Structural investigation of human cystine/glutamate antiporter system xc - (Sxc -) using homology modeling and molecular dynamics.

The cystine/glutamate antiporter system xc - (Sxc -) belongs to the SLC7 family of plasma membrane transporters. It exports intracellular glutamate along the latter's concentration gradient as a driving force for cellular uptake of cystine. Once imported, cystine is mainly used for the production of glutathione, a tripeptide thiol crucial in maintenance of redox homeostasis and protection of cells against oxidative stress. Overexpression of Sxc - has been found in several cancer cells, where it is thought to counteract the increased oxidative stress. In addition, Sxc - is important in the central nervous system, playing a complex role in regulating glutamatergic neurotransmission and glutamate toxicity. Accordingly, this transporter is considered a potential target for the treatment of cancer as well as neurodegenerative diseases. Till now, no specific inhibitors are available. We herein present four conformations of Sxc - along its transport pathway, obtained using multi-template homology modeling and refined by means of Molecular Dynamics. Comparison with a very recently released cryo-EM structure revealed an excellent agreement with our inward-open conformation. Intriguingly, our models contain a structured N-terminal domain that is unresolved in the experimental structures and is thought to play a gating role in the transport mechanism of other SLC7 family members. In contrast to the inward-open model, there is no direct experimental counterpart for the other three conformations we obtained, although they are in fair agreement with the other stages of the transport mechanism seen in other SLC7 transporters. Therefore, our models open the prospect for targeting alternative Sxc - conformations in structure-based drug design efforts.

[Multinodular diving goiters: 100 cases in Morocco]. / Les goitres multihétéronodulaires plongeants: à propos de 100 cas marocains.

OBJECTIVE: To assess 100 cases of multinodular diving goiters, the authors review the literature to compare the epidemiology, clinical pictures, additional required work-up, treatments, complications, and sequelae. METHOD: Records of 100 cases of multinodular diving goiters were collected in the surgical department of the Military Hospital of Marrakesh in Morocco from 1991 through 2004. They accounted for 6% of all goiters. The sex ratio was clearly female, and the mean age 50 years. The clinical symptoms of diving goiters involves mainly signs of compression, with dyspnea seen in 50% of cases. Thyroid dysfunction was found in only 25% of our patients. A diagnosis of diving goiter must be suspected when there are signs of mediastinal compression and a palpable cervical goiter, as seen in all our patients. The diagnosis can often be confirmed with thoracic radiography and thyroid scintigraphy. Treatment is mainly surgical and depends on disease course. Cervicotomy was performed in 97% of our patients and was sufficient to extract even most voluminous goiters and those deepest in the mediastinum. RESULTS: Immediate operative results were satisfactory. More long-term results were also generally satisfactory, except for 4 cases of recurrent paralysis and 5 cases of hypoparathyroidism. Both have been reported by several authors. CONCLUSION: Surgical management of multinodular diving goiters is necessary. In general, cervicotomy is sufficient, and the results generally satisfactory, except some complications and neoplasms.