进小肠生理机能的发展

IF 64.5 1区生物学

Cell Pub Date : 2024-10-19 DOI: 10.1016/j.cell.2024.08.012

Jian Zhang, Ruonan Tian, Jia Liu, Jie Yuan, Siwen Zhang, Zhexu Chi, Weiwei Yu, Qianzhou Yu, Zhen Wang, Sheng Chen, Mobai Li, Dehang Yang, Tianyi Hu, Qiqi Deng, Xiaoyang Lu, Yidong Yang, Rongbin Zhou, Xue Zhang, Wanlu Liu, Di Wang

{"title":"A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense","authors":"Jian Zhang, Ruonan Tian, Jia Liu, Jie Yuan, Siwen Zhang, Zhexu Chi, Weiwei Yu, Qianzhou Yu, Zhen Wang, Sheng Chen, Mobai Li, Dehang Yang, Tianyi Hu, Qiqi Deng, Xiaoyang Lu, Yidong Yang, Rongbin Zhou, Xue Zhang, Wanlu Liu, Di Wang","doi":"10.1016/j.cell.2024.08.012","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.012","url":null,"abstract":"The small intestine contains a two-front nutrient supply environment created by luminal dietary and microbial metabolites (enteral side) and systemic metabolites from the host (serosal side). Yet, it is unknown how each side contributes differentially to the small intestinal physiology. Here, we generated a comprehensive, high-resolution map of the small intestinal two-front nutrient supply environment. Using in vivo tracing of macronutrients and spatial metabolomics, we visualized the spatiotemporal dynamics and cell-type tropism in nutrient absorption and the region-specific metabolic heterogeneity within the villi. Specifically, glutamine from the enteral side fuels goblet cells to support mucus production, and the serosal side loosens the epithelial barrier by calibrating fungal metabolites. Disorganized feeding patterns, akin to the human lifestyle of skipping breakfast, increase the risk of metabolic diseases by inducing epithelial memory of lipid absorption. This study improves our understanding of how the small intestine is spatiotemporally regulated by its unique nutritional environment.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"40 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNA G-quadruplexes form scaffolds that promote neuropathological α-synuclein aggregation RNA G-四重链形成支架，促进神经病理α-突触核蛋白聚集

IF 64.5 1区生物学

Cell Pub Date : 2024-10-18 DOI: 10.1016/j.cell.2024.09.037

Kazuya Matsuo, Sefan Asamitsu, Kohei Maeda, Hiroyoshi Suzuki, Kosuke Kawakubo, Ginji Komiya, Kenta Kudo, Yusuke Sakai, Karin Hori, Susumu Ikenoshita, Shingo Usuki, Shiori Funahashi, Hideki Oizumi, Atsushi Takeda, Yasushi Kawata, Tomohiro Mizobata, Norifumi Shioda, Yasushi Yabuki

{"title":"RNA G-quadruplexes form scaffolds that promote neuropathological α-synuclein aggregation","authors":"Kazuya Matsuo, Sefan Asamitsu, Kohei Maeda, Hiroyoshi Suzuki, Kosuke Kawakubo, Ginji Komiya, Kenta Kudo, Yusuke Sakai, Karin Hori, Susumu Ikenoshita, Shingo Usuki, Shiori Funahashi, Hideki Oizumi, Atsushi Takeda, Yasushi Kawata, Tomohiro Mizobata, Norifumi Shioda, Yasushi Yabuki","doi":"10.1016/j.cell.2024.09.037","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.037","url":null,"abstract":"Synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, are triggered by α-synuclein aggregation, triggering progressive neurodegeneration. However, the intracellular α-synuclein aggregation mechanism remains unclear. Herein, we demonstrate that RNA G-quadruplex assembly forms scaffolds for α-synuclein aggregation, contributing to neurodegeneration. Purified α-synuclein binds RNA G-quadruplexes directly through the N terminus. RNA G-quadruplexes undergo Ca2+-induced phase separation and assembly, accelerating α-synuclein sol-gel phase transition. In α-synuclein preformed fibril-treated neurons, RNA G-quadruplex assembly comprising synaptic mRNAs co-aggregates with α-synuclein upon excess cytoplasmic Ca2+ influx, eliciting synaptic dysfunction. Forced RNA G-quadruplex assembly using an optogenetic approach evokes α-synuclein aggregation, causing neuronal dysfunction and neurodegeneration. The administration of 5-aminolevulinic acid, a protoporphyrin IX prodrug, prevents RNA G-quadruplex phase separation, thereby attenuating α-synuclein aggregation, neurodegeneration, and progressive motor deficits in α-synuclein preformed fibril-injected synucleinopathic mice. Therefore, Ca2+ influx-induced RNA G-quadruplex assembly accelerates α-synuclein phase transition and aggregation, potentially contributing to synucleinopathies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"64 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Light-induced targeting enables proteomics on endogenous condensates 光诱导靶向技术实现了对内源性凝聚物的蛋白质组学研究

IF 64.5 1区生物学

Cell Pub Date : 2024-10-18 DOI: 10.1016/j.cell.2024.09.040

Choongman Lee, Andrea Quintana, Ida Suppanz, Alejandro Gomez-Auli, Gerhard Mittler, Ibrahim I. Cissé

引用次数: 0

From periphery to center stage: 50 years of advancements in innate immunity 从外围到中心舞台：先天性免疫 50 年的发展历程

IF 64.5 1区生物学

Cell Pub Date : 2024-10-18 DOI: 10.1016/j.cell.2024.10.013

Susan Carpenter, Luke A.J. O’Neill

引用次数: 0

PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes PLD3 和 PLD4 合成 S,S-BMP，这是一种能在溶酶体中实现脂质降解的关键磷脂

IF 64.5 1区生物学

Cell Pub Date : 2024-10-17 DOI: 10.1016/j.cell.2024.09.036

Shubham Singh, Ulrich E. Dransfeld, Yohannes A. Ambaw, Joshua Lopez-Scarim, Robert V. Farese, Tobias C. Walther

{"title":"PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes","authors":"Shubham Singh, Ulrich E. Dransfeld, Yohannes A. Ambaw, Joshua Lopez-Scarim, Robert V. Farese, Tobias C. Walther","doi":"10.1016/j.cell.2024.09.036","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.036","url":null,"abstract":"Bis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, particularly gangliosides. Alterations in BMP levels are associated with neurodegenerative diseases. Unlike typical glycerophospholipids, lysosomal BMP has two chiral glycerol carbons in the S (rather than the R) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucial S,S-stereochemistry is achieved is unknown. Here, we report that phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomal S,S-BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reaction in vitro. Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where either enzyme is highly expressed (brain for PLD3; spleen for PLD4), leading to gangliosidosis and lysosomal abnormalities. PLD3 mutants associated with neurodegenerative diseases, including risk of Alzheimer’s disease, diminished PLD3 catalytic activity. We conclude that PLD3/4 enzymes synthesize lysosomal S,S-BMP, a crucial lipid for maintaining brain health.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"124 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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