Mutational screens highlight glycosylation as a modulator of colony-stimulating factor 3 receptor (CSF3R) activity.

The colony-stimulating factor 3 receptor (CSF3R) controls the growth of neutrophils, the most abundant type of white blood cell. In healthy neutrophils, signaling is dependent on CSF3R binding to its ligand, CSF3. A single amino acid mutation in CSF3R, T618I, instead allows for constitutive, ligand-independent cell growth and leads to a rare type of cancer called chronic neutrophilic leukemia. However, the disease mechanism is not well understood. Here, we investigated why this threonine to isoleucine substitution is the predominant mutation in chronic neutrophilic leukemia and how it leads to uncontrolled neutrophil growth. Using protein domain mapping, we demonstrated that the single CSF3R domain containing residue 618 is sufficient for ligand-independent activity. We then applied an unbiased mutational screening strategy focused on this domain and found that activating mutations are enriched at sites normally occupied by asparagine, threonine, and serine residues-the three amino acids which are commonly glycosylated. We confirmed glycosylation at multiple CSF3R residues by mass spectrometry, including the presence of GalNAc and Gal-GalNAc glycans at WT threonine 618. Using the same approach applied to other cell surface receptors, we identified an activating mutation, S489F, in the interleukin-31 receptor alpha chain. Combined, these results suggest a role for glycosylated hotspot residues in regulating receptor signaling, mutation of which can lead to ligand-independent, uncontrolled activity and human disease.

Discovery of potent and selective inhibitors of the Escherichia coli M1-aminopeptidase via multicomponent solid-phase synthesis of tetrazole-peptidomimetics.

The Escherichia coli neutral M1-aminopeptidase (ePepN) is a novel target identified for the development of antimicrobials. Here we describe a solid-phase multicomponent approach which enabled the discovery of potent ePepN inhibitors. The on-resin protocol, developed in the frame of the Distributed Drug Discovery (D3) program, comprises the implementation of parallel Ugi-azide four-component reactions with resin-bound amino acids, thus leading to the rapid preparation of a focused library of tetrazole-peptidomimetics (TPMs) suitable for biological screening. By dose-response studies, three compounds were identified as potent and selective ePepN inhibitors, as little inhibitory effect was exhibited for the porcine ortholog aminopeptidase. The study allowed for the identification of the key structural features required for a high ePepN inhibitory activity. The most potent and selective inhibitor (TPM 11) showed a non-competitive inhibition profile of ePepN. We predicted that both diastereomers of compound TPM 11 bind to a site distinct from that occupied by the substrate. Theoretical models suggested that TPM 11 has an alternative inhibition mechanism that doesn't involve Zn coordination. On the other hand, the activity landscape analysis provided a rationale for our findings. Of note, compound TMP 2 showed in vitro antibacterial activity against Escherichia coli. Furthermore, none of the three identified inhibitors is a potent haemolytic agent, and only two compounds showed moderate cytotoxic activity toward the murine myeloma P3X63Ag cells. These results point to promising compounds for the future development of rationally designed TPMs as antibacterial agents.

Rendimiento académico en Morfofisiología según los estilos de aprendizaje / Academic Performance in Morpho-physiology According to Learning Styles

Fundamento: el aprendizaje es más efectivo cuando a los estudiantes se les enseña de acuerdo a sus estilos de aprendizaje predominantes.Objetivo: caracterizar los estilos de aprendizaje de la Morfofisiología afrontados por estudiantes de la carrera de medicina, en el Policlínico Universitario “Romárico Oro” de Puerto Padre, en el curso académico 2014-2015.Métodos: se realizó un estudio descriptivo transversal en 87 estudiantes de la carrera, escenario docente y curso ya definidos. Se aplicó el cuestionario CHAEA de estrategias de aprendizaje. En el procesamiento estadístico se utilizaron pruebas descriptivas y en la comparación de variables el t-student y el test de Chicuadrado.Resultados: predominó el estilo reflexivo (media=16,89 p<0,001); la distribución según estilos de aprendizaje y sexo muestra predominio de este estilo en ambos (22,99 por ciento masculinos y 34,48 por ciento femeninos); sin embargo, la distribución general mostró homogeneidad (X 2 =7,91 p=0,0951); en los estudiantes donde predominaron más de un estilo, la media de la calificación fue de 3,6 (DE: ± 0,56) p=0,0048612, superior al resto de los estilos.Conclusiones: prevaleció en la muestra general y según sexo el estilo reflexivo, en ambos con predominio moderado; un número importante de estudiantes fueron multimodales. La baja preferencia del estilo activo mostró deficiencias en el ciclo de aprendizaje. El rendimiento académico fue superior en los estudiantes donde predominaba más de un estilo (AU)

Background: learning is more effective when students are taught according to their predominant learning styles.Objectives: to characterize the medical students learning styles of Morpho-physiology in “Romárico Oro” University Polyclinic in Puerto Padre during the academic year 2014 2015.Methods: a descriptive and cross-sectional study was carried out in 87 medical students in the place and time defined above. Learning strategies CHAEA questionnaire was applied. Descriptive tests were used in the statistical processing, and t-Student and Chi-Square tests in the variables comparison. Results: the reflexive style prevailed (average: 16,89 p<0.001); the distribution according to learning styles and sex showed prevalence of this style in both (22,99 percent males and 34,48 percent females); however, the general distribution showed homogeneity (X2=7,91 p=0,0951); in the students where more than one style prevailed the average score was 3,6 (SD: ±0,56) p=0,0048612, superior to the rest of the styles.Conclusions: the reflective style prevailed in the general and by sex samples, both with moderate predominance; a significant number of students preferred multimodal learning styles. The low preference for the active style showed deficiencies in the learning cycle. The academic performance was higher in students where more than one style predominated (AU)

Caracterización de la promoción en Morfofisiología de estudiantes de Puerto Padre durante seis cursos académicos / Characterization of the academic results in the discipline of morphophysiology in Puerto Padre during six academic years

Fundamento: la universalización de la educación superior en las ciencias médicas ha sido un baluarte en la preparación integral de los futuros profesionales de la salud. La disciplina Morfofisiología constituye una de las modificaciones más trascendentales en este contexto.Objetivo: describir los resultados de promoción en la disciplina Morfofisiología, en el escenario docente del Policlínico Universitario Romárico Oro Peña, de Puerto Padre, en el período comprendido entre septiembre de 2008 y septiembre de 2014.Métodos: se realizó un estudio descriptivo longitudinal de los resultados de promoción y calidad de la promoción, para lo cual se revisaron y analizaron las matrículas correspondientes a estos cursos académicos, así como los informes de promoción de los mismos. Para el procesamiento de los datos se utilizó la estadística descriptiva.Resultados: la matrícula se incrementó en más de un 600 por ciento. Se produjo un descenso global en un 22,38 por ciento en la promoción y de 41,87 por ciento en la calidad, respecto a las asignaturas que componen la disciplina Morfofisiología, durante los seis años analizados.Conclusiones: durante el período estudiado existió un aumento significativo en la matrícula; la promoción y la calidad han disminuido significativamente en la Morfofisiología I, III, IV, V y VI, no ocurriendo lo mismo en la Morfofisiología II, la cual ha mostrado estabilidad en los resultados (AU)

Background: distribute medical education in our country has been a stronghold in the comprehensive training of the future health professionals. The discipline of Morphophysiology has been one of the most significant modifications in this context.Objective: to describe the academic results in the discipline of Morphophysiology at the university site of Romárico Oro Polyclinic of Puerto Padre from September, 2008 to September, 2014.Methods: a descriptive longitudinal study was carried out in order to analyze the academic results and their quality. For the purposes of this study, the enrollments and the reports on the students results during these academic years were checked and analyzed. To process the data descriptive statistics was used.Results: enrollment increased in more than 600 percent. There was a global fall of 22,38 percent in the academic results and of 41,87 percent in the quality of these results, of all he subjects that make up the discipline of Morphophysiology, during the 6 years analyzed.Conclusions: during the studied period there was a significant increase in the enrollment. The academic results and their quality decreased significantly in Morphophysiology I, III, IV, V and VI. In Morphophysiology II, however, there have been stable results (AU)

Caracterización de defectos congénitos según diagnóstico ultrasonográfico y anatomopatológico. Hospital “Ramón González Coro” / Characterization of birth defects according to the ultrasonographic and pathological diagnosis. Hospital “Ramón González Coro”

En este trabajo se caracterizan los defectos congénitos identificados a través del examen ultrasonográfico y anatomopatológico. Se realizó un estudio descriptivo, transversal en el Hospital “Ramón González Coro” durante el periodo 2008 2012. Los datos se obtuvieron relacionando hallazgos del ultrasonido con información de las necropsias. Los productos fueron predominantemente masculinos, de madres entre 20 y 34 años y la defunción se produjo con edad gestacional menor a 26 semanas. Según el principal sistema anatómico afectado, los defectos congénitos fueron más frecuentes: cerebroespinales, cromosomopatías y osteomusculares. Existió un nivel de diagnóstico prenatal ultrasonográfico adecuado. La autopsia fue la mejor herramienta para el diagnóstico definitivo de defectos congénitos…(AU)