The ₉₅RGD₉₇ sequence on the A alpha chain of fibrinogen is essential for binding to its erythrocyte receptor

Background: Erythrocyte aggregation, a cardiovascular risk factor, is increased by high plasma fibrinogen levels. Here, the effect of different fibrinogen mutations on binding to its human erythrocyte receptor was assessed in order to identify the interaction sites. Methods: Three fibrinogen variants were tested, specifically mutated in their putative integrin recognition sites on the Aα chain (mutants D97E, D574E and D97E/D574E) and compared with wild-type fibrinogen. Results: Atomic force microscopy-based force spectroscopy measurements showed a significant decrease both on the fibrinogen–erythrocyte binding force and on its frequency for fibrinogen with the D97E mutation, indicating that the corresponding arginine–glycine–aspartate sequence (residues 95–97) is involved in this interaction, and supporting that the fibrinogen receptor on erythrocytes has a β3 subunit. Changes in the fibrin clot network structure obtained with the D97E mutant were observed by scanning electron microscopy. Conclusion: These findings may lead to innovative perspectives on the development of new therapeutic approaches to overcome the risks of fibrinogen-driven erythrocyte hyperaggregation

Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordPhysical exercise induces cell proliferation in the adult hippocampus in rodents. Serotonin (5-HT) and angiotensin (Ang) II are important mediators of the pro-mitotic effect of physical activity. Here, we examine precursor cells in the adult brain of mice lacking angiotensin-converting enzyme (ACE) 2, and explore the effect of an acute running stimulus on neurogenesis. ACE2 metabolizes Ang II to Ang-(1-7) and is essential for the intestinal uptake of tryptophan (Trp), the 5-HT precursor. In ACE2-deficient mice, we observed a decrease in brain 5-HT levels and no increase in the number of BrdU-positive cells following exercise. Targeting the Ang II/AT1 axis by blocking the receptor, or experimentally increasing Trp/5-HT levels in the brain of ACE2-deficient mice, did not rescue the running-induced effect. Furthermore, mice lacking the Ang-(1-7) receptor, Mas, presented a normal neurogenic response to exercise. Our results identify ACE2 as a novel factor required for exercise-dependent modulation of adult neurogenesis and essential for 5-HT metabolism

Sensing adhesion forces between erythrocytes and γ’ fibrinogen, modulating fibrin clot architecture and function

Plasma fibrinogen includes an alternatively spliced γ-chain variant (γ’), which mainly exists as a heterodimer (γAγ’) and has been associated with thrombosis. We tested γAγ’ fibrinogen-red blood cells (RBCs) interaction using atomic force microscopy-based force spectroscopy, magnetic tweezers, fibrin clot permeability, scanning electron microscopy and laser scanning confocal microscopy. Data reveal higher work necessary for RBC-RBC detachment in the presence of γAγ’ rather than γAγA fibrinogen. γAγ’ fibrinogen–RBCs interaction is followed by changes in fibrin network structure, which forms an heterogeneous clot structure with areas of denser and highly branched fibrin fibers. The presence of RBCs also increased the stiffness of γAγ’ fibrin clots, which are less permeable and more resistant to lysis than γAγA clots. The modifications on clots promoted by RBCs-γAγ’ fibrinogen interaction could alter the risk of thrombotic disorders

Informe de evaluación de Escritura en sexto grado 2013 ¿Qué logros de aprendizaje en Escritura muestran los estudiantes al finalizar la primaria?

Además de evaluar el desempeño de los estudiantes peruanos en comprensión de textos, la Evaluación Muestral (EM), aplicada a fines del 2013, incluyó una prueba de producción de textos escritos, cuyo objetivo es informar cuánto han logrado aprender nuestros estudiantes de sexto grado de primaria en la competencia de escritura. ¿Pueden organizar coherentemente sus ideas en un texto? ¿Pueden producir un cuento proporcionando detalles sobre los personajes y sus acciones? ¿Pueden ajustar sus escritos a las exigencias de la situación comunicativa? A partir de los resultados de la prueba, este informe apunta a responder estas y otras preguntas sobre el desempeño de los estudiantes de sexto grado de primaria al momento de escribir textos narrativos, así como a proporcionar recomendaciones para ayudarlos a mejorar su producción escrita. La prueba de escritura se aplicó a 4327 estudiantes, pertenecientes a 357 escuelas de todo el Perú. Las características de la muestra evaluada permiten proporcionar resultados representativos a nivel nacional y asegurar estimaciones confiables. En otras palabras, los resultados que se reportan en este documento revelan la situación de los niños de sexto de primaria del Perú al escribir textos narrativos, en particular, cuentos. Este informe consta de ocho capítulos. El primero presenta la manera cómo se concibe el aprendizaje de la escritura en la EM. El segundo y tercero señalan las características generales de la evaluación. El cuarto informa cómo se establecieron los niveles de logro para reportar los resultados: Nivel 3, Nivel 2 y Nivel 1. A continuación, el quinto capítulo muestra los resultados nacionales y se describen los niveles de logro. Estas descripciones van acompañadas de ejemplos comentados con el propósito de que el lector pueda tener una aproximación más clara a cada uno de los niveles. El sexto capítulo incluye otros hallazgos importantes obtenidos en la EM, tales como los resultados por área (urbana o rural), gestión (estatal o no estatal) y género. El sétimo presenta información complementaria a los resultados relacionada con el tratamiento que se dio a las diferentes variedades del castellano manejadas por los estudiantes al momento de evaluar sus textos. Finalmente, se presentan conclusiones y recomendaciones pedagógicas

Discrimination exposure and DNA methylation of stress-related genes in Latina mothers

© 2018 Elsevier Ltd. Latina mothers, who have the highest fertility rate among all ethnic groups in the US, are often exposed to discrimination. The epigenetic changes related to this discrimination are largely unknown. This study is the first to explore the relationship between discrimination and DNA methylation of stress regulatory genes in Latinas. Our sample was Latina women (n = 147) with a mean age of 27.6 years who were assessed at 24–32 weeks’ gestation (T1) and 4–6 weeks postpartum (T2) and reside in the U.S. Blood was collected at T1, and the Everyday Discrimination Scale (EDS) was administered at T1 and T2. DNA Methylation at candidate gene regions was determined by bisulphite pyrosequencing. Associations between EDS and DNA methylation were assessed via zero-inflated Poisson models, adjusting for covariates and multiple-test comparisons. Discrimination was negatively associated with methylation at CpG sites within the glucocorticoid receptor (NR3C1) and brain-derived neurotrophic factor (BDNF) genes that were consistent over time. In addition, discrimination was negatively associated with methylation of a CpG in the glucocorticoid binding protein (FKBP5) at T1 but not at T2. This study underscores associations between discrimination and epigenetic markers of DNA methylation in Latinas that warrant further investigation to better understand the biological pathways and psychopathological effects of discrimination on Latina mothers and their families

Stabilization of angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system (RAAS), is a promising candidate as a treatment for cancer that reflects its antiproliferative and anti-angiogenic properties. However, the peptide’s therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer