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Unveiling DNA methylation in Alzheimer’s disease:a review of array-based human brain studies

Neural Regeneration Research 2024年第11期19卷 2365-2376页

作者： Victoria Cunha Alves Eva Carro Joana Figueiro-Silva Neurodegenerative Diseases Group Hospital Universitario 12 de Octubre Research Institute(imas12)MadridSpain Network Center for Biomedical Research Neurodegenerative Diseases(CIBERNED)MadridSpain PhD Program in Neuroscience Autonoma de Madrid UniversityMadridSpain Neurotraumatology and Subarachnoid Hemorrhage Group Hospital Universitario 12 de Octubre Research Institute(imas12)MadridSpain Neurobiology of Alzheimer’s Disease Unit Functional Unit for Research Into Chronic DiseasesInstituto de Salud Carlos IIIMadridSpain Institute of Medical Genetics University of ZurichZurichSwitzerland Department of Molecular Life Science University of ZurichZurichSwitzerland

The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA *** review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease *** examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease *** entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the ***,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal ***,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory *** complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation *** the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease *** research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.

关键词： Alzheimer’s disease ANK1 BIN1 DNA methylation epigenome-wide association studies HOXA3 MCF2L RHBDF2

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Improved camptothecin encapsulation and efficacy by environmentally sensitive block copolymer/chitosan/fucoidan nanoparticles for targeting lung cancer cells

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International Journal of Biological Macromolecules 2024年第Part2期277卷 133901页

作者： Don, Trong-Ming Hong, Yu-Ting Jheng, Pei-Ru Chuang, Er-Yuan Huang, Yi-Cheng Department of Chemical and Materials Engineering Tamkang University New Taipei City Taiwan College of Life Sciences Department of Food Science National Taiwan Ocean University Keelung Taiwan Graduate Institute of Biomedical Materials and Tissue Engineering International PhD Program in Biomedical Engineering Taipei Medical University Taipei Taiwan Cell Physiology and Molecular Image Research Center Taipei Medical University–Wan Fang Hospital Taipei Taiwan

In this study, thermo-sensitive poly(N-isopropyl acrylamide) (PNP) was polymerized with pH-sensitive poly(acrylic acid) (PAA) to prepare a PAA-b-PNP block copolymer. Above its cloud point, the block copolymer self-assembled into nanoparticles (NPs), encapsulating the anticancer drug camptothecin (CPT) in situ. Chitosan (CS) and fucoidan (Fu) further modified these NPs, forming Fu-CPT-NPs to enhance biocompatibility, drug encapsulation efficiency (EE), and loading content (LC), crucially facilitating P-selectin targeting of lung cancer cells through a drug delivery system. The EE and LC reached 82 % and 3.5 %, respectively. According to transmission electron microscope observation, these Fu-CPT-NPs had uniform spherical shapes with an average diameter of ca. 250 nm. They could maintain their stability in a pH range of 5.0–6.8. In vitro experimental results revealed that the Fu-CPT-NPs exhibited good biocompatibility and had anticancer activity after encapsulating CPT. It could deliver CPT to cancer cells by targeting P-selectin, effectively increasing cell uptake and inducing cell apoptosis. Animal study results showed that the Fu-CPT-NPs inhibited lung tumor growth by increasing tumor cell apoptosis without causing significant tissue damage related to generating reactive oxygen species in lung cancer cells. This system can effectively improve drug-delivery efficiency and treatment effects and has great potential for treating lung cancer. © 2024 Elsevier B.V.

关键词： Nanoparticles

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Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2

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Nature Communications 2024年第1期15卷 7463页

作者： Wang, Rong-Hsuan Chen, Pin-Ru Chen, Yue-Ting Chen, Yi-Chang Chu, Yu-Hsin Chien, Chia-Chen Chien, Po-Chen Lo, Shao-Yun Wang, Zhong-Liang Tsou, Min-Chen Chen, Ssu-Yu Chiu, Guang-Shen Chen, Wen-Ling Wu, Yi-Hsuan Wang, Lily Hui-Ching Wang, Wen-Ching Lin, Shu-Yi Kung, Hsing-Jien Wang, Lu-Hai Cheng, Hui-Chun Lin, Kai-Ti Institute of Biotechnology National Tsing Hua University Hsinchu Taiwan Institute of Bioinformatics and Structural Biology National Tsing Hua University Hsinchu Taiwan Institute of Molecular and Genomic Medicine National Health Research Institutes Zhunan Taiwan Institute of Molecular and Cellular Biology National Tsing Hua University Hsinchu Taiwan Department of Medical Science National Tsing Hua University Hsinchu Taiwan School of Medicine National Tsing Hua University Hsinchu Taiwan Department of Life Science National Tsing Hua University Hsinchu Taiwan Institute of Biomedical Engineering and Nanomedicine National Health Research Institutes Zhunan Taiwan College of Medical Science and Technology PhD Program for Cancer Biology and Drug Discovery Taipei Medical University Taipei Taiwan Chiese Medicine Research Center and Institute of Integrated Medicine China Medical University Taichung City Taiwan

Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H₂S) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by H₂S inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism. © The Author(s) 2024.

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Fate and state transitions during human blood vessel organoid development

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Cell 2025年第12期188卷 3329-3348.e31页

作者： Nikolova, Marina T. He, Zhisong Seimiya, Makiko Jonsson, Gustav Cao, Wuji Okuda, Ryo Wimmer, Reiner A. Okamoto, Ryoko Penninger, Josef M. Camp, J. Gray Treutlein, Barbara Department of Biosystems Science and Engineering ETH Zurich Basel Switzerland Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna Austria Vienna BioCenter PhD Program Doctoral School of the University of Vienna and Medical University of Vienna Vienna 1030 Austria Roche Pharma Research and Early Development Roche Innovation Center Basel Switzerland Department of Medical Genetics Life Science Institute University of British Columbia Vancouver V6T 1Z3 BC Canada Department of Laboratory Medicine Medical University of Vienna Vienna Austria Helmholtz Centre for Infection Research Braunschweig Germany Institute of Human Biology Roche Pharma Research and Early Development Roche Innovation Center Basel Basel Switzerland Biozentrum University of Basel Basel Switzerland

Human blood vessel organoids (hBVOs) have emerged as a system to model human vascular development and disease. Here, we use single-cell multi-omics together with genetic and signaling pathway perturbations to reconstruct hBVO development. Mesodermal progenitors bifurcate into endothelial and mural fates in vitro, and xenografted BVOs acquire definitive arteriovenous endothelial cell specification. We infer a gene regulatory network and use single-cell genetic perturbations to identify transcription factors (TFs) and receptors involved in cell fate specification, including a role for MECOM in endothelial and mural specification. We assess the potential of BVOs to generate organotypic states, identify TFs lacking expression in hBVOs, and find that induced LEF1 overexpression increases brain vasculature specificity. Finally, we map vascular disease-associated genes to hBVO cell states and analyze an hBVO model of diabetes. Altogether, we provide a comprehensive cell state atlas of hBVO development and illuminate the power and limitation of hBVOs for translational research. © 2025 The Authors

关键词： arteriovenous specification human blood vessel organoid human development organoid cell atlas single-cell genomics single-cell perturbation screen

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Author Correction: Reversible amyloids of pyruvate kinase couple cell metabolism and stress granule disassembly

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Nature cell biology 2022年第1期24卷 123页

作者： Gea Cereghetti Caroline Wilson-Zbinden Vera M Kissling Maren Diether Alexandra Arm Haneul Yoo Ilaria Piazza Shady Saad Paola Picotti D Allan Drummond Uwe Sauer Reinhard Dechant Matthias Peter Institute of Biochemistry Department of Biology ETH Zurich Zurich Switzerland. PhD Program for Molecular Life Sciences Life Science Zurich Zurich Switzerland. PhD Program for Biomolecular Structure and Mechanism Life Science Zurich Zurich Switzerland. Institute of Molecular Systems Biology ETH Zurich Zurich Switzerland. Department of Biochemistry and Molecular Biology University of Chicago Chicago IL USA. Max Delbrück Center for Molecular Medicine Berlin Germany. Department of Chemical and Systems Biology Stanford University Stanford CA USA. Institute of Biochemistry Department of Biology ETH Zurich Zurich Switzerland. matthias.peter@bc.biol.ethz.ch.

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Corrigendum to "Curcumin-laden dual-targeting fucoidan/chitosan nanocarriers for inhibiting brain inflammation via intranasal delivery" [Int. J. Biol. Macromol. 181 (2021) 835-846]

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International journal of biological macromolecules 2022年 206卷 1040-1041页

作者： Trong-Ming Don Wan-Ju Chang Pei-Ru Jheng Yi-Cheng Huang Er-Yuan Chuang Department of Chemical and Materials Engineering Tamkang University New Taipei City Taiwan College of Life Sciences Department of Food Science National Taiwan Ocean University Keelung Taiwan Graduate Institute of Biomedical Materials and Tissue Engineering International PhD Program in Biomedical Engineering Graduate Institute of Biomedical Optomechatronics School of Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei Taiwan Research Center of Biomedical Device Taipei Medical University Taipei Taiwan Cell Physiology and Molecular Image Research Center Taipei Medical University-Wan Fang Hospital Taipei Taiwan. Cell Physiology and Molecular Image Research Center Taipei Medical University-Wan Fang Hospital Taipei Taiwan. Electronic address: ychuang@mail.ntou.edu.tw. Cell Physiology and Molecular Image Research Center Taipei Medical University-Wan Fang Hospital Taipei Taiwan. Electronic address: eychuang@tmu.edu.tw.

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Minocycline treatment improves cognitive and functional plasticity in a preclinical mouse model of major depressive disorder

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BEHAVIOURAL BRAIN RESEARCH 2023年第1期441卷 114295页

作者： Poggini, Silvia Lopez, Maria Banqueri Albanese, Naomi Ciano Golia, Maria Teresa Ibanez, Fernando Gonzalez Limatola, Cristina Furhmann, Martin Lalowski, Maciej Tremblay, Marie -Eve Maggi, Laura Kaminska, Bozena Branchi, Igor [a]Center for Behavioral Sciences and Mental Health Istituto Superiore di Sanità Viale Regina Elena 299 00161 Rome Italy [b]Laboratory of Molecular Neurobiology Nencki Institute of Experimental Biology Warsaw Poland [c]PhD program in Behavioral Neurosciences Sapienza University of Rome Piazzale Aldo Moro 5 00185 Rome Italy [d]Department of Physiology and Pharmacology Istituto Pasteur-Fondazione Cenci Bolognetti Sapienza University of Rome Piazzale Aldo Moro 5 00185 Rome Italy [e]Division of Medical Sciences University of Victoria Victoria BC Canada [f]Centre de recherche du CHU de Québec Université Laval Québec Canada [g]German Center for Neurodegenerative Diseases Bonn Germany [h]Helsinki Institute for Life Science (HiLIFE) and Faculty of Medicine Biochemistry/Developmental Biology Meilahti Clinical Proteomics Core Facility University of Helsinki Helsinki FI-00014 Finland [i]IRCCS Neuromed Pozzilli Italy

Major depressive disorder (MDD) is a chronic, recurring, and potentially life-threatening illness, which affects over 300 million people worldwide. MDD affects not only the emotional and social domains but also cognition. However, the currently available treatments targeting cognitive deficits in MDD are limited. Minocycline, an antibiotic with anti-inflammatory properties recently identified as a potential antidepressant, has been shown to attenuate learning and memory deficits in animal models of cognitive impairment. Here, we explored whether minocycline recovers the deficits in cognition in a mouse model of depression. C57BL6/J adult male mice were exposed to two weeks of chronic unpredictable mild stress to induce a depressive-like phenotype. Immediately afterward, mice received either vehicle or minocycline for three weeks in standard housing conditions. We measured anhedonia as a depressive-like response, and place learning to assess cognitive abilities. We also recorded long-term potentiation (LTP) as an index of hippocampal functional plasticity and ran immunohistochemical assays to assess microglial proportion and morphology. After one week of treatment, cognitive performance in the place learning test was significantly improved by minocycline, as treated mice displayed a higher number of correct responses when learning novel spatial configurations. Accordingly, minocycline-treated mice displayed higher LTP compared to controls. However, after three weeks of treatment, no difference between treated and control animals was found for behavior, neural plasticity, and microglial properties, suggesting that minocycline has a fast but short effect on cognition, without lasting effects on microglia. These findings together support the usefulness of minocycline as a potential treatment for cognitive impairment associated with MDD.

关键词： Antidepressant Minocycline Neural plasticity Cognition Stress response Microglia

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Validation of extracellular ligand-receptor interactions by Flow-TriCEPS

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BMC Research Notes 2018年第1期11卷 1-7页

作者： Lopez-Garcia, Laura A. Demiray, Levent Ruch-Marder, Sandra Hopp, Ann-Katrin Hottiger, Michael O. Helbling, Paul M. Pavlou, Maria P. Dualsystems Biotech A.G. Grabenstrasse 11a Schlieren 8952 Switzerland Department of Molecular Mechanisms of Disease University of Zurich Zurich 8057 Switzerland Molecular Life Science PhD Program Life Science Zurich Graduate School Zurich 8057 Switzerland

Objective: The advent of ligand-based receptor capture methodologies, allows the identification of unknown receptor candidates for orphan extracellular ligands. However, further target validation can be tedious, laborious and time-consuming. Here, we present a methodology that provides a fast and cost-efficient alternative for candidate target verification on living cells. Results: In the described methodology a ligand of interest (e.g. transferrin, epidermal growth factor or insulin) was conjugated to a linker (TriCEPS) that carries a biotin. To confirm ligand/receptor interactions, the ligand-TriCEPS conjugates were first added onto living cells and cells were subsequently labeled with a streptavidin-fluorophore and analyzed by flow cytometry (thus referred as Flow-TriCEPS). Flow-TriCEPS was also used to validate identified receptor candidates when combined with a siRNA knock down approach (i.e. reduction of expression levels). This approach is versatile as it can be applied for different classes of ligands (proteins, peptides, antibodies) and different cell lines. Moreover, the method is time-efficient since it takes advantage of the large variety of commercially available (and certified) siRNAs. © 2018 The Author(s).

关键词： Candidate verification Flow-TriCEPS HATRIC Knock down LRC siRNA

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Mixture-of-experts variational autoencoder for clustering and generating from similarity-based representations

arXiv

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arXiv 2019年

作者： Kopf, Andreas Fortuin, Vincent Somnath, Vignesh Ram Claassen, Manfred Institute of Molecular Systems Biology Department of Biology ETH Zürich Switzerland Biomedical Informatics Group Department of Computer Science ETH Zürich Switzerland Switzerland Life Science Graduate School Zurich PhD Program Systems Biology Switzerland

Clustering high-dimensional data, such as images or biological measurements, is a long-standing problem and has been studied extensively. Recently, Deep Clustering gained popularity due to the non-linearity of neural networks, which allows for flexibility in fitting the specific peculiarities of complex data. Here we introduce the Mixture-of-Experts Similarity Variational Autoencoder (MoE-Sim-VAE), a novel generative clustering model. The model can learn multi-modal distributions of high-dimensional data and use these to generate realistic data with high efficacy and efficiency. MoE-Sim-VAE is based on a Variational Autoencoder (VAE), where the decoder consists of a Mixture-of-Experts (MoE) architecture. This specific architecture allows for various modes of the data to be automatically learned by means of the experts. Additionally, we encourage the latent representation of our model to follow a Gaussian mixture distribution and to accurately represent the similarities between the data points. We assess the performance of our model on synthetic data, the MNIST benchmark data set, and a challenging real-world task of defining cell subpopulations from mass cytometry (CyTOF) measurements on hundreds of different datasets. MoE-Sim-VAE exhibits superior clustering performance on all these tasks in comparison to the baselines and we show that the MoE architecture in the decoder reduces the computational cost of sampling specific data modes with high fidelity. Copyright © 2019, The Authors. All rights reserved.

关键词： Clustering algorithms

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OpenMM 8: molecular Dynamics Simulation with Machine Learning Potentials

arXiv

引用

arXiv 2023年

作者： Eastman, Peter Galvelis, Raimondas Peláez, Raúl P. Abreu, Charlles R.A. Farr, Stephen E. Gallicchio, Emilio Gorenko, Anton Henry, Michael M. Hu, Frank Huang, Jing Krämer, Andreas Michel, Julien Mitchell, Joshua A. Pande, Vijay S. Rodrigues, João P.G.L.M. Rodriguez-Guerra, Jaime Simmonett, Andrew C. Singh, Sukrit Swails, Jason Turner, Philip Wang, Yuanqing Zhang, Ivy Chodera, John D. De Fabritiis, Gianni Markland, Thomas E. Department of Chemistry Stanford University StanfordCA94305 United States Acellera Labs C Dr Trueta 183 Barcelona08005 Spain C Dr. Aiguader 88 Barcelona08003 Spain Chemical Engineering Department School of Chemistry Federal University of Rio de Janeiro Rio de Janeiro68542 Brazil Redesign Science Inc. 180 Varick St. New YorkNY10014 United States EaStCHEM School of Chemistry University of Edinburgh EH9 3FJ United Kingdom Department of Chemistry and Biochemistry Brooklyn College The City University of New York NY United States Ph.D. Program in Chemistry Ph.D. Program in Biochemistry The Graduate Center of the City University of New York New YorkNY United States Stream HPC Koningin Wilhelminaplein 1 - 40601 Amsterdam1062 HG Netherlands Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New YorkNY10065 United States Key Laboratory of Structural Biology of Zhejiang Province School of Life Sciences Westlake University 18 Shilongshan Road Zhejiang Hangzhou310024 China Department of Mathematics and Computer Science Freie Universität Berlin Arnimallee 12 Berlin14195 Germany The Open Force Field Initiative Open Molecular Software Foundation DavisCA95616 United States Andreessen Horowitz 2865 Sand Hill Rd Menlo ParkCA94025 United States Department of Structural Biology Stanford University StanfordCA94305 United States Charité Universitätsmedizin Berlin In silico Toxicology and Structural Bioinformatics Virchowweg 6 Berlin10117 Germany Laboratory of Computational Biology National Heart Lung and Blood Institute National Institutes of Health BethesdaMD20892 United States Entos Inc. 9310 Athena Circle La Jolla CA92037 United States College of Engineering Virginia Polytechnic Institute State University BlacksburgVA24061 United States Simons Center for Computational Physical Chemistry Center for Data Science New York University 24 Waverly Place New YorkNY10004 United States T

Machine learning plays an important and growing role in molecular simulation. The newest version of the OpenMM molecular dynamics toolkit introduces new features to support the use of machine learning potentials. Arbitrary PyTorch models can be added to a simulation and used to compute forces and energy. A higher-level interface allows users to easily model their molecules of interest with general purpose, pretrained potential functions. A collection of optimized CUDA kernels and custom PyTorch operations greatly improves the speed of simulations. We demonstrate these features on simulations of cyclin-dependent kinase 8 (CDK8) and the green fluorescent protein (GFP) chromophore in water. Taken together, these features make it practical to use machine learning to improve the accuracy of simulations at only a modest increase in cost. Copyright © 2023, The Authors. All rights reserved.

关键词： Machine learning

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