This thesis describes the clinical investigation of a novel treatment strategy for type 2 diabetes mellitus (t2dm) using an antisense oligonucleotide(aon)to inhibit the sglt2 receptor. Furthermore... Show moreThis thesis describes the clinical investigation of a novel treatment strategy for type 2 diabetes mellitus (t2dm) using an antisense oligonucleotide(aon)to inhibit the sglt2 receptor. Furthermore it describes skin effects of oligonucleotides Show less
Programmed ribosomal frameshifting (PRF) is one kind of recoding events that is mostly utilized by RNA viruses to synthesize more proteins with defined ratio from their compact genome and it is... Show moreProgrammed ribosomal frameshifting (PRF) is one kind of recoding events that is mostly utilized by RNA viruses to synthesize more proteins with defined ratio from their compact genome and it is known that the stoichiometric is critical to virus infection and propagation. Two cis-acting RNA elements are critical to induce PRF: one is slippery sequence where the frameshifting occurs and the other is RNA secondary structure, either a stem-loop or pseudoknot, to stall ribosomes on the slip site. In this thesis, we first demonstrate that a stem-loop structure can efficient replace pseudoknot in inducing frameshifting, arguing previous assumption hairpins are efficient frameshiftors. Furthermore, we show antisense oligonucleotides (AON) that mimic hairpin or pseudoknot can promote efficient frameshifting suggesting the downstream secondary structures act as physical barriers in frameshifting. Finally, we report a novel ligand responsive frameshifting signal derived from non-frameshifting preQ1 riboswitch aptamer. This interesting finding may have potential to select compounds with anti-bacteria ability. In sum, we successfully use in trans AONs or metabolites to induce PRF. These findings not only address fundamental mechanism of PRF but have potential to develop drugs against frameshifting diseases or bacteria. Show less
