29 research outputs found

    Dissociating sticker dynamics from chain relaxation in supramolecular polymer networks—The importance of free partner!

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    Associating polymers constitute a fascinating class of materials because of the richness in their rheological behavior. Their rheology is known to be mainly dictated by the nature and intrinsic stabilities of transient associations. Here, we provide a direct observation of the importance of free associating sites in the macroscopic relaxation of supramolecular networks constructed from ultrahigh molecular weight polymers with sparsely distributed stickers of finite functionality. Their rheological signature affords evidence that the macroscopic relaxation of supramolecular networks can be apparently dissociated from the intrinsic lifetime of the associating units, provided that diffusion processes do not lead to successful chain relaxation at the microscopic leve

    Differential Effects on the Translation of Immune-Related Alternatively Polyadenylated mRNAs in Melanoma and T Cells by eIF4A Inhibition.

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    Targeting the translation initiation complex eIF4F, which binds the 5' cap of mRNAs, is a promising anti-cancer approach. Silvestrol, a small molecule inhibitor of eIF4A, the RNA helicase component of eIF4F, inhibits the translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor, which, in turn, reduces the transcription of the gene encoding one of the major immune checkpoint proteins, i.e., programmed death ligand-1 (PD-L1) in melanoma cells. A large proportion of human genes produce multiple mRNAs differing in their 3'-ends through the use of alternative polyadenylation (APA) sites, which, when located in alternative last exons, can generate protein isoforms, as in the STAT1 gene. Here, we provide evidence that the STAT1α, but not STAT1ÎČ protein isoform generated by APA, is required for silvestrol-dependent inhibition of PD-L1 expression in interferon-Îł-treated melanoma cells. Using polysome profiling in activated T cells we find that, beyond STAT1, eIF4A inhibition downregulates the translation of some important immune-related mRNAs, such as the ones encoding TIM-3, LAG-3, IDO1, CD27 or CD137, but with little effect on the ones for BTLA and ADAR-1 and no effect on the ones encoding CTLA-4, PD-1 and CD40-L. We next apply RT-qPCR and 3'-seq (RNA-seq focused on mRNA 3' ends) on polysomal RNAs to analyze in a high throughput manner the effect of eIF4A inhibition on the translation of APA isoforms. We identify about 150 genes, including TIM-3, LAG-3, AHNAK and SEMA4D, for which silvestrol differentially inhibits the translation of APA isoforms in T cells. It is therefore crucial to consider 3'-end mRNA heterogeneity in the understanding of the anti-tumor activities of eIF4A inhibitors
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