Pub Date : 2024-10-24DOI: 10.1038/s41575-024-01013-z
Katrina Ray
From 12–15 October, United European Gastroenterology (UEG) Week was held in person in Vienna, Austria, and online simultaneously. According to the organizers, there were 11,377 total registrants from 114 countries or territories, of whom 11% were registered for the virtual congress, with 4,701 individuals registered for the Postgraduate Teaching Programme, of whom 19% were registered for virtual attendance.
Alongside the usual variety of sessions on basic, translational and clinical science across the fields of gastroenterology and hepatology, there was an expansion in the scope of the topics covered, and indeed how they were delivered (so-called silent sessions with attendees listening on headphones). Sessions on metabolism and nutrition were noticeably prominent, highlighting the current interest in food as medicine and the new obesity management medications. A whole session was dedicated to the role of nutrition in the pathogenesis and treatment of lower gastrointestinal disease and a late-breaker abstract presented positive data for the ‘Tasty&Healthy’ flexible diet in children and young adults with mild–moderate Crohn’s disease. Attendees were also guided through the underlying mechanisms for GLP1 agonists and the ever-expanding list of dual and triple agonists for the management of obesity, as well as given practical advice on the therapeutic management of obesity, which included lifestyle interventions and surgery.
{"title":"UEG Week 2024","authors":"Katrina Ray","doi":"10.1038/s41575-024-01013-z","DOIUrl":"https://doi.org/10.1038/s41575-024-01013-z","url":null,"abstract":"<p>From 12–15 October, United European Gastroenterology (UEG) Week was held in person in Vienna, Austria, and online simultaneously. According to the organizers, there were 11,377 total registrants from 114 countries or territories, of whom 11% were registered for the virtual congress, with 4,701 individuals registered for the Postgraduate Teaching Programme, of whom 19% were registered for virtual attendance.</p><p>Alongside the usual variety of sessions on basic, translational and clinical science across the fields of gastroenterology and hepatology, there was an expansion in the scope of the topics covered, and indeed how they were delivered (so-called silent sessions with attendees listening on headphones). Sessions on metabolism and nutrition were noticeably prominent, highlighting the current interest in food as medicine and the new obesity management medications. A whole session was dedicated to the role of nutrition in the pathogenesis and treatment of lower gastrointestinal disease and a late-breaker abstract presented positive data for the ‘Tasty&Healthy’ flexible diet in children and young adults with mild–moderate Crohn’s disease. Attendees were also guided through the underlying mechanisms for GLP1 agonists and the ever-expanding list of dual and triple agonists for the management of obesity, as well as given practical advice on the therapeutic management of obesity, which included lifestyle interventions and surgery.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"125 1","pages":""},"PeriodicalIF":65.1,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1016/j.cell.2024.09.047
Merlin Lange, Alejandro Granados, Shruthi VijayKumar, Jordão Bragantini, Sarah Ancheta, Yang-Joon Kim, Sreejith Santhosh, Michael Borja, Hirofumi Kobayashi, Erin McGeever, Ahmet Can Solak, Bin Yang, Xiang Zhao, Yang Liu, Angela M. Detweiler, Sheryl Paul, Ilan Theodoro, Honey Mekonen, Chris Charlton, Tiger Lao, Loïc A. Royer
Elucidating organismal developmental processes requires a comprehensive understanding of cellular lineages in the spatial, temporal, and molecular domains. In this study, we introduce Zebrahub, a dynamic atlas of zebrafish embryonic development that integrates single-cell sequencing time course data with lineage reconstructions facilitated by light-sheet microscopy. This atlas offers high-resolution and in-depth molecular insights into zebrafish development, achieved through the sequencing of individual embryos across ten developmental stages, complemented by reconstructions of cellular trajectories. Zebrahub also incorporates an interactive tool to navigate the complex cellular flows and lineages derived from light-sheet microscopy data, enabling in silico fate-mapping experiments. To demonstrate the versatility of our multimodal resource, we utilize Zebrahub to provide fresh insights into the pluripotency of neuro-mesodermal progenitors (NMPs) and the origins of a joint kidney-hemangioblast progenitor population.
{"title":"A multimodal zebrafish developmental atlas reveals the state-transition dynamics of late-vertebrate pluripotent axial progenitors","authors":"Merlin Lange, Alejandro Granados, Shruthi VijayKumar, Jordão Bragantini, Sarah Ancheta, Yang-Joon Kim, Sreejith Santhosh, Michael Borja, Hirofumi Kobayashi, Erin McGeever, Ahmet Can Solak, Bin Yang, Xiang Zhao, Yang Liu, Angela M. Detweiler, Sheryl Paul, Ilan Theodoro, Honey Mekonen, Chris Charlton, Tiger Lao, Loïc A. Royer","doi":"10.1016/j.cell.2024.09.047","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.047","url":null,"abstract":"Elucidating organismal developmental processes requires a comprehensive understanding of cellular lineages in the spatial, temporal, and molecular domains. In this study, we introduce Zebrahub, a dynamic atlas of zebrafish embryonic development that integrates single-cell sequencing time course data with lineage reconstructions facilitated by light-sheet microscopy. This atlas offers high-resolution and in-depth molecular insights into zebrafish development, achieved through the sequencing of individual embryos across ten developmental stages, complemented by reconstructions of cellular trajectories. Zebrahub also incorporates an interactive tool to navigate the complex cellular flows and lineages derived from light-sheet microscopy data, enabling <em>in silico</em> fate-mapping experiments. To demonstrate the versatility of our multimodal resource, we utilize Zebrahub to provide fresh insights into the pluripotency of neuro-mesodermal progenitors (NMPs) and the origins of a joint kidney-hemangioblast progenitor population.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"5 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 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
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.
{"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":45,"journal":{"name":"Journal of Chemical Theory and Computation","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":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 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
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.
{"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":45,"journal":{"name":"Journal of Chemical Theory and Computation","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":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1016/j.cell.2024.09.042
John A. Ciemniecki, Chia-Lun Ho, Richard D. Horak, Akihiro Okamoto, Dianne K. Newman
Mechanistic studies of life’s lower metabolic limits have been limited due to a paucity of tractable experimental systems. Here, we show that redox-cycling of phenazine-1-carboxamide (PCN) by Pseudomonas aeruginosa supports cellular maintenance in the absence of growth with a low mass-specific metabolic rate of 8.7 × 10−4 W (g C)−1 at 25°C. Leveraging a high-throughput electrochemical culturing device, we find that non-growing cells cycling PCN tolerate conventional antibiotics but are susceptible to those that target membrane components. Under these conditions, cells conserve energy via a noncanonical, facilitated fermentation that is dependent on acetate kinase and NADH dehydrogenases. Across PCN concentrations that limit cell survival, the cell-specific metabolic rate is constant, indicating the cells are operating near their bioenergetic limit. This quantitative platform opens the door to further mechanistic investigations of maintenance, a physiological state that underpins microbial survival in nature and disease.
{"title":"Mechanistic study of a low-power bacterial maintenance state using high-throughput electrochemistry","authors":"John A. Ciemniecki, Chia-Lun Ho, Richard D. Horak, Akihiro Okamoto, Dianne K. Newman","doi":"10.1016/j.cell.2024.09.042","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.042","url":null,"abstract":"Mechanistic studies of life’s lower metabolic limits have been limited due to a paucity of tractable experimental systems. Here, we show that redox-cycling of phenazine-1-carboxamide (PCN) by <em>Pseudomonas aeruginosa</em> supports cellular maintenance in the absence of growth with a low mass-specific metabolic rate of 8.7 × 10<sup>−4</sup> W (g C)<sup>−1</sup> at 25°C. Leveraging a high-throughput electrochemical culturing device, we find that non-growing cells cycling PCN tolerate conventional antibiotics but are susceptible to those that target membrane components. Under these conditions, cells conserve energy via a noncanonical, facilitated fermentation that is dependent on acetate kinase and NADH dehydrogenases. Across PCN concentrations that limit cell survival, the cell-specific metabolic rate is constant, indicating the cells are operating near their bioenergetic limit. This quantitative platform opens the door to further mechanistic investigations of maintenance, a physiological state that underpins microbial survival in nature and disease.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"27 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1038/s41575-024-01000-4
Bahtiyar Yilmaz, Andrew J. Macpherson
The small intestinal microbiota has a crucial role in gastrointestinal health, affecting digestion, immune function, bile acid homeostasis and nutrient metabolism. The challenges of accessibility at this site mean that our knowledge of the small intestinal microbiota is less developed than of the colonic or faecal microbiota. Here, we summarize the features and fluctuations of the microbiota along the small intestinal tract, focusing on humans, and discuss physicochemical factors and assessment methods, including the technical challenges of investigating the low microbial biomass of the proximal small bowel. We highlight the essential protective mechanisms of the small intestine, including motility, the paracellular barrier and mucus, and secretory immunity, to show their roles in limiting excessive exposure of host tissues to microbial metabolites. We address current knowledge gaps, particularly the variability among individuals, the effects of dysbiosis of the small intestinal microbiota on health and how different taxa in small intestinal microbiota could compensate for each other functionally.
{"title":"Delving the depths of ‘terra incognita’ in the human intestine — the small intestinal microbiota","authors":"Bahtiyar Yilmaz, Andrew J. Macpherson","doi":"10.1038/s41575-024-01000-4","DOIUrl":"https://doi.org/10.1038/s41575-024-01000-4","url":null,"abstract":"<p>The small intestinal microbiota has a crucial role in gastrointestinal health, affecting digestion, immune function, bile acid homeostasis and nutrient metabolism. The challenges of accessibility at this site mean that our knowledge of the small intestinal microbiota is less developed than of the colonic or faecal microbiota. Here, we summarize the features and fluctuations of the microbiota along the small intestinal tract, focusing on humans, and discuss physicochemical factors and assessment methods, including the technical challenges of investigating the low microbial biomass of the proximal small bowel. We highlight the essential protective mechanisms of the small intestine, including motility, the paracellular barrier and mucus, and secretory immunity, to show their roles in limiting excessive exposure of host tissues to microbial metabolites. We address current knowledge gaps, particularly the variability among individuals, the effects of dysbiosis of the small intestinal microbiota on health and how different taxa in small intestinal microbiota could compensate for each other functionally.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"60 1","pages":""},"PeriodicalIF":65.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-21DOI: 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
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.
炎性细胞因子对免疫反应至关重要。细胞因子暴露后，细胞会进入一种 "警戒状态"，这种状态会提高细胞在免疫系统中的可见度。在这里，我们发现了一种警戒状态的核糖体亚群，其定义是 P-茎的存在。我们发现，P-茎核糖体（PSRs）的形成是对与肿瘤免疫相关的细胞因子的反应，而这至少部分是由 P-茎磷酸化介导的。通过更有效地翻译参与细胞因子介导过程的受体分子的跨膜结构域，PSRs 参与了对细胞因子反应至关重要的 mRNA 的优先翻译。重要的是，PSR 的缺失会抑制 CD8+ T 细胞的识别和杀伤，抑制性细胞因子（如转化生长因子 β (TGF-β)）会阻碍 PSR 的形成，这表明 PSR 是多种信号汇聚的中心调控枢纽。因此，PSR 是细胞因子暴露后通过翻译调控这一过程进行细胞重构的重要介质。
{"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":45,"journal":{"name":"Journal of Chemical Theory and Computation","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":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-21DOI: 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
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.
内切-β-N-乙酰葡糖胺酶（ENGases）能特异性水解免疫球蛋白 G（IgG）抗体上与 Asn297 连接的聚糖（IgG 是片段结晶（Fc）γ 受体（FcγR）结合的主要分子决定因素），但这种酶极为罕见。所有先前表征的 IgG 特异性恩格酶都是化脓性链球菌菌株作为一种免疫逃避策略分泌的多域蛋白。在这里，我们利用硅学分析和质谱技术，确定了致病性球孢子菌分泌的单链ENG酶家族，它们对IgG抗体具有严格的特异性。通过 X 射线晶体学和表面等离子体共振分析，我们发现催化效率最高的 IgG 特异性ENGase 家族成员既能识别 IgG 的蛋白质成分，也能识别 IgG 的聚糖成分。利用体内模型，我们证明了这种 IgG 特异性ENGase 在减轻依赖 FcγR 介导的效应器功能的多种病症（包括 T 淋巴细胞和 B 淋巴细胞耗竭、自身免疫性溶血性贫血和抗体依赖性登革热病增强）方面的显著功效，揭示了它在治疗和/或预防人类多种 IgG 介导的疾病方面的潜力。
{"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 <em>Streptococcus pyogenes</em> strains. Here, using <em>in silico</em> 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 <em>in vivo</em> 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":45,"journal":{"name":"Journal of Chemical Theory and Computation","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":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"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 <em>in vivo</em> 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":45,"journal":{"name":"Journal of Chemical Theory and Computation","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":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"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 Ca<sup>2+</sup>-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 Ca<sup>2+</sup> 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, Ca<sup>2+</sup> influx-induced RNA G-quadruplex assembly accelerates α-synuclein phase transition and aggregation, potentially contributing to synucleinopathies.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","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":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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