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Nature Communications

  2041-1723

 

 

Cơ quản chủ quản:  NATURE PORTFOLIO , Nature Publishing Group

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Biochemistry, Genetics and Molecular Biology (miscellaneous)Physics and Astronomy (miscellaneous)Chemistry (miscellaneous)

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Các bài báo tiêu biểu

Ubiquitination switches EphA2 vesicular traffic from a continuous safeguard to a finite signalling mode
Tập 6 Số 1
Ola Sabet, Rabea Stockert, Georgia Xouri, Yannick Brüggemann, Angel Stanoev, Philippe I. H. Bastiaens
AbstractAutocatalytic phosphorylation of receptor tyrosine kinases (RTKs) enables diverse, context-dependent responses to extracellular signals but comes at the price of autonomous, ligand-independent activation. Using a conformational biosensor that reports on the kinase activity of the cell guidance ephrin receptor type-A (EphA2) in living cells, we observe that autonomous EphA2 activation is suppressed by vesicular recycling and dephosphorylation by protein tyrosine phosphatases 1B (PTP1B) near the pericentriolar recycling endosome. This spatial segregation of catalytically superior PTPs from RTKs at the plasma membrane is essential to preserve ligand responsiveness. Ligand-induced clustering, on the other hand, promotes phosphorylation of a c-Cbl docking site and ubiquitination of the receptor, thereby redirecting it to the late endosome/lysosome. We show that this switch from cyclic to unidirectional receptor trafficking converts a continuous suppressive safeguard mechanism into a transient ligand-responsive signalling mode.
Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype
Tập 6 Số 1
Yamicia Connor, Sarah Tekleab, Shyama Nandakumar, Cherelle Walls, Yonatan Tekleab, Amjad Husain, Or Gadish, Venkata Sabbisetti, Shelly Kaushik, Seema Sehrawat, Ashish Kulkarni, Harold F. Dvorak, Bruce R. Zetter, Elazer R. Edelman, Shiladitya Sengupta
AbstractMetastasis is a major cause of mortality and remains a hurdle in the search for a cure for cancer. Not much is known about metastatic cancer cells and endothelial cross-talk, which occurs at multiple stages during metastasis. Here we report a dynamic regulation of the endothelium by cancer cells through the formation of nanoscale intercellular membrane bridges, which act as physical conduits for transfer of microRNAs. The communication between the tumour cell and the endothelium upregulates markers associated with pathological endothelium, which is reversed by pharmacological inhibition of these nanoscale conduits. These results lead us to define the notion of ‘metastatic hijack’: cancer cell-induced transformation of healthy endothelium into pathological endothelium via horizontal communication through the nanoscale conduits. Pharmacological perturbation of these nanoscale membrane bridges decreases metastatic foci in vivo. Targeting these nanoscale membrane bridges may potentially emerge as a new therapeutic opportunity in the management of metastatic cancer.
The transcriptional landscape of age in human peripheral blood
Tập 6 Số 1
Marjolein J. Peters, Roby Joehanes, Luke C. Pilling, Claudia Schurmann, Karen N. Conneely, Joseph E. Powell, Eva Reinmaa, George L. Sutphin, Alexandra Zhernakova, Katharina Schramm, Yana A. Wilson, Sayuko Kobes, Taru Tukiainen, Michael A. Nalls, Dena Hernández, Mark Cookson, J. Raphael Gibbs, John Hardy, Adaikalavan Ramasamy, Alan B. Zonderman, Allissa Dillman, Bryan J. Traynor, Colin Smith, Dan L. Longo, Daniah Trabzuni, Juan C. Troncoso, Marcel van der Brug, Michael E. Weale, Richard M. O’Brien, Robert Johnson, Robert Walker, Ronald H. Zielke, Henk W. Berendse, Mina Ryten, Andrew Singleton, Y.F. Ramos, Harald H.H. Göring, Myriam Fornage, Yongmei Liu, Sina A. Gharib, Barbara E. Stranger, Philip L. De Jager, Abraham Aviv, Daniel Levy, Joanne M. Murabito, Peter J. Munson, Tianxiao Huan, Albert Hofman, André G. Uitterlinden, Fernando Rivadeneira, Jeroen van Rooij, Lise Tarnow, Linda Broer, Michaël Verbiest, Mila Jhamai, Pascal P. Arp, Andres Metspalu, Liina Tserel, Lili Milani, Nilesh J. Samani, Pärt Peterson, Silva Kasela, Veryan Codd, Annette Peters, Cavin Ward‐Caviness, Christian Herder, Mélanie Waldenberger, Michael Roden, Paula Singmann, Sonja Kunze, Thomas Illig, Georg Homuth, Hans J. Grabe, Henry Völzke, Leif Steil, Thomas Kocher, Anna Murray, David Melzer, Hanieh Yaghootkar, Stefania Bandinelli, Eric K. Moses, Jack W. Kent, Joanne E. Curran, Matthew P. Johnson, Sarah Williams‐Blangero, Harm-Jan Westra, Allan F. McRae, Jennifer A. Smith, Sharon L. R. Kardia, Iiris Hovatta, Markus Perola, Samuli Ripatti, Veikko Salomaa, Anjali K. Henders, Nicholas G. Martin, Alicia K. Smith, Divya Mehta, Elisabeth B. Binder, K. Maria Nylocks, Elizabeth M. Kennedy, Torsten Klengel, Jingzhong Ding, Astrid Suchy‐Dicey, Daniel A. Enquobahrie, Jennifer A. Brody, Jerome I. Rotter, Nicole Soranzo, Jeanine J. Houwing‐Duistermaat, M. Kloppenburg, P. Eline Slagboom, Quinta Helmer, Wouter den Hollander, Shannon Bean, Towfique Raj, Noman Bakhshi, Qiao‐Ping Wang, Lisa J. Oyston, Bruce M. Psaty, Russell P. Tracy, Grant W. Montgomery, Stephen T. Turner, John Blangero, Ingrid B. Borecki, Kerry J. Ressler, Jian Yang, Lude Franke, Johannes Kettunen, Peter M. Visscher, G. Gregory Neely, Ron Korstanje, Robert L. Hanson, Holger Prokisch, Luigi Ferrucci, Tõnu Esko, Alexander Teumer, Joyce B. J. van Meurs, Andrew D. Johnson
AbstractDisease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the ‘transcriptomic age’ of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.
Metformin improves healthspan and lifespan in mice
Tập 4 Số 1
Alejandro Martín‐Montalvo, Evi M. Mercken, Sarah J. Mitchell, Hector H. Palacios, Patricia L. Mote, Morten Scheibye‐Knudsen, Ana P. Gomes, Theresa M. Ward, Robin K. Minor, Marie‐José Blouin, Matthias Schwab, Michaël Pollak, Yongqing Zhang, Yinbing Yu, Kevin G. Becker, Vilhelm A. Bohr, Donald K. Ingram, David Sinclair, Norman S. Wolf, Stephen R. Spindler, Michel Bernier, Rafael de Cabo
Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice
Tập 5 Số 1
Satomi Miwa, Howsun Jow, Karen Baty, Amy J. Johnson, Rafal Czapiewski, Gabriele Saretzki, Achim Treumann, Thomas von Zglinicki
Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression
Tập 8 Số 1
Kévin Contrepois, Clément Coudereau, Bérénice A. Benayoun, Nadine Schuler, Pierre‐François Roux, Oliver Bischof, Rëgis Courbeyrette, Cyril Carvalho, Jean‐Yves Thuret, Zhihai Ma, Céline Derbois, Marie‐Claire Nevers, Hervé Volland, Christophe E. Redon, William M. Bonner, Jean‐François Deleuze, Clotilde Wiel, David Bernard, M Snyder, Claudia E. Rübe, Robert Olaso, François Fenaille, Carl Mann
AbstractThe senescence of mammalian cells is characterized by a proliferative arrest in response to stress and the expression of an inflammatory phenotype. Here we show that histone H2A.J, a poorly studied H2A variant found only in mammals, accumulates in human fibroblasts in senescence with persistent DNA damage. H2A.J also accumulates in mice with aging in a tissue-specific manner and in human skin. Knock-down of H2A.J inhibits the expression of inflammatory genes that contribute to the senescent-associated secretory phenotype (SASP), and over expression of H2A.J increases the expression of some of these genes in proliferating cells. H2A.J accumulation may thus promote the signalling of senescent cells to the immune system, and it may contribute to chronic inflammation and the development of aging-associated diseases.
Chronic inflammation induces telomere dysfunction and accelerates ageing in mice
Tập 5 Số 1
Diana Jurk, Caroline Wilson, João F. Passos, Fiona Oakley, Clara Correia‐Melo, Laura C. Greaves, Gabriele Saretzki, Chris Fox, Conor Lawless, Rhys Anderson, Graeme Hewitt, Sylvia L.F. Pender, Nicola Fullard, Glyn Nelson, Jelena Mann, Bart van de Sluis, Derek A. Mann, Thomas von Zglinicki
AbstractChronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1−/− fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1−/− tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.
Small nucleoli are a cellular hallmark of longevity
Tập 8 Số 1
Varnesh Tiku, Chirag Jain, Yotam Raz, Shuhei Nakamura, Bree Heestand, Wei Liu, Martin R. Späth, H. Eka D. Suchiman, Roman‐Ulrich Müller, P. Eline Slagboom, Linda Partridge, Adam Antebi
AbstractAnimal lifespan is regulated by conserved metabolic signalling pathways and specific transcription factors, but whether these pathways affect common downstream mechanisms remains largely elusive. Here we show that NCL-1/TRIM2/Brat tumour suppressor extends lifespan and limits nucleolar size in the major C. elegans longevity pathways, as part of a convergent mechanism focused on the nucleolus. Long-lived animals representing distinct longevity pathways exhibit small nucleoli, and decreased expression of rRNA, ribosomal proteins, and the nucleolar protein fibrillarin, dependent on NCL-1. Knockdown of fibrillarin also reduces nucleolar size and extends lifespan. Among wildtype C. elegans, individual nucleolar size varies, but is highly predictive for longevity. Long-lived dietary restricted fruit flies and insulin-like-peptide mutants exhibit small nucleoli and fibrillarin expression, as do long-lived dietary restricted and IRS1 knockout mice. Furthermore, human muscle biopsies from individuals who underwent modest dietary restriction coupled with exercise also display small nucleoli. We suggest that small nucleoli are a cellular hallmark of longevity and metabolic health conserved across taxa.
Nucleolar expansion and elevated protein translation in premature aging
Tập 8 Số 1
Abigail Buchwalter, Martin W. Hetzer
AbstractPremature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging.
Gαs regulates the post-endocytic sorting of G protein-coupled receptors
Tập 5 Số 1
Stéphanie Rosciglione, Catherine Thériault, Marc-Olivier Boily, Marilène Paquette, Christine Lavoie