We have shown that nanoparticles (NPs) conjugated to trans-activating transcriptor (TAT) peptide bypass the efflux action of P-glycoprotein and increases the transport of the encapsulated ritonavir, a protease inhibitor (PI), across the blood-brain-barrier (BBB) to the central nervous system (CNS). A steady increase in the drug parenchyma/capillary ratio with time without disrupting the BBB integrity suggests that TAT-conjugated NPs are first immobilized in the brain vasculature prior to their transport into parenchyma. Localization of NPs in the brain parenchyma was further confirmed with histological analysis of the brain sections. The brain drug level with conjugated NPs was 800-fold higher than that with drug in solution at two weeks. Drug clearance was seen within four weeks. In conclusion, TAT-conjugated NPs enhance the CNS bioavailability of the encapsulated PI and maintained therapeutic drug level in the brain for a sustained period that could be effective in reducing the viral load in the CNS which acts as a reservoir for replicating HIV-1 virus.

A reverse microemulsion synthesis was used to prepare amine functionalized silica nanoparticles of three distinct sizes (i.e., 50, 100, and 200 nm) with identical amine concentrations. The resulting hybrid nanoparticles, consisting of N-(6 aminohexyl) aminopropyltrimethoxysilane and tetraethoxysilane, were highly monodisperse in size. N-diazeniumdiolate nitric oxide (NO) donors were subsequently formed on secondary amines while controlling reaction conditions to keep the total amount of nitric oxide (NO) released constant for each particle size. The bactericidal efficacy of the NO releasing nanoparticles against Pseudomonas aeruginosa increased with decreasing particle size. Additionally, smaller diameter nanoparticles were found to associate with the bacteria at a faster rate and to a greater extent than larger particles. Neither control (non-NO-releasing) nor NO releasing particles exhibited toxicity towards L929 mouse fibroblasts at concentrations above their respective minimum bactericidal concentrations. This study represents the first investigation of the bactericidal efficacy of NO-releasing silica nanoparticles as a function of particle size.

Feng et al. describe persistent neuronal microtubule minus end growth that depends on the CAMSAP protein Patronin and is needed for dendritic minus-end-out polarity.

Summary Axon regeneration allows neurons to repair circuits after trauma, but most of the molecular players remain to be identified. As microtubule rearrangements have been observed in injured neurons, we tested whether microtubule severing proteins might play a role in axon regeneration. We found that axon regeneration is extremely sensitive to levels of the microtubule severing protein spastin. While microtubule behavior in uninjured neurons was not perturbed in animals heterozygous for a spastin null allele, axon regeneration was severely disrupted in this background. Two types of axon regeneration, regeneration of an axon from a dendrite after proximal axotomy and regeneration of an axon from the stump after distal axotomy, were defective in Drosophila with one mutant copy of the spastin gene. Other types of axon and dendrite outgrowth, including regrowth of dendrites after pruning, were normal in heterozygotes. We conclude that regenerative axon growth is uniquely sensitive to spastin gene dosage.

A Drosophila model system is used to show that the hereditary spastic paraplegia proteins spastin and atlastin help axons but not dendrites regenerate. The endoplasmic reticulum concentrates at tips of regenerating axons but not dendrites, and this depends on spastin and atlastin.