A Conserved Kinase-Based Body-Temperature Sensor Globally Controls Alternative Splicing and Gene Expression.

Homeothermic organisms maintain their core body temperature in a narrow, tightly controlled range. Whether and how subtle circadian oscillations or disease-associated changes in core body temperature are sensed and integrated in gene expression programs remain elusive. Furthermore, a thermo-sensor capable of sensing the small temperature differentials leading to temperature-dependent sex determination (TSD) in poikilothermic reptiles has not been identified. Here, we show that the activity of CDC-like kinases (CLKs) is highly responsive to physiological temperature changes, which is conferred by structural rearrangements within the kinase activation segment. Lower body temperature activates CLKs resulting in strongly increased phosphorylation of SR proteins in vitro and in vivo. This globally controls temperature-dependent alternative splicing and gene expression, with wide implications in circadian, tissue-specific, and disease-associated settings. This temperature sensor is conserved across evolution and adapted to growth temperatures of diverse poikilotherms. The dynamic temperature range of reptilian CLK homologs suggests a role in TSD.

Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells.

Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.

Activation of the nociceptin/orphanin-FQ receptor promotes NREM sleep and EEG slow wave activity.

Sleep/wake control involves several neurotransmitter and neuromodulatory systems yet the coordination of the behavioral and physiological processes underlying sleep is incompletely understood. Previous studies have suggested that activation of the Nociceptin/orphanin FQ (N/OFQ) receptor (NOPR) reduces locomotor activity and produces a sedation-like effect in rodents. In the present study, we systematically evaluated the efficacy of two NOPR agonists, Ro64-6198 and SR16835, on sleep/wake in rats, mice, and Cynomolgus macaques. We found a profound, dose-related increase in non-Rapid Eye Movement (NREM) sleep and electroencephalogram (EEG) slow wave activity (SWA) and suppression of Rapid Eye Movement sleep (REM) sleep in all three species. At the highest dose tested in rats, the increase in NREM sleep and EEG SWA was accompanied by a prolonged inhibition of REM sleep, hypothermia, and reduced locomotor activity. However, even at the highest dose tested, rats were immediately arousable upon sensory stimulation, suggesting sleep rather than an anesthetic state. NOPR agonism also resulted in increased expression of c-Fos in the anterodorsal preoptic and parastrial nuclei, two GABAergic nuclei that are highly interconnected with brain regions involved in physiological regulation. These results suggest that the N/OFQ-NOPR system may have a previously unrecognized role in sleep/wake control and potential promise as a therapeutic target for the treatment of insomnia.

Calcitonin receptors are ancient modulators for rhythms of preferential temperature in insects and body temperature in mammals.

Daily body temperature rhythm (BTR) is essential for maintaining homeostasis. BTR is regulated separately from locomotor activity rhythms, but its molecular basis is largely unknown. While mammals internally regulate BTR, ectotherms, including Drosophila, exhibit temperature preference rhythm (TPR) behavior to regulate BTR. Here, we demonstrate that the diuretic hormone 31 receptor (DH31R) mediates TPR during the active phase in Drosophila DH31R is expressed in clock cells, and its ligand, DH31, acts on clock cells to regulate TPR during the active phase. Surprisingly, the mouse homolog of DH31R, calcitonin receptor (Calcr), is expressed in the suprachiasmatic nucleus (SCN) and mediates body temperature fluctuations during the active phase in mice. Importantly, DH31R and Calcr are not required for coordinating locomotor activity rhythms. Our results represent the first molecular evidence that BTR is regulated distinctly from locomotor activity rhythms and show that DH31R/Calcr is an ancient specific mediator of BTR during the active phase in organisms ranging from ectotherms to endotherms.

Temperature-controlled molecular switches in mammalian cells.

Temperature is an omnipresent factor impacting on many aspects of life. In bacteria and ectothermic eukaryotes various thermosensors and temperature-controlled switches have been described, ranging from RNA thermometers controlling the heat shock response in prokaryotes to temperature-dependent sex determination in reptiles, likely controlled through protein phosphorylation. However, the impact of subtle changes of human core body temperature are only beginning to be acknowledged. In this review, we will discuss thermosensing mechanisms and their functional implications with a focus on mammalian cells, also in the context of disease conditions. We will point out open questions and possible future directions for this emerging research field, which, in addition to molecular-mechanistic insights, holds the potential for the development of new therapeutic approaches.

Body Temperature Cycles Control Rhythmic Alternative Splicing in Mammals.

The core body temperature of all mammals oscillates with the time of the day. However, direct molecular consequences of small, physiological changes in body temperature remain largely elusive. Here we show that body temperature cycles drive rhythmic SR protein phosphorylation to control an alternative splicing (AS) program. A temperature change of 1°C is sufficient to induce a concerted splicing switch in a large group of functionally related genes, rendering this splicing-based thermometer much more sensitive than previously described temperature-sensing mechanisms. AS of two exons in the 5' UTR of the TATA-box binding protein (Tbp) highlights the general impact of this mechanism, as it results in rhythmic TBP protein levels with implications for global gene expression in vivo. Together our data establish body temperature-driven AS as a core clock-independent oscillator in mammalian peripheral clocks.

Thermoregulated transcriptomics: the molecular basis and biological significance of temperature-dependent alternative splicing.

Temperature-dependent alternative splicing (AS) is a crucial mechanism for organisms to adapt to varying environmental temperatures. In mammals, even slight fluctuations in body temperature are sufficient to drive significant AS changes in a concerted manner. This dynamic regulation allows organisms to finely tune gene expression and protein isoform diversity in response to temperature cues, ensuring proper cellular function and physiological adaptation. Understanding the molecular mechanisms underlying temperature-dependent AS thus provides valuable insights into the intricate interplay between environmental stimuli and gene expression regulation. In this review, we provide an overview of recent advances in understanding temperature-regulated AS across various biological processes and systems. We will discuss the machinery sensing and translating temperature cues into changed AS patterns, the adaptation of the splicing regulatory machinery to extreme temperatures, the role of temperature-dependent AS in shaping the transcriptome, functional implications and the development of potential therapeutics targeting temperature-sensitive AS pathways.

Adaptive variation in the upper limits of avian body temperature.

Physiological performance declines precipitously at high body temperature (Tb), but little attention has been paid to adaptive variation in upper Tb limits among endotherms. We hypothesized that avian maximum tolerable Tb (Tbmax) has evolved in response to climate, with higher Tbmax in species exposed to high environmental heat loads or humidity-related constraints on evaporative heat dissipation. To test this hypothesis, we compared Tbmax and related variables among 53 bird species at multiple sites in South Africa with differing maximum air temperature (Tair) and humidity using a phylogenetically informed comparative framework. Birds in humid, lowland habitats had comparatively high Tbmax (mean ± SD = 45.60 ± 0.58 °C) and low normothermic Tb (Tbnorm), with a significantly greater capacity for hyperthermia (Tbmax - Tbnorm gradient = 5.84 ± 0.77 °C) compared with birds occupying cool montane (4.97 ± 0.99 °C) or hot arid (4.11 ± 0.84 °C) climates. Unexpectedly, Tbmax was significantly lower among desert birds (44.65 ± 0.60 °C), a surprising result in light of the functional importance of hyperthermia for water conservation. Our data reveal a macrophysiological pattern and support recent arguments that endotherms have evolved thermal generalization versus specialization analogous to the continuum among ectothermic animals. Specifically, a combination of modest hyperthermia tolerance and efficient evaporative cooling in desert birds is indicative of thermal specialization, whereas greater hyperthermia tolerance and less efficient evaporative cooling among species in humid lowland habitats suggest thermal generalization.

Full-Color "Off-On" Thermochromic Fluorescent Fibers for Customizable Smart Wearable Displays in Personal Health Monitoring.

Responsive thermochromic fiber materials capable of miniaturization and integrating comfortably and compliantly onto the soft and dynamically deforming human body are promising materials for visualized personal health monitoring. However, their development is hindered by monotonous colors, low-contrast color changes, and poor reversibility. Herein, full-color "off-on" thermochromic fluorescent fibers are prepared based on self-crystallinity phase change and Förster resonance energy transfer for long-term and passive body-temperature monitoring, especially for various personalized customization purposes. The off-on switching luminescence characteristic is derived from the reversible conversion of the dispersion state and fluorescent emission by fluorophores and quencher molecules, which are embedded in the matrix of a phase-change material, during the crystallizing/melting processes. The achievement of full-color fluorescence is attributed to the large modulation range of fluorescence colors according to primary color additive theory. These thermochromic fluorescent fibers exhibit good mechanical properties, fluorescent emission contrast, and reversibility, showing their great potential in flexible smart display devices. Moreover, the response temperature of the thermochromic fibers is controllable by adjusting the phase-change material, enabling body-temperature-triggered luminescence; this property highlights their potential for human body-temperature monitoring and personalized customization. This work presents a new strategy for designing and exploring flexible sensors with higher comprehensive performances.

Torpor use in the wild by one of the world's largest bats.

Torpor is widespread among bats presumably because most species are small, and torpor greatly reduces their high mass-specific resting energy expenditure, especially in the cold. Torpor has not been recorded in any bat species larger than 50 g, yet in theory could be beneficial even in the world's largest bats (flying-foxes; Pteropus spp.) that are exposed to adverse environmental conditions causing energy bottlenecks. We used temperature telemetry to measure body temperature in wild-living adult male grey-headed flying-foxes (P. poliocephalus; 799 g) during winter in southern Australia. We found that all individuals used torpor while day-roosting, with minimum body temperature reaching 27°C. Torpor was recorded following a period of cool, wet and windy weather, and on a day with the coldest maximum air temperature, suggesting it is an adaptation to reduce energy expenditure during periods of increased thermoregulatory costs and depleted body energy stores. A capacity for torpor among flying-foxes has implications for understanding their distribution, behavioural ecology and life history. Furthermore, our discovery increases the body mass of bats known to use torpor by more than tenfold and extends the documented use of this energy-saving strategy under wild conditions to all bat superfamilies, with implications for the evolutionary maintenance of torpor among bats and other mammals.

Feeding behavior modifies the circadian variation in RR and QT intervals by distinct mechanisms in mice.

Rhythmic feeding behavior is critical for regulating phase and amplitude in the ≈24-h variation of heart rate (RR intervals), ventricular repolarization (QT intervals), and core body temperature in mice. We hypothesized changes in cardiac electrophysiology associated with feeding behavior were secondary to changes in core body temperature. Telemetry was used to record electrocardiograms and core body temperature in mice during ad libitum-fed conditions and after inverting normal feeding behavior by restricting food access to the light cycle. Light cycle-restricted feeding modified the phase and amplitude of 24-h rhythms in RR and QT intervals, and core body temperature to realign with the new feeding time. Changes in core body temperature alone could not account for changes in phase and amplitude in the ≈24-h variation of the RR intervals. Heart rate variability analysis and inhibiting ß-adrenergic and muscarinic receptors suggested that changes in the phase and amplitude of 24-h rhythms in RR intervals were secondary to changes in autonomic signaling. In contrast, changes in QT intervals closely mirrored changes in core body temperature. Studies at thermoneutrality confirmed that the daily variation in QT interval, but not RR interval, primarily reflected daily changes in core body temperature (even in ad libitum-fed conditions). Correcting the QT interval for differences in core body temperature helped unmask QT interval prolongation after starting light cycle-restricted feeding and in a mouse model of long QT syndrome. We conclude feeding behavior alters autonomic signaling and core body temperature to regulate phase and amplitude in RR and QT intervals, respectively.NEW & NOTEWORTHY We used time-restricted feeding and thermoneutrality to demonstrate that different mechanisms regulate the 24-h rhythms in heart rate and ventricular repolarization. The daily rhythm in heart rate reflects changes in autonomic input, whereas daily rhythms in ventricular repolarization reflect changes in core body temperature. This novel finding has major implications for understanding 24-h rhythms in mouse cardiac electrophysiology, arrhythmia susceptibility in transgenic mouse models, and interpretability of cardiac electrophysiological data acquired in thermoneutrality.

Body temperature, systemic inflammation and risk of adverse events in patients with acute coronary syndromes.

BACKGROUND: Inflammatory processes can trigger acute coronary syndromes (ACS) which may increase core body temperature (BT), a widely available low-cost marker of systemic inflammation. Herein, we aimed to delineate baseline characteristics of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation ACS (NSTE-ACS) patients stratified by initial BT and to assess its predictive utility towards major adverse cardiovascular events (MACE) after the index ACS. METHODS: From 2012 until 2017, a total of 1044 ACS patients, 517 with STEMI and 527 with NSTE-ACS, were prospectively recruited at the University Hospital Zurich. BT was measured by digital tympanic thermometer along with high-sensitivity C-reactive protein (hs-CRP) and cardiac troponin-T (hs-cTnT) levels prior to coronary angiography. Patients were stratified according to initial BT and uni- and multivariable regression models were fit to assess associations of BT with future MACE risk. RESULTS: Among patients with STEMI, BT was not predictive of 1-year MACE, but a U-shaped relationship between BT and MACE risk was noted in those with NSTE-ACS (p = .029), translating into a 2.4-fold (HR, 2.44, 95% CI, 1.16-5.16) increased 1-year MACE risk in those with BT >36.8°C (reference: 36.6-36.8°C). Results remained robust in multivariable-adjusted analyses accounting for sex, age, diabetes, renal function and hs-cTnT. However, when introducing hs-CRP, the BT-MACE association did not prevail. CONCLUSIONS: In prospectively recruited patients with ACS, initial BT shows a U-shaped relationship with 1-year MACE risk among those with NSTE-ACS, but not in those with STEMI. BT is a broadly available low-cost marker to identify ACS patients with high inflammatory burden, at high risk for recurrent ischaemic events, and thus potentially suitable for an anti-inflammatory intervention. REGISTRATION: ClinicalTrials.gov Identifier: NCT01000701.

Plasticity of mitochondrial function safeguards phosphorylating respiration during in vitro simulation of rest-phase hypothermia.

Many animals downregulate body temperature to save energy when resting (rest-phase hypothermia). Small birds that winter at high latitudes have comparatively limited capacity for hypothermia and so pay large energy costs for thermoregulation during cold nights. Available evidence suggests this process is fueled by adenosine triphosphate (ATP)-dependent mechanisms. Most ATP is produced by oxidative phosphorylation in the mitochondria, but mitochondrial respiration may be lower during hypothermia because of the temperature dependence of biological processes. This can create conflict between increased organismal ATP demand and a lower mitochondrial capacity to provide it. We studied this in blood cell mitochondria of wild great tits (Parus major) by simulating rest-phase hypothermia via a 6°C reduction in assay temperature in vitro. The birds had spent the night preceding the experiment in thermoneutrality or in temperatures representing mild or very cold winter nights, but night temperatures never affected mitochondrial respiration. However, across temperature groups, endogenous respiration was 14% lower in hypothermia. This did not reflect general thermal suppression of mitochondrial function because phosphorylating respiration was unaffected by thermal state. Instead, hypothermia was associated with a threefold reduction of leak respiration, from 17% in normothermia to 4% in hypothermia. Thus, the coupling of total respiration to ATP production was 96% in hypothermia, compared to 83% in normothermia. Our study shows that the thermal insensitivity of phosphorylation combined with short-term plasticity of leak respiration may safeguard ATP production when endogenous respiration is suppressed. This casts new light on the process by which small birds endure harsh winter cold and warrants future tests across tissues in vivo.

The role of Kupffer cells in microbiota-brain communication: Sleep and fever signaling in response to lipopolysaccharide.

Microbial molecules translocated from the intestinal lumen into the host's internal environment play a role in various physiological functions. Previously, we identified that butyrate, a short-chain fatty acid produced by intestinal bacteria, lipoteichoic acid, a cell wall component of gram-positive bacteria, and lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, induce sleep when their naturally occurring translocation is mimicked by direct delivery into the portal vein. Our findings suggested that these microbial molecules exert their sleep-promoting effects within the hepatoportal region. In the present experiments, we tested the hypothesis that resident liver macrophages, known as Kupffer cells, play a crucial role in the LPS-responsive, sleep-promoting mechanisms within the hepatoportal region. Intraportal administration of LPS induced increased sleep and fever in control rats. Remarkably, in Kupffer cell-depleted animals, both of these responses were significantly suppressed. These findings highlight the potential role of Kupffer cells in mediating the non-rapid-eye movement sleep-promoting and febrile effects of LPS translocated from the intestinal microbiota into the portal circulation. The strategic location of Kupffer cells within the hepatoportal region, coupled with their ability to rapidly take up LPS and other microbial molecules, together with their high secretory activity of multiple signaling molecules, underlie their key role in the communication between the intestinal microbiota and the brain.

Female thermal sensitivity and behaviour across the lifespan: A unique journey.

Women are a group of individuals that undergo unique anatomical, physiological and hormonal changes across the lifespan. For example, consider the impact of the menstrual cycle, pregnancy and menopause, all of which are accompanied by both short- and long-term effects on female body morphology (e.g., changes in breast size) and temperature regulation, heat tolerance, thermal sensitivity and comfort. However, empirical evidence on how skin thermal and wetness sensitivity might change across the lifespan of women, and the implications that this has for female-specific thermal behaviours, continues to be lacking. This paper is based on a symposium presentation given at Physiology 2023 in Harrogate, UK. It aims to review new evidence on anatomical and physiological mechanisms underpinning differences in skin thermal and wetness sensitivity amongst women varying in breast size and age, in addition to their role in driving female thermal behaviours. It is hoped that this brief overview will stimulate the development of testable hypotheses to increase our understanding of the behavioural thermal physiology of women across the lifespan and at a time of climate change.

Consumer wearables and personal devices for tracking the fertile window.

The market for technology that tracks ovulation to promote conception is rapidly expanding in the United States, targeting the growing audience of technologically proficient, reproductive-age female consumers. In this narrative review, 23 different, nonprescription wearables and devices designed to help women track their fertile window were identified as currently, commercially available in the United States. The majority of these utilize measurements of basal body temperature or combinations of various urinary hormones. This clinical opinion characterizes the scant available research validating the accuracy of these technologies. It further examines research oversight, discusses the utility of these wearables and devices to consumers, and considers these technologies through an equity lens. The discussion concludes with a call for innovation, describing promising new technologies that not only harness unique physiologic parameters to predict ovulation, but also focus on cost-effectiveness with the hope of increasing access to these currently costly devices and wearables.

The effects of humidity on thermoregulatory physiology of a small songbird.

Scholander-Irving curves describe the relationship between ambient temperature and metabolic rate and are fundamental to understanding the energetic demands of homeothermy. However, Scholander-Irving curves are typically measured in dry air, which is not representative of the humidity many organisms experience in nature. Consequently, it is unclear (1) whether Scholander-Irving curves (especially below thermoneutrality) are altered by humidity, given the effects of humidity on thermal properties of air, and (2) whether physiological responses associated with Scholander-Irving curves in the lab reflect organismal performance in humid field conditions. We used laboratory experiments and biophysical models to test the effects of humidity on the thermoregulatory physiology of tree swallows (Tachycineta bicolor). We also tested whether physiological responses measured under lab conditions were correlated with field body temperatures and nestling provisioning rates. We found that humidity reduced rates of evaporative water loss but did not have large effects on body temperature or metabolic rate, suggesting that swallows can decouple evaporative cooling, body temperature and metabolic rate. Although the effect of humidity on metabolic rate in the lab was small, our biophysical models indicated that energetic costs of thermoregulation were ∼8% greater in simulations that used metabolic rates from birds in humid compared with dry conditions. Finally, we found mixed evidence that physiological responses measured in the lab under humid or dry conditions were associated with body temperature and nest provisioning rates in the field. Our results help clarify the effect of humidity on endotherm thermoregulation, which may help forecast organismal responses to environmental change.

Feasibility and acceptability of an integrated mind-body intervention for depression: whole-body hyperthermia (WBH) and cognitive behavioral therapy (CBT).

OBJECTIVE: To examine the feasibility of an integrated mind-body MDD treatment combining cognitive behavioral therapy (CBT) and whole-body hyperthermia (WBH). METHODS: In this single-arm trial, 16 adults with MDD initially received 8 weekly CBT sessions and 8 weekly WBH sessions. Outcomes included WBH sessions completed (primary), self-report depression assessments completed (secondary), and pre-post intervention changes in depression symptoms (secondary). We also explored changes in mood and cognitive processes and assessed changes in mood as predictors of overall treatment response. RESULTS: Thirteen participants (81.3%) completed ≥ 4 WBH sessions (primary outcome); midway through the trial, we reduced from 8 weekly to 4 bi-weekly WBH sessions to increase feasibility. The n = 12 participants who attended the final assessment visit completed 100% of administered self-report depression assessments; all enrolled participants (n = 16) completed 89% of these assessments. Among the n = 12 who attended the final assessment visit, the average pre-post-intervention BDI-II reduction was 15.8 points (95% CI: -22.0, -9.70), p = 0.0001, with 11 no longer meeting MDD criteria (secondary outcomes). Pre-post intervention improvements in negative automatic thinking, but not cognitive flexibility, achieved statistical significance. Improved mood from pre-post the initial WBH session predicted pre-post treatment BDI-II change (36.2%; rho = 0.60, p = 0.038); mood changes pre-post the first CBT session did not. LIMITATIONS: Small sample size and single-arm design limit generalizability. CONCLUSION: An integrated mind-body intervention comprising weekly CBT sessions and bi-weekly WBH sessions was feasible. Results warrant future larger controlled clinical trials.Clinivaltrials.gov Registration: NCT05708976.

Perioperative Hypothermia in Elderly Patients During Pelvic Floor Reconstruction Surgery: An Observational Study.

INTRODUCTION AND HYPOTHESIS: The potential predictors of pelvic floor reconstruction surgery hypothermia remain unclear. This prospective cohort study was aimed at identifying these predictors and evaluating the outcomes associated with perioperative hypothermia. METHODS: Elderly patients undergoing pelvic floor reconstruction surgery were consecutively enrolled from April 2023 to September 2023. Perioperative temperature was measured at preoperative (T1), every 15 min after the start of anesthesia (T2), and 15 min postoperative (T3) using a temperature probe. Perioperative hypothermia was defined as a core temperature below 36°C at any point during the procedure. Multivariate logistic regression analysis was conducted to determine factors associated with perioperative hypothermia. RESULTS: A total of 229 patients were included in the study, with 50.7% experiencing hypothermia. Multivariate analysis revealed that the surgical method involving pelvic floor combined with laparoscopy, preoperative temperature < 36.5°C, anesthesia duration ≥ 120 min, and the high levels of anxiety were significantly associated with perioperative hypothermia. The predictive value of the multivariate model was 0.767 (95% CI, 0.706 to 0.828). CONCLUSIONS: This observational prospective study identified several predictive factors for perioperative hypothermia in elderly patients during pelvic floor reconstruction surgery. Strategies aimed at preventing perioperative hypothermia should target these factors. Further studies are required to assess the effectiveness of these strategies, specifically in elderly patients undergoing pelvic floor reconstruction surgery.

Intragastric administration of cinnamaldehyde induces changes in body temperature via TRPA1.

The transient receptor potential (TRP) channel family, including TRPA1, is known to be involved in temperature sensing and response. Previous studies have shown that intragastric administration of cinnamaldehyde (a typical TRPA1 agonist) can change body temperature, but the role of TRPA1 in this response is not clear. In this study, we found that intragastric administration of cinnamaldehyde increased in the intrascapular brown adipose tissue (IBAT) and rectal temperatures. However, this effect was not observed in TRPA1 knockout mice, suggesting that TRPA1 is involved in these temperature changes. Intravenous cinnamaldehyde also increased IBAT and rectal temperatures, only in the presence of TRPA1. We also explored the contribution of the vagus nerve to these temperature changes and found that it played a limited role. These results suggest that cinnamaldehyde can affect body temperature through TRPA1 activation, with the vagus nerve having a minor influence.