Gating elements for carvacrol activation of the OTOP1 proton channel.

Otopetrin 1 (OTOP1) is a proton-activated channel crucial for animals' perception of sour taste. Despite its significance, the gating mechanism of OTOP1 remains poorly understood. Here, we demonstrate that carvacrol activates the mouse OTOP1 (mOTOP1) channel under neutral and acidic conditions. Functional analysis showed that carvacrol enhances pH fluorescence signals in OTOP1-expressing cells, with reduced efficacy at lower pH levels. Carvacrol selectively activates mOTOP1, while mOTOP2, mOTOP3, and Chelonia mydas OTOP1 (CmOTOP1) are insensitive to carvacrol activation under neutral pH. Through chimera and point mutation experiments, swapping S134 in transmembrane segment 3 (TM3) and T247 in the TM5-6 linker abolished carvacrol activation of mOTOP1 and conferred activation on CmOTOP1, suggesting these two residues are critical for carvacrol sensitivity. These findings highlight TM3 and TM5-6 linker as pivotal gating apparatus of OTOP1 channels and potential docking sites for drug design.

Histological diversity in hyperkeratotic flexural erythema-Beyond granular parakeratosis?

The term 'hyperkeratotic flexural erythema' (HFE) has been used synonymously with granular parakeratosis (GP), to describe a scaly, typically intertriginous rash associated with contact factors such as benzalkonium chloride. However, clinical HFE can occur without the classical GP histological pattern. We reviewed skin biopsies from 10 patients with clinically diagnosed HFE. A progression of histopathological features is suggested. The absence of histological GP should not exclude the clinical diagnosis of HFE when there is a high index of suspicion.

Vertebrate OTOP1 is also an alkali-activated channel.

Although alkaline sensation is critical for survival, alkali-activated receptors are yet to be identified in vertebrates. Here, we showed that the OTOP1 channel can be directly activated by extracellular alkali. Notably, OTOP1 biphasically mediated proton influx and efflux with extracellular acid and base stimulation, respectively. Mutations of K221 and R554 at the S5-S6 and S11-S12 linkers significantly reduced alkali affinity without affecting acid activation, suggesting that different domains are responsible for acid- and alkali-activation of OTOP1. The selectivity for H+ was significantly higher in OTOP1 activated by alkali than that by acid, further suggesting that the two activations might be independent gating processes. Given that the alkali-activation of OTOP1 and the required key residues were conserved in the six representative vertebrates, we cautiously propose that OTOP1 participates in alkaline sensation in vertebrates. Thus, our study identified OTOP1 as an alkali-activated channel.

Centipede Venom: A Potential Source of Ion Channel Modulators.

Centipedes are one of the most ancient and successful living venomous animals. They have evolved spooky venoms to deter predators or hunt prey, and are widely distributed throughout the world besides Antarctica. Neurotoxins are the most important virulence factor affecting the function of the nervous system. Ion channels and receptors expressed in the nervous system, including NaV, KV, CaV, and TRP families, are the major targets of peptide neurotoxins. Insight into the mechanism of neurotoxins acting on ion channels contributes to our understanding of the function of both channels and centipede venoms. Meanwhile, the novel structure and selective activities give them the enormous potential to be modified and exploited as research tools and biological drugs. Here, we review the centipede venom peptides that act on ion channels.

Venom resistance mechanisms in centipede show tissue specificity.

Venomous animals utilize venom glands to secrete and store powerful toxins for intraspecific and/or interspecific antagonistic interactions, implying that tissue-specific resistance is essential for venom glands to anatomically separate toxins from other tissues. Here, we show the mechanism of tissue-specific resistance in centipedes (Scolopendra subspinipes mutilans), where the splice variant of the receptor repels its own toxin. Unlike the well-known resistance mechanism by mutation in a given exon, we found that the KCNQ1 channel is highly expressed in the venom gland as a unique splice variant in which the pore domain and transmembrane domain six, partially encoded by exon 6 (rather than 7 as found in other tissues), contain eleven mutated residues. Such a splice variant is sufficient to gain resistance to SsTx (a lethal toxin for giant prey capture) in the venom gland due to a partially buried binding site. Therefore, the tissue-specific KCNQ1 modification confers resistance to the toxins, establishing a safe zone in the venom-storing/secreting environment.

Role of residential college participation in sense of belonging and academic learning.

Objective: The present study examined the relationships among students' participation in Residential College (RC) activities, their sense of belonging, academic engagement, and academic achievement. Participants: Two hundred and forty-six undergraduate students from a public university in Macau participated in this study. Methods: A set of survey questions were responded by each participant via an online link. Results: Participation in RC activities cultivated students' sense of belonging toward RC which in turn contributed to their sense of belonging toward the university. Students' academic engagement mediated the relationship between sense of belonging toward UM and academic achievement. Conclusions: These findings confirmed previous studies demonstrating the important role of RC participation in student learning and development, and shed lights on the optimization of RC system in the university as well as student development in higher education.

Potent CaV3.2 channel inhibitors exert analgesic effects in acute and chronic pain models.

Pain is the most common presenting physical symptom and a primary reason for seeking medical care, which chronically affects people's mental health and social life. CaV3.2 channel plays an essential role in the peripheral processing maintenance of pain states. This study was designed to identify novel drug candidates targeting the CaV3.2 channel. Whole-cell patch-clamp, cellular thermal shift assay, FlexStation, in vivo and in vitro CaV3.2 knock-down, site-directed mutagenesis, and double-mutant cycle analysis were employed to explore the pain-related receptors and ligand-receptor direct interaction. We found that toddaculin efficiently inhibits the CaV3.2 channel and significantly reduced the excitability of dorsal root ganglion neurons and pain behaviors. The Carbonyl group of coumarins directly interacts with the pore domain of CaV3.2 via van der Waals (VDW) force. Docking with binding pockets further led us to identify glycycoumarin, which exhibited more potent inhibition on the CaV3.2 channel and better analgesic activity than the parent compound. Toddaculin and its analog showed beneficial therapeutic effects in pain models. Toddaculin binding pocket on CaV3.2 might be a promising docking site for the design of drugs.

Cutaneous adverse reactions following the Pfizer/BioNTech COVID-19 vaccine.

A growing number of cutaneous adverse reactions have been reported following the administration of a COVID-19 vaccine. We describe a series of twenty patients who developed a variety of cutaneous conditions within two weeks of receiving the Pfizer/ BioNTech BNT162b2 vaccine.

The role of TRPA1 channels in thermosensation.

Transient receptor potential ankyrin 1 (TRPA1) is a polymodal nonselective cation channel sensitive to different physical and chemical stimuli. TRPA1 is associated with many important physiological functions in different species and thus is involved in different degrees of evolution. TRPA1 acts as a polymodal receptor for the perceiving of irritating chemicals, cold, heat, and mechanical sensations in various animal species. Numerous studies have supported many functions of TRPA1, but its temperature-sensing function remains controversial. Although TRPA1 is widely distributed in both invertebrates and vertebrates, and plays a crucial role in tempreture sensing, the role of TRPA1 thermosensation and molecular temperature sensitivity are species-specific. In this review, we summarize the temperature-sensing role of TRPA1 orthologues in terms of molecular, cellular, and behavioural levels.

Peptide OPTX-1 From Ornithodoros papillipes Tick Inhibits the pS273R Protease of African Swine Fever Virus.

African swine fever virus (ASFV) is a large double-stranded DNA virus and causes high mortality in swine. ASFV can be transmitted by biological vectors, including soft ticks in genus Ornithodoros but not hard ticks. However, the underlying mechanisms evolved in the vectorial capacity of soft ticks are not well-understood. Here, we found that a defensin-like peptide toxin OPTX-1 identified from Ornithodoros papillipes inhibits the enzyme activity of the ASFV pS273R protease with a Ki =0.821±0.526µM and shows inhibitory activity on the replication of ASFV. The analogs of OPTX-1 from hard ticks show more inhibitory efficient on pS273R protease. Considering that ticks are blood-sucking animals, we tested the effects of OPTX-1 and its analogs on the coagulation system. At last, top 3D structures represented surface analyses of the binding sites of pS273R with different inhibitors that were obtained by molecular docking based on known structural information. In summary, our study provides evidence that different inhibitory efficiencies between soft tick-derived OPTX-1 and hard tick-derived defensin-like peptides may determine the vector and reservoir competence of ticks.

A plant-derived TRPV3 inhibitor suppresses pain and itch.

BACKGROUND AND PURPOSE: Itching is the most frequent pathology in dermatology that has significant impacts on people's mental health and social life. Transient receptor potential vanilloid 3 (TRPV3) channel is a promising target for treating pruritus. However, few selecetive and potent antagonists have been reported. This study was designed to identify selective TRPV3 antagonist and elucidate its anti-pruritus pharmacology. EXPERIMENTAL APPROACH: FlexStation and calcium fluorescence imaging were conducted to track the functional compounds. Whole-cell patch clamp was used to record itch-related ion channel currents. Homologous recombination and site-directed mutagenesis were employed to construct TRPV3 channel chimeras and point mutations for exploring pharmacological mechanism. Mouse models were used for in vivo anti-pruritus assay. KEY RESULTS: An acridone alkaloid (citrusinine-II) was purified and characterized from Atalantia monophylla. It directly interacts with Y564 within S4 helix of TRPV3 to selectively inhibit the channel with a half maximal inhibitory concentration (IC50 ) of 12.43 µM. Citrusinine-II showed potential efficacy to attenuate both chronic and acute itch. Intradermal administration of citrusinine-II (143 ng/skin site) nearly completely inhibited itch behaviours. It also shows significant analgesic effects. Little side effects of the compound are observed. CONCLUSION AND IMPLICATIONS: By acting as a selective and potent inhibitor of TRPV3 channel, citrusinine-II shows valuable therapeutic effects in pruritus animal models and is a promising candidate drug and/or lead molecule for the development of anti-pruritus drugs.

Why wild giant pandas frequently roll in horse manure.

Attraction to feces in wild mammalian species is extremely rare. Here we introduce the horse manure rolling (HMR) behavior of wild giant pandas (Ailuropoda melanoleuca). Pandas not only frequently sniffed and wallowed in fresh horse manure, but also actively rubbed the fecal matter all over their bodies. The frequency of HMR events was highly correlated with an ambient temperature lower than 15 °C. BCP/BCPO (beta-caryophyllene/caryophyllene oxide) in fresh horse manure was found to drive HMR behavior and attenuated the cold sensitivity of mice by directly targeting and inhibiting transient receptor potential melastatin 8 (TRPM8), an archetypical cold-activated ion channel of mammals. Therefore, horse manure containing BCP/BCPO likely bestows the wild giant pandas with cold tolerance at low ambient temperatures. Together, our study described an unusual behavior, identified BCP/BCPO as chemical inhibitors of TRPM8 ion channel, and provided a plausible chemistry-auxiliary mechanism, in which animals might actively seek and utilize potential chemical resources from their habitat for temperature acclimatization.

Target switch of centipede toxins for antagonistic switch.

Animal venoms are powerful, highly evolved chemical weapons for defense and predation. While venoms are used mainly to lethally antagonize heterospecifics (individuals of a different species), nonlethal envenomation of conspecifics (individuals of the same species) is occasionally observed. Both the venom and target specifications underlying these two forms of envenomation are still poorly understood. Here, we show a target-switching mechanism in centipede (Scolopendra subspinipes) venom. On the basis of this mechanism, a major toxin component [Ssm Spooky Toxin (SsTx)] in centipede venom inhibits the Shal channel in conspecifics but not in heterospecifics to cause short-term, recoverable, and nonlethal envenomation. This same toxin causes fatal heterospecific envenomation, for example, by switching its target to the Shaker channels in heterospecifics without inhibiting the Shaker channel of conspecific S. subspinipes individuals. These findings suggest that venom components exhibit intricate coevolution with their targets in both heterospecifics and conspecifics, which enables a single toxin to develop graded intraspecific and interspecific antagonistic interactions.

The Latoia consocia Caterpillar Induces Pain by Targeting Nociceptive Ion Channel TRPV1.

Accidental contact with caterpillar bristles causes local symptoms such as severe pain, intense heat, edema, erythema, and pruritus. However, there is little functional evidence to indicate a potential mechanism. In this study, we analyzed the biological characteristics of the crude venom from the larval stage of Latoia consocia living in South-West China. Intraplantar injection of the venom into the hind paws of mice induced severe acute pain behaviors in wild type (WT) mice; the responses were much reduced in TRPV1-deficit (TRPV1 KO) mice. The TRPV1-specific inhibitor, capsazepine, significantly attenuated the pain behaviors. Furthermore, the crude venom evoked strong calcium signals in the dorsal root ganglion (DRG) neurons of WT mice but not those of TRPV1 KO mice. Among the pain-related ion channels we tested, the crude venom only activated the TRPV1 channel. To better understand the venom components, we analyzed the transcriptome of the L. consocia sebaceous gland region. Our study suggests that TRPV1 serves as a primary nociceptor in caterpillar-induced pain and forms the foundation for elucidating the pain-producing mechanism.

Molecular game theory for a toxin-dominant food chain model.

Animal toxins that are used to subdue prey and deter predators act as the key drivers in natural food chains and ecosystems. However, the predators of venomous animals may exploit feeding adaptation strategies to overcome toxins their prey produce. Much remains unknown about the genetic and molecular game process in the toxin-dominant food chain model. Here, we show an evolutionary strategy in different trophic levels of scorpion-eating amphibians, scorpions and insects, representing each predation relationship in habitats dominated by the paralytic toxins of scorpions. For scorpions preying on insects, we found that the scorpion α-toxins irreversibly activate the skeletal muscle sodium channel of their prey (insect, BgNaV1) through a membrane delivery mechanism and an efficient binding with the Asp/Lys-Tyr motif of BgNaV1. However, in the predatory game between frogs and scorpions, with a single point mutation (Lys to Glu) in this motif of the frog's skeletal muscle sodium channel (fNaV1.4), fNaV1.4 breaks this interaction and diminishes muscular toxicity to the frog; thus, frogs can regularly prey on scorpions without showing paralysis. Interestingly, this molecular strategy also has been employed by some other scorpion-eating amphibians, especially anurans. In contrast to these amphibians, the Asp/Lys-Tyr motifs are structurally and functionally conserved in other animals that do not prey on scorpions. Together, our findings elucidate the protein-protein interacting mechanism of a toxin-dominant predator-prey system, implying the evolutionary game theory at a molecular level.

Ensemble perception of facial attractiveness.

Ensemble perception, the extraction of a statistical summary of multiple instances of a feature, enables efficient processing of information. Here we investigated whether ensemble representations can be formed for facial attractiveness, a socially important complex feature. After verifying that our face stimuli produced by geometric morphing represented a valid continuum of attractiveness (Experiment 1), we asked participants to compare the average attractiveness of four faces with a single probe face. Whether the four faces were homogeneous or heterogeneous resulted in highly similar performance levels, suggesting the visual system could extract an ensemble representation of the attractiveness of a heterogeneous group of faces. Statistical simulations with human-level bias and noise indicated participants did not rely on subsampling one random face or the most/least attractive face from the array (Experiment 2). Ensemble perception of facial attractiveness was not affected by variance in the stimulus array (Experiment 3), did not depend on memory of individual faces in the array (Experiment 4), and could be extended to larger arrays with faces asymmetrically distributed around the set mean (Experiment 5). Our findings give further evidence to the prevalence of perception of statistical regularities in vision.

Capacity limit of ensemble perception of multiple spatially intermixed sets.

The visual system is remarkably efficient at extracting summary statistics from the environment. Yet at any given time, the environment consists of many groups of objects distributed over space. Thus, the challenge for the visual system is to summarize over multiple groups. The current study investigates the capacity and computational efficiency of ensemble perception, in the context of perceiving mean sizes of multiple spatially intermixed groups of circles. In a series of experiments, participants viewed an array of one to eight sets of circles. Each set contained four circles in the same colors, but with different sizes. Participants estimated the mean size of a probed set. The set that would be probed was either known before onset of the array (pre-cue condition) or afterwards (post-cue condition). By comparing estimation error in the pre-cue and post-cue conditions, we found that participants could reliably estimate mean sizes for approximately two sets (Experiment 1). Importantly, this capacity was robust against attention bias toward individual objects in the sets (Experiment 2). Varying the exposure time to stimulus arrays did not increase the capacity limit, suggesting that ensemble perception could be limited by an internal resource constraint, rather than the speed of information encoding (Experiment 3). Moreover, we found that the visual system could not encode and hold more individual items than ensemble representations (Experiment 4). Taken together, these results suggest that ensemble perception provides an efficient way of information processing but with constraints.

Nocardioides litorisoli sp. nov., isolated from lakeside soil.

A Gram-stain-positive, rod-shaped, non-spore-forming bacterium, designated as x-2T, was isolated from lakeside soil of Sayram in the Xinjiang Uygur Autonomous Region, PR China. On the basis of 16S rRNA gene sequences, strain x-2T belongs to the genus Nocardioides in the family Nocardioidaceae, being most closely related to Nocardioides panacisoli Gsoil 346T (97.36 % 16S rRNA gene sequence similarity). Strain x-2T was characterized chemotaxonomically and found to have ll-diaminopimelic acid in the cell-wall peptidoglycan, phosphatidylglycerol, diphosphatidylglycerol, glycolipids and another three unknown phospholipids as the major polar lipids, MK-8(H4) as the predominant menaquinone and C18 : 1ω9c, iso-C16 : 0, C17 : 1ω8c and C16 : 0 as the major fatty acids. The genomic DNA G+C content of the novel strain was 71.1 mol%. The level of DNA-DNA relatedness between strain x-2T and N. panacisoli KCTC 19470T (=Gsoil 346T) was 29.8 %. These chemotaxonomic characters support the position of strain x-2T within the genus Nocardioides. The results of physiological and biochemical tests, as well as phylogenetic analysis, suggest that strain x-2T represents a novel species of the genus Nocardioides, for which the name Nocardioides litorisoli sp. nov. is proposed. The type strain is x-2T (=KCTC 39845T=CCTCCAB 2016255T).

A systematic review of the health benefits of Tai Chi for students in higher education.

BACKGROUND: The poor health consequences of stress are well recognized, and students in higher education may be at particular risk. Tai Chi integrates physical exercise with mindfulness techniques and seems well suited to relieve stress and related conditions. METHODS: We conducted a systematic review of the health benefits of Tai Chi for students in higher education reported in the English and Chinese literature, using an evidence hierarchy approach, allowing the inclusion of studies additional to randomized controlled trials. RESULTS: Sixty eight reports in Chinese and 8 in English were included - a combined study sample of 9263 participants. Eighty one health outcomes were extracted from reports, and assigned evidence scores according to the evidence hierarchy. Four primary and eight secondary outcomes were found. Tai Chi is likely to benefit participants by increasing flexibility, reducing symptoms of depression, decreasing anxiety, and improving interpersonal sensitivity (primary outcomes). Secondary outcomes include improved lung capacity, balance, 800/1000m run time, quality of sleep, symptoms of compulsion, somatization and phobia, and decreased hostility. CONCLUSIONS: Our results show Tai Chi yields psychological and physical benefits, and should be considered by higher education institutions as a possible means to promote the physical and psychological well-being of their students.