Oxidation-dependent regulation of the selective autophagy receptor SQSTM1/p62

PhD ThesisOxidative stress and impairment of autophagy can lead to the accumulation and aggregation of damaged proteins, a common feature of most age-related neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. SQSTM1/p62, a receptor and a substrate of selective autophagy, is implicated in the degradation of damaged and polyubiquitinated substrates. Importantly, p62 has been detected in many types of protein inclusions found in neurodegenerative diseases, together with other disease-related proteins. However, the mechanisms allowing p62 to selectively recruit and degrade autophagic substrates in conditions of oxidative stress remain unknown. The aim of this thesis work is to understand the mechanisms underlying the oligomerisation and the aggregation of p62 during oxidation, looking at post-translational modifications that can lead to the formation of protein aggregates. We found that p62 senses and is regulated by oxidative stress. In response to oxidation, two cysteine (Cys) residues C105 and C113 of p62 mediate the formation of disulphide-linked conjugates (DLC). The formation of p62 DLC was reduced upon antioxidants addition, while inhibitors of the antioxidant system enhanced their development. This feature was critical for the function of p62 as an autophagy receptor as well as for the accumulation of polyubiquitinated aggregates. Indeed, the accumulation and degradation of p62 and its substrates was impaired following mutation of the Cys residues implicated in DLC formation, while the interaction between p62 and polyubiquitinated substrates was not affected. Oxidation of p62 was also required for cell survival in conditions of oxidative stress, indicating the physiological importance of the correct function of p62 in selective autophagy. In addition, formation of p62 DLC was increased in ageing and age-related neurodegenerative diseases, possibly as a compensatory mechanism to protect cells in increased oxidative conditions. In conclusion, we reveal a new mechanism of p62 oligomerisation aiding the selective autophagy of dysfunctional proteins under oxidative stress conditions.NIHR Newcastle Biomedical Research Centr

Ingresantes en la universidad : rendimiento en química y competencia científica

Se evalúa el rendimiento en Química (RQ) y en la competencia científica (RCC) de un grupo de alumnas y alumnos ingresantes a la Facultad de Bioquímica y Ciencias Biológicas (FBCB), de la Universidad Nacional del Litoral (UNL), Argentina. Para ello se aplican dos pruebas: uno de los reactivos de Química del proyecto PISA para la evaluación de Ciencias, “El catalizador”, y un examen tradicional que condiciona el ingreso de los estudiantes a la Facultad. Se comparan los resultados de la evaluación mediante el reactivo PISA y los del examen. Se observa un elevado número de ingresantes en el nivel bajo de competencia científica. Con el fin de analizar la relación entre las dos variables ordinales (RQ/RCC) se aplica la prueba Tau-b de Kendall. La relación entre ambas variables ordinales, muestra una leve asociación.Se evalúa el rendimiento en Química (RQ) y en la competencia científica (RCC) de un grupo de alumnas y alumnos ingresantes a la Facultad de Bioquímica y Ciencias Biológicas (FBCB), de la Universidad Nacional del Litoral (UNL), Argentina. Para ello se aplican dos pruebas: uno de los reactivos de Química del proyecto PISA para la evaluación de Ciencias, “El catalizador”, y un examen tradicional que condiciona el ingreso de los estudiantes a la Facultad. Se comparan los resultados de la evaluación mediante el reactivo PISA y los del examen. Se observa un elevado número de ingresantes en el nivel bajo de competencia científica. Con el fin de analizar la relación entre las dos variables ordinales (RQ/RCC) se aplica la prueba Tau-b de Kendall. La relación entre ambas variables ordinales, muestra una leve asociación

EFFECTS OF THE APPLICATION OF AN EDUCATIONAL INTERVENTION PROGRAM ON GROSS MOTOR SKILLS IN INDIVIDUALS WITH AUTISM

Introduction: Autism is a neurodevelopment disorder called Autism Spectrum Disorder (ASD); it manifests in childhood, and it is characterized by limitations in social interactions and stereotyped behaviors. Objective: to evaluate the gross motor skills (GMS) development through a systematic program of general exercises in four adolescents with ASD. Methodology: conducting a longitudinal case study with two cross-sections; four adolescents aged 12 to14 years participated in a systematic education intervention program oriented to develop gross motor skills in twelve weeks (45-minute interventions, twice a week, one student per teacher). Before and after the systematic education intervention program to develop gross motor skills, the evaluation of students was made with the Assessment of Basic Language and Learning Skills (ABLL – R) score system. Results: after the intervention, the participants presented a positive result in improving physical activities compared to their results before the intervention. The most significant difficulty was in the activities of losing balance followed by a dynamic recovery, with or without objects. At the beginning of the intervention, all the participants presented deficiencies of gross motor skills. After the intervention, they showed an improvement in those skills. Conclusions: although people with ASD have permanent disabilities, the physical activity educationally oriented to adolescents ASD allowed significant progress in gross motor skills

Citicoline in Ophthalmological Neurodegenerative Disease: A Comprehensive Review

Cytidine 5'-diphosphocholine has been widely studied in systemic neurodegenerative diseases, like Alzheimer's disease, Parkinson's disease, and brain ischemia. The rationale for the use of citicoline in ophthalmological neurodegenerative diseases, including glaucoma, anterior ischemic optic neuropathy, and diabetic retinopathy, is founded on its multifactorial mechanism of action and the involvement in several metabolic pathways, including phospholipid homeostasis, mitochondrial dynamics, as well as cholinergic and dopaminergic transmission, all being involved in the complexity of the visual transmission. This narrative review is aimed at reporting both pre-clinical data regarding the involvement of citicoline in such metabolic pathways (including new insights about its role in the intracellular proteostasis through an interaction with the proteasome) and its effects on clinical psychophysical, electrophysiological, and morphological outcomes following its use in ophthalmological neurodegenerative diseases (including the results of the most recent prospective randomized clinical trials)

ANÁLISE DA ANOVA POR MEIO DE UM PROJETO DE INVESTIGAÇÃO

Statistics plays an important role in curricula, not only for university education, but also for middle and high school education. The changes that have occurred in recent years in the field of science and technology have generated a constant modernization of education; therefore, it becomes necessary for teachers to apply new didactic strategies that allow students to develop their learning processes. In this sense, the teaching of Statistics through research projects stands as one of the most appropriate pedagogical proposals for such purposes. Under this premise, the teachers in charge of the Statistics course of Licenciatura en Nutrición, Bioquímica and Licenciatura en Biotecnología from the Facultad de Bioquímica y Ciencias Biológicas de la Universidad Nacional del Litoral, Santa Fe, Argentina, proposed to address the content analysis of variance (ANOVA) under this methodology in order to analyze its impact. Teachers of Statistics courses worked with students from the Licenciatura en Nutrición, Licenciatura en Biotecnología y Bioquímica that attended Statistics course in 2018. After implementing the strategy, the students had to submit a report on the development and resolution of the proposed project. A statistically significant difference was observed between the group of students evaluated with this methodology in relation to those students evaluated in previous years where it was not applied. According to the observed results, we can be infer that the strategy would have a favorable action in the teaching-learning process of the topic, at least in those careers focused on health, biology or technique.La Estadística juega un papel importante en los currículums, no solo de formación universitaria, sino también secundaria. Los cambios ocurridos en los últimos años en el ámbito de las ciencias y tecnologías, han generado una constante modernización de la educación; por lo que se torna necesario que los docentes apliquen nuevas estrategias didácticas que permitan desarrollar los procesos de aprendizaje de los estudiantes. En este sentido la enseñanza de la Estadística por proyectos de investigación se erige como una de las propuestas pedagógicas más apropiada para tales fines. Bajo esta premisa, los docentes a cargo de la asignatura Estadística de las carreras Licenciatura en Nutrición, Bioquímica y Licenciatura en Biotecnología de la Facultad de Bioquímica y Ciencias Biológicas de la Universidad Nacional del Litoral, propusimos abordar el contenido: análisis de la varianza (ANOVA) bajo esta metodología con el objetivo de analizar su impacto. Se trabajó con alumnos de las carreras: Licenciatura en Biotecnología, Licenciatura en Nutrición y Bioquímica que cursaron Estadística en el año 2018. Luego de implementada la estrategia, los alumnos debían entregar un informe relativo al desarrollo y resolución del proyecto propuesto. Se observó una diferencia estadísticamente significativa entre el grupo de alumnos evaluados con esta metodología en relación con los evaluados de años anteriores en donde no fue aplicada. De acuerdo a los resultados observados, podemos inferir que la estrategia tendría una acción favorable en el proceso de la enseñanza aprendizaje del tema, al menos en aquellas carreras con orientación en salud, biología o técnica.A estatística desempenha um papel importante nos currículos, não apenas no ensino universitário, mas também no ensino médio. As mudanças que ocorreram nos últimos anos no campo da ciência e da tecnologia geraram uma constante modernização da educação; portanto, torna-se necessário que os professores apliquem novas estratégias didáticas que permitam aos alunos desenvolver seus processos de aprendizagem. Nesse sentido, o ensino de Estatística por meio de projetos de pesquisa se destaca como uma das propostas pedagógicas mais apropriadas para tais fins. Sob essa premissa, os professores responsáveis pelo curso de Estatística dos cursos de graduação em Nutrição, Bioquímica e Biotecnologia da Faculdad de Bioquímica e Ciencias Biológicas da Universidad Nacional del Litoral, propuseram abordar o conteúdo análise de variância (ANOVA) sob essa metodologia para analisar seu impacto. Trabalharam com estudantes dos cursos: Biotecnologia, Nutrição e Bioquímica, que cursaram Estatística em 2018. Após a implementação da estratégia, os alunos tiveram que enviar um relatório sobre o desenvolvimento e a resolução do projeto proposto. Observou-se diferença estatística entre o grupo de alunos avaliados com essa metodologia em relação aos avaliados nos anos anteriores quando não foi aplicada a estratégia avaliada. De acordo com os resultados observados, podemos inferir que a estratégia teria favoreceu o processo de ensino-aprendizagem do tópico, pelo menos nas carreiras voltadas à saúde, biologia ou técnica

ANÁLISE DA ANOVA POR MEIO DE UM PROJETO DE INVESTIGAÇÃO

Statistics plays an important role in curricula, not only for university education, but also for middle and high school education. The changes that have occurred in recent years in the field of science and technology have generated a constant modernization of education; therefore, it becomes necessary for teachers to apply new didactic strategies that allow students to develop their learning processes. In this sense, the teaching of Statistics through research projects stands as one of the most appropriate pedagogical proposals for such purposes. Under this premise, the teachers in charge of the Statistics course of Licenciatura en Nutrición, Bioquímica and Licenciatura en Biotecnología from the Facultad de Bioquímica y Ciencias Biológicas de la Universidad Nacional del Litoral, Santa Fe, Argentina, proposed to address the content analysis of variance (ANOVA) under this methodology in order to analyze its impact. Teachers of Statistics courses worked with students from the Licenciatura en Nutrición, Licenciatura en Biotecnología y Bioquímica that attended Statistics course in 2018. After implementing the strategy, the students had to submit a report on the development and resolution of the proposed project. A statistically significant difference was observed between the group of students evaluated with this methodology in relation to those students evaluated in previous years where it was not applied. According to the observed results, we can be infer that the strategy would have a favorable action in the teaching-learning process of the topic, at least in those careers focused on health, biology or technique.La Estadística juega un papel importante en los currículums, no solo de formación universitaria, sino también secundaria. Los cambios ocurridos en los últimos años en el ámbito de las ciencias y tecnologías, han generado una constante modernización de la educación; por lo que se torna necesario que los docentes apliquen nuevas estrategias didácticas que permitan desarrollar los procesos de aprendizaje de los estudiantes. En este sentido la enseñanza de la Estadística por proyectos de investigación se erige como una de las propuestas pedagógicas más apropiada para tales fines. Bajo esta premisa, los docentes a cargo de la asignatura Estadística de las carreras Licenciatura en Nutrición, Bioquímica y Licenciatura en Biotecnología de la Facultad de Bioquímica y Ciencias Biológicas de la Universidad Nacional del Litoral, propusimos abordar el contenido: análisis de la varianza (ANOVA) bajo esta metodología con el objetivo de analizar su impacto. Se trabajó con alumnos de las carreras: Licenciatura en Biotecnología, Licenciatura en Nutrición y Bioquímica que cursaron Estadística en el año 2018. Luego de implementada la estrategia, los alumnos debían entregar un informe relativo al desarrollo y resolución del proyecto propuesto. Se observó una diferencia estadísticamente significativa entre el grupo de alumnos evaluados con esta metodología en relación con los evaluados de años anteriores en donde no fue aplicada. De acuerdo a los resultados observados, podemos inferir que la estrategia tendría una acción favorable en el proceso de la enseñanza aprendizaje del tema, al menos en aquellas carreras con orientación en salud, biología o técnica.A estatística desempenha um papel importante nos currículos, não apenas no ensino universitário, mas também no ensino médio. As mudanças que ocorreram nos últimos anos no campo da ciência e da tecnologia geraram uma constante modernização da educação; portanto, torna-se necessário que os professores apliquem novas estratégias didáticas que permitam aos alunos desenvolver seus processos de aprendizagem. Nesse sentido, o ensino de Estatística por meio de projetos de pesquisa se destaca como uma das propostas pedagógicas mais apropriadas para tais fins. Sob essa premissa, os professores responsáveis pelo curso de Estatística dos cursos de graduação em Nutrição, Bioquímica e Biotecnologia da Faculdad de Bioquímica e Ciencias Biológicas da Universidad Nacional del Litoral, propuseram abordar o conteúdo análise de variância (ANOVA) sob essa metodologia para analisar seu impacto. Trabalharam com estudantes dos cursos: Biotecnologia, Nutrição e Bioquímica, que cursaram Estatística em 2018. Após a implementação da estratégia, os alunos tiveram que enviar um relatório sobre o desenvolvimento e a resolução do projeto proposto. Observou-se diferença estatística entre o grupo de alunos avaliados com essa metodologia em relação aos avaliados nos anos anteriores quando não foi aplicada a estratégia avaliada. De acordo com os resultados observados, podemos inferir que a estratégia teria favoreceu o processo de ensino-aprendizagem do tópico, pelo menos nas carreiras voltadas à saúde, biologia ou técnica

Calidad de la dieta y su relación con estados de estrés, ansiedad y depresión en estudiantes universitarios

Objetivo: Evaluar la asociación entre calidad de la alimentación y nivel de estrés, ansiedad y depresión en universitarios

Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis.

Cellular homoeostatic pathways such as macroautophagy (hereinafter autophagy) are regulated by basic mechanisms that are conserved throughout the eukaryotic kingdom. However, it remains poorly understood how these mechanisms further evolved in higher organisms. Here we describe a modification in the autophagy pathway in vertebrates, which promotes its activity in response to oxidative stress. We have identified two oxidation-sensitive cysteine residues in a prototypic autophagy receptor SQSTM1/p62, which allow activation of pro-survival autophagy in stress conditions. The Drosophila p62 homologue, Ref(2)P, lacks these oxidation-sensitive cysteine residues and their introduction into the protein increases protein turnover and stress resistance of flies, whereas perturbation of p62 oxidation in humans may result in age-related pathology. We propose that the redox-sensitivity of p62 may have evolved in vertebrates as a mechanism that allows activation of autophagy in response to oxidative stress to maintain cellular homoeostasis and increase cell survival

Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with {MeCP}2 non-sense mutations

Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder which affects about 1: 10000 live births. In >95% of subjects RTT is caused by a mutation in Methyl-CpG binding protein-2 (MECP2) gene, which encodes for a transcription regulator with pleiotropic genetic/epigenetic activities. The molecular mechanisms underscoring the phenotypic alteration of RTT are largely unknown and this has impaired the development of therapeutic approaches to alleviate signs and symptoms during disease progression. A defective proteasome biogenesis into two skin primary fibroblasts isolated from RTT subjects harbouring non-sense (early-truncating) MeCP2 mutations (i.e., R190fs and R255X) is herewith reported. Proteasome is the proteolytic machinery of Ubiquitin Proteasome System (UPS), a pathway of overwhelming relevance for post-mitotic cells metabolism. Molecular, transcription and proteomic analyses indicate that MeCP2 mutations down-regulate the expression of one proteasome subunit, α7, and of two chaperones, PAC1 and PAC2, which bind each other in the earliest step of proteasome biogenesis. Furthermore, this molecular alteration recapitulates in neuron-like SH-SY5Y cells upon silencing of MeCP2 expression, envisaging a general significance of this transcription regulator in proteasome biogenesis

Conversion to secondary progressive multiple sclerosis: patient awareness and needs. results from an online survey in Italy and Germany

Background: Few studies have investigated the experiences of patients around the conversion to secondary progressive multiple sclerosis (SPMS). ManTra is a mixed-method, co-production research project conducted in Italy and Germany to develop an intervention for newly-diagnosed SPMS patients. In previous project actions, we identified the needs and experiences of patients converting to SPMS via literature review and qualitative research which involved key stakeholders.Aims: The online patient survey aimed to assess, on a larger and independent sample of recently-diagnosed SPMS patients: (a) the characteristics associated to patient awareness of SPMS conversion; (b) the experience of conversion; (c) importance and prioritization of the needs previously identified.Methods: Participants were consenting adults with SPMS since <= 5 years. The survey consisted of three sections: on general and clinical characteristics; on experience of SPMS diagnosis disclosure (aware participants only); and on importance and prioritization of 33 pre-specified needs.Results: Of 215 participants, those aware of their SPMS diagnosis were 57% in Italy vs. 77% in Germany (p = 0.004). In both countries, over 80% of aware participants received a SPMS diagnosis from the neurologist; satisfaction with SPMS disclosure was moderate to high. Nevertheless, 28-35% obtained second opinions, and 48-56% reported they did not receive any information on SPMS. Participants actively seeking further information were 63% in Germany vs. 31% in Italy (p < 0.001).Variables independently associated to patient awareness were geographic area (odds ratio, OR 0.32, 95% CI 0.13-0.78 for Central Italy; OR 0.21, 95% CI 0.08-0.58 for Southern Italy [vs. Germany]) and activity limitations (OR 7.80, 95% CI 1.47-41.37 for dependent vs. autonomous patients).All pre-specified needs were scored a lot or extremely important, and two prioritized needs were shared by Italian and German patients: "physiotherapy" and "active patient care involvement." The other two differed across countries: "an individualized health care plan" and "information on social rights and policies" in Italy, and "psychological support" and "cognitive rehabilitation" in Germany.Conclusions: Around 40% of SPMS patients were not aware of their disease form indicating a need to improve patient-physician communication. Physiotherapy and active patient care involvement were prioritized in both countries