RESUMO
Core executive functions (EF) such as attention, and working memory have been strongly associated with academic achievement, language development and behavioral stability. In the case of children who are vulnerable to cognitive and learning problems because of an underlying intellectual disability, EF difficulties will likely exacerbate an already compromised cognitive system. The current review examines cognitive training programs that aim to improve EF, specifically focusing on the potential of this type of intervention for children who have intellectual disabilities. We conclude that despite considerable discrepancies regarding reported intervention effects, these inconsistencies can be attributed to flaws in both program and study design. We discuss the steps needed to address these limitations and to facilitate the advancement of non-pharmaceutical interventions for children with intellectual disabilities.
Assuntos
Atenção , Transtornos Cognitivos/reabilitação , Função Executiva , Deficiência Intelectual/reabilitação , Memória de Curto Prazo , Criança , Cognição , Transtornos Cognitivos/psicologia , Humanos , Deficiência Intelectual/psicologia , Resultado do TratamentoRESUMO
As part of a cDNA library screen for clones that induce transformation of NIH 3T3 fibroblasts, we have isolated a cDNA encoding the murine homolog of the guanine nucleotide exchange factor RasGRP. A point mutation predicted to prevent interaction with Ras abolished the ability of murine RasGRP (mRasGRP) to transform fibroblasts and to activate mitogen-activated protein kinases (MAP kinases). MAP kinase activation via mRasGRP was enhanced by coexpression of H-, K-, and N-Ras and was partially suppressed by coexpression of dominant negative forms of H- and K-Ras. The C terminus of mRasGRP contains a pair of EF hands and a C1 domain which is very similar to the phorbol ester- and diacylglycerol-binding C1 domains of protein kinase Cs. The EF hands could be deleted without affecting the ability of mRasGRP to transform NIH 3T3 cells. In contrast, deletion of the C1 domain or an adjacent cluster of basic amino acids eliminated the transforming activity of mRasGRP. Transformation and MAP kinase activation via mRasGRP were restored if the deleted C1 domain was replaced either by a membrane-localizing prenylation signal or by a diacylglycerol- and phorbol ester-binding C1 domain of protein kinase C. The transforming activity of mRasGRP could be regulated by phorbol ester when serum concentrations were low, and this effect of phorbol ester was dependent on the C1 domain of mRasGRP. The C1 domain could also confer phorbol myristate acetate-regulated transforming activity on a prenylation-defective mutant of K-Ras. The C1 domain mediated the translocation of mRasGRP to cell membranes in response to either phorbol ester or serum stimulation. These results suggest that the primary mechanism of activation of mRasGRP in fibroblasts is through its recruitment to diacylglycerol-enriched membranes. mRasGRP is expressed in lymphoid tissues and the brain, as well as in some lymphoid cell lines. In these cells, RasGRP has the potential to serve as a direct link between receptors which stimulate diacylglycerol-generating phospholipase Cs and the activation of Ras.
Assuntos
Proteínas de Ligação a DNA/genética , Fatores de Troca do Nucleotídeo Guanina , Acetato de Tetradecanoilforbol/farmacologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Linhagem Celular , Análise Mutacional de DNA , DNA Complementar/genética , Ativação Enzimática/fisiologia , Expressão Gênica/genética , Humanos , Camundongos , Microscopia de Fluorescência , Dados de Sequência Molecular , Mutação Puntual/genética , RNA Mensageiro/genética , Retroviridae/genética , Homologia de Sequência de Aminoácidos , Transdução de Sinais/fisiologia , Transformação Genética/genéticaRESUMO
We have characterized a flat cellular variant of HTLV-1 Tax-transformed rat fibroblasts, 5R, which is unresponsive to all tested NF-kappaB activating stimuli, and we report here its genetic complementation. The recovered full-length cDNA encodes a 48 kDa protein, NEMO (NF-kappaB Essential MOdulator), which contains a putative leucine zipper motif. This protein is absent from 5R cells, is part of the high molecular weight IkappaB kinase complex, and is required for its formation. In vitro, NEMO can homodimerize and directly interacts with IKK-2. The NEMO cDNA was also able to complement another NF-kappaB-unresponsive cell line, 1.3E2, in which the protein is also absent, allowing us to demonstrate that this factor is required not only for Tax but also for LPS, PMA, and IL-1 stimulation of NF-kappaB activity.
