82 research outputs found
TIMP-2 mediates the anti-invasive effects of the nitric oxide-releasing prodrug JS-K in breast cancer cells
IDN2 and Its Paralogs Form a Complex Required for RNA–Directed DNA Methylation
IDN2/RDM12 has been previously identified as a component of the RNA–directed DNA methylation (RdDM) machinery in Arabidopsis thaliana, but how it functions in RdDM remains unknown. By affinity purification of IDN2, we co-purified two IDN2 paralogs IDP1 and IDP2 (IDN2 PARALOG 1 and 2). The coiled-coil domain between the XS and XH domains of IDN2 is essential for IDN2 homodimerization, whereas the IDN2 C-terminal XH domain but not the coiled-coil domain is required for IDN2 interaction with IDP1 and IDP2. By introducing the wild-type IDN2 sequence and its mutated derivatives into the idn2 mutant for complementation testing, we demonstrated that the previously uncharacterized IDN2 XH domain is required for the IDN2-IDP1/IDP2 complex formation as well as for IDN2 function. IDP1 is required for de novo DNA methylation, siRNA accumulation, and transcriptional gene silencing, whereas IDP2 has partially overlapping roles with IDP1. Unlike IDN2, IDP1 and IDP2 are incapable of binding double-stranded RNA, suggesting that the roles of IDP1 and IDP2 are different from those of IDN2 in the IDN2-IDP1/IDP2 complex and that IDP1 and IDP2 are essential for the functioning of the complex in RdDM
Plant ARGONAUTEs: Features, Functions and Unknowns
ARGONAUTEs (AGOs) are the effector proteins in eukaryotic small RNA(sRNA)–
based gene silencing pathways controlling gene expression and transposon activity. In
plants, AGOs regulate key biological processes such as development, response to
stress, genome structure and integrity, and pathogen defense. Canonical functions of
plant AGO–sRNA complexes include the endonucleolytic cleavage or translational
inhibition of target RNAs, and the methylation of target DNAs. Here, I provide a brief
update on the major features, molecular functions and biological roles of plant AGOs.
A special focus is given to the more recent discoveries related to emerging molecular
or biological functions of plant AGOs, as well as to the major unknowns in the plant
AGO field.This work
was supported by an Individual Fellowship from the European
Union’s Horizon 2020 research and innovation program under
the Marie Skłodowska-Curie grant agreement No. 655841 to A.C.Carbonell Olivares, A. (2017). Plant ARGONAUTEs: Features, Functions and Unknowns. En Plant Argonaute Proteins: Methods and Protocols. Springer Link. 1-21. https://doi.org/10.1007/978-1-4939-7165-7_1121Meister G (2013) Argonaute proteins: functional insights and emerging roles. Nat Rev Genet 14(7):447–459. doi: 10.1038/nrg3462Huntzinger E, Izaurralde E (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12(2):99–110. doi: 10.1038/nrg2936Cerutti H, Casas-Mollano JA (2006) On the origin and functions of RNA-mediated silencing: from protists to man. Curr Genet 50(2):81–99. doi: 10.1007/s00294-006-0078-xFang X, Qi Y (2016) RNAi in plants: an argonaute-centered view. 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In acute myeloid leukemia, B7-H1 (PD-L1) protection of blasts from cytotoxic T cells is induced by TLR ligands and interferon-gamma and can be reversed using MEK inhibitors
Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11
The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting of proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond to these compounds, and those who do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop new drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs selectivity over several other metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy
The Effect of Fin Pitch on Fluid Elastic Instability of Tube Arrays Subjected to Cross Flow of Water
Foodhandler-Associated Salmonella Outbreak in a University Hospital Despite Routine Surveillance Cultures of Kitchen Employees
Unique Functionality of 22 nt miRNAs in Triggering RDR6-Dependent siRNA Biogenesis from Target Transcripts in Arabidopsis
RNA interference pathways may involve amplification of secondary siRNAs by RNA-dependent RNA polymerases. In plants, RDR6-dependent secondary siRNAs arise from transcripts targeted by some microRNA (miRNA). Here, Arabidopsis thaliana secondary siRNA from mRNA, and trans-acting siRNA, are shown to be triggered through initial targeting by 22 nt miRNA that associate with AGO1. In contrast to canonical 21 nt miRNA, 22 nt miRNA primarily arise from foldback precursors containing asymmetric bulges. Using artificial miRNA constructs, conversion of asymmetric foldbacks to symmetric foldbacks resulted in production of 21 nt forms of miR173, miR472 and miR828. Both 21 and 22 nt forms associated with AGO1 and guided accurate slicer activity, but only 22 nt miRNA were competent to trigger RDR6-dependent siRNA from target RNA. These data suggest that AGO1 functions differentially with 21 and 22 nt miRNA to engage the RDR6-associated amplification apparatus
Ophthalmic manifestations of multiple myeloma
PurposeTo describe ophthalmic manifestations in a series of patients with multiple myeloma (MM) and review the literature.DesignRetrospective case series.MethodsReview of all cases with ophthalmic manifestations of MM seen at the Department of Ophthalmology, Royal Adelaide Hospital, between 1987 and 2002.ResultsOf all patients with MM who were managed at the Royal Adelaide Hospital in the study period, only 8 were referred to the Ophthalmology Department with ophthalmic manifestations. Five males and 3 females with a mean age of 61.25 years (range 42-78) who exhibited ophthalmic manifestations were studied. Six patients (75%) had known MM at the time of their ophthalmic evaluation. Four patients (50%) had neuro-ophthalmic symptoms resulting in diplopia or visual disturbances. Three patients (37.5%) presented with orbital involvement and 1 (12.5%) with hyperviscosity retinopathy. Five patients (62.5%) died within 2 months of their ophthalmic presentation.ConclusionOphthalmic manifestations of MM are uncommon and diverse. They may appear at the initial presentation of the disease or occur late in the disease process. Awareness of the possible manifestations may lead to an earlier diagnosis and have a positive influence on the disease course
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