Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses

<p>Abstract</p> <p>Background</p> <p>Hereditary Hemochromatosis (HH) is a genetic disease associated with iron overload, in which individuals homozygous for the mutant C282Y <it>HFE </it>associated allele are at risk for the development of a range of disorders particularly liver disease. Conformational diseases are a class of disorders associated with the expression of misfolded protein. HFE C282Y is a mutant protein that does not fold correctly and consequently is retained in the Endoplasmic Reticulum (ER). In this context, we sought to identify ER stress signals associated with mutant C282Y HFE protein expression, which may have a role in the molecular pathogenesis of HH.</p> <p>Results</p> <p>Vector constructs of Wild type HFE and Mutant C282Y HFE were made and transfected into HEK293 cell lines. We have shown that expression of C282Y HFE protein triggers both an unfolded protein response (UPR), as revealed by the increased GRP78, ATF6 and CHOP expression, and an ER overload response (EOR), as indicated by NF-κB activation. Furthermore, C282Y HFE protein induced apoptotic responses associated with activation of ER stress. Inhibition studies demonstrated that tauroursodeoxycholic acid, an endogenous bile acid, downregulates these events. Finally, we found that the co-existence of both C282Y HFE and Z alpha 1-antitrypsin protein (the protein associated with the liver disease of Z alpha 1-antitrypsin deficiency) expression on ER stress responses acted as potential disease modifiers with respect to each other.</p> <p>Conclusion</p> <p>Our novel observations suggest that both the ER overload response (EOR) and the unfolded protein response (UPR) are activated by mutant C282Y HFE protein.</p

Auswirkungen der Protrusion der Zunge auf elektroglottographische Schwingungsparameter

Elektroglottographische Schwingungsparameter von 33 gesunden Stimmen (23 weibliche, 10 männliche) wurden zu zwei Zeitpunkten paarweise miteinander verglichen. Die elektroglottographische Untersuchung wurde einmal mit Protrusion der Zunge durchgeführt, das andere Mal ohne Manipulation der Zunge.Ziel der Studie war zu prüfen, ob die Protrusion der Zunge, wie sie bei stroboskopischen bzw. hochgeschwindigkeitsglottographischen Untersuchungen notwendig ist, die Schwingung der Stimmlippen beeinflusst.Im paarweisen, studentischen T-Test zeigten sich keine signifikanten Unterschiede (p<.05) zwischen elektroglottographischen Schwingungsparametern, die mit bzw. ohne Protrusion der Zunge erhoben wurden.Die Ergebnisse unterstützen indirekt die Beurteilung der Stimmlippenschwingung in ihrer Mikrostruktur mit Hilfe der Hochgeschwindigkeitsglottographie, da die Protrusion der Zunge keine signifikante Effekte auf die Stimmlippenschwingung zeigt

Long-term results following velopharyngoplasty with a cranially based pharyngeal flap

Between 1980 and 1989, 82 velopharyngoplasties have been carried out in the Department of Oral and Maxillofacial Surgery at the Medical University of Hannover. Speech results of 51 of these patients, including 39 patients with cleft lip and palate, could be followed up in the context of a clinical follow-up examination. Besides evaluation of speech results by two senior speech pathologists and two untrained listeners, a frequency analysis of the speech results with a sonograph was obtained. Nasal air loss was documented with a fogged-mirror test and computer aerometry. Whereas in 37 of 51 patients a normal or almost normal colloquial speech could be demonstrated, 30 of 39 patients with cleft lip and palate showed a normal or almost normal realization of the test sentences. Thirty of the 37 patients (81.08 percent) with normal or almost normal colloquial speech showed extensive mobility of the lateral pharyngeal wall. Symmetry of the velopharyngeal flaps seemed to have no influence on the speech result. With a fogged-mirror test, an average reduction of mirror fogging from 2.0 rings preoperatively to 0.9 rings postoperatively could be shown. In 31 patients, there was no longer any air loss postoperatively. Besides one rupture of a flap, two flaps had to be diminished in their lateral dimensions because of excessive size. We regard the cranially pedicled pharyngeal flap as an important operative procedure for improving speech results, especially in cleft lip and palate patients

Network Orchestration: Vodafone’s Journey to Globalization

Contains fulltext : 128786.pdf (author's version ) (Open Access) Contains fulltext : 128786_p.pdf (publisher's version ) (Closed access