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C3aR1 on β cells enhances β cell function and survival to maintain glucose homeostasis

Molecular Metabolism 2025年 96卷 102134-102134页

作者： Pereira de Lima, Renan Li, Ang Gilani, Ankit Rubio-Navarro, Alfonso Warren, Charles D. Kong, Isabella Y. Geri, Jacob B. Lo, James C. Division of Cardiology Weill Center for Metabolic Health Cardiovascular Research Institute Department of Medicine Weill Cornell Medicine New York NY United States Tri-Institutional PhD Program in Chemical Biology New York NY United States Department of Pharmacology Weill Cornell Medicine New York NY United States Division of Pediatric Hematology/Oncology Weill Cornell Medicine New York NY United States

Objective: Pancreatic β cell dysfunction is critical to the development of type 2 diabetes (T2D). Our previous studies suggested that C3aR1 on β cells promotes insulin secretion and cell survival. However, as C3aR1 is expressed on many other cell types including within the islets, whole-body C3aR1 knockout models confound the analyses of direct impacts on β cells. Methods: To clarify the role of C3aR1 in β cells under T2D conditions, we generated β cell-specific C3aR1 knockout mice. We assessed glucose homeostasis, focusing on β cell function and mass under metabolic stress conditions, to interrogate the effects of C3aR1 on β cells in a mouse model of T2D. We performed proteomic analyses on islets from control and β cell-specific C3aR1 knockout mice. To determine potential translational relevance, C3AR1 was assessed alongside glucose-stimulated insulin secretion in human islets. Results: We show that the complement receptor C3aR1 on β cells plays an essential role in maintaining β cell homeostasis, especially under the metabolic duress of obesity and T2D. Male mice with β cell specific deletion of C3ar1 (β-C3aR1 KO) exhibit worse glucose tolerance and lower insulin levels when fed regular or high fat diet. Under high fat diet, β-C3aR1 KO also have diminished β cell mass. Islets from β-C3aR1 KO mice demonstrate impaired insulin secretion. β cells lacking C3aR1 display increased susceptibility to lipotoxicity-mediated cell death. Markers of β cell identity are decreased in β-C3aR1 KO mice while stress markers are elevated. Disruption of C3ar1 on β cells ablates the insulin secretory response to C3a, establishing a signaling axis between C3a and β cell-derived C3aR1. Islet proteomic analyses highlight the MAPK pathway and mitochondrial dysfunction with C3aR1 loss in β cells. Finally, we show that C3AR1 is positively correlated with insulin secretion in human islets. Conclusions: These findings indicate that C3aR1 expression on β cells is necessary to maintain optimal β

关键词： Beta cell Beta cell failure Complement Insulin secretion Type 2 diabetes

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A panoramic view of cell population dynamics in mammalian aging

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Journal of Bio-X Research 2025年第6731期387卷 eadn3949页

作者： Zhang, Zehao Schaefer, Chloe Jiang, Weirong Lu, Ziyu Lee, Jasper Sziraki, Andras Abdulraouf, Abdulraouf Wick, Brittney Haeussler, Maximilian Li, Zhuoyan Molla, Gesmira Satija, Rahul Zhou, Wei Cao, Junyue Laboratory of Single-Cell Genomics and Population Dynamics The Rockefeller University New York NY USA The David Rockefeller Graduate Program in Bioscience The Rockefeller University New York NY USA The Tri-Institutional MD-PhD Program New York NY USA UC Santa Cruz Genomics Institute University of California Santa Cruz CA USA New York Genome Center New York NY USA Center for Genomics and Systems Biology New York University New York NY USA

To elucidate aging-associated cellular population dynamics, we present PanSci, a single-cell transcriptome atlas profiling >20 million cells from 623 mouse tissues across different life stages, sexes, and genotypes. This comprehensive dataset reveals >3000 different cellular states and >200 aging-associated cell populations. Our panoramic analysis uncovered organ-, lineage-, and sex-specific shifts in cellular dynamics during life-span progression. Moreover, we identify both systematic and organ-specific alterations in immune cell populations associated with aging. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte dependent. Our “cell-omics” strategy enhances comprehension of cellular aging and lays the groundwork for exploring the complex cellular regulatory networks in aging and aging-associated diseases. © 2025 American Association for the Advancement of Science. All rights reserved.

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Non-enzymatic covalent modifications:a new link between metabolism and epigenetics

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Protein & Cell 2020年第6期11卷 401-416页

作者： Qingfei Zheng Igor Maksimovic Akhil Upad Yael David Chemical Biology Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Tri-Institutional PhD Program in Chemical Biology New YorkNY 10065USA Department of Pharmacology Weill Cornell MedicineNew YorkNY 10065USA Department of Physiology Biophysics and Systems BiologyWeill Cornell MedicineNew YorkNY 10065USA

Epigenetic modifications,including those on DNA and histones,have been shown to regulate cellular metabolism by controlling expression of enzymes involved in the corresponding metabolic *** turn,metabolic flux influences epigenetic regulation by affecting the biosynthetic balance of enzyme cofactors or donors for certain chromatin ***,non-enzymatic covalent modifications(NECMs)by chemically reactive metabolites have been reported to manipulate chromatin architecture and gene transcription through multiple ***,we summarize these recent advances in the identification and characterization of NECMs on nucleic acids,histones,and transcription factors,providing an additional mechanistic link between metabolism and epigenetics.

关键词： epigenetics metabolism non-enzymatic modification chromatin human disease

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Aminoglycoside activity observed on single pre-translocation ribosome complexes (vol 6, pg 54, 2010)

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NATURE chemical biology 2010年第3期6卷 244-244页

作者： Feldman, Michael B. Terry, Daniel S. Altman, Roger B. Blanchard, Scott C. Department of Physiology and Biophysics Weill Medical College of Cornell University New York New York USA Weill Cornell/Rockefeller University/Sloan-Kettering Tri-Institutional MD-PhD Program New York New York USA Tri-Institutional Training Program in Computational Biology and Medicine New York New York USA.

Aminoglycoside-class antibiotics bind directly to ribosomal RNA, imparting pleiotropic effects on ribosome function. Despite in-depth structural investigations of aminoglycoside-RNA oligonucleotide and aminoglycoside-ribosome interactions, mechanisms explaining the unique ribosome inhibition profiles of chemically similar aminoglycosides remain elusive. Here, using single-molecule fluorescence resonance energy transfer (smFRET) methods, we show that high-affinity aminoglycoside binding to the conserved decoding site region of the functional pre-translocation ribosome complex specifically remodels the nature of intrinsic dynamic processes within the particle. The extents of these effects, which are distinct for each member of the aminoglycoside class, strongly correlate with their inhibition of EF-G-catalyzed translocation. Neomycin, a 4,5-linked aminoglycoside, binds with lower affinity to one or more secondary binding sites, mediating distinct structural and dynamic perturbations that further enhance translocation inhibition. These new insights help explain why closely related aminoglycosides elicit pleiotropic translation activities and demonstrate the potential utility of smFRET as a tool for dissecting the mechanisms of antibiotic action.

关键词： AMINOGLYCOSIDES

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Directed discovery of high-loading nanoaggregates enabled by drug-matched oligo-peptide excipients

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Chem 2025年

作者： Berisha, Naxhije Farahpour, Atena Ramakrishnan, Maithreyi Chen, Chen McPhee, Scott A. Wang, Tong Li, Tai-De Hema, Kuntrapakam Panagiotakopoulou, Magdalini Athiyarath, Vignesh Coste, Maeva Marciano, Yaron Sherman, Emmet Ulijn, Rein V. Heller, Daniel A. Nanoscience Initiative Advanced Science Research Center CUNY Graduate Center City University of New York New York 10031 NY United States Department of Chemistry and Biochemistry Hunter College City University of New York New York 10065 NY United States PhD Program in Chemistry CUNY Graduate Center City University of New York New York 10016 NY United States Molecular Pharmacology Program Memorial Sloan Kettering Cancer Center New York 10065 NY United States Tri-Institutional PhD Program in Chemical Biology Memorial Sloan Kettering Cancer Center New York 10065 NY United States Department of Physics City College of New York City University of New York New York 10031 NY United States Department of Chemistry Brooklyn College City University of New York 2900 Bedford Avenue Brooklyn 11210 NY United States PhD Program in Biochemistry CUNY Graduate Center City University of New York New York 10016 NY United States Weill Cornell Medicine Cornell University New York 10065 NY United States

Nanoparticles can improve drug pharmacokinetics, but low loading efficiencies can limit treatment efficacy. Drug-aggregation-based nanoparticles have demonstrated improved loadings of up to 90%, but few excipients facilitate efficient co-assembly. We investigated peptides as designer excipients because of their diverse chemical space and inherent biodegradability. We designed pentapeptide scaffolds to mimic the structure of known indocyanine excipients by modulating aromaticity, rigidity, and charge. We screened 184 formulations by using diverse drug cargoes. We found drug-peptide combinations that formed nanoparticles with up to 98% drug loading. Molecular dynamics simulations and mass spectrometry analysis demonstrated that tryptophan-drug interactions and solvent exposure of charged amino acid residues drove the formation of core-shell structures. Peptide-drug formulations containing the JAK2/FLT3 inhibitor lestaurtinib were investigated in acute myeloid leukemia models, resulting in enhanced anti-tumor efficacy. This work found that oligopeptides can be designed to efficiently co-assemble with therapeutic cargoes to result in high-loading nanoparticles that improve anti-tumor efficacy. © 2024

关键词： co-assembly directed discovery drug delivery excipient nanocarrier design nanoparticle oligopeptides SDG3: Good health and well-being

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BPS2025 - Molecular and biophysical determinants of group II mGluRs desensitization and internalization across a wide range of timescales

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Biophysical Journal 2025年第3期124卷 107a-108a页

作者： Alberto J. Gonzalez-Hernandez Anisul Arefin Sheida Sharghi Moshtaghin Alexa Strauss Nohely Abreu Johannes Broichhagen Marian Kalocsay Joshua Levitz Weill Cornell Medicine New York NY USA Tri-Institutional Program in Chemical Biology New York NY USA Leibniz-Forschungsinstitut für Molekulare Pharmakologie Berlin Germany University of Texas MD Anderson Cancer Center Houston TX USA

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Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology

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Neurobiology of Disease 2025年 211卷 106939-106939页

作者： Zhou, Constance Hardin, Evelyn J. Zimmer, Till S. Jackvony, Stephanie Barnett, Daniel Khobrekar, Noopur Giacomelli, Elisa Studer, Lorenz Orr, Adam L. Orr, Anna G. Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program New York NY United States Helen and Robert Appel Alzheimer's Disease Research Institute New York NY United States Feil Family Brain and Mind Research Institute New York NY United States Neuroscience Graduate Program Weill Cornell Medicine New York NY United States The Center for Stem Cell Biology Sloan-Kettering Institute for Cancer Research New York NY United States Developmental Biology Program Sloan-Kettering Institute for Cancer Research New York NY United States

Alterations in transactivating response region DNA-binding protein 43 (TDP-43) are prevalent in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurological disorders. TDP-43 influences neuronal functions and might also affect glial cells. However, specific intracellular effects of TDP-43 alterations on glial cells and underlying mechanisms are not clear. We report that TDP-43 dysregulation in mouse and human cortical astrocytes causes nucleoporin mislocalization, nuclear envelope remodeling, and changes in nucleocytoplasmic protein transport. These effects are dependent on interleukin-1 (IL-1) receptor activity and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and are associated with the formation of cytoplasmic stress granules. Stimulation of IL-1 receptors and NF-κB signaling are necessary and sufficient to induce astrocytic stress granules and rapid nucleocytoplasmic changes, which are broadly alleviated by inhibition of the integrated stress response. These findings establish that TDP-43 alterations and neuroimmune factors can induce nucleocytoplasmic changes through NF-κB signaling, revealing mechanistic convergence of proteinopathy and neuroimmune pathways onto glial nucleocytoplasmic disruptions that may occur in diverse neurological conditions. © 2025 The Author(s)

关键词： Astrocytes Integrated stress response Neurodegeneration Neuroimmune signaling Nuclear pore Stress granules TDP-43

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GPCR Biosensors to Study Conformational Dynamics and Signaling in Drug Discovery

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Organizational Psychology and Organizational Behavior 1000年第1期12卷 7-28页

作者： Victoria R. Saca Colin Burdette Thomas P. Sakmar 1Laboratory of Chemical Biology and Signal Transduction The Rockefeller University New York NY USA email: sakmar@rockefeller.edu 2Tri-Institutional PhD Program in Chemical Biology New York NY USA

G protein–coupled receptors (GPCRs) are a superfamily of transmembrane signal transducers that facilitate the flow of chemical signals across membranes. GPCRs are a desirable class of drug targets, and the activation and deactivation dynamics of these receptors are widely studied. Multidisciplinary approaches for studying GPCRs, such as downstream biochemical signaling assays, cryo-electron microscopy structural determinations, and molecular dynamics simulations, have provided insights concerning conformational dynamics and signaling mechanisms. However, new approaches including biosensors that use luminescence- and fluorescence-based readouts have been developed to investigate GPCR-related protein interactions and dynamics directly in cellular environments. Luminescence- and fluorescence-based readout approaches have also included the development of GPCR biosensor platforms that utilize enabling technologies to facilitate multiplexing and miniaturization. General principles underlying the biosensor platforms and technologies include scalability, orthogonality, and kinetic resolution. Further application and development of GPCR biosensors could facilitate hit identification in drug discovery campaigns. The goals of this review are to summarize developments in the field of GPCR-related biosensors and to discuss the current available technologies.

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Author Correction: Progressive plasticity during colorectal cancer metastasis

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Nature 2025年第8047期637卷 E28页

作者： Andrew Moorman Elizabeth K Benitez Francesco Cambuli Qingwen Jiang Ahmed Mahmoud Melissa Lumish Saskia Hartner Sasha Balkaran Jonathan Bermeo Simran Asawa Canan Firat Asha Saxena Fan Wu Anisha Luthra Cassandra Burdziak Yubin Xie Valeria Sgambati Kathleen Luckett Yanyun Li Zhifan Yi Ignas Masilionis Kevin Soares Emmanouil Pappou Rona Yaeger T Peter Kingham William Jarnagin Philip B Paty Martin R Weiser Linas Mazutis Michael D'Angelica Jinru Shia Julio Garcia-Aguilar Tal Nawy Travis J Hollmann Ronan Chaligné Francisco Sanchez-Vega Roshan Sharma Dana Pe'er Karuna Ganesh Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY USA. Molecular Pharmacology Program Memorial Sloan Kettering Cancer Center New York NY USA. Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program New York NY USA. New York Genome Center New York NY USA. Pharmacology Program Weill Cornell Graduate School New York NY USA. Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. Case Western Reserve University Cleveland OH USA. Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA. Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA. Tri-Institutional PhD Program in Computational Biology and Medicine New York NY USA. Bristol Myers Squibb Princeton NJ USA. Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY USA. peerd@***. Howard Hughes Medical Institute Chevy Chase MD USA. peerd@***. Molecular Pharmacology Program Memorial Sloan Kettering Cancer Center New York NY USA. ganeshk@***. Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. ganeshk@***.

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Structural basis of pH-dependent activation in a CLC transporter (jan, 10.1038/s41594-023-01210-5, 2023)

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NATURE STRUCTURAL & MOLECULAR biology 2024年第4期31卷 728-728页

作者： Fortea, Eva Lee, Sangyun Chadda, Rahul Argyros, Yiorgos Sandal, Priyanka Mahoney-Kruszka, Robyn Ciftci, Hatice Didar Falzone, Maria E. Huysmans, Gerard Robertson, Janice L. Boudker, Olga Accardi, Alessio Department of Physiology and Biophysics Weill Cornell Medical School New York NY USA Department of Anesthesiology Weill Cornell Medical School New York NY USA Department of Biochemistry and Molecular Biophysics Washington University School of Medicine St. Louis MO USA Department of Biochemistry Weill Cornell Medical School New York NY USA Department of Molecular Physiology and Biophysics The University of Iowa Iowa City IA USA Tri-Institutional Training Program in Chemical Biology New York NY USA Howard Hughes Medical Institute Chevy Chase MD USA

CLCs are dimeric chloride channels and anion/proton exchangers that regulate processes such as muscle contraction and endo-lysosome acidification. Common gating controls their activity; its closure simultaneously silences both protomers, and its opening allows them to independently transport ions. Mutations affecting common gating in human CLCs cause dominant genetic disorders. The structural rearrangements underlying common gating are unknown. Here, using single-particle cryo-electron microscopy, we show that the prototypical Escherichia coli CLC-ec1 undergoes large-scale rearrangements in activating conditions. The slow, pH-dependent remodeling of the dimer interface leads to the concerted opening of the intracellular H+ pathways and is required for transport. The more frequent formation of short water wires in the open H+ pathway enables Cl− pore openings. Mutations at disease-causing sites favor CLC-ec1 activation and accelerate common gate opening in the human CLC-7 exchanger. We suggest that the pH activation mechanism of CLC-ec1 is related to the common gating of CLC-7.

关键词： Cryoelectron microscopy Ion transport Single-molecule biophysics

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