Amplified Cold Transduction in Native Nociceptors by M-Channel Inhibition

Topically applied camphor elicits a sensation of cool, but nothing is known about how it affects cold temperature sensing. We found that camphor sensitizes a subpopulation of menthol-sensitive native cutaneous nociceptors in the mouse to cold, but desensitizes and partially blocks heterologously expressed TRPM8(transient receptor potential cation channel subfamily M member 8). In contrast, camphor reduces potassium outward currents in cultured sensory neurons and, in cold nociceptors, the cold-sensitizing effects of camphor and menthol are additive. Using a membrane potential dye-based screening assay and heterologously expressed potassium channels, we found that the effects of camphor are mediated by inhibition of K(v)7.2/3 channels subtypes that generate the M-current in neurons. In line with this finding, the specific M-current blocker XE991 reproduced the cold-sensitizing effect of camphor in nociceptors. However, the M-channel blocking effects of XE991 and camphor are not sufficient to initiate cold transduction but require a cold-activated inward current generated by TRPM8. The cold-sensitizing effects of XE991 and camphor are largest in high-threshold cold nociceptors. Low-threshold corneal cold thermoreceptors that express high levels of TRPM8 and lack potassium channels are not affected by camphor. We also found that menthol-like camphor-potently inhibits K(v)7.2/3 channels. The apparent functional synergism arising from TRPM8 activation and M-current block can improve the effectiveness of topical coolants and cooling lotions, and may also enhance TRPM8-mediated analgesia

Bitter taste signaling in tracheal epithelial brush cells elicits innate immune responses to bacterial infection

Constant exposure of the airways to inhaled pathogens requires efficient early immune responses protecting against infections. How bacteria on the epithelial surface are detected and first-line protective mechanisms are initiated are not well understood. We have recently shown that tracheal brush cells (BCs) express functional taste receptors. Here we report that bitter taste signaling in murine BCs induces neurogenic inflammation. We demonstrate that BC signaling stimulates adjacent sensory nerve endings in the trachea to release the neuropeptides CGRP and substance P that mediate plasma extravasation, neutrophil recruitment, and diapedesis. Moreover, we show that bitter tasting quorum-sensing molecules from Pseudomonas aeruginosa activate tracheal BCs. BC signaling depends on the key taste transduction gene Trpm5, triggers secretion of immune mediators, among them the most abundant member of the complement system, and is needed to combat P. aeruginosa infections. Our data provide functional insight into firstline defense mechanisms against bacterial infections of the lung

The Human Operculo-Insular Cortex Is Pain-Preferentially but Not Pain-Exclusively Activated by Trigeminal and Olfactory Stimuli

Increasing evidence about the central nervous representation of pain in the brain suggests that the operculo-insular cortex is a crucial part of the pain matrix. The pain-specificity of a brain region may be tested by administering nociceptive stimuli while controlling for unspecific activations by administering non-nociceptive stimuli. We applied this paradigm to nasal chemosensation, delivering trigeminal or olfactory stimuli, to verify the pain-specificity of the operculo-insular cortex. In detail, brain activations due to intranasal stimulation induced by non-nociceptive olfactory stimuli of hydrogen sulfide (5 ppm) or vanillin (0.8 ppm) were used to mask brain activations due to somatosensory, clearly nociceptive trigeminal stimulations with gaseous carbon dioxide (75% v/v). Functional magnetic resonance (fMRI) images were recorded from 12 healthy volunteers in a 3T head scanner during stimulus administration using an event-related design. We found that significantly more activations following nociceptive than non-nociceptive stimuli were localized bilaterally in two restricted clusters in the brain containing the primary and secondary somatosensory areas and the insular cortices consistent with the operculo-insular cortex. However, these activations completely disappeared when eliminating activations associated with the administration of olfactory stimuli, which were small but measurable. While the present experiments verify that the operculo-insular cortex plays a role in the processing of nociceptive input, they also show that it is not a pain-exclusive brain region and allow, in the experimental context, for the interpretation that the operculo-insular cortex splay a major role in the detection of and responding to salient events, whether or not these events are nociceptive or painful

Bitter taste signaling in tracheal epithelial brush cells elicits innate immune responses to bacterial infection.

peer reviewedConstant exposure of the airways to inhaled pathogens requires efficient early immune responses protecting against infections. How bacteria on the epithelial surface are detected and first-line protective mechanisms are initiated are not well understood. We have recently shown that tracheal brush cells (BCs) express functional taste receptors. Here we report that bitter taste signaling in murine BCs induces neurogenic inflammation. We demonstrate that BC signaling stimulates adjacent sensory nerve endings in the trachea to release the neuropeptides CGRP and substance P that mediate plasma extravasation, neutrophil recruitment, and diapedesis. Moreover, we show that bitter tasting quorum-sensing molecules from Pseudomonas aeruginosa activate tracheal BCs. BC signaling depends on the key taste transduction gene Trpm5, triggers secretion of immune mediators, among them the most abundant member of the complement system, and is needed to combat P. aeruginosa infections. Our data provide functional insight into first-line defense mechanisms against bacterial infections of the lung

Natural Laminar Flow Airfoil Behavior in Cruise Flight through Atmospheric Turbulence

Atmospheric turbulence is encountered frequently in flight. It creates oncoming flow disturbances for aircraft passing through turbulent zones. For natural laminar flow airfoils such conditions are potentially detrimental since their goal of maximizing laminar flow may be counteracted by increased disturbance levels. In this study the flow behavior of a natural laminar flow wing section is investigated in gliding flight experiments under calm and light to moderately turbulent conditions. A comprehensive measurement platform is integrated into a motorized glider to obtain insights into the flow processes acting on a laminar wing glove in cruise flight. Simultaneous measurements of characteristic airfoil quantities enable important correlations with the oncoming flow disturbances. To develop a comprehensive understanding for flight through turbulence, boundary-layer transition is investigated in detail under calm conditions. Differences of the transition behavior between the upper and the lower side of the airfoil are demonstrated. New insight into the weakly nonlinear transition stage in a low disturbance environment is presented. Due to the random nature of atmospheric turbulence, characteristic results under moderately turbulent conditions are presented as case studies. This enables a complete examination of the time-varying boundary conditions, the inviscid flow effects and the boundary-layer response to the turbulent forcing. It is shown that all these processes interact with each other. Furthermore, it is demonstrated that the unsteadiness of the oncoming flow assumes an important role in the laminar-turbulent transition process of the airfoil boundary layer. On the lower side of the airfoil significant and rapid upstream fluctuations of transition are verified under moderately turbulent conditions. It is shown that these fluctuations are driven by the time-varying pressure gradient and that transition is initiated by Tollmien-Schlichting waves. Indications for a premature transition behavior under such unsteady conditions are presented, which can only partially be explained by unsteady distortions of the boundary layer. The experimental observations are complemented by numerical investigations employing unsteady panel and boundary-layer methods as well as quasi-steady linear stability theory

Natural Laminar Flow Airfoil Behavior in Cruise Flight through Atmospheric Turbulence

Atmospheric turbulence is encountered frequently in flight. It creates oncoming flow disturbances for aircraft passing through turbulent zones. For natural laminar flow airfoils such conditions are potentially detrimental since their goal of maximizing laminar flow may be counteracted by increased disturbance levels. In this study the flow behavior of a natural laminar flow wing section is investigated in gliding flight experiments under calm and light to moderately turbulent conditions. A comprehensive measurement platform is integrated into a motorized glider to obtain insights into the flow processes acting on a laminar wing glove in cruise flight. Simultaneous measurements of characteristic airfoil quantities enable important correlations with the oncoming flow disturbances. To develop a comprehensive understanding for flight through turbulence, boundary-layer transition is investigated in detail under calm conditions. Differences of the transition behavior between the upper and the lower side of the airfoil are demonstrated. New insight into the weakly nonlinear transition stage in a low disturbance environment is presented. Due to the random nature of atmospheric turbulence, characteristic results under moderately turbulent conditions are presented as case studies. This enables a complete examination of the time-varying boundary conditions, the inviscid flow effects and the boundary-layer response to the turbulent forcing. It is shown that all these processes interact with each other. Furthermore, it is demonstrated that the unsteadiness of the oncoming flow assumes an important role in the laminar-turbulent transition process of the airfoil boundary layer. On the lower side of the airfoil significant and rapid upstream fluctuations of transition are verified under moderately turbulent conditions. It is shown that these fluctuations are driven by the time-varying pressure gradient and that transition is initiated by Tollmien-Schlichting waves. Indications for a premature transition behavior under such unsteady conditions are presented, which can only partially be explained by unsteady distortions of the boundary layer. The experimental observations are complemented by numerical investigations employing unsteady panel and boundary-layer methods as well as quasi-steady linear stability theory

Global model of a radio-frequency ion thruster based on a holistic treatment of electron and ion density profiles

We present a global model of a radio-frequency ion thruster. The model takes into account radial and axial density distributions for electrons and ions of the plasma inside the ionization vessel. These spatial distributions are based on analytical equations and heuristic assumptions and are used self-consistently in all conservation equations. They are considered in the 3D computation of electromagnetic fields and used to calculate the induced power generated by the coil current. We also consider the spatial ionization and excitation inside the plasma volume in the context of energy and charge conservation. Furthermore, the model includes effects of local charge and power losses on the walls. The extraction grid system is modeled in detail describing each extraction channel separately. The spatial dependence of the electron and ion density profile also leads to a radially varying ion beam current and ion focus across the grid system. Therefore, the parameters of each beamlet differ and need to be described individually by the 3D ion extraction code. An extension of the extraction code also simulates the neutral gas transmission coefficient of the aperture system. This approach enables us to determine the neutral gas density inside the ionization vessel as well as the neutral gas losses. The peripheral electric losses in the coil, the RF cables and the radio-frequency generator are derived by a circuit model