The potential benefits of subtitles for enhancing language acquisition and literacy in children: An integrative review of experimental research

While a considerable body of experimental work has been conducted since the beginning of the 1980s to study whether subtitles enhance the acquisition of other languages in adults, research of this type investigating subtitles as a tool for enhancing children’s language learning and literacy has received less attention. This study provides an integrative review of existing studies in this area and finds extensive evidence that subtitled AV content can indeed aid the acquisition of other languages in children and adolescents, and that it can moreover enhance the literacy skills of children learning to read in their L1 or the official language of the country in which they live and receive schooling. Recommendations for future research are also made, and it is highlighted that further research using eye tracking to measure children’s gaze behaviour could shed new light on their attention to and processing of subtitled AV content

The interpretation of the concepts ‘necessity’ and ‘sufficiency’ in forward unicausal relations

La nécessité et la suffisance sont deux concepts centraux de la littérature consacrée au raisonnement causal. Trois expériences analysant la manière qu’ont les individus de comprendre ces deux concepts sont exposées dans cet article. Les résultats indiquent que la nécessité est une notion plus complexe que celle de suffisance. Pour la suffisance, les sujets vérifient seulement si la cause est suivie de l’effet, alors que pour la nécessité, deux possibilités peuvent être examinées:“la cause précède-t-elle toujours l’effet?”et “l’effet peut-il apparaître sans la cause ?”. Plus important encore, ces deux concepts manifestent une structure différente: la nécessité est considérée comme une propriété de type tout ou rien alors que la suffisance est vue comme une propriété plus graduelle. Les résultats soulignent l’utilité d’une opérationnalisation appropriée afin de mesurer la nécessité et la suffisance telles qu’elles sont perçues par les individus.Necessity and sufficiency are two central concepts in the literature on causal reasoning. Three experiments are reported that investigate how people understand these two concepts. It is found that necessity is more a complex notion than the notion of sufficiency. For sufficiency, people only verify whether the cause is always followed by the effect, whereas for necessity, there are two possibilities that can be verified: ‘does the cause always precede the effect’ and ‘can the effect occur without the cause’. More importantly, it is found that both concepts have a different structure: necessity is considered as an all-or-none property whereas sufficiency is a more liberal characteristic. The present findings highlight the need for an appropriate operationalisation for measuring the perceived necessity and sufficiency of given cause-effect relations

The interpretation of the concepts ‘necessity’ and ‘sufficiency’ in forward unicausal relations

La nécessité et la suffisance sont deux concepts centraux de la littérature consacrée au raisonnement causal. Trois expériences analysant la manière qu’ont les individus de comprendre ces deux concepts sont exposées dans cet article. Les résultats indiquent que la nécessité est une notion plus complexe que celle de suffisance. Pour la suffisance, les sujets vérifient seulement si la cause est suivie de l’effet, alors que pour la nécessité, deux possibilités peuvent être examinées:“la cause précède-t-elle toujours l’effet?”et “l’effet peut-il apparaître sans la cause ?”. Plus important encore, ces deux concepts manifestent une structure différente: la nécessité est considérée comme une propriété de type tout ou rien alors que la suffisance est vue comme une propriété plus graduelle. Les résultats soulignent l’utilité d’une opérationnalisation appropriée afin de mesurer la nécessité et la suffisance telles qu’elles sont perçues par les individus.Necessity and sufficiency are two central concepts in the literature on causal reasoning. Three experiments are reported that investigate how people understand these two concepts. It is found that necessity is more a complex notion than the notion of sufficiency. For sufficiency, people only verify whether the cause is always followed by the effect, whereas for necessity, there are two possibilities that can be verified: ‘does the cause always precede the effect’ and ‘can the effect occur without the cause’. More importantly, it is found that both concepts have a different structure: necessity is considered as an all-or-none property whereas sufficiency is a more liberal characteristic. The present findings highlight the need for an appropriate operationalisation for measuring the perceived necessity and sufficiency of given cause-effect relations

Prospective memory impairments in Alzheimer's Disease and behavioral variant frontotemporal dementia: Clinical and neural correlates

BACKGROUND: Prospective memory (PM) refers to a future-oriented form of memory in which the individual must remember to execute an intended action either at a future point in time (Time-based) or in response to a specific event (Event-based). Lapses in PM are commonly exhibited in neurodegenerative disorders including Alzheimer's disease (AD) and frontotemporal dementia (FTD), however, the neurocognitive mechanisms driving these deficits remain unknown. OBJECTIVE: To investigate the clinical and neural correlates of Time- and Event-based PM disruption in AD and the behavioral-variant FTD (bvFTD). METHODS: Twelve AD, 12 bvFTD, and 12 healthy older Control participants completed a modified version of the Cambridge Prospective Memory test, which examines Time- and Event-based aspects of PM. All participants completed a standard neuropsychological assessment and underwent whole-brain structural MRI. RESULTS: AD and bvFTD patients displayed striking impairments across Time- and Event-based PM relative to Controls, however, Time-based PM was disproportionately affected in the AD group. Episodic memory dysfunction and hippocampal atrophy was found to correlate strongly with PM integrity in both patient groups, however, dissociable neural substrates were also evident for PM performance across dementia syndromes. CONCLUSION: Our study reveals the multifaceted nature of PM dysfunction in neurodegenerative disorders, and suggests common and dissociable neurocognitive mechanisms, which subtend these deficits in each patient group. Future studies of PM disturbance in dementia syndromes will be crucial for the development of successful interventions to improve functional independence in the patient's daily life

Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations

​Leucine-rich repeat kinase 2 (​LRRK2) mutations are the most common genetic cause of Parkinson’s disease. ​LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson’s disease, but whether ​LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that ​LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase ​αTAT1 prevents association of mutant ​LRRK2 with microtubules, and the deacetylase inhibitor ​trichostatin A (​TSA) restores axonal transport. In vivo knockdown of the deacetylases ​HDAC6 and ​Sirt2, or administration of ​TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson’s disease

Disruption of Axonal Transport in Motor Neuron Diseases

Motor neurons typically have very long axons, and fine-tuning axonal transport is crucial for their survival. The obstruction of axonal transport is gaining attention as a cause of neuronal dysfunction in a variety of neurodegenerative motor neuron diseases. Depletions in dynein and dynactin-1, motor molecules regulating axonal trafficking, disrupt axonal transport in flies, and mutations in their genes cause motor neuron degeneration in humans and rodents. Axonal transport defects are among the early molecular events leading to neurodegeneration in mouse models of amyotrophic lateral sclerosis (ALS). Gene expression profiles indicate that dynactin-1 mRNA is downregulated in degenerating spinal motor neurons of autopsied patients with sporadic ALS. Dynactin-1 mRNA is also reduced in the affected neurons of a mouse model of spinal and bulbar muscular atrophy, a motor neuron disease caused by triplet CAG repeat expansion in the gene encoding the androgen receptor. Pathogenic androgen receptor proteins also inhibit kinesin-1 microtubule-binding activity and disrupt anterograde axonal transport by activating c-Jun N-terminal kinase. Disruption of axonal transport also underlies the pathogenesis of spinal muscular atrophy and hereditary spastic paraplegias. These observations suggest that the impairment of axonal transport is a key event in the pathological processes of motor neuron degeneration and an important target of therapy development for motor neuron diseases

Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology

Imbalance of neuronal proteostasis associated with misfolding and aggregation of Tau protein is a common neurodegenerative feature in Alzheimer's disease (AD) and other Tauopathies. Consistent with suggestions that lifetime stress may be an important AD precipitating factor, we previously reported that environmental stress and high glucocorticoid (GC) levels induce accumulation of aggregated Tau; however, the molecular mechanisms for such process remain unclear. Herein, we monitor a novel interplay between RNA-binding proteins (RBPs) and autophagic machinery in the underlying mechanisms through which chronic stress and high GC levels impact on Tau proteostasis precipitating Tau aggregation. Using molecular, pharmacological and behavioral analysis, we demonstrate that chronic stress and high GC trigger mTOR-dependent inhibition of autophagy, leading to accumulation of Tau aggregates and cell death in P301L-Tau expressing mice and cells. In parallel, we found that environmental stress and GC disturb cellular homeostasis and trigger the insoluble accumulation of different RBPs, such as PABP, G3BP1, TIA-1, and FUS, shown to form stress granules (SGs) and Tau aggregation. Interestingly, an mTOR-driven pharmacological stimulation of autophagy attenuates the GC-driven accumulation of Tau and SG-related proteins as well as the related cell death, suggesting a critical interface between autophagy and the response of the SG-related protein in the neurodegenerative potential of chronic stress and GC. These studies provide novel insights into the RNA-protein intracellular signaling regulating the precipitating role of environmental stress and GC on Tau-driven brain pathology.We would like to thank Professor Juergen Gotz, (University of Queensland, Australia) for the kind offer of eGFP-P301LTau SH-SY5Y cells and Dr. Bruno Almeida for his technical assistance. J.M.S. was granted with a PhD fellowship (SRFH/BD/88932/2012) by Portuguese Foundation for Science & Technology (FCT); I.S. is holder of FCT Investigator grants (IF/01799/2013), C.D. is a recipient of PhD fellowship of PHDoc program and co-tutelle PhD student of UMinho-UPMC universities. This work was funded by FCT research grants "PTDC/SAU-NMC/113934/2009" (I.S.), the Portuguese North Regional Operational Program (ON. 2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER) as well as the Project Estrategico co-funded by FCT (PEst-C/SAU/LA0026/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298) as well as the project NORTE-01-0145-FEDER000013, supported by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). In addition, this work was partly funded by Canon Foundation in Europe. This work has been also funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145FEDER-007038. This study was also supported to BW by grants from NIH (AG050471, NS089544, and ES020395), the BrightFocus Foundation, the Alzheimer Association and the Cure Alzeimer Foundation. Human brain tissue was generously provided by the National Institute of Aging Boston University AD Center (P30AG13846).info:eu-repo/semantics/publishedVersio

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes

Molecular mechanisms underlying sensory-motor circuit dysfunction in SMA

Activation of skeletal muscle in response to acetylcholine release from the neuromuscular junction triggered by motor neuron firing forms the basis of all mammalian locomotion. Intricate feedback and control mechanisms, both from within the central nervous system and from sensory organs in the periphery, provide essential inputs that regulate and finetune motor neuron activity. Interestingly, in motor neuron diseases, such as spinal muscular atrophy (SMA), pathological studies in patients have identified alterations in multiple parts of the sensory-motor system. This has stimulated significant research efforts across a range of different animal models of SMA in order to understand these defects and their contribution to disease pathogenesis. Several recent studies have demonstrated that defects in sensory components of the sensory-motor system contribute to dysfunction of motor neurons early in the pathogenic process. In this review, we provide an overview of these findings, with a specific focus on studies that have provided mechanistic insights into the molecular processes that underlie dysfunction of the sensory-motor system in SMA. These findings highlight the role that cell types other than motor neurons play in SMA pathogenesis, and reinforce the need for therapeutic interventions that target and rescue the wide array of defects that occur in SMA