Effect of boundaries on displacements and motion in two-dimensional fluid or elastic films and membranes.

Thin fluid or elastic films and membranes are found in nature and technology, for instance, as confinements of living cells or in loudspeakers. When applying a net force, the resulting flows in an unbounded two-dimensional incompressible low-Reynolds-number fluid or displacements in a two-dimensional linearly elastic solid seem to diverge logarithmically with the distance from the force center, which has led to some debate. Recently, we have demonstrated that such divergences cancel when the total (net) force vanishes. Here, we illustrate that if a net force is present, the boundaries play a prominent role. Already a single no-slip boundary regulates the flow and displacement fields and leads to their decay to leading order inversely in distance from a force center and the boundary. In other words, it is the boundary that stabilizes the system in this situation, unlike the three-dimensional case, where an unbounded medium by itself is able to absorb a net force. We quantify the mobility and displaceability of an inclusion as a function of the distance from the boundary, as well as interactions between different inclusions. In the case of free-slip boundary conditions, a kinked boundary is necessary to achieve stabilization.

Fluvastatin protects cochleae from damage by high-level noise.

Exposure to noise and ototoxic drugs are responsible for much of the debilitating hearing loss experienced by about 350 million people worldwide. Beyond hearing aids and cochlear implants, there have been no other FDA approved drug interventions established in the clinic that would either protect or reverse the effects of hearing loss. Using Auditory Brainstem Responses (ABR) in a guinea pig model, we demonstrate that fluvastatin, an inhibitor of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, protects against loss of cochlear function initiated by high intensity noise. A novel synchrotron radiation based X-ray tomographic method that imaged soft tissues at micrometer resolution in unsectioned cochleae, allowed an efficient, qualitative evaluation of the three-dimensional internal structure of the intact organ. For quantitative measures, plastic embedded cochleae were sectioned followed by hair cell counting. Protection in noise-exposed cochleae is associated with retention of inner and outer hair cells. This study demonstrates the potential of HMG-CoA reductase inhibitors, already vetted in human medicine for other purposes, to protect against noise induced hearing loss.

Novel High Content Screen Detects Compounds That Promote Neurite Regeneration from Cochlear Spiral Ganglion Neurons.

The bipolar spiral ganglion neurons (SGN) carry sound information from cochlear hair cells to the brain. After noise, antibiotic or toxic insult to the cochlea, damage to SGN and/or hair cells causes hearing impairment. Damage ranges from fiber and synapse degeneration to dysfunction and loss of cells. New interventions to regenerate peripheral nerve fibers could help reestablish transfer of auditory information from surviving or regenerated hair cells or improve results from cochlear implants, but the biochemical mechanisms to target are largely unknown. Presently, no drugs exist that are FDA approved to stimulate the regeneration of SGN nerve fibers. We designed an original phenotypic assay to screen 440 compounds of the NIH Clinical Collection directly on dissociated mouse spiral ganglia. The assay detected one compound, cerivastatin, that increased the length of regenerating neurites. The effect, mimicked by other statins at different optimal concentrations, was blocked by geranylgeraniol. These results demonstrate the utility of screening small compound libraries on mixed cultures of dissociated primary ganglia. The success of this screen narrows down a moderately sized library to a single compound which can be elevated to in-depth in vivo studies, and highlights a potential new molecular pathway for targeting of hearing loss drugs.