Statistical methodology for ribosomal frameshift detection

During normal protein synthesis, the ribosome shifts along the messenger RNA (mRNA) by exactly three nucleotides for each amino acid added to the protein being translated. However, in special cases, the sequence of the mRNA somehow induces the ribosome to slip, which shifts the "reading frame"in which the mRNA is translated, and gives rise to an otherwise unexpected protein. Such "programmed frameshifts"are well-known in viruses, including coronavirus, and a few cases of programmed frameshifting are also known in cellular genes. However, there is no good way, either experimental or informatic, to identify novel cases of programmed frameshifting. Thus it is possible that substantial numbers of cellular proteins generated by programmed frameshifting in human and other organisms remain unknown. Here, we build on prior works observing that data from ribosome profiling can be analyzed for anomalies in mRNA reading frame periodicity to identify putative programmed frameshifts. We develop a statistical framework to identify all likely (even for very low frameshifting rates) frameshift positions in a genome. We also develop a frameshift simulator for ribosome profiling data to verify our algorithm. We show high sensitivity of prediction on the simulated data, retrieving 97.4% of the simulated frameshifts. Furthermore, our method found all three of the known yeast genes with programmed frameshifts. Our results suggest there could be a large number of un-Annotated alternative proteins in the yeast genome, generated by programmed frameshifting. This motivates further study and parallel investigations in the human genome. © 2022 ACM.

USE OF REMDESEVIR CAUSING SINUS BRADYCARDIA AND EVENTUALLY ASYMPTOMATIC MOBITZ TYPE 1 ATRIOVENTRICULAR BLOCK

Background: Remdesivir has emerged as a novel treatment in hospitalized COVID19 patients not requiring mechanical ventilation. Though there have been several case reports of remdesivir-associated sinus bradycardia, this association is still unclear. Furthermore, remdesivir's interaction with beta blockers has not been studied. Case: A 70-year-old woman with apical hypertrophic cardiomyopathy (HCM), heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation (AF) status post ablation presented with shortness of breath. She was tachycardic to 115 beats per minute (BPM) and hypoxemic to the 80’s, requiring supplemental oxygen via a non-rebreather mask. She was found to have COVID19 pneumonia, for which dexamethasone and remdesivir were started. She developed marked bradycardia and eventually asymptomatic Mobitz type 1 atrioventricular block (AVB). Decision-making: Once COVID19 pneumonia was diagnosed, dexamethasone and remdesivir were started. She immediately became bradycardic and remdesivir and beta blockade were held. Of note, she was taking metoprolol succinate at home for HFrEF. Bradycardia and AVB resolved with cessation of remdesivir and she was discharged home safely on metoprolol succinate. Conclusion: Patients on remdesivir, especially those with underlying cardiomyopathy, are at higher risk for bradyarrhythmia. Remdesivir may potentiate the effects of beta blockers and their concomitant use requires judicious monitoring. [Formula presented]