Desarrollo de ensayos "in vitro" para la identificación de nuevas moléculas con actividad antimalárica y bloqueantes de la transmisión de la enfermedad

La malaria aún constituye un grave problema de salud a nivel global, afectando amás de 200 millones de personas y provocando más de 400.000 muertes cada año.Esta enfermedad tiene la mayor tasa de mortalidad en niños menores de 5 años ymujeres embarazadas del África subsahariana, donde se concentra la mayorincidencia de casos producidos por la especie Plasmodium falciparum. Durante laúltima década se han desarrollado e implementado diversas estrategias tanto a nivelde control del vector (la hembra del mosquito Anopheles) como de quimioterapiapara el hospedador humano. Una de estas estrategias se ha centrado en eldescubrimiento y desarrollo de nuevos medicamentos que permitan una interrupciónde la transmisión del parásito desde el hospedador al mosquito. Para ello, se requierela eliminación de los estadios transmisibles de Plasmodium, los gametocitos enestadio V, frente a los cuales solo existe actualmente un antimalárico comercial, laprimaquina, cuya administración está contraindicada en una parte de la poblacióndonde la malaria es endémica..

Dimethylzinc-Mediated Addition of Phenylacetylene to α-Diketones Catalyzed by Chiral Perhydro-1,3-benzoxazines

Producción CientíficaAn efficient enantioselective Me2Zn-mediated mono addition of phenylacetylene to α-diketones in the presence of a chiral perhydro-1,3-benzoxazine ligand is described. At temperatures higher than -20 ºC a kinetic resolution of the resulting α-hydroxy ketone occurs which greatly improves the enantioselectivity although with moderate chemical yield. The alkynylation of nonsymmetrical aromatic diketones with electronically different substituents on the aromatic rings proceed with high regioselectivity. This procedure allows the preparation of α-hydroxy-α-ynyl-ketones as highly enantioenriched materials.2018-07-07Ministerio de Economía, Industria y Competitividad (Project CTQ2014-59870 P)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA064U13

Monitoring the phenolic ripening of red grapes using a multisensor system based on metal-oxide nanoparticles

Producción CientíficaThe maturity of grapes is usually monitored by means of the sugar concentration. However, the assessment of other parameters such as the phenolic content is also important because the phenolic maturity has an important impact on the organoleptic characteristics of wines. In this work, voltammetric sensors able to detect phenols in red grapes have been developed. They are based on metal oxide nanoparticles (CeO2, NiO, and TiO2,) whose excellent electrocatalytic properties toward phenols allows obtaining sensors with detection limits in the range of 10−8 M and coefficients of variation lower than 7%. An electronic tongue constructed using a combination of the nanoparticle-based sensors is capable to monitor the phenolic maturity of red grapes from véraison to maturity. Principal Component Analysis (PCA) can be successfully used to discriminate samples according to the ripeness. Regression models performed using Partial Least Squares (PLS-1) have established good correlations between voltammetric data obtained with the electrochemical sensors and the Total Polyphenolic Index, the Brix degree and the Total Acidity, with correlation coefficients close to 1 and low number of latent variables. An advantage of this system is that the electronic tongue can be used for the simultaneous assessment of these three parameters which are the main factors used to monitor the maturity of grapes. Thus the electronic tongue based on metal oxide nanoparticles can be a valuable tool to monitor ripeness. These results demonstrate the exciting possible applications of metal oxide nanoparticles in the field of electronic tongues.Ministerio de Economía, Industria y Competitividad - Fondo Europeo de Desarrollo Regional (project AGL2015-67482- R)Junta de Castilla y Leon - Fondo Europeo de Desarrollo Regional (project VA011U16)Junta de Castilla y León (grant BOCYL-D-24112015-9

Machine learning-based phenotypic imaging to characterise the targetable biology of <i>Plasmodium falciparum</i> male gametocytes for the development of transmission-blocking antimalarials

Preventing parasite transmission from humans to mosquitoes is recognised to be critical for achieving elimination and eradication of malaria. Consequently developing new antimalarial drugs with transmission-blocking properties is a priority. Large screening campaigns have identified many new transmission-blocking molecules, however little is known about how they target the mosquito-transmissible Plasmodium falciparum stage V gametocytes, or how they affect their underlying cell biology. To respond to this knowledge gap, we have developed a machine learning image analysis pipeline to characterise and compare the cellular phenotypes generated by transmission-blocking molecules during male gametogenesis. Using this approach, we studied 40 molecules, categorising their activity based upon timing of action and visual effects on the organisation of tubulin and DNA within the cell. Our data both proposes new modes of action and corroborates existing modes of action of identified transmission-blocking molecules. Furthermore, the characterised molecules provide a new armoury of tool compounds to probe gametocyte cell biology and the generated imaging dataset provides a new reference for researchers to correlate molecular target or gene deletion to specific cellular phenotype. Our analysis pipeline is not optimised for a specific organism and could be applied to any fluorescence microscopy dataset containing cells delineated by bounding boxes, and so is potentially extendible to any disease model

Propuesta de los criterios generales de valoración en preguntas de desarrollo para los residentes de Medicina Interna de la Facultad de Ciencias Médicas “Finlay-Albarrán”

Introducción: En nuestro país existe un plan de estudios de la residencia de Medicina Interna que incluye exámenes de promoción con un componente teórico de preguntas de desarrollo. Objetivo: Proponer criterios generales de valoración en preguntas de desarrollo para los residentes de Medicina Interna en la Facultad de Ciencias Médicas “Finlay Albarrán”. Material y Métodos: Se realizó una investigación de desarrollo tecnológico en dos etapas: la primera, de creación de criterios generales de valoración de las preguntas; la segunda, de validación. La información procedente de los datos aparece en las tablas de resultados y su interpretación por los autores en el contenido de la discusión. Resultados: El tipo de preguntas que predominó fueron las relacionadas con la conducta a seguir y el diagnóstico positivo. Los problemas de salud más frecuentes incluidos en las preguntas fueron las enfermedades infecciosas y crónicas no transmisibles. Los indicadores de calidad de la respuesta más relevantes lo constituyeron el grado de completamiento para el que se establecieron criterios generales, los elementos fisiopatológicos, la expresión oral del examinado, el manejo de los resultados investigativos, la actualidad en la información, así como la organización de la respuesta. Conclusiones: Se estableció la propuesta de los criterios generales de evaluación para los residentes de Medicina Interna en la Facultad de Ciencias Médicas “Finlay-Albarrán”, en aras de elevar el nivel de asimilación mediante preguntas a partir de problemas conceptuales o clínicos. Palabras clave: Residencia, medicina interna, preguntas de desarrollo, indicadores de calidad, criterios generales de evaluación, validación. ABSTRACTIntroduction: There is a plan of residents of Internal Medicine. This plan includes theoretical tests with question of large answers. Objective: To propose general criteria of assessment in questions of large answers for Internal Medicine's residents in Faculty of medical sciences “Finlay Albarrán”. Material and methods: We made a technological development´s research in two stages: the first one belonging to creation of general criteria of assessment of the questions; the second one of validation.  Information appears in charts of the results and their interpretations are in the content of the discussion. Results: Predominate questions about the behavior to follow and the positive diagnoses. The more frequent problems of health were infective disease and chronic illnesses. The most relevant quality indicators of answers were the completing, physiopathology’s elements, the student’s oral expression, the management of the researching results, the updated information and the organization of the answer. Conclusions: It was established a proposal of the general criteria of evaluation for Internal Medicine's residents in Faculty of medical science Finlay Albarrán, in order to increase the level of assimilation by means of questions about conceptual or clinical problems. Key words: Residence, internal medicine, questions of large answers, indicators of quality, general criteria of evaluation, validation.</p

Desarrollo de método para la evaluación de la rotación de alumnos en hospital universitario para realizar prácticas clínicas

El objetivo de este proyecto es el de diseñar y desarrollar un método de evaluación que permita valorar, de manera objetiva, a los alumnos de la asignatura de Prácticas Clínicas del Master de Optometría y Visión de la Facultad de Óptica y Optometría durante la realización de dichas prácticas en un Hospital Universitario con pacientes reales

Hundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen.

Plasmodium falciparum stage V gametocytes are responsible for parasite transmission, and drugs targeting this stage are needed to support malaria elimination. We here screen the Tres Cantos Antimalarial Set (TCAMS) using the previously developed P. falciparum female gametocyte activation assay (Pf FGAA), which assesses stage V female gametocyte viability and functionality using Pfs25 expression. We identify over 400 compounds with activities <2 μM, chemically classified into 57 clusters and 33 singletons. Up to 68% of the hits are chemotypes described for the first time as late-stage gametocyte-targeting molecules. In addition, the biological profile of 90 compounds representing the chemical diversity is assessed. We confirm in vitro transmission-blocking activity of four of the six selected molecules belonging to three distinct scaffold clusters. Overall, this TCAMS gametocyte screen provides 276 promising antimalarial molecules with dual asexual/sexual activity, representing starting points for target identification and candidate selection

A simple approach to obtain hybrid Au-loaded polymeric nanoparticles with a tunable metal load

A new strategy to nanoengineer multi-functional polymer–metal hybrid nanostructures is reported. By using this protocol the hurdles of most of the current developments concerning covalent and noncovalent attachment of polymers to preformed inorganic nanoparticles (NPs) are overcome. The strategy is based on the in situ reduction of metal precursors using the polymeric nanoparticle as a nanoreactor. Gold nanoparticles and poly(DL-lactic-co-glycolic acid), PLGA, are located in the core and shell, respectively. This novel technique enables the production of PLGA NPs smaller than 200 nm that bear either a single encapsulated Au NP or several smaller NPs with tunable sizes and a 100% loading efficiency. In situ reduction of Au ions inside the polymeric NPs was achieved on demand by using heat to activate the reductive effect of citrate ions. In addition, we show that the loading of the resulting Au NPs inside the PLGA NPs is highly dependent on the surfactant used. Electron microscopy, laser irradiation, UV-Vis and fluorescence spectroscopy characterization techniques confirm the location of Au nanoparticles. These promising results indicate that these hybrid nanomaterials could be used in theranostic applications or as contrast agents in dark-field imaging and computed tomograph

The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957.

New antimalarial therapeutics are needed to ensure that malaria cases continue to be driven down, as both emerging parasite resistance to frontline chemotherapies and mosquito resistance to current insecticides threaten control programmes. Plasmodium, the apicomplexan parasite responsible for malaria, causes disease pathology through repeated cycles of invasion and replication within host erythrocytes (the asexual cycle). Antimalarial drugs primarily target this cycle, seeking to reduce parasite burden within the host as fast as possible and to supress recrudescence for as long as possible. Intense phenotypic drug screening efforts have identified a number of promising new antimalarial molecules. Particularly important is the identification of compounds with new modes of action within the parasite to combat existing drug resistance and suitable for formulation of efficacious combination therapies. Here we detail the antimalarial properties of DDD01034957-a novel antimalarial molecule which is fast-acting and potent against drug resistant strains in vitro, shows activity in vivo, and possesses a resistance mechanism linked to the membrane transporter PfABCI3. These data support further medicinal chemistry lead-optimization of DDD01034957 as a novel antimalarial chemical class and provide new insights to further reduce in vivo metabolic clearance