Browsing by Author "Kim, Seong-Ho"

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    Predicted Functional RNAs within Coding Regions Constrain Evolutionary Rates of Yeast Proteins
    (PLOS, 2008-02-13) Warden, Charles D.; Kim, Seong-Ho; Yi, Soojin V.; Biostatistics, School of Public Health
    Functional RNAs (fRNAs) are being recognized as an important regulatory component in biological processes. Interestingly, recent computational studies suggest that the number and biological significance of functional RNAs within coding regions (coding fRNAs) may have been underestimated. We hypothesized that such coding fRNAs will impose additional constraint on sequence evolution because the DNA primary sequence has to simultaneously code for functional RNA secondary structures on the messenger RNA in addition to the amino acid codons for the protein sequence. To test this prediction, we first utilized computational methods to predict conserved fRNA secondary structures within multiple species alignments of Saccharomyces sensu strico genomes. We predict that as much as 5% of the genes in the yeast genome contain at least one functional RNA secondary structure within their protein-coding region. We then analyzed the impact of coding fRNAs on the evolutionary rate of protein-coding genes because a decrease in evolutionary rate implies constraint due to biological functionality. We found that our predicted coding fRNAs have a significant influence on evolutionary rates (especially at synonymous sites), independent of other functional measures. Thus, coding fRNA may play a role on sequence evolution. Given that coding regions of humans and flies contain many more predicted coding fRNAs than yeast, the impact of coding fRNAs on sequence evolution may be substantial in genomes of higher eukaryotes.
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    Results of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial
    (American Heart Association, 2020-02-25) Goldberg, David J.; Zak, Victor; Goldstein, Bryan H.; Schumacher, Kurt R.; Rhodes, Jonathan; Penny, Daniel J.; Petit, Christopher J.; Ginde, Salil; Menon, Shaji C.; Kim, Seong-Ho; Kim, Gi Beom; Nowlen, Todd T.; DiMaria, Michael V.; Frischhertz, Benjamin P.; Wagner, Jonathan B.; McHugh, Kimberly E.; McCrindle, Brian W.; Shillingford, Amanda J.; Sabati, Arash A.; Yetman, Anji T.; John, Anitha S.; Richmond, Marc E.; Files, Matthew D.; Payne, R. Mark; Mackie, Andrew S.; Davis, Christopher K.; Shahanavaz, Shabana; Hill, Kevin D.; Garg, Ruchira; Jacobs, Jeffrey P.; Hamstra, Michelle S.; Woyciechowski, Stacy; Rathge, Kathleen A.; McBride, Michael G.; Frommelt, Peter C.; Russell, Mark W.; Urbina, Elaine M.; Yeager, James L.; Pemberton, Victoria L.; Stylianou, Mario P.; Pearson, Gail D.; Paridon, Stephen M.; Pediatrics, School of Medicine
    Background: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold.