Terapia génica de la enfermedad de Stargardt

El gen humano ABCA4 (=ABCR) se caracterizó en 1997 como el principal causante de la enfermedad de Stargardt, una distrofia macular hereditaria generalmente autosómica recesiva. Poco tiempo después se encontraron otras enfermedades asociadas a mutaciones en este gen, como son distrofia de conos y bastones, determinados casos de retinosis pigmentaria y un aumento de la susceptibilidad a la degeneración macular asociada a la edad. No existen tratamientos curativos para ninguna de estas distrofias. No obstante, dado que están causadas por un solo gen, cuya función es bien conocida, su curación se hace abordable mediante estrategias de terapia génica. En este artículo se resume el estado actual de las opciones de tratamientos basados en terapia génica de las enfermedades asociadas al gen ABCA4, las cuales implican el desarrollo de nuevos vectores derivados de virus adeno-asociados (AAV), lentivirus, y nanopartículas de ADN compactadas. Aunque este gen ha demostrado ser una diana de investigación difícil, los notables progresos realizados en los estudios genéticos, funcionales y traslacionales han permitido importantes avances en las aplicaciones terapéuticas de estas patologías, las cuales se espera que estén disponibles para los afectados en un futuro próximo. Resulta esperanzador, en este sentido, que ya están en marcha dos ensayos clínicos en fase I/II para tratar pacientes con la enfermedad de Stargardt

La complejidad de las distrofias hereditarias de la retina: un obstáculo y un reto

ACTO conjunto de FARPE-FUNDALUCE con la SEBBM en el marco de su XXXVII Congreso. Conferencia: La complejidad de las distrofias hereditarias de la retina: Un obstáculo y un reto (José Martín Nieto)

Incorporating Wheelchair Users in People Detection

A wheelchair users detector is presented to extend people detection, providing a more general solution to detect people in environments such as houses adapted for independent and assisted living, hospitals, healthcare centers and senior residences. A wheelchair user model is incorporated in a detector whose detections are afterwards combined with the ones obtained using traditional people detectors (we define these as standing people detectors). We have trained a model for classical (DPM) and for modern (Faster-RCNN) detection algorithms, to compare their performance. Besides the extensibility proposed with respect to people detection, a dataset of video sequences has been recorded in a real in-door senior residence environment containing wheelchairs users and standing people and it has been released together with the associated groundtruthThis work has been partially supported by the Spanish government under the project TEC2014-53176-R (HAVideo) and by the Spanish Government FPU grant programme (Ministerio de Educación, Cultura y Deporte

Involvement of abnormal dystroglycan expression and matriglycan levels in cancer pathogenesis

Dystroglycan (DG) is a glycoprotein composed of two subunits that remain non-covalently bound at the plasma membrane: α-DG, which is extracellular and heavily O-mannosyl glycosylated, and β-DG, an integral transmembrane polypeptide. α-DG is involved in the maintenance of tissue integrity and function in the adult, providing an O-glycosylation-dependent link for cells to their extracellular matrix. β-DG in turn contacts the cytoskeleton via dystrophin and participates in a variety of pathways transmitting extracellular signals to the nucleus. Increasing evidence exists of a pivotal role of DG in the modulation of normal cellular proliferation. In this context, deficiencies in DG glycosylation levels, in particular those affecting the so-called matriglycan structure, have been found in an ample variety of human tumors and cancer-derived cell lines. This occurs together with an underexpression of the DAG1 mRNA and/or its α-DG (core) polypeptide product or, more frequently, with a downregulation of β-DG protein levels. These changes are in general accompanied in tumor cells by a low expression of genes involved in the last steps of the α-DG O-mannosyl glycosylation pathway, namely POMT1/2, POMGNT2, CRPPA, B4GAT1 and LARGE1/2. On the other hand, a series of other genes acting earlier in this pathway are overexpressed in tumor cells, namely DOLK, DPM1/2/3, POMGNT1, B3GALNT2, POMK and FKTN, hence exerting instead a pro-oncogenic role. Finally, downregulation of β-DG, altered β-DG processing and/or impaired β-DG nuclear levels are increasingly found in human tumors and cell lines. It follows that DG itself, particular genes/proteins involved in its glycosylation and/or their interactors in the cell could be useful as biomarkers of certain types of human cancer, and/or as molecular targets of new therapies addressing these neoplasms.Research at the authors’ laboratory is funded by the Federación Española para la Ciencia y la Tecnología (FECYT) crowdfunding ref. PR320 (including donations from Alsa, PiperLab, Raquel Serradilla, Javier Aroca and Jesús García Sánchez-Reyes, among many other people), by the Rotary Club Torrevieja donation ref. 1-19XPA, and by the Universidad de Alicante grants ref. VIGROB21-237, UADIF21-77 and UAUSTI21-12 to JMN

Acucela recibe la designación de medicamento huérfano por parte de la FDA de Estados Unidos para el tratamiento de la enfermedad de Stargardt [Traducción]

Acucela Inc. es una compañía de oftalmología en fase clínica especializada en identificar y desarrollar nuevas terapias para tratar y retardar la progresión de enfermedades que amenazan la visión. Esta compañía ha anunciado el pasado 6 de enero que la FDA (Administración de Alimentos y Fármacos de Estados Unidos) ha otorgado la designación de medicamento huérfano al fármaco estrella de Acucela, el llamado Emixustat clorhidrato (ACU-4429), para el tratamiento de la enfermedad de Stargardt

A Practical Example for Model-Driven Web Requirements

The number of approaches for Web environments has grown very fast in the last years: HDM, OOHDM, and WSDM were among the first, and now a large number can be found in the literature. With the definition of MDA (Model- Driven Architecture) and the acceptance of MDE (Model-Driven Engineering) techniques in this environment, some groups are working in the use of metamodels and transformations to make their approaches more powerful. UWE (UMLBased Web Engineering) or OOWS (Object-Oriented Web Solutions) are only some examples. However, there are few real experiences with Web Engineering in the enterprise environment, and very few real applications of metamodels and MDE techniques. In this chapter the practical experience of a Web Engineering approach, NDT, in a big project developed in Andalusia is presented. Besides, it shows the usability of metamodels in real environments

Phosphorylation of calmodulin by permeabilized fibroblasts overexpressing the human epidermal growth factor receptor

Detergent-permeabilized EGFR-T17 fibroblasts, which overexpress the human epidermal growth factor (EGF) receptor, phosphorylate both poly-L-(glutamic acid, tyrosine) and exogenous calmodulin in an EGF-stimulated manner. Phosphorylation of calmodulin requires the presence of cationic polypeptides, such as poly-L-(lysine) or histones, which exert a biphasic effect toward calmodulin phosphorylation. Optimum cationic polypeptide/calmodulin molar ratios of 0.3 and 7 were determined for poly-L-(lysine) and histones, respectively. Maximum levels of calmodulin phosphorylation were attained in the absence of free calcium, and a strong inhibition of this process was observed at very low concentrations (Ki = 0.2 μM) of this cation. The incorporation of phosphate into calmodulin occurred predominantly on tyrosine residue(s) and was stimulated 34-fold by EGF.This work was supported by research grants to A.V. from the Comisión Interministerial de Ciencia y Tecnología (SAF93/392 and SAF96/35) and from the Dirección General de Investigación Científica y Técnica (PR94/343). J.M.-N. is the recipient of a postdoctoral research contract from the Ministerio de Educación y Ciencia.Peer Reviewe

Synthesis of Enantiopure Oxygen- and Nitrogen-Containing Heterocycles by Diastereoselective Ring-Closing Metathesis Reaction in Perhydro-1,3-benzoxazine Derivatives

Producción CientíficaDiastereoselective ring‐closing metathesis reactions on chiral trienic perhydro‐1,3‐benzoxazines derived from (−)‐8‐aminomenthol featuring two diastereotopic olefin chains is described. The diastereochemical outcome of the cyclization appeared to be dependent on the length and position of the olefin chains in perhydro‐1,3‐benzoxazine, the degree of substitution of the double bonds and the ruthenium catalyst used. After separation of the diastereomers, and removal of the chiral auxiliary, enantiopure oxygen‐ and nitrogen‐containing heterocycles were obtained.Ministerio de Economía, Industria y Competitividad (Project FEDER-CTQ2014-59870-P)Junta de Castilla y León (Ref. Project FEDER-VA115P17

Automatic vacant parking places management system using multicamera vehicle detection

This paper presents a multicamera system for vehicles detection and their corresponding mapping into the parking spots of a parking lot. Approaches from the state-of-the-art, which work properly in controlled scenarios, have been validated using small amount of sequences and without more challenging realistic conditions (illumniation changes, different weather). On the other hand, most of them are not complete systems, but provide only parts of them, usually detectors. The proposed system has been designed for realistic scenarios considering different cases of occlussion, ilumination changes and different climatic conditions; a real scenario (the International Pittsburgh Airport parking lot) has been targeted with the condition that existing parking security cameras can be used, avoiding the deployment of new cameras or other sensors infrastructures. For design and validation, a new multicamera dataset has been recorded. The system is based on existing object detectors (the results of two of them are shown) and different proposed postprocessing stages. The results clearly show that the proposed system works correctly in challenging scenarios including almost total occlusions, illumination changes and different weather conditionsThis work has been partially supported by the Spanish Government FPU grant programme (Ministerio de Educación, Cultura y Deporte) and by the Spanish government under the project TEC2014-53176-R (HAVideo