Abstract figure legend Blood flow is normally shunted from the right side to the left side of the fetal circulation via two essential vascular channels, the foramen ovale (FO) and ductus arteriosus (Duct). In the absence of antenatal steroid therapy with betamethasone (BM), blood flow across these channels is reversed after delayed cord clamping (DCC) preceded by a short period of initial ventilation in the preterm birth transition. These blood flow reversals increase lung blood flow after birth, but decrease blood flow to vital systemic organs such as the brain and kidneys. After antenatal BM treatment, however, an earlier flow reversal occurs across the FO during initial ventilation, and is followed by a greater flow reversal across the ductus after DCC. These enhanced flow reversals augment increases in lung blood flow during the birth transition, but are associated with a more pronounced redistribution of left ventricular output away from the upper body region that further reduces perfusion of upper body organs, while maintaining lower body perfusion. Abbreviations: Ao, aorta; LA, left atrium; LV, left ventricle; PA pulmonary artery; PV, pulmonary veins; RA, right atrium; RV right ventricle; VC, vena cavae. Created in BioRender.com

Abstract figure legend Eleven young healthy males underwent 10 days of unilateral lower limb suspension (ULLS) followed by a 21 day period of active recovery (AR) using resistance exercise performed three times a week at 70% of the one repetition maximum (1RM), equating to a total of nine training sessions. At baseline, immediately after ULLS, and 3 days after the last training session of the AR period, we assessed maximal isometric muscle force production by dynamometry, and we estimated muscle volume through panoramic ultrasound techniques. Vastus lateralis biopsies were collected at the same time points. After 10 days of ULLS, we observed decreased muscle force and volume, accompanied by reductions in proteins related to mitochondrial fusion and downregulation of the expressions of gene pathways related to oxidative phosphorylation, fatty acid metabolism and mitochondrial biogenesis. After only nine sessions of resistance exercise, muscle force was restored and muscle volume was markedly increased (even exceeding baseline values); however, most of the molecular and gene expression findings pointed towards a marked regulation of oxidative phenotype and metabolism in contrast with what is usually observed in response to resistance exercise.

Abstract figure legend Magnetoencephalography data from stroke survivors, healthy, age-matched control participants and healthy young participants were measured during the execution of a thumb movement task. Movement-related high-gamma power was evident in all three groups with a maximum over motor cortical areas contralateral to the performed movement. High gamma power showed a strong positive relation to participants’ movement rate (left), whereas no significant relation to motor skill acquisition was present (right). Stroke survivors showed reduced cortical high-gamma power mainly as a result of their reduced movement rate (middle).

Abstract figure legend The Kcna1 knockout mouse model of sudden unexpected death in epilepsy (SUDEP) exhibits sex-specific differences in SUDEP risk. Female mice exhibit a lower SUDEP risk than males, despite similar seizure characteristics and interictal cardiac function across sexes. During seizures, females display a higher incidence of bradycardia and demonstrate resistance to inducible ventricular tachyarrhythmias. Organomics analysis indicates that females have more effective resetting of brain–heart interactions in the postictal period, suggesting a protective mechanism that may contribute to their reduced SUDEP susceptibility. During a SUDEP event captured for one male and one female, the terminal neurocardiac events were similar between the sexes. These findings highlight the importance of sex-specific factors in SUDEP risk and brain–heart communication.

Abstract figure legend CMD-35647 treatment reduces muscle lipid hydroperoxides and mitigates sarcopenia in aged mice. By 26 months of age, muscle mass, muscle force generation and mitochondrial respiration are reduced in vehicle-treated mice relative to middle aged control mice (18 months of age). Treatment with CMD-35647 lowers muscle atrophy, muscle dysfunction, and reduces mitochondrial respiration in aged mice. LOOH, lipid hydroperoxides.

Abstract figure legend Metabolic stimulation improves bioenergetics, redox state, hydration and hematologic indices of circulating erythrocytes from sickle cell mice. Retained mitochondria in circulating RBCs from sickle mice are a source of RBC ATP as mitochondria function (ETC, electron transport chain) inhibitors [rotenone, a mitochondrial complex I inhibitor; 3-nitropropionic acid, a complex II inhibitor; carbonyl cyanide 3-chlorophenylhydrazone, a H⁺ ionophore, which dissipates H⁺ gradient; and oligomycin A, a mitochondrial ATP synthase inhibitor] decrease RBC ATP levels. Conversely, metabolic stimulation of isolated RBCs with metabolites/substrates of glycolysis, tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) including adenosine 5′-diphosphate potassium salt hydrate (ADP), l-glutamic acid monosodium salt (glutamate), l-(−)-malic acid sodium salt (malate), sodium pyruvate (pyruvate), sodium succinate dibasic hexahydrate (succinate) and all metabolites combined (all) improves RBC redox state by decreasing ROS levels, favourably controls baseline calcium and its accumulation (possibly via ATP production and PMCA stimulation), increases RBC volume and hydration and decreases intra-RBC haemoglobin concentration. Created with BioRender.com.

Abstract figure legend Proposed schematic of the ancestral (left) and mammalian (right) rod signalling pathways with signal flow indicated by green (ON) and red (OFF) arrows. In the ancestral pathway, rods connect to rod ON and rod OFF bipolar cells (orange), which in turn make connections to ON and OFF retinal ganglion cells. In the mammalian retina, rods synapse only onto rod ON bipolar cells, which in turn make synaptic connections with AII amacrine cells (yellow). The AII amacrine cells then synapse onto cone ON bipoand cone OFF, which carry the rod signals to ganglion cells.

Abstract figure legend Prehabilitative exercise is the process of preparing, through structured exercise, for anticipated disuse (e.g. bed rest or limb immobilization). Despite positive findings in clinical studies, the underlying physiological mechanisms of prehabilitation remain poorly understood. This review discusses three key potential avenues: (1) Prehabilitative exercise may increase the capacity of certain parameters, such as muscle strength, so that losses as a result of disuse less probably force an individual below a critical threshold of function. (2) Muscle memory refers to the retention of adaptations to past stimuli, which can protect the muscle or brain when re-exposed to similar stressors. The location of this ‘memory’ remains uncertain, but it may involve myonuclear permanence and/or epigenetic modifications in muscle, or changes in neural pathways. (3) Structural reinforcement involves exercise-induced adaptations that strengthen tissues without necessarily increasing their measurable size or function, such as the enhancement of neuromuscular junction integrity and optimization of vascular beds.

Abstract figure legend The study assessed plasma-derived extracellular vesicles (EVs) from control patients and those with first-ever ischaemic stroke, divided into mild and severe groups. Stroke patients had lower EV concentrations than controls, with mild-stroke patients showing fewer and smaller EVs. Stroke-derived EVs exhibited elevated levels of proinflammatory markers (IL-6, interleukin 6; TNF-α, tumour necrosis factor α), oxidative stress markers (NTR, nitrotyrosine), and angiogenic factors (VEGF, vascular endothelial growth factor) but lower levels of placental growth factor (PlGF) than controls. Some differences were observed between mild- and severe-stroke-derived EVs. Thus severe-stroke EVs have a higher level of VEGF, whereas mild-stroke EVs have higher levels of IL-6. Therefore severe-stroke EVs enhanced angiogenesis more significantly than those from mild-stroke or control groups. In an in vitro blood–brain barrier (BBB) model, EVs from severe-stroke patients caused less disruption and increased the expression of claudin-5 (CLDN5) protein, suggesting that these EVs may support BBB integrity while promoting angiogenesis.

Abstract figure legend Fetal lambs were instrumented with deflated left atrial balloons at ∼120 days gestational age. Top left: following recovery, balloons remained deflated in Sham fetuses and were gradually inflated in impaired left ventricular inflow (ILVI) fetuses over the course of this 8 day study. Top right: net-antegrade flow through the ascending aorta was eliminated by balloon inflation in ILVI fetuses. Bottom left: morphometric assessment at the study end-point showed a significant reduction in left ventricular free wall mass, but no significant change in right ventricular free wall mass. Bottom right: coronary microvascular perfusion was assessed by myocardial contrast echocardiography at the study end-point; ILVI fetuses had 3-fold greater left ventricular perfusion and 5.6-fold greater right ventricular perfusion than Shams.

Abstract figure legend Participants cycled through virtual reality environments comprising a flat road and differently graded inclines (3%, 6%, 9%). During one visit the pedalling resistance was identical despite the different virtual hill gradients. Steeper virtual hills transiently augmented perceptions of exertion and cardiovascular responses, although the opposite was not found with less-steep hills.

Abstract figure legend Relationship between neural tube vascularization and behavioural outcomes. This figure illustrates the proposed link between neural tube vascularization and behavioural development. The neural tube is divided by a central arrow, showing two pathways: typical vascularization on the left and altered vascularization on the right. On the left, typical vascularization is shown to result in typical behavioural outcomes, highlighting the importance of normal vascular development. On the right, reduced vascularization is associated with autistic traits, suggesting that compromising vascularization during neural tube development may contribute to atypical behavioural outcomes. Created in BioRender. Manzo, J. (2024) https://BioRender.com/l21m980.

Abstract figure legend ACh released from the NMJ can activate α7 nAChRs on terminal Schwann cells, releasing GABA that activates GABAB receptors on the nerve terminal which then reduces further ACh release from the nerve. At the mature NMJ, before reaching α7 nAChRs on terminal Schwann cells ACh is normally hydrolyzed by both AChE clustered in the synaptic cleft and by BChE anchored to the TSC. ACh can activate the α7/GABAB receptor-mediated pathway and depress the further release of ACh when AChE at the NMJ is low either during development or in congenital myasthenic syndrome, in the latter case observed as a component of fatigue.

Abstract figure legend This Topical Review offers a comprehensive examination of how electrical stimulation affects neural function across various levels. At the cellular level, we investigate the influence of exogenous electricity on voltage-gated channels, action potential generation, synaptic transmission, membrane properties, and neurotransmitter release. (1) Exogenous electricity can have direct effects on neural cells by either depolarizing them beyond the action potential threshold (supra-threshold) or by shifting the resting membrane potential closer to this threshold, thereby increasing the cells' susceptibility to intrinsic inputs (sub-threshold; 2). (3) We also discuss the impact of exogenous electricity on electrical synapses and explore non-physiological effects on neurotransmitter release probability, including presynaptic saturation. (4) At the circuit level, this review explores how exogenous electricity can selectively activate clusters of cells by targeting specific axon bundles within the central nervous system. (5) It also addresses how non-physiological stimulation, such as high-frequency stimulation, can silence axons and specific groups of cells. (6) Further, we explore the effects of exogenous electricity on cell type and size diversity, layer-specific variations, and cell-to-cell interactions – including neural precursor cell migration (not shown in this figure). (7) At the circuit and systems levels, the review discusses how electrical stimulation can activate pathways and cells or change brain rhythms. (8) For this, we highlight advances facilitated by genetic techniques such as chemogenetics and optogenetics, and their contributions to the field of neuromodulation.

Abstract figure legend Schematic representation of the experimental workflow and main results of left and right ventricular outflows obtained before and after ablation of the pericardium, on isolated pig hearts perfused in biventricular working mode. Left and right ventricular haemodynamics were assessed in response to changes in left and right atrial or arterial pressures. Pericardium removal induced alterations in the preload-dependent ventricular interaction, as well as right ventricle haemodynamics.

Abstract figure legend Excessive hypercholesterolaemia during pregnancy impairs maternal endothelial function, which, in turn, drives the development of pre-eclampsia and may also contribute to the increased risk of later-life cardiovascular disease in women. Mechanistically, excessively high cholesterol levels during pregnancy increase the release of circulating factors, such as oxidized low-density lipoprotein (LDL) and placental factors. These factors, then, activate membrane-bound receptors, particularly the scavenger receptor lectin-like oxidized LDL receptor 1 (LOX-1) and the innate immune receptor toll-like receptor 4 (TLR4), which are known mediators of endothelial dysfunction. Created with BioRender.com

Abstract figure legend We studied two lines of laboratory mice divergently selected for high or low level of basal metabolic rate (BMR). We found that BMR was negatively correlated not only with fat mass but also with the magnitude of non-shivering thermogenesis and the total uncoupling protein-1 (UCP1) level in interscapular brown adipose tissue. Both effects were significant even after acclimation to thermoneutrality. Because variation in BMR may affect both fat content and non-shivering thermogenesis (i.e. potential anti-obesity factor), it should always be taken into account in studies investigating the potential links between thermogenesis and obesity.

Abstract figure legend With ageing and age-related neurodegenerative diseases, the amount of GABA and GABAergic inhibition as well as the modulation (indicated by sine wave) of GABAergic inhibition is reduced, whereas excitation is increased. In many parts of the brain, this leads to a mismatch of facilitatory (green neurons) and inhibitory (red neurons) neurotransmitters usually indicated by a weakening of inhibition, as illustrated by excitation (E) weighing heavier than inhibition (I). On the behavioural level, this is not only apparent by impaired motor control (yellow arrow), but also associated with cognitive decline and reduced well-being such as impaired sleep behaviour and pain perception. On the other side indicated by the blue arrow, balance learning was shown to act as a countermeasure to enhance the levels of GABA, increase GABA-mediated intracortical inhibition and improve task-specific modulation of inhibition leading not only to better motor control, but also more general improvements in well-being.

Abstract figure legend The baroreflex adapts to compensate for the decrease in cardiac function after myocardial infarction. We used in silico patient cohorts representing afferent and efferent loci of neural adaptation to explore neural remodelling that allowed individuals to maintain higher baroreflex sensitivity after cardiac injury. The model suggests that adaptation along the vagal efferent pathway can help maintain higher baroreflex sensitivity after cardiac injury. Created with BioRender.com.

Abstract figure legend Model depicting role of DMH MC3R signaling in energy rheostasis.

Abstract figure legend Poor functional recovery after surgical repair is frequently disappointing. In an experimental rat model, we found that by isolating the effects of prolonged motoneurone isolation from targets (prolonged axotomy), reduced regenerative capacity and prolonged isograft denervation, and muscle denervation each reduced regeneration and muscle reinnervation. By electrically stimulating the proximal stump of a repaired nerve in rats and human patients after carpal tunnel release surgery, to evoke action potential propagation to the neuronal cell bodies (20 Hz for 1 h immediately after repair), the outgrowth of axons across the surgical site was accelerated, promoting earlier reinnervation of target muscles. The acceleration occurred both after immediate and delayed nerve repair.

Abstract figure legend Stimulation of the Shaffer collateral pathway at 3 Hz activates non-ionotropic NMDA receptors. This subsequently leads to Src kinase mediated phosphorylation of pannexin-1 (Panx1), which releases ATP from the postsynaptic cell. ATP acts as a ligand for P2X4 receptors to induce long-term depression (LTD).

Abstract figure legend The volume-regulated anion channel (VRAC), composed of leucine-rich repeat-containing 8 (LRRC8) proteins, serves both canonical and non-canonical functions in vertebrate cells. The canonical function of this channel relates to its original description, which is homeostatic regulation of cell volume in response to hypotonic challenges. In this context, LRRC8-containing VRACs facilitate the regulatory volume decrease process by releasing Cl⁻ and organic osmolytes. However, most mammalian cells, including immune cells, are not typically exposed to the extreme and prolonged hypotonic conditions that activate VRACs. Emerging evidence suggests that intracellular signalling mechanisms – such as phosphorylation, oxidation and others – may also contribute to the activation of LRRC8-containing VRACs, allowing for the influx of extracellular molecules. Many of these molecules play significant immunomodulatory roles in immune cells. These observations have positioned LRRC8-containing VRACs in the spotlight as a promising target for future immunotherapeutic approaches.

Abstract figure legend Knee post-traumatic osteoarthritis (PTOA) is a common consequence of prior joint injury, and mounting evidence suggests a key role for inflammation in its development and associated functional deficits. Prior work from our group demonstrated colony stimulating factor one receptor (CSF1-R) is positively associated with knee trauma severity, which prompted the current study in which we sought to determine if inhibition of CSF1-R would attenuate articular cartilage degradation and muscle atrophy and weakness following direct joint injury in a murine model of PTOA. Transcriptomic and histomorphological analyses across multiple tissues revealed that targeted CSF1-R inhibition mitigated the severity of PTOA and associated muscle atrophy after joint injury, offering evidence for CSF1-R as a therapeutic target to support post-injury recovery.

Abstract figure legend Homeostatic plasticity is critical for the stabilization of synaptic function in the face of disturbances. At the wild-type Drosophila neuromuscular junction (NMJ), inhibition of postsynaptic glutamate receptor activity (reduction in miniature excitatory postsynaptic potential) triggers a compensatory increase in presynaptic neurotransmitter release (increase in quantal content), which allows the maintenance of baseline level excitation in the postsynaptic cell (stabilized excitatory postsynaptic potential). This process is known as presynaptic homeostatic potentiation (PHP, upper right panel). Histone acetylation (H3K9ac)-mediated epigenetic signalling in glia is critical for PHP. Neuronal overexpression of human Aβ (hAβ42 OE) results in decreased histone acetylation in glia, leading to a disruption of the glial epigenome-dependent downstream signalling and impairment in PHP (lower right panel). Glial sphingosine kinase 2 (Sk2) can activate either endogenous sphingosine or exogenous FTY720 (fingolimod, an analogue of sphingosine), which act as histone deacetylase inhibitors, thereby restoring histone acetylation and homeostatic plasticity in Drosophila models of Alzheimer's disease (upper right panel). These findings indicate that glial epigenome-mediated activities, such as the synthesis and secretion of signalling factors, are crucial for glia–neuron interactions, thus facilitating PHP and synapse stabilization.

Abstract figure legend To investigate volitional breathing control, intracranial electroencephalograms (iEEG) and respiratory signals were recorded in six pharmaco-resistant epilepsy patients during breath-holding and sniffing manoeuvres. In both manoeuvres, and across both the preparatory and execution phases, a shared network comprising the amygdala, posterior insula, and the superior, middle and inferior temporal gyri was activated, exhibiting theta and alpha activity. During apnoea, theta activity initially decreased before progressively increasing, eventually returning to baseline levels at the conclusion of the apnoea in the amygdala and hippocampus.

Abstract figure legend Experimentally obtained and computed neuromechanical variables characterizing sensorimotor functions of cat forelimb muscles during locomotion.

Abstract figure legend Patients with chronic kidney disease (CKD) stages III–IV were randomized to the 8 week Mindfulness-Based Stress Reduction (MBSR, n = 17) programme or Health Enhancement Program (HEP; a structurally parallel, active control group, n = 12). Muscle sympathetic nerve activity (MSNA) via microneurography was assessed during 3 min of mental arithmetic stress at baseline and post-intervention. A reduction of ∆MSNA reactivity to mental stress was observed following 8 weeks of MBSR but not after HEP. This study's results suggest the feasibility and clinical benefits of MSBR on autonomic function in CKD.

Abstract figure legend Overexpression of individual PDE4A isoforms in the dorsal hippocampus results in disparate effects on cAMP-dependent forms of long-lasting plasticity. PDE4A5, but not PDE4A1, overexpression impairs expression of long-term potentiation (LTP) induced by theta burst stimulation (TBS-LTP), while neither affects LTP induced by spaced tetanic stimulation. The N-terminus of PDE4A5 is necessary for TBS-LTP deficit because expression of PDE4A5Δ4, the N-terminus-truncated form of PDE4A5, does not impair TBS-LTP. Overexpression of PDE4A5 in area CA1 is sufficient to recapitulate the effects of whole hippocampal overexpression of PDE4A5 on TBS-LTP.

Abstract figure legend Non-Newtonian modelling and GPEs for stroke risk in atrial fibrilation patients.

Abstract figure legend This study explores how humans adapt their grip force to sudden changes in friction and/or load during object manipulation. Using a novel friction-modulating device integrated into an object suspended by a pulley system, we measured participants’ grip force across three phases: lifting, holding, and reacting to perturbations. The results reveal how the sensorimotor system finely tunes grip force in response to grip safety requirements presented on the table on the right.

Abstract figure legend This study used drone-based photogrammetry to quantify the body size and condition (BC) of humpback whales on their Hawaiʻi (HI) breeding and Southeast Alaska (SEAK) feeding grounds. A total of 2410 measurements were taken from 1659 individuals, with 405 repeat measurements from 137 lactating females used to track changes in maternal body volume (BV). HI mothers lost an average of 0.106 m³ (96.84 kg day⁻¹) while fasting, equivalent to 2641 MJ day⁻¹ or 830 kg of krill and 424 kg of Pacific herring daily. SEAK females gained 0.015 m³ (14.54 kg day⁻¹; 367 MJ day⁻¹). We then quantified differences in female BC on the SEAK feeding ground, with pregnant female BC increasing at the fastest rate, followed by unclassified and lactating females. Calf length growth rates were highest in HI, while BV growth remained constant throughout the year. Maternal investment in calf growth was correlated with female length and BC, with larger females producing bigger, faster-growing calves.

Abstract figure legend This study estimated the energetic cost of gestation in humpback whales. First, relative birth size was estimated from body length measurements of mother–fetus pairs from historical whaling records, and mother–calf pairs were measured in situ using aerial photogrammetry. Relative birth length (33.75% of maternal length) was used to back-calculate fetal age and to model fetal growth (FG). FG rates and absolute birth size increased with maternal length, characterized by slow early development, increasing exponentially before birth. The energetic cost of FG was estimated by combining fetal mass estimates with tissue-specific energy content from a post-mortem newborn humpback whale. Placental tissue (PT) development costs were derived from the energy content of humpback whale placental tissue, and gestational heat (GH) was calculated using published equations. The total cost of gestation combines FG, placental tissue development and GH.

Abstract figure legend An endogenous AhR ligand (ITE) elevates maternal blood pressure and proteinuria in pregnant rats, and decreases uteroplacental blood flow and fetal and placental growth, all of which are hallmarks of preeclampsia. ITE also reduces vascular density, alters immune cell distribution and fetal sex-specifically disturbs transcriptomes in rat placentas. These ITE-dysregulated genes are highly relevant to diseases of heart, vascular functions and inflammatory responses.

Abstract figure legend Human intestinal organoids were genetically modified to express a fluorescent protein in enteroendocrine cells (EECs), which were then separated by flow cytometry and analysed by single-cell RNA sequencing. High numbers of human EECs were thereby available for cluster analysis and differential gene expression, revealing transcriptomic differences between EEC populations.

Abstract figure legend In this study, we used best-practice methodology to establish menstrual cycle phases of women. We used stable isotope methodologies to assess muscle protein synthesis (MPS) in the mid-follicular and mid-luteal phases of their menstrual cycles. One leg performed two bouts of resistance exercise with the contralateral rested leg acting as a control; this was reversed in the opposite menstrual cycle phase. We also assessed whole-body protein myofibrillar protein breakdown (MPB). We saw, as expected, that resistance exercise stimulated MPS but that there was no effect of menstrual cycle phase on the MPS or MPB responses. There appears to be no anabolic ‘advantage’ to performing resistance exercise in any particular phase of a woman's menstrual cycle.

Abstract figure legend Kv₄ channel improves temporal precision of auditory nerve-evoked spikes in cochlear nucleus bushy neurons. Bushy neurons are specialized cells in processing information about temporal fine structure of sound critical for auditory tasks. They express Kv₄ channels that help sharpen the action potential width and improve auditory nerve-evoked spike timing. Blocking Kv₄ channels with JZ-X leads to broader spike waveform and higher spike jitter in bushy neurons, which are expected to negatively impact the temporal processing in central auditory circuits.

Abstract figure legend The primary visual cortex (V1) in mammals is essential for processing complex visual stimuli, with neurons exhibiting selectivity for edge orientation and position. Extracellular recordings and non-linear input model analysis were used to recover spatial receptive fields and to compare visual processing mechanisms in marsupials with those in eutherian mammals.

Abstract figure legend Muscle blood flow redistribution during submaximal exercise in rats with monocrotaline-induced pulmonary hypertension (PH).

Abstract figure legend The perineuronal space contains high concentrations of immobile glycoproteins and glycolipids bearing sialic acid (such as glycosides) and sulfate groups (such as sulfatides and glycosaminoglycans) that together account for more than 50 mEq L⁻¹ anionic charge. Left: ion concentrations in the perineuronal space are typically treated as equivalent to cerebrospinal fluid (CSF) values, requiring that the component ion concentrations of CSF are unaltered in the extracellular space. Right: however, the large pool of membrane-associated immobile anionic species that account for almost half the total extracellular anionic charge results in Donnan exclusion, redistributing the mobile anionic charge to maintain a constant total charge (immobile plus mobile charges) in accordance with Gauss’ Law of electroneutrality. Note that the same number of positive charges are present, but that the presence of the rectangular structures representing perineuronal membrane-associated immobile anions, from sialic acid-bearing glycosides to chondroitin sulfate-decorated aggrecan family proteoglycans, make up roughly half the total anionic charge. The total extracellular charge is the same on the left and right sides of the schematic, both for cations and anions, even though the number of mobile anions on the right is half the number on the left. Because the immobile anions are known to be heterogeneously distributed, Gauss’ Law implies that mobile anions, principally chloride, must also be heterogeneously distributed in the extracellular space to maintain total anionic charge. Because transmembrane chloride flux underlies GABAergic inhibition, we directly and non-invasively measure extracellular chloride to better understand the influence of Donnan exclusion on chloride distribution and inhibitory function in vitro and in vivo.

Abstract figure legend Pituitary hormones are essential to life because they regulate important physiological processes, such as growth and development, metabolism, reproduction, and the stress response. This is achieved via signalling interplay between the brain, mainly through hypothalamic neurohormone secretion, and peripheral feedback signals that shape pituitary cell excitability. Hormonal secretion relies on the spontaneous electrical activity of pituitary cells that regulates the intracellular calcium ([Ca²⁺]_i) level, an essential signalling conduit for hormonal secretion. The sodium leak channel NALCN is integral for regulating pituitary excitability by tuning cellular resting membrane potential to support spontaneous firing activity, raising [Ca²⁺]_i for hormonal secretion.

Abstract figure legend Effects of ageing in cognitive decline. Ageing induces a cascade of changes, including increased oxidative stress, mitochondrial dysfunction, chronic inflammation and anabolic resistance. These alterations disrupt the homeostasis of the skeletal muscle and endothelium, creating an altered environment of different factors at the cellular level, ultimately contributing to cognitive impairment.

Abstract figure legend Scaling up ultrastructural heterogeneities and subcellular conduction to arrhythmogenesis in the heart. Lower panels: T-tubular network in a ventricular myocyte (left); Cx43 distribution (green) in a ventricular myocyte (middle); and in an intercalated disc linking two myocytes. AC, area composita; D, desmosome; GJ, gap junction; Mf, myofibrils; and Mt, mitochondria. Upper panels: ECG showing initiation of arrhythmias (left) and colour map of voltage of the epicardial surface during an arrhythmia from a computer simulation (right).

Abstract figure legend Postprandial release of incretin hormones is associated with increased insulin secretion from pancreatic β cells improving glycaemic control, as well as reduced appetite, and slowing of gastric emptying that result in weight loss with reduced risks from co-morbidities, including cardiovascular diseases and metabolic-associated steatotic liver disease.

Abstract figure legend The incretin system in obesity. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) (yellow) and glucagon-like peptide-1 (GLP-1) (blue) are produced by the proximal and distal small intestinal epithelium, where they are released postprandially into the bloodstream to modulate a myriad of physiological and metabolic functions. GIP is mostly produced by K-cells in the duodenum and jejunum, whereas GLP-1 is produced by L-cells mostly in the ileum and large intestine. These incretin hormones act on the pancreas causing an increase in insulin secretion. GIP increases glucagon production, whereas GLP-1 decreases it. These hormones have been shown to reduce food intake, causing weight loss. Central GLP-1 increases nausea, whereas GIP has been shown to decrease nausea by acting on GIP receptors in the brainstem.

Abstract figure legend PANX1 and PANX3 show opposite expression patterns in patient-derived normal skin and cutaneous squamous cell carcinoma (cSCC) tumours, with PANX1 increased and PANX3 mRNA decreased in cSCC tumours compared to skin. Within the tumour PANX1 localizes to all regions, including tumour nests which house cSCC cancer cells and tumour stroma which contains tumour-infiltrating lymphocytes, cancer-associated fibroblasts and blood vessels. PANX1 deletion by CRISPR/Cas9 editing and PANX1 channel inhibition via probenecid (PBN) and spironolactone (SPL) reduces SCC-13 cancer cell properties of SCC-13 such as growth and migration. Conversely, global Panx3 (knockout) KO mice subjected to the 7,12-dimethylbenz(a)anthracene/12-otetradecanoylphorbol-13-acetate (DMBA/TPA) cutaneous carcinogenesis model have increased papilloma growth and incidence. Created with Biorender.com.

Abstract figure legend In silico trials were conducted in 654 virtual patients with atrial fibrillation (AF) to assess the cardioversion efficacy of three pharmacological treatments: single SK and K₂P channel block and combined SK+K₂P channel inhibition. Left: representative virtual AF patient with the atria inside the torso. Screenshot of the simulated transmembrane voltage and the ECG (dimensionless, only showing atrial activity) in control conditions and after all three pharmacological interventions. Successful AF cardioversion and recovery of P-waves only occurs for combined SK+K₂P channel block. Right: cardioversion efficacy in the 654 virtual patients.

Abstract figure legend A total of 15 Yorkshire pigs were used as either healthy controls (n = 5) or given chronic infarctions (n = 10). Ventricular programmed pacing was used as a stressor to analyze the effects of bioelectric block Axonal Modulation Therapy (AMT) of the right sympathetic chain. Noradrenaline (NA) and Neuropeptide Y (NPY) were measured as outputs, as well as various hemodynamic and electrophysiologic parameters. Blocking the signals on the right sympathetic chain appeared to reduce the release of NA in both control animals and healthy tissue in MI animals. The region close to the infarction scar appeared to see less of an effect, but the AMT lessened the heterogeneities between the infarcted and healthy regions of the heart.

Abstract figure legend Receptors and channels on thin fiber (group III and IV) afferents are stimulated by muscle contraction, evoking reflexive decreases in parasympathetic activity and increases in sympathetic activity. These autonomic responses, in turn, increase heart rate, cardiac contractility, cardiac output, and peripheral resistance. This is referred to as the exercise pressor reflex. In rats with type 2 diabetes mellitus (T2DM), chronic low-grade inflammation may lead to increased IL-1β levels and/or activation of IL-1 receptors (IL-1R), sensitizing thin fiber afferents and resulting in an exaggerated exercise pressor reflex compared to healthy rats. In healthy rats, stimulation of IL-1R with exogenous IL-1β exaggerates the normal exercise pressor reflex, while IL-1R blockade in T2DM rats attenuates the exaggerated response.

Abstract figure legend Monomeric and multimeric α-synuclein were purified from HEK cells and delivered to lamprey reticulospinal (RS) synapses via axonal microinjection, followed by stimulation (20 Hz, 5 min). Ultrastructural analysis showed that both α-synuclein species impaired intracellular vesicle trafficking, leading to synaptic vesicle loss and endosome buildup. While multimeric α-synuclein reduced synaptic vesicle docking, monomeric α-synuclein induced a greater expansion of the plasma membrane (PM), inhibited clathrin-mediated endocytosis and caused atypical fusion at the active zone. This highlights the distinct effects of monomeric and multimeric α-synuclein on synaptic function. Created with BioRender.com.

Abstract figure legend A microdialysis method to detect hydrogen peroxide and superoxide within skeletal muscle and determine nutritive blood flow, while also assessing microvascular endothelial function in response to acetylcholine stimulation. This technique for physiology has the potential to identify mechanistic insights involved in the development of age-related hypertension.

Abstract figure legend During handgrip exercise in hypoxia, brain perfusion is suboptimal and muscle sympathetic nerve activity is potentiated (left panel). During the exercise in hypercapnia, brain perfusion is supraoptimal and muscle sympathetic nerve activity is suppressed (right panel). These observations support the notion that Cushing's mechanism is activated during hypoxic exercise while inhibited during hypercapnic exercise.

Abstract figure legend Neurons clustered into ganglia at the heart's surface, referred to as intrinsic cardiac neurons (ICNs), supply innervation to the heart and control cardiac function. While studied in mammalian and non-mammalian species, data from human ICNs are largely unavailable. To fill this gap, we conducted a comprehensive study of ICNs from mice, pigs and humans using a combination of biological techniques. Intracellular recording, dye filling of single neurons, immunohistochemistry of whole and sectioned ganglia, and transmission electron microscopy of single cells were used to generate a dataset encompassing the physiology, morphology, histochemistry and ultrastructure of these neurons from each species. The resulting publicly available database identifies both similarities and differences in ICNs across mammals, highlighting structural and functional properties unique to humans.

Abstract figure legend Physiological influences of OXM and its emerging insights from evidence on bariatric surgery effects.

CCK, cholecystokinin; FGF21, fibroblast growth factor 21; GLUT4, glucose transporter type 4; IRS1, insulin receptor substrate-1; NNMT, nicotinamide N-methyltransferase; OXM, oxyntomodulin

Abstract figure legend Sphingosine-1-phosphate (S1P) binds to Gi protein-coupled receptor S1PR1. Upon S1PR1 activation, Gβγ is released from the Gαi-Gβγ heterotrimer, allowing it to recruit phospholipase Cβ (PLCβ) to the plasma membrane. PLCβ cleaves phosphatidylinositol-4,5-bisphosphate (PIP₂) into inositol trisphosphate (IP₃) and diacylglycerol (DAG). DAG recruits and activates protein kinase D (PKD), which in turn may lead to leucin-rich repeat containing 8 (LRRC8)/volume-regulated anion channel (VRAC) activation. Created with BioRender.com.

Abstract figure legend Neuromuscular disuse scenarios of limb immobilization, reduced activity and bed rest result in impairments of muscle strength that exceed losses of muscle size. Neural adaptations are an assured consequence of disuse. The available evidence garnered from human and animal models highlights suppressed motor unit firing rate (MUFR) that is more evident in lower-threshold motor units, in which electrophysiological methods indicate no discernible impairment of the neuromuscular junction (NMJ). Numerous other methods corroborate NMJ impairment following disuse, and this may be applicable only to higher-threshold motor units. The dashed arrow indicates the theoretical and simplified relationship between motor unit recruitment and muscle force generation.

Abstract figure legend This diagram summarises the many dimensions of fatigue, its behavioural presentation, the multiple models that have attempted to explain fatigue, the winning model of sensory attenuation model, which provides a basis for identifying phenotypes of fatigue along with the need for tailoring treatment to the presenting symptom.

Abstract figure legend Experience-dependent variations in patterns of post-stroke neural reorganization. M1, primary motor cortex.

Abstract figure legend The large-pore calcium homeostasis modulators (CALHMs) have diverse functions, structures and biological roles. CALHM1, the heteromeric CALHM1/3 and possibly CALHM2 facilitate ATP and ion conductance. Both CALHM1 and CALHM2 have critical roles in neuromodulation, neuroinflammation, and learning and memory, while CALHM1 and CALHM1/3 are involved in taste perception. Recent evidence also suggests a role for CALHM6 in innate immunity.

Abstract figure legend The generation and release of extracellular vesicles (EVs) are influenced by the cell source and by differences in the age, sex, ethnicity, health and weight of donors. These factors, along with the protocols used, result in varied physiological effects owing to differences in biological actions, cargo content, quantity and the receptivity and effectiveness of target tissues.

Abstract figure legend Muscle unloading induces declines in muscle function, particularly in maximal and explosive strength. The decline in explosive strength (quantified as rate of force development, RFD) is greater than the decline in maximal strength (quantified as maximal force, F_max). This selective decline of explosive strength is the result of the interplay of neural, muscular, and tendinous adaptations with muscle disuse, which are hereby presented.

Abstract figure legend Loss of plakophilin2 (PKP2) in the mouse atrium leads to impaired cell–cell contact and extensive fibrotic remodelling (middle). PKP2-deficient atrial cardiomyocytes exhibit enhanced sarcomere shortening and impaired relaxation, potentially related to reduced abundance of myosin binding protein C (left). In addition, PKP2-deficient atrial cardiomyocytes present increased spontaneous sarcoplasmic reticulum (SR) calcium (Ca²⁺) release events, further enhanced by isoproterenol exposure and reversible by a ryanodine receptor (RyR) blocker (dantrolene). SR Ca²⁺ leak is probably caused by elevated levels of oxidative stress (ROS) in the mitochondria (right).

Abstract figure legend Basket cells represent critical building blocks of neuronal circuits in cortical regions by providing GABAergic innervation to the perisomatic region of their postsynaptic partners. In the mouse prelimbic cortex, the two basket cell types expressing parvalbumin or cholecystokinin/type I cannabinoid receptor receive unitary excitatory postsynaptic currents from local principal neurons with contrasting amplitude and latency. Basket cells also give rise to unitary inhibitory postsynaptic currents on principal cells that differ in terms of their reliability, latency and short-term plasticity. Moreover, the two basket cell types innervate each other in this cortical area. These fundamental features of the synaptic communication within the microcircuitry composed of pyramidal cells and two types of basket cells in the prelimbic cortex are critical for local information processing underlying complex network operation.

Abstract figure legend Twenty-seven pre-menopausal, untrained females performed a 12-week resistance training programme to explore the association between androgen concentrations, androgen receptor signalling and skeletal muscle size and strength. Total testosterone was not associated with muscle mass or strength, nor with resistance training-induced muscle hypertrophy or strength gains. Bioavailable testosterone and nuclear-localised androgen receptor (AR) were associated with muscle size and strength. In vitro, supra-physiological doses of testosterone increased muscle cell size, but not via the Akt/mTOR pathway. Instead, testosterone significantly increased AR protein content and nuclear localisation. Figure created with biorender.com.

Abstract figure legend This study introduces a pioneering approach to assess cardio-muscular network interactions by examining the synchronization of cardiac function with muscle activity during exercise and fatigue. Participants performed two sets of bodyweight squats until exhaustion, with a 5 min rest period between sets. During the protocol, electrocardiogram (EKG) signals were recorded alongside electromyography (EMG) signals from the left and right vastus lateralis (Leg Left, Leg Right) and erector spinae (Back Left, Back Right) muscles. We decomposed EMG signals into 10 frequency bands (F1–F10) and then cross-correlated these bands with heart rate derived from the EKG. We uncover the first profiles of cardio-muscular interactions characterized by specific hierarchical organization of link strength. We observed a significant decline in the degree of cardio-muscular coupling with fatigue (∼65%), marked by complex transitions from synchronous to asynchronous behaviour.

Abstract figure legend An integrated model of human ventricular myocyte with excitation-contraction-energetics coupling was created to systematically analyse the contribution of Ca²⁺ regulation of mitochondrial enzymes to cardiomyocyte functions during workload transition; i.e. exercise. During exercise, the mitochondria-sarcoplasmic reticulum Ca²⁺ interaction, via uneven distributions of the mitochondrial Ca²⁺ uniporter protein MCU, Na⁺-Ca²⁺ exchanger protein NCLX, sarcoplasmic reticulum ryanodine receptor RyR and Ca²⁺ pump SERCA, optimizes the homeostasis of NADH, a key intermediate connecting mitochondrial metabolism and oxidative phosphorylation.

Abstract figure legend During development, Intersectin-1 (Itsn1) translocates near voltage-gated calcium channels (VGCCs) to enhance Ca²⁺-dependent replenishment of readily releasable synaptic vesicles (SVs). In the presynaptic terminal, SVs undergo a cycle involving formation (step 1), docking (step 2), exocytosis (step 3), endocytosis (step 4) and refilling (step 5) to sustain transmitter release. The developmental repositioning of Itsn1 (purple) to the vicinity of VGCCs, forming a Ca²⁺ domain (pink), potentially facilitates recovery from exocytosis and thereby supports faithful synaptic transmission during repetitive activity.

Abstract figure legend Computational approaches to understanding permeation of molecules through wide pores. [< bold] The figure depicts several types of wide pore channels embedded in a plasma membrane (left to right: CAHLM, connexin, pannexin). Structures of several molecules known to permeate various types of wide pores are shown. A general equation in Molecular dynamics (MD) is F(x) = −∇U(x), in which U(x) is the potential energy as a function of atom positions, and F(x) is the force acting on each atom computed from the negative gradient of the potential energy. The plot below depicts an example of the free energy profile of a molecular permeant at each position within a pore. The free energy computed from MD simulation includes components arising from the flexibility and anisotropic nature of a permeating molecule, coupled with the dynamics and interactions with pore-lining residues.

Abstract figure legend Sensory hair cells of the inner ear and lateral-line system exhibit strong synaptic-vesicle enrichment at the presynapse, around specialized structures called ribbons. We find that hair cells in the zebrafish lateral-line system rely on the kinesin motor protein Kif1a and microtubules to enrich synaptic vesicles at presynaptic ribbons. Light and electron microscopy reveal that kif1aa mutants have fewer synapses and fail to properly enrich synaptic vesicles at the ribbons. Functional assessments show that kif1aa mutants have reduced spontaneous spikes at the afferent cell body and smaller evoked calcium responses at the afferent terminals compared with controls. These synaptic deficiencies significantly impact the zebrafish's ability to rheotax, a behaviour that requires the lateral-line system to orient against water flow. While wild-type zebrafish maintain their position in flow, kif1aa mutants are unable to sustain this behaviour.

Abstract figure legend Synaptic vesicle proteins are axonally transported in precursor vesicles (PVs) before conversion into mature synaptic vesicles (SVs) that are reformed by local recycling at synapses.

Abstract figure legend The synaptic vesicle cluster acts as a master regulator of synaptic structure and function, through various involvements in processes that range from synaptic initiation to plasticity and synaptic loss.

Abstract figure legend Depicted is the ubiquitin ligase network that positively (arrows) and negatively (bars) affects different processes that influence presynaptic development and function.

Abstract figure legend Afferent signalling pathways of the autonomic nervous system and their efferent targets in the heart, kidneys and vasculature.

Abstract figure legend The activity of single neurones was isolated from microneurographic recordings of the human cervical vagus nerve. The firing of these neurones was then cross-correlated with the heartbeat to identify neurones that fire with a cardiac rhythm. Such neurones are of interest because the presence of cardiac rhythmicity implicates them as having a cardiovascular function. A fluctuation in firing frequency that occurred with a similar frequency to that of the cardiac rhythm was taken as evidence of cardiac rhythmicity. Once identified as cardiac rhythmic, further functional classification of these neurones was attempted based on the temporal relationship between the peak in their firing frequency and the cardiac or respiratory cycles.

Abstract figure legend Synaptic cellular adhesion molecules are surface transmembrane receptors that have been shown to internalize via endocytosis, and possibly also recycle, in a process that has been linked to the function and the turnover of the synaptic contact site.

Abstract figure legend Cells and conductances contributing to spontaneous activity in the lower urinary tract. Bladder and urethra exhibit spontaneous contractions at both cellular and tissue levels. Both detrusor and urethral smooth muscle cells display activity that is regular and rhythmic. Distinct populations of interstitial cells exist in muscle layers of both organs, with platelet derived growth factor receptor-α⁺ cells present in detrusor, and Kit⁺ cells (interstitial cell of Cajal-like cells) in urethra. These cells may influence activity of detrusor and urethral smooth muscle, respectively. Detrusor and urethral smooth muscle cells rely on varying complements of ion channels to regulate spontaneous activity. In bladder, small and large conductance potassium channels (SK3/BK) and voltage-dependent calcium channels (Cav1.2) are consistently found to be important. In urethra, there is disparity among species and investigators as to the importance of Cav1.2, calcium activated chloride (Ano1) channels and Orai calcium channels. This review summarizes the current thoughts of the field on these similarities and discrepancies.

Abstract figure legend Spontaneous firing of action potentials in pacemaking neurons (here illustrated by spontaneous firing at 65 Hz in a dissociated mouse cerebellar Purkinje neuron studied at 37°C) is often driven by a subthreshold ‘persistent’ sodium current from voltage-dependent sodium channels (here shown from a voltage clamp recording in the same Purkinje neuron, with steady-state tetrodoxin-sensitive current evoked by a slow, 10 mV s^–1, voltage ramp from −98 to −48 mV). Green segments show the voltage range between −80 and −70 mV, illustrating presence of increasing persistent sodium current during the spontaneous depolarization in the interspike interval. Experiment by Brett Carter.

Abstract figure legend K_V4 channel availability regulates inferior olive action potential duration. The durations of action potentials in inferior olive neurons (blue) depend strongly on preceding membrane potential, with afterdepolarizations varying over the physiological range by almost two orders of magnitude (open circles). Voltage clamp recordings reveal large, inactivating K_V4 channel potassium currents (red), with a steep availability curve (closed circles), which accounts for the graded voltage-dependent changes in action potential waveforms.