Journal of Physiology-London最新文献

Regenerative rehabilitation is an emerging interdisciplinary field that combines regenerative medicine principles with rehabilitation science to improve recovery in musculoskeletal trauma cases such as volumetric muscle loss (VML). This article reviews preclinical and clinical studies, aiming to bridge the gap between these domains, summarize recent advancements and identify areas for further exploration. The review delves into preclinical studies, which explore the potential of regenerative approaches, including cellular and acellular scaffolds, to augment exercise-based rehabilitation. These studies demonstrate that regenerative rehabilitation can aid in functional recovery post-VML through various mechanisms such as modulation of fibrosis, angiogenesis, myogenesis and innervation. However, the approach in clinical studies differs significantly, involving diverse exercise therapy regimens both before and after surgical interventions. To date, only acellular extracellular matrix scaffolds have been combined with physical therapy in VML-injured patients, resulting in modest improvements in functional recovery. The field of regenerative rehabilitation is nascent but has seen noteworthy progress, with ample room for improvement. This article also highlights the need for closer collaboration between researchers in the fields of tissue engineering, orthopaedic surgery and physical therapy to improve recovery outcomes following traumatic muscle injuries.

Homeostatic and Hebbian plasticity co-operate during the critical period, refining neuronal circuits; however, the interaction between these two forms of plasticity is still unclear, especially in adulthood. Here, we directly investigate this issue in adult humans using two consolidated paradigms to elicit each form of plasticity in the visual cortex: the long-term potentiation-like change of the visual evoked potential (VEP) induced by high-frequency stimulation (HFS) and the shift of ocular dominance induced by short-term monocular deprivation (MD). We tested homeostatic and Hebbian plasticity independently, then explored how they interacted by inducing them simultaneously in a group of adult healthy volunteers. We successfully induced both forms of plasticity: 60 min of MD induced a reliable change in ocular dominance and HFS reliably modulated the amplitude of the P1 component of the VEP. Importantly, we found that, across participants, homeostatic and Hebbian plasticity were negatively correlated, indicating related neural mechanisms, potentially linked to intracortical excitation/inhibition balance. On the other hand, we did not find an interaction when the two forms of plasticity were induced simultaneously. Our results indicate a largely preserved plastic potential in the visual cortex of the adult brain, for both short-term homeostatic and Hebbian plasticity. Crucially, we show for the first time a direct relationship between these two forms of plasticity in the adult human visual cortex, which could inform future research and treatment protocols for neurological diseases. KEY POINTS: Homeostatic and Hebbian plasticity co-operate during the critical period to refine neuronal circuits in the visual cortex. The interaction between these two forms of plasticity is still unknown, especially after the closure of the critical periods and in humans. We directly investigate the interplay between Hebbian and homeostatic visual plasticity in adult humans using non-invasive paradigms. We found a negative correlation between these forms of plasticity showing for the first time a direct relationship between Hebbian and homeostatic plasticity. Our results could inform future research and treatment protocols for neurological diseases.

Upper respiratory tract infection (URTI) has a significant economic and social impact and is a major factor compromising athletes' training and competition. The effects of ColdZyme® Mouth Spray on URTI were investigated using an in vivo study in athletes, combined with a novel in vitro air-liquid interface human airway model. Endurance athletes were randomised to ColdZyme (n = 78) or placebo (n = 76) and monitored over 3 months. They completed daily symptom and training logs and collected throat swabs over 7 days during perceived URTI. In vitro studies examined rhinovirus infectivity and epithelial barrier integrity of airway epithelial cells. Eighty-two in vivo episodes were analysed with significantly lower (P = 0.012) episode duration in the ColdZyme vs. Placebo group (mean ± SD, 6.2 ± 2.6, (median [interquartile range]) 5.5 [4-9] days vs. 10.7 ± 10.2, 7.0 [5-11]). There was no difference in incidence (P = 0.149). Training absence and symptom ratings were lower (P < 0.05) in the ColdZyme group. Swabs were returned for 50 episodes, with at least one pathogen detected in all (rhinovirus was most abundant). Absolute quantification (qPCR) for rhinovirus revealed a significantly lower 7-day area under the curve in ColdZyme vs. placebo (median reduction, 94%, P = 0.029). In vitro, viral load was significantly lower (median reductions 80-100%), and epithelial barrier integrity better maintained, and no virus was detected by immunofluorescence analyses of pseudostratified epithelia, with ColdZyme treatment (all P < 0.05). ColdZyme is beneficial for reducing URTI duration, symptom ratings and missed training days. These novel data suggest that the mechanisms involve the protection of epithelial cells against rhinovirus infection and damage. KEY POINTS: Upper respiratory tract infections (URTI) are a common complaint in the general population and athletes alike, with social, well-being and economic consequences, including performance detriments in athletes and reduced work productivity in the general population. Strategies to minimise the risk of contracting a URTI and/or reduce the time taken to clear an infection are desirable to athletes and the general population alike. The present study employed an in vivo study with athletes in combination with a novel in vitro human airway cell model to examine the effects of ColdZyme Mouth Spray on URTI and viral infectivity. The duration for which URTI symptoms persisted was lower with ColdZyme treatment, which also resulted in fewer training absence days. Swabs from participants in the in vivo study and supernatants from the in vitro studies showed lower rhinovirus viral load with ColdZyme treatment compared with placebo or control.

Astrocytes, the most abundant glial cells in the brain, are wired into neural circuits through close contact with neuronal pre- and post-synapses, called tripartite synapses. The mutual communication between neurons and astrocytes is crucial for neural circuit dynamics and animal behaviour. Recent advancements in imaging, manipulation and transcriptomics in astrocytes have revealed that astrocytes exhibit spatiotemporally complex computations and represent circuit-specialised functions and molecular makeups. However, understanding the neuron-astrocyte circuitry by means of conventional anatomical methods is hindered due to technical limitations. In this review, we highlight recently developed optical, genetic and viral techniques that enable high-throughput identification of connected neuron-astrocyte pairs with circuit and genetic specificity. These approaches will accelerate anatomical and functional dissections of the neuron-astrocyte circuits in health and disease in future studies.

Regular activation of the heart originates from cyclic spontaneous depolarisations of sinoatrial node cells (SANCs). Variations in electrolyte levels, commonly observed in haemodialysis (HD) patients, and the autonomic nervous system (ANS) profoundly affect the SANC function. Thus we investigated the effects of hypocalcaemia and sympathetic stimulation on the SANC beating rate (BR). The β-adrenergic receptor (β-AR) signalling cascade, as described by Behar et al., was incorporated into the SANC models of Severi et al. (rabbit) and Fabbri et al. (human). Simulations were conducted across various extracellular calcium ([Ca²⁺]_o) (0.6-1.8 mM) and isoprenaline concentrations [ISO] (0-1000 nM) for a sufficient period of time to allow transient oscillations to equilibrate and reach a limit cycle. The β-AR cell response of the extended models was validated against new Langendorff-perfused rabbit heart experiments and literature data. The extended models revealed that decreased [Ca²⁺]_o necessitated an exponential-like increase in [ISO] to restore the basal BR. Specifically at 1.2 mM [Ca²⁺]_o, the Severi and Fabbri models required 28.0 and 9.6 nM [ISO], respectively, to restore the initial BR. Further reduction in [Ca²⁺]_o to 0.6 mM required 170.0 and 43.6 nM [ISO] to compensate for hypocalcaemia. A sudden loss of sympathetic tone at low [Ca²⁺]_o resulted in a loss of automaticity within seconds. These findings suggest that hypocalcaemic bradycardia can be compensated for by an elevated sympathetic tone. The integration of the β-AR pathways led to a logarithmic BR increase and offers insights into potential pathomechanisms underlying sudden cardiac death (SCD) in HD patients. KEY POINTS: We extended the sinoatrial node cell (SANC) models of Severi et al. (rabbit) and Fabbri et al. (human) using the β-adrenergic receptor (β-AR) signalling cascade Behar et al. described. Simulations were conducted across various extracellular calcium ([Ca²⁺]_o) (0.6-1.8 mM) and isoprenaline concentrations [ISO] (0-1000 nM) to reflect conditions in haemodialysis (HD) patients. An exponential-like increase in [ISO] compensated for hypocalcaemia-induced bradycardia in both models, whereas interspecies differences increased the sensitivity of the extended Fabbri model towards hypocalcaemia and increased sympathetic tone. The extended models may help to further understand the pathomechanisms of several cardiovascular diseases affecting pacemaking, such as the high occurrence of sudden cardiac death (SCD) in chronic kidney disease (CKD) patients.

MicroRNAs (miRNAs) are regulators of mRNA translation and play crucial roles in various physiological and pathological processes. In this study, we profiled miRNAs in umbilical cord plasma (UCP) to explore the association of neonatal circulating miRNAs with maternal metabolic parameters and neonatal anthropometric, metabolic and inflammatory characteristics in healthy pregnancies. Data and UCP samples were collected from 16 pregnancies, equally divided between normal-weight and overweight mothers and between male and female newborns. Using next-generation sequencing, we identified and quantified miRNAs in UCP, alongside the analysis of metabolic and inflammatory parameters. Our results revealed that the majority of UCP miRNAs are sensitive to maternal and neonatal characteristics, particularly maternal body mass index, gestational weight gain, placental weight, UCP leptin, UCP C-reactive protein and UCP insulin levels. Notably, we identified a strong association between the placenta-derived chromosome 19 microRNA cluster (C19MC) and placental weight, gestational weight gain, UCP insulin and neonatal weight. Likewise, the pregnancy-specific chromosome 14 microRNA cluster (C14MC) was associated with maternal body mass index and UCP leptin. Our study highlights the sensitivity of UCP miRNAs to maternal metabolic conditions, demonstrates their association with neonatal metabolic and inflammatory traits, and underscores the potential role of circulating cord blood miRNAs in fetal metabolism and development. KEY POINTS: MicroRNAs (miRNAs) are regulatory RNA molecules that modulate protein expression. They are present in all body fluids and umbilical cord plasma and are affected by metabolic changes. Pregnancy is a state of metabolic change in the mother, and maternal metabolism affects fetal development. We found that the composition of umbilical cord blood miRNAs is associated with maternal and neonatal metabolism. Pregnancy-specific groups of miRNAs showed particular patterns, with miRNAs encoded by a region of chromosome 14 associated with maternal body mass index and with miRNAs encoded by a specific region of chromosome 19 associated with umbilical cord plasma insulin. MicroRNAs represent a separate dimension through which maternal metabolism can influence fetal development.

First described in native cardiac pacemaker cells, the 'funny' (I_f) current provided a novel mechanism able to underlie rhythmic activity and autonomic control of heart rate. Increasing the impact of this finding, the new mechanism replaced a previous pacemaking model based on a 'fake' K⁺ current (I_K2), shown in fact to be a 'camouflaged' I_f; also, a similar current in neurons (I_h) was found to regulate neuronal excitability. I_f, the first described inward current activated on hyperpolarization, had several other peculiar features, when investigated in sinoatrial node tissue and isolated cells. It had a mixed Na⁺/K⁺ permeability, had the lowest patch clamp recorded single-channel conductance, and was dually activated by voltage and intracellular cyclic nucleotides. I_f activation by internal cAMP, a property key to autonomic modulation of heart rate, was shown to involve direct cAMP binding to channels. Finally, an I_f blocking drug, ivabradine, was found to be suitable for the pharmacological control of heart rate in therapies against angina and heart failure. Later cloning of HCN channels, comprising the subunit components of funny channels, allowed molecular insight into the properties of I_f, carried by HCN4. Recently, cryogenic electron microscopy has resolved details of the HCN4 structure with unprecedented precision, providing a way to validate or refute, on a structural basis, original interpretation/modelling of experimental data. This review aims to compare elementary functional properties of I_f vs. HCN4 protein structure. Does structure 'mirror' function? We show that the peculiar I_f characteristics originally described are elegantly explained and 'mirrored' by structural features of the channel protein.