RNA interference mitigates motor and neuropathological deficits in a cerebellar mouse model of machado-joseph disease.

Machado-Joseph disease or Spinocerebellar ataxia type 3 is a progressive fatal neurodegenerative disorder caused by the polyglutamine-expanded protein ataxin-3. Recent studies demonstrate that RNA interference is a promising approach for the treatment of Machado-Joseph disease. However, whether gene silencing at an early time-point is able to prevent the appearance of motor behavior deficits typical of the disease when initiated before onset of the disease had not been explored. Here, using a lentiviral-mediated allele-specific silencing of mutant ataxin-3 in an early pre-symptomatic cerebellar mouse model of Machado-Joseph disease we show that this strategy hampers the development of the motor and neuropathological phenotypic characteristics of the disease. At the histological level, the RNA-specific silencing of mutant ataxin-3 decreased formation of mutant ataxin-3 aggregates, preserved Purkinje cell morphology and expression of neuronal markers while reducing cell death. Importantly, gene silencing prevented the development of impairments in balance, motor coordination, gait and hyperactivity observed in control mice. These data support the therapeutic potential of RNA interference for Machado-Joseph disease and constitute a proof of principle of the beneficial effects of early allele-specific silencing for therapy of this disease.

Bondat i Literatura: el Machado de Xirau, a 'Por una senda clara'

A partir del text del filòsof Joaquim Xirau «Por una senda clara», considerat com a text literari, s"analitza l"ideal de bondat compartit per Xirau i Machado. El corriol clar (la senda clara), com el descriu Xirau, és camí d"educació moral, segons els ideals de la Institución Libre de Enseñanza i els valors de la fenomenologia; és la vida del mestre Giner de los Ríos, és el camí cap a l"exili i és la pròpia vida. El text literari no es limita a descriure una qüestió moral, fa una acció moral.

O autor de si mesmo: Machado de Assis leitor de Schopenhauer

Esse texto tem por objetivo mostrar que Machado de Assis construiu a crônica "O autor de si mesmo" fazendo uso da metafísica do amor de Schopenhauer.

O bruxo contra o comunista ou: o incômodo ceticismo de Machado de Assis

O artigo comenta a presença do ceticismo na obra de Joaquim Maria Machado de Assis a partir da crítica que lhe faz Octávio Brandão em O niilista Machado de Assis, publicado em 1958. Brandão iguala os termos "ceticismo", "niilismo", "cinismo" e "pessimismo" para melhor desqualificar a obra de Machado de Assis. O artigo procura demonstrar que esses termos designam filosofias muito diferentes, reconhecendo o ceticismo em Machado para sustentar que seu valor artístico deriva precisamente deste ceticismo.

Molecular characteristics of Machado-Joseph disease mutation in 25 newly described Brazilian families

Machado-Joseph disease (MJD) is a form of autosomal dominant spinocerebellar ataxia first described in North-American patients originating from the Portuguese islands of the Azores. Clinically this disorder is characterized by late onset progressive ataxia with associated features, such as: ophthalmoplegia, pyramidal and extrapyramidal signs and distal muscular atrophies. The causative mutation is an expansion of a CAG repeat in the coding region of the MJD1 gene. We have identified 25 unrelated families segregating the MJD mutation during a large collaborative study of spinocerebellar ataxias in Brazil. In the present study a total of 62 family members were genotyped for the CAG repeat in the MJD1 gene, as well as 63 non-MJD individuals (126 normal chromosomes), used as normal controls. We observed a wide gap between the size range of the normal and expanded CAG repeats: the normal allele had from 12 to 33 CAGs (mean = 23 CAGs), whereas the expanded alleles ranged from 66 to 78 CAGs (mean = 71.5 CAGs). There were no differences in CAG tract length according to gender of affected individuals or transmitting parent. We observed a significant negative correlation between age at onset of the disease and length of the CAG tract in the expended allele (r = -0.6, P = 0.00006); however, the size of the expanded CAG repeat could explain only about 40% of the variability in age at onset (r2 = 0.4). There was instability of the expanded CAG tract during transmission from parent to offspring, both expansions and contractions were observed; however, there was an overall tendency for expansion, with a mean increase of +2.4 CAGs. The tendency for expansion appeared to the greater in paternal (mean increase of +3.5 CAGs) than in maternal transmissions (mean increase of +1.3 CAGs). Anticipation was observed in all transmissions in which ages at onset for parent and offspring were known; however, anticipation was not always associated with an increase in the expanded CAG repeat length. Our results indicate that the molecular diagnosis of MJD can be confirmed or excluded in all suspected individuals, since alleles of intermediary size were not observed.

O grotesco em Machado de Assis: uma leitura de a causa secreta

Na primeira parte deste trabalho -"Grotesco, literatura, leitor" - discutiu-se o conceito de grotesco, configurado em termos literários, nas suas articulações com a ficcionalidade e a recepção. Na segunda parte - "O leitor e o grotesco em A CAUSA SECRETA" - procedeu-se à leitura do conto machadiano na perspectiva de um texto onde o grotesco, resultado da estruturação do conto, encontra-se configurado em termos ficcionais.

A educação do leitor em Machado de Assis: da crítica literária às Memórias Póstumas de Brás Cubas

Os textos de crítica literária de Machado de Assis mostram a preocupação do autor com o leitor; mas será em Memórias Póstumas de Brás Cubas que o leitor terá uma participação decisiva na estrutura do romance.

Un análisis estilístico del poema XIII de Antonio Machado

UANL

Suma moral, y resumen brevissimo de todas las obras del Doctor Machado

UANL

El último Antonio Machado : Juan de Mairena y el ideal pedagógico machadiano.

Resumen tomado del recurso