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Conti B.J.,Oregon Health And Science University | Devaraneni P.K.,Oregon Health And Science University | Yang Z.,Oregon Health And Science University | David L.L.,Oregon Health And Science University | And 2 more authors.
Molecular Cell | Year: 2015

The ER Sec61 translocon is a large macromolecular machine responsible for partitioning secretory and membrane polypeptides into the lumen, cytosol, and lipid bilayer. Because the Sec61 protein-conducting channel has been isolated in multiple membrane-derived complexes, we determined how the nascent polypeptide modulates translocon component associations during defined cotranslational translocation events. The model substrate preprolactin (pPL) was isolated principally with Sec61αβγ upon membrane targeting, whereas higher-order complexes containing OST, TRAP, and TRAM were stabilized following substrate translocation. BlockingpPL translocation by passenger domain folding favored stabilization of an alternate complex that contained Sec61, Sec62, and Sec63. Moreover, Sec62/63 stabilization within the translocon occurred for native endogenous substrates, such as the prion protein, and correlated with a delay in translocationinitiation. These data show that cotranslational translocon contacts are ultimately controlled by the engaged nascent chain and the resultant substrate-driven translocation events. © 2015 Elsevier Inc.

Solomon G.M.,University of Alabama at Birmingham | Konstan M.W.,Case Western Reserve University | Wilschanski M.,Hadassah University Hospitals | Billings J.,University of Minnesota | And 12 more authors.
Chest | Year: 2010

Background: The transepithelial nasal potential difference (NPD) is used to assess cystic fibrosis transmembrane conductance regulator (CFTR) activity. Unreliability, excessive artifacts, and lack of standardization of current testing systems can compromise its use as a diagnostic test and outcome measure for clinical trials. Methods: To determine whether a nonperfusing (agar gel) nasal catheter for NPD measurement is more reliable and less susceptible to artifacts than a continuously perfusing nasal catheter, we performed a multicenter, randomized, crossover trial comparing a standardized NPD protocol using an agar nasal catheter with the same protocol using a continuously perfusing catheter. The data capture technique was identical in both protocols. A total of 26 normal adult subjects underwent NPD testing at six different centers. Results: Artifact frequency was reduced by 75% (P < .001), and duration was less pronounced using the agar catheter. The measurement of sodium conductance was similar between the two catheter methods, but the agar catheter demonstrated significantly greater CFTR-dependent hyperpolarization, because Δ zero Cl- + isoproterenol measurements were significantly more hyperpolarized with the agar catheter (-24.2 ± 12.9 mV with agar vs 18.2 ± 9.1 mV with perfusion, P < .05). Conclusions: The agar nasal catheter approach demonstrates superior reliability compared with the perfusion nasal catheter method for measurement of NPD. This nonperfusion catheter method should be considered for adoption as a standardized protocol to monitor CFTR activity in clinical trials. © 2010 American College of Chest Physicians.

Cystic Fibrosis Foundation Therapeutics Inc. and Altus Pharmaceuticals | Date: 2007-09-12

Proteins, protein formulations and protein combinations, namely, enzymes and enzyme combinations, for use in medical, veterinary and clinical research. Proteins, protein formulations and protein combinations, namely, enzymes and enzyme combinations for medical treatment, veterinary treatment, clinical treatment and medical diagnostic use; and proteins, protein formulations and protein combinations, namely, enzymes and enzyme combinations for medical and therapeutic use in the treatment of endocrine diseases, nutritional deficiencies, metabolic diseases and disorders, gastrointestinal diseases and disorders, diseases and disorders of the circulatory system, diseases and disorders of the digestive system, and congenital anomalies, in humans, livestock, domestic pets, and exotic animals.

Cystic Fibrosis Foundation Therapeutics Inc. | Date: 2010-04-05

The present invention relates to compositions for the treatment of conditions, including pancreatic insufficiency. The compositions of the present invention comprise lipase, protease and amylase in a particular ratio that provides beneficial results in patients, such as those afflicted with pancreatic insufficiency. This invention also relates to methods using such compositions for the treatment of pancreatic insufficiency.

Wetmore D.R.,Cystic Fibrosis Foundation Therapeutics Inc. | Joseloff E.,Cystic Fibrosis Foundation Therapeutics Inc. | Pilewski J.,University of Pittsburgh | Lee D.P.,Metabolon | And 5 more authors.
Journal of Biological Chemistry | Year: 2010

Cystic fibrosis (CF) is a life-shortening disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To gain an understanding of the epithelial dysfunction associated with CF mutations and discover biomarkers for therapeutics development, untargeted metabolomic analysis was performed on primary human airway epithelial cell cultures from three separate cohorts of CF patients and non-CF subjects. Statistical analysis revealed a set of reproducible and significant metabolic differences between the CF and non-CF cells. Aside from changes that were consistent with known CF effects, such as diminished cellular regulation against oxidative stress and osmotic stress, new observations on the cellular metabolism in the disease were generated. In the CF cells, the levels of various purine nucleotides, which may function to regulate cellular responses via purinergic signaling, were significantly decreased. Furthermore, CF cells exhibited reduced glucose metabolism in glycolysis, pentose phosphate pathway, and sorbitol pathway, which may further exacerbate oxidative stress and limit the epithelial cell response to environmental pressure. Taken together, these findings reveal novel metabolic abnormalities associated with the CF pathological process and identify a panel of potential biomarkers for therapeutic development using this model system. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

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