Dynamics of generalized PT-symmetric dimers with time-periodic gain–loss

A parity-time (PT)-symmetric system with periodically varying-in-time gain and loss modeled by two coupled Schrödinger equations (dimer) is studied. It is shown that the problem can be reduced to a perturbed pendulum-like equation. This is done by finding two constants of motion. Firstly, a generalized problem using Melnikov-type analysis and topological degree arguments is studied for showing the existence of periodic (libration), shift- periodic (rotation), and chaotic solutions. Then these general results are applied to the PT-symmetric dimer. It is interestingly shown that if a sufficient condition is satisfied, then rotation modes, which do not exist in the dimer with constant gain–loss, will persist. An approximate threshold for PT-broken phase corresponding to the disappearance of bounded solutions is also presented. Numerical study is presented accompanying the analytical results

Identification of Widespread Ultra-Edited Human RNAs

Adenosine-to-inosine modification of RNA molecules (A-to-I RNA editing) is an important mechanism that increases transciptome diversity. It occurs when a genomically encoded adenosine (A) is converted to an inosine (I) by ADAR proteins. Sequencing reactions read inosine as guanosine (G); therefore, current methods to detect A-to-I editing sites align RNA sequences to their corresponding DNA regions and identify A-to-G mismatches. However, such methods perform poorly on RNAs that underwent extensive editing (“ultra”-editing), as the large number of mismatches obscures the genomic origin of these RNAs. Therefore, only a few anecdotal ultra-edited RNAs have been discovered so far. Here we introduce and apply a novel computational method to identify ultra-edited RNAs. We detected 760 ESTs containing 15,646 editing sites (more than 20 sites per EST, on average), of which 13,668 are novel. Ultra-edited RNAs exhibit the known sequence motif of ADARs and tend to localize in sense strand Alu elements. Compared to sites of mild editing, ultra-editing occurs primarily in Alu-rich regions, where potential base pairing with neighboring, inverted Alus creates particularly long double-stranded RNA structures. Ultra-editing sites are underrepresented in old Alu subfamilies, tend to be non-conserved, and avoid exons, suggesting that ultra-editing is usually deleterious. A possible biological function of ultra-editing could be mediated by non-canonical splicing and cleavage of the RNA near the editing sites

Lessons from non-canonical splicing

Recent improvements in experimental and computational techniques that are used to study the transcriptome have enabled an unprecedented view of RNA processing, revealing many previously unknown non-canonical splicing events. This includes cryptic events located far from the currently annotated exons and unconventional splicing mechanisms that have important roles in regulating gene expression. These non-canonical splicing events are a major source of newly emerging transcripts during evolution, especially when they involve sequences derived from transposable elements. They are therefore under precise regulation and quality control, which minimizes their potential to disrupt gene expression. We explain how non-canonical splicing can lead to aberrant transcripts that cause many diseases, and also how it can be exploited for new therapeutic strategies

Selective α4β2 Nicotinic Acetylcholine Receptor Agonists Target Epigenetic Mechanisms in Cortical GABAergic Neurons

Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD67) expression. Here we explored the impact of synthetic α4β2 and α7 nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at α4β2 and a lower affinity full agonist at α7 neuronal nAChR, injected in doses of 1–5 mg/kg/s.c. twice daily for 5 days, elicited a 30–40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD67 mRNA and protein. This upregulation of GAD67 was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP2 binding to GAD67 promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD67 expression were obtained after administration of A–85380, an agonist that binds to α4β2 but has negligible affinity for α3β4 or α7 subtypes containing nAChR. In contrast, PNU–282987, an agonist of the homomeric α7 nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD67 expression. The present study suggests that the α4β2 nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the α7 nAChR agonists