Translational readthrough generates proteins with extended C‐termini, which often possess distinct properties. Here, we have used various reporter assays to demonstrate translational readthrough of AGO1 mRNA. Analysis of ribosome profiling data and mass spectrometry data provided additional evidence for translational readthrough of AGO1. The endogenous readthrough product, Ago1x, could be detected by a specific antibody both in vitro and in vivo. This readthrough process is directed by a cis sequence downstream of the canonical AGO1 stop codon, which is sufficient to drive readthrough even in a heterologous context. This cis sequence has a let‐7a miRNA‐binding site, and readthrough is promoted by let‐7a miRNA. Interestingly, Ago1x can load miRNAs on target mRNAs without causing post‐transcriptional gene silencing, due to its inability to interact with GW182. Because of these properties, Ago1x can serve as a competitive inhibitor of miRNA pathway. In support of this, we observed increased global translation in cells overexpressing Ago1x. Overall, our results reveal a negative feedback loop in the miRNA pathway mediated by the translational readthrough product of AGO1.

Ice and solid H2S look as different as pears and oranges, leading Pauling to conclude that H2O has hydrogen bonds and H2S has van der Waals interactions. Now it is shown that the H2S dimer, like the H2O dimer, is indeed hydrogen‐bonded.

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The present invention is related to a simple and efficient process for the preparation of tofacitinib citrate 1, a Pfizer molecule approved for the treatment of rheumatoid arthritis. The process relies upon an improved process for the preparation of a key intermediate (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methylamine as tartarate salt 3 and its simple and impurity-free conversion to tofacitinib citrate 1. The current invention is aimed at addressing process development issues related to quality and yields. The disclosed process is capable of delivering much higher yield compared to the prior state-of-the-art process and is able to yield very highly pure compound.

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