Journal of Physiology-London最新文献

{"title":"Sympathetic stimulation can compensate for hypocalcaemia-induced bradycardia in human and rabbit sinoatrial node cells.","authors":"Moritz Linder, Tomas Stary, Gergő Bitay, Norbert Nagy, Axel Loewe","doi":"10.1113/JP287557","DOIUrl":"https://doi.org/10.1113/JP287557","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA profiling in umbilical cord plasma: links to maternal metabolism and neonatal metabolic and inflammatory traits","authors":"Jasmin Zaunschirm-Strutz,&nbsp;Anna Rieder,&nbsp;Carolina Tocantins,&nbsp;Mariana S. Diniz,&nbsp;Elisa Weiss,&nbsp;Ursula Hiden","doi":"10.1113/JP287672","DOIUrl":"10.1113/JP287672","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;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.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;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.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Pregnancy is a state of metabolic change in the mother, and maternal metabolism affects fetal development.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;We found that the composition of umbilical cord blood miRNAs is associated with maternal and neonatal metabolism.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;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.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;MicroRNAs represent a separate dimension through which maternal metabolism ca","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 6","pages":"1663-1680"},"PeriodicalIF":4.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287672","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure mirroring function: What's the 'matter' with the funny current?","authors":"Andrea Saponaro, Dario DiFrancesco","doi":"10.1113/JP287209","DOIUrl":"https://doi.org/10.1113/JP287209","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply from R. G. Carson","authors":"Richard G. Carson","doi":"10.1113/JP288210","DOIUrl":"10.1113/JP288210","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 5","pages":"1331-1333"},"PeriodicalIF":4.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143505813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-definition transcranial direct-current stimulation of left primary motor cortices modulates beta and gamma oscillations serving motor control","authors":"Peihan J. Huang,&nbsp;Yasra Arif,&nbsp;Maggie P. Rempe,&nbsp;Jake J. Son,&nbsp;Jason A. John,&nbsp;Kellen M. McDonald,&nbsp;Nathan M. Petro,&nbsp;Grant M. Garrison,&nbsp;Hannah J. Okelberry,&nbsp;Kennedy A. Kress,&nbsp;Giorgia Picci,&nbsp;Tony W. Wilson","doi":"10.1113/JP287085","DOIUrl":"10.1113/JP287085","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Recent studies have linked non-invasive transcranial direct-current stimulation (tDCS) with altered neural processing near the site of stimulation and across a distributed network of brain regions, with some evidence for a possible therapeutic role. However, negative results also exist and the potential impacts on motor-related neural oscillations have rarely been studied. Herein, we applied high-definition tDCS to the left primary motor cortex of 62 healthy adults in three sessions (anodal, cathodal and sham). Participants then performed a motor task with two conditions (i.e. cognitive interference and no interference) during magnetoencephalography (MEG). The MEG data were imaged in the time–frequency domain and whole-brain, voxel-wise maps were probed for task condition and stimulation effects. Our results indicated the classic pattern of slower behavioural responses and stronger neural oscillations in frontal and parietal cortices during interference relative to no-interference trials. Importantly, we found task condition-by-stimulation interactions involving motor-related gamma oscillations, with weaker interference effects after cathodal stimulation relative to anodal and sham in the right prefrontal, left temporoparietal junction and left cerebellar cortices. Conversely, stronger gamma interference responses were found in the right motor and superior parietal cortices following anodal relative to cathodal and sham. Lastly, main effects of stimulation indicated stronger beta oscillations following anodal stimulation in the left supplementary motor area. Taken together, these data provide key mechanistic insight into the polarity-specific effects of tDCS on the neural oscillatory dynamics serving motor control. Such findings reflect the modulatory effects of tDCS on population-level neural oscillatory responses distant from the stimulation site.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Neurophysiological studies have indicated that beta and gamma oscillations are critical to motor control and that their dynamics are modulated by higher-order features of the task.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Recent investigations have shown that transcranial direct-current stimulation (tDCS) affects neural activity both locally and in brain regions distant from the stimulation site, but the mechanisms remain poorly understood.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Sixty-two adults underwent anodal, cathodal and sham high-definition tDCS of the left motor cortices and completed a motor task with two levels of cognitive interfer","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 6","pages":"1627-1644"},"PeriodicalIF":4.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143505810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute exogenous oestradiol augments endothelial and smooth muscle vasodilatory responsiveness in premenopausal but not postmenopausal females.","authors":"Gabrielle A Dillon, Ronée E Harvey, Jacqueline K Limberg, Wayne T Nicholson, Michael J Joyner, Sarah E Baker, Virginia M Miller, Sushant M Ranadive","doi":"10.1113/JP287719","DOIUrl":"https://doi.org/10.1113/JP287719","url":null,"abstract":"<p><p>Menopause is associated with vascular dysfunction. During the menopausal transition, endogenous oestradiol concentrations diminish. Oestradiol is vasoprotective because it has direct and indirect effects on the vasculature. The present study aimed to determine the effect of acute exogenous oestradiol on endothelium-dependent, endothelium independent and β₂-adrenergic receptor-induced vasodilatation in females. Forearm blood flow (venous occlusion plethysmography) was measured during brachial intraarterial infusions of ACh (endothelium-dependent agonist), sodium nitroprusside (endothelium independent agonist) and terbutaline (β₂-adrenergic receptor agonist) with and without concurrent infusion of 17β-oestradiol. Nine young premenopausal (age: 26 ± 4 years) and nine postmenopausal (PM, age: 58 ± 4 years, 8 ± 1 years post-menopause) females completed the study. Concurrent oestradiol infusion augmented the vasodilatory response to ACh, sodium nitroprusside and terbutaline in young premenopausal (all P < 0.05) but not older postmenopausal (all P > 0.05), females. Local infusion of exogenous 17β-oestradiol augmented endothelial and smooth muscle microvascular vasodilatation in premenopausal but not postmenopausal, females. KEY POINTS: Menopause is associated with vascular dysfunction. Because oestradiol has vasoprotective effects, the menopause-associated drop in oestradiol concentrations is hypothesized to contribute to vascular dysfunction during the menopause transition. The present study shows that local infusion of exogenous oestradiol augmented microvascular vasodilatation in premenopausal but not postmenopausal females.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary nitrate supplementation mitigates age-related changes at the neuromuscular junction in mice.","authors":"Maira Rossi, Lucrezia Zuccarelli, Lorenza Brocca, Cristiana Sazzi, Clarissa Gissi, Paola Rossi, Bruno Grassi, Simone Porcelli, Roberto Bottinelli, Maria Antonietta Pellegrino","doi":"10.1113/JP287592","DOIUrl":"https://doi.org/10.1113/JP287592","url":null,"abstract":"<p><p>In ageing, denervation and neuromuscular junction (NMJ) instability occur alongside mitochondrial alterations and redox unbalance, potentially playing a significant role in the process. Moreover, the synthetic pathway was shown to be critical for proper innervation and NMJ stability. Nitric oxide (NO) modulates redox status, mitochondrial function and the synthetic pathway. Its bioavailability declines with age. We hypothesize that nitrate supplementation could counteract age-related neuromuscular alterations. We compared young (Y) (7 months old), old (O) (24 months old) and old mice supplemented daily with 1.5 mm inorganic NaNO₃ dissolved in drinking water for 8 weeks (ON) (24 months old). Compared to Y, O mice displayed impaired NO signalling and transport (lower phosphorylated-neuronal NO synthase and sialin content); greater nitrosative and oxidative stress (higher 3-nitrotyrosine levels and protein carbonylation); lower glutathione peroxidase (GPX antioxidant enzyme); smaller muscle fibres; and larger muscle fibrosis. NMJ integrity was impaired, exhibiting age-related alterations such as larger fragmentation, lower overlap, larger endplate areas and lower compactness. Consistently, greater expression of denervation-associated markers (Gadd45α, MyoG, RUNX1, AChRγ and NCAM1) and higher NCAM1+ fibres percentage suggested denervation. Importantly, mitochondrial content, dynamics and function were unchanged. Compared to O, ON mice showed improved NO bioavailability in muscle (higher nitrate-nitrite concentration); lower fibrosis and improved muscle fibre size; higher phosphorylation of P70S6K and S6, downstream factors of Akt/mammalian target of rapamycin synthetic pathway; lower oxidative stress (lower carbonylated proteins and mitochondrial hydrogen peroxide production, higher GPX protein levels); reverted age-related alterations of NMJ morphology; and lower percentage of NCAM1+ fibres. Nitrate supplementation could be a therapeutic strategy to counteract muscle decline with ageing. KEY POINTS: Ageing leads to instability at the neuromuscular junction (NMJ), which is crucial for muscle size and function, ultimately giving rise to denervation and muscle fibres loss. Mitochondrial function, redox status and activation of synthetic pathway are critical processes for proper muscle innervation and stability of the NMJ. Nitric oxide was shown to modulate intracellular processes involved in NMJ stability such as balance of reactive oxygen species, mitochondrial function and protein synthesis. Its bioavailability decreases with ageing. Our study shows that nitrate supplementation in old mice improved redox balance, enhanced the anabolic pathway and stabilized nerve-muscle interactions, suggesting a potential strategy to mitigate the neuromuscular decline associated with ageing.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sympathetic neurons can modify the intrinsic structural and functional properties of human pluripotent stem cell-derived cardiomyocytes","authors":"Neda Mohammadi,&nbsp;Laura Fedele,&nbsp;Poornaa Chakravarthy,&nbsp;Vlad Leonov,&nbsp;Lorenza Tsansizi,&nbsp;Hui Gu,&nbsp;Sama Seyedmousavi,&nbsp;Marie-Victoire Cosson,&nbsp;Andreia S. Bernardo,&nbsp;Julia Gorelik,&nbsp;Jose L. Sanchez-Alonso","doi":"10.1113/JP287569","DOIUrl":"10.1113/JP287569","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;The sympathetic nervous system densely innervates all cardiac chambers and is a key player in cardiac control, yet this relationship has scarcely been investigated using a stem cell-based model. This study investigates the effects that sympathetic neurons (SNs) have on human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) &lt;i&gt;in vitro&lt;/i&gt;, and whether they induce any degree of functional or structural maturity in these conventionally immature cells. SNs were isolated from neonatal rat pups, and cocultured with hPSC-CMs for up to 15 days. Structural changes in hPSC-CMs were analysed by microscopy techniques. Fluorescence resonance energy transfer was used to measure second messenger molecule cAMP production and β-adrenergic receptor (βAR) response. Contractile and Ca&lt;sup&gt;2+&lt;/sup&gt; transient activity was measured using CytoCypher. These cocultures promoted hPSC-CM structural elongation and increased sarcomere organization. Furthermore, the βAR response of cocultured hiPSC-CMs was larger, indicated by increased cAMP production upon neuronal nicotinic stimulation. Faster contraction and ratiometric Ca&lt;sup&gt;2+&lt;/sup&gt; transient peak height and kinetic parameters strongly indicate increased chronotropic response in coculture. Coculture with SNs also elicited an increase in action potential amplitude and depolarization velocity, further confirming that SNs contribute to hiPSC-CM functional maturation. Overall, we have found that SNs modulate hPSC-CMs &lt;i&gt;in vitro&lt;/i&gt;, inducing a more mature functional response. As an &lt;i&gt;in vitro&lt;/i&gt; tool, these cocultures could serve as a model of sympathoadrenergic disease, enabling new discovery avenues.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;The sympathetic nervous system controls the involuntary ‘fight-or-flight’ response, with the heart being one of key target organs.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;In certain neuro-cardiac diseases, the input from the sympathetic nervous system is hyperregulated, and can lead to increased speed or force of the heart's contraction.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Human induced pluripotent stem cells (hiPSCs) represent a rapidly evolving field which allow us to create a cell of interest and model its structural and functional activity in a dish. Here we have created hiPSC-derived cardiomyocytes (hiPSC-CMs) and cocultured them with sympathetic neurons (SNs).&lt;/li&gt;\u0000 \u0000 &lt;li&gt;We found that SNs are able to modulate structure of the hiPSC-","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 7","pages":"2089-2118"},"PeriodicalIF":4.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287569","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Memoriam: Gary Mawe","authors":"David Linden,&nbsp;Brigitte Lavoie","doi":"10.1113/JP287402","DOIUrl":"10.1113/JP287402","url":null,"abstract":"&lt;p&gt;&lt;/p&gt;&lt;p&gt;Dr Gary M. Mawe&lt;/p&gt;&lt;p&gt;Professor of Neurological Sciences&lt;/p&gt;&lt;p&gt;University of Vermont&lt;/p&gt;&lt;p&gt;1956–2024&lt;/p&gt;&lt;p&gt;On 17 February 2024, the field of enteric neuroscience lost a highly respected colleague, mentor and friend. Dr. Gary M. Mawe, PhD, Professor of Neurological Sciences at the University of Vermont Larner College of Medicine, passed away peacefully after a long illness.&lt;/p&gt;&lt;p&gt;Gary was an internationally renowned neurobiologist who devoted his career to the study of the gastrointestinal (GI) system. His unquenchable curiosity and enthusiasm for both science and life led him to pursue numerous interests and passions. His pioneering studies of the neural mechanisms regulating gallbladder motor function, enteroendocrine serotonin signalling in health and disease, and inflammatory neuroplasticity of the enteric nervous system were recognized and praised by the scientific community.&lt;/p&gt;&lt;p&gt;Gary's work was continuously funded by the National Institutes of Health (NIH) for his entire research career. Over his distinguished career, he published more than 130 peer-reviewed primary scientific articles and coauthored more than 14 review articles and chapters, including those published in &lt;i&gt;Nature Reviews Gastroenterology &amp; Hepatology&lt;/i&gt; (Mawe &amp; Hoffman, &lt;span&gt;2013&lt;/span&gt;; Spohn &amp; Mawe, &lt;span&gt;2017&lt;/span&gt;) and &lt;i&gt;Journal of Clinical Investigation&lt;/i&gt; (Mawe, &lt;span&gt;2015&lt;/span&gt;), that have become central references in understanding gastrointestinal autonomic biology. The comprehensive review of the enteric nervous system (Sharkey &amp; Mawe, &lt;span&gt;2023&lt;/span&gt;) written with his collaborator of over 20 years, Dr. Keith Sharkey, will certainly stand as his Magnum Opus. This project started in the Fall of 2019 when Keith was on sabbatical leave in Vermont. Although Gary was unwell at the time of writing this article, his fascination in the field remained as strong then as it ever was, and he enjoyed the hours of discussion it generated. Gary was extremely proud of his publications and worked very hard to ensure impactful comprehensive work. This virtual issue of &lt;i&gt;The Journal of Physiology&lt;/i&gt; compiles all of the published work. Gary aimed for his primary research to be submitted and published in &lt;i&gt;The Journal of Physiology&lt;/i&gt; and each of these manuscripts beautifully illustrates his lasting impact on the field of gastrointestinal physiology.&lt;/p&gt;&lt;p&gt;Gary received numerous awards recognizing his contribution to the field, including the Janssen Award for Basic Research in Gastrointestinal Motility in 1996, the Basmajian/Williams &amp; Wilkins Award of the American Association of Anatomists in 1997 and the University Scholar Award, Graduate College, The University of Vermont in 2003. In 2023, he received the American Neurogastroenterology and Motility Society Dodds-Sarna Award, honouring an investigator who made major contributions to the field of Neurogastroenterology and Motility.&lt;/p&gt;&lt;p&gt;At the time of his death, Gary was the Samuel Thayer P","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 6","pages":"1337-1346"},"PeriodicalIF":4.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287402","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143505811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneous metabolic response of endothelial cells from different vascular beds to experimental hyperglycaemia and metformin.","authors":"C McAleese, G Joudah, I P Salt, J R Petrie, J M Leiper, Laura B Dowsett","doi":"10.1113/JP288006","DOIUrl":"https://doi.org/10.1113/JP288006","url":null,"abstract":"<p><p>Endothelial cells (ECs) are highly glycolytic, with mitochondria primarily serving a signalling function. Metabolic disruptions are early contributors to endothelial dysfunction, a primary feature of diabetic vascular complications, such as retinopathy, impaired wound healing and cerebral small vessel disease. The degree to which metabolism varies amongst such different vascular beds is unknown. Mitochondrial function was therefore characterised in human aortic, dermal, retinal and cerebral ECs in vitro, aiming to determine whether basal metabolism influences the response and susceptibility of vascular beds experimental hyperglycaemia (HG). Furthermore, the potential of metformin to maintain endothelial function independent of glycaemic control was assessed. Using a Seahorse analyser, metabolic function of human primary ECs from different vascular beds was compared under basal conditions, as well as HG and metformin treatment. ECs differed significantly in respiratory profile and glycolytic function. For example aortic ECs were preferentially aerobic, whereas dermal ECs were glycolytic. HG significantly lowered mitochondrial network area but elicited modest effects upon respiratory function at the same time as influencing glycolytic function in a manner that was possibly conditional upon basal utilisation. Metformin inhibited basal respiratory function at the same time as significantly enhancing glycolysis in retinal and brain ECs. These data suggest that EC responses to HG and metformin are influenced by the basal metabolic profile, highlighting the potential of targeting EC metabolism to preserve function in a diabetic condition. A nuanced approach is needed to address diabetic vascular complications and endothelial metabolic health in diabetes, both in the investigation of pathophysiology and in prospective therapeutics. KEY POINTS: Endothelial dysfunction is an early feature of diabetes-associated cardiovascular complications Endothelial cells (ECs) are highly glycolytic, with mitochondria serving a signalling function ECs are known to be heterogeneous in function, but how this is reflected in metabolism is not fully understood, in addition to how this influences their response to hyperglycaemia Using experimental hyperglycaemia (HG) in vitro, we demonstrate that ECs differed significantly in respiratory profile and glycolytic function. Their response to HG is possibly contingent upon this basal utilisation. These results suggest a nuanced approach is needed when investigating diabetic vascular complications, both in the investigation of pathophysiology and in prospective therapeutics.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143494066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}