BRCA1 polymorphism in breast cancer patients from Argentina

Breast cancer is the most common type of cancer in females in Argentina, with an incidence rate similar to that in the USA. However, the contribution of the BRCA1 or BRCA2 mutation in breast cancer incidence has not yet been investigated in Argentina. In order to evaluate which BRCA1 polymorphisms or mutations characterize female breast cancer in Argentina, the current study enrolled 206 females with breast cancer from several hospitals from the southeast of Argentina. A buccal smear sample was obtained in duplicate from each patient and the DNA samples were processed for polymorphism analysis using the single-strand conformational polymorphism technique. The polymorphisms in BRCA1 were investigated using a combination of 15 primers to analyze exons 2, 3, 5, 20 and 11 (including the 11.1 to 11.12 regions). The BRCA1 mutations were confirmed by direct sequencing. Samples were successfully examined from 154 females and, among these, 16 mutations were identified in the BRCA1 gene representing 13.9% of the samples analyzed. One patient was identified with a polymorphism in exon 2 (0.86%), four in exon 20 (3.48%), four in exon 11.3 (3.48%), one in exon 11.7 (0.86%), two in exon 11.8 (1.74%), one in exon 11.10 (0.86%) and one in exon 11.11 (0.86%). The most prevalent alteration in BRCA1 was located in exon 11 (11 out of 16 patients; 68.75%). The objective of our next study is to evaluate the prevalence of mutations in the BRCA2 gene and analyze the BRCA1 gene in the healthy relatives of BRCA1 mutation carriers.Fil: Jaure, Omar David Argentino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; ArgentinaFil: Alonso, Eliana Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; ArgentinaFil: Aguilera Braico, Diego Máximo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; ArgentinaFil: Nieto, Alvaro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; ArgentinaFil: Orozco, Manuela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; ArgentinaFil: Morelli, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; ArgentinaFil: Ferro, Alejandro M.. Hospital Italiano; ArgentinaFil: Barutta, Elena. Medifem; ArgentinaFil: Vincent, Esteban. Medifem; ArgentinaFil: Martínez, Domingo. Provincia de Buenos Aires. Ministerio de Salud. Hospital Municipal de Agudos Dr. Leónidas Lucero; ArgentinaFil: Martínez, Ignacio. Provincia de Buenos Aires. Ministerio de Salud. Hospital Municipal de Agudos Dr. Leónidas Lucero; ArgentinaFil: Maegli, Maria Ines. Provincia de Buenos Aires. Ministerio de Salud. Hospital Municipal de Agudos Dr. Leónidas Lucero; ArgentinaFil: Frizza, Alejandro. Medifem; ArgentinaFil: Kowalyzyn, Ruben. Clínica Viedma; ArgentinaFil: Salvadori, Marisa. Hospital Dr. Lucio Molas; ArgentinaFil: Ginestet, Paul. Provincia de Buenos Aires. Ministerio de Salud. Hospital y Maternidad Municipal Pigüé; ArgentinaFil: Gonzalez Donna, Maria L.. Hospital Italiano; ArgentinaFil: Balogh, Gabriela Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; Argentin

Role of charged residues in the protein membrane and protein-protein interaction during activation of the mitochondrial pathway of apoptosis

The intrinsic pathway of apoptosis is activated by signals of cellu-lar stress and regulated at the mitochondrial level. Such regulationis carried out by members of the Bcl-2 protein family (B leukemiacell lymphoma 2). Protein-protein and membrane-protein interac-tions allow the exposure of hidden domains in the initial conforma-tion of pro-apoptotic members. Bax and Bid are members of theBcl-2 family of proteins that promote apoptosis by an external mi-tochondrial membrane permeabilization mechanism (MOMP). Theinteraction between Bax, Bid and membrane, triggers a series ofevents that include; opening of a pore in the external mitochondrialmembrane, release of apoptogenic factors from the intermembranespace and activation of caspases, to finally culminate in a processof cell death program by apoptosis. Although there is a broad knowl-edge at the structural level of proteins belonging to the Bcl-2 family,the mechanisms involved in MOMP require a better understandingof the conformational changes and specific contacts required to trig-ger apoptosis.In a previous work we demonstrated the influence of non-specificelectrostatic interactions in the first approach between Bax-mem-brane and between Bax-Bid. In the present work, we computational-ly model the interaction between Bid and membrane, determine theamino acids important for the interaction between Bax and mem-brane by in silico mutagenesis, and try to elucidate the mechanisminvolved in the formation of the apoptogenic pore in the externalmitochondrial membrane. Free Electrostatic Energy of Binding,was computed using Finite Difference Poisson Boltzmann Equation(FDPB) method as implemented in software APBS (Adaptive Pois-son Boltzmann Solver). This type of calculations provided a startingpoint for further computational analysis through molecular dynam-ics simulations (MD). To this end, we used GROMACS simulationpackage.Fil: Jaure, Omar David Argentino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Viso, Juan Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Amundarain, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Zamarreño, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Costabel, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaReunión Conjunta de Sociedades de BiocienciasCiudad Autonoma de Buenos AiresArgentinaSociedad Argentina de BiofísicaSociedad Argentina de Investigación ClínicaSociedad Argentina de Investigación Bioquímica y Biología MolecularSociedad Argentina de InformaciónSociedad Argentina de Farmacología ExperimentalSociedad Argentina AndrologíaSociedad Argentina de HematologíaSociedad Argentina ProtozoologíaSociedad Argentina FisiologíaSociedad Argentina de Biologí

A Molecular Dynamic approach to the differential interaction between unsaturated free fatty acids and the nicotinic acetylcholine receptor

Free fatty acids (FFAs) are important cellular components that increase under certainpathological conditions. One of the effects of FFAs is a protection mechanism through themodulation of ion channels. The activity of the nicotinic acetylcholine receptor (nAchR) isblocked by certain FFAs and its binding site is located at the lipid-protein interface. Theobjective of this work was to determine, by means of molecular dynamics (MD), thepossible points of contact and the effect produced by five different FFAs, located inannular and non-annular sites. The study was carried out on a system composed by amodel of AChR from Torpedo marmorata (PDB ID: 2BG9) that was elaborated from PDBID: 4COF as a template because the e-values were the lowest for each subunit andbecause it represented the closed desensitized state. The evaluation of thestereochemical parameters for the refined model was improved with respect to 2BG9.The refined model was incorporated into a lipid bilayer composed with a ratio of 1:1:3 ofcholesterol, POPA and POPC respectively. We replaced three phospholipids from the lipidbilayer with three of the corresponding free fatty acids: cis-18:1ω-6, cis-18:1ω-9,cis-18:1ω-11, cis-18:1ω-13 and trans-18:1ω-9 in annular or non-annular areas. From theMD runs we obtained the most statistically relevant conformations of each FFAs in eachof the systems, we determined the possible contacts with residues of the nAChR and theresulting profile of pore radius. In general, the results show that more contacts areestablished when FFAs are located in non-annular regions. As expected, contacts areestablished in a much greater proportion with non-polar residues. cis-18:1ω-11 in nonannular sites leads to conformations that open the pore of the channel, while in annularsites it stabilizes the desensitized state. With cis-18:1ω-13 a similar behavior isobserved, although in non-annular sites it produces a pronounced constriction in theextracellular domain.Fil: Obiol, Diego Javier. Universidad Nacional del Sur. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; ArgentinaFil: Amundarain, María Julia. Universidad Nacional del Sur. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; ArgentinaFil: Jaure, Omar David Argentino. Universidad Nacional del Sur. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; ArgentinaFil: Zamarreño, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Antollini, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Costabel, M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaXLVIII Reunión Anual de la Sociedad Argentina de BiofísicaSan LuisArgentinaSociedad Argentina de Biofísic