The formyl peptide receptor agonist FPRa14 induces differentiation of Neuro2a mouse neuroblastoma cells into multiple distinct morphologies which can be specifically inhibited with FPR antagonists and FPR knockdown using siRNA.

The N-formyl peptide receptors (FPRs) have been identified within neuronal tissues and may serve as yet undetermined functions within the nervous system. The FPRs have been implicated in the progression and invasiveness of neuroblastoma and other cancers. In this study the effects of the synthetic FPR agonist FPRa14, FPR antagonists and FPR knockdown using siRNA on mouse neuroblastoma neuro2a (N2a) cell differentiation plus toxicity were examined. The FPRa14 (1-10µM) was found to induce a significant dose-dependent differentiation response in mouse neuroblastoma N2a cells. Interestingly, three distinct differentiated morphologies were observed, with two non-archetypal forms observed at the higher FPRa14 concentrations. These three forms were also observed in the human neuroblastoma cell-lines IMR-32 and SH-SY5Y when exposed to 100µM FPRa14. In N2a cells combined knockdown of FPR1 and FPR2 using siRNA inhibited the differentiation response to FPRa14, suggesting involvement of both receptor subtypes. Pre-incubating N2a cultures with the FPR1 antagonists Boc-MLF and cyclosporin H significantly reduced FPRa14-induced differentiation to near baseline levels. Meanwhile, the FPR2 antagonist WRW4 had no significant effect on FPRa14-induced N2a differentiation. These results suggest that the N2a differentiation response observed has an FPR1-dependent component. Toxicity of FPRa14 was only observed at higher concentrations. All three antagonists used blocked FPRa14-induced toxicity, whilst only siRNA knockdown of FPR2 reduced toxicity. This suggests that the toxicity and differentiation involve different mechanisms. The demonstration of neuronal differentiation mediated via FPRs in this study represents a significant finding and suggests a role for FPRs in the CNS. This finding could potentially lead to novel therapies for a range of neurological conditions including neuroblastoma, Alzheimer's disease, Parkinson's disease and neuropathic pain. Furthermore, this could represent a potential avenue for neuronal regeneration therapies.

Source-tract interaction with prescribed vocal fold motion.

An equation describing the time-evolution of glottal volume velocity with specified vocal fold motion is derived when the sub- and supra-glottal vocal tracts are present. The derivation of this Fant equation employs a property explicated in Howe and McGowan [(2011) J. Fluid Mech. 672, 428-450] that the Fant equation is the adjoint to the equation characterizing the matching conditions of sub- and supra-glottal Green's functions segments with the glottal segment. The present aeroacoustic development shows that measurable quantities such as input impedances at the glottis, provide the coefficients for the Fant equation when source-tract interaction is included in the development. Explicit expressions for the Green's function are not required. With the poles and zeros of the input impedance functions specified, the Fant equation can be solved. After the general derivation of the Fant equation, the specific cases where plane wave acoustic propagation is described either by a Sturm-Liouville problem or concatenated cylindrical tubes is considered. Simulations show the expected skewing of the glottal volume velocity pulses depending on whether the fundamental frequency is below or above a sub- or supra-glottal formant. More complex glottal wave forms result when both the first supra-glottal fundamental frequencies are high and close to the first sub-glottal formant.

Comments on single-mass models of vocal fold vibration.

Proposed mechanisms for single-mass oscillation in the vocal tract are examined critically. There are two areas that distinguish single-mass models: in the sophistication of the air flow modeling near the oscillator and whether or not oscillation depends on acoustic feedback. Two recent models that do not depend on acoustic feedback are examined in detail. One model that depends on changing flow separation points is extended with approximate calculations.

Influence of the ventricular folds on a voice source with specified vocal fold motion.

The unsteady drag on the vocal folds is the major source of sound during voiced speech. The drag force is caused by vortex shedding from the vocal folds. The influence of the ventricular folds (i.e., the "false" vocal folds that protrude into the vocal tract a short distance downstream of the glottis) on the drag and the voice source are examined in this paper by means of a theoretical model involving vortex sheets in a two-dimensional geometry. The effect of the ventricular folds on the output acoustic pressure is found to be small when the movement of the vocal folds is prescribed. It is argued that the effect remains small when fluid-structure interactions account for vocal fold movement. These conclusions can be justified mathematically when the characteristic time scale for change in the velocity of the glottal jet is large compared to the time it takes for a vortex disturbance to be convicted through the vocal fold and ventricular fold region.