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Bitterness is an important physiological function in the defense responses to avoid toxic foods. The taste receptor 2 family is well known to mediate bitter taste perception in Type II taste cells. Here, we report that the polycystic kidney disease 2-like 1 (PKD2L1) channel is a novel sensor for the bitter aftertaste in Type III taste cells. The PKD2L1 channel showed rebound activation after the washout of quinine, a bitter tastant, in electrophysiological whole-cell recordings of the PKD2L1-expressing HEK293T cells and Ca2+-imaging analysis of Type III taste cells isolated from wild-type PKD2L1 mice. In the short-term two-bottle preference and lick tests in vivo, the wild-type mice avoided normal water while the PKD2L1-knockout mice preferred normal water after they ingested the quinine-containing water. These results may explain the new mechanism of the quinine-triggered bitter aftertaste perception in Type III taste cells.

FK506 (tacrolimus) is an immunosuppressant widely used as an ointment in the treatment of atopic dermatitis. However, local application of FK506 can evoke burning sensations in atopic dermatitis patients, and its mechanisms are unknown. In this study, we found that FK506 activates transient receptor potential ankyrin 1 (TRPA1) channels. In Ca2+-imaging experiments, increases in intracellular Ca2+ concentrations ([Ca2+]i) by FK506 were observed in HEK293T cells expressing hTRPA1 or hTRPM8. FK506-induced currents were observed in HEK293T cells expressing hTRPA1 or mTRPA1, but less or not at all in cells expressing hTRPV1 or hTRPM8 using a patch-clamp technique. FK506 also evoked single-channel opening of hTRPA1 in an inside-out configuration. FK506-induced [Ca2+]i increases were also observed in TRPA1-expressing mouse primary sensory neurons. Furthermore, injection of FK506 evoked licking or biting behaviors and these behaviors were almost abolished in TRPA1 knockout mice. These results indicate that FK506 might cause pain sensations through TRPA1 activation.

This article presents a discretization scheme for a nonlinear differential equation using a regression analysis technique. As with many other numerical solvers such as finite difference methods and finite element methods, the presented scheme discretizes a simulation field into a finite number of points. Although other solvers “directly and mathematically” discretize a differential equation governing the field, the presented scheme “indirectly and statistically” constructs the discretized equation using regression analyses. The regression model learns a pre-prepared training data including dependent-variable values at neighboring points in the simulation field. Each trained regression model expresses the relation between the variables and returns a variable value for a point (output) referring to the variables for its surrounding points (input). In other words, the regression model performs a role as the discretized equation of the variable. The presented approach can be applied to many kinds of nonlinear problems. This study employs artificial neural networks and polynomial functions as the regression models. The main aim here is to assess whether the neural network-based spatial discretization approach can solve a nonlinear problem. In this work, I apply the presented scheme to nonlinear steady-state heat conduction problems. The computational accuracy of the presented technique was compared with a standard finite difference method and a homogenization method that is one of representative multiscale modeling approaches.

Hypotonic solutions can cause painful sensations in nasal and ocular mucosa through molecular mechanisms that are not entirely understood. We clarified the ability of human TRPA1 (hTRPA1) to respond to physical stimulus, and evaluated the response of hTRPA1 to cell swelling under hypotonic conditions. Using a Ca2+-imaging method, we found that modulation of AITC-induced hTRPA1 activity occurred under hypotonic conditions. Moreover, cell swelling in hypotonic conditions evoked single-channel activation of hTRPA1 in a cell-attached mode when the patch pipette was attached after cell swelling under hypotonic conditions, but not before swelling. Single-channel currents activated by cell swelling were also inhibited by a known hTRPA1 blocker. Since pre-application of thapsigargin or pretreatment with the calcium chelator BAPTA did not affect the single-channel activation induced by cell swelling, changes in intracellular calcium concentrations are likely not related to hTRPA1 activation induced by physical stimuli.

The placenta is required to transport calcium (Ca2+) from mother to fetus during fetal bone mineralization. In an attempt to clarify the molecular basis of Ca2+ entry for this transport, we identified TRPM6 as a candidate for apical Ca2+ entry pathway. TRPM6 mRNA increased during the last 4 days of pregnancy, coinciding with fetal bone mineralization in mice. TRPM6 mRNA and protein was localized in the trophoblasts in labyrinth where the maternal–fetal Ca2+ transport occurs. In patch-clamp recordings, we observed TRPM6/TRPM7-like currents in mouse trophoblasts after starting fetal bone mineralization but not before mineralization. Plasma membrane Ca2+ permeability was significantly increased in TRPM6/TRPM7 expressed HEK293 cells under physiological Mg2+ and ATP concentration but not in TRPM6 or TRPM7 homomer-expressing cells. These results suggest that TRPM6 is functionally expressed in mouse placental trophoblasts, implicating in maternal–fetal Ca2+ transport likely with TRPM7, which might enable to sustain fetal bone mineralization.

Transient receptor potential ankyrin 1 (TRPA1) protein is a nonselective cation channel. Although many studies suggest that TRPA1 is involved in inflammatory and neuropathic pain, its mechanism remains unclear. Here we identify an alternative splice variant of the mouse Trpa1 gene. TRPA1a (full-length) and TRPA1b (splice variant) physically interact with each other and TRPA1b increases the expression of TRPA1a in the plasma membrane. TRPA1a and TRPA1b co-expression significantly increases current density in response to different agonists without affecting their single-channel conductance. Exogenous overexpression of Trpa1b gene in wild-type and TRPA1KO DRG neurons also increases TRPA1a-mediated AITC responses. Moreover, expression levels of Trpa1a and Trpa1b mRNAs change dynamically in two pain models (complete Freund’s adjuvant-induced inflammatory pain and partial sciatic nerve ligation-induced neuropathic pain models). These results suggest that TRPA1 may be regulated through alternative splicing under these pathological conditions., TRPA1 is a transient receptor potential channel family member and is involved in the detection of nociceptive stimuli. Zhou et al. identify an alternative splice variant of TRPA1, which increases TRPA1 plasma expression and channel function, and enhances pain-like behaviour in mice.

Transient receptor potential (TRP) channels play important roles in thermal, chemical, and mechanical sensation in various tissues. In this study, we investigated the differences in urothelial TRP channels between normal urothelial cells and bladder cancer cells. TRPV2 and TRPM7 expression levels and TRPV2 activator-induced intracellular Ca(2+) increases were significantly higher, whereas TRPV4 expression and TRPV4 activator-induced intracellular Ca(2+) increases were significantly lower in mouse bladder cancer (MBT-2) cells compared to normal mouse urothelial cells. The proliferation rate of MBT-2 cells overexpressing dominant-negative TRPV2 was significantly increased. In contrast, treatment with TRPV2 activators significantly decreased the proliferation rate. TRPM7-overexpressing MBT-2 cells proliferated more slowly, as compared to mock-transfected cells. Moreover, expression of dominant-negative TRPV2 significantly decreased plasma membrane Ca(2+) permeability of MBT-2 cells as compared to that in mock-transfected cells. Increases in the expression of TRPV2 mRNA, immunoreactivity, and TRPV2 activator-induced intracellular Ca(2+) were also observed in T24 human bladder cancer cells. These results suggested that TRPV2 and TRPM7 were functionally expressed in bladder cancer cells and served as negative regulators of bladder cancer cell proliferation, most likely to prevent excess mechanical stresses.

Recently, Rozvany and Maute presented a simple problem of topology optimization under uncertainty with a single load condition that can be solved without Monte Carlo simulation. This note extends this idea to a two-bar truss under two load conditions for the purpose of illustrating differences between deterministic designs and reliability–based ones in terms of risk allocation. For this example, for the same probability of failure, a deterministic design based on the same safety factor for both loads can be substantially heavier than the reliability–based design. The difference in weight is due to very different risk allocation between the two failure modes.

Traditionally, Asians have been thought to age more gracefully than Caucasians. The resistance to aging in the Asian patient was credited to the thicker dermis of Asian skin that contains greater collagen and the darker pigment that protects against photoaging. Although these statements are true, the authors propose a new paradigm that explains how the illusion of Asian youthfulness may be understood. The "baby model" purports that the Asian face has many attributes similar to an infant, including a wider and rounder face, higher eyebrow, fuller upper lid, lower nasal bridge, flatter midface, apparently more protuberant lips, and more receded chin. These commonalities between the infant and the Asian compel the viewer to perceive the Asian face as more youthful. However, the Asian face is subjected to a greater amount of gravitational force due to weaker skeletal support, heavier soft tissue, larger amount of malar fat, thicker skin, and a weaker chin. Facial rejuvenative surgery should always be cognizant of the propensity of the Asian skin to unfavorable healing, need for greater tissue suspension, and more conspicuous temporal alopecia. Asian aesthetics that differ and converge with Western ideals are reviewed so that the Western surgeon in particular can comprehend the Asian conception of youthful beauty.

Transient receptor potential ankyrin 1 (TRPA1) protein is a nonselective cation channel. Although many studies suggest that TRPA1 is involved in inflammatory and neuropathic pain, its mechanism remains unclear. Here we identify an alternative splice variant of the mouse Trpa1 gene. TRPA1a (full-length) and TRPA1b (splice variant) physically interact with each other and TRPA1b increases the expression of TRPA1a in the plasma membrane. TRPA1a and TRPA1b co-expression significantly increases current density in response to different agonists without affecting their single-channel conductance. Exogenous overexpression of Trpa1b gene in wild-type and TRPA1KO DRG neurons also increases TRPA1a-mediated AITC responses. Moreover, expression levels of Trpa1a and Trpa1b mRNAs change dynamically in two pain models (complete Freund's adjuvant-induced inflammatory pain and partial sciatic nerve ligation-induced neuropathic pain models). These results suggest that TRPA1 may be regulated through alternative splicing under these pathological conditions.