Mitochondrial dysfunction increases oxidative stress and decreases chronological life span in fission yeast

Background: Oxidative stress is a probable cause of aging and associated diseases. Reactive oxygen species (ROS) originate mainly from endogenous sources, namely the mitochondria. Methodology/Principal Findings: We analyzed the effect of aerobic metabolism on oxidative damage in Schizosaccharomyces pombe by global mapping of those genes that are required for growth on both respiratory-proficient media and hydrogen-peroxide-containing fermentable media. Out of a collection of approximately 2700 haploid yeast deletion mutants, 51 were sensitive to both conditions and 19 of these were related to mitochondrial function. Twelve deletion mutants lacked components of the electron transport chain. The growth defects of these mutants can be alleviated by the addition of antioxidants, which points to intrinsic oxidative stress as the origin of the phenotypes observed. These respiration-deficient mutants display elevated steady-state levels of ROS, probably due to enhanced electron leakage from their defective transport chains, which compromises the viability of chronologically-aged cells. Conclusion/Significance: Individual mitochondrial dysfunctions have often been described as the cause of diseases or aging, and our global characterization emphasizes the primacy of oxidative stress in the etiology of such processes.

Análisis de sistemas bucoadhesivos

[spa]Objetivo: El objetivo de este estudio es el diseño de un parche bucoadhesivo para la administración transbucal de clorhidrato de doxepina utilizando diferentes polímeros así como la caracterización de dichos sistemas en cuanto al análisis calorimétrico y la capacidad de hinchamiento.Materiales y métodos: Se ha utilizado clorhidrato de doxepina y diferentes polímeros, carboximetilcelulosa sódica, hidroxipropilmetilcelulosa y chitosan. La calorimetría diferencial de barrido (DSC) se ha realizado en un dispositivo Mettler FP 80 equipado con un horno FP 85 y la capacidad de hinchamiento utilizando placas de agar.Resultados: Se obtienen termogramas de los parches y las mezclas físicas donde se observan transiciones endotérmicas entre 30 y 120º C y el pico endotérmico del principio activo en las mezclas físicas binarias. La entalpía de deshidratación es similar en los polímeros de carboximetilcelulosa sódica y chitosan (281 J/g) siendo menor en la película de hidroxipropilmetilcelulosa (251 J/g), al igual que el porcentaje de hidratación donde se demuestra que los parches elaborados con hidroxipropilmetilcelulosa presenta menor tendencia a captar agua (55,91 %) frente al 67,04 % y 67,30 % de la carboximetilcelulosa sódica y chitosan, respectivamente.Conclusión: Los resultados obtenidos muestran que existe compatibilidad entre los componentes de la formulación y los datos de entalpía se correlacionan con los datos obtenidos en el ensayo de hinchamiento.[eng]The aim of this study is to design a bucoadhesive patch for the transbuccal administration of doxepin hydrochloride using different polymers as well as the characterization of these systems for calorimetric analysis and the swelling capacity. Materials and methods: Doxepin hydrochloride was used as well as various polymers; carboxymethylcellulose sodium, hydroxypropylmethyl cellulose and chitosan. Differential scanning calorimetry (DSC) was carried out using a Mettler FP 80 device equipped with a FP 85 oven and the swelling capacity using agar plates. Results: Thermograms obtained patches and physical mixtures where there are endothermic transitions between 30 and 120º C and the endothermic peak of the active principle in binary physical mixtures. Dehydration enthalpy is similar in polymers of carboxymethylcellulose sodium and chitosan (281 J/g), the film having less hydroxypropylmethylcellulose (251 J/g), the percentage of moisture shows that the patches prepared with hydroxypropylmethylcellulose have less tendency to collect water (55.91 %) compared to 67.04 % and 67.30 % with sodium carboxymethylcellulose and chitosan, respectively. Conclusion: The results show that there is compatibility between the components of the formulation and the enthalpy data correlate

N-myc controls proliferation, morphogenesis, and patterning of the inner ear

Myc family members play crucial roles in regulating cell proliferation, size, and differentiation during organogenesis. Both N-myc and c-myc are expressed throughout inner ear development. To address their function in the mouse inner ear, we generated mice with conditional deletions in either N-myc or c-myc. Loss of c-myc in the inner ear causes no apparent defects, whereas inactivation of N-myc results in reduced growth caused by a lack of proliferation. Reciprocally, the misexpression of N-myc in the inner ear increases proliferation. Morphogenesis of the inner ear in N-myc mouse mutants is severely disturbed, including loss of the lateral canal, fusion of the cochlea with the sacculus and utriculus, and stunted outgrowth of the cochlea. Mutant cochleas are characterized by an increased number of cells exiting the cell cycle that express the cyclin-dependent kinase inhibitor p27Kip1 and lack cyclin D1, both of which control the postmitotic state of hair cells. Analysis of different molecular markers in N-myc mutant ears reveals the development of a rudimentary organ of Corti containing hair cells and the underlying supporting cells. Differentiated cells, however, fail to form the highly ordered structure characteristic for the organ of Corti but appear as rows or clusters with an excess number of hair cells. The Kölliker's organ, a transient structure neighboring the organ of Corti and a potential source of ectopic hair cells, is absent in the mutant ears. Collectively, our data suggest that N-myc regulates growth, morphogenesis, and pattern formation during the development of the inner ear.