Frontiers in Physiology

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ISSN / EISSN : 1664-042X / 1664-042X
Published by: Frontiers Media SA (10.3389)
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, Nilima Nigam, James M. Wakeling, Stephanie A. Ross
Published: 26 January 2022
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.804188

Abstract:
Cerebral palsy results from an upper motor neuron lesion and significantly affects skeletal muscle stiffness. The increased stiffness that occurs is partly a result of changes in the microstructural components of muscle. In particular, alterations in extracellular matrix, sarcomere length, fibre diameter, and fat content have been reported; however, experimental studies have shown wide variability in the degree of alteration. Many studies have reported changes in the extracellular matrix, while others have reported no differences. A consistent finding is increased sarcomere length in cerebral palsy affected muscle. Often many components are altered simultaneously, making it difficult to determine the individual effects on muscle stiffness. In this study, we use a three dimensional modelling approach to isolate individual effects of microstructural alterations typically occurring due to cerebral palsy on whole muscle behaviour; in particular, the effects of extracellular matrix volume fraction, stiffness, and sarcomere length. Causation between the changes to the microstructure and the overall muscle response is difficult to determine experimentally, since components of muscle cannot be manipulated individually; however, utilising a modelling approach allows greater control over each factor. We find that extracellular matrix volume fraction has the largest effect on whole muscle stiffness and mitigates effects from sarcomere length.
, Ana C. Takakura, Eduardo Colombari
Published: 26 January 2022
Frontiers in Physiology, Volume 13; https://doi.org/10.3389/fphys.2022.841001

Abstract:
Editorial on the Research TopicIntegrative Physiology: Systemic Hypertension and Respiratory-Sympathetic Coupling The brainstem has an essential role in the maintenance of vasomotor tonus, cardiac output, and consequently arterial blood pressure at physiological levels. Several interconnected neuronal groups provide tonic excitation to the sympathetic nerves, which innervate blood vessels and the heart (Dampney, 1994; Guyenet, 2006). Among these nuclei involved with the generation of baseline sympathetic activity to the cardiovascular system, a cluster of bulbospinal neurons located in the rostral ventrolateral aspect of the medulla oblongata (RVLM) is considered the core of the sympathetic nervous system (Guertzenstein and Silver, 1974; Guyenet, 2006). The RVLM contains a large collection of neurons that innervate the preganglionic sympathetic neurons (SPGNs) monosynaptically (presympathetic neurons). In addition, these neurons are an important convergence point for sympathetic reflexes elicited by cardiopulmonary receptors and descending inputs from the hypothalamus and higher in the neuraxis (Guyenet, 2006). The presympathetic neurons of the RVLM are presumably glutamatergic (Stornetta et al., 2002), but a large subset of them, defined as C1 neurons, also express the entire complement of catecholamine-biosynthetic enzymes inclusive of the epinephrine-producing phenylethanolamine N-methyl transferase (PNMT) (Hokfelt et al., 1974; Ross et al., 1984). The C1 neurons are not exclusively presympathetic as many C1 cells do not innervate sympathetic preganglionic neurons, but target instead of the hypothalamus, basal forebrain, and periaqueductal gray matter. Not least, the brainstem region also contains several nuclei with interconnected structures that are necessary to produce cardiorespiratory homeostasis. The components of this complex network include many types of neurons and satellite cells and are in a long column in the lateral brainstem that extends from the caudal medulla along the ventrolateral medulla to the dorsolateral pons, and dorsally to the nucleus of the solitary tract (NTS) (Feldman et al., 2013; Machado et al., 2017). Based on functional and anatomical criteria, the ventral respiratory column (VRC) located in the ventral lateral medulla is divided into at least five functionally distinct structures (For details, see Del Negro et al., 2018). A similar, if not overlapping, distribution of neurons has been identified for the cardiovascular control system (Guyenet, 2014). Within the same region of the ventrolateral medulla, cardiovascular physiologists have divided the region into three rostrocaudal regions which contain a complex neural network responsible for the generation, modulation, and integration of the sympathetic activity (For details, see Guyenet, 2006). In this Research Topic in Frontiers in Physiology, we have 5 original articles and 1 review article based on the topic entitled “Integrative Physiology: Systemic Hypertension and Respiratory-Sympathetic Coupling.” The articles drew together an international collection of ideas that highlighted network mechanisms that underlie cardiorespiratory control and their clinical implications. Recent advances in neurobiology have provided novel insights into the cellular and network mechanisms that underlie cardiorespiratory control. The use of slices, in situ and in vivo preparations, combined with modern genetic, molecular and optogenetic techniques have led to a new level of understanding of the mechanisms that govern not only the normal physiological integration of cardiovascular and respiratory functions but also the mechanisms that lead to pathologies such as those seen in hypertension, sleep apnea associated with obesity, inflammation, and fetal undernutrition. The first article “Medullary Noradrenergic Neurons Mediate Hemodynamic Responses to Osmotic and Volume Challenges” by Marques et al. provides experimental evidence based on loss of function pharmacological technique that both the A1 and A2 catecholaminergic neurons of the brainstem are essential to hypertonic saline-induced cardiovascular recovery in hypovolemia. Briefly, simultaneous A1 and A2 dysfunctions could impair the efficacy of hypertonic saline-induced recovery in a condition of hemorrhage. The authors discussed based on the literature and previous work from their laboratories that both A1 and A2 cells project to forebrain regions involved in hydroelectrolytic adjustments, and lesion of these groups could lead to signaling deficit and impairment of the recruitment settings of other pathways before the attenuation of hypertonic saline-induced recovery after hemorrhage. The second article authored by Kim et al. entitled “Leptin Receptor Blockade Attenuates Hypertension but Does Not Affect Ventilatory Response to Hypoxia in a Model of Polygenic Obesity” provides key information about the link that obesity can cause hypertension and exacerbates sleep-disordered breathing (SDB). The authors used New Zealand obese mice, a model of polygenic obesity, that have high levels of circulating leptin and hypertension, and are prone to develop SDB, similarly to human obesity. The data showed that leptin receptors blockade attenuated hypertension without exacerbating obesity or SDB, suggesting that obesity-related hypertension is, at least in part, related to leptin signaling. The article highlights the potential applicability of pharmacological blockade of leptin signaling as a therapy for patients with obesity-induced hypertension. Obstructive sleep apnea (OSA) is a common breathing disorder affecting a significant percentage of the adult population. OSA is an independent risk factor for cardiovascular disease; however, the underlying mechanisms are not completely understood. The data presented by Cetin-Atalay et al. investigated the effect of...
Wolfgang Goettler, Martin Kaltenpoth, Samuel McDonald,
Published: 26 January 2022
Frontiers in Physiology, Volume 13; https://doi.org/10.3389/fphys.2022.815494

Abstract:
Females of the solitary digger wasp tribe Philanthini, called the beewolves (Hymenoptera, Crabronidae), cultivate strains of symbiotic bacteria that belong to the genus Streptomyces in unique and highly specialized glands in their antennae. The glands consist of large reservoirs that are surrounded by numerous gland cell complexes (class III). The symbionts are cultivated inside the reservoirs and are probably provisioned with nutrients secreted from the surrounding glands and/or sequestered from the hemolymph. The wasp female delivers the bacteria into the subterranean brood cell prior to oviposition. Fully grown larvae take up the bacteria and apply them to their cocoon. There the bacteria produce several antibiotics that protect the wasp offspring against fungus infestation. Hitherto Streptomyces bacteria were detected in the antennae of 38 species of the Philanthini. However, a detailed morphological analysis of the antennal glands is only available for a few species. In order to shed light on the evolutionary history of the association between beewolf wasps and bacteria, we investigated the morphology of the antennal glands of another 14 Philanthus species from the Palearctic, Paleotropic, and Nearctic. We generated 3D-models of the glands based on serial semithin sections and/or micro-CT (μCT). Despite broad similarities in number and structure of antennal glands, the results revealed interspecific differences with regard to overall shape, complexity, and relative size of the reservoirs as well as the number of the surrounding gland cell units. Mapping the morphology of all species studied so far on the phylogeny (that parallels geographical distribution) revealed that related species share similarities in gland morphology, but there are notable differences between lineages. In particular, compared to the North American species the European and African species possess more complex gland structures with a higher number of gland cells. We discuss morphological, ecological, and physiological aspects and provide scenarios for the evolution of the antennal glands of the Philanthini as symbiont cultivation organs.
, Jonathan Ozik, Remy Spliet, Nicholson T. Collier, Iris Lansdorp-Vogelaar, Reinier G. S. Meester
Published: 26 January 2022
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.718276

Abstract:
Background: Fecal immunochemical testing (FIT) is an established method for colorectal cancer (CRC) screening. Measured FIT-concentrations are associated with both present and future risk of CRC, and may be used for personalized screening. However, evaluation of personalized screening is computationally challenging. In this study, a broadly applicable algorithm is presented to efficiently optimize personalized screening policies that prescribe screening intervals and FIT-cutoffs, based on age and FIT-history. Methods: We present a mathematical framework for personalized screening policies and a bi-objective evolutionary algorithm that identifies policies with minimal costs and maximal health benefits. The algorithm is combined with an established microsimulation model (MISCAN-Colon), to accurately estimate the costs and benefits of generated policies, without restrictive Markov assumptions. The performance of the algorithm is demonstrated in three experiments. Results: In Experiment 1, a relatively small benchmark problem, the optimal policies were known. The algorithm approached the maximum feasible benefits with a relative difference of 0.007%. Experiment 2 optimized both intervals and cutoffs, Experiment 3 optimized cutoffs only. Optimal policies in both experiments are unknown. Compared to policies recently evaluated for the USPSTF, personalized screening increased health benefits up to 14 and 4.3%, for Experiments 2 and 3, respectively, without adding costs. Generated policies have several features concordant with current screening recommendations. Discussion: The method presented in this paper is flexible and capable of optimizing personalized screening policies evaluated with computationally-intensive but established simulation models. It can be used to inform screening policies for CRC or other diseases. For CRC, more debate is needed on what features a policy needs to exhibit to make it suitable for implementation in practice.
Mitchell Masterson, Riyan Bittar, Hannah Chu, Naoki Yamanaka,
Published: 26 January 2022
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.816058

Abstract:
Steroid hormones control development and homeostasis in a wide variety of animals by interacting with intracellular nuclear receptors. Recent discoveries in the fruit fly Drosophila melanogaster revealed that insect steroid hormones or ecdysteroids are incorporated into cells through a membrane transporter named Ecdysone Importer (EcI), which may become a novel target for manipulating steroid hormone signaling in insects. In this study, we established an assay system that can rapidly assess EcI-mediated ecdysteroid entry into cultured cells. Using NanoLuc Binary Technology (NanoBiT), we first developed an assay to detect ligand-dependent heterodimerization of the ecdysone receptor (EcR) and retinoid X receptor (RXR) in human embryonic kidney (HEK) 293T cells. We also developed HEK293 cells that stably express EcI. By combining these tools, we can monitor ecdysteroid entry into the cells in real time, making it a reliable system to assess EcI-mediated steroid hormone incorporation into animal cells.
Ceren Eyileten, Zofia Wicik, Alex Fitas, Mikolaj Marszalek, Jenny E. Simon, Salvatore De Rosa, Szczepan Wiecha, Jeffrey Palatini, , Lukasz A. Malek
Published: 25 January 2022
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.792931

Abstract:
Background: Despite the positive effects of endurance training on the cardiovascular (CV) system, excessive exercise induces not only physiological adaptations but also adverse changes in CV system, including the heart. We aimed to evaluate the selected miRNAs expression based on bioinformatic analysis and their changes before and after an ultramarathon run.Materials and Methods: Cardiac tissue-specific targets were identified with the Tissue 2.0 database. Gene-gene interaction data were retrieved from the STRING app for Cytoscape. Twenty-three endurance athletes were recruited to the study. Athletes ran to completion (100 km) or exhaustion (52–91 km, median 74 km). All participants completed pre- and post-run testing. miRNAs expressions were measured both before and after the race.Results: Enrichment analysis of the signaling pathways associated with the genes targeted by miRNAs selected for qRT-PCR validation (miR-1-3p, miR-126, miR-223, miR-125a-5p, miR-106a-5p, and miR-15a/b). All selected miRNAs showed overlap in regulation in pathways associated with cancer, IL-2 signaling, TGF-β signaling as well as BDNF signaling pathway. Analysis of metabolites revealed significant regulation of magnesium and guanosine triphosphate across analyzed miRNA targets. MiR-1-3p, miR-125a-5p, miR-126, and miR-223 expressions were measured in 23 experienced endurance athletes, before and after an ultramarathon wherein athletes ran to completion (100 km) or exhaustion (52–91 km, median 74 km). The expressions of miR-125a-5p, miR-126, and miR-223 were significantly increased after the race (p = 0.007, p = 0.001, p = 0.014, respectively). MiR-1-3p expression post-run showed a negative correlation with the post-run levels of high-sensitivity C-reactive protein (hs-CRP) (r = −0.632, p = 0.003). Higher miR-1-3p expression was found in runners, who finished the race under 10 h compared to runners who finished over 10 h (p = 0.001). Post-run miR-125a-5p expression showed a negative correlation with the peak lactate during the run (r = −0.576, p = 0.019).Conclusion: Extreme physical activity, as exemplified by an ultramarathon, is associated with changes in circulating miRNAs’ expression related to inflammation, fibrosis, and cardiac muscle function. In particular, the negative correlations between miR-125a-5p and lactate concentrations, and miR-1-3p and hs-CRP, support their role in specific exercise-induced adaptation. Further studies are essential to validate the long-term effect of these observations.
, Simon Valentin, Silvia Demoulin-Alexikova, Bruno Demoulin, Laurent Foucaud, Delphine Gérard, Celso Pouget, Edem Allado, Bruno Chenuel, Mathias Poussel
Published: 25 January 2022
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.804577

Abstract:
Introduction: Cough is a major lower airway defense mechanism that can be triggered by exercise in asthma patients. Studies on cough reflex in experimental animal models revealed a decrease of cough reflex sensitivity during exercise in healthy animals, but a lack of desensitization in ovalbumin-sensitized rabbits. The aim of our study is to evaluate the impact of inhaled corticosteroids on cough reflex during artificial limb exercise in an animal model of eosinophilic airway inflammation.Materials and Methods: Sixteen adult ovalbumin-sensitized rabbits were randomly divided into two groups. The “OVA-Corticoid” group (n = 8) received inhaled corticosteroids (budesonide; 1 mg/day during 2 consecutive days) while the “OVA-Control” (n = 8) group was exposed to saline nebulization. The sensitivity of defensive reflexes induced by direct mechanical stimulation of the trachea was studied in anesthetized animals, at rest and during artificial limb exercise. Cell count was performed on bronchoalveolar lavage fluid and middle lobe tissue sections to assess the level of eosinophilic inflammation.Results: All rabbits were significantly sensitized but there was no difference in eosinophilic inflammation on bronchoalveolar lavage or tissue sections between the two groups. Artificial limb exercise resulted in a significant (p = 0.002) increase in minute ventilation by 30% (+ 209 mL.min–1, ± 102 mL/min–1), with no difference between the two groups. 322 mechanical tracheal stimulations were performed, 131 during exercise (40.7%) and 191 at rest (59.3%). Cough reflex was the main response encountered (46.9%), with a significant increase in cough reflex threshold during artificial limb exercise in the “OVA-Corticoid” group (p = 0.039). Cough reflex threshold remained unchanged in the “OVA-Control” group (p = 0.109).Conclusion: Inhaled corticosteroids are able to restore desensitization of the cough reflex during artificial limb exercise in an animal model of airway eosinophilic inflammation. Airway inflammation thus appears to be involved in the physiopathology of exercise-induced cough in this ovalbumin sensitized rabbit model. Inhaled anti-inflammatory treatments could have potential benefit for the management of exercise-induced cough in asthma patients.
, Haiyong Chen, Ying Tang, David J. Nikolic-Paterson,
Published: 25 January 2022
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.827537

Abstract:
Editorial on the Research TopicImmune Landscape of Kidney Pathology Kidney disease is an emerging cause of morbidity and mortality. More than 6 million patients worldwide receive renal replacement therapy. The global prevalence of chronic kidney disease (CKD) is between 11.7 and 15.1% of the adult population. Nevertheless, we still lack effective treatments to stop the progression of CKD, which makes it an urgent area with unmet clinical need. CKD is defined as abnormal kidney structure and/or function caused by primary and secondary glomerular diseases (including diabetes, hypertension, autoimmune diseases, etc.). Renal fibrosis is a common feature of CKD and is widely regarded as the main driver of the progression to end-stage renal disease. However, the underlying mechanisms of the renal fibrotic response are complex and still poorly understood. Emerging research shows that unresolved inflammation may be a necessary condition to promote the transition from acute kidney injury to chronic renal fibrosis. Various white blood cell populations are recruited into injured kidneys and play important roles in pathogen clearance and tissue repair. However, if this inflammatory response does not subside, it will instead promote progressive fibrosis of the damaged kidney. Interestingly, a large number of studies have shown that infiltrating leukocytes, including macrophages, dendritic cells, natural killer cells, and T and B cells, actively promote the transition from renal inflammation to fibrosis (Tang et al., 2020a). In addition, changes in the microenvironment in different kidney compartments also play a key role in the immune response and disease pathogenesis. A better understanding of the immune process in the development of CKD may reveal direct and indirect immunomodulation methods as new therapeutic strategies to prevent the progression of different forms of kidney disease. Therefore, we initiated this research project co-sponsored by Frontiers in Physiology and Frontiers in Medicine, aiming to bring together research from multiple disciplines, with special attention to immunology, renal physiology and pathology. We invited researchers to share their latest insights into how host immunity and its effectors reshape the kidney microenvironment to achieve the physiological and/or pathogenic effects of diseased kidneys. We are very pleased that this Research Topic has been welcomed by basic researchers and clinical scientists from all over the world. A total of 22 high-quality papers have been published, including nine original studies, six reviews, four mini-reviews, one case report and a brief research report. These papers are written by 159 authors from around the world, providing cross-sectional and multi-disciplinary approaches in the latest kidney disease research. Broadly speaking, these papers focus on five core topics: (i) immunodynamics; (ii) pathogenic mechanisms; (iii) advanced research technology; (iv) therapeutic development; and (v) social impact on patients with kidney disease. The following is a brief overview of each study. The kidney is one of the main organs for detoxification in our body. Its failure is an important cause of patient death. In addition, kidney disease is a major contributor to patient death in a wide range of diseases such as diabetes, cancer, bacterial and viral infections (including COVID-19; Tang et al., 2021a; Wang et al., 2021); leading to more than 6 million deaths worldwide each year. Thus, developing a better understanding, and treatment of, kidney disease is critical. Renal fibrosis is a key pathological mechanism in the loss of normal structure and function of the kidney, resulting in progressive kidney damage. Encouragingly, scientists have begun to realize that the over-activation of the immune system is an essential component in this process, and this feature is summarized by Tang et al. in this Research Topic. Macrophages are a type of immune cell that maintains the health of our kidneys (Tang et al., 2019). They are responsible for detecting, engulfing, and destroying pathogens and unhealthy cells as discussed by Cantero-Navarro et al. Paradoxically, new research finds that macrophages can also accelerate kidney failure as highlighted by a systematic review from Wang et al. A better understanding of the underlying mechanisms can isolate the adverse effects of macrophages from their protective effects. For example, a new phenomenon “macrophage-myofibroblast transition (MMT)” has been identified as a pathway promoting the tissue scarring (Figure 1), and dissecting this MMT pathway may identify novel druggable therapeutic targets for kidney fibrosis (Tang et al., 2018a, 2020b). Figure 1. Occurrence of MMT (yellow) in a human kidney with chronic allograft dysfunction, indicating by the presence of macrophage (CD68, red) expressing myofibroblast marker (alpha-SMA, green). Changes in the immune landscape are essential components in both disease pathogenesis and tissue repair in states of inflammation, but much remains to be done to fully describe such changes in kidney diseases. Vonbrunn et al. investigated the potential significance of glomerular immune reactivity for allograft survival by analyzing the immune profile of time zero kidney specimens and how this impact clinical outcomes. Albino et al. elucidated how innate immunity contributes to the transition of acute kidney injury to renal fibrosis in a gentamicin-induced renal inflammation model. Furthermore, Rodriguez-Carrio et al. found changes in several novel T cell and monocyte subsets during the progression of chronic kidney disease which were significantly associated with vascular outcomes. Unresolved renal inflammation can drive the progression of renal fibrosis, leading to end-stage renal disease. Understanding the mechanisms underlying this unrelenting renal fibrosis is critical for the development of new therapies...
Feng Li, Zhen-Ya Wang, Zhi-Jie Zhang, Su-Hong Shen, Jia-Yi Guo, Yan-Xing Guo, Yi-Ran Feng, Lin Zhang, Yong-Bing Wen, Yun-Fei Zhang, et al.
Published: 25 January 2022
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.752455

Abstract:
Background: Some patients with knee osteoarthritis (KOA) show pain, stiffness and limited flexion and extension at the back of the knee, leading to dysfunction and affecting life. This may be related to changes in the biomechanical properties of skeletal muscles. Shear wave elastography (SWE) can detect these changes by measuring muscle shear modulus.Aims: To investigate hamstring muscle shear modulus of healthy people and patients was studied using SWE method, and the correlation analysis between the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score of patients’ subjective feeling and shear modulus of objective quantification was conducted.Methods: The hamstring shear modulus was measured by SWE in 50 patients and 50 healthy individuals. Pearson correlation coefficient was used to evaluate the correlation between hamstring stiffness and shear modulus in patients.Results: The hamstring shear modulus were significantly higher in the KOA group [the semimembranosus (SM) 15.23 ± 7.23, the semitendinosus (ST) 15.94 ± 5.40, the biceps femoris long tendinitis (BFL) 14.21 ± 6.55] than in the control group (the SM 10.95 ± 2.41, the ST 11.25 ± 2.23, the BFL 9.98 ± 2.81) (p = 0.000, p = 0.000, p = 0.001). The hamstring shear modulus in the KOA group was moderately positively correlated with pain, shear modulus, and physical function score.Conclusion: Preliminary results show that the shear modulus of the hamstring of KOA patients is higher than that of healthy people, the WOMAC score and the shear modulus of patients are moderately correlated. These preliminary results show that ultrasonic shear wave elastography measurement of shear modulus may be enough to sensitive, can detect these effects, more targeted in order to assist the doctor’s diagnosis and treatment.
Yafang Lu, YaQiong Lu, Jun Meng, Zuo Wang
Published: 25 January 2022
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.791848

Abstract:
Diabetic cardiomyopathy (DbCM) is a prevalent disease, characterized by contractile dysfunction and left ventricular hypertrophy. Patients with DbCM have high morbidity and mortality worldwide. Recent studies have identified that pyroptosis, a kind of cell death, could be induced by hyperglycemia involved in the formation of DbCM. This review summarizes the regulatory mechanisms of pyroptosis in DbCM, including NOD-like receptor3, AIM2 inflammasome, long non-coding RNAs, microRNAs, circular RNA, autophagy, and some drugs.
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