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In this sabbatical, Paul (together with D Cleworth) pioneered the use of laser diffraction to follow sarcomere length changes in contracting striated muscle.3 He not only used to talk about this period with joy but also mentioned how he lost a single muscle fiber in an earthquake while dissecting. Critical sarcomere extension required to recruit a decaying component of extra force during stretch in tetanic contractions of frog skeletal muscle fibers. In the 1960s and 1970s, Paul's research interests shifted back to striated muscle, with published work on both cardiac and skeletal muscle with several well-cited papers (eg Ref. [2]), but from the end of the 1970s his main field of interest was skeletal muscle. The work of Paul Edman at UCLA was a starting point for his interest in the functional variability between different sarcomeres and neighboring segments along a single muscle fiber. [Extracted from the article]

The article offers instructions for authors regarding the submission of original papers.

Save imaging techniques like MRI and PET scanning are of great advantage here and these techniques also play an important role in refining animal experiments.20 Nevertheless, it is extremely difficult to eliminate all animal models from physiological research. Recent 3D tissue models of human colonic epithelium have been developed which will improve the mechanistic understanding of human intestinal function.11 The possibility of obtaining the information required through ethical research on human subjects or human tissue should be considered. Factors that confound the prediction of renal medullary oxygenation and risk of acute kidney injury from measurement of bladder urine oxygen tension. In recent years, most of the manuscripts published as a regular paper in ACTA Physiologica are based on animal experiments. [Extracted from the article]

Chemically skinned fibres allow the study of human muscle contractile function in vitro. A particularly important parameter is specific force (SF), that is, maximal isometric force divided by cross‐sectional area, representing contractile quality. Although SF varies substantially between studies, the magnitude and cause of this variability remains puzzling. Here, we aimed to summarize and explore the cause of variability in SF between studies. A systematic search was conducted in Medline, Embase and Web of Science databases in June 2020, yielding 137 data sets from 61 publications which studied healthy, young adults. Five‐fold differences in mean SF data were observed. Adjustments to the reported data for key methodological differences allowed between‐study comparisons to be made. However, adjustment for fibre shape, swelling and sarcomere length failed to significantly reduce SF variance (I2 = 96%). Interestingly, grouping papers based on shared authorship did reveal consistency within research groups. In addition, lower SF was found to be associated with higher phosphocreatine concentrations in the fibre activating solution and with Triton X‐100 being used as a skinning agent. Although the analysis showed variance across the literature, the ratio of SF in single fibres containing myosin heavy chain isoforms IIA or I was found to be consistent across research groups. In conclusion, whilst the skinned fibre technique is reliable for studying in vitro force generation of single fibres, the composition of the solution used to activate fibres, which differs between research groups, is likely to heavily influence SF values. [ABSTRACT FROM AUTHOR]

The paper by Pedersen et al1 published in this issue of I Acta Physiologica i provides compelling evidence that ClC-1 Cl SP - sp channels are important not only in the regulation of skeletal muscle excitability in mammals,2 but also in modulating the threshold for signal transmission at the neuromuscular junction (NMJ). In turn, the action potential in the muscle fibre triggers a series of events that cause the fibre to contract.4 Therefore, if the action potentials reaching the neuron terminal at an NMJ do not translate consistently into to an equivalent number of action potentials at the surface of the muscle fibre, the muscle fibre will not contract as it should, resulting in muscle weakness. Generally, the NMJs of twitch muscles in vertebrates are robust all-or-none excitatory synapses that display a high safety margin under normal physiological conditions to ensure that each action potential at the neuron terminal results in the generation of one action potential in the surface membrane of the muscle fibre. [Extracted from the article]

In the current issue of I Acta Physiologica, i Nielsen and co-workers publish a paper entitled "Regulation of integrin alpha6 by lactogenic hormones in rat pancreatic beta-cells: Implications for the physiological adaptation to pregnancy" in which the authors describe a novel pathway for increased beta-cell replication in response to lactogenic hormones like prolactin and growth hormone, both key players in the enlargement of pancreatic beta-cell mass during pregnancy.[1] This pathway involves selective upregulation of the integrin subunit alpha6 and was also observed during pregnancy in vivo I . i Furthermore, the authors show that this process involves synergistic activation of STAT5 signalling by both laminin-integrin interaction and hormonal stimulation. Interestingly, alpha6beta1 represents an integrin receptor that specifically binds to laminins, complex heterotrimeric glycoproteins of the basal membrane that have been shown to promote beta-cell proliferation and prolong beta-cell survival.[3] Thus, the paper by Nielsen and co-workers highlights a new axis between lactogenic hormones and the integrin-ECM interaction that is required for adaptational regulation of pancreatic beta-cell mass, a process playing a key role during pregnancy. Beyond GDM, pancreatic beta-cell replacement is another topic where adhesion of the beta-cell to elements of the basal membrane is of key importance. [Extracted from the article]

The present paper deals with a fundamental issue in neuroscience: the inter-neuronal communication. The paper gives a brief account of our previous and more recent theoretical contributions to the subject and also reports new recent data that support some aspects of our proposal on two major modes of communication in the central nervous system: the wiring and the volume transmission. There exist two competing theories on inter-neuronal communication: the neuron doctrine and the theory of the diffuse nerve network, supported by Cajal and Golgi, respectively (see their respective Nobel Lectures). The present paper gives a brief account of a view on inter-neuronal communication in the brain, the volume and wiring transmission concept that to a great extent reconcile these two theories. Thus, the theory of volume and wiring transmission are summarized and its recent developments that allow to extend these two modes of communication from the cellular network to the molecular network level is also briefly illustrated. The explanatory value of this broadened view is further enhanced by our recent proposal on the existence of a Global Molecular Network enmeshing the entire central nervous system. It may be interesting to note that also the Global Molecular Network theory is reminiscent of the old reticular theory of Apathy. Finally, the so-called ‘tide hypothesis’ for diffusion of signals in the brain is briefly discussed and its possible extension to the molecular level is for the first time introduced. Early indirect evidence supporting volume transmission in the brain was the discovery of transmitter-receptor mismatches. Thus, as an experimental part of the present paper a new approach to evaluate transmitter-receptor mismatches is given and evidence for inter-relationships between temperature micro-gradients and mismatches is provided. [ABSTRACT FROM AUTHOR]

The most in-depth study is probably the report by Andrei et al from 2016.5 They observed a TRPA1 immunolabelling on freshly isolated mouse cardiomyocytes and modifications of Ca SP 2+ sp -transient of these cells after the application of allyl isothiocyanate (AITC), the classical TRPA1 agonist, given that TRPA1 is permeable to cations (five times more permeable for Ca SP 2+ sp than for Na SP + sp ).6 The same group has further demonstrated that TRPA1 is involved in cardiomyocytes contraction7 and protects against ischemia-induced cardiomyocytes death,8 highlighting physiological and pathological implication in cardiomyocytes. In the specific case of TRPA1, few studies have reported the presence of a functional channel in mouse cardiomyocytes as well as TRPA1 protein revealed by western blot. Some of their detection of TRPA1 or TRPV1 are probably questionable as extensively discussed in the paper by Hoebart et al.1 Commercially available antibodies against TRPA1 are often not really efficient or specific as recently reported.15 At the functional level, a whole-cell NSC current can be composed of several entities carried by many supporting molecules. [Extracted from the article]

In the current issue of I Acta Physiologica i , two papers are published investigating the development of arterial hypertension under conditions of pathological loss of free water in two disease models. Aestivation motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect. The contribution of a tentative aestivation versus natriuresis component to CKD-induced hypertension might therefore increase with higher ratio of salt to water intake and minimize for isotonic intake. Aestivation motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect. [Extracted from the article]

The response to exercise training (trainability) has been shown to have a strong heritable component. There is growing evidence suggesting that traits such as trainability do not only depend on the genetic code, but also on epigenetic signals. Epigenetic signals play an important role in the modulation of gene expression, through mechanisms such as DNA methylation and histone modifications. There is an emerging evidence to show that physical activity influences DNA methylation in humans. The present review aims to summarize current knowledge on the link between DNA methylation and physical activity in humans. We have critically reviewed the literature and only papers focused on physical activity and its influence on DNA methylation status were included; a total of 25 papers were selected. We concluded that both acute and chronic exercises significantly impact DNA methylation, in a highly tissue- and gene-specific manner. This review also provides insights into the molecular mechanisms of exercise-induced DNA methylation changes, and recommendations for future research. [ABSTRACT FROM AUTHOR]

The skeletal muscle excitation-contraction coupling leading to tension development and increased mechanical stimuli change in concert, leaving it difficult to study their respective effect on molecular signalling and following adaptations. In conclusion, although the interest for mechanotransduction and deciphering relative effects of tension development and excitation in skeletal muscle has had a steep increase in later years, there is still work to do. Indeed, the present paper by Rindom et al1 is a valuable contribution to the field of mechanotransduction, as it establishes a better foundation to explore the complex network of skeletal muscle plasticity. [Extracted from the article]

Thus, although the gut microbiota undoubtedly plays a key role in the development of obesity, several studies have challenged the view that diet-induced obesity is causally related to intestinal microbiota. In the current issue of I Acta Physiologica, i Lundberg and co-workers publish a paper entitled "Germ-free mice are not protected against diet-induced obesity and metabolic dysfunction" in which the authors show that feeding a Western diet to both conventionally raised and germ-free mice results in weight gain, increased fat mass, fatty liver, glucose intolerance and adipose tissue inflammation.1 This indicates that the development of obesity and components of the metabolic syndrome is not dependent on the presence of gut microbiota and adds to the ongoing discussion regarding the causal role of intestinal microbiota in the development of obesity.2 More than 15 years ago, pioneering gnotobiotic studies were conducted by Bäckhed and co-workers providing compelling evidence that germ-free mice are protected against diet-induced obesity.3 This original concept, which considers the gut microbiota as a hub between environmental factors, mostly diet, and the host metabolism has been extensively developed by the Bäckhed group and successfully translated to humans. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. [Extracted from the article]

Aim: The role of the calcium-conducting ion channel transient receptor potential canonical 6 (TRPC6) in macrophage inflammatory protein-2 (MIP-2) induced migration of mouse neutrophils was investigated. Methods: Neutrophil granulocytes isolated from murine bone marrow of wild-type (TRPC6+/+) and TRPC6 knockout (TRPC6−/−) mice were tested for the presence of TRPC6 channel expression using quantitative real-time polymerase chain reactions and immunocytochemistry. The effect of different stimuli (e.g. MIP-2, 1-oleoyl-2-acetyl-sn-glycerol, formyl-methionyl-leucyl-phenylalanin) on migration of isolated neutrophils was tested by two-dimensional (2D) migration assays, phalloidin staining and intracellular calcium imaging. Results: We found that neutrophil granulocytes express TRPC6 channels. MIP-2 induced fast cell migration of isolated neutrophils in a 2D cell-tracking system. Strikingly, MIP-2 was less potent in neutrophils derived from TRPC6−/− mice. These cells showed less phalloidin-coupled fluorescence and the pattern of cytosolic calcium transients was altered. Conclusions: We describe in this paper for the first time a role for transient receptor potential (TRP) channels in migration of native lymphocytes as a new paradigm for the universal functional role of TRPs. Our data give strong evidence that TRPC6 operates downstream to CXC-type Gq-protein-coupled chemokine receptors upon stimulation with MIP-2 and is crucial for the arrangement of filamentous actin in migrating neutrophils. This is a novel cell function of TRP channel beyond their well-recognized role as universal cell sensors. [ABSTRACT FROM AUTHOR]

The article provides instructions for authors who want to submit their manuscripts to "Acta Physiologica," the official journal of the Federation of European Physiological Societies. The journal contains original contributions to physiology and related sciences such as pharmacology and biochemistry. It provides instructions for electronic submission.

The article reports on the instructions for authors who wish to contribute their works in the journal "Acta Physiologica." A guide on the use of statistics, language, manuscripts, references, figures, colors, tables, mathematics, electronic artwork, supplements, check list, abbreviations and terminology, proofs, offprints and how to submit are presented.

Scientific data output, as measured by the number of peer-reviewed publications, is growing exponentially. 17 McDougle M, Quinn D, Diepenbroek C, Singh A, de la Serre C, de Lartigue G. Intact vagal gut-brain signalling prevents hyperphagia and excessive weight gain in response to high-fat high-sugar diet. Scientific data output will continue to rise, rendering it impossible for any reader to honour all valuable publications in a given field of interest.2 Therefore, we use technology to aid and customize the information I allocation i process. Exercise-dependent increases in protein synthesis are accompanied by chromatin modifications and increased MRTF-SRF signalling. [Extracted from the article]

22 Pontecorvi G, Bellenghi M, Ortona E, Carè A. microRNAs as new possible actors in gender disparities of Covid-19 pandemic. The recent global pandemic has lead to a surge in biomedical publications,1 which came at a time when a rather intense discussion on quality control for research results was already ongoing. In how far the COVID-19 pandemic has fostered sustainable extensive cooperation among biomedical disciplines and researchers worldwide (now more than ever easily connected through eg online meetings), remains to be seen. Covid-19 pandemic analogies to everyday life in medical sciences. [Extracted from the article]

Neither the total cell number nor the percentage of Pax-7-positive cells was changed by the treatment of Yoda 1 at a concentration which would activate most Piezo1 channels. Screened from ~3.25 million compounds with an unbiased cell-based fluorescence assay, Yoda1 with its specificity against Piezo1 has been widely tested.4 Many studies have convincingly demonstrated that Yoda1 is highly selective for the Piezo1 channel. Mechanical signals generated from the cellular environment initiate and promote myogenesis during which satellite cells (SC cells), the muscle precursor cells, are directed to proliferate, differentiate and migrate with temporal and spatial patterns. [Extracted from the article]

This will importantly include a Young Physiologists' symposium focused on scientific career building and critical themes for early career physiologists. For many of us, the COVID-19 pandemic has taken a serious toll. Finally, we will be able to meet and share our enthusiasm for physiology with real coffee, biscuits, paper posters, laser-pointers, and post-symposium drinks with our newfound collaborators. [Extracted from the article]

The reported I P i -value indicated a positive effect of ASS for MI risk reduction beyond any measure of reasonable doubt. Gail Sullivan and Richard Feinn have authored a highly impactful editorial about the correct interpretation of I P i -values and effect sizes which can be recommended as a short handbook for scientific reporting.7 Equally important to reporting effect sizes is to interpret them correctly and comprehensibly. What is to be learned from the ASS example is that there are more layers to statistical interpretation than just the calculation of I P i -values and that the sizes of discovered effects often add more to our medical understanding than I P i -values. The researchers reported a I P i -value, indicating an effect, which in this case was the reduction of MI events in patients under ASS treatment. [Extracted from the article]

Dr De Groat and Wickens has reviewed the central neural mechanisms controlling the lower urinary tract with a major focus on the brain stem circuitry that mediates the switch-like characteristics of micturition, in particular the periaqueductal grey and the pontine micturition centre (de 2012). The review culminates in a computer model of how the brainstem switch operates in animals in which forebrain influences on micturition have been removed by decerebration. In this complementary paper, we review the mechanisms of forebrain involvement in the voluntary control of human micturition and the maintenance of continence with evidence based heavily on the results of functional brain imaging experiments. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "The discovery of a new class of synaptic transmitters in smooth muscle 50 years ago and amelioration of coronary artery thrombosis" in the February 2013 issue.

Studies on the regulation of cellular activity mainly focus on signal generation, but termination of signalling is an equally important factor, which prevents inappropriate activity. This paper reviews the mechanisms, which can cause termination of signalling, and provides examples that illustrate the importance of these processes. Inactivation of voltage-gated Na+ channels and the photoactivated rhodopsin molecule is caused by rapid conformational rearrangements. Negative feedback can also contribute to the termination of signalling for various mechanisms, including plasma membrane ion channels or c AMP signal generation. In immune cells, the tyrosine-based inhibitory motif ( ITIM)-containing molecules are essential negative regulatory components. Desensitization of G-protein-coupled receptors can occur with homologous and heterologous mechanisms, mediated by β-arrestin molecules and second messenger-induced kinases respectively. In NF-κ B signalling, resynthetized Iκ B and other enzymes form negative feedback loops. GTPase-activating proteins are also dedicated to termination of signalling, because they can switch off the small G proteins by increasing their endogenous GTP hydrolysis. In many systems, signal termination is a result of a combined action of several different mechanisms, which underlines the importance of these processes. [ABSTRACT FROM AUTHOR]

The comorbidity of cardiovascular disease (CVD) and depression/anxiety disorders is well established, but the mechanisms are not well understood. This paper will review the epidemiological and biological evidence for the role of depression in CVD, as well as the pathophysiological process underlying both depression and CVD. The focus will be on the roles of serotonin, platelets, and the immune system, with an emphasis on the relevance of sex differences in both depression/anxiety and CVD as they pertain to women. [ABSTRACT FROM AUTHOR]

Aim: To identify the mechanisms of P2X3 receptor inhibition by extracellular cyclic adenosine monophosphate (cAMP) in rat dorsal root ganglion (DRG) neurones. Methods: Whole-cell currents were measured in cultured DRG neurones using the combination of voltage and concentration clamp. Results: We have found that extracellular cAMP inhibits P2X3-mediated currents in a concentration- and use-dependent manner. The P2X3 currents, activated by ATP applied every 4 min, were inhibited by 55% in the presence of 10 μm cAMP and by 81% in the presence of 30 μm cAMP. At 8 min interval between ATP applications the same concentration of cAMP did not alter the currents. Addition of 0.5 mm of guanosine 5′- O-(2-thiodiphosphate) to intracellular solution blocked the inhibitory action of cAMP. The inhibitory effects of cAMP were not mimicked by extracellular application of 30 μm adenosine. Conclusions: In this paper, we demonstrate, for the first time, that extracellular application of cAMP to rat sensory neurones inhibits P2X3 receptors via a G protein-coupled mechanism in a use-dependent manner, thus indicating the neuronal expression of specific plasmalemmal cAMP receptor. [ABSTRACT FROM AUTHOR]

Physiologically, macro- and microcirculation differ markedly as macrocirculation deals with pulsatile pressure and flow and microcirculation with steady pressure and flow. Various such haemodynamic aspects correspond to a large heterogeneity in the structure and function of the vascular tree. In the past, diseases such as hypertension and diabetes mellitus were classified on the basis of the structure and function of small and large arteries. The purpose of this paper is to review the cross-talk between the micro- and macrocirculation. We shall discuss this cross-talk from the perspective of the development, physiology and pathology of the entire arterial tree. [ABSTRACT FROM AUTHOR]

Long chain fatty acids (LCFAs) are an important substrate for ATP production within the skeletal muscle. The process of LCFA delivery from adipose tissue to muscle mitochondria involves many regulatory steps. Recently, it has been recognized that LCFA oxidation is not only dependent on LCFA delivery to the muscle, but also on regulatory steps within the muscle. Increasing selected fatty acid binding proteins/transporters on the plasma membrane facilitates a very rapid LCFA increase into the muscle, independent of any changes in LCFA delivery to the muscle. Such a mechanism of LCFA transporter translocation is activated by muscle contraction. Intramuscular triacylglycerols may also be hydrolysed to provide fatty acids for mitochondrial oxidation, particularly during exercise, when hormone-sensitive lipase and other enzymes are activated. Mitochondrial LCFA entry is also highly regulated. This however does not involve only the malonyl CoA carnitine palmitoyltransferase-I (CPTI) axis. Exercise-induced fatty acid entry into mitochondria is also regulated by at least one of the proteins (FAT/CD36) that also regulates plasma membrane fatty acid transport. Among individuals, differences in mitochondrial fatty acid oxidation appear to be correlated with the content of mitochondrial CPTI and FAT/CD36. This paper provides a brief overview of mechanisms that regulate LCFA uptake and oxidation in skeletal muscle during exercise and in obesity. We focus largely on our own work on FAT/CD36, which contributes to regulating, in a coordinated fashion, LCFA uptake across the plasma membrane and the mitochondrial membrane. Very little is known about the roles of FATP1-6 on fatty acid transport in skeletal muscle. [ABSTRACT FROM AUTHOR]

Voltage-gated Ca2+ channels (Cav) are highly expressed in the adrenal chromaffin cells of mammalian species. Besides shaping action potential waveforms, they are directly involved in the excitation–secretion coupling underlying catecholamine release and, possibly, control other Ca2+-dependent events that originate near the membrane. These functions are shared by a number of Cav channel types (L, N, P/Q, R and T) which have different structure–function characteristics and whose degree of expression changes remarkably among mammalian species. Understanding precisely the functioning of each voltage-gated Ca2+ channels is a crucial task that helps clarifying the Ca2+-dependent mechanisms controlling exocytosis during physiological and pathological conditions. In this paper, we focus on classical and new roles that L- and T-type channels play in the control of chromaffin cell excitability and neurotransmitter release. Interestingly, L-type channels are shown to be implicated in the spontaneous autorhythmicity of chromaffin cells, while T-type channels, which are absent in adult chromaffin cells, are coupled with secretion and can be recruited following long-term β-adrenergic stimulation or chronic hypoxia. This suggests that like other cells, adrenal chromaffin cells undergo effective remodelling of membrane ion channels and cell functioning during prolonged stress conditions. [ABSTRACT FROM AUTHOR]

The paper reviews findings in humans regarding interindividual differences in sympathetic nerve activity. Data come predominantly from microneurographic multi- or single fibre recordings of sympathetic nerve activity in healthy subjects. Findings relate to interindividual differences in muscle sympathetic nerve activity (MSNA) during resting conditions and in response to surprising sensory stimuli. At rest there are marked interindividual differences in the number of multiunit MSNA bursts. At the single fibre level the differences are because of more vasoconstrictor fibres being active in subjects with high than in subjects with low number of bursts. There are inverse relationships between (i) sympathetic burst incidence and cardiac output (CO) and (ii) between sympathetic burst incidence and vascular responsiveness to noradrenaline. Both findings contribute to explaining the absence of correlation between resting levels of MSNA and blood pressure. Surprising visual, somatosensory or auditory stimuli of sufficient strength cause a short lasting inhibition of MSNA in approx. 50–60% of healthy subjects. In subjects who display significant inhibition, the stimulus-induced blood pressure increase is smaller than in subjects without inhibition. The underlying mechanism may be related to fear of blood/injury. It is concluded that analysis of interindividual differences in sympathetic activity improves the understanding of central nervous control of the circulation. [ABSTRACT FROM AUTHOR]

We thank Sandal et al for taking an interest in our paper[1] and the intriguing question on the determinants of mean arterial blood pressure (MAP) in mammals. Sandal et al[2] present a correlation between MAP and the vertical distance between the heart and the brain in 16 different species of (predominantly large) mammals. 1 Poulsen CB, Wang T, Assersen K, Iversen NK, Damkjaer M. Does mean arterial blood pressure scale with body mass in mammals?. [Extracted from the article]

Epithelia are physiologically exposed to osmotic stress resulting in alteration of cell volume in several aspects of their functioning; therefore, the activation of ‘emergency’ systems of rapid cell volume regulation is fundamental in their physiology. In this review, the physiological response to osmotic stress, particularly hypertonic stress, was described in a salt-transporting epithelium, the intestine of the euryhaline teleost European eel. This epithelium is physiologically exposed to changes in extracellular osmolarity and represents a good physiological model for functional studies on cellular volume regulation, permitting the study of volume regulated ion transport mechanisms in a native tissue. An absorptive form of the cotransporter, homologue of the renal NKCC2, localized on the apical membrane, was found in the intestine of the euryhaline teleost European eel. This cotransporter accounts for the luminal uptake of Cl−; it operates in series with a basolateral Cl− conductance and presumably a basolateral electroneutral KCl cotransport and in parallel with a luminal K+ conductance. The ion transport model described for eel intestine, based on the operation of an absorptive luminal Na+–K+–2Cl−, is basically the same as the model that has been proposed for the thick ascending limb (cTAL) of the mammalian renal cortex. This paper focuses on the role of Na+–K+–2Cl− cotransport in the responses to hypertonic stress in the eel intestine and the role of cytoskeleton (either actin-based or tubulin based) is discussed. [ABSTRACT FROM AUTHOR]

An injury often starts with acute physiological pain, which becomes inflammatory or neuropathic, and may sometimes become chronic. It has been proposed recently that activated glial cells, astrocytes and microglia within the central nervous system could maintain the pain sensation even after the original injury or inflammation has healed, and convert it into chronic by altering neuronal excitability. Glial cell activation has also been proposed to be involved in the phenomenon of spread of pain sensation ipsilaterally or to the contralateral side (i.e. mirror image pain). Substance P and calcitonin gene-related peptide, released due to an inflammatory process, interact with the endothelial cells of the blood–spinal cord and blood–brain barriers. The barriers open partially and substances may influence adjacent glial cells. Such substances are also released from neurones carrying the ‘pain message’ all the way from the injury to the cerebral cortex. Pro-inflammatory cytokines may be released from the microglial cells, and astroglial Ca2+-transients or oscillations may spread within the astroglial networks. One theory is that Ca2+-oscillations could facilitate the formation of new synapses. These new synapses could establish neuronal contacts for maintaining and spreading the pain sensation. If this theory holds true, it is possible that Ca2+ waves, production of cytokines and growth factors could be modified by selective anti-inflammatory drugs to achieve a balance in the activities of the different intercellular and intracellular processes. This paper reviews current knowledge about glial mechanisms underlying the phenomena of chronic pain and spread of the pain sensation. [ABSTRACT FROM AUTHOR]

Aims: Nfix is a transcription factor belonging to the Nuclear Factor I (NFI) family comprising four members (Nfia, b, c, x). Nfix plays important roles in the development and function of several organs. In muscle development, Nfix controls the switch from embryonic to fetal myogenesis by promoting fast twitching fibres. In the adult muscle, following injury, lack of Nfix impairs regeneration, inducing higher content of slow‐twitching fibres. Nfix is expressed also in the heart, but its function has been never investigated before. We studied Nfix role in this organ. Methods: Using Nfix‐null and wild type (WT) mice we analyzed: (1) the expression pattern of Nfix during development by qPCR and (2) the functional alterations caused by its absence, by in vivo telemetry and in vitro patch clamp analysis. Results and Conclusions: Nfix expression start in the heart from E12.5. Adult hearts of Nfix‐null mice show a hearts morphology and sarcomeric proteins expression similar to WT. However, Nfix‐null animals show tachycardia that derives form an intrinsic higher beating rate of the sinus node (SAN). Molecular and functional analysis revealed that sinoatrial cells of Nfix‐null mice express a significantly larger L‐type calcium current (Cacna1d + Cacna1c). Interestingly, downregulation of Nfix by sh‐RNA in primary cultures of neonatal rat ventricular cardiomyocytes induced a similar increase in their spontaneous beating rate and in ICaL current. In conclusion, our data provide the first demonstration of a role of Nfix that, increasing the L‐type calcium current, modulates heart rate. [ABSTRACT FROM AUTHOR]

Aim: General anesthesia can induce cognitive deficits in both humans and rodents, correlating with pathological alterations in the hippocampus. However, whether general anesthesia affects olfactory behaviors remains controversial as clinical studies have produced inconsistent results. Therefore, we aimed to investigate how olfactory behaviors and neuronal activity are affected by isoflurane exposure in adult mice. Methods: The olfactory detection test, olfactory sensitivity test, and olfactory preference/avoidance test were used to examine olfactory function. In vivo electrophysiology was performed in awake, head‐fixed mice to record single‐unit spiking and local field potentials in the olfactory bulb (OB). We also performed patch‐clamp recordings of mitral cell activity. For morphological studies, immunofluorescence and Golgi–Cox staining were applied. Results: Repeated exposure to isoflurane impaired olfactory detection in adult mice. The main olfactory epithelium, the first region exposed to anesthetics, displayed increased proliferation of basal stem cells. In the OB, a crucial hub for olfactory processing, repeated isoflurane exposure increased the odor responses of mitral/tufted cells. Furthermore, the odor‐evoked high gamma response was decreased after isoflurane exposure. Whole‐cell recordings further indicated that repeated isoflurane exposure increased the excitability of mitral cells, which may be due to weakened inhibitory input in isoflurane‐exposed mice. In addition, elevated astrocyte activation and glutamate transporter‐1 expression in the OB were observed in isoflurane‐exposed mice. Conclusions: Our findings indicate that repeated isoflurane exposure impairs olfactory detection by increasing neuronal activity in the OB in adult mice. [ABSTRACT FROM AUTHOR]

Aim: Histidine‐containing dipeptides (HCDs) are pleiotropic homeostatic molecules with potent antioxidative and carbonyl quenching properties linked to various inflammatory, metabolic, and neurological diseases, as well as exercise performance. However, the distribution and metabolism of HCDs across tissues and species are still unclear. Methods: Using a sensitive UHPLC–MS/MS approach and an optimized quantification method, we performed a systematic and extensive profiling of HCDs in the mouse, rat, and human body (in n = 26, n = 25, and n = 19 tissues, respectively). Results: Our data show that tissue HCD levels are uniquely produced by carnosine synthase (CARNS1), an enzyme that was preferentially expressed by fast‐twitch skeletal muscle fibres and brain oligodendrocytes. Cardiac HCD levels are remarkably low compared to other excitable tissues. Carnosine is unstable in human plasma, but is preferentially transported within red blood cells in humans but not rodents. The low abundant carnosine analogue N‐acetylcarnosine is the most stable plasma HCD, and is enriched in human skeletal muscles. Here, N‐acetylcarnosine is continuously secreted into the circulation, which is further induced by acute exercise in a myokine‐like fashion. Conclusion: Collectively, we provide a novel basis to unravel tissue‐specific, paracrine, and endocrine roles of HCDs in human health and disease. [ABSTRACT FROM AUTHOR]

Abstract: Aim: The “voltage hypothesis” of H+ secretion states that urinary acidification following increased Na+ delivery to the collecting duct (CD) is ENaC dependent leading to transepithelial voltage‐dependent increase in H+ secretion. We recently showed that furosemide acidifies the urine independently of ENaC activity. If the voltage hypothesis holds, hydrochlorothiazide (HCT) must acidify the urine. We here tested the acute effect of HCT on urine pH under normal and high ENaC expression. Methods: Mice subjected to a control or a low‐Na+ diet were anesthetized and infused (0.5 mL h−1) with saline. Catheterization of the urinary bladder allowed real‐time measurement of diuresis and urine pH. Mice received either HCT (1 mg mL−1) or vehicle. Urinary Na+ and K+ excretions were determined by flame photometry. ENaC expression levels were measured by semi‐quantitative Western blotting. Results: (1) HCT increased diuresis and natriuresis in both diet groups. (2) K+ excretion rates increased after HCT administration from 18.6 ± 1.3 to 31.7 ± 2.5 μmol h−1 in the control diet group and from 23.0 ± 1.3 to 48.7 ± 3.0 μmol h−1 in the low‐Na+ diet group. (3) Mice fed a low‐Na+ diet showed a marked upregulation of ENaC. (4) Importantly, no acute changes in urine pH were observed after the administration of HCT in either group. Conclusion: Acute administration of HCT has no effect on urine pH. Similarly, substantial functional and molecular upregulation of ENaC did not cause HCT to acutely change urine pH. Thus, an increased Na+ load to the CD does not alter urine pH. This supports our previous finding and likely falsifies the voltage hypothesis of H+ secretion. [ABSTRACT FROM AUTHOR]

Abstract: Chance events led me to a lifelong career in scientific research. They paved the way for being the first to see long‐term potentiation of synaptic efficiency (LTP) in Per Andersen's laboratory in Oslo in 1966. Here I describe my way to this discovery and the experiments with Tim Bliss in 1968–1969 that led to Bliss and Lømo, 1973. Surprisingly, we later failed to reproduce these results. I discuss possible reasons for this failure, which made us both leave LTP research, in my case for good, in Tim's case for several years. After 30 years of work in a different field, I renewed my interest in the hippocampus and LTP in the early 2000s and published, for the first time, results that I had obtained 40 years earlier. Here I present my take on how interest in and research on LTP evolved after the early years. This includes a discussion of the functions of hippocampus as seen in those early days, the case of patient H.M., Donald Hebb's place in the story, the search for ‘memory molecules’ such as PKMζ, and the primary site for LTP expression (pre‐ and/or post‐synaptic?). Throughout, I reflect on my life in science, how science is done and what drives it. The reflections are quite personal and I admit to mixed feelings about broadcasting them. [ABSTRACT FROM AUTHOR]

In this article, the author discusses a research titled "SLC26A3 deficiency is associated with loss of colonic HCO3- secretion, absence of a firm mucus layer and barrier impairment in mice" by F. Xiao and colleagues, present in the issue. Topics discussed include mucus is a barrier against luminal environment and pathogens in the gastrointestinal tract, intestinal inflammation and the genetic defect of SLC26A3, and regulated ion transport for mucosal defense in airway.

Aim: We aimed to investigate the inter‐individual variability in redox and physiological responses of antioxidant‐deficient subjects after antioxidant supplementation. Methods: Two hundred individuals were sorted by plasma vitamin C levels. A low vitamin C group (n = 22) and a control group (n = 22) were compared in terms of oxidative stress and performance. Subsequently, the low vitamin C group received for 30 days vitamin C (1 g) or placebo, in randomized, double‐blind, crossover fashion, and the effects were examined through a mixed‐effects model, while individual responses were calculated. Results: The low vitamin C group exhibited lower vitamin C (−25 μmol/L; 95%CI[−31.7, −18.3]; p < 0.001), higher F2‐isoprostanes (+17.1 pg/mL; 95%CI[6.5, 27.7]; p = 0.002), impaired VO2max (−8.2 mL/kg/min; 95%CI[−12.8, −3.6]; p < 0.001) and lower isometric peak torque (−41.5 Nm; 95%CI[−61.8, −21.2]; p < 0.001) compared to the control group. Regarding antioxidant supplementation, a significant treatment effect was found in vitamin C (+11.6 μmol/L; 95%CI[6.8, 17.1], p < 0.001), F2‐isoprostanes (−13.7 pg/mL; 95%CI[−18.9, −8.4], p < 0.001), VO2max (+5.4 mL/kg/min; 95%CI[2.7, 8.2], p = 0.001) and isometric peak torque (+18.7; 95%CI[11.8, 25.7 Nm], p < 0.001). The standard deviation for individual responses (SDir) was greater than the smallest worthwhile change (SWC) for all variables indicating meaningful inter‐individual variability. When a minimal clinically important difference (MCID) was set, inter‐individual variability remained for VO2max, but not for isometric peak torque. Conclusion: The proportion of response was generally high after supplementation (82.9%–95.3%); however, a few participants did not benefit from the treatment. This underlines the potential need for personalized nutritional interventions in an exercise physiology context. [ABSTRACT FROM AUTHOR]

Many neuromuscular disorders can have a differential impact on a specific myofibre type, forming the central premise of this review. The many different skeletal muscles in mammals contain a spectrum of slow‐ to fast‐twitch myofibres with varying levels of protein isoforms that determine their distinctive contractile, metabolic, and other properties. The variations in functional properties across the range of classic 'slow' to 'fast' myofibres are outlined, combined with exemplars of the predominantly slow‐twitch soleus and fast‐twitch extensor digitorum longus muscles, species comparisons, and techniques used to study these properties. Other intrinsic and extrinsic differences are discussed in the context of slow and fast myofibres. These include inherent susceptibility to damage, myonecrosis, and regeneration, plus extrinsic nerves, extracellular matrix, and vasculature, examined in the context of growth, ageing, metabolic syndrome, and sexual dimorphism. These many differences emphasise the importance of carefully considering the influence of myofibre‐type composition on manifestation of various neuromuscular disorders across the lifespan for both sexes. Equally, understanding the different responses of slow and fast myofibres due to intrinsic and extrinsic factors can provide deep insight into the precise molecular mechanisms that initiate and exacerbate various neuromuscular disorders. This focus on the influence of different myofibre types is of fundamental importance to enhance translation for clinical management and therapies for many skeletal muscle disorders. [ABSTRACT FROM AUTHOR]

Aim: Enhanced cardiac sympathetic afferent reflex (CSAR) promotes sympathetic hyperactivation in chronic heart failure (CHF). Salusin‐β is a torsin family 2 member A (TOR2A) gene product and a cardiovascular active peptide closely associated with cardiovascular diseases. We aimed to determine the roles of salusin‐β in the paraventricular nucleus (PVN) in modulating enhanced CSAR and sympathetic hyperactivation in rats with CHF induced by coronary artery ligation and elucidate the underlying molecular mechanisms. Methods: CSAR was evaluated based on the responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to the epicardial administration of capsaicin in rats under anesthesia. Results: Salusin‐β protein expression was upregulated in the PVN of the CHF compared with sham‐operated rats. Salusin‐β microinjection into the PVN dose‐dependently increased MAP and RSNA and enhanced CSAR, while anti‐salusin‐β IgG exerted opposite effects. The effect of salusin‐β was inhibited by reactive oxygen species (ROS) scavenger or NAD(P)H oxidase inhibitor but promoted by superoxide dismutase inhibitor. The effect of anti‐salusin‐β IgG was interdicted by nitric oxide (NO) synthase inhibitor. Furthermore, chronic salusin‐β gene knockdown in PVN attenuated CSAR, reduced sympathetic output, improved myocardial remodeling and cardiac function, decreased NAD(P)H oxidase activity and ROS levels, and increased NO levels in the CHF rats. Conclusion: Increased salusin‐β activity in the PVN contributes to sympathetic hyperactivation and CSAR in CHF by inhibiting NO release and stimulating NAD(P)H oxidase‐ROS production. Reducing endogenous central salusin‐β expression might be a novel strategy for preventing and treating CHF in the future. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this study was to 1. investigate if glucose tolerance is affected after one acute bout of different types of exercise; 2. assess if potential differences between two exercise paradigms are related to changes in mitochondrial function; and 3. determine if endurance athletes differ from nonendurance‐trained controls in their metabolic responses to the exercise paradigms. Methods: Nine endurance athletes (END) and eight healthy nonendurance‐trained controls (CON) were studied. Oral glucose tolerance tests (OGTT) and mitochondrial function were assessed on three occasions: in the morning, 14 h after an overnight fast without prior exercise (RE), as well as after 3 h of prolonged continuous exercise at 65% of VO2max (PE) or 5 × 4 min at ~95% of VO2max (HIIT) on a cycle ergometer. Results: Glucose tolerance was markedly reduced in END after PE compared with RE. END also exhibited elevated fasting serum FFA and ketones levels, reduced insulin sensitivity and glucose oxidation, and increased fat oxidation during the OGTT. CON showed insignificant changes in glucose tolerance and the aforementioned measurements compared with RE. HIIT did not alter glucose tolerance in either group. Neither PE nor HIIT affected mitochondrial function in either group. END also exhibited increased activity of 3‐hydroxyacyl‐CoA dehydrogenase activity in muscle extracts vs. CON. Conclusion: Prolonged exercise reduces glucose tolerance and increases insulin resistance in endurance athletes the following day. These findings are associated with an increased lipid load, a high capacity to oxidize lipids, and increased fat oxidation. [ABSTRACT FROM AUTHOR]

Aim: This study mapped the spatiotemporal positions and connectivity of Onecut3+ neuronal populations in the developing and adult mouse brain. Methods: We generated fluorescent reporter mice to chart Onecut3+ neurons for brain‐wide analysis. Moreover, we crossed Onecut3‐iCre and Mapt‐mGFP (Tau‐mGFP) mice to visualize axonal projections. A dual Cre/Flp‐dependent AAV construct in Onecut3‐iCre cross‐bred with Slc17a6‐FLPo mice was used in an intersectional strategy to map the connectivity of glutamatergic lateral hypothalamic neurons in the adult mouse. Results: We first found that Onecut3 marks a hitherto undescribed Slc17a6+/Vglut2+ neuronal cohort in the lateral hypothalamus, with the majority expressing thyrotropin‐releasing hormone. In the adult, Onecut3+/Vglut2+ neurons of the lateral hypothalamus had both intra‐ and extrahypothalamic efferents, particularly to the septal complex and habenula, where they targeted other cohorts of Onecut3+ neurons and additionally to the neocortex and hippocampus. This arrangement suggests that intrinsic reinforcement loops could exist for Onecut3+ neurons to coordinate their activity along the brain's midline axis. Conclusion: We present both a toolbox to manipulate novel subtypes of hypothalamic neurons and an anatomical arrangement by which extrahypothalamic targets can be simultaneously entrained. [ABSTRACT FROM AUTHOR]

Aim: Accurate evaluation of glomerular filtration rate (GFR) is crucial in Oncology as drug eligibility and dosing depend on estimates of GFR. However, there are no clear guidelines on the optimal method of determining kidney function in patients with cancer. We aimed to summarize the evidence on estimation of kidney function in patients with cancer. Methods: We searched PubMed for literature discussing the performance of GFR estimating equations in patients with malignancy to create a table of the evidence for creatinine‐ and cystatin c‐based equations. We further reviewed novel estimation techniques such as panel eGFR, real‐time measured GFR, and functional magnetic resonance imaging. Results: The commonly used GFR estimating equations were derived from populations of patients without cancer. These equations may be less applicable in Oncology due to severe sarcopenia, inflammation, and other physiologic changes in patients with cancer. The Cockcroft‐Gault equation currently dominates in clinical Oncology despite significant limitations and accumulating evidence for use of the CKD‐EPICr formula. Additional considerations in the practice of Oncology include a recently developed equation (CamGFRv2, also called the Janowitz formula) and the use of cystatin c‐based equations to overcome some of the barriers to accurate GFR estimation based on creatinine alone. Conclusion: Overall, we suggest using the CKD‐EPI equations (either cystatin c or creatinine‐based) among patients with cancer in routine clinical practice and measured GFR for patients at a critical threshold for treatment decisions. [ABSTRACT FROM AUTHOR]

The author reflects on ageing. The author mentions that the basis of ageing is still unidentified despite the papers published about the topic particularly in the journal "Acta Physiologica." He also explores the concept of change and its role on ageing. Moreover, he adds that people cannot change the fact that they are ageing.

The global north is facing an unprecedented rise in the prevalence of neurodegenerative diseases. The increasing incidence of Parkinson's disease is being referred to as a pandemic. The reason for the enormous increase is only partly understood. Lifestyle factors are known to play a role, but they alone cannot account for the surge. One factor that—although being recognized as important—has not been explored in detail so far is the influence of circadian rhythms. Sleep and circadian rhythm disruption are known as key factors in neurodegeneration, and their occurrence during early disease stages suggests a causal role in the pathogenesis. Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) has been identified as a prodromal state of α‐synucleinopathies, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy offering a window for insights into the early development of these diseases. Even though REM sleep is the sleep state most pronounced, driven and modulated by the circadian timing system, specific circadian abnormalities have not been described in iRBD. Novel experimental and clinical approaches exploiting the molecular circuitry underlying circadian timekeeping hold promise to disentangle some of the pathophysiologic mechanisms of α‐synucleinopathies. In this review, we summarize current knowledge on sleep and circadian rhythm disruptions in α‐synucleinopathies with an emphasis on molecular aspects and therapeutic potentials. These insights might contribute to our understanding of the pathogenesis of neurodegenerative diseases and may allow therapeutic interventions addressing the disturbed circadian system at the early stage of disease. [ABSTRACT FROM AUTHOR]

Extreme environments are powerful drivers of physiological adaptation. Naked mole‐rats offer an informative example of this relationship as they putatively encounter intermittent hypoxia and hypercapnia in their subterranean habitat. This has presumably driven the evolution of a suite of cellular and physiological adaptations that enable life in these conditions. Recently, my laboratory and others have begun to examine physiological responses to environmental hypoxia and hypercapnia in naked mole‐rats, and the underlying cellular and molecular mechanisms that differentiate the responses of this species from those of other small mammals. Prominent among these adaptations are a robust hypoxic metabolic response and blunted ventilatory responses to hypoxia and hypercapnia. These responses are mediated in part by modifications to the central nervous system signaling pathways that sense and communicate changes in environmental gas levels and initiate and maintain downstream physiological responses. For example, naked mole‐rats retain the signaling architecture necessary for "normal" ventilatory responses to hypoxia and hypercapnia; however, the underlying signaling pathways are muted, resulting in reduced, or even the absence of, sensitivity to otherwise powerful environmental stimuli. Herein, I discuss what we have learned about the manifestation and control of ventilatory and metabolic responses to hypoxia and hypercapnia in naked mole‐rats. I also highlight areas where additional work is warranted and consider the implications of what we have learned for the ecophysiology of a species that thrives in conditions that are deleterious or lethal to most adult mammals. [ABSTRACT FROM AUTHOR]

Data integration, data sharing, and standardized analyses are important enablers for data‐driven medical research. Circadian medicine is an emerging field with a particularly high need for coordinated and systematic collaboration between researchers from different disciplines. Datasets in circadian medicine are multimodal, ranging from molecular circadian profiles and clinical parameters to physiological measurements and data obtained from (wearable) sensors or reported by patients. Uniquely, data spanning both the time dimension and the spatial dimension (across tissues) are needed to obtain a holistic view of the circadian system. The study of human rhythms in the context of circadian medicine has to confront the heterogeneity of clock properties within and across subjects and our inability to repeatedly obtain relevant biosamples from one subject. This requires informatics solutions for integrating and visualizing relevant data types at various temporal resolutions ranging from milliseconds and seconds to minutes and several hours. Associated challenges range from a lack of standards that can be used to represent all required data in a common interoperable form, to challenges related to data storage, to the need to perform transformations for integrated visualizations, and to privacy issues. The downstream analysis of circadian rhythms requires specialized approaches for the identification, characterization, and discrimination of rhythms. We conclude that circadian medicine research provides an ideal environment for developing innovative methods to address challenges related to the collection, integration, visualization, and analysis of multimodal multidimensional biomedical data. [ABSTRACT FROM AUTHOR]