Análisis genético y funcional de la frataxina y otras proteínas mitocrondriales relacionadas con ataxias cerebelosas.

RESUMEN El déficit de frataxina es la causa principal de la ataxia de Friedreich, una enfermedad hereditaria neurodegenerativa que afecta a las neuronas sensitivas del ganglio dorsal y del tracto espinocerebelar. Desde que se describi¨® el gen responsable de la enfermedad y sobre todo gracias a la generaci¨®n de organismos modelos para su estudio, se han postulado diferentes funciones para la frataxina: homeostasis del hierro mitocondrial, almacenamiento del hierro, respuesta al estr¨¦s oxidativo. Biog¨¦nesis de los clusters Fe-S, modulaci¨®n en la actividad de la aconitasa mitocondrial y un papel en la fosforilaci¨®n oxidativa. Nuestro planteamiento ha sido que la frataxina realiza su funci¨®n en la mitocondria mediante la interacci¨®n con otras prote¨ªnas y es posible que participe en diferentes procesos biol¨®gicos mitocondriales interactuando con distintas prote¨ªnas en cada uno de ellos. Por lo tanto, el objetivo del trabajo de tesis era la identificaci¨®n de prote¨ªnas capaces de interaccionar con Yfh1p, la frataxina de Sacchararomyces cerevisiae. En este trabajo mostramos que Yfh1p interacciona f¨ªsicamente con proteinas de la cadena de transporte de electrones mitocondrial. Hemos demostrado que Yfh1p coinmunoprecipita con succinato deshidrogenasa, concretamente con las subunidades Sdh1p y Sdh2p, de la cadena de transporte electr¨®nico mitocondrial de levadura, y tambi¨¦n con las subunidades ETFa y ETFb de la flavoprote¨ªna transferidora de electrones. Con el fin de confirmar la relaci¨®n funcional entre YFH1 y los genes SDH estudiamos si ambos genes manifestaban interacci¨®n sint¨¦tica. Nuestros resultados permiten afirmar que existe una relaci¨®n funcional entre el gen YFH1 y los genes de succinato deshidrogenasa SDH1 y SDH2, y seguramente su relaci¨®n sea a nivel de la misma ruta bioqu¨ªmica. Tambi¨¦n hemos demostrado una interacci¨®n f¨ªsica entre la frataxina humana y las subunidades SDHA y SDHB de la succinato deshidrogenasa humana. De estos hallazgos se infiere que la capacidad de interaccionar de frataxina con el complejo II de la cadena de transporte electr¨®nico est¨¢ conservada en humanos, sugiriendo que la frataxina tiene un papel en la cadena de transporte electr¨®nico mitocondrial en humanos. Nosotros planteamos que la frataxina puede intervenir en la entrada de electrones a la cadena de transporte electr¨®nico. Por lo tanto, proponemos una participaci¨®n directa de la cadena respiratoria en la patog¨¦nesis de la ataxia de Friedreich, la cual entendemos que se puede considerar como una enfermedad de la fosforilaci¨®n oxidativa (OXPHOS). Desde el descubrimiento de la frataxina y su localizaci¨®n como mol¨¦cula de la matriz mitocondrial, la ataxia de Friedreich se ha convertido en el prototipo de enfermedad mitocondrial causada por un gen nuclear. No obstante, no es la ¨²nica ataxia que se puede considerar como mitocondrial. Otro ejemplo es la anemia siderobl¨¢stica ligada al X asociada con ataxia cerebelosa (XLSA/A), causada por mutaciones en el gen del transportador mitocondrial ABC7. Esta enfermedad est¨¢ directamente relacionada con la homeostasis del hierro, al igual que la ataxia de Friedreich. Realizamos el aislamiento y caracterizaci¨®n del gen hom¨®logo del ABC7 en Caenorhabditis elegans y posteriormente la generaci¨®n de un knock-donw transitorio en C. elegans para el gen Y74C10AM.1 por RNAi. Los gusanos Y74C10AM.1(RNAi) presentan el siguiente fenotipo: letalidad embrionaria (Emb), retraso en el crecimiento (Gro), reducci¨®n en la puesta de huevos (Egl), defecaci¨®n alterada y aumento en la longevidad. Este fenotipo es similar a otros fenotipos asociados a mutantes transitorios de genes relacionados con la biog¨¦nesis de los clusters Fe-S en levadura. __________________________________________________________________________________________________Frataxin deficiency causes Friedreich ataxia, a neurodegenerative genetic disorder affecting sensory neurons of dorsal root ganglia and spinocerebellar tracts. Physiological function of frataxin in mitochondria has not been established yet, although several hypotheses have been postulated including mitochondrial iron homeostasis, iron storing, response to oxidative stress, iron-sulphur cluster biogenesis, modulation of mitochondrial aconitase activity and a role in oxidative phosphorylation. We showed that frataxin and its orthologue Saccharomyces cerevisiae, Yfh1p, interacts physically with proteins from the mitochondrial electron transfer chain. We demonstrated that Yfh1p co-immunoprecipitates with yeast succinate dehydrogenase complex subunits Sdh1p and Sdh2p, and with yeast orthologues of the electron transfer flavoprotein complex subunits ETFa and ETF¦Â. Genetic synthetic interaction experiments confirmed a functional relationship between YFH1 and succinate dehydrogenase genes SDH1 and SDH2. We postulate that Yfh1p might regulate the delivery of electrons via complex II and ETF systems towards ubiquinone in yeast. We also demonstrate a physical interaction between human frataxin and human succinate dehydrogenase complex subunits, suggesting also a key role of frataxin in the mitochondrial electron transport chain in humans. Consequently, we postulate a direct participation of the respiratory chain in the pathogenesis of the Friedreich ataxia, which we propose to be considered as an OXPHOS disease. Since the discovery of frataxin and its location within the mitocondrial matrix, Friedreich ataxia has become the prototype of mitocondrial disease caused by a nuclear gene. However, it is not the unique Mendelian ataxia that can be considered mitocondrial. Another example is the X-linked sideroblastic anemia with ataxia (XLSA/A), due to mutations in the gene encoding the mitocondrial transporter ABC7. This disease is directly related to the iron homeostasis, as Friedreich ataxia. We have characterized the genomic structure of Y74C10AM.1, the Caenorhabditis elegans ABC7 gene, and we have developed a transient knock-down model of C. elegans ABC7 deficiency by RNA interference. Y74C10AM.1(RNAi) worms show a phenotype that includes embryonic lethality (Emb), slow growth (Gro), egg laying defects (Egl), altered defecation and lifespan increase. This phenotype is similar to other phenotypes associated to transient knock-down models in C. elegans of genes related to the iron-sulphur cluster biogenesis in yeast

Comics in the classroom: graphic narrative to promote active learning in the teaching of physiology in the Degree in Human Nutrition and Dietetics

[EN] The use of graphic material as support in the teaching of basic disciplines in Health Sciences constitutes a key factor in the teaching-learning process. Traditionally said graphic material have consisted of illustrations and diagrams, although in recent years the availability of audiovisual multimedia materials has boosted the use of these resources in the classroom. In the present work, we propose the use of activities that combine the potential of images with the typical narrative characteristic of comic-books, thus enhancing the narrative potential, the emotional impact and the ability to stimulate critical thinking inherent in said format. For this, we use two specific works for different tutoring activities in subjects from different courses of the Degree in Human Nutrition and Dietetics, and we evaluate the students' perception of their usefulness as academic resources, on the motivation to review concepts of the subjects, as well as on the characteristics of the comics used as teaching materials. The preliminary results obtained show a positive reception by students and suggest an important potential of comics to work on concepts and generate relevant debates in the context of the Degree in Human Nutrition and Dietetics.[ES] La utilización de material gráfico como apoyo en la enseñanza de disciplinas básicas en Ciencias de la Salud constituye un factor clave en el proceso de enseñanza-aprendizaje. Tradicionalmente dicho material gráfico ha consistido en ilustraciones y esquemas, aunque durante los últimos años la disponibilidad de materiales multimedia audiovisuales ha provocado un auge de estos recursos en las aulas. En el presente trabajo, planteamos la utilización de actividades que aúnan el potencial de la imagen con la narrativa típica del formato característico del cómic, potenciando así el carácter narrativo, el impacto emocional y la capacidad de estimular el pensamiento crítico inherentes a dicho formato. Para ello, utilizamos dos obras específicas para diferentes actividades de tutorización en asignaturas de distintos cursos del Grado de Nutrición Humana y Dietética, y evaluamos la percepción de los estudiantes sobre su utilidad como recursos académicos, sobre la motivación para repasar conceptos de las asignaturas, así como sobre las características de los cómics utilizados como material docente. Los resultados preliminares obtenidos muestran una recepción positiva por parte de los estudiantes y sugieren un importante potencial de los cómics para trabajar conceptos y generar debates de relevancia en el contexto del Grado de Nutrición humana y Dietética.Romá-Mateo, C.; González-Cabo, P.; Olaso-González, G. (2022). Cómics en el aula: narrativa gráfica para potenciar el aprendizaje activo en la enseñanza de la fisiología en el Grado en Nutrición Humana y Dietética. Editorial Universitat Politècnica de València. 807-818. https://doi.org/10.4995/INRED2022.2022.1581580781

Survival of lactic acid bacteria in sea water. A factorial study

6 páginas, 3 figuras, 4 tablas.-- The final publication is available at www.springerlink.comA feasibility study of lactic bacteria as potential probiotics in larval cultures of marine fish was performed by investigating the survival of five strains of lactic bacteria in seawater by readily standardized procedures at different temperatures and salinities. These conditions were chosen in such a way that their combinations define a complete first-order factorial design. Depending on the strain and the ambient conditions, the survival adhered to first-order kinetics in some cases, and to the Gompertz equation in others. The half lives (t0.5) calculated from these models were subsequently introduced as responses to the factorial designs, estimating the coefficients of empirical equations that describe the group effect of temperature and salinity on t0.5. Simply additive effects were found in two cases, a negative first-order interaction in another case, while another two required second-order models.Xunta de Galicia (Project PGIDT99MAR40203)Peer reviewe

Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich's ataxia

Frataxin (FXN) deficiency causes Friedreich's ataxia (FRDA), a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG), sensory nerves, dorsal columns and other central nervous structures. A dying-back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, affected individuals have non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies, we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in the posterior columns and brain, which agree with the existence of a dying-back process similar to that described in individuals with FRDA. In YG8R mice, we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cells might underlie the nerve pathology. In the pancreas, we found a high proportion of senescent islets of Langerhans in YG8R mice, which decreases the β-cell number and islet mass to pathological levels, being unable to maintain normoglycemia. As a whole, these results confirm that the lack of FXN induces different pathogenic mechanisms in the nervous system and pancreas in the mouse model of FRDA: dying back of the sensory nerves, and pancreatic senescence.This work was supported by grants from Ministerio de Economía y Competitividad (Spanish Ministry of Economy and Competitiveness) [grant no. PI11/00678] within the framework of the National R+D+I Plan and co-funded by the Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y Fomento de la Investigación and FEDER funds; the European Community's Seventh Framework Programme FP7/2007-2013 [grant agreement no. 242193 EFACTS]; the Generalitat Valenciana (Prometeo programme); the Fundació la Marató de TV3; the Fundación Alicia Koplowitz. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) is an initiative developed by the Instituto de Salud Carlos III in cooperative and translational research on rare diseases.Peer Reviewe

La reforma de la formación inicial del profesorado de ciencias de secundaria: propuesta de un diseño del currículo basado en competencias

El principal objetivo de este trabajo es proponer un mecanismo de selección de competencias específicas para la formación inicial del profesorado de ciencias experimentales, contando para ello con distintas fuentes relevantes para dicha formación. Con tal fin hemos hecho uso de un procedimiento consistente en ir incorporando de forma crítica las competencias procedentes de las siguientes fuentes curriculares: los modelos de formación inicial del profesorado vigentes en la literatura educativa, el currículo actual de ciencias en la educación secundaria obligatoria en España, el Programa internacional de evaluación PISA, la opinión del profesorado en activo mediante una encuesta cuyos resultados más relevantes son mostrados, las concepciones epistemológicas del profesorado, la profesionalización docente y las demandas que genera y, finalmente, la dimensión social de la ciencia.The primary objective of this paper is to propose a mechanism for selecting specific competences for preservice science teacher training, referring to relevant sources for such training. To this end we have used an trans-disciplinary procedure consistent with incorporating critical competences from the following curricular sources: Models of current preservice teacher training in educational literature, the current curriculum of Science in Compulsory Secondary Education in Spain, the Program for International Student Assessment (PISA), the views of in-service secondary school teachers (through a survey whose most relevant results are given), teachers' epistemological conceptions, the professionalization of teaching and the demands it generates and, finally the social dimension of science

Antioxidant therapies and oxidative stress in Friedreich's ataxia: the right path or just a diversion?

Friedreich's ataxia is the commonest autosomal recessive ataxia among population of European descent. Despite the huge advances performed in the last decades, a cure still remains elusive. One of the most studied hallmarks of the disease is the increased production of oxidative stress markers in patients and models. This feature has been the motivation to develop treatments that aim to counteract such boost of free radicals and to enhance the production of antioxidant defenses. In this work, we present and critically review those 'antioxidant' drugs that went beyond the disease's models and were approved for its application in clinical trials. The evaluation of these trials highlights some crucial aspects of the FRDA research. On the one hand, the analysis contributes to elucidate whether oxidative stress plays a central role or whether it is only an epiphenomenon. On the other hand, it comments on some limitations in the current trials that complicate the analysis and interpretation of their outcome. We also include some suggestions that will be interesting to implement in future studies and clinical trials

La reforma de la formación inicial del profesorado de ciencias de secundaria: propuesta de un diseño del currículo basado en competencias

El principal objetivo de este trabajo es proponer un mecanismo de selección de competencias específicas para la formación inicial del profesorado de ciencias experimentales, contando para ello con distintas fuentes relevantes para dicha formación. Con tal fin hemos hecho uso de un procedimiento consistente en ir incorporando de forma crítica las competencias procedentes de las siguientes fuentes curriculares: los modelos de formación inicial del profesorado vigentes en la literatura educativa, el currículo actual de ciencias en la educación secundaria obligatoria en España, el Programa internacional de evaluación PISA, la opinión del profesorado en activo mediante una encuesta cuyos resultados más relevantes son mostrados, las concepciones epistemológicas del profesorado, la profesionalización docente y las demandas que genera y, finalmente, la dimensión social de la ciencia.The primary objective of this paper is to propose a mechanism for selecting specific com petences for preservice science teacher training, referring to relevant sources for such training. To this end we have used an trans-disciplinary procedure consistent with incorporating critical competences from the following curricular sources: Models of current preservice teacher training in educational literature, the current curriculum of Science in Compulsory Secondary Education in Spain, the Program for International Student Assessment (PISA), the views of in-service secondary school teachers (through a survey whose most relevant results are given), teachers’ epistemological conceptions, the professionalization of teaching and the demands it generates and, finally the social dimension of science.Departamento de Didáctica de las Ciencias Experimentale

Enfermedades neurológicas hereditarias: genes, mutaciones, clínica y epidemiologia genética (premio Reina Sofía 2004, de prevención de deficiencias)

Esta memoria quiere ser un resumen de los estudios y hallazgos de laboratorio y de las contribuciones científicas de la Unidad de Genética Molecular en el campo de la genética molecular de las enfermedades neurológicas, trastornos que se encuadran en el término de enfermedades raras, así como las aplicaciones en medicina clínica a las que han dado lugar, concretamente por lo que respecta al diagnóstico molecular y al consejo genético. La memoria está dividida en cuatro capítulos que hacen referencia a las ataxias hereditarias, las neuropatías periféricas hereditarias, los trastornos del movimiento y las distrofias musculares. En todos ellos se mencionan explícitamente los aspectos clínicos del diagnóstico molecular, incluidos los diagnósticos prenatal y presintomático, así como el consejo genético

The science of storytelling: different levels of narrative integration in teaching innovation applied to Human Physiology

[EN] The incorporation of narrative features into teaching materials of different formats, such as graphic and audiovisual ones, has proven to be an efficient way of encouraging student motivation. Besides, it strengthens the teaching of abstract concepts like those frequent in experimental sciences, such as Physiology, a basic subject in life sciences studies. From the Department of Physiology of the University of Valencia we present the creation of a teaching innovation group focused on the development of Narrative Physiology, FISIONARR, with the aim of promoting the narrative nature of teaching Physiology through two strategic lines. The first one focuses on graphic narrative and its integration as a teaching tool at different levels; the second deals with the generation of audiovisual narrative. In this sense, specific audiovisual material has been prepared for a series of videos entitled " Invisible Physiology", and as a conductive element of the digital educational escape room "Alimental, querida Watson".[ES] La incorporación de elementos narrativos en material docente de distintos formatos gráficos y audiovisuales es una manera eficiente de incentivar la motivación del estudiantado y de reforzar la docencia de conceptos abstractos como los relacionados con ciencias experimentales como la Fisiología, materia básica en estudios de ciencias de la salud. Desde el Departamento de Fisiología de la Universitat de València presentamos la creación de un grupo de innovación docente centrado en el uso de la Fisiología Narrativa, FISIONARR, con el objetivo de potenciar el carácter narrativo de la docencia en Fisiología a través de dos líneas estratégicas. La primera de ellas se centra en la narrativa gráfica y en su integración como herramienta docente a distintos niveles. La segunda trata sobre la generación de narrativa audiovisual y concretamente de ha elaborado material para una serie de videos titulados “La Fisiología Invisible” y como elemento conductor de la escape room educacional digital “Alimental, querida Watson”.Olaso Gonzalez, G.; Calvo Saiz, C.; González Cabo, P.; García Giménez, JL.; Gómez-Cabrera, MC.; Arribas Rodríguez, S.; Gal Iglesias, B.... (2023). La ciencia de contar historias: distintos niveles de integración narrativa en innovación docente aplicada a la Fisiología Humana. Editorial Universitat Politècnica de València. 1050-1060. https://doi.org/10.4995/INRED2023.2023.166551050106

Sleep Problems Are Related to a Worse Quality of Life and a Greater Non-Motor Symptoms Burden in Parkinson’s Disease

COPPADIS Study Group.[Introduction] The aim of the present study was to examine the frequency of self-reported sleep problems and their associated factors in a large cohort of PD patients.[Methods] PD patients and controls, recruited from 35 centers of Spain from the COPPADIS cohort were included in this cross-sectional study. Sleep problems were assessed by the Spanish version of the Parkinson’s disease Sleep Scale version 1 (PDSS-1). An overall score below 82 or a score below 5 on at least 1 item was defined as sleep problems.[Results] The frequency of sleep problems was nearly double in PD patients compared to controls: 65.8% (448/681) vs 33.5% (65/206) (p < 0.0001). Mean total PDSS score was lower in PD patients than controls: 114.9 ± 28.8 vs 132.8 ± 16.3 (p < 0.0001). Quality of life (QoL) was worse in PD patients with sleep problems compared to those without: PDQ-39SI, 19.3 ± 14 vs 13 ± 11.6 (p < 0.0001); EUROHIS-QoL8, 3.7 ± 0.5 vs 3.9 ± 0.5 (p < 0.0001). Non-motor symptoms burden (NMSS; OR = 1.029; 95%CI 1.015–1.043; p < 0.0001) and impulse control behaviors (QUIP-RS; OR = 1.054; 95%CI 1.009–1.101; p = 0.018) were associated with sleep problems after adjustment for age, gender, disease duration, daily equivalent levodopa dose, H&Y, UPDRS-III, UPDRS-IV, PD-CRS, BDI-II, NPI, VAS-Pain, VAFS, FOGQ, and total number of non-antiparkinsonian treatments.[Conclusion] Sleep problems were frequent in PD patients and were related to both a worse QoL and a greater non-motor symptoms burden in PD. These findings call for increased awareness of sleep problems in PD patients.Peer reviewe