Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expansion of a translated CAG repeat in the N terminus of the huntingtin (htt) protein. Here we describe the generation and characterization of a full-length HD Drosophila model to reveal a previously unknown disease mechanism that occurs early in the course of pathogenesis, before expanded htt is imported into the nucleus in detectable amounts. We find that expanded full-length htt (128Qhtt(FL)) leads to behavioral, neurodegenerative, and electrophysiological phenotypes. These phenotypes are caused by a Ca2+-dependent increase in neurotransmitter release efficiency in 128Qhtt(FL) animals. Partial loss of function in synaptic transmission (syntaxin, Snap, Rop) and voltage-gated Ca2+ channel genes suppresses both the electrophysiological and the neurodegenerative phenotypes. Thus, our data indicate that increased neurotransmission is at the root of neuronal degeneration caused by expanded full-length htt during early stages of pathogenesis.

Leucyl-tRNA synthetase-dependent and -independent activation of a group I intron.

Leucyl-tRNA synthetase (LeuRS) is an essential RNA splicing factor for yeast mitochondrial introns. Intracellular experiments have suggested that it works in collaboration with a maturase that is encoded within the bI4 intron. RNA deletion mutants of the large bI4 intron were constructed to identify a competently folded intron for biochemical analysis. The minimized bI4 intron was active in RNA splicing and contrasts with previous proposals that the canonical core of the bI4 intron is deficient for catalysis. The activity of the minimized bI4 intron was enhanced in vitro by the presence of the bI4 maturase or LeuRS.

Huntingtin interacting proteins are genetic modifiers of neurodegeneration.

Huntington's disease (HD) is a fatal neurodegenerative condition caused by expansion of the polyglutamine tract in the huntingtin (Htt) protein. Neuronal toxicity in HD is thought to be, at least in part, a consequence of protein interactions involving mutant Htt. We therefore hypothesized that genetic modifiers of HD neurodegeneration should be enriched among Htt protein interactors. To test this idea, we identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. This effort led to the identification of 234 high-confidence Htt-associated proteins, 104 of which were found with the yeast method and 130 with the pull downs. We then tested an arbitrary set of 60 genes encoding interacting proteins for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This high-content validation assay showed that 27 of 60 orthologs tested were high-confidence genetic modifiers, as modification was observed with more than one allele. The 45% hit rate for genetic modifiers seen among the interactors is an order of magnitude higher than the 1%-4% typically observed in unbiased genetic screens. Genetic modifiers were similarly represented among proteins discovered using yeast two-hybrid and pull-down/mass spectrometry methods, supporting the notion that these complementary technologies are equally useful in identifying biologically relevant proteins. Interacting proteins confirmed as modifiers of the neurodegeneration phenotype represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, and transcription. Among the modifiers were 17 loss-of-function suppressors of neurodegeneration, which can be considered potential targets for therapeutic intervention. Finally, we show that seven interacting proteins from among 11 tested were able to co-immunoprecipitate with full-length Htt from mouse brain. These studies demonstrate that high-throughput screening for protein interactions combined with genetic validation in a model organism is a powerful approach for identifying novel candidate modifiers of polyglutamine toxicity.

Juventud y universidad: sujetos y escenarios para el debate crítico y autorreflexivo sobre el consumo de sustancias psicoactivas de uso legal e ilegal / Youth and University: Subjects and Scenarios for Critical and Self-Reflective Debate on the Use of Legal and Illegal Psychoactive Drugs / Juventude e universidade: sujeitos e cenários para o debate crítico e autorreflexivo sobre o consumo de substancias psicoativas de uso legal e ilegal

El objetivo de esta investigación fue la comprensión de los motivos que llevaron a un grupo de jóvenes universitarios a optar por el consumo de sustancias psicoactivas de uso legal e ilegal. Se trató de una investigación cualitativa de estudio de caso, con diseño fenomenológico, en la cual participaron 32 estudiantes. Las técnicas investigativas fueron la observación participante, la observación no participante y los grupos focales. Para el análisis de datos se aplicó la distinción de momentos y reducciones fenomenológicas y criterios de codificación abierta, axial y selectiva. Los principales resultados fueron que las sustancias más consumidas son el alcohol, el tabaco y la marihuana, en tanto que las motivaciones se asocian al ámbito familiar, académico, de la relación entre pares, a la decisión personal, el microtráfico de sustancias de uso ilegal y el comercio de sustancias legales. El consumo de drogas resulta de una red de determinaciones sociales, en relación con la cual, la Universidad podría abrir un debate crítico y autorreflexivo en función del sujeto y no de las sustancias.

The purpose of this research was to understand the reasons that led a group of young university students into the use of legal and illegal psychoactive drugs. This is a qualitative case study research, with a phenomenological design, with the participation of 32 students. The research techniques used were participant observation, non-participant observation, and focus groups. For data analysis we applied moment distinction, phenomenological reductions; and open, axial, and selective codification criteria. The main results show that the most used substances are alcohol, tobacco, and marihuana; regarding motivations, these are associated to family and academic settings, relationship with peers, personal decision, micro-traffic of illegal substances, and commerce of legal substances. Drug use turns into a network of social determinations around which the University could open a critical and self-reflective debate, focused on the subject and not on the substances.

O objetivo desta pesquisa foi a compreensao das motivações que levaram uma turma de jovens universitários optar pelo consumo de substancias psicoativas de uso legal e ilegal. Tratou-se de pesquisa qualitativa de estudo de caso, com desenho fenomenológico, na qual participaram 32 discentes. As técnicas investigativas foram a observação participante, observação nao participante e grupos focais. Para a análise de dados aplicou-se a distinção de momentos e reducoes fenomenológicas e criterios de codificação aberta, axial e seletiva. Os principais resultados foram que substancias mais consumidas sao álcool, tabaco e maconha, entanto que as motivações associam-se ao ámbito familiar, académico, do relacionamento entre pares, decisao pessoal, microtráfico de substancias de uso ilegal e comercio de substancias legais. O consumo de droga resulta de uma rede de determinações sociais, em relação com a qual, a universidade poderia abrir debate crítico e autorreflexivo em função do sujeito e nao das substancias.

Curva de crecimiento intrauterino y su aplicación en el diagnósticode restricción del crecimiento intrauterino / Intrauterine growth curve and application in intrauterine growth restriction diagnosis

Introducción: La restricción de crecimiento intrauterino (RCIU) incrementa el riesgo de morbimortalidad perinatal. Su diagnóstico puede variar de acuerdo con las curvas de crecimientode referencia. En el Hospital Nacional Edgardo Rebagliati Martins (HNERM) se usa principalmente la curva de Lubchenco. Objetivos: Construir una curva de crecimiento intrauterino (CCIU) propia del hospital y compararla con la de Lubchenco y la del Ministerio de Salud del Perú (MINSA), en su relación con el diagnóstico de RCIU. Diseño: Estudio observacional, retrospectivo, comparativo. Institución: Departamento de Ginecología y Obstetricia, Servicio de Cuidados Críticos Obstétricos, Hospital Nacional Edgardo Rebagliati Martins, EsSalud, Lima, Perú. Participantes: Neonatos. Métodos: Se revisó la información materna y de los neonatos cuyo parto fue atendido en el HNERM entre el 1 de enero de 2003 y 30 de junio de 2010. Se incluyó gestantes con feto único, con 24 a 43 semanas de gestación, calculadas por fecha de última regla (FUR) confiable y/o ecografía del primer trimestre. Se incluyó 29 239 recién nacidos. La fuente fue la base de datos del Servicio de Vigilancia Fetal del mismo hospital. Se construyó una curva de crecimiento fetal intrauterino (CCIU) y se la comparó con la de Lubchenco y la del MINSA. Se usó t de student, ANOVA y pruebas no paramétricas. Se consideró p < 0,05 para la significancia estadística. Se usó SPSS y Microsoft Excel. Principales medidas de resultados: Curva de crecimiento fetal intrauterino. Resultados: Construida la CCIU, los percentiles de nuestra curva fueron significativamente superiores a los de Lubchenco y a los MINSA. El peso neonatal estuvo influido por la talla materna, el peso pregestacional, edad materna (ANOVA: F = 3,8; F = 214,7 y F = 11,2, respectivamente; p < 0,05), el sexo fetal masculino y la multiparidad (t de student; p < 0,001). Las curvas de crecimiento del MINSA y la de Lubchenco no diagnosticaron un porcentaje significativo.

Obstetrics Critical Care Service, Hospital Nacional Edgardo Rebagliati Martins (HNERM), EsSalud, Lima, Peru. Participants: Neonates. Methods: We reviewed information of mothers and neonates born at HNERM between January 1, 2003, and June 30, 2010. Mothers with only one fetus were included, 24 to 43 weeks of gestation by reliable last menstrual period and/or first trimester ultrasound exam; 29 239 newborns were included. Data was obtained from the hospital’s Fetal surveillance Service data base. An intrauterine growth curve (IUGC) was built and compared with Lubchenko's and MINSA's growth curves by Student t, ANOVA and non-parametric tests. Differences were considered significant when p < 0.05. We used SPSS and Microsoft Excel for data processing. Main outcome measures: Intrauterine fetal growth curve. Results: The IUGC was built and percentiles were significantly higher to both Lubchenco’sand MINSA’s curves. Neonatal weight was influenced by maternal height, pregestational weight, maternal age (ANOVA: F = 3,8; F = 214,7; and, F = 11,2, respectively; p < 0,05), male fetal sex and multiparity (student t; p<0,001). Both MINSA’s and Lubchenco’s growth curves missed diagnosis of a significant percentage of fetuses with perinatal morbidity and mortality proper of IUGR. Conclusions: Intrauterine fetal growth curve built with HNERM patients differed significatively from those of both Lubchenco and MINSA. The latter subdiagnosed a significant percentage of fetuses with IUGR, reason to recommend the use of growth curves built with our hospital population. Conclusions: Intrauterine growth curve built with HNERM patients differed significantly from that of Lubchenko's and MINSA's. The latter underdiagnosed a significant percentage of fetuses with IUGR. Thus we recommend the use of our own curves in our hospital influenced area population.