Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder belonging to the group of vacuolating leukodystrophies. It is characterized by megalencephaly, loss of motor functions, epilepsy, and mild mental decline. In brain biopsies of MLC patients, vacuoles were observed in myelin and in astrocytes surrounding blood vessels. It is mainly caused by recessive mutations in MLC1 and HEPACAM (also called GLIALCAM) genes. These disease variants are called MLC1 and MLC2A with both types of patients sharing the same clinical phenotype. Besides, dominant mutations in HEPACAM were also identified in a subtype of MLC patients (MLC2B) with a remitting phenotype. MLC1 and GlialCAM proteins form a complex mainly expressed in brain astrocytes at the gliovascular interface and in Bergmann glia at the cerebellum. Both proteins regulate several ion channels and transporters involved in the control of ion and water fluxes in glial cells, either directly influencing their location and function, or indirectly regulating associated signal transduction pathways. However, the MLC1/GLIALCAM complex function and the related pathological mechanisms leading to MLC are still unknown. It has been hypothesized that, in MLC, the role of glial cells in brain ion homeostasis is altered in both physiological and inflammatory conditions. There is no therapy for MLC patients, only supportive treatment. As MLC2B patients show an MLC reversible phenotype, we speculated that the phenotype of MLC1 and MLC2A patients could also be mitigated by the re-introduction of the correct gene even at later stages. To prove this hypothesis, we injected in the cerebellar subarachnoid space of Mlc1 knockout mice an adeno-associated virus (AAV) coding for human MLC1 under the control of the glial-fibrillary acidic protein promoter. MLC1 expression in the cerebellum extremely reduced myelin vacuolation at all ages in a dose-dependent manner. This study could be considered as the first preclinical approach for MLC. We also suggest other potential therapeutic strategies in this review

Megalencephalic Leukoencephalopathy : Insights Into Pathophysiology and Perspectives for Therapy

UDHEBRONMegalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder belonging to the group of vacuolating leukodystrophies. It is characterized by megalencephaly, loss of motor functions, epilepsy, and mild mental decline. In brain biopsies of MLC patients, vacuoles were observed in myelin and in astrocytes surrounding blood vessels. It is mainly caused by recessive mutations in MLC1 and HEPACAM (also called GLIALCAM) genes. These disease variants are called MLC1 and MLC2A with both types of patients sharing the same clinical phenotype. Besides, dominant mutations in HEPACAM were also identified in a subtype of MLC patients (MLC2B) with a remitting phenotype. MLC1 and GlialCAM proteins form a complex mainly expressed in brain astrocytes at the gliovascular interface and in Bergmann glia at the cerebellum. Both proteins regulate several ion channels and transporters involved in the control of ion and water fluxes in glial cells, either directly influencing their location and function, or indirectly regulating associated signal transduction pathways. However, the MLC1/GLIALCAM complex function and the related pathological mechanisms leading to MLC are still unknown. It has been hypothesized that, in MLC, the role of glial cells in brain ion homeostasis is altered in both physiological and inflammatory conditions. There is no therapy for MLC patients, only supportive treatment. As MLC2B patients show an MLC reversible phenotype, we speculated that the phenotype of MLC1 and MLC2A patients could also be mitigated by the re-introduction of the correct gene even at later stages. To prove this hypothesis, we injected in the cerebellar subarachnoid space of Mlc1 knockout mice an adeno-associated virus (AAV) coding for human MLC1 under the control of the glial-fibrillary acidic protein promoter. MLC1 expression in the cerebellum extremely reduced myelin vacuolation at all ages in a dose-dependent manner. This study could be considered as the first preclinical approach for MLC. We also suggest other potential therapeutic strategies in this review

La connectivitat ecològica a Catalunya: un estudi a través de l'ecologia del paisatge

Treballs Finals de Grau en Geografia, Facultat de Geografia i Història, Universitat de Barcelona, Curs: 2017-2018, Tutor: Carles Barriocanal LozanoLa societat contemporània és testimoni de l’actual crisi de biodiversitat: una crisi que porta associada el que molts experts han anomenat la sisena gran extinció. Aquesta, a diferència de les anteriors, té un origen totalment diferent: l'ésser humà. Per ésser humà, per suposat, entenem totes aquelles activitats que aquest, com a societat, desenvolupa. Aquestes activitats tenen un impacte sobre el territori, i els paisatges en són u n viu reflex. La urbanització accelerada, la destrucció d’ àrees naturals, les substitucions de cultius, el traçat de cada vegada més infraestructures lineals de transport i, en general, els canvis en l'ús del sol, són els clars responsables de l'augment de la fragmentació del territori i, com a conse üencia directe, deis habitats naturals. És per això que l'Ecologia del Paisatge, nodrida de la Geografia i l'Ecologia, es posiciona com u na disciplina útil en aquest àmbit, ja que permet estudiar i analitzar molts deis canvis soferts precisament sobre el seu objecte d'estudi des d'una òptica i amb uns mètodes innovadors. Els models de conservació habitualment desplegats pels Estats s'han provat altament ineficaços en la lluita contra l'extinció d'espècies i la gestió deis ecosistemes i les seves comunitats. Des del món científic s'advoca per nous models de conservació, basats en xarxes ecològiques que permetin reduir la fragmentació deis habitats tot permeabilitzant el territori. Catalunya no n'és u na excepció i, tot i que s'han endegat certes iniciatives en la planificació territorial i sectorial, encara queda camí per recórrer. El present treball tracta de recollir el cos teòric i metodològic d'aquesta disciplina , d'analitzar els canvis en els usos del sol i l'estat de fragmentació dels habitats a Catalunya, valorar el model de conservació i tractar de millorar-lo dissenyant una proposta de corredors ecològics en una de les àrees identificades com a clau al territori català, tot aprofitant les avantatges i eines que ofereixen els Sistemes d' Informació Geogràfica

Análisis de los Fenómenos de Transporte y Ruido Electrónico en Transistores MOSFET y SOI Submicrométricos

[ES]En este trabajo hemos desarrollado un simulador bidimensional Monte Carlo de Dispositivos de Silicio basado en un modelo microscópico con el fin de investigar los procesos de transporte de carga y el ruido electrónico a alta frecuencia en transistores de efecto de campo Metal-Óxido-Semiconductor (MOSFET) convencionales y Silicon-On-Insulator (SOI). La principal aportación de este trabajo radica en la utilización de una única herramienta de simulación numérica para el estudio global del comportamiento de los dispositivos, lo que constituye una aproximación altamente novedosa al problema con respecto a los estudios usualmente encontrados en la literatura. El escalado de los dispositivos MOSFET convencionales por debajo del cuarto de micra ha sido analizado en profundidad, encontrándose discrepancias con respecto a las predicciones del escalado ideal en algunas de las principales figuras de mérito. Asimismo, se ha evaluado el efecto de variar de manera aislada algunos parámetros dado su interés desde el punto de vista tecnológico, tales como la longitud de puerta o la impurificación del substrato. Las características del simulador han permitido efectuar un análisis comparativo global entre estructuras MOSFET convencionales y SOI con topologías totalmente equivalentes, lo que consituye una importante novedad dentro del estudio de este tipo de estructuras a nivel internacional. Finalmente, se ha procedido al estudio de estructuras SOI fabricadas en laboratorio, obteniéndose un acuerdo altamente satisfactorio entre los resultados de la simulación y las medidas experimentales para los principales parámetros estáticos, dinámicos y de ruido a alta frecuencia. El comportamiento de estos parámetros ha sido interpretado en relación con las principales magnitudes internas del transporte en los dispositivos. También se ha efectuado un análisis de las posibilidades de optimización de los dispositivos experimentales mediante el estudio de la variación de determinados parámetros de interés de la topología de los mismos

Enseñando ajedrez a niños con dibujos animados

Esta tesina profesional trata sobre la creación de una pieza audiovisual con el objeto de familiarizar a niños de cuatro años con el ajedrez. En ella se explica detalladamente todos los contenidos que se han realizado en las distintas etapas de preproducción, producción y postproducción. La idea clave del proyecto es la adaptación de la animación a una estética dirigida a un público infantil, mediante el diseño de dibujos animados en 2D, empleando los conocimientos aprendidos en el máster de Postproducción digital.This professional thesis is about the creation of an audiovisual piece in order to familiarize four years children with chess. It explains in detail all the contents that have been made in different stages of preproduction, production and postproduction. The key idea of the project is the adaptation of animation to an aesthetics focused at children, by designing in 2D cartoons using the knowledge learned in the master of digital postproduction.Estévez Montero, R. (2015). Enseñando ajedrez a niños con dibujos animados. Universitat Politècnica de València. http://hdl.handle.net/10251/56795TFG

Valoración comparativa de la eco-eficiencia de los paneles de madera contralaminada

La aparición de nuevas tecnologías y sistemas de construcción están dando lugar a nuevos materiales que pueden sustituir a los hasta ahora conocidos. Los paneles de madera contralaminada tienen gran libertad de diseño y sus posibilidades de uso son prácticamente ilimitadas. El proyecto se centra en el análisis comparativo entre los paneles de madera contralaminada y los materiales de construcción convencional en cuanto a costo, rendimiento y eficiencia energética. Los resultados demuestran que en cuanto a estos tres parámetros, se pueden construir edificios con paneles de madera contralaminada de forma sostenible con un balance ecológico positivo

Expression of LRRC8/VRAC currents in Xenopus oocytes: advantages and caveats

Volume-regulated anion channels (VRACs) play a role in controlling cell volume by opening upon cell swelling. Apart from controlling cell volume, their function is important in many other physiological processes, such as transport of metabolites or drugs, and extracellular signal transduction. VRACs are formed by heteromers of the pannexin homologous protein LRRC8A (also named Swell1) with other LRRC8 members (B, C, D, and E). LRRC8 proteins are difficult to study, since they are expressed in all cells of our body, and the channel stoichiometry can be changed by overexpression, resulting in non-functional heteromers. Two different strategies have been developed to overcome this issue: complementation by transient transfection of LRRC8 genome-edited cell lines, and reconstitution in lipid bilayers. Alternatively, we have used Xenopus oocytes as a simple system to study LRRC8 proteins. Here, we have reviewed all previous experiments that have been performed with VRAC and LRRC8 proteins in Xenopus oocytes. We also discuss future strategies that may be used to perform structure-function analysis of the VRAC in oocytes and other systems, in order to understand its role in controlling multiple physiological functions

Chloride channels in astrocytes: structure, roles in brain homeostasis and implications in disease

Astrocytes are the most abundant cell type in the CNS (central nervous system). They exert multiple functions during development and in the adult CNS that are essential for brain homeostasis. Both cation and anion channel activities have been identified in astrocytes and it is believed that they play key roles in astrocyte function. Whereas the proteins and the physiological roles assigned to cation channels are becoming very clear, the study of astrocytic chloride channels is in its early stages. In recent years, we have moved from the identification of chloride channel activities present in astrocyte primary culture to the identification of the proteins involved in these activities, the determination of their 3D structure and attempts to gain insights about their physiological role. Here, we review the recent findings related to the main chloride channels identified in astrocytes: the voltage-dependent ClC-2, the calcium-activated bestrophin, the volume-activated VRAC (volume-regulated anion channel) and the stress-activated Maxi-Cl−. We discuss key aspects of channel biophysics and structure with a focus on their role in glial physiology and human disease

Identification and characterization of the zebrafish ClC-2 chloride channel orthologs

ClC-2 is a Cl− channel that belongs to the CLC family of chloride channel/transport proteins. ClC-2 molecular role is not clear, and Clcn2 knockout mice develop blindness, sterility, and leukodystrophy by unknown reasons. ClC-2 is associated in the brain with the adhesion molecule GlialCAM, which is defective in a type of leukodystrophy, involving ClC-2 in the homeostasis of myelin. To get more insight into the functions of ClC-2, we have identified in this work the three ClC-2 orthologs in zebrafish. clcn2a and clcn2b resulted from the teleost-specific whole genome duplication, while clcn2c arose from a gene duplication from clcn2b. The expression patterns in adult tissues and embryos of zebrafish clcn2 paralogs support their subfunctionalization after the duplications, with clcn2a being enriched in excitable tissues and clcn2c in ionocytes. All three zebrafish clc-2 proteins interact with human GLIALCAM, that is able to target them to cell junctions, as it does with mammalian ClC-2. We could detect clc-2a and clc-2b inward rectified chloride currents with different voltage-dependence and kinetics in Xenopus oocytes, while clc-2c remained inactive. Interestingly, GlialCAM proteins did not modify clc-2b inward rectification. Then, our work extends the repertoire of ClC-2 proteins and provides new tools for structure-function and physiology studies

Elaboración de cuadernos para el aprendizaje autónomo de la resolución de ejercicios en asignaturas básicas de Electrónica

Memoria ID-0199. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2017-2018