Brain Derived Neurotrophic Factor (BDNF) Expression Is Regulated by MicroRNAs miR-26a and miR-26b Allele-Specific Binding

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an essential role in neuronal development and plasticity. MicroRNA (miRNAs) are small non-coding RNAs of about 22-nucleotides in length regulating gene expression at post-transcriptional level. In this study we explore the role of miRNAs as post-transcriptional inhibitors of BDNF and the effect of 3′UTR sequence variations on miRNAs binding capacity. Using an in silico approach we identified a group of miRNAs putatively regulating BDNF expression and binding to BDNF 3′UTR polymorphic sequences. Luciferase assays demonstrated that these miRNAs (miR-26a1/2 and miR-26b) downregulates BDNF expression and that the presence of the variant alleles of two single nucleotide polymorphisms (rs11030100 and rs11030099) mapping in BDNF 3′UTR specifically abrogates miRNAs targeting. Furthermore we found a high linkage disequilibrium rate between rs11030100, rs11030099 and the non-synonymous coding variant rs6265 (Val66Met), which modulates BDNF mRNA localization and protein intracellular trafficking. Such observation led to hypothesize that miR-26s mediated regulation could extend to rs6265 leading to an allelic imbalance with potentially functional effects, such as peptide's localization and activity-dependent secretion. Since rs6265 has been previously implicated in various neuropsychiatric disorders, we evaluated the distribution of rs11030100, rs11030099 and rs6265 both in a control and schizophrenic group, but no significant difference in allele frequencies emerged. In conclusion, in the present study we identified two novel miRNAs regulating BDNF expression and the first BDNF 3′UTR functional variants altering miRNAs-BDNF binding

Free Vibration of Fully Coupled Thermoelastic Multilayered Composites with Imperfect Interfaces

A fully coupled thermoelastic framework is formulated to cope with the free vibration response of anisotropic multilayered plates in three dimensions. The laminated structure consists of homogeneous laminae of arbitrary thickness and width under simply supported edge conditions in thermal environment. The general and exact field expressions of the temperature, heat flux, displacement and stress components are expressed in terms of double Fourier series expansions in any rectangular plate, which lead to the extended Stroh formalism with thermomechanical coupling effects in a concise and compact matrix form. Different imperfect interface conditions are introduced to characterize specific structural and thermal contact properties at the bounding interfaces, and further to determine the finite complex valued coefficients in the suitable series relations. The complete time-harmonic solutions in the laminated composites in the presence of perfect/imperfect interfaces are recursively obtained by means of the modified dual variable and position technique with explicit layer-to-layer transfer matrices. Results are obtained for different layups, length-to-thickness ratios and interfacial boundary conditions for two application examples, namely the graphite/epoxy cross-ply composites and the thermal barrier coatings on superalloys, without suffering from numerical exponential instability. These investigations reveal that the natural frequencies and first and higher vibration mode shapes of the multilayered structures can be considerably affected by increasing the environmental temperature and the severity of the interfacial imperfections. Since the through-thickness stress distribution in 2, 5, and 10 layered composites appears to be strongly correlated to the layups, such modal stress analysis could be exploited to locate the fatigue hotspots operated in dynamic structures and to guide the structural design of aircraft and spacecraft composite laminates subjected to residual vibrations