Early cortical processing of pitch height and the role of adaptation and musicality.

Pitch is an important perceptual feature; however, it is poorly understood how its cortical correlates are shaped by absolute vs relative fundamental frequency (f0), and by neural adaptation. In this study, we assessed transient and sustained auditory evoked fields (AEFs) at the onset, progression, and offset of short pitch height sequences, taking into account the listener's musicality. We show that neuromagnetic activity reflects absolute f0 at pitch onset and offset, and relative f0 at transitions within pitch sequences; further, sequences with fixed f0 lead to larger response suppression than sequences with variable f0 contour, and to enhanced offset activity. Musical listeners exhibit stronger f0-related AEFs and larger differences between their responses to fixed vs variable sequences, both within sequences and at pitch offset. The results resemble prominent psychoacoustic phenomena in the perception of pitch contours; moreover, they suggest a strong influence of adaptive mechanisms on cortical pitch processing which, in turn, might be modulated by a listener's musical expertise.

Polyethylenimines for RNAi-mediated gene targeting in vivo and siRNA delivery to the lung.

RNA interference (RNAi) is a promising strategy to inhibit the expression of pathologically relevant genes, which show aberrant (over-)expression, e.g. in tumors or other pathologies. The induction of RNAi relies on small interfering RNAs (siRNAs), which trigger the specific mRNA degradation. Their instability and poor delivery into target tissues including the lung, however, so far severely limits the therapeutic use of siRNAs and requires the development of nanoscale delivery systems. Polyethylenimines (PEIs) are synthetic polymers, which are able to form non-covalent complexes with siRNAs. These nanoscale complexes ('nanoplexes') allow the protection of siRNAs from nucleolytic degradation, their efficient cellular uptake through endocytosis and intracellular release through the 'proton sponge effect'. Chemical modifications of PEIs as well as the coupling of cell/tissue-specific ligands are promising approaches to increase the biocompatibility, specificity and efficacy of PEI-based nanoparticles. This review article gives a comprehensive overview of pre-clinical in vivo studies on the PEI-mediated delivery of therapeutic siRNAs in various animal models. It discusses the chemical properties of PEIs and PEI modifications, and their influences on siRNA knockdown efficacy, on adverse effects of the polymer or the nanoplex and on siRNA biodistribution in vivo. Beyond systemic application, PEI-based complexation allows the local siRNA application to the lung. Biodistribution studies demonstrate cellular uptake of PEI-complexed, but not of naked siRNAs in the lung with little systemic availability of the siRNAs, indicating the usefulness of this approach for the targeting of genes, which are pathologically relevant in lung tumors or lung metastases. Taken together, (i) PEI and PEI derivatives may represent an efficient delivery platform for siRNAs, (ii) siRNA-mediated induction of RNAi is a promising approach for the knockdown of pathologically relevant genes, and (iii) when sufficiently addressing biocompatibility issues, the locoregional delivery of PEI/siRNA complexes may become an attractive therapeutic strategy for the treatment of lung diseases with little systemic side effects.