Formation of Amyloid-Like Fibrils by Y-Box Binding Protein 1 (YB-1) Is Mediated by Its Cold Shock Domain and Modulated by Disordered Terminal Domains

YB-1, a multifunctional DNA- and RNA-binding nucleocytoplasmic protein, is involved in the majority of DNA- and mRNA-dependent events in the cell. It consists of three structurally different domains: its central cold shock domain has the structure of a β-barrel, while the flanking domains are predicted to be intrinsically disordered. Recently, we showed that YB-1 is capable of forming elongated fibrils under high ionic strength conditions. Here we report that it is the cold shock domain that is responsible for formation of YB-1 fibrils, while the terminal domains differentially modulate this process depending on salt conditions. We demonstrate that YB-1 fibrils have amyloid-like features, including affinity for specific dyes and a typical X-ray diffraction pattern, and that in contrast to most of amyloids, they disassemble under nearly physiological conditions

Inhaled nicotine replacement therapy

There are a large number of smokers who want to quit smoking but have failed in their attempts to do so, with many having been unsuccessful at quitting multiple times over their lifetime. The existing marketed nicotine replacement therapies (NRT) have only marginal effectiveness and none provide a comparable physiological response to that derived from cigarette smoking; that is, rapid absorption of nicotine from the lung leading to peak levels of nicotine in the bloodstream to target the receptors in the brain. Instead, existing NRTs produce a slower and delayed rise in nicotine blood levels which is less effective at reducing the craving sensations. Published data for electronic cigarettes show that they typically deliver nicotine with a profile closer to that for nicotine patches, with a slow rise that can take 30–60 min, or longer, to reach the same peak nicotine concentration that is produced in less than 3 min from a single cigarette. A number of attempts have been made to develop an inhaled product which would deliver the nicotine through the lung and mimic the physiological response from smoking, but many of them produced intolerable aversive reactions or delivered an ineffective dose. This paper discusses examples of the potential for the recent inhaled nicotine products in development to be effective as NRTs, but is not meant to be a comprehensive review

Development of Liposomal Ciprofloxacin to Treat Lung Infections

Except for management of Pseudomonas aeruginosa (PA) in cystic fibrosis, there are no approved inhaled antibiotic treatments for any other diseases or for infections from other pathogenic microorganisms such as tuberculosis, non-tuberculous mycobacteria, fungal infections or potential inhaled biowarfare agents including Francisella tularensis, Yersinia pestis and Coxiella burnetii (which cause pneumonic tularemia, plague and Q fever, respectively). Delivery of an antibiotic formulation via the inhalation route has the potential to provide high concentrations at the site of infection with reduced systemic exposure to limit side effects. A liposomal formulation may improve tolerability, increase compliance by reducing the dosing frequency, and enhance penetration of biofilms and treatment of intracellular infections. Two liposomal ciprofloxacin formulations (Lipoquin® and Pulmaquin®) that are in development by Aradigm Corporation are described here

Comparison of Three Jet Nebulizer Aerosol Delivery Systems Used to Administer Recombinant Human DNase I to Patients With Cystic Fibrosis

Study objective: To compare the degree of improvement in pulmonary function achieved with recombinant human DNase I (rhDNase) administered by three different aerosol delivery systems: DeVilbiss Pulmo-Aide compressor with the Marquest Acorn II nebulizer, the Hudson T Up-draft nebulizer, and the Pari LC Jet Plus nebulizer with the Pari Inhalier Boy compressor. These produce similar aerosols in vitro in terms of size distribution and activity of delivered rhDNase. Study design: Multicenter, randomized, open-label, parallel-group comparison of changes from baseline in pulmonary function variables in each test group. Patients were treated with rhDNase (2.5 mg bid) for 15 days, administered with three different aerosol delivery systems. Setting: Outpatient clinics at 26 sites in the United States. Patients: 397 patients >5 years of age with cystic fibrosis and baseline forced vital capacity (FVC) values between 40 and 70% of predicted values. Results: All three nebulizers gave comparable improvements in pulmonary function. FEV1 increased by an average of 13.2 to 14.1%, FVC by 10.9 to 11.8%, and forced midexpiratory flow (FEF25-75) by 16.5 to 17.1%. No unusual or unexpected adverse events were reported other than those that would be expected in patients with cystic fibrosis. Conclusions: Recombinant human DNase I produced a similar magnitude of improvement in the pulmonary function of patients with cystic fibrosis when the drug was administered using three different types of nebulizer systems with similar in vitro delivery and safety characteristics