29 research outputs found

    Rapid transport of muco-inert nanoparticles in cystic fibrosis sputum treated with N -acetyl cysteine

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    Sputum poses a critical diffusional barrier that strongly limits the efficacy of drug and gene carriers in the airways of individuals with cystic fibrosis (CF). Previous attempts to enhance particle penetration of CF sputum have focused on either reducing its barrier properties via mucolytics, or decreasing particle adhesion to sputum constituents by coating the particle surface with non-mucoadhesive polymers, including polyethylene glycol (PEG). Neither approach has enabled particles to penetrate expectorated sputum at rates previously observed for non-mucoadhesive nanoparticles in human cervicovaginal mucus. Here, we sought to investigate whether a common mucolytic, N-acetyl cysteine (NAC), in combination with dense PEG coatings on particles, can synergistically enhance particle penetration across fresh undiluted CF sputum

    Common Gene Therapy Viral Vectors Do Not Efficiently Penetrate Sputum from Cystic Fibrosis Patients

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    Norwalk virus and human papilloma virus, two viruses that infect humans at mucosal surfaces, have been found capable of rapidly penetrating human mucus secretions. Viral vectors for gene therapy of Cystic Fibrosis (CF) must similarly penetrate purulent lung airway mucus (sputum) to deliver DNA to airway epithelial cells. However, surprisingly little is known about the rates at which gene delivery vehicles penetrate sputum, including viral vectors used in clinical trials for CF gene therapy. We find that sputum spontaneously expectorated by CF patients efficiently traps two viral vectors commonly used in CF gene therapy trials, adenovirus (d∼80 nm) and adeno-associated virus (AAV serotype 5; d∼20 nm), leading to average effective diffusivities that are ∼3,000-fold and 12,000-fold slower than their theoretical speeds in water, respectively. Both viral vectors are slowed by adhesion, as engineered muco-inert nanoparticles with diameters as large as 200 nm penetrate the same sputum samples at rates only ∼40-fold reduced compared to in pure water. A limited fraction of AAV exhibit sufficiently fast mobility to penetrate physiologically thick sputum layers, likely because of the lower viscous drag and smaller surface area for adhesion to sputum constituents. Nevertheless, poor penetration of CF sputum is likely a major contributor to the ineffectiveness of viral vector based gene therapy in the lungs of CF patients observed to date

    Aquatic frontier : oysters and aquaculture in the progressive era

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    Although few remember their former significance, oysters were one of the largest U.S. fisheries at their peak in the late nineteenth century. As the fishery industrialized on-and offshore, oyster farms and canning factories spread along the Eastern Seaboard, with overharvesting becoming increasingly common. During the Progressive Era, state governments founded new agencies to cope with this problem and control this expanding economy. Regulators faced a choice: keep elaborate conservation systems based on common property rights or develop new ones with private, hatchery-stocked aquaculture farms. The tradition-preserving solution won, laying the groundwork for modern oyster management. The Aquatic Frontier explores the forms this debate took between 1870 and 1920 in law enforcement, legislative advising, natural science, and oyster cartography. Samuel P. Hanes argues that the effort to centralize and privatize the industry failed due to a lack of understanding of the complex social-ecological systems in place—a common dilemma for environmental managers in this time period and for fisheries management confronting dangers from dwindling populations today.https://digitalcommons.library.umaine.edu/fac_monographs/1309/thumbnail.jp

    Theoretical model of particle penetration across a sputum layer.

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    <p>(A) <i>S</i>chematic of the model, where particles are deposited in airway lumen on top of the CF sputum layer and must penetrate a 10 µm sputum layer to reach the epithelial cells. The pericilliary layer is much smaller in CF patients due to the collapsed cilia from the accumulated sputum <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019919#pone.0019919-Boucher2" target="_blank">[60]</a>. (B) Estimated fraction of viral and synthetic particles that are capable of penetrating a 10 µm thick layer of CF sputum over time using Fick's second law. *Statistically significant difference when compared with AAV5, AdV or PS (p<0.05).</p

    Sample 20 s trajectories.

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    <p>Representative trajectories of (A) Adenovirus (Adv), (B) AAV5, (C) muco-adhesive PS control nanoparticles and (D) muco-inert control PS-PEG nanoparticles. All trajectories have MSD values within one standard deviation of the ensemble average.</p

    Transport mode distributions of AdV, AAV5, PS and PS-PEG particles.

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    <p>Particles were classified into either (i) immobile or hindered and (ii) diffusive <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019919#pone.0019919-Lai4" target="_blank">[12]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019919#pone.0019919-Lai5" target="_blank">[15]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019919#pone.0019919-Suk2" target="_blank">[17]</a>. *Statistically significant difference when compared with AAV5, AdV or PS within the same transport mode classification (p<0.05).</p
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