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  1. Abstract

    C9ORF72hexanucleotide repeat expansion is the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism is the accumulation of toxic dipeptide repeat (DPR) proteins like poly-GA, GP and GR, produced by the noncanonical translation of the expanded RNA repeats. However, how different DPRs are synthesized remains elusive. Here, we use single-molecule imaging techniques to directly measure the translation dynamics of different DPRs. Besides initiation, translation elongation rates vary drastically between different frames, with GP slower than GA and GR the slowest. We directly visualize frameshift events using a two-color single-molecule translation assay. The repeat expansion enhances frameshifting, but the overall frequency is low. There is a higher chance of GR-to-GA shift than in the reversed direction. Finally, the ribosome-associated protein quality control (RQC) factors ZNF598 and Pelota modulate the translation dynamics, and the repeat RNA sequence is important for invoking the RQC pathway. This study reveals that multiple translation steps modulate the final DPR production. Understanding repeat RNA translation is critically important to decipher the DPR-mediated pathogenesis and identify potential therapeutic targets in C9ORF72-ALS/FTD.

     
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  2. Abstract

    High‐speed video records of a single‐stroke positive cloud‐to‐ground (+CG) flash were used to examine the evolution of eight needles developing more or less radially from the +CG channel. All these eight needles occurred during the later return‐stroke stage and the following continuing current stage. Six needles, after their initial extension from the lateral surface of the parent channel core, elongated via bidirectional recoil events, which are responsible for flickering, and two of them evolved into negative stepped leaders. For the latter two, the mean extension speed decreased from 5.3 × 106to 3.4 × 105and then to 1.3 × 105 m/s during the initial, recoil‐event, and stepping stages, respectively. The initial needle extension ranged from 70 to 320 m (N = 8), extension via recoil events from 50 to 210 m (N = 6), and extension via stepping from 810 to 1,870 m (N = 2). Compared with needles developing from leader channels, the different behavior of needle flickering, the longer length, the faster extension speed, and the higher flickering rate observed in this work may be attributed to a considerably higher current (rate of charge supply) during the return‐stroke and early continuing‐current stages of +CG flashes.

     
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