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Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimers disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.

Spastic paraparesis has been described to occur in 13.7% of PSEN1 mutations and can be the presenting feature in 7.5%. In this paper, we describe a family with a particularly young onset of spastic paraparesis due to a novel mutation in PSEN1 (F388S). Three affected brothers underwent comprehensive imaging protocols, two underwent ophthalmological evaluations and one underwent neuropathological examination after his death at age 29. Age of onset was consistently at age 23 with spastic paraparesis, dysarthria and bradyphrenia. Pseudobulbar affect followed with progressive gait problems leading to loss of ambulation in the late 20s. Cerebrospinal fluid levels of amyloid-β, tau and phosphorylated tau and florbetaben PET were consistent with Alzheimer's disease. Flortaucipir PET showed an uptake pattern atypical for Alzheimer's disease, with disproportionate signal in posterior brain areas. Diffusion tensor imaging showed decreased mean diffusivity in widespread areas of white matter but particularly in areas underlying the peri-Rolandic cortex and in the corticospinal tracts. These changes were more severe than those found in carriers of another PSEN1 mutation, which can cause spastic paraparesis at a later age (A431E), which were in turn more severe than among persons carrying autosomal dominant Alzheimer's disease mutations not causing spastic paraparesis. Neuropathological examination confirmed the presence of cotton wool plaques previously described in association with spastic parapresis and pallor and microgliosis in the corticospinal tract with severe amyloid-β pathology in motor cortex but without unequivocal disproportionate neuronal loss or tau pathology. In vitro modelling of the effects of the mutation demonstrated increased production of longer length amyloid-β peptides relative to shorter that predicted the young age of onset. In this paper, we provide imaging and neuropathological characterization of an extreme form of spastic paraparesis occurring in association with autosomal dominant Alzheimer's disease, demonstrating robust diffusion and pathological abnormalities in white matter. That the amyloid-β profiles produced predicted the young age of onset suggests an amyloid-driven aetiology though the link between this and the white matter pathology remains undefined.

This paper examines current practices that embrace the union between foreign language (L2) teaching and translation in higher education (HE). The rejection of monolingualism and prescriptive principles in favour of bi-, multi-, or plurilingualism; a diversified interdisciplinarity; new sociocultural realities characterised by greater international mobility; different needs and challenges in foreign language teaching; and an openness of translation studies, are only some of the reasons why the link between both areas remains pertinent. However, while the advocacy of integrating the use of translation in language teaching seems to be gaining steady ground in the last decade, specific ways of introducing translation into the L2 curriculum are not always clear. This paper discusses issues related to the design and implementation of a module that would tackle L2 learning while serving as an exploratory course on translation within a degree in languages in HE. The discussion aims to add to the debate on practical issues by explaining the rationale of the module, as well as any difficulties prior to designing the module, and those encountered in the implementation phase.

This paper examines current practices that embrace the union between foreign language (L2) teaching and translation in higher education (HE). The rejection of monolingualism and prescriptive principles in favour of bi-, multi-, or plurilingualism; a diversified interdisciplinarity; new sociocultural realities characterised by greater international mobility; different needs and challenges in foreign language teaching; and an openness of translation studies, are only some of the reasons why the link between both areas remains pertinent. However, while the advocacy of integrating the use of translation in language teaching seems to be gaining steady ground in the last decade, specific ways of introducing translation into the L2 curriculum are not always clear. This paper discusses issues related to the design and implementation of a module that would tackle L2 learning while serving as an exploratory course on translation within a degree in languages in HE. The discussion aims to add to the debate on practical issues by explaining the rationale of the module, as well as any difficulties prior to designing the module, and those encountered in the implementation phase.

The gradual reintroduction of translation into the foreign language classroom in the last few decades has generated considerable interest among teachers and scholars. A renewed focus on translation as an aspect of language teaching has simultaneously originated from and resulted in the publication of theoretical and empirical studies as well as monographs that recognise 'pedagogical translation' as a beneficial and increasingly accepted practice. However, conceptual and terminological inconsistencies persist that blur the boundaries between the general idea of using translation in the language classroom and more specific practices that involve translation tasks (also known as 'pedagogical translation') or code-switching. The article addresses these terminological incongruities by exploring the impact of conceptualisations of translation in language education and, specifically, its use in pedagogical translation. The goal is to consider the plethora of concepts related to translation in language teaching (TILT) and to explore how they may be connected with the reconceptualisation of translation in language pedagogy. This will open up useful avenues for a more thorough incorporation of translation into foreign language education, particularly at the secondary and college level, and will propose future lines of research and pedagogical sound praxis.

Copyright of Revista Espacios is the property of Talleres de Impresos Oma and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Today, higher education (HE) faces new challenges, such as incorporating consideration of diversity and inclusion into its operations. Such challenges, many of which are part of strategic institutional plans, offer teachers an opportunity to introduce new practices in the classroom. In this paper, we look at introducing language students to the task of audio description (AD) – that is, making visual content available to blind and visually impaired people by verbal means. We first present a framework for evaluating the learning that might derive from such an activity in the context of FL study, and then use this framework to evaluate a sequence of five tasks undertaken with Irish learners of Spanish. The tasks provided opportunities for the students to reflect on the communication needs of blind and visually impaired people and to understand how these could be addressed effectively in AD. The students practised AD in various contexts: both 'improvised' or 'spontaneous' AD as well as more carefully prepared AD, and undertaking AD in both the L1 (English) and the FL (Spanish). The pedagogic approach investigated here was inherently multidisciplinary and aimed to help learners become self-reflecting agents and mediators in their L1 and FL. [ABSTRACT FROM AUTHOR]

This article explores the agency of the student in translation in language teaching and learning (or TILT). The purpose of the case study discussed here is to gain an overview of students' perceptions of translation into the foreign language (FL) (also known as "inverse translation") following a module on language and translation, and to analyse whether there is any correlation between students' attitude to translation, its impact on their language learning through effort invested, and the improvement of language skills. The results of the case study reveal translation to be a potentially exciting skill that can be central to FL learning and the analysis gives indications of how and why language teachers may optimise the implementation of translation in the classroom. The outcome of the study suggests that further research is needed on the impact of translation in the language classroom focussing on both teachers' expectations and students' achievements.

Copyright of Revista Espacios is the property of Talleres de Impresos Oma and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Revista Espacios is the property of Talleres de Impresos Oma and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)