The molecular genetics of selective tooth agenesis.

Selective tooth agenesis is a congenital disorder divided into two types based on the number of missing teeth, i.e. hypodontia which is the absence of <6 teeth and oligodontia which is agenesis of >6 permanent teeth excluding the third molars. As the prevalence of tooth agenesis is higher in populations with Arab and Asian descent, it is intriguing to probe deeper into the molecular aspects of this disorder. Selective tooth agenesis inherits as autosomal dominant, autosomal recessive or X-linked dominant mode of inheritance. The 10 loci identified are selective tooth agenesis 1 through 9 and selective tooth agenesis X1. Genes for 8 of these loci have been characterised while the causative genes for selective tooth agenesis 2 and 5 still remain to be elucidated. The current broad-spectrum review was planned to discuss the molecular genetics of all 10 loci mapped with selective tooth agenesis, their mode of inheritance as well as the proteins encoded by these genes, their roles and their interactions.

In silico mechanistic analysis of IRF3 inactivation and high-risk HPV E6 species-dependent drug response.

The high-risk human papillomavirus E6 (hrHPV E6) protein has been widely studied due to its implication in cervical cancer. In response to viral threat, activated kinases phosphorylate the IRF3 autoinhibitory domain, inducing type1 interferon production. HPV circumvents the antiviral response through the possible E6 interaction with IRF3 and abrogates p53's apoptotic activity by recruiting E6-associated protein. However, the molecular mechanism of IRF3 inactivation by hrHPV E6 has not yet been delineated. Therefore, we explored this mechanism through in silico examination of protein-protein and protein-ligand docking, binding energy differences, and computational alanine mutagenesis. Our results suggested that the LxxLL motifs of IRF3 binds within the hydrophobic pocket of E6, precluding Ser-patch phosphorylation, necessary for IRF3 activation and interferon induction. This model was further supported by molecular dynamics simulation. Furthermore, protein-ligand docking and drug resistance modeling revealed that the polar patches in the pocket of E6, which are crucial for complex stability and ligand binding, are inconsistent among hrHPV species. Such variabilities pose a risk of treatment failure owing to point mutations that might render drugs ineffective, and allude to multi-drug therapy. Overall, this study reveals a novel perspective of innate immune suppression in HPV infections and suggests a plausible therapeutic intervention.

Structure based sequence analysis & epitope prediction of gp41 HIV1 envelope glycoprotein isolated in Pakistan.

BACKGROUND: Gp41 is an envelope glycoprotein of human immune deficiency virus (HIV). HIV viral glycoprotein gp41, present in complex with gp120, assists the viral entry into host cell. Over eighty thousands individuals are HIV infected in Pakistan which makes about 0.2% of 38.6 million infected patients worldwide. Hence, HIV gp41 protein sequences isolated in Pakistan were analyzed for the CD4 and CD8 T cells binding epitopes. RESULTS: Immunoinformatics tools were applied for the study of variant region of HIV gp41envelope protein. The protein nature was analyzed using freely accessible computational software. About 90 gp41 sequences of Pakistani origin were aligned and variable and conserved regions were found. Four segments were found to be conserved in gp41 viral protein. A method was developed, involving the secondary structure, surface accessibility, hydrophobicity, antigenicity and molecular docking for the prediction and location of epitopes in the viral glycoprotein. Some highly conserved CD4 and CD8 binding epitopes were also found using multiple parameters. The predicted continuous epitopes mostly fall in the conserved region of 1-12; 14-22 and 25-46 and can be used as effective vaccine candidates. CONCLUSIONS: The study revealed potential HIV subtype a derived cytotoxic T cell (CTL) epitopes from viral proteome of Pakistani origin. The conserved epitopes are very useful for the diagnosis of the HIV 1 subtype a. This study will also help scientists to promote research for vaccine development against HIV 1 subtype a, isolated in Pakistan.