The stasis of mucus secretions in the lungs of cystic fibrosis (CF) patients leads to recurrent infections and pulmonary exacerbations, resulting in decreased survival. Prior studies have assessed the biochemical and biophysical features of airway mucus in individuals with CF. However, these measurements are unable to probe mucus structure on microscopic length scales relevant to key players in the progression of CF-related lung disease, namely, viruses, bacteria, and neutrophils. In this study, we quantitatively determined sputum microstructure based on the diffusion of muco-inert nanoparticle probes in CF sputum and found that a reduction in sputum mesh pore size is characteristic of CF patients with reduced lung function, as indicated by measured FEV. We also discovered that the effect of ex vivo treatment of CF sputum with rhDNase I (Pulmozyme) on microstructure is dependent upon the time interval between the most recent inhaled rhDNase I treatment and the sample collection. Microstructure of mucus may serve as a marker for the extent of CF lung disease and as a parameter for assessing the effectiveness of mucus-altering agents.
1. Neurons in nucleus laminaris (NL) of birds are the first to receive binaural information and are presumed to play a role in encoding interaural time differences (ITDs). We studied extracellular single-unit responses of NL neurons in slices of the auditory brain stem of the chick. The afferents to NL were activated by electrical stimulation of nucleus magnocellularis (NM) or the auditory nerve. Changes in responses were measured as the delay between trains of bilateral stimuli (the simulated interaural time difference or S-ITD, n = 26) was varied and as the interstimulus interval and stimulus amplitude were varied (n = 61). 2. The probability of an action potential and the action-potential latency varied as a function of interstimulus interval. Most NL neurons showed a greater response probability and a shorter response latency to an interstimulus interval between 2.5 and 3.5 ms. The interstimulus interval that produced the minimum response latency was slightly longer than the interval that produced the maximum response probability. In contrast, NM neurons (n = 4) showed no preferred rate, instead, the probability of firing increased as the interstimulus interval increased. 3. Responses to bilateral stimulation showed that NL neurons can act as coincidence detectors. NL neurons responded most reliably when activated simultaneously by their two inputs and, at favorable S-ITDs, two subthreshold inputs combined to produce an action potential. 4. NL neurons also exhibited inhibition during bilateral stimulation. At unfavorable S-ITDs a subthreshold input combined with a suprathreshold input produced fewer action potentials than evoked by the suprathreshold input alone. 5. The latency of the bilateral response varied as a function of S-ITD. At S-ITDs near coincidence the latency of the bilateral response was shorter than the latency of either of the unilateral responses. Away from coincidence, the latency of the bilateral response was largely determined by the latency of the stronger unilateral response. When the unilateral responses were of similar strength, the earlier stimulus determined the latency of the bilateral response. 6. The range of S-ITDs producing a maximal response varied as a function of stimulus strength but was never less than approximately 300 microseconds. This is greater than the maximum possible ITD of sound calculated for the chick's head size. From these data we hypothesize that, in the chick, single units cannot uniquely encode ITDs, but rather ITDs may be coded by the proportion of maximally firing cells along an isofrequency band in NL.
Cerebral ischemia is a major cause of death in both neonates and adults, and currently has no cure. Nanotechnology represents one promising area of therapeutic development for cerebral ischemia due to the ability of nanoparticles to overcome biological barriers in the brain. ex vivo injury models have emerged as a highthroughput alternative that can recapitulate disease processes and enable nanoscale probing of the brain microenvironment. In this study, we used oxygen-glucose deprivation (OGD) to model ischemic injury and studied nanoparticle interaction with microglia, resident immune cells in the brain that are of increasing interest for therapeutic delivery. By measuring cell death and glutathione production, we evaluated the effect of OGD exposure time and treatment with azithromycin (AZ) on slice health. We found a robust injury response with 0.5 hr of OGD exposure and effective treatment after immediate application of AZ. We observed an OGD-induced shift in microglial morphology toward increased heterogeneity and circularity, and a decrease in microglial number, which was reversed after treatment. OGD enhanced diffusion of polystyrene-poly(ethylene glycol) (PS-PEG) nanoparticles, improving transport and ability to reach target cells. While microglial uptake of dendrimers or quantum dots (QDs) was not enhanced after injury, internalization of PS-PEG was significantly increased. For PS-PEG, AZ treatment restored microglial uptake to normal control levels. Our results suggest that different nanoparticle platforms should be carefully screened before application and upon doing so; disease-mediated changes in the brain microenvironment can be leveraged by nanoscale drug delivery devices for enhanced cell interaction.
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