RESUMO
Proteins of the major histocompatibility complex class I (MHCI) are known for their role in immunity and have recently been implicated in long-term plasticity of excitatory synaptic transmission. However, the mechanisms by which MHCI influences synaptic plasticity remain unknown. Here we show that endogenous MHCI regulates synaptic responses mediated by NMDA-type glutamate receptors (NMDARs) in the mammalian central nervous system (CNS). The AMPA/NMDA ratio is decreased at MHCI-deficient hippocampal synapses, reflecting an increase in NMDAR-mediated currents. This enhanced NMDAR response is not associated with changes in the levels, subunit composition, or gross subcellular distribution of NMDARs. Increased NMDAR-mediated currents in MHCI-deficient neurons are associated with characteristic changes in AMPA receptor trafficking in response to NMDAR activation. Thus, endogenous MHCI tonically inhibits NMDAR function and controls downstream NMDAR-induced AMPA receptor trafficking during the expression of plasticity.
Assuntos
Hipocampo/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia , Animais , Antígenos de Histocompatibilidade Classe I/genética , Camundongos , Camundongos Knockout , Transporte Proteico/fisiologia , Receptores de AMPA/genética , Receptores de N-Metil-D-Aspartato/genéticaRESUMO
The purpose of risk analysis in the determination of medical factors in road vehicle accidents is to evaluate the risks that are associated with different strategies for accident reduction, so that the subsequent decision making process can be based on a best assessment of the likely benefits. However, it is vital to appreciate the limitations of such an approach, especially where the conclusions depend heavily on the accuracy of the assumptions made. In this paper the assumptions used in some recent analyses concerned with incapacitation, epilepsy, hypoglycaemia and psycho-active medication are explored, and the additional information required to reduce the uncertainty in the estimation of risk indicated. The conclusions from this analysis do not invalidate the use of risk assessment, but draw attention to its limitations and show how a sensitivity analysis can help to identify those areas where more precise information is needed before such an approach can be used confidently in a policy setting.
Assuntos
Acidentes de Trânsito/estatística & dados numéricos , Condução de Veículo/psicologia , Medição de Risco/métodos , Antipsicóticos/efeitos adversos , Epilepsia/complicações , Humanos , Hipoglicemia/complicações , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
The basis of the QinetiQ alertness model used at the heart of the System for Aircrew Fatigue Evaluation (SAFE) free-standing software tool is described. A number of extensions to the basic model that are applicable to the civil aviation environment are outlined, based on the analysis of eight studies involving sleep diaries gathered from pilots undertaking a range of duty schedules. The relationship between subjective alertness and performance of laboratory tasks is described and it is concluded that different tasks are affected differentially by fatigue. In general, there is a larger impact on the incidence of errors than on response time. The implementation of the full model in the Integrated Performance Modeling Environment is described and the application of both the alertness and performance models to two scenarios provided by the workshop organizers is outlined. It is concluded that further work is needed in three areas: cumulative fatigue, the impact of sleep architecture, and the prediction of performance for complex tasks in systems.