AGEs trigger autophagy in diabetic skin tissues and fibroblasts

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16 10月 2019

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Author : 伤口世界

流星中山二院糖尿病足中心

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伤口世界

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Jumbo phage killer immune system targets early infection of nucleus-forming phages 2025-06-24 00:00

Li Yuping,1,7,* Linlin Guan,2 Isabelle Becher,3 Kira S. Makarova,4 Xueli Cao,2 Surabhi Hareendranath,1 Jingwen Guan,1 Frank Stein,3 Siqi Yang,2 Arne Boergel,3 Karine Lapouge,3 Kim Remans,3 David Agard,5 Mikhail Savitski,3 Athanasios Typas,3 Eugene V. Koonin,4 Yue Feng,2,* and Joseph Bondy-Denomy1,6,8,*

1 Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94403, USA

2 State Key Laboratory of Green Biomanufacturing, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China

3 European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany

4 Computational Biology Branch, Division of Intramural Research, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA

5 The Chan-Zuckerberg Institute for Advanced Biological Imaging and the Department of Biochemistry, University of California, San Francisco, San Francisco, CA 94143, USA

6 Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94403, USA

7 Present address: Biozentrum, University of Basel, Basel 4056, Switzerland

8 Lead contact

*Correspondence: yuping.li@unibas.ch (L.Y.), fengyue@mail.buct.edu.cn (Y.F.), joseph.bondy-denomy@ucsf.edu (J.B.-D.)

https://doi.org/10.1016/j.cell.2025.02.016

SUMMARY

Jumbo bacteriophages of the fKZ-like family assemble a lipid-based early phage infection (EPI) vesicle and a proteinaceous nucleus-like structure during infection. These structures protect the phage from nucleases and may create selective pressure for immunity mechanisms targeting this specific phage family. Here, we identify ‘‘jumbo phage killer’’ (Juk), a two-component immune system that terminates infection of fKZ-like phages, suppressing the expression of early phage genes and preventing phage DNA replication and phage nucleus assembly while saving the cell. JukA (formerly YaaW) rapidly senses the EPI vesicle by binding to an early-expressed phage protein, gp241, and then directly recruits JukB. The JukB effector structurally resembles a pore-forming toxin and destabilizes the EPI vesicle. Functional anti-fKZ JukA homologs are found across bacterial phyla, associated with diverse effectors. These findings reveal a widespread defense system that specifically targets early events executed by fKZ-like jumbo phages prior to phage nucleus assembly.
n-cell structure and snapshots of copia retrotransposons in intact tissue by cryo-ET 2025-06-23 00:00

Sven Klumpe,1,9,* Kirsten A. Senti,2 Florian Beck,1 Jenny Sachweh,3 Bernhard Hampoelz,3 Paolo Ronchi,4 Viola Oorschot,4 Marlene Brandstetter,6 Assa Yeroslaviz,5 John A.G. Briggs,7 Julius Brennecke,2,* Martin Beck,3,8,* and Ju¨ rgen M. Plitzko1,*

1 Research Group CryoEM Technology, Max Planck Institute of Biochemistry, Martinsried, Germany

2 Institute of Molecular Biotechnology Austria (IMBA), Vienna, Austria

3 Department Molecular Sociology, Max Planck Institute of Biophysics, Frankfurt, Germany

4 EMBL EM Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany

5 Computational Systems Biochemistry, Bioinformatics Core Facility, Max Planck Institute of Biochemistry, Martinsried, Germany

6 Electron Microscopy Facility, Vienna BioCenter Core Facilities, Vienna, Austria

7 Department of Cell and Virus Structure, Max Planck Institute of Biochemistry, Martinsried, Germany

8 Institute of Biochemistry, Goethe University Frankfurt, Frankfurt, Germany

9 Lead contact

*Correspondence: klumpe@biochem.mpg.de (S.K.), julius.brennecke@imba.oaew.ac.at (J.B.), martin.beck@biophys.mpg.de (M.B.), plitzko@biochem.mpg.de (J.M.P.)

https://doi.org/10.1016/j.cell.2025.02.003

SUMMARY

Long terminal repeat (LTR) retrotransposons belong to the transposable elements (TEs), autonomously replicating genetic elements that integrate into the host,s genome. Among animals, Drosophila melanogaster serves as an important model organism for TE research and contains several LTR retrotransposons, including the Ty1-copia family, which is evolutionarily related to retroviruses and forms viruslike particles (VLPs). In this study, we use cryo-focused ion beam (FIB) milling and lift-out approaches to visualize copia VLPs in ovarian cells and intact egg chambers, resolving the in situ copia capsid structure to 7.7 A˚ resolution by cryoelectron tomography (cryo-ET). Although cytoplasmic copia VLPs vary in size, nuclear VLPs are homogeneous and form densely packed clusters, supporting a model in which nuclear import acts as a size selector. Analyzing flies deficient in the TE-suppressing PIWI-interacting RNA (piRNA) pathway, we observe copia,s translocation into the nucleus during spermatogenesis. Our findings provide insights into the replication cycle and cellular structural biology of an active LTR retrotransposon.
Human trials exploring anti-aging medicines 2025-06-18 00:00

Leonard Guarente,1,2, * David A. Sinclair,2,3 and Guido Kroemer2,4,5,6, *

1 Department of Biology, Massachusetts Institute for Technology, Cambridge, MA 02139

2 Academy for Healthspan and Lifespan Research (AHLR), New York, NY, USA

3 Blavatnik Institute, Genetics Department, Harvard Medical School, Boston, MA 02115, USA

4 Centre de Recherche des Cordeliers, Equipe labellise´ e par la Ligue contre le cancer, Universite´ Paris Cite´ , Sorbonne Universite´ , Inserm U1138, Institut Universitaire de France, Paris, France

5 Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France

6 Institut du Cancer Paris CARPEM, Department of Biology, Hoˆ pital Europe´ en Georges Pompidou, AP-HP, Paris, France

*Correspondence: leng@mit.edu (L.G.), kroemer@orange.fr (G.K.)

https://doi.org/10.1016/j.cmet.2023.12.007

SUMMARY

Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic: metformin, NAD+ precursors, glucagon-like peptide-1 receptor agonists, TORC1 inhibitors, spermidine, senolytics, probiotics, and anti-inflammatories. Multiple clinical trials have commenced to evaluate the efficacy of such agents against age-associated diseases including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases. There are reasonable expectations that drugs able to decelerate or reverse aging processes will also exert broad disease-preventing or -attenuating effects. Hence, the outcome of past, ongoing, and future disease-specific trials may pave the way to the development of new anti-aging medicines. Drugs approved for specific disease indications may subsequently be repurposed for the treatment of organism-wide aging consequences.

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主任医师、教授、博导，南方医科大学第三附属医院（广东省骨科医院）院长

AGEs trigger autophagy in diabetic skin tissues and fibroblasts

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AGEs trigger autophagy in diabetic skin tissues and fibroblasts

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