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61.
62.
An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function 下载免费PDF全文
Daniel Mateju Titus M Franzmann Avinash Patel Andrii Kopach Edgar E Boczek Shovamayee Maharana Hyun O Lee Serena Carra Anthony A Hyman Simon Alberti 《The EMBO journal》2017,36(12):1669-1687
Stress granules (SG) are membrane‐less compartments involved in regulating mRNAs during stress. Aberrant forms of SGs have been implicated in age‐related diseases, such as amyotrophic lateral sclerosis (ALS), but the molecular events triggering their formation are still unknown. Here, we find that misfolded proteins, such as ALS‐linked variants of SOD1, specifically accumulate and aggregate within SGs in human cells. This decreases the dynamics of SGs, changes SG composition, and triggers an aberrant liquid‐to‐solid transition of in vitro reconstituted compartments. We show that chaperone recruitment prevents the formation of aberrant SGs and promotes SG disassembly when the stress subsides. Moreover, we identify a backup system for SG clearance, which involves transport of aberrant SGs to the aggresome and their degradation by autophagy. Thus, cells employ a system of SG quality control to prevent accumulation of misfolded proteins and maintain the dynamic state of SGs, which may have relevance for ALS and related diseases. 相似文献
63.
Shana V. Stoddard Colin L. Welsh Maggie M. Palopoli Serena D. Stoddard Mounika P. Aramandla Riya M. Patel Hong Ma Laurence H. Beck Jr 《Proteins》2019,87(2):136-145
The thrombospondin type-1 domain containing 7A (THSD7A) protein is known to be one of the antigens responsible for the autoimmune disorder idiopathic membranous nephropathy. The structure of this antigen is currently unsolved experimentally. Here we present a homology model of the extracellular portion of the THSD7A antigen. The structure was evaluated for folding patterns, epitope site prediction, and function was predicted. Results show that this protein contains 21 extracellular domains and with the exception of the first two domains, has a regular repeating pattern of TSP-1-like followed by F-spondin-like domains. Our results indicate the presence of a novel Trp-ladder sequence of WxxxxW in the TSP-1-like domains. Of the 21 domains, 18 were shown to have epitope binding sites as predicted by epitopia. Several of the F-spondin-like domains have insertions in the canonical TSP fold, most notably the coiled coil region in domain 4, which may be utilized in protein-protein binding interactions, suggesting that this protein functions as a heparan sulfate binding site. 相似文献
64.
Cutrona G Boffa LC Mariani MR Matis S Damonte G Millo E Roncella S Ferrarini M 《Oligonucleotides》2007,17(1):146-150
The present study aims to evaluate the antigenicity of a PNA complementary to the Emu sequence (PNAEmu) with cancer therapeutic potential properties in Burkitt's lymphoma (BL). In BL cells, the c-myc oncogene is repositioned next to the Emu enhancer of the immunoglobulin (Ig) locus, due to chromosomal translocation, and up-regulated. PNAEmu linked to a nuclear localization signal peptide was shown specifically to block c-myc hyperexpression by inhibiting cell growth in vitro and in vivo. Recently, we reported that the administration of PNAEmu to mice, following inoculation with BL cells, hinders tumor growth without toxic effects. To investigate the potential use of PNAEmu in clinical applications further, we tested its antigenicity. Mice were inoculated with an emulsion of free PNA or PNA crosslinked to the immunogenic carrier keyhole limpet hemocyanin (KLH) with Freund's adjuvant. Antibodies to free PNA were undetected, whereas both IgG and IgM antibodies to PNA-KLH were detected in mouse serum 28 and 38 days after inoculation. 相似文献
65.
Carolina Serena Enrique Calvo Mari Paz Clares María Luisa Diaz Javier U. Chicote Raúl Beltrán-Debon Ramón Fontova Alejandro Rodriguez Enrique García-Espa?a Antonio García-Espa?a 《PloS one》2015,10(3)
Background
The clinical use of purified SOD enzymes has strong limitations due to their large molecular size, high production cost and immunogenicity. These limitations could be compensated by using instead synthetic SOD mimetic compounds of low molecular weight.Background/Methodology
We have recently reported that two SOD mimetic compounds, the MnII complexes of the polyamines Pytren2Q and Pytren4Q, displayed high antioxidant activity in bacteria and yeast. Since frequently molecules with antioxidant properties or free-radical scavengers also have anti-inflammatory properties we have assessed the anti-inflammatory potential of Pytren2Q and Pytren4Q MnII complexes, in cultured macrophages and in a murine model of inflammation, by measuring the degree of protection they could provide against the cellular injury produced by lipopolisacharide, a bacterial endotoxin.Principal Findings
In this report we show that the MnII complex of Pytren4Q but not that of Pytren2Q effectively protected human cultured THP-1 macrophages and whole mice from the inflammatory effects produced by LPS. These results obtained with two molecules that are isomers highlight the importance of gathering experimental data from animal models of disease in assessing the potential of candidate molecules.Conclusion/Significance
The effective anti-inflammatory activity of the MnII complex of Pytren4Q in addition to its low toxicity, water solubility and ease of production would suggest it is worth taking into consideration for future pharmacological studies. 相似文献66.
Elena Turola Salvatore Petta Ester Vanni Fabiola Milosa Luca Valenti Rosina Critelli Luca Miele Livia Maccio Vincenza Calvaruso Anna L. Fracanzani Marcello Bianchini Nazarena Raos Elisabetta Bugianesi Serena Mercorella Marisa Di Giovanni Antonio Craxì Silvia Fargion Antonio Grieco Calogero Cammà Franco Cotelli Erica Villa 《Disease models & mechanisms》2015,8(9):1037-1046
67.
Cinzia Scambi Sara Ugolini T. Sakari Jokiranta Lucia De Franceschi Oscar Bortolami Valentina La Verde Patrizia Guarini Paola Caramaschi Viviana Ravagnani Guido Martignoni Chiara Colato Serena Pedron Fabio Benedetti Marco Sorio Fabio Poli Domenico Biasi 《PloS one》2015,10(2)
ObjectiveThe role of complement system in the pathogenesis of systemic sclerosis (SSc) has been debated during the last decade but an evident implication in this disease has never been found. We carried out an explorative study on SSc patients to evaluate the expression of soluble and local C5b-9 complement complex and its relation with a complement regulator, the Membrane Cofactor Protein (MCP, CD46) on skin vascular bed as target distinctive of SSc disease. We also analyzed two polymorphic variants in the complement activation gene cluster involving the MCP region.MethodsC5b-9 plasma levels of SSc patients and healthy subjects were analyzed by ELISA assay. Archival skin biopsies of SSc patients and controls were subjected to immunofluorescence analysis to detect C5b-9 and MCP on vascular endothelial cells. The expression of MCP was validated by immunoblot analysis with specific antibody. Polymorphic variants in the MCP gene promoter were tested by a quantitative PCR technique-based allelic discrimination method.ResultsEven though circulating levels of C5b-9 did not differ between SSc and controls, C5b-9 deposition was detected in skin biopsies of SSc patients but not in healthy subjects. MCP was significantly lower in skin vessels of SSc patients than in healthy controls and was associated with the over-expression of two polymorphic variants in the MCP gene promoter, which has been related to more aggressive phenotypes in other immune-mediated diseases.ConclusionsOur results firsty document the local complement activation with an abnormal expression of MCP in skin vessels of SSc patients, suggesting that a subset of SSc patients might be exposed to more severe organ complications and clinical evolution due to abnormal local complement activation. 相似文献
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69.
Serena P. Koenig Alexandra Bornstein Karine Severe Elizabeth Fox Jessy G. Dévieux Patrice Severe Patrice Joseph Adias Marcelin Dgndy Alexandre Bright Ngoc Pham Pierre Cremieux Jean William Pape 《PloS one》2015,10(11)
Objective
We assessed the association between gender and mortality on antiretroviral therapy (ART) using identical models with and without sex-specific categories for weight and hemoglobin.Design
Cohort study of adult patients on ART.Setting
GHESKIO Clinic in Port-au-Prince, Haiti.Participants
4,717 ART-naïve adult patients consecutively enrolled on ART at GHESKIO from 2003 to 2008.Main Outcome Measure
Mortality on ART; multivariable analyses were conducted with and without sex-specific categories for weight and hemoglobin.Results
In Haiti, male gender was associated with mortality (OR 1.61; 95% CI: 1.30–2.00) in multivariable analyses with hemoglobin and weight included as control variables, but not when sex-specific interactions with hemoglobin and weight were used.Conclusions
If sex-specific categories are omitted, multivariable analyses indicate a higher risk of mortality for males vs. females of the same weight and hemoglobin. However, because males have higher normal values for weight and hemoglobin, the males in this comparison would generally have poorer health status than the females. This may explain why gender differences in mortality are sometimes observed after controlling for differences in baseline variables when gender-specific interactions with weight and hemoglobin are omitted. 相似文献70.
Alessandra Silvestri Francesco Palumbo Ignazio Rasi Daniela Posca Theodora Pavlidou Serena Paoluzi Luisa Castagnoli Giovanni Cesareni 《PloS one》2015,10(8)