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Majadahonda, Spain

Perrinjaquet M.,Karolinska Institutet | Vilar M.,Karolinska Institutet | Vilar M.,Institute Of Salud Carlos Iii | Ibanez C.F.,Karolinska Institutet
Journal of Biological Chemistry | Year: 2010

The signaling mechanisms by which neurotrophic receptors regulate neuronal survival and axonal growth are still incompletely understood. In the receptor tyrosine kinase RET, a receptor for GDNF (glial cell line-derived neurotrophic factor), the functions of the majority of tyrosine residues that become phosphorylated are still unknown. Here we have identified the protein-tyrosine phosphatase SHP2 as a novel direct interactor of RET and the first effector known to bind to phosphorylated Tyr687 in the juxtamembrane region of the receptor. We show that SHP2 is recruited to RET upon ligand binding in a cooperative fashion, such that both interaction with Tyr687 and association with components of the Tyr1062 signaling complex are required for stable recruitment of SHP2 to the receptor. SHP2 recruitment contributes to the ability of RET to activate the PI3K/AKT pathway and promote survival and neurite outgrowth in primary neurons. Furthermore, we find that activation of protein kinase A (PKA) by forskolin reduces the recruitment of SHP2 to RET and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of Ser696, a known PKA phosphorylation site in RET, enhances SHP2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth. Together, these findings establish SHP2 as a novel positive regulator of the neurotrophic activities of RET and reveal Tyr687 as a critical platform for integration of RET and PKA signals. We anticipate that several other phosphotyrosines of unknown function in neuronal receptor tyrosine kinases will also support similar regulatory functions. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Infantes S.,Institute Of Salud Carlos Iii | Infantes S.,Institute Salud Carlos III | Lorente E.,Institute Of Salud Carlos Iii | Lorente E.,Institute Salud Carlos III | And 9 more authors.
Molecular and Cellular Proteomics | Year: 2010

Cytotoxic T lymphocyte (CTL)-mediated death of virus-infected cells requires prior recognition of short viral peptide antigens that are presented by human leukocyte antigen (HLA) class I molecules on the surface of infected cells. The CTL response is critical for the clearance of human respiratory syncytial virus (HRSV) infection. Using mass spectrometry analysis of complex HLA-bound peptide pools isolated from large amounts of HRSV-infected cells, we identified nine naturally processed HLA-B27 ligands. The isolated peptides are derived from six internal, not envelope, proteins of the infective virus. The sequences of most of these ligands are not conserved between different HRSV strains, suggesting a mechanism to explain recurrent infection with virus of different HRSV antigenic subgroups. In addition, these nine ligands represent a significant fraction of the proteome of this virus, which is monitored by the same HLA class I allele. These data have implications for vaccine development as well as for analysis of the CTL response. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

De Diego Damia A.,Hospital Universitari i Politecnic la Fe | Cortijo Gimeno J.,Consorcio Hospital General Universitario | Cortijo Gimeno J.,Institute Of Salud Carlos Iii | Cortijo Gimeno J.,University of Valencia | And 6 more authors.
Archivos de Bronconeumologia | Year: 2011

Introduction: Cigarette smoke is the main cause of inflammation in COPD. The mechanisms that differentiate smokers who develop COPD are diverse. In this study, we analyzed the presence of cytokines in the respiratory secretions of smokers with or without COPD and the secretory properties of the differentiated bronchial epithelium obtained from the individuals themselves after exposure to tobacco smoke. Material and methods: Twenty-seven smokers were studied, 12 of whom had COPD that had not been previously treated with steroids. In 11, samples were obtained by means of induced sputum, and the remaining samples were collected from bronchial aspiration after bronchoscopy. Concentrations of IL-8, IL-13 and TNFα in the supernatant were determined. The results obtained were compared between individuals with and without COPD, and we studied their relationship with the severity of COPD as expressed by the degree of obstruction, dyspnea, presence of hypersecretion and intensity of smoking. Bronchial epithelial cell cultures were obtained by air-liquid interface in 4 smokers. The samples were exposed to increasing concentrations of cigarette smoke (5-20%) and the epithelial mRNA expressions of MUC5AC, IL8 and TNFα were determined. Results: COPD patients had significantly higher values of IL-8 than healthy smokers (41 [22] vs. 21 [12] pM). The values of IL-8 correlated significantly with the severity of the obstruction (r = 0.6; p < 0.05), dyspnea (r = 0.45; p < 0.05) and the presence of hypersecretion. There was no relationship between cytokines and the intensity or duration of the tobacco habit. Cigarette smoke produced a dose-dependent increase in the expression of RNAm for Muc5AC, IL8 and TNFα. Conclusions: There are differences in cytokine production (fundamentally IL8) between smokers and smokers with COPD which could be explained by the direct action of cigarette smoke on epithelial cells. © 2011 SEPAR.

Fernandez A.,Sant Joan de Deu SSM | Saameno J.A.B.,Institute Of Salud Carlos Iii | Saameno J.A.B.,University of Malaga | Pinto-Meza A.,Sant Joan de Deu SSM | And 8 more authors.
British Journal of Psychiatry | Year: 2010

The World Health organization (WHO) has stated that the three leading causes of burden of disease In 2030 are projected to include HIV/AIDS, unipolar depression and schaemic heart disease. Aims To estimate health-related quality of life (HRQoL) and qualityadjusted life-year (QALY) losses associated with mental disorders and chronic physical conditions in primary healthcare using data from the diagnosis and treatment of mental disorders In primary care (DASMAP) study, an epidemiological survey carried out with primary care patients in Catalonia (Spain). Method A cross-sectional survey of a representative sample of 3815 primary care patients. A preference-based measure of health was derived from the 12-ltem Short Form Health Survey (SF-12): the Short Form-6D (SF-6D) multi-attribute healthstatus classification. Each profile generated by this questionnaire has a utility (or weight) assigned, we used non-parametric quantile regressions to model the association between both mental disorders and chronic physical condition and SF-6D scores. Results Conditions associated with SF-6D were: mood disorders, ß=-0.20 (95% Cl -0.18 to -0.21); pain, ß=-0.08 (95%Cl -0.06 to -0.09) and anxiety, ß=-0.04 (95% Cl -0.03 to -0.06). The top three causes of QALY losses annually per 100000 participants were pain (5064), mood disorders (2634) and anxiety (805). Conclusions Estimation of QALY losses showed that mood disorders ranked second behind pain-related chronic medical conditions.

Turrientes M.-C.,Ramon y Cajal Hospital | de Ayala A.P.,Ramon y Cajal Hospital | Norman F.,Ramon y Cajal Hospital | Navarro M.,Ramon y Cajal Hospital | And 4 more authors.
Emerging Infectious Diseases | Year: 2011

To determine whether increased migration is associated with an increase in incidence of toxocariasis (visceral larva migrans), we analyzed clinical data obtained from immigrants from Latin America. Although infection with Toxocara sp. roundworm larvae is distributed worldwide, seroprevalence is highest in tropical and subtropical areas.

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