Cutaneous mechanoreceptor input from the foot sole is critical for balance and gait, yet ageing and disease can compromise skin sensitivity, increasing risks for falls and related injuries. Heating improves perceptual sensitivity, but its direct effects on afferent firing remain unknown. This study examined how topical heating alters Aβ afferent responses to mechanical loads that closely emulate walking. Single tibial nerve afferents were recorded using microneurography and classified as fast-adapting (FA) or slowly adapting (SA), type I or II. Ramp-and-hold compressions, normalized to regional stance pressure distributions, were applied over receptive fields using a 1 cm2 probe before and after heating. Dynamic (ramp) and static (hold) firing rates were compared between temperatures. Thirty-seven afferents (11 SAI, 13 SAII, 9 FAI, 4 FAII) were tested. Heating increased skin temperature by 9.5± 2.4°C (P<0.001) and significantly elevated SAI (P=0.001) and SAII (P < 0.001) static firing, as well as SAI (P=0.03), SAII (P=0.028) and FAI dynamic firing (P < 0.001). These findings provide the first direct physiological evidence that heating enhances cutaneous mechanoreceptor activity, offering mechanistic basis for previously observed improvements in perceptual sensitivity. By using gait-like compressions this work also demonstrates that the augmented encoding persists under functionally relevant conditions. Together these findings reveal that heating amplifies static and dynamic mechanoreceptor responses in ways essential to postural control, supporting heat-based stimulation as a practical, non-invasive strategy for improving plantar feedback and reducing fall risk. KEY POINTS: The sole of the foot contains touch receptors that provide critical information for balance and walking, which decline with age and disease, increasing fall risk. Heating can improve touch perception, but the underlying mechanisms are unclear. Single nerve fibre activity from the foot sole was recorded in healthy young adults while applying natural, walking-like loads before and after skin heating. Heating increased nerve activity in three classes of touch receptors, enhancing sensitivity during application of pressure (dynamic) and steady pressure (static). Static activity relays standing balance input, whereas dynamic activity relays gait and slip feedback. Notably in dynamic receptors increases in heat-related nerve activity were more prevalent when loads were applied at faster rates. For the first time this work shows how heating differentially affects touch receptor classes and provides a physiological basis for using heat to support balance in future clinical studies.

Domesticated honey bees (Apis mellifera) remain highly active year-round, even in northern climates, requiring a tight regulation of their energetic metabolism. However, the overwintering process, particularly the mitochondrial mechanisms sustaining it, remains poorly understood. Here we investigated honey bee energetic metabolism across four seasons by measuring mitochondrial oxygen consumption, ATP production, site-specific reactive oxygen species (ROS) production, markers of oxidative stress and supercomplex (SC) assembly in thorax-isolated mitochondria. Complex I (CI)-linked respiration decreased by half in winter compared to summer, yet ATP production remained stable, indicating tighter energetic efficiency. This came at a cost, as winter bees exhibited higher ROS emission across multiple sites, which was somehow buffered as no clear evidence of oxidative damage to proteins was detected. Strikingly spring bees displayed elevated CI respiration together with greater ROS generation and protein carbonyl accumulation, identifying this stage as a critical window of oxidative vulnerability. Further in-gel activity revealed marked remodelling of mitochondrial complexes and SC. CI assembled into multiple SC, but their activity remained largely stable across seasons and did not reflect respiration shifts. By contrast CII and mG3PDH in-gel activities increased in winter, consistent with enhanced succinate and G3P oxidation, whereas CIV-containing SCs were also more abundant. Finally CV dimers and oligomers were only detected in fall and winter, structural features associated with higher oxidative phosphorylation (OXPHOS) efficiency. Overall this study provides the first integrative view of seasonal mitochondrial remodelling in honey bees and identifies winter and spring as critical physiological windows for colony survival. KEY POINTS: Honey bees remain active and generate heat by shivering throughout winter, but how their mitochondria adapt across seasons is still poorly understood. Previous work showed that winter bee mitochondria rely less on one major metabolic pathway and more on alternative fuels, but the consequences on energetic efficiency and oxidative stress were unknown. We show that mitochondria from winter bees maintain energy output despite major changes in fuel use, while producing more reactive oxygen species, a byproduct of metabolism that can cause oxidative damage. Spring bees displayed the highest levels of mitochondrial activity and oxidative damage, suggesting that this season may represent a critical period of physiological vulnerability for colonies. These results reveal that honey bee mitochondria are seasonally remodelled to balance energy homoeostasis, heat generation and oxidative stress, providing new insight into how colonies survive winter and transition into spring.

Female fertility relies heavily on the health of the oviduct and uterus. Each of these organs consist of a muscular tube lined by epithelial cells. In this review, we discuss the role of the TMEM16A chloride ion channel, expressed in the epithelial and smooth muscle cells in these organs, with a focus on function and dysfunction. In the oviduct, infection and endometriosis are major causes of infertility and TMEM16A plays a major role. Oviduct epithelial TMEM16A is also essential for egg and sperm health and for the process of fertilization, which takes place in the oviduct. The role of TMEM16A in uterine function has focussed on the smooth muscle component. TMEM16A plays a major role in determining the sustained plateau component of the action potential in human myometrium. The plateau sits at the chloride equilibrium potential of -25 to -30mV and, at this potential, calcium channels are active, permitting calcium influx and contraction. TMEM16A expression doubles in human labour and this is associated with a major increase in plateau and hence contraction duration. This prolongation of calcium influx permits contraction amplitude and duration to increase and appears to be important for successful labour.

Excitable tissues like the brain, peripheral nerves, skeletal muscles and the heart share a common dependence on voltage-gated sodium (Nav) channels for the initiation and propagation of action potentials (APs). These Nav channels exhibit unique biophysical properties tailored to their specific cellular environments. Here, we explore the interactions between Nav channel availability and resting membrane potential across a spectrum of cell types, including inhibitory GABAergic neurons, excitatory glutamatergic neurons, skeletal muscles, cardiomyocytes and dorsal root ganglion neurons. We highlight how these interactions, modulated by post-translational modifications and in relation to spatial localizations, are critical for maintaining physiological function and how even small shifts in channel properties can have significant pathophysiological consequences. In addition, we discuss the implications for drug discovery, emphasizing the need to consider the native cellular environment in developing Nav-targeting therapies. This perspective provides a framework for understanding the nuanced role of Nav channels in health and disease.

Cerebral blood flow is stabilized through dynamic adjustments across both macro‐ and microvascular compartments. While dynamic cerebral autoregulation (dCA) quantifies upstream pressure–flow coupling, downstream microvascular responses are less well characterized and may represent a distinct but functionally linked process. This study tested whether a two‐component cascade model, treating dCA and an empirically derived index of microvascular function (MF) as sequential stages can represent the integrated regulation of cortical oxygenation. Data from 41 healthy adults (20–45 years) were analysed. Beat‐to‐beat mean arterial pressure (MAP), middle cerebral artery flow velocity (CBFV) and cortical oxyhaemoglobin (O2Hb) were recorded during supine spontaneous oscillations and forced oscillations at 0.05 Hz using repeated sit–stand manoeuvres. Transfer function analysis quantified frequency‐domain gain, phase and coherence for MAP→CBFV (dCA), CBFV→O2Hb (MF) and MAP→O2Hb (total pathway). The cascade model was computed as the product of dCA and MF transfer functions. The cascade model derived indices showed strong correlations with total pathway gain, phase and coherence measures during both spontaneous and forced oscillations, with improved linear coupling under forced oscillations. These results support the applicability of a two‐component cascade model for integrated cerebrovascular regulation and suggest that serial interactions between macrovascular and microvascular regulatory mechanisms jointly shape the frequency‐dependent propagation of arterial pressure to brain‐tissue oxygenation dynamics.Key pointsCerebral blood flow is stabilized by coordinated regulation across large arteries and microvessels, but their dynamic interaction has not been experimentally modelled.We examined whether a two‐component cascade model linking upstream dynamic cerebral autoregulation and downstream microvascular function can explain how blood pressure oscillations influence cortical oxygenation.In 41 healthy adults, we recorded beat‐to‐beat blood pressure, middle cerebral artery blood flow velocity and near‐infrared spectroscopy‐derived oxygenation during rest and sit–stand manoeuvres, and analysed them using transfer function analysis.Gains, phases and coherences derived from the cascade model closely matched those from the direct blood pressure–O2Hb relationship, particularly under forced oscillations during sit–stand, demonstrating the model's physiological relevance.The cascade model provides a mechanistic framework to separate and quantify large‐ and small‐vessel contributions to cerebral blood flow regulation, with potential application in future studies of ageing and cerebrovascular disease.

ATP acting on P2X3 receptors contributes to carotid body (CB) hyperexcitability in spontaneously hypertensive rats (SHRs). We investigated whether this reflects altered ATP release and/or impaired ATP metabolism. Using in vitro CB preparations, we quantified ATP release in Wistar rats and SHRs (n=10 each) and found significantly greater ATP release in SHRs (P=0.00062). Intracellular ATP depletion in dissociated glomus cells was similar between strains (n=4 each). Morphometric analysis revealed a disproportionate increase in glomus tissue, measured as tyrosine hydroxylase-positive area, in juvenile SHRs compared with Wistar rats (n=8 each; P=5.44 × 10- 6). This enlargement was associated with upregulated Epas1 mRNA (n=8 each), encoding HIF‑2α, a driver of CB hyperplasia. Transcripts for ATP‑degrading enzymes Enpp1, Enpp3 and Entpd2 were also downregulated in SHRs (n=8 each), suggesting reduced extracellular ATP breakdown. Electrophysiological recordings in vitro and reflex testing in situ showed that topical ATP or α,β‑methylene-ATP applied to the CB evoked tachypnoea and sympathoexcitation in both strains, but SHRs displayed a greater sympathetic reflex (n=4 each; P=0.037), indicating increased sensitivity to purinergic stimulation. In contrast, testing adenosine transmission revealed no difference between strains; adenosine did not contribute to CB hyperexcitability in SHRs (n=11 each; P=0.53). Overall, increased ATP release in SHRs likely reflects CB enlargement from glomus cell expansion, compounded by reduced ATP‑degrading enzyme expression, thereby enhancing purinergic drive and chemoreflex sensitivity. KEY POINTS: The carotid bodies (CBs) of spontaneously hypertensive rats (SHRs) release more ATP than those of Wistar rats. Glomus cell expansion underpins CB hyperplasia and contributes to increased ATP release in juvenile SHRs. Upregulated Epas1 (i.e. HIF-2α) gene expression is likely responsible for CB hyperplasia in SHRs. ATP transmission is linked to exacerbated chemoreflex sympathoexcitation. Adenosine transmission does not contribute to CB hyperexcitability in SHRs.

Mitochondrial damage is a conserved feature of coronavirus infection, occurring with human (SARS-CoV-2, HCoV-OC43) and murine (MHV-1) coronaviruses. Coronaviruses damage mitochondria in airway epithelial cells (AEC), pulmonary artery smooth muscle cells (PASMC), pulmonary artery endothelial cells, immune cells and cardiomyocytes by causing rapid transcriptomic changes in nuclear-encoded genes regulating mitochondria and by viral proteins interacting with host mitochondrial proteins. Coronavirus infection causes mitochondrial depolarization, mitochondrial transition pore (MTP) opening, inhibition of the electron transport chain (ETC) and ATP synthetic apparatus, increased mitochondrial fission, apoptosis, and impaired mitochondrial oxygen sensing. Within hours of infection, SARS-CoV-2 induces transcriptional reprogramming of genes relevant to the mitochondrial matrix in AECs, downregulating mRNA encoding ETC complex I components and the ATP synthesis complex. These bioenergetic consequences of SARS-CoV-2mitochondriopathy may contribute to long COVID. Infection also upregulates dynamin-related protein 1 (DRP1), activating mitochondrial fission while promoting apoptosis by activating apoptosis inducing factor (AIF) and caspase 7. Even without infection, transfection with specific coronaviral proteins opens the MTP and depolarizes the mitochondria, or activates DRP1 and AIF, promoting AEC damage or apoptosis, thereby contributing to diffuse alveolar damage. In human PASMCs, coronaviral M and Nsp9 proteins suppress hypoxic pulmonary vasoconstriction (HPV), a homeostatic mechanism in PASMCs that uses a mitochondrial oxygen sensor to redistribute blood flow to well-ventilated lung regions during pneumonia. Impairment of HPV, seen as intrapulmonary shunting, contributes to the profound hypoxaemia in COVID-19 pneumonia. Coronavirus-induced mitochondriopathy may have therapeutic relevance as blocking AIF-induced apoptosis or enhancing HPV appears beneficial in a MHV-1model of COVID-19 pneumonia.

Fibromyalgia (FM) is a chronic pain disorder with a severe impact on a person's health-related quality of life. In addition to the characteristic widespread pain and fatigue, people with FM regularly experience sensory abnormalities and report lingering, often painful sensations after mechanical probing of the skin. The neurobiological changes which underlie the varied symptoms in FM are incompletely understood, but many symptoms and signs can be transferred from patients to mice by administration of patient IgG. The present study aimed to explore whether sensory afferents, including nociceptors, in rodents injected with FM patient IgG displayed ongoing firing after mechanical stimulation. Skin saphenous nerve recordings were retrospectively analyzed to assess the presence and quality of ongoing discharges following mechanical stimulation of sensory afferents in mouse skin after passive-transfer of FM patient IgG. Our analysis revealed that C-mechano and Aδ-mechano afferents innervating the skin in FM-IgG treated animals fired significantly more action potentials after, but not during, mechanical force steps compared to healthy control-IgG treated afferents. This sustained mechanically evoked activity mirrors the nociceptor hyperexcitability observed in people with FM, suggesting that autoreactive IgG might underly this phenomenon in patients. This adds to the growing body of evidence demonstrating that FM symptoms arise from changes in the peripheral nervous system generated by circulating autoreactive IgG. KEY POINTS: Passive transfer of fibromyalgia (FM)-IgG causes sensitization of mechano-sensitive afferents in the skin of mice. Aδ-mechano and C-mechano sensitive afferents in skin from mice injected with FM-IgG display more after-discharge following mechanical stimulation than mice injected with healthy control-IgG. Changes in the peripheral nervous system caused by circulating autoreactive IgG play a role in FM signs and symptoms.