Role and Regulation of Sperm Gelsolin Prior to Fertilization

To acquire fertilization competence, spermatozoa should undergo several biochemical changes in the female reproductive tract, known as capacitation. The capacitated spermatozoon can interact with the egg zona pellucida resulting in the occurrence of the acrosome reaction, a process that allowed its penetration into the egg and fertilization. Sperm capacitation requires actin polymerization, whereas F-actin must disperse prior to the acrosome reaction. Here, we suggest that the actin-severing protein, gelsolin, is inactive during capacitation and is activated prior to the acrosome reaction. The release of bound gelsolin from phosphatidylinositol 4,5-bisphosphate (PIP2) by PBP10, a peptide containing the PIP2-binding domain of gelsolin, or by activation of phospholipase C, which hydrolyzes PIP2, caused rapid Ca2+-dependent F-actin depolymerization as well as enhanced acrosome reaction. Using immunoprecipitation assays, we showed that the tyrosine kinase SRC and gelsolin coimmunoprecipitate, and activating SRC by adding 8-bromo-cAMP (8-Br-cAMP) enhanced the amount of gelsolin in this precipitate. Moreover, 8-Br-cAMP enhanced tyrosine phosphorylation of gelsolin and its binding to PIP2(4,5), both of which inactivated gelsolin, allowing actin polymerization during capacitation. This actin polymerization was blocked by inhibiting the Src family kinases, suggesting that gelsolin is activated under these conditions. These results are further supported by our finding that PBP10 was unable to cause complete F-actin breakdown in the presence of 8-Br-cAMP or vanadate. In conclusion, inactivation of gelsolin during capacitation occurs by its binding to PIP2 and tyrosine phosphorylation by SRC. The release of gelsolin from PIP2 together with its dephosphorylation enables gelsolin activation, resulting in the acrosome reaction

Nationalizing efavirenz : compulsory licence, collective invention and neo--developmentalism in Brazil

International audienceThis chapter examines the legal, technological and industrial trajectory of an antiretroviral drug, efavirenz, which has been distributed free of charge to HIV/Aids patients by the Brazilian Ministry of Health since the early 2000s. In May 2007 a presidential decree suspended the exclusive rights of the patent owner, Merck, to the exploitation of the molecule in Brazil, and authorized the production of a generic version by local laboratories. This compulsory license by the Brazilian state is also intended to perpetuate the policy of universal access to treatment, with a view to combatting the Aids epidemic and boosting the country’s pharmaceutical industry. Nationalization of efavirenz has given rise to experimentation with collective production in the form of an industrial consortium and inaugurated a policy of partnerships between public and private pharmaceutical laboratories