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Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that anoctamin 1 (ANO1), a Ca 2+ -activated chloride channel, is a transduction channel mediating Mrgpr-dependent itch signals. Genetic ablation of Ano1 in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgpr-dependent itch models and the epidermal hyperplasia induced by dry skin. In vivo Ca 2+ imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgprs excited DRG neurons via ANO1. More importantly, the overexpression of Ano1 in DRG neurons of Ano1 -deficient mice rescued the impaired itching observed in Ano1 -deficient mice. These results demonstrate that ANO1 mediates the Mrgpr-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes.

This paper focuses on numerical computation and experimental examination of Bernoulli picker, which is the essential module for the 3D stacking process for heterogeneous integration devices, to reveal the fundamental physics of non-contact die handling and to seek optimized design. We estimated the pick-up performance of the Bernoulli picker and the deformation of the die using pseudo-coupling of flow and structural analysis. We simulated the flow field around the target die and picker using the RANS equation with the k-w SST turbulence model to predict the levitation height between the picker surface and target die. Then we estimated the deformation of the die using the inertial relief approach of ABAQUS with computed pressure field information. Based on the numerical investigations, we made a prototype of a Bernoulli picker and conducted experimental measures to verify the feasibility of our design. The measured results indicate that the present numerical approach can be utilized for further optimization.

Industrialization around the globe has rapidly increased fine dust concentration in the air, deteriorating the air quality. Deteriorated air quality greatly affects human health, causing diseases, ...

In this study, a new lithium-silicon-oxynitride (LiSiON) solid-state thin-film electrolyte was investigated for the first time. The LiSiON thin-film electrolyte was deposited by using the RF sputtering technique. In order to compare the LiSiON thin-film electrolyte to lithium phosphorous oxynitride (LiPON), a conventional thin-film electrolyte, were deposited LiPON thin-film electrolytes by using RF sputtering. Surface morphologies and cross-sectional views of the thin-film electrolytes were characterized by using field emission scanning electron microscopy (FE-SEM). The thin-films showed smooth surfaces without any cracks and pinholes. The smooth surfaces are thought to decrease the interfacial resistance between the electrolyte and the electrodes. In addition, surface morphologies were characterized by using atomic force microscopy (AFM). The sputtering rates were calculated using the thicknesses of the thin-films, as obtained from cross-sectional views. The structural properties of the thin-films were characterized using X-ray diffraction (XRD). All thinfilms showed amorphous properties compared to the target material which is a crystalline material. The ionic conductivity of the LiSiON thin-film was 2.47 × 10 −6 (S/cm), which is slightly higher than that of a common thin-film electrolyte LiPON.

The patterning of electrospun fibers is a key technology applicable to various fields. This study reports a novel focused patterning method for electrospun nanofibers that uses a cylindrical dielectric guide. The finite elements method (FEM) was used to analyze the electric field focusing phenomenon and ground its explanation in established theory. The horizontal and vertical electric field strengths in the simulation are shown to be key factors in determining the spatial distribution of nanofibers. The experimental results demonstrate a relationship between the size of the cylindrical dielectric guide and that of the electrospun area accumulated in the collector. By concentrating the electric field, we were able to fabricate a pattern of less than 6 mm. The demonstration of continuous line and square patterning shows that the electrospun area can be well controlled. This novel patterning method can be used in a variety of applications, such as sensors, biomedical devices, batteries, and composites.

Significance Radial glial cells (RGCs), a type of neural stem cell in the developing brain, not only generate progenitors, newly born neurons and glial cells, but also deliver neurons through its process to the appropriate cortical target layers. Thus, the function of RGCs is crucial for cortex development, in which Cl− channels are thought to play a role. Here we highlight that Anoctamin 1 (ANO1)/TMEM16A, a Ca2+-activated Cl− channel, mediates the process extension in RGCs. ANO1-null mice show a decrease in cortical thickness with disorganized cortical layers. Thus, as a Cl− channel, ANO1 is involved in the process maturation of RGCs and contributes to cortex development., Neural stem cells (NSCs) are primary progenitor cells in the early developmental stage in the brain that initiate a diverse lineage of differentiated neurons and glia. Radial glial cells (RGCs), a type of neural stem cell in the ventricular zone, are essential for nurturing and delivering new immature neurons to the appropriate cortical target layers. Here we report that Anoctamin 1 (ANO1)/TMEM16A, a Ca2+-activated chloride channel, mediates the Ca2+-dependent process extension of RGCs. ANO1 is highly expressed and functionally active in RGCs of the mouse embryonic ventricular zone. Knockdown of ANO1 suppresses RGC process extension and protrusions, whereas ANO1 overexpression stimulates process extension. Among various trophic factors, brain-derived neurotrophic factor (BDNF) activates ANO1, which is required for BDNF-induced process extension in RGCs. More importantly, Ano1-deficient mice exhibited disrupted cortical layers and reduced cortical thickness. We thus conclude that the regulation of RGC process extension by ANO1 contributes to the normal formation of mouse embryonic brain.

Photoelectrochemical (PEC) water splitting has been studied extensively as an environmentally friendly technology for hydrogen production using solar energy. WO

Correction for ‘Nanofibrous sunscreen’ by Byeongjun Lee et al., J. Mater. Chem. C, 2022, https://doi.org/10.1039/d2tc00933a.

TRPM2 a cation channel is also known to work as an enzyme that hydrolyzes highly reactive, neurotoxic ADP-ribose (ADPR). Although ADPR is hydrolyzed by NUT9 pyrophosphatase in major organs, the enzyme is defective in the brain. The present study questions the role of TRPM2 in the catabolism of ADPR in the brain. Genetic ablation of Trpm2 results in the disruption of ADPR catabolism that leads to the accumulation of ADPR and reduction in AMP. Trpm2−/− mice elicit the reduction in autophagosome formation in the hippocampus. Trpm2−/− mice also show aggregations of proteins in the hippocampus, aberrant structural changes and neuronal connections in synapses, and neuronal degeneration. Trpm2−/− mice exhibit learning and memory impairment, enhanced neuronal intrinsic excitability, and imbalanced synaptic transmission. These results respond to long-unanswered questions regarding the potential role of the enzymatic function of TRPM2 in the brain, whose dysfunction evokes protein aggregation. In addition, the present finding answers to the conflicting reports such as neuroprotective or neurodegenerative phenotypes observed in Trpm2−/− mice. Electronic supplementary material The online version of this article (10.1007/s12035-018-1309-0) contains supplementary material, which is available to authorized users.

TMEM16A, a Ca(2+)‐activated Cl(−) channel, is known to modulate the excitability of various types of cells; however, its function in central neurons is largely unknown. Here, we show the specific expression of TMEM16A in the medial habenula (mHb) via RNAscope in situ hybridization, immunohistochemistry, and electrophysiology. When TMEM16A is ablated in the mHb cholinergic neurons (TMEM16A cKO mice), the slope of after‐hyperpolarization of spontaneous action potentials decreases and the firing frequency is reduced. Reduced mHb activity also decreases the activity of the interpeduncular nucleus (IPN). Moreover, TMEM16A cKO mice display anxiogenic behaviors and deficits in social interaction without despair‐like phenotypes or cognitive dysfunctions. Finally, chemogenetic inhibition of mHb cholinergic neurons using the DREADD (Designer Receptors Exclusively Activated by Designer Drugs) approach reveals similar behavioral phenotypes to those of TMEM16A cKO mice. We conclude that TMEM16A plays a key role in anxiety‐related behaviors regulated by mHb cholinergic neurons and could be a potential therapeutic target against anxiety‐related disorders.

Harmful maternal behaviors, such as drinking and smoking, negatively affect embryonic development. In contrast, regular maternal exercise is believed to be beneficial to the fetus. Although it is not surprising that voluntary physical activities are advantageous to fetal development, it remains unclear whether involuntary maternal exercise has similar effects. The constituents of the amniotic fluid (AF) inevitably reflect the maternal plasma. Therefore, it is speculated that exercise-induced changes in maternal plasma can influence fetal development through changes in AF composition. Therefore, we investigated the effect of AF on fetal neurodevelopment and changes in AF composition after involuntary swimming exercise (SE) in an animal model. We found that there was a severe reduction in the number of embryos implanted in the uterus of SE rats. Surprisingly, cortisol level (an inducible stress hormone) was significantly increased in AF from SE rats. In contrast, the growth factors NGF and VEGF were reduced in the AF from SE rats. In the cultured embryonic cortical neurons, the treatment of control (CTL) rat-derived AF significantly increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated signaling that is essential for fetal neurodevelopment. However, the AF extracted from SE rats reversely suppressed the phosphorylation of ERK1/2-mediated signaling in cortical neurons compared to that in CTL rats. Indeed, the co-treatment with control AF and dexamethasone, a synthetic glucocorticoid, inhibited the phosphorylation of ERK1/2 in a dose-dependent manner. This finding suggests that the inhibition of ERK1/2 can be attributed to increased cortisol level in AF resulting from involuntary exercise. Therefore, involuntary maternal swimming increases cortisol level in AF, which ultimately hinders the ERK1/2 signaling pathway in embryonic neurons. These findings also suggest that involuntary maternal exercise can have undesirable effects on fetal neurodevelopment, which is potentially mediated by elevated AF cortisol level.

Photoelectrochemical (PEC) water splitting has been studied extensively as an environmentally friendly technology for hydrogen production using solar energy. WO3 is considered a promising semiconducting material for photoanodes due to its high electron mobility, good hole diffusion length, and chemical stability. Periodic nanostructures of WO3 have been investigated for enhancing the PEC performance of WO3-based photoanodes. In this study, facile fabrication of periodic nanostructures of WO3 was achieved using reverse nanoimprint lithography, and the multilayer stacking of nanopatterned WO3 film was also confirmed. The multilayer nanopatterned WO3 films were used as photoanodes for PEC water splitting. The performance of the fabricated photoanodes in PEC was 2 times higher than that of planar WO3 films due to its higher light absorbance and lower charge transfer resistance.

A method to infer the terrain of unobserved fields as well as navigation paths using vibrations from vehicle-terrain interactions is presented. The relationships between adjacent terrain grids and robot paths are modelled by Markov random field (MRF) for inferring the classes of unobserved field. In order to approximate the complex likelihood of vibration features as a tractable distribution, a variational auto-encoder is adopted. By projecting intractable features to the latent space, an approximated likelihood that gives similar performance to a neural network classifier is obtained. Then the numerical maximum a posterior inference for MRF is obtained. The result of inferred terrain maps are compared with that from the feature likelihood as a Gaussian-mixture model.

Calcium-activated chloride channels (CaCCs) mediate numerous physiological functions and are best known for the transport of electrolytes and water in epithelia. In the intestine, CaCC currents are considered necessary for the secretion of fluid to protect the intestinal epithelium. Although genetic ablation of ANO1/TMEM16A, a gene encoding a CaCC, reduces the carbachol-induced secretion of intestinal fluid, its mechanism of action is still unknown. Here, we confirm that ANO1 is essential for the secretion of intestinal fluid. Carbachol-induced transepithelial currents were reduced in the proximal colon of Ano1-deficient mice. Surprisingly, cholera toxin-induced and cAMP-induced fluid secretion, believed to be mediated by CFTR, were also significantly reduced in the intestine of Ano1-deficient mice. ANO1 is largely expressed in the apical membranes of intestines, as predicted for CaCCs. The Ano1-deficient colons became edematous under basal conditions and had a greater susceptibility to dextran sodium sulfate-induced colitis. However, Ano1 depletion failed to affect tumor development in a model of colorectal cancer. We thus conclude that ANO1 is necessary for cAMP- and carbachol-induced Cl− secretion in the intestine, which is essential for the protection of the intestinal epithelium from colitis., Colitis: Intestinal membrane protein implicated in defective fluid secretion An ion channel, a membrane protein allowing ion transport, that controls the flow of chloride is needed for proper secretion of protective fluids in the intestine. Uhtaek Oh from the Korea Institute of Science & Technology in Seoul, South Korea, and colleagues showed that cells lining the intestinal surface express a calcium-activated chloride channel called anoctamin-1 (ANO1) that regulates fluid secretion in the gut. Compared to control animals, ANO1-deficient mice released less fluid into their intestines following exposure to a diarrhea-inducing toxin or to a chloride transport–stimulating signaling molecule. This fluid secretion was previously thought to be mediated via a different ion channel. The ANO1-deficient mice accumulated fluid within colonic tissues, which increased their susceptibility to colitis. The findings point to ANO1 activation as a potential therapeutic strategy for treating colitis.

Touch sensation or proprioception requires the transduction of mechanical stimuli into electrical signals by mechanoreceptors in the periphery. These mechanoreceptors are equipped with various transducer channels. Although Piezo1 and 2 are mechanically activated (MA) channels with rapid inactivation, MA molecules with other inactivation kinetics have not been identified. Here we report that heterologously expressed Tentonin3 (TTN3)/TMEM150C is activated by mechanical stimuli with distinctly slow inactivation kinetics. Genetic ablation of Ttn3/Tmem150c markedly reduced slowly adapting neurons in dorsal-root ganglion neurons. The MA TTN3 currents were inhibited by known blockers of mechanosensitive ion channels. Moreover, TTN3 was localized in muscle spindle afferents. Ttn3-deficient mice exhibited the loss of coordinated movements and abnormal gait. Thus, TTN3 appears to be a component of a mechanosensitive channel with a slow inactivation rate and contributes to motor coordination. Identification of this gene advances our understanding of the various types of mechanosensations, including proprioception.

A dynamic key-frame selection technique is proposed for enhanced odometry estimation. The odometry estimation problem has a drift problem in which errors are accumulated over time. The proposed technique finds the key-frame which reduces the odometry drift for every time step based on scan similarity comparisons. The enhancement of the proposed method is verified through the performance comparison with the frame-to-frame and the conventional frame to key-frame methods.

This reported work addresses a collaborative approach to path planning in continuous space for the energy constrained robot collection problem. The objective is to minimise the overall duration the mobile robots return from where the given tasks are completed. For time- and energy-efficient collection, the authors use a large-scale ground vehicle that can load and transport relatively small mobile robots. However, determining time-optimal collection locations requires too much computation in this problem setting. Therefore, a heuristic algorithm for a set of mobile robots is proposed and verified through simulations.

A new smoothing algorithm to obtain surface normals for superpixels in the noisy depth image is proposed. For smoothing surface normals, the plane normal that indicates a surface characteristic is obtained by considering the inherent geometric similarity. This process results in smoothed surface normals which are free from noise of the depth image. The superpixels method with suggested smoothing algorithm outperforms in higher quality than the state-of-the art oversegmentation algorithms. The proposed technique can also be applied to any smoothing algorithms using surface normals for 3D features. Experimental results to demonstrate the effectiveness of the proposed smoothing surface normal technique is provided.

Anoctamins (ANOs) are multifunctional membrane proteins that consist of 10 homologs. ANO1 (TMEM16A) and ANO2 (TMEM16B) are anion channels activated by intracellular calcium that meditate numerous physiological functions. ANO6 is a scramblase that redistributes phospholipids across the cell membrane. The other homologs are not well characterized. We found ANO9/TMEM16J is a cation channel activated by a cAMP-dependent protein kinase A (PKA). Intracellular cAMP-activated robust currents in whole cells expressing ANO9, which were inhibited by a PKA blocker. A cholera toxin that persistently stimulated adenylate cyclase activated ANO9 as did the application of PKA. The cAMP-induced ANO9 currents were permeable to cations. The cAMP-dependent ANO9 currents were augmented by intracellular Ca2+. Ano9 transcripts were predominant in the intestines. Human intestinal SW480 cells expressed high levels of Ano9 transcripts and showed PKA inhibitor-reversible cAMP-dependent currents. We conclude that ANO9 is a cation channel activated by a cAMP/PKA pathway and could play a role in intestine function.

Mechanosensation is essential for various physiological processes, and it is mediated by mechanotransduction channels. Recently, we reported that TMEM150C/Tentonin 3 (TTN3) confers mechanically activated currents with slow inactivation kinetics in several cell types, including dorsal root ganglion neurons (Hong et al., 2016). The accompanying Matters Arising by Dubin, Murthy, and colleagues confirms that naive heterologous cells demonstrate a mechanically activated current, but finds that this response is absent in CRISPR-Cas9 Piezo1 knockout cell lines and suggests that TTN3 is a modulator of Piezo1. We present and discuss evidence based on co-expression of TTN3 and Peizo1 and mutant variants of the pore region of TTN3 to support that TTN3 is a pore-forming unit, not an amplifying adaptor for Piezo1 activity. This Matters Arising Response paper, along with Zhao et al. (2017), addresses the Matters Arising from Dubin et al. (2017), published concurrently in this issue of Neuron.

This reported work addresses the deployment problem of unmanned aerial vehicles (UAVs) for multiple scattered tasks. The objective is to minimise the duration of all UAVs in reaching their assigned task locations so that the overall time needed to accomplish a mission is minimised. Taking speed and energy constraints into account, it is advantageous to transport UAVs by a large-scale ground vehicle in the shortest time. However, computation of the deployment points requires too much time for an optimal operation to accomplish a task. Therefore, an approximate solution is pursued by an algorithm for efficient deployment. The feasibility of the proposed algorithm is demonstrated through simulations.

A new Gaussian mixture model (GMM) estimation technique is presented for three-dimensional (3D) spatial representation. The GMM generated by the proposed technique is compact with bounded information loss as a result of using robust estimators and the Kullback-Leibler divergence-based Gaussian mixture reduction method. In addition, the proposed technique is not only robust to outliers, but quite close to invariant under similarity transformation. Experiments have demonstrate that the compactness and the consistency of the GMM are improved compared with existing 3D spatial representation models.

An efficient three-dimensional (3D) object registration method considering the point cloud distribution for a mobile robot platform is suggested. This technique adjusts overlapping areas between two consecutive scan data according to the property of the observed object's surface. The proposed technique can reduce computational load and increase the accuracy of 3D object registration with less total number of scan data. The improved performance is verified by comparing the estimated pose with the ground truth pose for observation robots.

Background The quantification of pain intensity in vivo is essential for identifying the mechanisms of various types of pain or for evaluating the effects of different analgesics. A variety of behavioral tests for pain measurement have been devised, but many are limited because animals are physically restricted, which affects pain sensation. In this study, pain assessment was attempted with minimal physical restriction, and voluntary movements of unrestrained animals were used to evaluate the intensities of various types of pain. Results The number of times animals reared or total distances traveled was measured using a motion-tracking device and found to be markedly reduced in carrageenan-induced inflammatory, acetic acid-induced visceral, and streptozotocin-induced neuropathic pain tests. These two voluntary movement parameters were found to be highly correlated with paw withdrawal latency from irradiating heat. In addition, these parameters were markedly reversed by morphine and by non-steroidal anti-inflammatory drugs in inflammatory pain models. These parameters were also useful to detect hypoalgesia in TRPV1−/− mice. Conclusions These results suggest that parameters of voluntary movement, such as, number of rearing and total distance moved, are effective indicators of pain intensity for many types of pain and that they can be used to evaluate degree of pain perception.

The real-time navigation problem of a holonomic mobile robot in dynamic environments is addressed. The robot's footprint and obstacles are approximated with the smallest enclosing ellipses, known as the Lowner-John ellipses. The robot avoids collisions with obstacles by selecting a translational velocity outside of the ellipse-based velocity obstacle (EBVO) described in this Letter at each time step. Furthermore, the rotational velocity of the robot is controlled to gradually change the EBVO so that the robot can efficiently reach the destination. Finally, the proposed algorithm is demonstrated through simulations.

Bipolar disorder (BD) is a psychiatric disease that causes mood swings between manic and depressed states. Although genetic linkage studies have shown an association between BD and TRPM2, a Ca(2+)-permeable cation channel, the nature of this association is unknown. Here, we show that D543E, a mutation of Trpm2 that is frequently found in BD patients, induces loss of function. Trpm2-deficient mice exhibited BD-related behavior such as increased anxiety and decreased social responses, along with disrupted EEG functional connectivity. Moreover, the administration of amphetamine in wild-type mice evoked a notable increase in open-field activity that was reversed by the administration of lithium. However, the anti-manic action of lithium was not observed in the Trpm2(−/−) mice. The brains of Trpm2(−/−) mice showed a marked increase in phosphorylated glycogen synthase kinase-3 (GSK-3), a key element in BD-like behavior and a target of lithium. In contrast, activation of TRPM2 induced the dephosphorylation of GSK-3 via calcineurin, a Ca(2+)-dependent phosphatase. Importantly, the overexpression of the D543E mutant failed to induce the dephosphorylation of GSK-3. Therefore, we conclude that the genetic dysfunction of Trpm2 causes uncontrolled phosphorylation of GSK-3, which may lead to the pathology of BD. Our findings explain the long-sought etiologic mechanism underlying the genetic link between Trpm2 mutation and BD. SIGNIFICANCE STATEMENT Bipolar disorder (BD) is a mental disorder that causes changes in mood and the etiology is still unknown. TRPM2 is highly associated with BD; however, its involvement in the etiology of BD is still unknown. We show here that TRPM2 plays a central role in causing the pathology of BD. We found that D543E, a mutation of Trpm2 frequently found in BD patients, induces the loss of function. Trpm2-deficient mice exhibited mood disturbances and impairments in social cognition. TRPM2 actively regulates the phosphorylation of GSK-3, which is a main target of lithium, a primary medicine for treating BD. Therefore, abnormal regulation of GSK-3 by hypoactive TRPM2 mutants accounts for the pathology of BD, providing the possible link between BD and TRPM2.

Significance Benign prostatic hyperplasia (BPH) is characterized by an enlargement of the prostate gland, a common disease in elderly men. Excessive testosterone is considered to cause BPH. However, its etiologic mechanisms are elusive. We found that ANO1, a Ca 2+ -activated Cl − channel, is essential for the testosterone-induced BPH. ANO1 was highly expressed in dihydrotestosterone (DHT)-treated prostate epithelial cells. The selective knockdown of ANO1 suppressed DHT-induced cell proliferation. Surprisingly, we found that there were three androgen-response elements in the ANO1 promoter region, which were relevant for the DHT-dependent induction of ANO1. Intraprostate treatment of Ano1 siRNA inhibited the prostate enlargement in vivo. Thus, ANO1 appears essential for the development of prostate hyperplasia and becomes a useful target for treating BPH.

A new grid map-merging technique which consists of virtual emphasis by one-way observation, curvature-based map matching and particle swarm optimisation is proposed. The proposed technique can improve not only the accuracy of map merging, but also the flexibility of multi-robot systems. The improved performance is verified by showing higher similarities than the existing map-merging techniques in experiments.

Aim of the study Poncirus fructus (PF) – also known as the dried, immature fruit of Poncirus trifoliata (L.) Raf. (Rutaceae) – is a natural substance that has long been used for various gastrointestinal disorders in eastern Asia. An aqueous extract of PF (PF-W) has particularly potent gastroprokinetic effects, but its molecular mechanism was not well understood. Identification of the underlying prokinetic mechanism of PF-W was pursued in the present study. Materials and methods Changes in in vitro cAMP levels and in vivo intestinal transit rate (ITR) caused by PF-W were measured after pretreatment with GR125487, an antagonist for serotonin receptor subtype 4 (5-HT4R). An [ 3 H] astemizole binding assay and electrophysiology experiments were performed to determine if PF-W has any interaction with the human ether-a-go-go related gene (hERG) potassium channel. Results PF-W induced an increase in intracellular cAMP in 5-HT4R-expressing HEK293T cells, indicating that PF-W does activate 5-HT4R. Moreover, pretreatment with GR125487 successfully blocked the increase, suggesting that the response was 5-HT4R-specific. More importantly, pretreatment of GR125487 in rats inhibited the elevation of ITR by PF-W, indicating that the prokinetic effect of PF-W was indeed exerted via 5-HT4R. On the other hand, both [ 3 H]-astemizole binding assay and electrophysiological experiments revealed that PF-W did not interfere at all with the hERG channel. Conclusion It was found that PF-W exerts its prokinetic activity through a 5-HT4R-mediated pathway, with no interaction with hERG channels. Therefore, PF-W is a good candidate that might be developed as a prokinetic agent with fewer expected cardiac side effects.

Calcium (Ca2+)-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca2+-activated chloride channel that is activated by intracellular Ca2+ and Ca2+-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca2+-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca2+-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca2+-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes. Calcium-activated chloride channels play a fundamental role in many physiological processes, but their molecular identity has so far evaded characterization. This paper shows that the transmembrane protein TMEM16A, also known as anoctamin 1 or ANO1, is a Ca2+-activated chloride channel. TMEM16A has a novel trimeric structure composed of eight transmembrane domains, very different from all previously characterized ionic channels. Its knock-down reduced native Ca2+activated chloride currents and impairs salivary secretion in mice.

It is demonstrated that a nanoscale multilevel memristive device using titanium oxide can be used to form programmable analogue circuits without an active transistor. A multilevel memristive device enables a high a degree of programmability particularly for analogue applications since it will not introduce any significant parasitic components. Also, the ring oscillator application with the memristive device is merely a demonstrative example of the enabled high programmability.

Background Various pathological conditions such as inflammation or injury can evoke pain hypersensitivity. That represents the response to innocuous stimuli or exaggerated response to noxious stimuli. The molecular mechanism based on the pain hypersensitivity is associated with changes in many of ion channels in dorsal-root ganglion (DRG) neurons. Anoctamin 1 (ANO1/TMEM16A), a Ca2+ activated chloride channel is highly visible in small DRG neurons and responds to heat. Mice with an abolished function of ANO1 in DRG neurons demonstrated attenuated pain-like behaviors when exposed to noxious heat, suggesting a role in acute thermal nociception. In this study, we further examined the function of ANO1 in mediating inflammation- or injury-induced hyperalgesia or allodynia. Results Using Advillin/Ano1 fl/fl (Adv/Ano1 fl/fl ) mice that have a functional ablation of Ano1 mainly in DRG neurons, we were able to determine its role in mediating thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury. The thermal hyperalgesia and mechanical allodynia induced by carrageenan injection and spared-nerve injury were significantly reduced in Adv/Ano1 fl/fl mice. In addition, flinching or licking behavior after bradykinin or formalin injection was also significantly reduced in Adv/Ano1 fl/fl mice. Since pathological conditions augment nociceptive behaviors, we expected ANO1′s contribution to the excitability of DRG neurons. Indeed, the application of inflammatory mediators reduced the threshold for action potential (rheobase) or time for induction of the first action potential in DRG neurons isolated from control (Ano1 fl/fl ) mice. These parameters for neuronal excitability induced by inflammatory mediators were not changed in Adv/Ano1 fl/fl mice, suggesting an active contribution of ANO1 in augmenting the neuronal excitability. Conclusions In addition to ANO1's role in mediating acute thermal pain as a heat sensor, ANO1 is also capable of augmenting the excitability of DRG neurons under inflammatory or neuropathic conditions and thereby aggravates inflammation- or tissue injury-induced pathological pain.