The Journal of Physiology最新文献

{"title":"Rates of oxidative ATP synthesis are not augmented beyond the pH threshold in human vastus lateralis muscles during a stepwise contraction protocol.","authors":"Miles F Bartlett, Liam F Fitzgerald, Jane A Kent","doi":"10.1113/JP280851","DOIUrl":"https://doi.org/10.1113/JP280851","url":null,"abstract":"<p><strong>Key points: </strong>The oxygen cost of high-intensity exercise at power outputs above an individual's lactate threshold (LT) is greater than would be predicted by the linear oxygen consumption-power relationship observed below the LT. However, whether these augmentations are caused by an increased ATP cost of force generation (ATP<sub>COST</sub> ) or an increased oxygen cost of ATP synthesis is unclear. We used <sup>31</sup> P-MRS to measure changes in cytosolic [ADP] (intramyocellular marker of oxidative metabolism), oxidative ATP synthesis (ATP<sub>OX</sub> ) and ATP<sub>COST</sub> during a 6-stage, stepwise knee extension protocol. ATP<sub>COST</sub> was unchanged across stages. The relationship between [ADP] and muscle power output was augmented at workloads above the pH threshold (pH<sub>T</sub> ; proxy for LT), whereas increases in ATP<sub>OX</sub> were attenuated. These results suggest the greater oxygen cost of contractions at workloads beyond the pH<sub>T</sub> is not caused by mechanisms that increase ATP<sub>COST</sub> , but rather mechanisms that alter intrinsic mitochondrial function or capacity.</p><p><strong>Abstract: </strong>Increases in skeletal muscle metabolism and oxygen consumption are linearly related to muscle power output for workloads below the lactate threshold (LT), but are augmented (i.e. greater rate of increase relative to workload) thereafter. Presently, it is unclear whether these metabolic augmentations are caused by increases in the ATP cost of force generation (ATP<sub>COST</sub> ) or changes in the efficiency of mitochondrial oxygen consumption and oxidative ATP synthesis (ATP<sub>OX</sub> ). To partition these two hypotheses in vivo, we used <sup>31</sup> P-MRS to calculate slopes relating step-changes in muscle work to concurrent changes in cytosolic phosphates and ATP<sub>OX</sub> before and after the pH threshold (pH<sub>T</sub> ; used here as a proxy for LT) within the vastus lateralis muscle of eight young adults during a stepwise knee extension test. Changes in muscle phosphates and ATP<sub>OX</sub> were linearly related to workload below the pH<sub>T</sub> . However, slopes above the pH<sub>T</sub> were greater for muscle phosphates (P < 0.05) and lower for ATP<sub>OX</sub> (P < 0.05) than were the slopes observed below the pH<sub>T</sub> . The maximal capacity for ATP<sub>OX</sub> ( <math><msub><mover><mi>V</mi><mo>̇</mo></mover><mi>max</mi></msub></math> ) and ADP-specific ATP<sub>OX</sub> also declined beyond the pH<sub>T</sub> (P < 0.05), whereas ATP<sub>COST</sub> was unchanged (P = 0.10). These results oppose the hypothesis that high-intensity contractions increase ATP<sub>COST</sub> and suggest that greater oxidative metabolism at workloads beyond the pH<sub>T</sub> is caused by mechanisms that affect intrinsic mitochondrial function or capacity, such as alterations in substrate selection or electron entry into the electron transport chain, temperature-mediated changes in mitochondri","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1997-2013"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25360557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of the mode of heating on cerebral blood flow, non-invasive intracranial pressure and thermal tolerance in humans.","authors":"Travis D Gibbons,&nbsp;Philip N Ainslie,&nbsp;Kate N Thomas,&nbsp;Luke C Wilson,&nbsp;Ashley P Akerman,&nbsp;Joseph Donnelly,&nbsp;Holly A Campbell,&nbsp;Jim D Cotter","doi":"10.1113/JP280970","DOIUrl":"https://doi.org/10.1113/JP280970","url":null,"abstract":"<p><strong>Key points: </strong>The human brain is particularly vulnerable to heat stress; this manifests as impaired cognition, orthostatic tolerance, work capacity and eventually, brain death. The brain's limitation in the heat is often ascribed to inadequate cerebral blood flow (CBF), but elevated intracranial pressure is commonly observed in mammalian models of heat stroke and can on its own cause functional impairment. The CBF response to incremental heat strain was dependent on the mode of heating, decreasing by 30% when exposed passively to hot, humid air (sauna), while remaining unchanged or increasing with passive hot-water immersion (spa) and exercising in a hot environment. Non-invasive intracranial pressure estimates (nICP) were increased universally by 18% at volitional thermal tolerance across all modes of heat stress, and therefore may play a contributing role in eliciting thermal tolerance. The sauna, more so than the spa or exercise, poses a greater challenge to the brain under mild to severe heating due to lower blood flow but similarly increased nICP.</p><p><strong>Abstract: </strong>The human brain is particularly vulnerable to heat stress; this manifests as impaired cognitive function, orthostatic tolerance, work capacity, and eventually, brain death. This vulnerability is often ascribed to inadequate cerebral blood flow (CBF); however, elevated intracranial pressure (ICP) is also observed in mammalian models of heat stroke. We investigated the changes in CBF with incremental heat strain under three fundamentally different modes of heating, and assessed whether heating per se increased ICP. Fourteen fit participants (seven female) were heated to thermal tolerance or 40°C core temperature (T_c ; oesophageal) via passive hot-water immersion (spa), passive hot, humid air exposure (sauna), cycling exercise, and cycling exercise with CO₂ inhalation to prevent heat-induced hypocapnia. CBF was measured with duplex ultrasound at each 0.5°C increment in T_c and ICP was estimated non-invasively (nICP) from optic nerve sheath diameter at thermal tolerance. At thermal tolerance, CBF was decreased by 30% in the sauna (P < 0.001), but was unchanged in the spa or with exercise (P ≥ 0.140). CBF increased by 17% when end-tidal <math><msub><mi>P</mi><mrow><mi>C</mi><msub><mi>O</mi><mn>2</mn></msub></mrow></msub></math> was clamped at eupnoeic pressure (P < 0.001). On the contrary, nICP increased universally by 18% with all modes of heating (P < 0.001). The maximum T_c was achieved with passive heating, and preventing hypocapnia during exercise did not improve exercise or thermal tolerance (P ≥ 0.146). Therefore, the regulation of CBF is dramatically different depending on the mode and dose of heating, whereas nICP responses are not. The sauna, more so than the spa or exercise, poses a greater challenge to the brain under equivalent heat strain.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1977-1996"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25372895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"1,25(OH)₂ vitamin D₃ stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine.","authors":"Nati Hernando,&nbsp;Eva Maria Pastor-Arroyo,&nbsp;Joanne Marks,&nbsp;Udo Schnitzbauer,&nbsp;Thomas Knöpfel,&nbsp;Matthias Bürki,&nbsp;Carla Bettoni,&nbsp;Carsten A Wagner","doi":"10.1113/JP280345","DOIUrl":"https://doi.org/10.1113/JP280345","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Key points: &lt;/strong&gt;Intestinal absorption of phosphate proceeds via an active/transcellular route mostly mediated by NaPi-IIb/Slc34a2 and a poorly characterized passive/paracellular pathway. Intestinal phosphate absorption and expression of NaPi-IIb are stimulated by 1,25(OH)&lt;sub&gt;2&lt;/sub&gt; vitamin D&lt;sub&gt;3&lt;/sub&gt; but whether NaPi-IIb is the only target under hormonal control remains unknown. We report that administration of 1,25(OH)&lt;sub&gt;2&lt;/sub&gt; vitamin D&lt;sub&gt;3&lt;/sub&gt; to wild-type mice resulted in the expected increase in active transport of phosphate in jejunum, without changing paracellular fluxes. Instead, the same treatment failed to alter phosphate transport in intestinal-depleted Slc34a2-deficient mice. In both genotypes, 1,25(OH)&lt;sub&gt;2&lt;/sub&gt; vitamin D&lt;sub&gt;3&lt;/sub&gt; induced similar hyperphosphaturic responses and changes in the plasma levels of FGF23 and PTH. While urinary phosphate loss induced by administration of 1,25(OH)&lt;sub&gt;2&lt;/sub&gt; vitamin D&lt;sub&gt;3&lt;/sub&gt; did not alter plasma phosphate, further studies should investigate whether chronic administration would lead to phosphate imbalance in mice with reduced active intestinal absorption.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Abstract: &lt;/strong&gt;Intestinal absorption of phosphate is stimulated by 1,25(OH)&lt;sub&gt;2&lt;/sub&gt; vitamin D&lt;sub&gt;3.&lt;/sub&gt; At least two distinct mechanisms underlie phosphate absorption in the gut, an active transcellular transport requiring the Na&lt;sup&gt;+&lt;/sup&gt; /phosphate cotransporter NaPi-IIb/Slc34a2, and a poorly characterized paracellular passive pathway. 1,25(OH)&lt;sub&gt;2&lt;/sub&gt; vitamin D&lt;sub&gt;3&lt;/sub&gt; stimulates NaPi-IIb expression and function, and loss of NaPi-IIb reduces intestinal phosphate absorption. However, it is remains unknown whether NaPi-IIb is the only target for hormonal regulation by 1,25(OH)&lt;sub&gt;2&lt;/sub&gt; vitamin D&lt;sub&gt;3&lt;/sub&gt; . Here we compared the effects of intraperitoneal administration of 1,25(OH)&lt;sub&gt;2&lt;/sub&gt; vitamin D&lt;sub&gt;3&lt;/sub&gt; (2 days, once per day) in wild-type and intestinal-specific Slc34a2-deficient mice, and analysed trans- vs. paracellular routes of phosphate absorption. We found that treatment stimulated active transport of phosphate only in jejunum of wild-type mice, though NaPi-IIb protein expression was upregulated in jejunum and ileum. In contrast, 1,25(OH)&lt;sub&gt;2&lt;/sub&gt; vitamin D&lt;sub&gt;3&lt;/sub&gt; administration had no effect in Slc34a2-deficient mice, suggesting that the hormone specifically regulates NaPi-IIb expression. In both groups, 1,25(OH)&lt;sub&gt;2&lt;/sub&gt; vitamin D&lt;sub&gt;3&lt;/sub&gt; elicited the expected increase of plasma fibroblast growth factor 23 (FGF23) and reduction of parathyroid hormone (PTH). Treatment resulted in hyperphosphaturia (and hypercalciuria) in both genotypes, though mice remained normophosphataemic. While increased intestinal absorption and higher FGF23 can trigger the hyperphosphaturic response in wild types, only higher FGF23 can explain the renal response in Slc34a2-deficient mice. Thus, 1,25(OH)&lt;sub&gt;2&lt;/sub&gt; vitamin D&lt;sub&gt;3&lt;/sub&gt; stimulates intestina","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1131-1150"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280345","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38611017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiological roles of heteromerization: focus on the two-pore domain potassium channels.","authors":"Lamyaa Khoubza,&nbsp;Franck C Chatelain,&nbsp;Sylvain Feliciangeli,&nbsp;Florian Lesage,&nbsp;Delphine Bichet","doi":"10.1113/JP279870","DOIUrl":"https://doi.org/10.1113/JP279870","url":null,"abstract":"<p><p>Potassium channels form the largest family of ion channels with more than 80 members involved in cell excitability and signalling. Most of them exist as homomeric channels, whereas specific conditions are required to obtain heteromeric channels. It is well established that heteromerization of voltage-gated and inward rectifier potassium channels affects their function, increasing the diversity of the native potassium currents. For potassium channels with two pore domains (K_2P ), homomerization has long been considered the rule, their polymodal regulation by a wide diversity of physical and chemical stimuli being responsible for the adaptation of the leak potassium currents to cellular needs. This view has recently evolved with the accumulation of evidence of heteromerization between different K_2P subunits. Several functional intragroup and intergroup heteromers have recently been identified, which contribute to the functional heterogeneity of this family. K_2P heteromerization is involved in the modulation of channel expression and trafficking, promoting functional and signalling diversity. As illustrated in the Abstract Figure, heteromerization of TREK1 and TRAAK provides the cell with more possibilities of regulation. It is becoming increasingly evident that K_2P heteromers contribute to important physiological functions including neuronal and cardiac excitability. Since heteromerization also affects the pharmacology of K_2P channels, this understanding helps to establish K_2P heteromers as new therapeutic targets for physiopathological conditions.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1041-1055"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP279870","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38733947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A closer look at physiological indicators of cardiovascular function post-transplantation.","authors":"Brent Jeffrey Tschirhart,&nbsp;Xin Tong Ma","doi":"10.1113/JP280523","DOIUrl":"https://doi.org/10.1113/JP280523","url":null,"abstract":"Currently, the clinical diagnosis and treatment of cardiovascular diseases rely on minimally or non-invasive measures that statistically correlate to the treatment. For example, cardiovascular function is assessed using measurements from the minimally invasive right heart catheterization (RHC) procedure after heart transplants to advise on treatment (Colunga et al. 2020). Repeated RHC measurements of ventricular and pulmonary arterial pressure are used to observe post-transplant pulmonary hypertension to identify potential further complications in post-transplant recovery. While close monitoring of these measurements is associated with better outcomes, RHC measures only depict the broader cardiovascular phenotype and do not assess the underlying physiological mechanisms, such as pressure, volume, and flow relationships in the cardiovascular system. Previous studies have suggested that a detailed assessment of the cardiovascular system may improve the diagnosis/treatment of cardiovascular dysfunction post-transplantation (Stobierska-Dzierzek et al. 2001). Similarly, other non-invasive measures are used to evaluate cardiac function post-transplantation, including echocardiography, magnetic resonance, and Doppler imaging. Clinically, these measurements are used in conjunction with RHC measurements as they may not provide enough information individually regarding a patient’s cardiovascular function. The current study uses a patient-specific computational methodology which incorporates clinical measures and is used to predict time-dependent measures of pressure, flow, and volume, as well as mechanistic measures, many of which presented are not easily measured in the clinic. This study presented mechanistic parameter predictions of an individual patient at specific cardiovascular recovery time points. Thus, this study combines the physiology of the cardiovascular system with patient-specific measurements to better describe the cardiovascular health of a specific patient. The authors aim to use measures that monitor the health and condition of heart transplant patients to provide early indications regarding the success of the heart transplant.","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1031-1032"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280523","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38454375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxygen transport kinetics underpin rapid and robust diaphragm recovery following chronic spinal cord injury.","authors":"Philippa M Warren, Roger W P Kissane, Stuart Egginton, Jessica C F Kwok, Graham N Askew","doi":"10.1113/JP280684","DOIUrl":"10.1113/JP280684","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Key points: &lt;/strong&gt;Spinal treatment can restore diaphragm function in all animals 1 month following C2 hemisection induced paralysis. Greater recovery occurs the longer after injury the treatment is applied. Through advanced assessment of muscle mechanics, innovative histology and oxygen tension modelling, we have comprehensively characterized in vivo diaphragm function and phenotype. Muscle work loops reveal a significant deficit in diaphragm functional properties following chronic injury and paralysis, which are normalized following restored muscle activity caused by plasticity-induced spinal reconnection. Injury causes global and local alterations in diaphragm muscle vascular supply, limiting oxygen diffusion and disturbing function. Restoration of muscle activity reverses these alterations, restoring oxygen supply to the tissue and enabling recovery of muscle functional properties. There remain metabolic deficits following restoration of diaphragm activity, probably explaining only partial functional recovery. We hypothesize that these deficits need to be resolved to restore complete respiratory motor function.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Abstract: &lt;/strong&gt;Months after spinal cord injury (SCI), respiratory deficits remain the primary cause of morbidity and mortality for patients. It is possible to induce partial respiratory motor functional recovery in chronic SCI following 2 weeks of spinal neuroplasticity. However, the peripheral mechanisms underpinning this recovery are largely unknown, limiting development of new clinical treatments with potential for complete functional restoration. Utilizing a rat hemisection model, diaphragm function and paralysis was assessed and recovered at chronic time points following trauma through chondroitinase ABC induced neuroplasticity. We simulated the diaphragm's in vivo cyclical length change and activity patterns using the work loop technique at the same time as assessing global and local measures of the muscles histology to quantify changes in muscle phenotype, microvascular composition, and oxidative capacity following injury and recovery. These data were fed into a physiologically informed model of tissue oxygen transport. We demonstrate that hemidiaphragm paralysis causes muscle fibre hypertrophy, maintaining global oxygen supply, although it alters isolated muscle kinetics, limiting respiratory function. Treatment induced recovery of respiratory activity normalized these effects, increasing oxygen supply, restoring optimal diaphragm functional properties. However, metabolic demands of the diaphragm were significantly reduced following both injury and recovery, potentially limiting restoration of normal muscle performance. The mechanism of rapid respiratory muscle recovery following spinal trauma occurs through oxygen transport, metabolic demand and functional dynamics of striated muscle. Overall, these data support a systems-wide approach to the treatment of SCI, and identify new targets to mediate ","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1199-1224"},"PeriodicalIF":0.0,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38564719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum.","authors":"","doi":"10.1113/JP281223","DOIUrl":"https://doi.org/10.1113/JP281223","url":null,"abstract":"","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1357"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25393712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Store-operated Ca²⁺ influx in native vascular smooth muscle cells relies on interactions between PKCδ, PIP₂ and TRPC1 channels.","authors":"Bernard T Drumm,&nbsp;Keith D Thornbury,&nbsp;Mark A Hollywood,&nbsp;Gerard P Sergeant","doi":"10.1113/JP280807","DOIUrl":"https://doi.org/10.1113/JP280807","url":null,"abstract":"Store-operated-Ca2+-entry (SOCE) is increasingly recognized as an important signalling pathway mediating smooth muscle cell (SMC) contraction, proliferation, migration and growth (Trebak et al. 2013). In both excitable and non-excitable cells, SOCE is mediated by depletion of endoplasmic/sarcoplasmic reticulum (SR) Ca2+ stores. Store depletion is sensed by stromal interaction molecule (STIM) proteins on the SR membrane that undergo a conformation change and bind to and activate Orai1 Ca2+ channels in the plasma membrane, facilitating Ca2+ entry (Yeung et al. 2020). In synthetic vascular SMC (VSMC), interactions between STIM and Orai1 are well characterized and are assumed to play key roles in migration and proliferation. However, in native contractile VSMC, SOCE is considered to be mediated by other store-operated channels, such as canonical transient receptor potential 1 (TRPC1) channels, independently of Orai1 (Baudel et al. 2020a). The mechanisms linking SR store depletion to activation of TRPC1 channels in VSMC are controversial, although there is evidence that TRPC1 opening relies on interactions with protein kinase C (PKC) and phosphatidylinositol 4,5-bisphosphate (PIP2). Shi et al. (2017) reported that SOCE via TRPC1 channels may involve a STIM1-mediated Gαq/phospholipase C (PLC) β1 pathway that induces TRPC1 opening by regulating PKC and PIP2 interactions. A recent study also suggested that activation of TRPC1 channels in VSMC relies on a PKC-dependent phosphorylation of TRPC1 channels as a perquisite for PIP2-mediated channel opening (Baudel et al. 2020a). The exact mechanisms underlying these pathways are not well understood, in part because the identification of the PKC isoform that interacts with TRPC1 channels to facilitate channel opening by PIP2 is not known. This issue was addressed in a recent issue of The Journal of Physiology by Baudel et al. (2020b). In their study, SOCEwas instigated in VSMC from rat mesenteric arteries by passive depletion of SR by incubation with the high-affinity Ca2+ chelator, BAPTA. The resultant store-operated whole cell currents in VSMC were greatly reduced by Pico 145, a TRPC1/4/5 blocker, as well as an externally acting TRPC1 antibody (T1E3). Furthermore, store-operated currents in VSMCswere reduced by a pan-PKC isoform inhibitor (GF109203X), demonstrating the importance not only of TRPC1 channels, but also PKC with respect to mediating SOCE. Although the PKC family consists of 11 different isoforms of different structures and functions, previous investigators had surmised that the specific isoform regulating TRPC1 channels in VSMCs required diacylglycerol for its activation, andwas insensitive to Ca2+. This eliminated all PKC isoforms with the exception of PKC δ, ε, η and θ (Baudel et al. 2020a). The specific PKC isoforms expressed in VSMC were therefore investigated at both the tissue and cellular level using western blot analysis and immunocytochemistry, respectively. The experiments concluded tha","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1037-1038"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280807","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38604550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose-dependent sensorimotor impairment in human ocular tracking after acute low-dose alcohol administration.","authors":"Terence L Tyson,&nbsp;Nathan H Feick,&nbsp;Patrick F Cravalho,&nbsp;Erin E Flynn-Evans,&nbsp;Leland S Stone","doi":"10.1113/JP280395","DOIUrl":"https://doi.org/10.1113/JP280395","url":null,"abstract":"<p><strong>Key points: </strong>Oculomotor behaviours are commonly used to evaluate sensorimotor disruption due to ethanol (EtOH). The current study demonstrates the dose-dependent impairment in oculomotor and ocular behaviours across a range of ultra-low BACs (<0.035%). Processing of target speed and direction, as well as pursuit eye movements, are significantly impaired at 0.015% BAC, suggesting impaired neural activity within brain regions associated with the visual processing of motion. Catch-up saccades during steady visual tracking of the moving target compensate for the reduced vigour of smooth eye movements that occurs with the ingestion of low-dose alcohol. Saccade dynamics start to become 'sluggish' at as low as 0.035% BAC. Pupillary light responses appear unaffected at BAC levels up to 0.065%.</p><p><strong>Abstract: </strong>Changes in oculomotor behaviours are often used as metrics of sensorimotor disruption due to ethanol (EtOH); however, previous studies have focused on deficits at blood-alcohol concentrations (BACs) above about 0.04%. We investigated the dose dependence of the impairment in oculomotor and ocular behaviours caused by EtOH administration across a range of ultra-low BACs (≤0.035%). We took repeated measures of oculomotor and ocular performance from sixteen participants, both pre- and post-EtOH administration. To assess the neurological impacts across a wide range of brain areas and pathways, our protocol measured 21 largely independent performance metrics extracted from a range of behavioural responses ranging from ocular tracking of radial step-ramp stimuli, to eccentric gaze holding, to pupillary responses evoked by light flashes. Our results show significant impairment of pursuit and visual motion processing at 0.015% BAC, reflecting degraded neural processing within extrastriate cortical pathways. However, catch-up saccades largely compensate for the tracking displacement shortfall caused by low pursuit gain, although there still is significant residual retinal slip and thus degraded dynamic acuity. Furthermore, although saccades are more frequent, their dynamics are more sluggish (i.e. show lower peak velocities) starting at BAC levels as low as 0.035%. Small effects in eccentric gaze holding and no effect in pupillary response dynamics were observed at levels below 0.07%, showing the higher sensitivity of the pursuit response to very low levels of blood alcohol, under the conditions of our study.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1225-1242"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280395","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38725318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-duration spaceflight alters estimated intracranial pressure and cerebral blood velocity.","authors":"Ken-Ichi Iwasaki,&nbsp;Yojiro Ogawa,&nbsp;Takuya Kurazumi,&nbsp;Syed M Imaduddin,&nbsp;Chiaki Mukai,&nbsp;Satoshi Furukawa,&nbsp;Ryo Yanagida,&nbsp;Tomokazu Kato,&nbsp;Toru Konishi,&nbsp;Ari Shinojima,&nbsp;Benjamin D Levine,&nbsp;Thomas Heldt","doi":"10.1113/JP280318","DOIUrl":"https://doi.org/10.1113/JP280318","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Key points: &lt;/strong&gt;During long-duration spaceflights, some astronauts develop structural ocular changes including optic disc oedema that resemble signs of intracranial hypertension. In the present study, intracranial pressure was estimated non-invasively (nICP) using a model-based analysis of cerebral blood velocity and arterial blood pressure waveforms in 11 astronauts before and after long-duration spaceflights. Our results show that group-averaged estimates of nICP decreased significantly in nine astronauts without optic disc oedema, suggesting that the cephalad fluid shift during long-duration spaceflight rarely increased postflight intracranial pressure. The results of the two astronauts with optic disc oedema suggest that both increases and decreases in nICP are observed post-flight in astronauts with ocular alterations, arguing against a primary causal relationship between elevated ICP and spaceflight associated optical changes. Cerebral blood velocity increased independently of nICP and spaceflight-associated ocular alterations. This increase may be caused by the reduced haemoglobin concentration after long-duration spaceflight.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Abstract: &lt;/strong&gt;Persistently elevated intracranial pressure (ICP) above upright values is a suspected cause of optic disc oedema in astronauts. However, no systematic studies have evaluated changes in ICP from preflight. Therefore, ICP was estimated non-invasively before and after spaceflight to test whether ICP would increase after long-duration spaceflight. Cerebral blood velocity in the middle cerebral artery (MCAv) was obtained by transcranial Doppler sonography and arterial pressure in the radial artery was obtained by tonometry, in the supine and sitting positions before and after 4-12 months of spaceflight in 11 astronauts (10 males and 1 female, 46 ± 7 years old at launch). Non-invasive ICP (nICP) was computed using a validated model-based estimation method. Mean MCAv increased significantly after spaceflight (ANOVA, P = 0.007). Haemoglobin decreased significantly after spaceflight (14.6 ± 0.8 to 13.3 ± 0.7 g/dL, P &lt; 0.001). A repeated measures correlation analysis indicated a negative correlation between haemoglobin and mean MCAv (r = -0.589, regression coefficient = -4.68). The nICP did not change significantly after spaceflight in the 11 astronauts. However, nICP decreased significantly by 15% in nine astronauts without optic disc oedema (P &lt; 0.005). Only one astronaut increased nICP to relatively high levels after spaceflight. Contrary to our hypothesis, nICP did not increase after long-duration spaceflight in the vast majority (&gt;90%) of astronauts, suggesting that the cephalad fluid shift during spaceflight does not systematically or consistently elevate postflight ICP in astronauts. Independently of nICP and ocular alterations, the present results of mean MCAv suggest that long-duration spaceflight may increase cerebral blood flow, possibly due to reduced haemoglobin con","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1067-1081"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280318","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38531578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}