ABSTRACT
Understanding the structure and recognition of highly conserved regulatory segments of the integrated viral DNA genome that forms unique topologies can greatly aid in devising novel therapeutic strategies to counter chronic infections. In this study, we configured a probe system using highly environment-sensitive nucleoside analogs, 5-fluoro-2'-deoxyuridine (FdU) and 5-fluorobenzofuran-2'-deoxyuridine (FBFdU), to investigate the structural polymorphism of HIV-1 long terminal repeat (LTR) G-quadruplexes (GQs) by fluorescence and 19F NMR. FdU and FBFdU, serving as hairpin and GQ sensors, produced distinct spectral signatures for different GQ topologies adopted by LTR G-rich oligonucleotides. Importantly, systematic 19F NMR analysis in Xenopus laevis oocytes gave unprecedented information on the structure adopted by the LTR G-rich region in the cellular environment. The results indicate that it forms a unique GQ-hairpin hybrid architecture, a potent hotspot for selective targeting. Furthermore, structural models generated using MD simulations provided insights on how the probe system senses different GQs. Using the responsiveness of the probes and Taq DNA polymerase stop assay, we monitored GQ- and hairpin-specific ligand interactions and their synergistic inhibitory effect on the replication process. Our findings suggest that targeting GQ and hairpin motifs simultaneously using bimodal ligands could be a new strategy to selectively block the viral replication.
ABSTRACT
Objective Hearing loss as a comorbidity of type 2 diabetes mellitus (type 2 DM) is frequently overlooked by patients and healthcare professionals because of a lack of awareness. This cross-sectional study aims to investigate the impact of DM on sensorineural hearing loss (SNHL) in the population of Eastern India. The primary objectives are to assess the prevalence and severity of SNHL among individuals with DM, explore demographic and clinical factors associated with hearing impairment, and contribute valuable insights to the understanding of this relationship in a specific regional context. Methods An institutional-based cross-sectional study was conducted on 198 patients with type 2 DM. Of these, 46 patients were excluded based on exclusion criteria. All patients underwent detailed demographic and clinical assessments, including glycemic control, DM duration, and associated complications. Pure tone audiometry was used to evaluate hearing thresholds. Otoacoustic emission testing was performed to assess cochlear dysfunction. Results A high prevalence of SNHL (70.4%) was observed among the 152 participants meeting the inclusion criteria. Females exhibited a higher prevalence than males, and most participants experienced mild SNHL. Rural residence, lower socioeconomic status, and poor glycemic control were associated with increased SNHL. Significant associations were found between hearing loss severity and DM duration, glycosylated hemoglobin (HbA1c) levels, and complications. Among complications, a strong association was noted with diabetic neuropathy. No significant association was observed with the presence or absence of otoacoustic-emission. Conclusion This study reveals a substantial impact of DM on SNHL in Eastern India, emphasizing the importance of routine hearing assessments in diabetic populations. The findings contribute to regional understanding and have implications for targeted healthcare interventions and preventive strategies.