RESUMEN
G protein-coupled receptors strongly modulate neuronal excitability but there has been little evidence for G protein mechanisms in genetic epilepsies. Recently, four patients with epileptic encephalopathy (EIEE17) were found to have mutations in GNAO1, the most abundant G protein in brain, but the mechanism of this effect is not known. The GNAO1 gene product, Gαo, negatively regulates neurotransmitter release. Here, we report a dominant murine model of Gnao1-related seizures and sudden death. We introduced a genomic gain-of-function knock-in mutation (Gnao1 (+/G184S)) that prevents Go turnoff by Regulators of G protein signaling proteins. This results in rare seizures, strain-dependent death between 15 and 40 weeks of age, and a markedly increased frequency of interictal epileptiform discharges. Mutants on a C57BL/6J background also have faster sensitization to pentylenetetrazol (PTZ) kindling. Both premature lethality and PTZ kindling effects are suppressed in the 129SvJ mouse strain. We have mapped a 129S-derived modifier locus on Chromosome 17 (within the region 41-70 MB) as a Modifer of G protein Seizures (Mogs1). Our mouse model suggests a novel gain-of-function mechanism for the newly defined subset of epileptic encephalopathy (EIEE17). Furthermore, it reveals a new epilepsy susceptibility modifier Mogs1 with implications for the complex genetics of human epilepsy as well as sudden death in epilepsy.
Asunto(s)
Modelos Animales de Enfermedad , Epilepsia/genética , Epilepsia/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Mutación , Animales , Encéfalo/metabolismo , Encéfalo/patología , Epilepsia/mortalidad , Epilepsia/patología , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Técnicas de Sustitución del Gen , Humanos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: To explore career transitions using an occupational perspective. PARTICIPANT: One man shared his views on career transitions to elaborate concepts on work-life balance, choice and meaning. METHOD: Narrative reflection and theoretical exploration of occupational concepts underscoring career transitions. RESULTS: Three concepts are important to understanding career transitions, work-life balance, making meaning choices, and place. CONCLUSIONS: Further development in work transitions can be elaborated using an occupational understanding.
Asunto(s)
Selección de Profesión , Conducta de Elección , Empleo/psicología , Satisfacción Personal , Chile , Humanos , Satisfacción en el Trabajo , Masculino , Calidad de Vida , Tolerancia al Trabajo Programado , Lugar de TrabajoRESUMEN
Perception is a product of the interaction between bottom-up sensory processing and top-down higher order cognitive activity. For example, when the initial phoneme of a word is obliterated and replaced with noise, listeners hear it as intact provided there is semantic context. We modified this phonemic restoration paradigm by masking (not obliterating) the initial phoneme of a target word and presenting it within a carrier phrase which was informative (I), uninformative (U), or misinformative (M). Bias in favor of top-down context was measured as the extent to which M trials mislead listeners into reporting a target word other than that which was presented (relative to U trials that have irrelevant top-down semantic context). Forty-one participants (20 men) completed 600 test trials (300 delayed report of the phrase, 300 forced choice). Relative to the U condition, women were more affected by both the I and M cues than men, at certain levels of audibility during the forced choice condition. Moreover, the semantic strength of the I carrier phrases was correlated with the rate of correct reports of the target words in women but not in men.This suggests that women can be more affected by top-down semantic context than men.