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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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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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The grand biological universe: A comprehensive geometric construction of genome space

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The Innovation 2025年

作者： Hongyu Yu Nan Sun Ruohan Ren Tao Zhou Mengcen Guan Leqi Zhao Stephen S.-T. Yau Department of Mathematical Sciences Tsinghua University Beijing 100084 China Beijing Institute of Mathematical Sciences and Applications (BIMSA) Beijing 100084 China Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York City NY 10065 USA Tri-Institutional Training Program in Computational Biology and Medicine Weill Cornell Medicine New York City NY 10065 USA

Analyzing the geometric relationships among genomic sequences from a mathematical perspective and revealing the laws hidden within these relationships is a crucial challenge in bioinformatics. The natural vector method constructs a genome space by extracting statistical moments of k-mers to illuminate the relationships among genomes. This approach highlights a fundamental law in biology known as the convex hull principle, which states that natural vectors corresponding to different types of biological sequences form distinct, non-overlapping convex hulls. Previous studies have validated this important principle across various datasets. However, they often focused on specific kingdoms and did not thoroughly analyze the significance of the dimensions required for the convex hull separation. In this study, we integrate all reliable sequences from different kingdoms to construct the grand biological universe, within which we comprehensively validate the multi-level convex hull principle. We demonstrate that the separation of convex hulls arises from biological properties rather than mathematical characteristics of high-dimensional spaces. Furthermore, we develop suitable metrics within the grand biological universe to facilitate efficient sequence classification. This research advances the convex hull principle through both theoretical development and experimental validation, making significant contributions to the understanding of the geometric structure of genome space.

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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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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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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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Wasserstein Wormhole: Scalable Optimal Transport Distance with Transformer 41

Wasserstein Wormhole: Scalable Optimal Transport Distance wi...

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41st International Conference on Machine Learning, ICML 2024

作者： Haviv, Doron Kunes, Russell Zhang Dougherty, Thomas Burdziak, Cassandra Nawy, Tal Gilbert, Anna Pe'Er, Dana Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center United States Tri-Institutional Training Program in Computational Biology and Medicine Weill Cornell Medicine United States Department of Statistics Columbia University United States Department of Mathematics and Statistics Yale University United States Howard Hughes Medical Institute United States

Optimal transport (OT) and the related Wasserstein metric (W) are powerful and ubiquitous tools for comparing distributions. However, computing pairwise Wasserstein distances rapidly becomes intractable as cohort size grows. An attractive alternative would be to find an embedding space in which pairwise Euclidean distances map to OT distances, akin to standard multidimensional scaling (MDS). We present Wasserstein Wormhole, a transformer-based autoencoder that embeds empirical distributions into a latent space wherein Euclidean distances approximate OT distances. Extending MDS theory, we show that our objective function implies a bound on the error incurred when embedding non-Euclidean distances. Empirically, distances between Wormhole embeddings closely match Wasserstein distances, enabling linear time computation of OT distances. Along with an encoder that maps distributions to embeddings, Wasserstein Wormhole includes a decoder that maps embeddings back to distributions, allowing for operations in the embedding space to generalize to OT spaces, such as Wasserstein barycenter estimation and OT interpolation. By lending scalability and interpretability to OT approaches, Wasserstein Wormhole unlocks new avenues for data analysis in the fields of computational geometry and single-cell biology. Software is available at http://***/en/latest/. Copyright 2024 by the author(s)

关键词： Embeddings

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Real-valued (medical) time series generation with recurrent conditional GANs

arXiv

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arXiv 2017年

作者： Hyland, Stephanie L. Esteban, Cristóbal Rätsch, Gunnar ETH Zurich Switzerland Tri-Institutional Training Program in Computational Biology and Medicine Weill Cornell Medical

Generative Adversarial Networks (GANs) have shown remarkable success as a framework for training models to produce realistic-looking data. In this work, we propose a Recurrent GAN (RGAN) and Recurrent Conditional GAN (RCGAN) to produce realistic real-valued multi-dimensional time series, with an emphasis on their application to medical data. RGANs make use of recurrent neural networks (RNNs) in the generator and the discriminator. In the case of RCGANs, both of these RNNs are conditioned on auxiliary information. We demonstrate our models in a set of toy datasets, where we show visually and quantitatively (using sample likelihood and maximum mean discrepancy) that they can successfully generate realistic time-series. We also describe novel evaluation methods for GANs, where we generate a synthetic labelled training dataset, and evaluate on a real test set the performance of a model trained on the synthetic data, and vice-versa. We illustrate with these metrics that RCGANs can generate time-series data useful for supervised training, with only minor degradation in performance on real test data. This is demonstrated on digit classification from ‘serialised’ MNIST and by training an early warning system on a medical dataset of 17,000 patients from an intensive care unit. We further discuss and analyse the privacy concerns that may arise when using RCGANs to generate realistic synthetic medical time series data, and demonstrate results from differentially private training of the RCGAN. Copyright © 2017, The Authors. All rights reserved.

关键词： Recurrent neural networks

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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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Author Correction: ChromaFold predicts the 3D contact map from single-cell chromatin accessibility

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Nature communications 2025年第1期16卷 684页

作者： Vianne R Gao Rui Yang Arnav Das Renhe Luo Hanzhi Luo Dylan R McNally Ioannis Karagiannidis Martin A Rivas Zhong-Min Wang Darko Barisic Alireza Karbalayghareh Wilfred Wong Yingqian A Zhan Christopher R Chin William S Noble Jeff A Bilmes Effie Apostolou Michael G Kharas Wendy Béguelin Aaron D Viny Danwei Huangfu Alexander Y Rudensky Ari M Melnick Christina S Leslie Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY USA. Tri-Institutional Program in Computational Biology and Medicine New York NY USA. University of Washington Seattle WA USA. Developmental Biology Program Sloan Kettering Institute New York NY USA. Molecular Pharmacology Program Experimental Therapeutics Center and Center for Stem Cell Biology Memorial Sloan Kettering Cancer Center New York NY USA. Caryl and Israel Englander Institute for Precision Medicine Institute for Computational Biomedicine Weill Cornell Medicine Cornell University New York NY USA. Division of Hematology and Medical Oncology Department of Medicine Weill Cornell Medical College New York NY USA. Department of Biochemistry & Molecular Biology Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine Miami FL USA. Howard Hughes Medical Institute and Immunology Program Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center New York NY USA. Center for Epigenetics Research Memorial Sloan Kettering Cancer Center New York NY USA. Joan and Sanford I. Weill Department of Medicine Sandra and Edward Meyer Cancer Center Weill Cornell Medicine New York NY USA. Departments of Medicine Division of Hematology & Oncology and of Genetics & Development Columbia Stem Cell Initiative Herbert Irving Comprehensive Cancer Center Columbia University Irving Medical Center New York NY USA. Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY USA. lesliec@***.

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