Dynamic temperature control in microfluidics for in vivo imaging of cold-sensing in C. elegans.

The ability to perceive temperature is crucial for most animals. It enables them to maintain their body temperature and swiftly react to noxiously cold or hot objects. Caenorhabditis elegans is a powerful genetic model for the study of thermosensation as its simple nervous system is well characterized and its transparent body is suited for in vivo functional imaging of neurons. The behavior triggered by experience-dependent thermosensation has been well studied in C. elegans under temperature-gradient environments. However, how C. elegans senses temperature via its nervous system is not well understood due to the limitations of currently available technologies. One major bottleneck is the difficulty in creating fast temperature changes, especially cold stimuli. Here, we developed a microfluidic-based platform that allowed the in vivo functional imaging of C. elegans responding to well-controlled temporally varying temperature stimulation by rapidly switching fluid streams at different temperatures. We used computational models to enable rational design and optimization of experimental conditions. We validated the design and utility of our system with studies of the functional role of thermosensory neurons. We showed that the responses of PVD polymodal nociceptor neurons observed in previous studies can be recapitulated. Further, we highlighted how this platform may be used to dissect neuronal circuits with an example of activity recording in PVC interneurons. Both of these neuron types show sensitization phenotypes. We envision that both the engineered system and the findings in this work will spur further studies of molecular and cellular mechanisms underlying cold-sensing through the nervous system.

A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure.

Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized1. Tanycytes are a specialized cell type along the wall of the third ventricle2 that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system3-8. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.

Separation of Oral Cooling and Warming Requires TRPM8.

Cooling sensations arise inside the mouth during ingestive and homeostasis behaviors. Oral presence of cooling temperature engages the cold and menthol receptor TRPM8 (transient receptor potential melastatin 8) on trigeminal afferents. Yet, how TRPM8 influences brain and behavioral responses to oral temperature is undefined. Here we used in vivo neurophysiology to record action potentials stimulated by cooling and warming of oral tissues from trigeminal nucleus caudalis neurons in female and male wild-type and TRPM8 gene deficient mice. Using these lines, we also measured orobehavioral licking responses to cool and warm water in a novel, temperature-controlled fluid choice test. Capture of antidromic electrophysiological responses to thalamic stimulation identified that wild-type central trigeminal neurons showed diverse responses to oral cooling. Some neurons displayed relatively strong excitation to cold <10°C (COLD neurons) while others responded to only a segment of mild cool temperatures below 30°C (COOL neurons). Notably, TRPM8 deficient mice retained COLD-type but lacked COOL cells. This deficit impaired population responses to mild cooling temperatures below 30°C and allowed warmth-like (≥35°C) neural activity to pervade the normally innocuous cool temperature range, predicting TRPM8 deficient mice would show anomalously similar orobehavioral responses to warm and cool temperatures. Accordingly, TRPM8 deficient mice avoided both warm (35°C) and mild cool (≤30°C) water and sought colder temperatures in fluid licking tests, whereas control mice avoided warm but were indifferent to mild cool and colder water. Results imply TRPM8 input separates cool from warm temperature sensing and suggest other thermoreceptors also participate in oral cooling sensation.

Plant thermosensors.

Plants dynamically regulate their genes expression and physiological outputs to adapt to changing temperatures. The underlying molecular mechanisms have been extensively studied in diverse plants and in multiple dimensions. However, the question of exactly how temperature is detected at molecular level to transform the physical information into recognizable intracellular signals remains continues to be one of the undetermined occurrences in plant science. Recent studies have provided the physical and biochemical mechanistic breakthrough of how temperature changes can influence molecular thermodynamically stability, thus changing molecular structures, activities, interaction and signaling transduction. In this review, we focus on the thermosensing mechanisms of recognized and potential plant thermosensors, to describe the multi-level thermal input system in plants. We also consider the attributes of a thermosensor on the basis of thermal-triggered changes in function, structure, and physical parameters. This study thus provides a reference for discovering more plant thermosensors and elucidating plant thermal adaptive mechanisms.

Thermal sensation prediction model for high-speed train occupants based on skin temperatures and skin wettedness.

Passenger thermal comfort in high-speed train (HST) carriages presents unique challenges due to factors such as extensive operational areas, longer travel durations, larger spaces, and higher passenger capacities. This study aims to propose a new prediction model to better understand and address thermal comfort in HST carriages. The proposed prediction model incorporates skin wettedness, vertical skin temperature difference (ΔTd), and skin temperature as parameters to predict the thermal sensation vote (TSV) of HST passengers. The experiments were conducted with 65 subjects, evenly distributed throughout the HST compartment. Thermal environmental conditions and physiological signals were measured to capture the subjects' thermal responses. The study also investigated regional and overall thermal sensations experienced by the subjects. Results revealed significant regional differences in skin temperature between upper and lower body parts. By analyzing data from 45 subjects, We analyzed the effect of 25 variables on TSV by partial least squares (PLS), from which we singled out 3 key factors. And the optimal multiple regression equation was derived to predict the TSV of HST occupants. Validation with an additional 20 subjects demonstrated a strong linear correlation (0.965) between the actual TSV and the predicted values, confirming the feasibility and accuracy of the developed prediction model. By integrating skin wettedness and ΔTd with skin temperature, the model provides a comprehensive approach to predicting thermal comfort in HST environments. This research contributes to advancing thermal comfort analysis in HST and offers valuable insights for optimizing HST system design and operation to meet passengers' comfort requirements.

Pain Classification using Evoked EEG Induced by Thermal Grill Illusion - Deep Neural Network Approach.

As the quantification of pain has emerged in biomedical engineering today, studies have been developing biomarkers associated with pain actively by measuring bio-signals such as electroencephalogram (EEG). Recently, some EEG studies of cold and hot pain have been reported. However, they used one type of stimulus condition for each trial and a relatively long stimulation time to collect EEG features. In this study, EEG signals during Cool (20 °C), Warm (40 °C), and Thermal Grill Illusion (TGI, 20-40 °C) stimuli were collected from 43 subjects, and were classified by a deep convolutional neural network referred to as EEGNet. Three binary classifications for the three conditions (TGI, Cool, Warm) were conducted for each subject individually. Classification accuracies for TGI-Cool, TGI-Warm, and Warm-Cool were 0.74±0.01, 0.71±0.01, and 0.74±0.01, respectively. For subjects who rated the TGI significantly hotter than the Warm stimulus, the classification accuracy for TGI-Cool (0.74±0.01) was significantly higher than for TGI-Warm (0.71±0.01). In contrast, the classification accuracy for TGI-Cool (0.72±0.03) did not differ statistically from TGI-Warm (0.73±0.01) in subjects without illusion. We found that the TGI and Cool stimuli were classified better than the TGI and Warm stimuli, implying that objective EEG features are consistent with subjective behavioral results. Further, we observed that most discriminative features between the TGI and the Cool or Warm conditions appeared in the parietal area for subjects who perceived the illusion. We postulate that the somato-sensory cortex may be activated when TGI is perceived to be hot pain.

The gender and age differences in the passengers' thermal comfort during cooling and heating conditions in vehicles.

The thermal physiological and psychological responses in vehicles, influenced by gender and age, play a crucial role in ensuring passengers' comfort. However, these differences have often been overlooked. This study aims to comprehensively examine passengers' thermal comfort and investigate gender and age disparities based on their physiological and psychological responses. Experiments were conducted inside a vehicle placed in a climate chamber under cooling and heating conditions, with the collected data subjected to statistical analysis. The findings reveal that males had significantly higher mean skin temperatures in cooling conditions and lower skin temperatures in heating conditions than females. However, overall thermal sensation and comfort did not significantly differ between genders. Interestingly, age-related differences were observed to a limited extent in both conditions. This study provides valuable insights into passengers' thermal responses in vehicles, considering the factors of gender and age, thereby contributing to a comprehensive understanding of thermal comfort in a vehicle environment.

Validating an advanced smartphone application for thermal advising in cold environments.

The ClimApp smartphone application was developed to merge meteorological forecast data with personal information for individualized and improved thermal warning during heat and cold stress and for indoor comfort in buildings. For cold environments, ClimApp predicts the personal thermal stress and strain by the use of the Insulation REQuired model that combines weather and personal physiological data with additional consideration of the Wind Chill index based on the local weather forecast. In this study, we validated the individualized ClimApp index relative to measurements and compared it with the Universal Temperature Climate Index (UTCI). To this aim, 55 participants (27 females) were exposed to at least 1 h in an outdoor environment of 10 °C or below (average 1.4 °C air temperature, 74.9% relative humidity, and 4.7 m/s air velocity) inputting their activity level and clothing insulation as instructed by ClimApp. The UTCI and ClimApp indices were calculated and compared to the participants' perceived thermal sensation. The ClimApp index root mean square deviation (RMSD) was below the standard deviation of the perceived thermal sensation which indicates a valid prediction and the UTCI RMSD was higher than the standard deviation which indicates an invalid prediction. The correlation of ClimApp and UTCI to the perceived thermal sensation was statistically significant for both models.

Association between physiological and perceptual heat strain while wearing stab-resistant body armor.

In this study, we explored the association between physiological and perceptual heat strain while wearing stab-resistant body armor (SRBA). Human trials were performed on ten participants in warm and hot environments. Physiological responses (core temperature, skin temperature, and heart rate), and perceptual responses (thermal sensation vote, thermal comfort vote, restriction of perceived exertion (RPE), wetness of skin, and wetness of clothing) were recorded throughout the trials, and subsequently, the physiological strain index (PSI), and perceptual strain index (PeSI) were calculated. The results indicated that the PeSI showed a significant moderate association with the PSI, and was capable of predicting PSI for low (PSI = 3) and high (PSI = 7) levels of physiological strain with the areas under the curves of 0.80 and 0.64, respectively. Moreover, Bland-Altman analysis indicated that the majority of the PSI ranged within the 95% confidence interval, and the mean difference between PSI and PeSI was 0.14 ± 2.02 with the lower 95% limit and upper 95% limit being -3.82 to 4.10, respectively. Therefore, the subjective responses could be used as an indicator for predicting physiological strain while wearing SRBA. This study could provide fundamental knowledge for the usage of SRBA, and the development of physiological heat strain assessment.

It is one or the other: No overlap between healthy individuals perceiving thermal grill illusion or paradoxical heat sensation.

Paradoxical heat sensation (PHS) and the thermal grill illusion (TGI) are both related to the perception of warmth or heat from innocuous cold stimuli. Despite being described as similar perceptual phenomena, recent findings suggested that PHS is common in neuropathy and related to sensory loss, while TGI is more frequently observed in healthy individuals. To clarify the relationship between these two phenomena, we conducted a study in a cohort of healthy individuals to investigate the association between PHS and TGI. We examined the somatosensory profiles of 60 healthy participants (34 females, median age 25 years) using the quantitative sensory testing (QST) protocol from the German Research Network on Neuropathic Pain. The number of PHS was measured using a modified thermal sensory limen (TSL) procedure where the skin was transiently pre-warmed, or pre-cooled before the PHS measure. This procedure also included a control condition with a pre-temperature of 32 °C. The number of TGI responses was quantified during simultaneous application of warm and cold innocuous stimuli. All participants had normal thermal and mechanical thresholds compared to the reference values from the QST protocol. Only two participants experienced PHS during the QST procedure. In the modified TSL procedure, we found no statistically significant differences in the number of participants reporting PHS in the control condition (N = 6) vs. pre-warming (N = 3; min = 35.7 °C, max = 43.5 °C) and pre-cooling (N = 4, min = 15.0 °C, max = 28.8 °C) conditions. Fourteen participants experienced TGI, and only one participant reported both TGI and PHS. Individuals with TGI had normal or even increased thermal sensation compared to individuals without TGI. Our findings demonstrate a clear distinction between individuals experiencing PHS or TGI, as there was no overlap observed when using identical warm and cold temperatures that were alternated either temporally or spatially. While PHS was previously related to sensory loss, our study revealed that TGI is associated with normal thermal sensitivity. This suggests that an efficient thermal sensory function is essential in generating the illusory sensation of pain of the TGI.

Thermoregulation and thermal sensation during whole-body water immersion at different water temperatures in healthy individuals: A scoping review.

BACKGROUND: Severe thermal discomfort may increase risk of drowning due to hypothermia or hyperthermia from prolonged exposure to noxious water temperatures. The importance of using a behavioral thermoregulation model with thermal sensation may predict the thermal load that the human body receives when exposed to various immersive water conditions. However, there is no thermal sensation "gold standard" model specific for water immersion. This scoping review aims to present a comprehensive overview regarding human physiological and behavioral thermoregulation during whole-body water immersion and explore the feasibility for an accepted defined sensation scale for cold and hot water immersion. METHODS: A standard literary search was performed on PubMed, Google Scholar, and SCOPUS. The words "Water Immersion," "Thermoregulation," "Cardiovascular responses" were used either as independent searched terms and MeSH terms (Medical Subject Headings) or in combination with other text words. The inclusion criteria for clinical trials terms to thermoregulatory measurements (core or skin temperature), whole-body immersion, 18-60 years old and healthy individuals. The prementioned data were analyzed narratively to achieve the overall study objective. RESULTS: Twenty-three published articles fulfilled the review inclusion/exclusion criteria (with nine measured behavioral responses). Our outcomes illustrated a homogenous thermal sensation in a variety of water temperatures ranges, that was strongly associated with thermal balance, and observed different thermoregulatory responses. This scoping review highlights the impact of water immersion duration on human thermoneutral zone, thermal comfort zone, and thermal sensation. CONCLUSION: Our findings enlighten the significance of thermal sensation as a health indicator for establishing a behavioral thermal model applicable for water immersion. This scoping review provides insight for the needed development of subjective thermal model of thermal sensation in relation to human thermal physiology specific to immersive water temperature ranges within and outside the thermal neutral and comfort zone.

Association between thermal response and endogenous dopamine: Step-change environments in winter.

Temperature step change is the typical transient thermal environment. The purpose of this study was to explore the association of subjective and objective parameters in a step-change environment, including thermal sensation vote (TSV), thermal comfort vote (TCV), mean skin temperature (MST) and endogenous dopamine (DA). Three temperature step changes defined as I3 (15 °C-18 °C to 15 °C), I9 (15 °C-24 °C to 15 °C) and I15 (15 °C-30 °C to 15 °C) were designed for this experiment. Eight male and eight female healthy subjects who participated in the experiment reported thermal perception (TSV and TCV). Skin temperatures of six body parts and DA were measured. Results show that the inverted U-shaped in TSV and TCV was deviated by seasonal factors of the experiment. The deviation direction of TSV in winter was to the warm sensation side, which was opposite to the inherent cold and hot impression of people in winter and summer. The association between dimensionless dopamine (DA*), TSV and MST were described as follows: DA* was the U-shaped change with exposure times when MST was not greater than 31 °C, and TSV was at -2 and -1, and DA* increased with exposure times when MST was greater than 31 °C, and TSV was at 0, 1 and 2. The changes in the body heat storage and autonomous thermal regulation under temperature step changes may potentially be related to the concentration of DA. The human state on thermal nonequilibrium and stronger thermal regulation would correspond to a higher concentration of DA. This work is conducive to exploring the human regulation mechanism in a transient environment.

The effects of manipulating the visual environment on thermal perception: A structured narrative review.

When exposed to ambient temperatures that cause thermal discomfort, a human's behavioral responses are more effective than autonomic ones at compensating for thermal imbalance. These behavioral thermal responses are typically directed by an individual's perception of the thermal environment. Perception of the environment is a holistic amalgamation of human senses, and in some circumstances, humans prioritize visual information. Existing research has considered this in the specific case of thermal perception, and this review investigates the state of the literature examining this effect. We identify the frameworks, research rationales, and potential mechanisms that underpin the evidence base in this area. Our review identified 31 experiments, comprising 1392 participants that met the inclusion criteria. Methodological heterogeneity was observed in the assessment of thermal perception, and a variety of methods were employed to manipulate the visual environment. However, the majority of the included experiments (80%) reported a difference in thermal perception after the visual environment was manipulated. There was limited research exploring any effects on physiological variables (e.g. skin and core temperature). This review has wide-ranging implications for the broad discipline of (thermo)physiology, psychology, psychophysiology, neuroscience, ergonomics, and behavior.

Thermal grill illusion of pain in patients with chronic pain: a clinical marker of central sensitization?

ABSTRACT: The thermal grill illusion of pain (TGIP) is a paradoxical burning pain sensation elicited by the simultaneous application of innocuous cutaneous warm and cold stimuli with a thermode ("thermal grill") consisting of interlaced heated and cooled bars. Its neurophysiological mechanisms are unclear, but TGIP may have some mechanisms in common with pathological pain, including central sensitization in particular, through the involvement of N-methyl- d -aspartate receptors. However, few studies have investigated TGIP in patients with chronic pain and its clinical relevance is uncertain. We hypothesized that the TGIP would be increased in comparison with controls in patients with fibromyalgia or irritable bowel syndrome, which are regarded as typical "nociplastic" primary pain syndromes related to changes in central pain processing. We compared the sensations elicited by a large range of combinations of temperature differentials between the warm and cold bars of a thermal grill applied to the hand between patients with fibromyalgia (n = 30) or irritable bowel syndrome (n= 30) and controls (n = 30). The percentage of TGIP responses and the intensity and unpleasantness of TGIP were significantly greater in patients than controls. Furthermore, positive correlations were found between TGIP intensity and clinical pain intensity and between TGIP intensity and the cold pain threshold measured on the hand. These results are consistent with our working hypothesis of shared mechanisms between TGIP and clinical pain mechanisms in patients with nociplastic chronic pain syndromes and suggest that TGIP might represent a clinical marker of central sensitization in these patients.

A novel method to selectively elicit cold sensations without touch.

BACKGROUND: Thermal and tactile stimuli are transduced by different receptor classes. However, mechano- and thermo-sensitive afferents interact at spinal and supraspinal levels. Yet, most studies on responses to cooling stimuli are confounded by mechanical contact, making these interactions difficult to isolate. Methods for precise control of non-mechanical thermal stimulations remain challenging, particularly in the cold range. NEW METHOD: We developed a non-tactile, focal, temperature-controlled, multi-purpose cooling stimulator. This method controls the exposure of a target skin region to a dry-ice source. Using a thermal camera to monitor skin temperature, and adjusting the source-skin distance accordingly, we could deliver non-tactile cooling stimuli with customisable profiles, for studying different aspects of cold sensation. RESULTS: To validate our method, we measured absolute and relative thresholds for cold sensation without mechanical contact in 13 human volunteer participants, using the method of limits. We found that the absolute cold detection threshold was 32.71 oC ± 0.88 oC. This corresponded to a threshold relative to each participant's baseline skin temperature of - 1.08 oC ± 0.37 oC. COMPARISONS WITH EXISTING METHOD: Our method allows cooling stimulation without the confound of mechanical contact, in a controllable and focal manner. CONCLUSIONS: We report a non-contact cooling stimulator and accompanying control system. We used this to measure cold thresholds in the absence of confounding touch. Our method enables more targeted studies of both cold sensory pathways, and of cold-touch interactions.

Prediction of Individual Dynamic Thermal Sensation in Subway Commute Using Smart Face Mask.

Wearable sensors and machine learning algorithms are widely used for predicting an individual's thermal sensation. However, most of the studies are limited to controlled laboratory experiments with inconvenient wearable sensors without considering the dynamic behavior of ambient conditions. In this study, we focused on predicting individual dynamic thermal sensation based on physiological and psychological data. We designed a smart face mask that can measure skin temperature (SKT) and exhaled breath temperature (EBT) and is powered by a rechargeable battery. Real-time human experiments were performed in a subway cabin with twenty male students under natural conditions. The data were collected using a smartphone application, and we created features using the wavelet decomposition technique. The bagged tree algorithm was selected to train the individual model, which showed an overall accuracy and f-1 score of 98.14% and 96.33%, respectively. An individual's thermal sensation was significantly correlated with SKT, EBT, and associated features.

Human thermal sensation and its algorithmic modelization under dynamic environmental thermal characteristics of vehicle cabin.

Thermal conditions are strongly changeable in a vehicle cabin, where passengers could suffer consecutive self-thermoregulation to such dynamic changing thermal stresses, though its HVAC system works well. To observe human overall and local thermal sensations in dynamic thermal conditions, a series of experiments under various conditions were carried out in a cabin-like climate chamber. The results showed that the head, chest, back, and hands during hot exposure are warmer leading to the overall thermal sensation being hot. The thermal sensation of the head was warmer than the overall thermal sensation. During cold exposure, arms, hands, legs, and feet were the main areas causing coldness. In a dynamic thermal environment, the previous skin temperature state and thermal sensation form a thermal sensation overshoot, causing a shift in the body's neutral temperature point. This study proposes a thermal sensation model for the prediction of human thermal sensation local and overall based on skin temperature changes in a dynamic environment. Considering the airflow characteristics in the cabin, the human body is set into seven local parts in the local thermal sensation model. To compensate for sensation overshoot from this, defining recovery points rp for local parts differentiate temperature setpoints according to the experienced thermal state so that the effect resulting from the dynamic condition is integrated into the model algorithm. The model provides a scientific basis for guiding design optimization and intelligent regulation in the dynamic environment of the vehicle cabin, so as to achieve efficient energy utilization.

Human thermal sensation algorithm modelization via physiological thermoregulatory responses based on dynamic thermal environment tests on males.

BACKGROUND AND OBJECTIVES: Thermal conditions are changeable in cabin space, where occupants could suffer consecutive self-thermoregulation to such changing thermal stresses. Thermal environment management is expected to be purposefully auto-adjustable for the environment by recognizing individual real-time thermal sensations. Current thermal sensation evaluation models are developed for virtual simulations rather than for realistic scenarios, challenging to evaluate human thermal sensation in the field surveys. METHODS: The study constructs a human thermal sensation model via human physiological responses to evaluate the human thermal sensation in the actual vehicle environment. The thermal sensation model forms with exponential functions to clarify the relationship between thermal sensation and pulse rate and blood pressure, which successfully expresses the approximately linear trend around neutral sensation and compensates for the end-points bias. The study set up experimental cases to determine the parameter states in the thermal sensation model. Firstly, subjective thermal sensation scoring was performed by combing with an established seven-point-scale questionnaire survey system for human thermal sensation. Wearable sensors are then applied to measure the human physiological response, including blood pressure BP, pulse rate PR and blood oxygen saturation SpO2. RESULTS: The subjects revealed significantly higher pulse rates (positively correlated) and lower blood pressure (negatively correlated) in the warm chamber than in the cool chamber. The defined parameter change rate effectively reveals the trend of human thermal sensation and avoids the inconsistency of raw physiological response levels. The change rate in PR and MAP between the thermal sensation in cold -3 and hot +3 is about a 10% difference. CONCLUSIONS: Based on the thermal sensation model algorithm, model parameters were fitted by the subjects' thermal sensation voting and the change rate of their physiological responses. With the coefficient of determination (R2) of the regression over 0.8, the proposed thermal sensation model can be employed for human thermal sensation evaluation. The physiological thermoregulatory responses effectively indicate the thermal state of the human body and can be used in thermal environments in conjunction with human smart wearable devices.

Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP2.

The transient receptor potential melastatin 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is controlled by cooling compounds together with the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2). Our knowledge of cold sensation and the therapeutic potential of TRPM8 for neuroinflammatory diseases and pain will be enhanced by understanding the structural basis of cooling agonist- and PIP2-dependent TRPM8 activation. We present cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP2-dependent gating pathway. Our results uncover two discrete agonist sites, state-dependent rearrangements in the gate positions, and a disordered-to-ordered transition of the gate-forming S6-elucidating the molecular basis of chemically induced cool sensation in mammals.

Real-time regulation of room temperature based on individual thermal sensation using an online brain-computer interface.

Regulation of indoor temperature based on neurophysiological and psychological signals is one of the most promising technologies for intelligent buildings. In this study, we developed a system for closed-loop control of indoor temperature based on brain-computer interface (BCI) technology for the first time. Electroencephalogram (EEG) signals were collected from subjects for two room temperature categories (cool comfortable and hot uncomfortable) and used to build a thermal-sensation discrimination model (TSDM) with an ensemble learning method. Then, an online BCI system was developed based on the TSDM. In the online room temperature control experiment, when the TSDM detected that the subjects felt hot and uncomfortable, BCI would automatically turn on the air conditioner, and when the TSDM detected that the subjects felt cool and comfortable, BCI would automatically turn off the air conditioner. The results of online experiments in a hot environment showed that a BCI could significantly improve the thermal comfort of subjects (the subjective thermal comfort score decreased from 2.45 (hot uncomfortable) to 0.55 (cool comfortable), p < 0.001). A parallel experiment further showed that if the subjects wore thicker clothes during the experiment, the BCI would turn on the air conditioner for a longer time to ensure the thermal comfort of the subjects. This has further confirmed the effectiveness of TSDM model in evaluating thermal sensation under the dynamic change of room temperature and showed the model's good robustness. This study proposed a new paradigm of human-building interaction, which is expected to play a promising role in the development of human-centered intelligent buildings.