Differential Levels of Telomeric Oxidized Bases and TERRA Transcripts in Childhood Autism

The underlying molecular mechanisms responsible for the etiology of autism and its sex-biased prevalence remain largely elusive. Abnormally shortened telomeres have recently been associated with autism. We have previously shown that children with non-syndromic autism exhibit a sexually dimorphic pattern of relative telomere length (RTL). Only male children with autism have significantly shorter RTLs than the healthy controls and paired siblings. Autistic females have substantially longer RTLs than autistic males. Aberrantly high levels of oxidative stress plays a fundamental role in the pathophysiology of autism, and telomeres are thought to be susceptible to oxidative damage due to their high guanine-repeat content. Employing a quantitative PCR (qPCR)-based method, telomeric oxidized base lesions were measured using genomic DNA extracted from saliva samples, and levels of telomeric RNA transcripts know as TERRA were evaluated using reverse transcriptase qPCR technique. Our data show that the autistic children exhibit substantially higher levels of oxidative base lesions at their telomeres than the healthy controls and paired siblings. Intriguingly, despite having significantly longer RTLs, female children with autism have even higher levels of telomeric oxidized bases than their male counterparts. Furthermore, despite having significantly shorter RTLs, the male children with autism exhibit lower levels of TERRA expression from the short arms of chromosomes 17 and X/P compared to their individually-matched healthy controls. These findings open a fresh angle into autism. Abnormal TL and high levels of telomeric oxidized bases may serve as biomarkers for childhood autism.

Computer-based techniques for lead identification and optimization I: Basics

This chapter focuses on computational techniques for identifying and optimizing lead molecules, with a special emphasis on natural compounds. A number of case studies have been specifically discussed, such as the case of the naphthyridine scaffold, discovered through a structure-based virtual screening (SBVS) and proposed as the starting point for further lead optimization process, to enhance its telomeric RNA selectivity. Another example is the case of Liphagal, a tetracyclic meroterpenoid extracted from Aka coralliphaga, known as PI3Kα inhibitor, provide an evidence for the design of new active congeners against PI3Kα using molecular dynamics (MD) simulations. These are only two of the numerous examples of the computational techniques’ powerful in drug design and drug discovery fields. Finally, the design of drugs that can simultaneously interact with multiple targets as a promising approach for treating complicated diseases has been reported. An example of polypharmacological agents are the compounds extracted from mushrooms identified by means of molecular docking experiments. This chapter may be a useful manual of molecular modeling techniques used in the lead-optimization and lead identification processes.