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Oligodendrocytes in Alzheimer's disease pathophysiology.

Nat Neurosci

January 2025

Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany.

Our understanding of Alzheimer's disease (AD) has transformed from a purely neuronal perspective to one that acknowledges the involvement of glial cells. Despite remarkable progress in unraveling the biology of microglia, astrocytes and vascular elements, the exploration of oligodendrocytes in AD is still in its early stages. Contrary to the traditional notion of oligodendrocytes as passive bystanders in AD pathology, emerging evidence indicates their active participation in and reaction to amyloid and tau pathology.

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Neuroinflammation has been acknowledged as being one of the main pathologies that occur following chronic cerebral hypoperfusion (CCH). Since it significantly contributes to neuronal cell damage and thereby leads to cognitive impairment, the signals related to inflammation in hypoperfusion injury have been extensively investigated over the past few years. Toll-like receptor 4 (TLR4) is the key receptor responsible for immune and inflammatory reactions.

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To ensure their survival, animals must be able to respond adaptively to threats within their environment. However, the precise neural circuit mechanisms that underlie flexible defensive behaviors remain poorly understood. Using neuronal manipulations, machine learning-based behavioral detection, electron microscopy (EM) connectomics and calcium imaging in Drosophila larvae, we map second-order interneurons that are differentially involved in the competition between defensive actions in response to competing aversive cues.

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Spirals are a special class of excitable waves that have its significance in the understanding of cardiac arrests and neuronal transduction. In a theoretical model of the chemical Belousov-Zhabotinsky reaction system, we explore the dynamics of the spatiotemporal patterns that emerge out of competing reaction and diffusion phenomena. By modifying the existing mathematical models of the reaction kinetics, we have been able to explore the explicit effect of hydrogen ion concentration in the system, so as to achieve various regimes of wave activity, from stable spirals to oscillation death.

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Autoimmunity affects 10% of the population. Within this umbrella, autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the developmental pathway of disease-causing B cells and autoantibodies. While such autoreactivities are believed to be generated during germinal centre reactions, the roles of earlier immune checkpoints in autoantigen-specific B cell tolerance are poorly understood.

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