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      JC Virus Inclusions in Progressive Multifocal Leukoencephalopathy: Scaffolding Promyelocytic Leukemia Nuclear Bodies Grow With Cell Cycle Transition Through an S-to-G2–Like State in Enlarging Oligodendrocyte Nuclei

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          Abstract

          In progressive multifocal leukoencephalopathy, JC virus–infected oligodendroglia display 2 distinct patterns of intranuclear viral inclusions: full inclusions in which progeny virions are present throughout enlarged nuclei and dot-shaped inclusions in which virions are clustered in subnuclear domains termed “promyelocytic leukemia nuclear bodies” (PML-NBs). Promyelocytic leukemia nuclear bodies may serve a scaffolding role in viral progeny production. We analyzed the formation process of intranuclear viral inclusions by morphometry and assessed PML-NB alterations in the brains of 2 patients with progressive multifocal leukoencephalopathy. By immunohistochemistry, proliferating cell nuclear antigen was most frequently detected in smaller nuclei; cyclin A was detected in larger nuclei. This suggests an S-to-G2 cell cycle transition in infected cells associated with nuclear enlargement. Sizes of PML-NBs were variable, but they were usually either small speckles 200 to 400 nm in diameter or distinct spherical shells with a diameter of 1 μm or more. By confocal microscopy, JC virus capsid proteins were associated with both small and large PML-NBs, but disruption of large PML-NBs was observed by ground-state depletion fluorescence nanoscopy. Clusters of progeny virions were also detected by electron microscopy. Our data suggest that, in progressive multifocal leukoencephalopathy, JC virus produces progeny virions in enlarging oligodendrocyte nuclei in association with growing PML-NBs and with cell cycle transition through an S-to-G2-like state.

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          Fluorescence nanoscopy by ground-state depletion and single-molecule return.

          We introduce far-field fluorescence nanoscopy with ordinary fluorophores based on switching the majority of them to a metastable dark state, such as the triplet, and calculating the position of those left or those that spontaneously returned to the ground state. Continuous widefield illumination by a single laser and a continuously operating camera yielded dual-color images of rhodamine- and fluorescent protein-labeled (living) samples, proving a simple yet powerful super-resolution approach.
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            Virus factories: associations of cell organelles for viral replication and morphogenesis

            Abstract Genome replication and assembly of viruses often takes place in specific intracellular compartments where viral components concentrate, thereby increasing the efficiency of the processes. For a number of viruses the formation of ‘factories’ has been described, which consist of perinuclear or cytoplasmic foci that mostly exclude host proteins and organelles but recruit specific cell organelles, building a unique structure. The formation of the viral factory involves a number of complex interactions and signalling events between viral and cell factors. Mitochondria, cytoplasmic membranes and cytoskeletal components frequently participate in the formation of viral factories, supplying basic and common needs for key steps in the viral replication cycle.
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              A manually curated network of the PML nuclear body interactome reveals an important role for PML-NBs in SUMOylation dynamics

              Promyelocytic Leukaemia Protein nuclear bodies (PML-NBs) are dynamic nuclear protein aggregates. To gain insight in PML-NB function, reductionist and high throughput techniques have been employed to identify PML-NB proteins. Here we present a manually curated network of the PML-NB interactome based on extensive literature review including database information. By compiling 'the PML-ome', we highlighted the presence of interactors in the Small Ubiquitin Like Modifier (SUMO) conjugation pathway. Additionally, we show an enrichment of SUMOylatable proteins in the PML-NBs through an in-house prediction algorithm. Therefore, based on the PML network, we hypothesize that PML-NBs may function as a nuclear SUMOylation hotspot.
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                Author and article information

                Journal
                J Neuropathol Exp Neurol
                J. Neuropathol. Exp. Neurol
                NEN
                Journal of Neuropathology and Experimental Neurology
                American Association of Neuropathologists
                0022-3069
                1554-6578
                May 2014
                16 April 2014
                : 73
                : 5
                : 442-453
                Affiliations
                From the Departments of Pathology (YS-H, TY, HK) and Neurosurgery (MN), Kyorin University School of Medicine, Shinkawa, Mitaka; Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute for Medical Science, Kamikitazawa, Setagaya-ku (YS-H, TU); Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku (SA-S, Mku, MKi), Tokyo; and Section of Pathology, Aizawa Hospital, Honjo, Matsumoto, Nagano (KH), Japan.
                Author notes
                Send correspondence and reprint requests to: Yukiko Shishido-Hara, MD, PhD, Department of Pathology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan; E-mail: yhara@ 123456ks.kyorin-u.ac.jp
                Article
                NEN13253 00007
                10.1097/NEN.0000000000000066
                3995394
                24709678
                dc43acbc-2a5e-4e9b-b3f3-c6ff7f1c8dc5
                Copyright © 2014 by the American Association of Neuropathologists, Inc.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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                cell cycle,cell stress,intranuclear viral inclusions,jc virus,pml-nbs,progressive multifocal leukoencephalopathy

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