The recent outbreak of coronavirus disease 2019 highlights an urgent need for therapeutics. Through a series of drug repurposing screening campaigns, niclosamide, an FDA-approved anthelminthic drug, was found to be effective against various viral infections with nanomolar to micromolar potency such as SARS-CoV, MERS-CoV, ZIKV, HCV, and human adenovirus, indicating its potential as an antiviral agent. In this brief review, we summarize the broad antiviral activity of niclosamide and highlight its potential clinical use in the treatment of COVID-19.

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This paper develops a model in which investors who are prohibited from short selling agree to disagree on the precision of a publicly observed signal. The model implies that the equilibrium price is a convex function of the public signal. The model predicts that (1) the stock price reacts more to good news than to bad news; (2) the skewness of stock returns is positively correlated with contemporaneous returns, but negatively correlated with lagged returns; (3) short sale constraints increase rather than decrease skewness; and (4) disagreement about information precision increases skewness. Empirical tests conducted find supportive evidence for all these predictions. Copyright 2007 by The American Finance Association.

5,6-Dihydrouridine (D) is a modified base found abundantly in the D-loops of tRNA from Archaea, Bacteria, and Eukarya. D is thought to be formed post-transcriptionally by the reduction of uridines in tRNA transcripts. Despite its abundance, no enzymes that catalyze D-formation have been identified. Using comparative genomics and computational methods we have identified members of the cluster of orthologous genes, COG0042, as putative dihydrouridine synthase encoding genes. Escherichia coli contains three COG0042 family members (yjbN, yhdG, and yohI). Strains were created where one, two, or all three of the COG0042 genes were deleted. Purified tRNA samples were investigated from the three single and the three double knockout strains, as well as from the triple deletion strain. The results showed that the COG0042 gene family is responsible for tRNA-dihydrouridine synthase activity in E. coli. They also suggest that the COG0042-encoded family members act site-specifically on the tRNA D-loop and contain nonredundant catalytic functions in vivo. 5,6-Dihydrouridine (D)1 is the most abundant modified base in prokaryote and eukaryote tRNA (1). This non-aromatic base is found almost exclusively at conserved positions in the D-loop ( Despite the widespread occurrence of this non-aromatic base, little is known about its biochemical roles. Evidence that dihydrouridine may destabilize the structure and thus enhance conformational flexibility of tRNA was presented by McCloskey and coworkers (3). They showed that a short D-containing oligonucleotide favors the C2Ј-endoribose conformation as compared with the equivalent U-containing oligonucleotide that favors the C3Ј-endo conformation. The C3Ј-endo conformation is necessary for base-stacked RNA. The same group argued that thermophilic organisms generally possess lower levels of D in their tRNA because of the lesser need for inherent tRNA conformational flexibility at high growth temperatures (4).Despite the abundance of D in tRNA of prokaryotes and eukaryotes, the genes encoding the enzymes for dihydrouridine synthesis have not been identified. Aware that D occurs in specific positions in the D-loop and that different tRNA from the same organism contain varying amounts of D, we hypothesized that prokaryote and eukaryote genomes encoded more than one enzyme and that their substrate specificities were distinct. However, without genetic selections or screens that utilize in vivo phenotypes, identifying the gene(s) responsible for dihydrouridine synthesis has been difficult. To address this problem in a new way, we took advantage of the growing number of complete genomic data bases. To reduce the number of possible candidates, we used computational algorithms to identify genes that are specific to organisms that synthesize dihydrouridine. This approach ultimately narrowed down the candidates to three E. coli genes encoding putative DUS activity. Their associated biochemical phenotypes were investigated. EXPERIMENTAL PROCEDURES Strains and Growth ConditionsBacteria were routinely g...

Fis is a nucleoid-associated protein in Escherichia coli that has been shown to regulate recombination, replication, and transcription reactions. It is expressed in a transient manner under batch culturing conditions such that high levels are present during early exponential phase and low levels are present during late exponential phase and stationary phase. We have screened a random collection of transposon-induced lac fusions for those which give decreased expression in the presence of Fis. Thirteen different Fis-repressed genes were identified, including glnQ (glutamine high-affinity transport), mglA (methyl-galactoside transport), xylF (D-xylose-binding protein), sdhA (succinate dehydrogenase flavoprotein subunit), and a newly identified aldehyde dehydrogenase, aldB. The LacZ expression patterns revealed that many of the fusions were maximally expressed at different stages of growth, including early log phase, mid-to late log phase, and stationary phase. The expression of some of the late-exponential-and stationary-phase genes was dependent on the RpoS sigma factor, whereas that of others was affected negatively by RpoS. We conclude that Fis negatively regulates a diverse set of genes and that RpoS can function to both activate and inhibit the expression of specific genes.Fis is a small DNA-binding protein that was originally identified because of its prominent role in site-specific DNA inversion reactions (18,19). It has a relaxed target specificity and has been shown to bind to many different sites throughout the Escherichia coli chromosome (8). DNA binding is mediated by helix-turn-helix motifs located in the carboxy termini of the Fis dimer and results in a high degree of bending of the DNA (22,50). A region in the amino terminus is required to stimulate Hin-and Gin-mediated DNA inversion and may play a role in transcriptional activation but does not influence excision (12,20,35).The expression of Fis is growth phase dependent (4,31,32,46). Its intracellular levels increase rapidly in a transient manner in response to nutritional upshift. The number of Fis dimers per cell increases about 500-fold within the first cell division when a stationary-phase culture is inoculated into a rich medium, reaching a peak level of 40,000 to 50,000 dimers per cell. Under standard batch culturing conditions, Fis expression is largely turned off in mid-exponential phase and the intracellular levels of Fis decline rapidly as a function of each cell division. Fis levels in cells maintained in stationary phase are extremely low.In addition to functioning in site-specific recombination reactions, Fis has been shown to enhance transcription of rRNA and certain tRNA operons (29,30,38,41) and to stimulate DNA replication from oriC (7, 11). The activation of the rRNA and tRNA operons by Fis is associated with the binding of the protein to specific DNA sequences upstream of the promoters (31, 38). Fis has also been shown to negatively regulate its own expression by binding to multiple sites within the fis promoter region (4, 32). ...