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Pflugers Archiv European Journal of Physiology
Journal Prestige (SJR): 1.479
Citation Impact (citeScore): 3
Number of Followers: 3  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0031-6768 - ISSN (Online) 1432-2013
Published by Springer-Verlag Homepage  [2658 journals]
  • The role of voltage-gated ion channels in visual function and disease in
           mammalian photoreceptors

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      Abstract: Light activation of the classical light-sensing retinal neurons, the photoreceptors, results in a graded change in membrane potential that ultimately leads to a reduction in neurotransmitter release to the post-synaptic retinal neurons. Photoreceptors show striking powers of adaptation, and for visual processing to function optimally, they must adjust their gain to remain responsive to different levels of ambient light intensity. The presence of a tightly controlled balance of inward and outward currents modulated by several different types of ion channels is what gives photoreceptors their remarkably dynamic operating range. Part of the resetting and modulation of this operating range is controlled by potassium and calcium voltage-gated channels, which are involved in setting the dark resting potential and synapse signal processing, respectively. Their essential contribution to visual processing is further confirmed in patients suffering from cone dystrophy with supernormal rod response (CDSRR) and congenital stationary night blindness type 2 (CSNB2), both conditions that lead to irreversible vision loss. This review will discuss these two types of voltage-gated ion channels present in photoreceptors, focussing on their structure and physiology, and their role in visual processing. It will also discuss the use and benefits of knockout mouse models to further study the function of these channels and what routes to potential treatments could be applied for CDSRR and CSNB2.
      PubDate: 2021-07-13
      DOI: 10.1007/s00424-021-02595-2
       
  • Another route of CO2 gas excretion independent of red blood cells in human
           lungs

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      Abstract: We demonstrated pulmonary arteriolar blood flow-mediated CO2 gas excretion in rabbit lungs. The shear stress stimulation produced CO2 gas in cultured human endothelial cells of pulmonary arterioles via the activation of F1/Fo ATP synthase. To confirm the findings in human subjects undergoing the operation with heart–lung machines, we aimed to evaluate the effects of a stepwise switch, from a partial to a complete cardiopulmonary bypass, of the circulatory blood volume (BV, 100% = 2.4 × cardiac index), on the end-expiratory CO2 pressure (PetCO2), maximal flow velocity in the pulmonary artery (Max Vp), the inner diameter (ID) of pulmonary artery, pulmonary arterial CO2 pressure (P mix v CO2), pulmonary arterial O2 pressure (P mix v O2), hematocrit (Hct), pH, the concentration of HCO3−, and base excess (BE) in mixed venous blood in 9 patients with a mean age of 72.3 ± 3.4 years. In addition, the effects of the decrease in Hct infused with physiological saline solution (PSS) on PetCO2 were investigated in the human subjects. An approximately linear relationship between the PetCO2 and Max Vp was observed. The pumping out of 100% BV produced little or no change in the Hct, pH, P mix v CO2, and P mix v O2, respectively. The hemodilution produced by intravenous infusion of PSS caused a significant decrease in the Hct, but not in the PetCO2. In conclusion, another route of CO2 gas excretion, independent of red blood cells, may be involved in human lungs.
      PubDate: 2021-07-12
      DOI: 10.1007/s00424-021-02586-3
       
  • (H)IF applicable: promotion of neurogenesis by induced HIF-2 signalling
           after ischaemia

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      Abstract: HIF-2 represents a tissue-specific isoform of the hypoxia-inducible factors (HIFs) which regulate oxygen homeostasis in the cell. In acute oxygen deficiency, HIF transcription factors ensure the timely restoration of adequate oxygen supply. Particularly in medical conditions such as stroke, which have a high mortality risk due to ischaemic brain damage, rapid recovery of oxygen supply is of extraordinary importance. Nevertheless, the endogenous mechanisms are often not sufficient to respond to severe hypoxic stress with restoring oxygenation and fail to protect the tissue. Herein, we analysed murine neurospheres without functioning HIF-2α and found that special importance in the differentiation of neurons can be attributed to HIF-2 in the brain. Other processes, such as cell migration and signal transduction of different signalling pathways, appear to be mediated to some extent via HIF-2 and illustrate the function of HIF-2 in brain remodelling. Without hypoxic stress, HIF-2 in the brain presumably focuses on the fine-tuning of the neural network. However, a therapeutically increase of HIF-2 has the potential to regenerate or replace destroyed brain tissue and help minimize the consequences of an ischaemic stroke.
      PubDate: 2021-07-12
      DOI: 10.1007/s00424-021-02600-8
       
  • HIF-2: an important player in neuronal response to ischemia

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      PubDate: 2021-07-10
      DOI: 10.1007/s00424-021-02601-7
       
  • The role of adrenergic and muscarinic receptors in stress-induced cardiac
           injury

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      Abstract: Takotsubo syndrome (TS) is a rare but dangerous disease that can be fatal. The pathogenesis of TS is not well understood because there is no animal model of TS that fully mimics TS. It has now been documented that stress exposure (24 h) of rats induced the state which is similar TS in human: contracture damage of myofibrils, elevation of the serum creatine kinase MB level, increased 99mTc-pyrophosphate (99mTc-PYP) accumulation in the heart, QTc interval prolongation, and contractility dysfunction of the heart. Immobilization stress resulted in an increase in coronary blood flow. Emotional stress increased the serum catecholamine level. Blockade of β1-adrenergic receptor (AR) prevented stress-induced cardiac injury (SICI). Blockade of β2-AR aggravated stress-induced cardiac injury. Stimulation of β2-AR increased cardiac tolerance to stress. Inhibition of β3-AR, α1-AR had no effect on SICI. Blockade of peripheral muscarinic receptors or α2-AR aggravated SICI. Pretreatment with the selective β1-AR antagonist atenolol attenuates stress-induced cardiac contractility dysfunction, but recovery of cardiac contractility is not complete. There is indirect evidence that circulating catecholamines play an important role in SICI. Consequently, the activation of β1-AR plays a significant role in SICI. However, there are other receptors which are also involved in SICI and require further investigation.
      PubDate: 2021-07-10
      DOI: 10.1007/s00424-021-02602-6
       
  • Where vision begins

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      PubDate: 2021-07-10
      DOI: 10.1007/s00424-021-02605-3
       
  • Common and discrete mechanisms underlying chronic pain and itch:
           peripheral and central sensitization

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      Abstract: Normally, an obvious antagonism exists between pain and itch. In normal conditions, painful stimuli suppress itch sensation, whereas pain killers often generate itch. Although pain and itch are mediated by separate pathways under normal conditions, most chemicals are not highly specific to one sensation in chronic pathologic conditions. Notably, in patients with neuropathic pain, histamine primarily induces pain rather than itch, while in patients with atopic dermatitis, bradykinin triggers itch rather than pain. Accordingly, repetitive scratching even enhances itch sensation in chronic itch conditions. Physicians often prescribe pain relievers to patients with chronic itch, suggesting common mechanisms underlying chronic pain and itch, especially peripheral and central sensitization. Rather than separating itch and pain, studies should investigate chronic itch and pain including neuropathic and inflammatory conditions. Here, we reviewed chronic sensitization leading to chronic pain and itch at both peripheral and central levels. Studies investigating the connection between pain and itch facilitate the development of new therapeutics against both chronic dysesthesias based on the underlying pathophysiology.
      PubDate: 2021-07-10
      DOI: 10.1007/s00424-021-02599-y
       
  • “Nomen not est omen”: the (pro)renin receptor and receptor-mediated
           endocytosis in the proximal tubule—a new (pro)renin-independent role
           forATP6ap2

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      PubDate: 2021-07-09
      DOI: 10.1007/s00424-021-02597-0
       
  • Responsiveness of afferent renal nerve units in renovascular hypertension
           in rats

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      Abstract: Previous data suggest that renal afferent nerve activity is increased in hypertension exerting sympathoexcitatory effects. Hence, we wanted to test the hypothesis that in renovascular hypertension, the activity of dorsal root ganglion (DRG) neurons with afferent projections from the kidneys is augmented depending on the degree of intrarenal inflammation. For comparison, a nonhypertensive model of mesangioproliferative nephritis was investigated. Renovascular hypertension (2-kidney, 1-clip [2K1C]) was induced by unilateral clipping of the left renal artery and mesangioproliferative glomerulonephritis (anti-Thy1.1) by IV injection of a 1.75-mg/kg BW OX-7 antibody. Neuronal labeling (dicarbocyanine dye [DiI]) in all rats allowed identification of renal afferent dorsal root ganglion (DRG) neurons. A current clamp was used to characterize neurons as tonic (sustained action potential [AP] firing) or phasic (1–4 AP) upon stimulation by current injection. All kidneys were investigated using standard morphological techniques. DRG neurons exhibited less often tonic response if in vivo axonal input from clipped kidneys was received (30.4% vs. 61.2% control, p < 0.05). However, if the nerves to the left clipped kidneys were cut 7 days prior to investigation, the number of tonic renal neurons completely recovered to well above control levels. Interestingly, electrophysiological properties of neurons that had in vivo axons from the right non-clipped kidneys were not distinguishable from controls. Renal DRG neurons from nephritic rats also showed less often tonic activity upon current injection (43.4% vs. 64.8% control, p < 0.05). Putative sympathoexcitatory and impaired sympathoinhibitory renal afferent nerve fibers probably contribute to increased sympathetic activity in 2K1C hypertension.
      PubDate: 2021-07-07
      DOI: 10.1007/s00424-021-02591-6
       
  • Carbonic anhydrase IX and hypoxia-inducible factor 1 attenuate cardiac
           dysfunction after myocardial infarction

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      Abstract: Myocardial infarction (MI) is one of the leading causes of death worldwide. Prognosis and mortality rate are directly related to infarct size and post-infarction pathological heart remodeling, which can lead to heart failure. Hypoxic MI-affected areas increase the expression of hypoxia-inducible factor (HIF-1), inducing infarct size reduction and improving cardiac function. Hypoxia translocates HIF-1 to the nucleus, activating carbonic anhydrase IX (CAIX) transcription. CAIX regulates myocardial intracellular pH, critical for heart performance. Our objective was to investigate CAIX participation and relation with sodium bicarbonate transporters 1 (NBC1) and HIF-1 in cardiac remodeling after MI. We analyzed this pathway in an “in vivo” rat coronary artery ligation model and isolated cardiomyocytes maintained under hypoxia. Immunohistochemical studies revealed an increase in HIF-1 levels after 2 h of infarction. Similar results were observed in 2-h infarcted cardiac tissue (immunoblotting) and in hypoxic cardiomyocytes with a nuclear distribution (confocal microscopy). Immunohistochemical studies showed an increase CAIX in the infarcted area at 2 h, mainly distributed throughout the cell and localized in the plasma membrane at 24 h. Similar results were observed in 2 h in infarcted cardiac tissue (immunoblotting) and in hypoxic cardiomyocytes (confocal microscopy). NBC1 expression increased in cardiac tissue after 2 h of infarction (immunoblotting). CAIX and NBC1 interaction increases in cardiac tissue subjected to MI for 2h when CAIX is present (immunoprecipitation). These results suggest that CAIX interacts with NBC1 in our infarct model as a mechanism to prevent acidic damage in hypoxic tissue, making it a promising therapeutic target.
      PubDate: 2021-07-06
      DOI: 10.1007/s00424-021-02592-5
       
  • The (pro)renin receptor (ATP6ap2) facilitates receptor-mediated
           endocytosis and lysosomal function in the renal proximal tubule

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      Abstract: The ATP6ap2 (Pro)renin receptor protein associates with H+-ATPases which regulate organellar, cellular, and systemic acid–base homeostasis. In the kidney, ATP6ap2 colocalizes with H+-ATPases in various cell types including the cells of the proximal tubule. There, H+-ATPases are involved in receptor-mediated endocytosis of low molecular weight proteins via the megalin/cubilin receptors. To study ATP6ap2 function in the proximal tubule, we used an inducible shRNA Atp6ap2 knockdown rat model (Kd) and an inducible kidney-specific Atp6ap2 knockout mouse model. Both animal lines showed higher proteinuria with elevated albumin, vitamin D binding protein, and procathepsin B in urine. Endocytosis of an injected fluid-phase marker (FITC- dextran, 10 kDa) was normal whereas processing of recombinant transferrin, a marker for receptor-mediated endocytosis, to lysosomes was delayed. While megalin and cubilin expression was unchanged, abundance of several subunits of the H+-ATPase involved in receptor-mediated endocytosis was reduced. Lysosomal integrity and H+-ATPase function are associated with mTOR signaling. In ATP6ap2, KO mice mTOR and phospho-mTOR appeared normal but increased abundance of the LC3-B subunit of the autophagosome was observed suggesting a more generalized impairment of lysosomal function in the absence of ATP6ap2. Hence, our data suggests a role for ATP6ap2 for proximal tubule function in the kidney with a defect in receptor-mediated endocytosis in mice and rats.
      PubDate: 2021-07-06
      DOI: 10.1007/s00424-021-02598-z
       
  • Correction to: New ways for an old cation

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      PubDate: 2021-07-01
      DOI: 10.1007/s00424-021-02593-4
       
  • Toward an in vitro human pacemaker

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      PubDate: 2021-07-01
      DOI: 10.1007/s00424-021-02585-4
       
  • A detailed characterization of the hyperpolarization-activated “funny”
           current (If) in human-induced pluripotent stem cell (iPSC)–derived
           cardiomyocytes with pacemaker activity

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      Abstract: Properties of the funny current (If) have been studied in several animal and cellular models, but so far little is known concerning its properties in human pacemaker cells. This work provides a detailed characterization of If in human-induced pluripotent stem cell (iPSC)–derived pacemaker cardiomyocytes (pCMs), at different time points. Patch-clamp analysis showed that If density did not change during differentiation; however, after day 30, it activates at more negative potential and with slower time constants. These changes are accompanied by a slowing in beating rate. If displayed the voltage-dependent block by caesium and reversed (Erev) at − 22 mV, compatibly with the 3:1 K+/Na+ permeability ratio. Lowering [Na+]o (30 mM) shifted the Erev to − 39 mV without affecting conductance. Increasing [K+]o (30 mM) shifted the Erev to − 15 mV with a fourfold increase in conductance. pCMs express mainly HCN4 and HCN1 together with the accessory subunits CAV3, KCR1, MiRP1, and SAP97 that contribute to the context-dependence of If. Autonomic agonists modulated the diastolic depolarization, and thus rate, of pCMs. The adrenergic agonist isoproterenol induced rate acceleration and a positive shift of If voltage-dependence (EC50 73.4 nM). The muscarinic agonists had opposite effects (Carbachol EC50, 11,6 nM). Carbachol effect was however small but it could be increased by pre-stimulation with isoproterenol, indicating low cAMP levels in pCMs. In conclusion, we demonstrated that pCMs display an If with the physiological properties expected by pacemaker cells and may thus represent a suitable model for studying human If-related sinus arrhythmias.
      PubDate: 2021-07-01
      DOI: 10.1007/s00424-021-02571-w
       
  • Vascularisation of pluripotent stem cell–derived myocardium:
           biomechanical insights for physiological relevance in cardiac tissue
           engineering

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      Abstract: The myocardium is a diverse environment, requiring coordination between a variety of specialised cell types. Biochemical crosstalk between cardiomyocytes (CM) and microvascular endothelial cells (MVEC) is essential to maintain contractility and healthy tissue homeostasis. Yet, as myocytes beat, heterocellular communication occurs also through constantly fluctuating biomechanical stimuli, namely (1) compressive and tensile forces generated directly by the beating myocardium, and (2) pulsatile shear stress caused by intra-microvascular flow. Despite endothelial cells (EC) being highly mechanosensitive, the role of biomechanical stimuli from beating CM as a regulatory mode of myocardial-microvascular crosstalk is relatively unexplored. Given that cardiac biomechanics are dramatically altered during disease, and disruption of myocardial-microvascular communication is a known driver of pathological remodelling, understanding the biomechanical context necessary for healthy myocardial-microvascular interaction is of high importance. The current gap in understanding can largely be attributed to technical limitations associated with reproducing dynamic physiological biomechanics in multicellular in vitro platforms, coupled with limited in vitro viability of primary cardiac tissue. However, differentiation of CM from human pluripotent stem cells (hPSC) has provided an unlimited source of human myocytes suitable for designing in vitro models. This technology is now converging with the diverse field of tissue engineering, which utilises in vitro techniques designed to enhance physiological relevance, such as biomimetic extracellular matrix (ECM) as 3D scaffolds, microfluidic perfusion of vascularised networks, and complex multicellular architectures generated via 3D bioprinting. These strategies are now allowing researchers to design in vitro platforms which emulate the cell composition, architectures, and biomechanics specific to the myocardial-microvascular microenvironment. Inclusion of physiological multicellularity and biomechanics may also induce a more mature phenotype in stem cell–derived CM, further enhancing their value. This review aims to highlight the importance of biomechanical stimuli as determinants of CM-EC crosstalk in cardiac health and disease, and to explore emerging tissue engineering and hPSC technologies which can recapitulate physiological dynamics to enhance the value of in vitro cardiac experimentation.
      PubDate: 2021-07-01
      DOI: 10.1007/s00424-021-02557-8
       
  • Human-induced pluripotent stem cells as models for rare cardiovascular
           diseases: from evidence-based medicine to precision medicine

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      Abstract: Rare cardiovascular diseases (RCDs) refer to those cardiovascular diseases that display a low prevalence as well as morbidity. Due to the vast variety of underlying genetic mutations and the relatively low patient population, RCDs present additional challenges for diagnosis. Precision medicine may offer opportunities for designing patient-specific therapies in particular for carriers of variants with undetermined significance. Moreover, precision medicine strategies provide benefit to patients with “common” symptoms but carry in rare genetic variants. Induced pluripotent stem cells (iPSCs) present a state-of-the-art precision medicine approach which recently made contributions to the study of RCDs via patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). Human iPSC-CMs are derived from a patient’s somatic cells and thus recapitulate a personalized genomics background, serving as patient-specific disease models. In light of these advantages, iPSC-CMs evolved as an effective tool for modeling cardiac disease phenotypes and accurately evaluating the toxicity of potential therapeutic compounds. This review covers approaches for studying RCDs and iPSC-CM models generated so far for different RCDs, such as long QT syndrome (LQT), short QT syndrome (SQT), Brugada syndrome (BrS), arrhythmogenic right ventricular cardiomyopathy (ARVC), and other rare diseases accomplished by cardiac-related syndromes like Fabry disease (FD) and Marfan syndrome (MFS). This overview aims to aid better understanding of the utility of iPSC-CM models, their various features, and future prospects.
      PubDate: 2021-07-01
      DOI: 10.1007/s00424-020-02486-y
       
  • Human-induced pluripotent stem cell-derived cardiomyocytes, 3D cardiac
           structures, and heart-on-a-chip as tools for drug research

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      Abstract: Development of new drugs is of high interest for the field of cardiac and cardiovascular diseases, which are a dominant cause of death worldwide. Before being allowed to be used and distributed, every new potentially therapeutic compound must be strictly validated during preclinical and clinical trials. The preclinical studies usually involve the in vitro and in vivo evaluation. Due to the increasing reporting of discrepancy in drug effects in animal and humans and the requirement to reduce the number of animals used in research, improvement of in vitro models based on human cells is indispensable. Primary cardiac cells are difficult to access and maintain in cell culture for extensive experiments; therefore, the human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) became an excellent alternative. This technology enables a production of high number of patient- and disease-specific cardiomyocytes and other cardiac cell types for a large-scale research. The drug effects can be extensively evaluated in the context of electrophysiological responses with a use of well-established tools, such as multielectrode array (MEA), patch clamp, or calcium ion oscillation measurements. Cardiotoxicity, which is a common reason for withdrawing drugs from marketing or rejection at final stages of clinical trials, can be easily verified with a use of hiPSC-CM model providing a prediction of human-specific responses and higher safety of clinical trials involving patient cohort. Abovementioned studies can be performed using two-dimensional cell culture providing a high-throughput and relatively lower costs. On the other hand, more complex structures, such as engineered heart tissue, organoids, or spheroids, frequently applied as co-culture systems, represent more physiological conditions and higher maturation rate of hiPSC-derived cells. Furthermore, heart-on-a-chip technology has recently become an increasingly popular tool, as it implements controllable culture conditions, application of various stimulations and continuous parameters read-out. This paper is an overview of possible use of cardiomyocytes and other cardiac cell types derived from hiPSC as in vitro models of heart in drug research area prepared on the basis of latest scientific reports and providing thorough discussion regarding their advantages and limitations.
      PubDate: 2021-07-01
      DOI: 10.1007/s00424-021-02536-z
       
  • Cell surface markers for immunophenotyping human pluripotent stem
           cell-derived cardiomyocytes

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      Abstract: Human pluripotent stem cells (hPSC) self-renew and represent a potentially unlimited source for the production of cardiomyocytes (CMs) suitable for studies of human cardiac development, drug discovery, cardiotoxicity testing, and disease modelling and for cell-based therapies. However, most cardiac differentiation protocols yield mixed cultures of atrial-, ventricular-, and pacemaker-like cells at various stages of development, as well as non-CMs. The proportions and maturation states of these cell types result from disparities among differentiation protocols and time of cultivation, as well as hPSC reprogramming inconsistencies and genetic background variations. The reproducible use of hPSC-CMs for research and therapy is therefore limited by issues of cell population heterogeneity and functional states of maturation. A validated method that overcomes issues of cell heterogeneity is immunophenotyping coupled with live cell sorting, an approach that relies on accessible surface markers restricted to the desired cell type(s). Here we review current progress in unravelling heterogeneity in hPSC-cardiac cultures and in the identification of surface markers suitable for defining cardiac identity, subtype specificity, and maturation states.
      PubDate: 2021-07-01
      DOI: 10.1007/s00424-021-02549-8
       
  • Cellular pathology of the human heart in Duchenne muscular dystrophy
           (DMD): lessons learned from in vitro modeling

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      Abstract: Duchenne muscular dystrophy is a genetic disorder where an X-linked mutation in the DMD gene initiates pathogenic development caused by the absence of dystrophin protein. This impacts primarily the evolution of a functional muscle tissue resulting in muscle weakness and later severe disability in young male patients leading to an early death. Patients in the final stage develop dilated cardiomyopathy leading ultimately to cardiac or respiratory failure as the cause of death. This review discusses recent advances in modeling the DMD pathology in vitro. It describes in detail the molecular abnormalities found on the cellular and organoid levels. The in vitro pathology is compared to that found in patients. Likewise, the drawbacks and limitations of current models are discussed.
      PubDate: 2021-06-24
      DOI: 10.1007/s00424-021-02589-0
       
  • Correction to: Importance of evaluating protein glycosylation in
           pluripotent stem cell‑derived cardiomyocytes for research and clinical
           applications

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      Abstract: A Correction to this paper has been published: https://doi.org/10.1007/s00424-021-02566-7
      PubDate: 2021-06-01
      DOI: 10.1007/s00424-021-02566-7
       
 
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