Plos One
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Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate the pacemaking current, I(h), which regulates neuronal excitability, burst firing activity, rhythmogenesis, and synaptic integration. The physiological consequence of HCN activation depends on regulation of channel gating by endogenous modulators and stabilization of the channel complex formed by principal and ancillary subunits. KCNE2 is a voltage-gated potassium channel ancillary subunit that also regulates heterologously expressed HCN channels; whether KCNE2 regulates neuronal HCN channel function is unknown. ⋯ Loss of KCNE2 leads to downregulation of HCN channel function associated with increased excitability in neurons in the cortico-thalamo-cortical loop. Such findings further our understanding of the normal physiology of brain circuitry critically involved in cognition and have implications for our understanding of various disorders of consciousness.
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Clinical Trial
An fMRI study exploring the overlap and differences between neural representations of physical and recalled pain.
Implementing a recall paradigm without hypnosis, we use functional MRI (fMRI) to explore and compare nociceptive and centrally-driven pain experiences. We posit that a trace of a recent nociceptive event can be used to create sensory-re-experiencing of pain that can be qualified in terms of intensity and vividness. Fifteen healthy volunteers received three levels of thermal stimuli (warm, low pain and high pain) and subsequently were asked to recall and then rate this experience. ⋯ Nociceptive-specific activation of this structure and the rated intensity difference between physical and recalled pain events allow us to investigate the link between the quality of the original nociceptive stimulus and the mental trace, as well as the differences between the accompanying neural responses. Additionally, by incorporating the behavioural ratings, we explored which brain regions were separately responsible for generating either an accurate or vivid recall of the physical experience. Together, these observations further our understanding of centrally-mediated pain experiences and pain memory as well as the potential relevance of these factors in the maintenance of chronic pain.
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Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI. ⋯ CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.
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Neural substrates underlying motor learning have been widely investigated with neuroimaging technologies. Investigations have illustrated the critical regions of motor learning and further revealed parallel alterations of functional activation during imagination and execution after learning. However, little is known about the functional connectivity associated with motor learning, especially motor imagery learning, although benefits from functional connectivity analysis attract more attention to the related explorations. We explored whether motor imagery (MI) and motor execution (ME) shared parallel alterations of functional connectivity after MI learning. ⋯ These computational results may provide the following insights: (1) The establishment of motor schema through MI learning may induce the significant decrease of connectivity degree in the posterior parietal lobe; (2) The decreased interregional connectivity between the supplementary motor area and the right posterior parietal lobe in post-test implicates the dissociation between motor learning and task performing. These findings and explanations further revealed the neural substrates underpinning MI learning and supported that the potential value of MI learning in motor function rehabilitation and motor skill learning deserves more attention and further investigation.
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Cancer-associated fibroblasts, comprised of activated fibroblasts or myofibroblasts, are found in the stroma surrounding solid tumors. These myofibroblasts promote invasion and metastasis of cancer cells. Mechanisms regulating the activation of the fibroblasts and the initiation of invasive tumorigenesis are of great interest. Upregulation of the cytoskeletal protein, palladin, has been detected in the stromal myofibroblasts surrounding many solid cancers and in expression screens for genes involved in invasion. Using a pancreatic cancer model, we investigated the functional consequence of overexpression of exogenous palladin in normal fibroblasts in vitro and its effect on the early stages of tumor invasion. ⋯ Overall, palladin expression can impart myofibroblast properties, in turn promoting the invasive potential of these peri-tumoral cells with invadopodia-driven degradation of extracellular matrix. Palladin expression in fibroblasts can be triggered by k-ras expression in adjacent epithelial cells. This data supports a model whereby palladin-activated fibroblasts facilitate stromal-dependent metastasis and outgrowth of tumorigenic epithelium.