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ABSTRACTIt was noticed that the mortality rate of SARS-CoV-2 infection experienced a significant declination in the early stage of the epidemic. We suspect that the sharp deterioration of virus toxicity is related to the deletion of the untranslated region (UTR) of the virus genome. It was found that the genome length of SARS-CoV-2 engaged a significant truncation due to UTR deletion after a mega-sequence analysis. Sequence similarity analysis further indicated that short UTR strains originated from its long UTR ancestors after an irreversible deletion. A good correlation was discovered between genome length and mortality, which demonstrated that the deletion of the virus UTR significantly affected the toxicity of the virus. This correlation was further confirmed in a significance analysis of the genetic influence on the clinical outcomes. The viral genome length of hospitalized patients was significantly more extensive than that of asymptomatic patients. In contrast, the viral genome length of asymptomatic was considerably longer than that of ordinary patients with symptoms. A genome-level mutation scanning was performed to systematically evaluate the influence of mutations at each position on virulence. The results indicated that UTR deletion was the primary driving force in alternating virus virulence in the early evolution. In the end, we proposed a mathematical model to explain why this UTR deletion was not continuous.

The planktonic-biofilm transition is reported to facilitate the survival of disease-causing pathogens in a hostile environment, as the ability of pathogens to resist antibiotic treatment is 10 to 1000 times higher in a biofilm than in the planktonic mode. The availability of nutrient components such as amino acids in the surrounding environment plays an important role in the initiation of the biofilm formation. This work proposes a metabolic modeling framework to study the influence of availability of amino acids on the biofilm formation capability of Pseudomonas aeruginosa, one of the major pathogens causing nosocomial infections. Specifically, the genes that are up-regulated during the biofilm initiation were used to determine the metabolic reactions that are positively associated with P. aeruginosabiofilm formation. A criterion was then defined from the change of fluxes of these biofilm-associated reactions and the biomass growth rates to quantify the chance of biofilm formation upon the change of amino acid uptake rates. It was found that adding one of the following eleven amino acids, including Arg, Tyr, Phe, His, Iso, Orn, Pro, Glu, Leu, Val, and Asp, into the minimal medium may trigger P. aeruginosabiofilm formation. These results are perfectly consistent with the existing experimental data. The developed modeling framework was further used as an in silicoplatform to investigate the impact of the availability of two amino acids on the biofilm formation. It was found that the availability of additional amino acids can enhance biofilm formation and that there may be synergistic mechanisms for multiple amino acids to promote the biofilm formation.

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Targeting a regulatory subunit in the phosphatase PP2A could limit arrhythmias caused by excessive adrenergic stimulation.