Concatemerization increases the inhibitory activity of short, cell-penetrating, cationic and tryptophan-rich antifungal peptides

There are short cationic and tryptophan-rich antifungal peptides such as the hexapeptide PAF26 (RKKWFW) that have selective toxicity and cell penetration properties against fungal cells. This study demonstrates that concatemeric peptides with tandem repeats of the heptapeptide PAF54 (which is an elongated PAF26 sequence) show increased fungistatic and bacteriostatic activities while maintaining the absence of hemolytic activity of the monomer. The increase in antimicrobial activity of the double-repeated PAF sequences (diPAFs), compared to the nonrepeated PAF, was higher (4-8-fold) than that seen for the triple-repeated sequences (triPAFs) versus the diPAFs (2-fold). However, concatemerization diminished the fungicidal activity against quiescent spores of the filamentous fungus Penicillium digitatum. Peptide solubility and sensitivity to proteolytic degradation were affected by the design of the concatemers: incorporation of the AGPA sequence hinge to separate PAF54 repeats increased solubility while the C-terminal addition of the KDEL sequence decreased in vitro stability. These results led to the design of the triPAF sequence PAF102 of 30 amino acid residues, with increased antimicrobial activity and minimal inhibitory concentration (MIC) value of 1-5 μM depending on the fungus. Further characterization of the mode-of-action of PAF102 demonstrated that it colocalizes first with the fungal cell wall, it is thereafter internalized in an energy dependent manner into hyphal cells of the filamentous fungus Fusarium proliferatum, and finally kills hyphal cells intracellularly. Therefore, PAF102 showed mechanistic properties against fungi similar to the parental PAF26. These observations are of high interest in the future development of PAF-based antimicrobial molecules optimized for their production in biofactories.Fil: Lopez Garcia, Belén. Consejo Superior de Investigaciones Cientificas. Centre for Research in Agricultural Genomics; EspañaFil: Harries, Eleonora del Milagro. Consejo Superior de Investigaciones Cientificas. Instituto de Agroquimica y Tecnologia de Alimentos; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Salta; ArgentinaFil: Carmona, Lourdes. Consejo Superior de Investigaciones Cientificas. Instituto de Agroquimica y Tecnologia de Alimentos; EspañaFil: Campos Soriano, Lidia. Consejo Superior de Investigaciones Cientificas. Centre for Research in Agricultural Genomics; EspañaFil: López, José Javier. Consejo Superior de Investigaciones Cientificas. Instituto de Agroquimica y Tecnologia de Alimentos; EspañaFil: Manzanares, Paloma. Consejo Superior de Investigaciones Cientificas. Instituto de Agroquimica y Tecnologia de Alimentos; EspañaFil: Gandía, Mónica. Consejo Superior de Investigaciones Cientificas. Instituto de Agroquimica y Tecnologia de Alimentos; EspañaFil: Coca, María. Consejo Superior de Investigaciones Cientificas. Centre for Research in Agricultural Genomics; EspañaFil: Marcos, Jose F.. Consejo Superior de Investigaciones Cientificas. Instituto de Agroquimica y Tecnologia de Alimentos; Españ

Uso de Internet como herramienta de comunicación

Resumen basado en el del proyecto. Premiado en la convocatoria: Premios para proyectos de innovación concluidos durante el curso 2006-2007, en los centros educativos no universitarios sostenidos con fondos públicos de la Comunidad Autónoma de Castilla-La Mancha (Orden 30-01-2008, de la Consejería de Educación y Ciencia de la Junta de Comunidades de Castilla-La Mancha. Resolución de 15-05-2009, de la Viceconsejería de Educación)El proyecto se desarrolla en el CRA Molinos del Júcar que agrupa los pueblos conquenses de Casas de Benítez, El Picazo, Pozoamargo, Rubielos Bajos y Tébar. Se pretende profundizar en las habilidades lingüísticas de la lengua inglesa y desarrollar la competencia digital del alumnado. Se lleva a cabo junto a colegios de Polonia y Estados Unidos, con los que se intercambian mensajes y cartas en inglés. Los objetivos y contenidos del proyecto se trabajan de forma global y van encaminados a desarrollar la competencia comunicativa en el alumnado en cuatro vertientes: competencia sociocultural, gramática discusiva y estratégica. Se persigue, además, aprender el uso de las nuevas tecnologías de la información y comunicación y a integrarlas en su actividad diaria, así como comunicarse en situaciones reales basadas en sus intereses y experiencias más cercanas, reconociendo y apreciando el valor comunicativo de las lenguas extranjeras y la propia capacidad para aprender a utilizarlas, mostrando una actitud de comprensión y respeto hacia otras lenguas, sus hablantes y su cultura. Se contribuye al desarrollo integral del niño (social, psicológico, cognitivo, emocional, estético, físico), y se les ayuda a aprender a aprender, potenciando la responsabilidad, la autonomía y la reflexión. Se promueve una atmósfera de cooperación y colaboración en el aula, así como herramientas para tratar la diversidad de los diferentes estilos de aprendizaje; para ello se elabora, además, el periódico escolar 'El Molinete'.Castilla La ManchaConsejería de Educación, Ciencia y Cultura. Viceconsejería de Educación y Cultura. Servicio de Documentación; Bulevar del Río Alberche, s. n. - 1 Planta; 45071 Toledo; Tel. +34925286045; Fax +34925247410; [email protected]

Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER); Agencia Española del Medicamento; Consejería de Salud de Andalucía.Background & Aims: Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period. Methods: Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. Results: A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%). Conclusions: AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management. Lay summary: Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes