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GCN2 inhibition reduces mutant SOD1 clustering and toxicity and delays disease progression in an amyotrophic lateral sclerosis mouse model

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Translational Neurodegeneration 2024年第1期13卷 351-355页

作者： Didio Alberto Ortiz Nuria Peregrín Miguel Valencia Rodrigo Vinueza-Gavilanes Elisa Marín-Ordovas Roberto Ferrero María Jesús Nicolás Gloria González-Aseguinolaza Montserrat Arrasate Tomás Aragón DNA and RNA Medicine Program Center for Applied Medical Research(CIMA)University of NavarraPamplonaSpain Biomedical Engineering Program Center for Applied Medical Research(CIMA)University of NavarraPamplonaSpain Institute of Data Science and Artificial Intelligence(DATAI) University of NavarraPamplonaSpain Navarra Institute for Health Research(IdiSNA) PamplonaSpain Neuroimmunology Department Multiple Sclerosis Center of Catalonia(Cemcat)Vall d’Hebron Research Institute(VHIR)BarcelonaSpain School of Medicine University of NavarraPamplonaSpain Brain Lab Biobizkaia Health Research InstituteBarakaldoSpain Present Address:Ikerbasque Basque Foundation for ScienceBilbaoSpain

Main text The disruption of protein folding homeostasis in motoneurons(MNs)and the accumulation of protein aggregates are some of the main molecular hallmarks of amyotrophic lateral sclerosis(ALS).Evidence from sporadic and familial ALS(fALS)patients and from ALS models suggests that protein aggregation directly participates in *** turn,the loss of MN homeostasis triggers a coping mechanism,the integrated stress response(ISR)[1].The ISR is initiated by four independent stress-sensing kinases,each of them activated by distinct stresses:protein kinase R(PKR)by double-strand RNA,protein kinase RNA-like endoplasmic reticulum kinase(PERK)by protein misfolding at the endoplasmic reticulum(ER),general control nonderepressible 2(GCN2)by nutrient starvation,and heme-regulated inhibitor(HRI)by heme deprivation.

关键词： homeostasis amyotrophic sclerosis

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Machine learning for improved current-density reconstruction from two-dimensional vector magnetic images

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Physical Review Applied 2025年第3期23卷 034035-034035页

作者： Niko R. Reed Danyal Bhutto Matthew J. Turner Declan M. Daly Sean M. Oliver Jiashen Tang Kevin S. Olsson Nicholas Langellier Mark J.H. Ku Department of Physics University of Maryland College Park Maryland USA Quantum Technology Center University of Maryland College Park Maryland USA Joint Quantum Institute University of Maryland College Park Maryland USA Department of Biomedical Engineering Boston University Boston Massachusetts USA A. A. Martinos Center for Biomedical Imaging Massachusetts General Hospital Charlestown Massachusetts USA Department of Electrical and Computer Engineering University of Maryland College Park Maryland USA The MITRE Corporation McLean Virginia 22102 USA Intelligence Community Postdoctoral Research Fellowship Program University of Maryland College Park Maryland 20742 USA Department of Physics Harvard University Cambridge Massachusetts USA Present address: VideaHealth Inc. Boston MA. Department of Materials Science and Engineering University of Delaware Newark Delaware 19716 USA Department of Physics and Astronomy University of Delaware Newark Delaware 19716 USA Present address: Northrop Grumman Mission Systems Linthicum Maryland 21090 USA.

The reconstruction of electrical current densities from magnetic field measurements is an important technique with applications in materials science, circuit design, quality control, plasma physics, and biology. Analytic reconstruction methods exist for planar currents, but break down in the presence of high-spatial-frequency noise or large standoff distance, restricting the types of systems that can be studied. Here, we demonstrate the use of a deep convolutional neural network for current density reconstruction from two-dimensional images of vector magnetic fields acquired by a quantum diamond microscope . Trained network performance significantly exceeds analytic reconstruction for data with high noise or large standoff distances. This machine learning technique can perform quality inversions on lower-signal-to-noise-ratio data, significantly reducing the data collection time and permitting reconstructions of weaker and three-dimensional current sources.

关键词： Signal to noise ratio

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Theoretical identification of thermostabilizing amino acid mutations for G-protein-coupled receptors

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Biophysical Reviews 2020年第2期12卷 323-332页

作者： Murata, Takeshi Yasuda, Satoshi Hayashi, Tomohiko Kinoshita, Masahiro Graduate School of Science Chiba University 1-33 Yayoi-cho Inage Chiba 263-8522 Japan Molecular Chirality Research Center Chiba University 1-33 Yayoi-cho Inage Chiba 263-8522 Japan Institute of Advanced Energy Kyoto University Uji Kyoto 611-0011 Japan Present address: Interdisciplinary Program of Biomedical Engineering Assistive Technology and Art and Sports Sciences Faculty of Engineering Niigata University 8050 Ikarashi 2-no-cho Nishi-ku Niigata 950-2181 Japan

Thermostabilization of a membrane proteins, especially G-protein-coupled receptors (GPCRs), is often necessary for biochemical applications and pharmaceutical studies involving structure-based drug design. Here we review our theoretical, physics-based method for identifying thermostabilizing amino acid mutations. Its novel aspects are the following: The entropic effect originating from the translational displacement of hydrocarbon groups within the lipid bilayer is treated as a pivotal factor;a reliable measure of thermostability is introduced and a mutation which enlarges the measure to a significant extent is chosen;and all the possible mutations can be examined with moderate computational effort. It was shown that mutating the residue at a position of N_BW = 3.39 (N_BW is the Ballesteros-Weinstein number) to Arg or Lys leads to the stabilization of significantly many different GPCRs of class A in the inactive state. Up to now, we have been successful in stabilizing several GPCRs and newly solving three-dimensional structures for the muscarinic acetylcholine receptor 2 (M2R), prostaglandin E receptor 4 (EP4), and serotonin 2A receptor (5-HT_2AR) using X-ray crystallography. The subjects to be pursued in future studies are also discussed. © 2020, International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature.

关键词： G-protein-coupled receptor Integral equation theory Lipid bilayer Membrane protein Morphometric approach Protein folding Solvation thermodynamics Thermostabilizing mutation

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Corrigendum to "Mathematical model of modified hybrid pump mechanism for cardiopulmonary resuscitation" [Computer methods and programs in biomedicine 206 (2021) 106106]

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Computer methods and programs in biomedicine 2022年 218卷 106711页

作者： Dong Ah Shin Jung Chan Lee Interdisciplinary Program in Bioengineering Graduate School Seoul National University Seoul 08826 Republic of Korea. Department of Biomedical Engineering College of Medicine and Institute of Medical and Biological Engineering Medical Research Center Seoul National University Seoul 03080 Republic of Korea Institute of BioEngineering Bio-MAX Institute Seoul National University Seoul 08826 Republic of Korea. Electronic address: ljch@snu.ac.kr.

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Corrigendum to "Dual regulatory effects of neferine on amyloid-β and tau aggregation studied by in silico, in vitro, and lab-on-a-chip technology" [Biomed. Pharmacother. 172 (2024) 1-14/116226]

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Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2024年 181卷 117686页

作者： Yunkwon Nam Ritu Prajapati Sujin Kim Soo Jung Shin Da Yeon Cheong Yong Ho Park Hyun Ha Park Danyou Lim Yoojeong Yoon Gyudo Lee Hyun Ah Jung Insu Park Dong-Hyun Kim Jae Sue Choi Minho Moon Department of Biochemistry College of Medicine Konyang University 158 Gwanjeodong-ro Seo-gu Daejeon 35365 Republic of Korea. Department of Food and Life Science Pukyong National University Busan 48513 Republic of Korea. Department of Biochemistry College of Medicine Konyang University 158 Gwanjeodong-ro Seo-gu Daejeon 35365 Republic of Korea Research Institute for Dementia Science Konyang University 158 Gwanjeodong-ro Seo-gu Daejeon 35365 Republic of Korea. Department of Biotechnology and Bioinformatics Korea University Sejong 30019 Republic of Korea Interdisciplinary Graduate Program for Artificial Intelligence Smart Convergence Technology Korea University Sejong 30019 Republic of Korea. Department of Biomedical Engineering Konyang University Daejeon 35365 Republic of Korea. Department of Food Science and Human Nutrition Chonbuk National University Jeonju 54896 Republic of Korea. Department of Biomedical Engineering Konyang University Daejeon 35365 Republic of Korea. Electronic address: insupark@konyang.ac.kr. Departments of Pharmacology and Advanced Translational Medicine School of Medicine Konkuk University Seoul 05029 Republic of Korea. Electronic address: mose79@kku.ac.kr. Department of Food and Life Science Pukyong National University Busan 48513 Republic of Korea. Electronic address: choijs@pknu.ac.kr. Research Institute for Dementia Science Konyang University 158 Gwanjeodong-ro Seo-gu Daejeon 35365 Republic of Korea. Electronic address: hominmoon@konyang.ac.kr.

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scTenifoldXct: A semi-supervised method for predicting cell-cell interactions and mapping cellular communication graphs

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Cell systems 2023年第4期14卷 302-311.e4页

作者： Yongjian Yang Guanxun Li Yan Zhong Qian Xu Yu-Te Lin Cristhian Roman-Vicharra Robert S Chapkin James J Cai Department of Electrical and Computer Engineering Texas A&M University College Station TX 77843 USA. Department of Statistics Texas A&M University College Station TX 77843 USA. Key Laboratory of Advanced Theory and Application in Statistics and Data Science-MOE School of Statistics East China Normal University 3663 North Zhongshan Road Shanghai 200062 China. Department of Veterinary Integrative Biosciences Texas A&M University College Station TX 77843 USA. Graduate Institute of Biomedical Electronics and Bioinformatics National Taiwan University Taipei Taiwan. Department of Nutrition and the Program in Integrative Nutrition & Complex Diseases Texas A&M University College Station TX 77843 USA. Electronic address: r-chapkin@tamu.edu. Department of Electrical and Computer Engineering Texas A&M University College Station TX 77843 USA Department of Veterinary Integrative Biosciences Texas A&M University College Station TX 77843 USA Interdisciplinary Program of Genetics Texas A&M University College Station TX 77843 USA. Electronic address: jcai@tamu.edu.

We present scTenifoldXct, a semi-supervised computational tool for detecting ligand-receptor (LR)-mediated cell-cell interactions and mapping cellular communication graphs. Our method is based on manifold alignment, using LR pairs as inter-data correspondences to embed ligand and receptor genes expressed in interacting cells into a unified latent space. Neural networks are employed to minimize the distance between corresponding genes while preserving the structure of gene regression networks. We apply scTenifoldXct to real datasets for testing and demonstrate that our method detects interactions with high consistency compared with other methods. More importantly, scTenifoldXct uncovers weak but biologically relevant interactions overlooked by other methods. We also demonstrate how scTenifoldXct can be used to compare different samples, such as healthy vs. diseased and wild type vs. knockout, to identify differential interactions, thereby revealing functional implications associated with changes in cellular communication status.

关键词： cell-cell interaction cellular communication gene regression network machine learning manifold alignment neural networks scRNA-seq single-cell RNA sequencing

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Corrigendum to "Variations of oxidative potential of PM2.5 in a medium-sized residential city in South Korea measured using three different chemical assays" [920 (2024) 171053]

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The Science of the total environment 2024年 926卷 172075页

作者： Pyung-Rae Kim Sung-Won Park Young-Ji Han Myong-Hwa Lee Thomas M Holsen Cheol-Heon Jeong Greg Evans Agriculture and Life Sciences Research Institute Kangwon National University Chuncheon Gangwon-do 24341 Republic of Korea. Dept. of Interdisciplinary Graduate Program in Environmental and Biomedical Convergence Kangwon National University Chuncheon Gangwon-do 24341 Republic of Korea. Dept. of Environmental Science Kangwon National University Chuncheon Gangwon-do 24341 Republic of Korea Gangwon particle pollution research and management center Kangwon National University Chuncheon Gangwon-do 24341 Republic of Korea. Electronic address: youngji@kangwon.ac.kr. Gangwon particle pollution research and management center Kangwon National University Chuncheon Gangwon-do 24341 Republic of Korea Dept. of Environmental Engineering Kangwon National University Chuncheon Gangwon-do 24341 Republic of Korea. Dept. of Civil and Environmental Engineering Clarkson University Potsdam NY 13699 USA. Dept. of Chemical Engineering and Applied Chemistry University of Toronto Toronto Ontario MS5 3E5 Canada.

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Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates

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Cell 2025年

作者： Xiao Yan David Kuster Priyesh Mohanty Jik Nijssen Karina Pombo-García Jorge Garcia Morato Azamat Rizuan Titus M Franzmann Aleksandra Sergeeva Anh M Ly Feilin Liu Patricia M Passos Leah George Szu-Huan Wang Jayakrishna Shenoy Helen L Danielson Busra Ozguney Alf Honigmann Yuna M Ayala Nicolas L Fawzi Dennis W Dickson Wilfried Rossoll Jeetain Mittal Simon Alberti Anthony A Hyman Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) Dresden 01307 Saxony Germany. Artie McFerrin Department of Chemical Engineering Texas A&M University College Station TX 77843 USA. Department of Neuroscience Mayo Clinic Jacksonville FL 32224 USA. Biotechnology Center (BIOTEC) Center for Molecular and Cellular Bioengineering Technische Universität Dresden Dresden 01307 Saxony Germany. Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) Dresden 01307 Saxony Germany Edward Doisy Department of Biochemistry and Molecular Biology Saint Louis University St. Louis MO 63104 USA. Department of Molecular Biology Cell Biology & Biochemistry Brown University Providence RI 02912 USA. Center for Biomedical Engineering Brown University Providence RI 02912 USA. Artie McFerrin Department of Chemical Engineering Texas A&M University College Station TX 77843 USA Department of Chemistry Texas A&M University College Station TX 77843 USA Interdisciplinary Graduate Program in Genetics and Genomics Texas A&M University College Station TX 77843 USA. Electronic address: jeetain@tamu.edu. Biotechnology Center (BIOTEC) Center for Molecular and Cellular Bioengineering Technische Universität Dresden Dresden 01307 Saxony Germany. Electronic address: simon.alberti@tu-dresden.de. Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) Dresden 01307 Saxony Germany. Electronic address: hyman@mpi-cbg.de.

Cytosolic aggregation of the nuclear protein TAR DNA-binding protein 43 (TDP-43) is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43-enriched phase within stress granules, which subsequently transition into pathological aggregates. Intra-condensate demixing of TDP-43 is observed in iPS-motor neurons, a disease mouse model, and patient samples. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We suggest that up-concentration inside condensates followed by intra-condensate demixing could be a general pathway for protein aggregation.

关键词： ALS FTD TDP-43 biomolecular condensate intra-condensate demixing neurodegenerative diseases oxidative stress phase separation protein aggregation stress granules

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A disordered linker in the Polycomb protein Polyhomeotic tunes phase separation and oligomerization

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Molecular cell 2025年第11期85卷 2128-2146.e15页

作者： Tim M Gemeinhardt Roshan M Regy Tien M Phan Nanu Pal Jyoti Sharma Olga Senkovich Andrea J Mendiola Heather J Ledterman Amy Henrickson Daniel Lopes Utkarsh Kapoor Ashish Bihani Djamouna Sihou Young C Kim David Jeruzalmi Borries Demeler Chongwoo A Kim Jeetain Mittal Nicole J Francis Montreal Clinical Research Institute (IRCM) Montreal QC Canada Division of Experimental Medicine McGill University Montreal QC Canada. Artie McFerrin Department of Chemical Engineering Texas A&M University College Station TX USA. Department of Biochemistry and Molecular Medicine University of Montreal Montreal QC Canada. Montreal Clinical Research Institute (IRCM) Montreal QC Canada. Department of Biochemistry and Molecular Genetics Midwestern University Glendale AZ USA. Department of Chemistry and Biochemistry The University of Lethbridge Lethbridge AB Canada. Department of Chemistry and Biochemistry City College of New York New York NY USA. Department of Chemical and Biomedical Engineering University of Wyoming Laramie WY USA. Center for Materials Physics and Technology Naval Research Laboratory Washington DC USA. Department of Chemistry and Biochemistry City College of New York New York NY USA Ph.D. Program in Biochemistry The Graduate Center of the City University of New York New York NY USA Ph.D. Program in Biology The Graduate Center of the City University of New York New York NY USA Ph.D. Program in Chemistry The Graduate Center of the City University of New York New York NY USA. Department of Chemistry and Biochemistry The University of Lethbridge Lethbridge AB Canada Department of Chemistry and Biochemistry University of Montana Missoula MT USA. Artie McFerrin Department of Chemical Engineering Texas A&M University College Station TX USA Department of Chemistry Texas A&M University College Station TX USA Interdisciplinary Graduate Program in Genetics and Genomics Texas A&M University College Station TX USA. Electronic address: jeetain@tamu.edu. Division of Experimental Medicine McGill University Montreal QC Canada Department of Biochemistry and Molecular Medicine University of Montreal Montreal QC Canada. Electronic address: nicole.francis@ircm.qc.ca.

Biomolecular condensates are increasingly recognized as key regulators of chromatin organization, yet how their formation and properties arise from protein sequences remains incompletely understood. Cross-species comparisons can reveal both conserved functions and significant evolutionary differences. Here, we integrate in vitro reconstitution, molecular dynamics simulations, and cell-based assays to examine how Drosophila and human variants of Polyhomeotic (Ph)-a subunit of the PRC1 chromatin regulatory complex-drive condensate formation through their sterile alpha motif (SAM) oligomerization domains. We identify divergent interactions between SAM and the disordered linker connecting it to the rest of Ph. These interactions enhance oligomerization and modulate both the formation and properties of reconstituted condensates. Oligomerization influences condensate dynamics but minimally impacts condensate formation. Linker-SAM interactions also affect condensate formation in Drosophila and human cells and growth in Drosophila imaginal discs. Our findings show how evolutionary changes in disordered linkers can fine-tune condensate properties, providing insights into sequence-function relationships.

关键词： CRISPR Drosophila Polycomb analytical ultracentrifugation biochemistry biomolecular condensates gene regulation intrinsically disordered regions molecular dynamics simulations oligomerization phase separation sterile alpha motif

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Corrigendum to "Metal-organic frameworks, NH2-MIL-88(Fe), as carriers for ophthalmic delivery of brimonidine" [Acta Biomater. 79 (2018) 344-353]

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Acta biomaterialia 2019年 85卷 321页

作者： Se-Na Kim Chun Gwon Park Beom Kang Huh Seung Ho Lee Chang Hee Min Yun Young Lee Young Kook Kim Ki Ho Park Young Bin Choy Interdisciplinary Program in Bioengineering College of Engineering Seoul National University Seoul 08826 Republic of Korea. Department of Biomedical Engineering SKKU Institute for Convergence Sungkyunkwan University (SKKU) Suwon 16419 Republic of Korea. Institute of Medical & Biological Engineering Medical Research Center Seoul National University Seoul 03080 Republic of Korea. Department of Biomedical Engineering Seoul National University College of Medicine Seoul 03080 Republic of Korea. Department of Ophthalmology Seoul National University Hospital Seoul 03080 Republic of Korea Department of Ophthalmology Seoul National University College of Medicine Seoul 03080 Republic of Korea. Interdisciplinary Program in Bioengineering College of Engineering Seoul National University Seoul 08826 Republic of Korea Institute of Medical & Biological Engineering Medical Research Center Seoul National University Seoul 03080 Republic of Korea Department of Biomedical Engineering Seoul National University College of Medicine Seoul 03080 Republic of Korea. Electronic address: ybchoy@snu.ac.kr.

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