In the United States, West Nile virus (WNV) infects approximately 2500 people per year, of which 100−200 cases are fatal. No antiviral drug or vaccine is currently available for WNV. In this study, we designed gamma-modified peptide nucleic acid (γPNA) oligomers to target a newly identified guanine-rich gene sequence in the WNV genome. The target is found in the NS5 protein-coding region and was previously predicted to fold into a G-quadruplex (GQ) structure. Biophysical techniques such as UV melting analysis, circular dichroism spectroscopy, and fluorescence spectroscopy demonstrated that the target RNA indeed folds into a moderately stable GQ structure at physiological temperature and potassium concentration. Successful invasion of the GQ by three complementary γPNAs was also characterized by the above-mentioned biophysical techniques. The γPNAs showed very strong binding to the target with low femtomolar affinity at physiological temperature. Targeting this potential guanine quadruplex forming sequence (PQS) and other related sequences with γPNA may represent a new approach for inhibiting both WNV replication and transcription, thereby representing a generally useful antiviral strategy.
Growing interest in i-motif DNA as a transcriptional regulatory element motivates development of synthetic molecules capable of targeting these structures. In this study, we designed unmodified peptide nucleic acid (PNA) and gamma-modified PNA (γPNA) oligomers complementary to an i-motif forming sequence derived from the promoter of the KRAS oncogene. Biophysical techniques such as circular dichroism (CD) spectroscopy, CD melting, and fluorescence spectroscopy demonstrated the successful invasion of the i-motif by PNA and γPNA. Both PNA and γPNA showed very strong binding to the target sequence with high thermal stability of the resulting heteroduplexes. Interestingly fluorescence and CD experiments indicated formation of an intermolecular i-motif structure via the overhangs of target-probe heteroduplexes formed by PNA/γPNA invasion of the intramolecular i-motif. Targeting promoter i-motif forming sequences with high-affinity oligonucleotide mimics like γPNAs may represent a new approach for inhibiting KRAS transcription, thereby representing a potentially useful anti-cancer strategy.
Proclined upper incisors are the reasons for lip incompetence, excessive incisor display and very unesthetic smile characters for a good number of patients seeking orthodontic treatment. Majority of these cases are treated following extraction of premolars and intrusion and retraction of incisors, which became much more feasible through usage of temporary anchorage devices like miniscrew implants. Before titanium orthodontic miniscrew were available in the market, surgical screws for fixation of boneplates were started to be used for orthodontic anchorage. This article presents a case to show how surgical miniscrews can be utilized to intrude and retract severely proclined upper incisors to bring upon noticeable improvement in facial appearance and smile.
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