Editorial on the Research Topic The evolving picture of Ca²⁺leak from endoplasmic reticulum in health and diseases The endoplasmic reticulum (ER) is one of the two main reservoirs for releasable Ca²⁺ in the cell and usually maintains free Ca²⁺ concentrations of 100–800 μM, which amounts to at least three orders of magnitude higher than in the cytosol (Berridge et al., 2000; Berridge, 2002) (Figure 1A). Therefore, it is remarkable that the ER membrane is not tight to ions; it has indeed a distinct permeability to ions and even small molecules. When the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATP-ases (SERCA), which pump Ca²⁺ into the ER, is blocked, e.g., by thapsigargin, the Ca²⁺ concentration in the ER decreases, unmasking the Ca²⁺ leak/leakage or passive Ca²⁺ efflux from the ER. In the absence of extracellular Ca²⁺, the SERCA inhibition typically leads to a decrease in ER Ca²⁺ with the corresponding transient increase of cytosolic Ca²⁺ (Gamayun et al., 2019). Within several molecular pathways for Ca²⁺ leakage that co-exist in ER membranes, Sec61 translocons are unparalleled because they support both translocation of proteins into the ER and Ca²⁺ leakage from the ER, suggesting a dynamic coupling between ER membrane permeability and protein synthesis (Figure 1B). Therefore, it is not surprising that the Sec61-mediated Ca²⁺ leakage from the ER has been implicated in the etiology of various cancers, neurodegeneration, and infectious diseases (such as Buruli ulcer) as well as inherited diseases, such as immunodeficiency, neutropenia and tubulointerstitial kidney disease (Bolar et al., 2016; Schubert et al., 2018; Van Nieuwenhove et al., 2020; Bhadra et al., 2021; Sicking et al., 2022). Notably, the other ER membrane resident Ca²⁺ leak channels are, in alphabetical order, Bcl-2 (Pinton et al., 2001; Chami et al., 2004), CALHM1 (Gallego-Sandín et al., 2011), Pannexin 1 (Abeele et al., 2006), Presenillins 1 and 2 (Tu et al., 2006), truncated SERCA variants (Chami et al., 2001; Chami et al., 2008) and transient receptor potential superfamily members TRPC1 (Berbey et al., 2009) and TRPP2 (see below). In contrast to the latter proteins, however, the Sec61 translocons are ubiquitous and highly abundant, depending on secretory capacity of the cell, i.e., the extension of the ER (Pick et al., 2021). In HeLa cells, for example, the concentration of heterotrimeric Sec61 complexes is between 139 and 456 nM (judging from the concentration of the subunit with the lowest and highest cellular concentration, respectively, (Lang et al., 2017), and Sec61 channels support about 60% of the Ca²⁺ leakage from the ER (Lang et al., 2011; Gamayun et al., 2019). FIGURE 1. I The endoplasmic reticulum (ER) of nucleated human cells has major functions in cellular calcium homeostasis and contains the abundant and ubiquitous Sec61 channel. (A) The ER is shown here in a HEK293 cell after fluorescence microscopy after staining with ER-Tracker™ Red (BODIPY™ TR Glibenclamide), the plasma membrane was stained with CellMask™ Green Plasma Membrane Stain (details are given by Pick et al.). The image was kindly provided by Tillman Pick (Experimental and Clinical Pharmacology and Toxicology, Saarland University). (B) The Sec61 channel is shown in its modeled closed (top) and open (bottom) conformational states, as indicated (adopted from Lang et al., 2017). These two states are proposed to be in a dynamic equilibrium with each other. The fully open state of the Sec61 channel allows the initial entry of precursor polypeptides from the cytosol into the ER lumen and ER membrane, respectively. In addition, it allows the passive efflux of Ca²⁺ from the ER lumen into the cytosol after termination of the translocation process and, therefore, it can be quantified in live cell Ca²⁺ imaging in cytosol and ER lumen using ratiometric dyes and fluorescent proteins. Ca²⁺ efflux may also be possible in the transition state (not shown), which can be detected in the presence of Sec61 channel inhibitors such as Eeyarestatins or Mycolactone and may be identical to the so-called primed state that can be induced by ribosomes in co-translational- and by the Sec62/Sec63 complex in post-translational-transport (Gamayun et al., 2019; Bhadra et al., 2021). Originally, the Ca²⁺ leakage from the ER and specifically, the Sec61-mediated Ca²⁺ leakage from the ER represented a new and unexpected mechanisms of the ER Ca²⁺ homeostasis. It first came up in the early 2,000 years in seminal papers on human cells (Camello et al., 2002; Lomax et al., 2002; Van Coppenolle et al., 2004; Flourakis et al., 2006; Giunti et al., 2007) and, subsequently, was confirmed in vivo by a global RNAi screen for genes that are involved in store-operated Ca²⁺ entry (SOCE) in Drosophila (Zhang et al., 2006) as well as by biochemical and biophysical approaches (Wirth et al., 2003; Erdmann et al., 2011; Lang et al., 2011; Schäuble et al., 2012). The latter experimental approaches involved single channel recordings from purified and reconstituted Sec61 complexes and live cell calcium imaging in cytosol and ER lumen of human cells in combination with siRNA treatment or plasmid driven mutant variant expression. Several studies also identified various interaction partners of the Sec61 channel that are involved in tight control of the Ca²⁺ leak (Figure 1B), i.e., the ER-lumenal chaperone BiP and its cochaperones ERj3 and ERj6 (Schäuble et al., 2012; Schorr et al., 2015) as well as cytosolic calmodulin (CaM) and the ER membrane protein Sec62 (Erdmann et al., 2011; Linxweiler et al., 2013), thereby preventing excessive Ca²⁺ leakage that may lead to apoptosis...

Background: Neurological disorders with dyskinesia would seriously affect older people’s daily activities, which is not only associated with the degeneration or injury of the musculoskeletal or the nervous system but also associated with complex linkage between them. This study aims to review the relationship between motor performance and cortical activity of typical older neurological disorder patients with dyskinesia during walking and balance tasks.Methods: Scopus, PubMed, and Web of Science databases were searched. Articles that described gait or balance performance and cortical activity of older Parkinson’s disease (PD), multiple sclerosis, and stroke patients using functional near-infrared spectroscopy were screened by the reviewers. A total of 23 full-text articles were included for review, following an initial yield of 377 studies.Results: Participants were mostly PD patients, the prefrontal cortex was the favorite region of interest, and walking was the most popular test motor task, interventional studies were four. Seven studies used statistical methods to interpret the relationship between motor performance and cortical activation. The motor performance and cortical activation were simultaneously affected under difficult walking and balance task conditions. The concurrent changes of motor performance and cortical activation in reviewed studies contained the same direction change and different direction change.Conclusion: Most of the reviewed studies reported poor motor performance and increased cortical activation of PD, stroke and multiple sclerosis older patients. The external motor performance such as step speed were analyzed only. The design and results were not comprehensive and profound. More than 5 weeks walking training or physiotherapy can contribute to motor function promotion as well as cortices activation of PD and stroke patients. Thus, further study is needed for more statistical analysis on the relationship between motor performance and activation of the motor-related cortex. More different type and program sports training intervention studies are needed to perform.

Editorial on the Research Topic Insights in integrative physiology: 2021 The past decade has seen significant advancements in the field of Integrative Physiology. This series, Insights in Integrative Physiology 2021, published in Frontiers in Physiology, aims to highlight these developments, providing a comprehensive overview of what has been achieved and future challenges, in order to inform, inspire and provide direction and guidance to researchers in the field. The series is unified by the exploration of interconnected metabolic, endocrine, immune, cardiovascular, respiratory, renal, and neural systems that work together to maintain homeostasis. Each paper offers a distinct perspective on this topic. And while the papers are organised thematically in this editorial, it should be apparent to readers that it is challenging to examine each system independently of the others. As a perfect start to the Research Topic, the commentary provided by Curtis provides a perspective on the importance of integrative physiology education, seen through the lens of angiotensin II research over the last 30 years. The author argues that the field of physiology has shifted towards the cellular, molecular and genetic, resulting in inadequate understanding of whole body integrative physiological function. The author contends that while students have extensive knowledge of the molecular biology of angiotensin signalling, they do not know about the outcome of that signalling, which is crucial for understanding the interrelated and complementary neural, cardiovascular, renal, and endocrine elements. The take home message is that integrative physiology should be given more attention to ensure its significance and appreciation are reinforced in both education and research. The paper by Simões-Alves et al. reviews the cardiometabolic effects resulting from postnatal hyperlipidic diets in protein-restricted subjects, and the epigenetic repercussions occasioned by a phenomenon termed nutritional transition. The authors describe a trend over the last decade whereby maternal protein undernutrition during pregnancy and lactation followed by a high-fat diet has been linked to the development of cardiometabolic diseases in the offspring. Nutritional transition is associated with growth restriction, increased blood pressure, dyslipidaemia, and insulin resistance, as well as sympathetic overactivity, hypertension, and disruptions in respiratory control. They examine the epigenetic mechanisms proposed to be involved in these cardiometabolic effects including changes in DNA methylation and increased transcription of genes involved in the regulation of blood pressure and insulin sensitivity. The paper highlights how our understanding of complex epigenetic mechanisms may help understand cardiovascular disease risk with intergenerational and transgenerational implications. Original research in this Research Topic also examines the consequences of protein restriction during sensitive windows of postnatal growth and how this can also predispose to cardiovascular disease. Oliveira Ferreira et al. demonstrate that the peri-pubertal period in male rats is a sensitive period that is vulnerable to the programming of autonomic dysfunction and cardiovascular remodelling in adulthood. Moreover, this research team revealed that a brief exposure to the low protein diet and subsequent catch-up growth evoked elevated peripheral sympathetic activity (hypertension with increased arterial pressure low frequency power spectral density) and altered redox state in both the brainstem and the heart that led to the onset of cardiac remodelling. The topic also attracted a number of in-depth reviews covering other aspects of metabolism. Shi and Qiu reviewed some of the newer reports on myocardial energy substrate metabolism, cardiac metabolic remodelling during exercise and cardiac development. Tan and Naylor reviewed how new knowledge of metabolic, protein and transcriptional pathways that occur in breast and prostate cancer can be influenced by modifiable lifestyle factors to change cancer cell physiology to reduce risk and benefit prognosis. Blood pressure regulation and sodium-water homeostasis are modulated by the mineralocorticoid receptor (MR) through endogenous aldosterone and corticosteroids. For this reason, MR antagonists have received considerable attention as valuable first line therapies for hypertension and heart failure. However, beyond the vasculature, chronic activation of MR in cardiomyocytes is shown by Bienvenu et al. to adversely alter extracellular matrix composition and myocardial inflammatory state, redox balance, intracellular ion composition and apoptosis, leading to increased vulnerability of the heart to ischaemia. This mini-review presents compelling evidence for sex-specific differences in MR signaling involving estrogen receptor interactions that need to be further explored if we are to reduce the greater heart failure burden that exists in women. Another key process that regulates sodium-water homeostasis is osmoregulation and vital to the regulation of osmolarity is the neuroendocrine supraoptic nucleus (SON) of the hypothalamus. Mecawi et al. provide an overview of the current understanding of the mechanisms that regulate plasma osmolarity within the SON, including osmosensing, transcriptomic plasticity of during long term hyperosmolality and the somatodendritic release of neuropeptides in response to osmotic challenge. Touching on several themes within the Research Topic Badoer reviews the important contributions of circulating cytokines and locally-induced inflammation in the brain and overactivation of the sympathoadrenal and central renin angiotensin (RAS) systems in the promotion and potentiation of autonomic dysfunction in heart failure. The work highlights likely reasons why anti-inflammatory therapies have often been ineffective in preventing central inflammation in heart failure and the...

Thapsigargin (TG) inhibits the sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) pump and, when applied acutely, it initiates a Ca²⁺ mobilisation that begins with the loss of Ca²⁺ from the endoplasmic reticulum (ER) and culminates with store-operated Ca²⁺ entry (SOCE) from the extracellular space. Using the popular model cell line HEK-293, we quantified TG-induced changes in cytosolic and ER Ca²⁺ levels using FURA-2 and the FRET-based ER Ca²⁺ sensor D1ER, respectively. Our analysis predicts an ER Ca²⁺ leak of 5–6 µM⋅s⁻¹ for the typical basal ER Ca²⁺ level of 335–407 µM in HEK-293 cells. The resulting cytosolic Ca²⁺ transients reached peak amplitudes of 0.6–1.0 µM in the absence of external Ca²⁺ and were amplified by SOCE that amounted to 28–30 nM⋅s⁻¹ in 1 mM external Ca²⁺. Additionally, cytosolic Ca²⁺ transients were shaped by a Ca²⁺ clearance of 10–13 nM⋅s⁻¹. Using puromycin (PURO), which enhances the ER Ca²⁺ leak, we show that TG-induced cytosolic Ca²⁺ transients are directly related to ER Ca²⁺ levels and to the ER Ca²⁺ leak. A one-compartment model incorporating ER Ca²⁺ leak and cytosolic Ca²⁺ clearance accounted satisfactorily for the basic features of TG-induced Ca²⁺ transients and underpinned the rule that an increase in amplitude associated with shortening of TG-induced cytosolic Ca²⁺ transients most likely reflects an increase in ER Ca²⁺ leak.

Genes of the cytochrome P450 (CYP450) superfamily are known to be involved in the evolution of insecticide resistance. In this study, the transcriptomes of two Megalurothrips usitatus Bagnall (Thysanoptera: Thripidae) strains (resistant and susceptible) were screened for detoxification genes. MusiDN2722 encodes a protein composed of 504 amino acid residues with a relative molecular mass of 57.3 kDa. Multiple sequence alignment and phylogenetic analysis showed that MusiDN2722 is a member of the CYP450 family and has characteristics of the conserved CYP6 domain shared by typical CYP450 family members. RT-qPCR (real-time quantitative polymerase chain reaction) analysis showed that MusiDN2722 was upregulated in the acetamiprid-resistant strain compared with the susceptible strain (p < 0.05), and the relative expression level was significantly higher at 48 h after exposure than at 24 h after exposure. The interference efficiency of the injection method was higher than that of the membrane-feeding method. Silencing of MusiDN2722 through RNA interference significantly increased the sensitivity of M. usitatus to acetamiprid. Overall, this study revealed that MusiDN2722 plays a crucial role in the resistance of M. usitatus to acetamiprid. The findings will not only advance our understanding of the role of P450s in insecticide resistance but also provide a potential target for the sustainable control of destructive pests such as thrips.

Freshwater crayfish are considered as aquatic products of high quality and high nutritional value. The increasing demand has led to populations reduction in several locations throughout their range. Thus, the development of appropriate rearing conditions is considered necessary, among which, optimization of their diet is a basic part. Towards this direction, in the present study, a 98-day feeding trial was carried out to evaluate the impact of dietary fishmeal substitution by Hermetia illucens meal on Pontastacus leptodactylus juveniles kept under laboratory conditions. Insect meals represent an environmentally friendly alternative solution, considered as a high-value feed source, rich in nutrients such as protein and fat. Three dietary regimens were utilized with a fishmeal-based without Hermetia meal (HM) defined as the control diet (HM0), and two diets, the first with 50% (HM50) and the second with 100% (HM100) of fishmeal substitution by HM, respectively. Growth performance, whole-body composition, and fatty acid profiles of individuals were studied in the different treatments. At the end of the feeding trial, statistically significant differences were observed in the mean survival rate (SR), specific growth rate (SGR), feed conversion ratio (FCR) and weight gain (WG) values. More specifically, animals fed with HM-based diets had higher mean SR, while the control group performed better regarding FCR and SGR. The HM inclusion in the diet significantly altered the whole-body chemical composition of the crayfish signifying a different metabolic utilization compared to fishmeal (FM). The fatty acid analysis revealed that 16:0 (palmitic acid) was the predominant saturated fatty acid (SFA), 18:1ω9 (oleic acid) was found to be the main monounsaturated fatty acid (MUFA), while 18:2ω6 (linoleic acid) represented the major polyunsaturated fatty acid (PUFA) followed by C20:3 cis ω3 (cis-11-14-17-eicosatrienoate) and C22:6 cis ω3 (cis-4,7,10,13,16,19-Docosahexaenoic) fatty acids. The inclusion of dietary HM significantly reduced the contents of ∑SFAs, ∑PUFAs and ∑ω6 fatty acids, as well as those of C22:6 cis ω3 and increased the ω6/ω3 and hypocholesterolemic to hypercholesterolemic ratios in the body. In parallel with improvements in balanced diets and in culture conditions that need to be optimised for rearing of freshwater crayfish, our study provides new data that enlighten the suitability of insect meals in the nutrition of P. leptodactylus.

Background: Anterior cruciate ligament reconstruction (ACLR) is a common treatment for anterior cruciate ligament (ACL) injury. However, after ACLR, a significant proportion of patients do not return to pre-injury levels. Research on muscle function during movement has important implications in rehabilitation.Methods: Sixty patients with unilateral ACL injury were recruited for this study and assigned into three groups: group A, individuals with an ACL injury before 6 months; group B, individuals with ACLR from 6 months to 1 year; and group C, individuals with ACLR 1 year later. Surface electromyography (SEMG) signals were collected from the bilateral rectus femoris (RF), vastus medialis (VM), vastus lateralis (VL), biceps femoris (BF), and semitendinosus (ST). The tasks performed during the experiment included straight leg raising (SLR) training at 30°, SLR training at 60°, ankle dorsiflexion, walking, and fast walking.Results: In the maximum muscle strength test, the affected side of the BF in group A (199.4 ± 177.12) was significantly larger than in group B (53.91 ± 36.61, p = 0.02) and group C (75.08 ± 59.7, p = 0.023). In the walking test, the contralateral side of the RF in group B (347.53 ± 518.88) was significantly greater than that in group C (139.28 ± 173.78, p = 0.029). In the SLR training (60°) test, the contralateral side of the RF in group C (165.37 ± 183.06) was significantly larger than that in group A (115.09 ± 62.47, p = 0.023) and smaller than that in group B (226.21 ± 237.17, p = 0.046); In the ankle dorsiflexion training test, the contralateral side of the RF in group B (80.37 ± 87.9) was significantly larger than that in group C (45.61 ± 37.93, p = 0.046).Conclusion: This study showed the EMG characteristics of patients with ACL injury helped to determine which muscle requires more training and which exercise model would be best suited for intervention.

Sigma1 receptor protein (Sigmar1) is a small, multifunctional molecular chaperone protein ubiquitously expressed in almost all body tissues. This protein has previously shown its cardioprotective roles in rodent models of cardiac hypertrophy, heart failure, and ischemia-reperfusion injury. Extensive literature also suggested its protective functions in several central nervous system disorders. Sigmar1’s molecular functions in the pulmonary system remained unknown. Therefore, we aimed to determine the expression of Sigmar1 in the lungs. We also examined whether Sigmar1 ablation results in histological, ultrastructural, and biochemical changes associated with lung pathology over aging in mice. In the current study, we first confirmed the presence of Sigmar1 protein in human and mouse lungs using immunohistochemistry and immunostaining. We used the Sigmar1 global knockout mouse (Sigmar1^−/−) to determine the pathophysiological role of Sigmar1 in lungs over aging. The histological staining of lung sections showed altered alveolar structures, higher immune cells infiltration, and upregulation of inflammatory markers (such as pNFκB) in Sigmar1^−/− mice compared to wildtype (Wt) littermate control mice (Wt). This indicates higher pulmonary inflammation resulting from Sigmar1 deficiency in mice, which was associated with increased pulmonary fibrosis. The protein levels of some fibrotic markers, fibronectin, and pSMAD2 Ser 245/250/255 and Ser 465/467, were also elevated in mice lungs in the absence of Sigmar1 compared to Wt. The ultrastructural analysis of lungs in Wt mice showed numerous multilamellar bodies of different sizes with densely packed lipid lamellae and mitochondria with a dark matrix and dense cristae. In contrast, the Sigmar1^−/− mice lung tissues showed altered multilamellar body structures in alveolar epithelial type-II pneumocytes with partial loss of lipid lamellae structures in the lamellar bodies. This was further associated with higher protein levels of all four surfactant proteins, SFTP-A, SFTP-B, SFTP-C, and SFTP-D, in the Sigmar1^−/− mice lungs. This is the first study showing Sigmar1’s expression pattern in human and mouse lungs and its association with lung pathophysiology. Our findings suggest that Sigmar1 deficiency leads to increased pulmonary inflammation, higher pulmonary fibrosis, alterations of the multilamellar body stuructures, and elevated levels of lung surfactant proteins.

Inflammatory bowel disease (IBD) is caused by a variety of pathogenic factors, including chronic recurrent inflammation of the ileum, rectum, and colon. Immune cells and adhesion molecules play an important role in the course of the disease, which is actually an autoimmune disease. During IBD, CD34 is involved in mediating the migration of a variety of immune cells (neutrophils, eosinophils, and mast cells) to the inflammatory site, and its interaction with various adhesion molecules is involved in the occurrence and development of IBD. Although the function of CD34 as a partial cell marker is well known, little is known on its role in IBD. Therefore, this article describes the structure and biological function of CD34, as well as on its potential mechanism in the development of IBD.

With reports of its emergence as far back as the early 1900s, human immunodeficiency virus (HIV) has become one of the deadliest and most difficult viruses to treat in the era of modern medicine. Although not always effective, HIV treatment has evolved and improved substantially over the past few decades. Despite the major advancements in the efficacy of HIV therapy, there are mounting concerns about the physiological, cardiovascular, and neurological sequelae of current treatments. The objective of this review is to (Blattner et al., Cancer Res., 1985, 45(9 Suppl), 4598s–601s) highlight the different forms of antiretroviral therapy, how they work, and any effects that they may have on the cardiovascular health of patients living with HIV, and to (Mann et al., J Infect Dis, 1992, 165(2), 245–50) explore the new, more common therapeutic combinations currently available and their effects on cardiovascular and neurological health. We executed a computer-based literature search using databases such as PubMed to look for relevant, original articles that were published after 1998 to current year. Articles that had relevance, in any capacity, to the field of HIV therapy and its intersection with cardiovascular and neurological health were included. Amongst currently used classes of HIV therapies, protease inhibitors (PIs) and combined anti-retroviral therapy (cART) were found to have an overall negative effect on the cardiovascular system related to increased cardiac apoptosis, reduced repair mechanisms, block hyperplasia/hypertrophy, decreased ATP production in the heart tissue, increased total cholesterol, low-density lipoproteins, triglycerides, and gross endothelial dysfunction. The review of Integrase Strand Transfer Inhibitors (INSTI), Nucleoside Reverse Transcriptase Inhibitors (NRTI), and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) revealed mixed results, in which both positive and negative effects on cardiovascular health were observed. In parallel, studies suggest that autonomic dysfunction caused by these drugs is a frequent and significant occurrence that needs to be closely monitored in all HIV + patients. While still a relatively nascent field, more research on the cardiovascular and neurological implications of HIV therapy is crucial to accurately evaluate patient risk.

Introduction: With the widespread use of wearable sensors, various methods to evaluate external physical loads using acceleration signals measured by inertial sensors in sporting activities have been proposed. Acceleration-derived external physical loads have been evaluated as a simple indicator, such as the mean or cumulative values of the target interval. However, such a conventional simplified indicator may not adequately represent the features of the external physical load in sporting activities involving various movement intensities. Therefore, we propose a method to evaluate the external physical load of tennis player based on the histogram of acceleration-derived signal obtained from wearable inertial sensors.Methods: Twenty-eight matches of 14 male collegiate players and 55 matches of 55 male middle-aged players wore sportswear-type wearable sensors during official tennis matches. The norm of the three-dimensional acceleration signal measured using the wearable sensor was smoothed, and the rest period (less than 0.3 G of at least 5 s) was excluded. Because the histogram of the processed acceleration signal showed a bimodal distribution, for example, high- and low-intensity peaks, a Gaussian mixture model was fitted to the histogram, and the model parameters were obtained to characterize the bimodal distribution of the acceleration signal for each player.Results: Among the obtained Gaussian mixture model parameters, the linear discrimination analysis revealed that the mean and standard deviation of the high-intensity side acceleration value accurately classified collegiate and middle-aged players with 93% accuracy; however, the conventional method (only the overall mean) showed less accurate classification results (63%).Conclusion: The mean and standard deviation of the high-intensity side extracted by the Gaussian mixture modeling is found to be the effective parameter representing the external physical load of tennis players. The histogram-based feature extraction of the acceleration-derived signal that exhibit multimodal distribution may provide a novel insight into monitoring external physical load in other sporting activities.

As an emerging training method, blood flow restriction training has been proved to promote the growth of muscle mass and strength. In recent years, it has been gradually applied in different populations. However, there are few studies on how blood flow restriction training affects muscle mass and strength in the elderly. The relevant literature is compiled and summarized in this study. Through the comparison of blood flow restriction training with traditional training methods and its application in the elderly, it shows that blood flow restriction training can effectively increase muscle mass and strength, prevent muscle atrophy, improve cardiopulmonary function, facilitate injury and postoperative rehabilitation, and intervene in related degenerative diseases as a training method suitable for the elderly,. The main mechanism of blood flow restriction training promoting muscle mass and strength growth is metabolic stress response, including muscle fiber recruitment, protein synthesis signal pathway activation, hormone secretion, etc., and is also related to cell swelling caused by pressure. At present, although the application of blood flow restriction training in the elderly population is increasing, there is a lack of personalized programs. In the future, more research on the dose effect and safety of blood flow restriction training is needed to develop more accurate personalized training programs.

Introduction: Vascular stiffness is a predictor of cardiovascular disease and pulse wave velocity (PWV) is the current standard for measuring in vivo vascular stiffness. Mean arterial pressure is the largest confounding variable to PWV; therefore, in this study we aimed to test the hypothesis that increased aortic PWV in type 2 diabetic mice is driven by increased blood pressure rather than vascular biomechanics.Methods and Results: Using a combination of in vivo PWV and ex vivo pressure myography, our data demonstrate no difference in ex vivo passive mechanics, including outer diameter, inner diameter, compliance (Db/db: 0.0094 ± 0.0018 mm²/mmHg vs. db/db: 0.0080 ± 0.0008 mm²/mmHg, p > 0.05 at 100 mmHg), and incremental modulus (Db/db: 801.52 ± 135.87 kPa vs. db/db: 838.12 ± 44.90 kPa, p > 0.05 at 100 mmHg), in normal versus diabetic 16 week old mice. We further report no difference in basal or active aorta biomechanics in normal versus diabetic 16 week old mice. Finally, we show here that the increase in diabetic in vivo aortic pulse wave velocity at baseline was completely abolished when measured at equivalent pharmacologically-modulated blood pressures, indicating that the elevated PWV was attributed to the concomitant increase in blood pressure at baseline, and therefore “stiffness.”Conclusions: Together, these animal model data suggest an intimate regulation of blood pressure during collection of pulse wave velocity when determining in vivo vascular stiffness. These data further indicate caution should be exerted when interpreting elevated PWV as the pure marker of vascular stiffness.

Schizothorax esocinus, commonly known as snow trout, is one of the main contributors of food and livelihood in the colder zone of Himalayan region. The comprehensive information on its hematological and serum biochemical reference intervals is not reported yet. In the present study an attempt has been made to elucidate the hematological and serum biochemical reference intervals of S. esocinus from River Jhelum using protocols of the American Society of Veterinary Clinical Pathology (ASVCP). Wild fish were sampled over a period of 2 years from the pollution free sites of river Jhelum. Fish blood was harvested through caudal venipuncture and hemato-biochemical analysis performed thereof. Data values from a total of healthy 432 adult fish specimens (216 male, 216 female) were systematically recorded. The reference intervals for hematological and serum biochemical parameters of S. esocinus were established using Reference Value Advisor software v 2.1. RIs for hematological and serum analytes ranged as: hemoglobin (Hb) 78.38–116.35 (g/L); white blood cells (WBC) 10–20 (×10⁹/L); red blood cells (RBC) 1.30–2.15 (×10¹²/L); packed cell volume 27.00–39.45 (%); total protein 39.21–61.62 (g/L); albumin 8.20–22.02 (g/L); globulin 27.58–49.55 (g/L); glucose 3.25–7.18 (mmol/L); urea 0.96—2.38 (mmol/L); cholesterol 3.80–6.90 (mmol/L). The study also depicted that certain blood measurands were influenced with respect to sex. Significantly (p &lt; 0.05) higher values of Hb, red blood cells count and serum glucose were noted in male as compared to female which, on the other hand, registered higher white blood cells count and serum cholesterol level (Mann Whitney U test, p &lt; 0.05). The work, therefore, provides baseline information on hematological and serum biochemical analytes of this species which holds high commercial importance. RIs reported here can help monitor the health status of fish by improving the use of non-lethal diagnostic methods in piscine medicine.

The present study aimed to investigate sex differences in measures of cardiac chronotropy and heart rate variability (HRV) in 132 young adult wild-type Groningen rats (n = 45 females). Electrocardiographic signals were recorded for 48 h in freely moving rats to quantify heart rate (HR) and inter-beat interval (IBI) as measures of cardiac chronotropy, and time- and frequency-domain HRV parameters as physiological readouts of cardiac vagal modulation. Females showed greater vagally-mediated HRV despite having higher HR and shorter IBI than males during undisturbed conditions. Such differences were evident i) at any given level of HRV, and ii) both during the 12-h light/inactive and 12-h dark/active phase of the daily cycle. These findings replicate the paradoxical cardiac chronotropic control reported by human meta-analytic findings, since one would expect greater vagally-mediated HRV to be associated with lower HR and longer IBI. Lastly, the association between some HRV measures and HR was stronger in female than male rats. Overall, the current study in young adult rats provides data illustrating a sex-dependent association between vagally-mediated HRV and indexes of cardiac chronotropy. The current results i) are in line with human findings, ii) suggest to always consider biological sex in the analysis and interpretation of HRV data in rats, and iii) warrant the use of rats for investigating the neuro-hormonal basis and temporal evolution of the impact of sex on the association between vagally-mediated HRV and cardiac chronotropy, which could inform the human condition.

Conduction system pacing (CSP) has evolved rapidly to become the pacing method of choice for many adults with structurally normal hearts. Studies in this population have repeatedly demonstrated superior hemodynamics and outcomes compared to conventional pacing with the recruitment of the native conduction system. Children and patients with congenital heart disease (CHD) are also likely to benefit from CSP but were excluded from original trials. However, very recent studies have begun to demonstrate the feasibility and efficacy of CSP in these patients, with growing evidence that some outcomes may be superior in comparison to conventional pacing techniques. Concerns regarding the technical challenges and long-term lead parameters of His Bundle Pacing (HBP) have been overcome to many extents with the development of Left Bundle Branch Area Pacing (LBBAP), and both techniques are likely to play an important role in pediatric and CHD pacing in the future. This review aims to assimilate the latest developments in CSP and its application in children and CHD patients.

Introduction: CRISPR/Cas9 is a gene-editing technology which could specifically cleave dsDNA and induce target gene mutation. CRISPR/Cas9 has been widely used in gene functional studies in many fields, such as medicine, biology, and agriculture due to its simple design, low cost, and high efficiency. Although it has been well developed in model fish and freshwater fish for gene function analysis, it is still novel in the studies dealing with economic crustacean species.Methods: In this study, we established a CRISPR/Cas9 system based on microinjection for M. nipponense, an important economic crustacean aquaculture species. The vitellogenin (Vg) gene and the eyeless (Ey) gene were selected as the targeted genes for mutation. Two sgRNAs were designed for Mn-Vg and Mn-Ey gene editing, respectively.Results and Discussion: For sg-Vg-1, the gastrula survival ratio was 8.69%, and the final hatching ratio was 4.83%. The blastula mutant ratio was 10%, and the hatching individual mutant ratio was 30%. For sg-Vg-2, the gastrula survival ratio was 5.85%, and the final hatching ratio was 3.89%. The blastula mutant ratio was 16.67%, and no mutant sequences were detected in hatching individuals. For sg-Ey-1, the gastrula survival ratio was 6.25%, and the final hatching ratio was 2.34%. The blastula mutant ratio was 10.00%, and the hatching individual mutant ratio was 66.67%. For sg-Ey-2, the gastrula survival ratio was 6.00%, and the final hatching ratio was 2.67%. No mutant sequence was detected in both blastula stage and hatching individuals. There were no significant morphological changes observed in the Mn-Vg group. Two deformed types were detected in sg-Ey-1-injected embryos. An evident developmental delay of the compound eye was detected in Ey-sg1-H1 in the zoea stage. The compound eyes of the Ey-sg1-H2 embryo could not form well-defined spheres, and the whole compound eye appeared to diffuse at the end of the late zoea stage. The establishment of a gene-editing platform based on CRISPR/Cas9 will not only provide an efficient and convenient method for gene function analysis but also provide a powerful tool for molecular-assisted breeding of Macrobrachium nipponense.

Background: Functional ankle instability (FAI) is the primary classification of ankle injuries. Competitive activities have complicated movements that can result in ankle re-injury among patients with FAI. Unanticipated movement state (MS) and mental fatigue (MF) could also happen in these activities, which may further increase their joint injury risk.Objective: This study aimed to clarify the biomechanical characteristics difference of the lower extremity (LE) between the injured side and the uninjured side among patients with FAI when they perform unanticipated side-step cutting after MF.Methods: Fifteen males with unilateral FAI participated in this study (age: 20.7 ± 1.3 years, height: 173.6 ± 4.4 cm, weight: 70.1 ± 5.0 kg). They used the injured side and the uninjured side of LE to complete anticipated and unanticipated side-step cutting before and after MF. The kinematic and kinetics data were evaluated using three-way ANOVA with repeated measures.Results: During patients with FAI performed anticipated side-step cutting, the ankle stiffness of both sides showed no significant change after MF; During they performed unanticipated side-step cutting, their injured side presented significantly lower ankle stiffness after MF, while the uninjured side did not have such change. In addition, after MF, the injured side exhibited increased ankle inversion, knee valgus and LR, but the uninjured side did without these changes.Conclusion: Influenced by MF, when patients with FAI use their injured side of LE to perform side-step cutting, this side LE has a higher risk of musculoskeletal injuries such as lateral ankle sprains and anterior cruciate ligament injury. The ankle stiffness of the injured side will be further reduced when patients with FAI perform unanticipated side-step cutting, which increases ankle instability and the risk of re-injury.

Pulmonary arterial hypertension is associated with skeletal muscle myopathy and atrophy and impaired exercise tolerance. Aerobic exercise training has been recommended as a non-pharmacological therapy for deleterious effects imposed by pulmonary arterial hypertension. Aerobic physical training induces skeletal muscle adaptations via reduced inflammation, improved anabolic processes, decreased hypoxia and regulation of mitochondrial function. These benefits improve physical exertion tolerance and quality of life in patients with pulmonary arterial hypertension. However, the mechanisms underlying the therapeutic potential of aerobic exercise to skeletal muscle disfunctions in patients with pulmonary arterial hypertension are not well understood yet. This minireview highlights the pathways involved in skeletal muscle adaptations to aerobic exercise training in patients with pulmonary arterial hypertension.

Pericytes are a heterogeneous population of mesenchymal cells located on the abluminal surface of microvessels, where they provide structural and biochemical support. Pericytes have been implicated in numerous lung diseases including pulmonary arterial hypertension (PAH) and allergic asthma due to their ability to differentiate into scar-forming myofibroblasts, leading to collagen deposition and matrix remodelling and thus driving tissue fibrosis. Pericyte-extracellular matrix interactions as well as other biochemical cues play crucial roles in these processes. In this review, we give an overview of lung pericytes, the key pro-fibrotic mediators they interact with, and detail recent advances in preclinical studies on how pericytes are disrupted and contribute to lung diseases including PAH, allergic asthma, and chronic obstructive pulmonary disease (COPD). Several recent studies using mouse models of PAH have demonstrated that pericytes contribute to these pathological events; efforts are currently underway to mitigate pericyte dysfunction in PAH by targeting the TGF-β, CXCR7, and CXCR4 signalling pathways. In allergic asthma, the dissociation of pericytes from the endothelium of blood vessels and their migration towards inflamed areas of the airway contribute to the characteristic airway remodelling observed in allergic asthma. Although several factors have been suggested to influence this migration such as TGF-β, IL-4, IL-13, and periostin, recent evidence points to the CXCL12/CXCR4 pathway as a potential therapeutic target. Pericytes might also play an essential role in lung dysfunction in response to ageing, as they are responsive to environmental risk factors such as cigarette smoke and air pollutants, which are the main drivers of COPD. However, there is currently no direct evidence delineating the contribution of pericytes to COPD pathology. Although there is a lack of human clinical data, the recent available evidence derived from in vitro and animal-based models shows that pericytes play important roles in the initiation and maintenance of chronic lung diseases and are amenable to pharmacological interventions. Therefore, further studies in this field are required to elucidate if targeting pericytes can treat lung diseases.

Protein S-acylation is a reversible lipid post-translational modification that allows dynamic regulation of processes such as protein stability, membrane association, and localization. Palmitoyltransferase ZDHHC9 (DHHC9) is one of the 23 human DHHC acyltransferases that catalyze protein S-acylation. Dysregulation of DHHC9 is associated with X-linked intellectual disability and increased epilepsy risk. Interestingly, activation of DHHC9 requires an accessory protein—GCP16. However, the exact role of GCP16 and the prevalence of a requirement for accessory proteins among other DHHC proteins remain unclear. Here, we report that one role of GCP16 is to stabilize DHHC9 by preventing its aggregation through formation of a protein complex. Using a combination of size-exclusion chromatography and palmitoyl acyltransferase assays, we demonstrate that only properly folded DHHC9-GCP16 complex is enzymatically active in vitro. Additionally, the ZDHHC9 mutations linked to X-linked intellectual disability result in reduced protein stability and DHHC9-GCP16 complex formation. Notably, we discovered that the C-terminal cysteine motif (CCM) that is conserved among the DHHC9 subfamily (DHHC14, -18, -5, and -8) is required for DHHC9 and GCP16 complex formation and activity in vitro. Co-expression of GCP16 with DHHCs containing the CCM improves DHHC protein stability. Like DHHC9, DHHC14 and DHHC18 require GCP16 for their enzymatic activity. Furthermore, GOLGA7B, an accessory protein with 75% sequence identity to GCP16, improves protein stability of DHHC5 and DHHC8, but not the other members of the DHHC9 subfamily, suggesting selectivity in accessory protein interactions. Our study supports a broader role for GCP16 and GOLGA7B in the function of human DHHCs.

An Addendum on Addendum: Engineered extracellular vesicles from human periodontal-ligament stem cells increase VEGF/VEGFR2 expression during bone regeneration by Pizzicannella J, Gugliandolo A, Orsini T, Fontana A, Ventrella A, Mazzon E, Bramanti P, Diomede F and Trubiani O (2019). Front. Physiol. 10:512. doi: 10.3389/fphys.2019.00512 In the published article, we would to like to add the merge relative to panel C1 and C2 of the Figure 2 as Supplementary Figure S3. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphys.2023.1148929/full#supplementary-material Supplementary Figure S3 | Confocal laser scanning microscopy figure. Keywords: mesenchymal stem cells, bone regeneration, VEGF, VEGFR2, collagen membrane, extracellular vesicles, polyethylenimine Citation: Pizzicannella J, Gugliandolo A, Orsini T, Fontana A, Ventrella A, Mazzon E, Bramanti P, Diomede F and Trubiani O (2023) Addendum: Engineered extracellular vesicles from human periodontal-ligament stem cells increase VEGF/VEGFR2 expression during bone regeneration. Front. Physiol. 14:1148929. doi: 10.3389/fphys.2023.1148929 Received: 23 January 2023; Accepted: 24 February 2023; Published: 23 March 2023. Edited and reviewed by: Copyright © 2023 Pizzicannella, Gugliandolo, Orsini, Fontana, Ventrella, Mazzon, Bramanti, Diomede and Trubiani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Emanuela Mazzon, [email protected]

Preeclampsia (PE) is a devastating hypertensive disorder of pregnancy closely linked to obesity. Long-term adverse outcomes may occur in offspring from preeclamptic pregnancies. Accordingly, sex-specific changes in pubertal development have been described in children from preeclamptic women, but the underlying mechanisms remain vastly unexplored. Features of PE are spontaneously recapitulated by the blood pressure high subline 5 (BPH/5) mouse model, including obesity and dyslipidemia in females before and throughout pregnancy, superimposed hypertension from late gestation to parturition and fetal growth restriction. A sexually dimorphic cardiometabolic phenotype has been described in BPH/5 offspring: while females are hyperphagic, hyperleptinemic, and overweight, with increased reproductive white adipose tissue (rWAT), males have similar food intake, serum leptin concentration, body weight and rWAT mass as controls. Herein, pubertal development and adiposity were further investigated in BPH/5 progeny. Precocious onset of puberty occurs in BPH/5 females, but not in male offspring. When reaching adulthood, the obese BPH/5 females display hypoestrogenism and hyperandrogenism. Kisspeptins, a family of peptides closely linked to reproduction and metabolism, have been previously shown to induce lipolysis and inhibit adipogenesis. Interestingly, expression of kisspeptins (Kiss1) and their cognate receptor (Kiss1r) in the adipose tissue seem to be modulated by the sex steroid hormone milieu. To further understand the metabolic-reproductive crosstalk in the BPH/5 offspring, Kiss1/Kiss1r expression in male and female rWAT were investigated. Downregulation of Kiss1/Kiss1r occurs in BPH/5 females when compared to males. Interestingly, dietary weight loss attenuated circulating testosterone concentration and rWAT Kiss1 downregulation in BPH/5 females. Altogether, the studies demonstrate reproductive abnormalities in offspring gestated in a PE-like uterus, which appear to be closely associated to the sexually dimorphic metabolic phenotype of the BPH/5 mouse model.

A 30-day feeding trial was designed to evaluate the effect of supplemental fulvic acid (FA) on survival, growth performance, digestive ability and immunity of large yellow croaker (Larimichthys crocea) larvae (initial body weight 11.33 ± 0.57 mg). Four isonitrogenous and isolipids diets containing 0.00%, 0.01%, 0.02% and 0.04% FA were formulated, respectively. Results showed that the supplementation of 0.04% FA significantly improved survival rate of large yellow croaker larvae. Meanwhile, supplemental FA significantly increased final body weight and specific growth rate. Based on the specific growth rate, the optimal supplementation was 0.0135% FA. Larvae fed the diet with 0.01% FA had significantly higher villus height than the control. The supplementation of 0.01%–0.02% FA significantly increased the muscular thickness of intestine. Moreover, supplementation of FA significantly increased mRNA expression of intestinal epithelial proliferation and barrier genes (pcna, zo-1 and zo-2). Diets supplemented with 0.02%–0.04% FA significantly increased the activity of trypsin in the intestinal segment, while 0.01%–0.02% FA significantly increased the activity of trypsin in the pancreatic segment. Compared with the control, supplementation of FA remarkably increased activities of alkaline phosphatase and leucine aminopeptidase in the brush border membrane of intestine. Larvae fed the diet with 0.01% FA significantly increased activities of lysozyme and total nitric oxide synthase. Furthermore, the supplementation of 0.01% to 0.02% FA significantly decreased the mRNA expression of pro-inflammatory cytokines (tnf-α and il-6). Concurrently, supplemental FA significantly increased anti-inflammatory cytokine (il-10) mRNA expression level. In conclusion, this study indicated that the supplementation of FA could improve the survival rate and growth performance of larvae by promoting intestinal development, digestive enzymes activities and innate immunity.

The freshwater gastropod Pomacea canaliculata fulfills the ideal conditions of a bioindicator species since its digestive gland bioconcentrates elements toxic for human and ecosystems health. The aim of this work was to study the balance between production of free radicals and antioxidant defenses, and the generation of oxidative damage in the digestive gland of this mollusk after exposure (96 h) to three elements with differential affinities for functional biological groups: mercury (5.5 μg/L of Hg⁺² as HgCl₂), arsenic [500 μg/L of (AsO₄)⁻³ as Na₃AsO₄7H₂O], or uranium [700 μg/L of (UO₂)⁺² as UO₂(CH₂COOH)₂]. Bioconcentration factors of Hg, As, and U were 25, 23, and 53, respectively. Snails exhibited a sustained increase of reactive species (RS), and protein and lipid damage. Lipid radicals increased between 72 and 96 h, respectively, in snails exposed to U and Hg while this parameter changed early (24 h) in As- exposed snails. Snails showed protein damage, reaching maximum values at different endpoints. This redox disbalance was partially compensated by non-enzymatic antioxidant defenses α-tocopherol (α-T), β-carotene (β-C), uric acid, metallothionein (MTs). Snails consumed α-T and β-C in an element-dependent manner. The digestive gland consumed rapidly uric acid and this molecule was not recovered at 96 h. Digestive gland showed a significant increase in MTs after elemental exposure at different endpoints. The enzymatic antioxidant defenses, represented by the catalase and glutathione-S-transferase activities, seems to be not necessary for the early stages of the oxidative process by metals. This work is the first attempt to elucidate cellular mechanisms involved in the tolerance of this gastropod to non-essential elements. The bioconcentration factors and changes in the oxidative status and damage confirm that this species can be used as a bioindicator species of metal pollution in freshwater bodies.

Objective: This study aims to investigate the validity of machine learning-derived amount of real-world functional upper extremity (UE) use in individuals with stroke. We hypothesized that machine learning classification of wrist-worn accelerometry will be as accurate as frame-by-frame video labeling (ground truth). A second objective was to validate the machine learning classification against measures of impairment, function, dexterity, and self-reported UE use.Design: Cross-sectional and convenience sampling.Setting: Outpatient rehabilitation.Participants: Individuals (>18 years) with neuroimaging-confirmed ischemic or hemorrhagic stroke >6-months prior (n = 31) with persistent impairment of the hemiparetic arm and upper extremity Fugl-Meyer (UEFM) score = 12–57.Methods: Participants wore an accelerometer on each arm and were video recorded while completing an “activity script” comprising activities and instrumental activities of daily living in a simulated apartment in outpatient rehabilitation. The video was annotated to determine the ground-truth amount of functional UE use.Main outcome measures: The amount of real-world UE use was estimated using a random forest classifier trained on the accelerometry data. UE motor function was measured with the Action Research Arm Test (ARAT), UEFM, and nine-hole peg test (9HPT). The amount of real-world UE use was measured using the Motor Activity Log (MAL).Results: The machine learning estimated use ratio was significantly correlated with the use ratio derived from video annotation, ARAT, UEFM, 9HPT, and to a lesser extent, MAL. Bland–Altman plots showed excellent agreement between use ratios calculated from video-annotated and machine-learning classification. Factor analysis showed that machine learning use ratios capture the same construct as ARAT, UEFM, 9HPT, and MAL and explain 83% of the variance in UE motor performance.Conclusion: Our machine learning approach provides a valid measure of functional UE use. The accuracy, validity, and small footprint of this machine learning approach makes it feasible for measurement of UE recovery in stroke rehabilitation trials.

Sap-feeding hemipteran insects live in associations with diverse heritable symbiotic microorganisms (bacteria and fungi) that provide essential nutrients deficient in their hosts’ diets. These symbionts typically reside in highly specialized organs called bacteriomes (with bacterial symbionts) or mycetomes (with fungal symbionts). The organization of these organs varies between insect clades that are ancestrally associated with different microbes. As these symbioses evolve and additional microorganisms complement or replace the ancient associates, the organization of the symbiont-containing tissue becomes even more variable. Planthoppers (Hemiptera: Fulgoromorpha) are ancestrally associated with bacterial symbionts Sulcia and Vidania, but in many of the planthopper lineages, these symbionts are now accompanied or have been replaced by other heritable bacteria (e.g., Sodalis, Arsenophonus, Purcelliella) or fungi. We know the identity of many of these microbes, but the symbiont distribution within the host tissues and the bacteriome organization have not been systematically studied using modern microscopy techniques. Here, we combine light, fluorescence, and transmission electron microscopy with phylogenomic data to compare symbiont tissue distributions and the bacteriome organization across planthoppers representing 15 families. We identify and describe seven primary types of symbiont localization and seven types of the organization of the bacteriome. We show that Sulcia and Vidania, when present, usually occupy distinct bacteriomes distributed within the body cavity. The more recently acquired gammaproteobacterial and fungal symbionts generally occupy separate groups of cells organized into distinct bacteriomes or mycetomes, distinct from those with Sulcia and Vidania. They can also be localized in the cytoplasm of fat body cells. Alphaproteobacterial symbionts colonize a wider range of host body habitats: Asaia-like symbionts often colonize the host gut lumen, whereas Wolbachia and Rickettsia are usually scattered across insect tissues and cell types, including cells containing other symbionts, bacteriome sheath, fat body cells, gut epithelium, as well as hemolymph. However, there are exceptions, including Gammaproteobacteria that share bacteriome with Vidania, or Alphaproteobacteria that colonize Sulcia cells. We discuss how planthopper symbiont localization correlates with their acquisition and replacement patterns and the symbionts’ likely functions. We also discuss the evolutionary consequences, constraints, and significance of these findings.

Lipid metabolism is essential in maintaining energy homeostasis in multicellular organisms. In vertebrates, the peroxisome proliferator-activated receptors (PPARs, NR1C) regulate the expression of many genes involved in these processes. Atlantic cod (Gadus morhua) is an important fish species in the North Atlantic ecosystem and in human nutrition, with a highly fatty liver. Here we study the involvement of Atlantic cod Ppar a and b subtypes in systemic regulation of lipid metabolism using two model agonists after in vivo exposure. WY-14,643, a specific PPARA ligand in mammals, activated cod Ppara1 and Ppara2 in vitro. In vivo, WY-14,643 caused a shift in lipid transport both at transcriptional and translational level in cod. However, WY-14,643 induced fewer genes in the fatty acid beta-oxidation pathway compared to that observed in rodents. Although GW501516 serves as a specific PPARB/D ligand in mammals, this compound activated cod Ppara1 and Ppara2 as well as Pparb in vitro. In vivo, it further induced transcription of Ppar target genes and caused changes in lipid composition of liver and plasma. The integrative approach provide a foundation for understanding how Ppars are engaged in regulating lipid metabolism in Atlantic cod physiology. We have shown that WY-14,643 and GW501516 activate Atlantic cod Ppara and Pparb, affect genes in lipid metabolism pathways, and induce changes in the lipid composition in plasma and liver microsomal membranes. Particularly, the combined transcriptomic, proteomics and lipidomics analyses revealed that effects of WY-14,643 on lipid metabolism are similar to what is known in mammalian studies, suggesting conservation of Ppara functions in mediating lipid metabolic processes in fish. The alterations in the lipid profiles observed after Ppar agonist exposure suggest that other chemicals with similar Ppar receptor affinities may cause disturbances in the lipid regulation of fish. Model organism: Atlantic cod (Gadus morhua). LSID: urn:lsid:zoobank.org:act:389BE401-2718-4CF2-BBAE-2E13A97A5E7B. COL Identifier: 6K72F.

Due to the close interaction of lung morphology and functions, repeatable measurements of pulmonary function during longitudinal studies on lung pathophysiology and treatment efficacy have been a great area of interest for lung researchers. Spirometry, as a simple and quick procedure that depends on the maximal inspiration of the patient, is the most common lung function test in clinics that measures lung volumes against time. Similarly, in the preclinical area, plethysmography techniques offer lung functional parameters related to lung volumes. In the past few decades, many innovative techniques have been introduced for in vivo lung function measurements, while each one of these techniques has their own advantages and disadvantages. Before each experiment, depending on the sensitivity of the required pulmonary functional parameters, it should be decided whether an invasive or non-invasive approach is desired. On one hand, invasive techniques offer sensitive and specific readouts related to lung mechanics in anesthetized and tracheotomized animals at endpoints. On the other hand, non-invasive techniques allow repeatable lung function measurements in conscious, free-breathing animals with readouts related to the lung volumes. The biggest disadvantage of these standard techniques for lung function measurements is considering the lung as a single unit and providing only global readouts. However, recent advances in lung imaging modalities such as x-ray computed tomography and magnetic resonance imaging opened new doors toward obtaining both anatomical and functional information from the same scan session, without the requirement for any extra pulmonary functional measurements, in more regional and non-invasive manners. Consequently, a new field of study called pulmonary functional imaging was born which focuses on introducing new techniques for regional quantification of lung function non-invasively using imaging-based techniques. This narrative review provides first an overview of both invasive and non-invasive conventional methods for lung function measurements, mostly focused on small animals for preclinical research, including discussions about their advantages and disadvantages. Then, we focus on those newly developed, non-invasive, imaging-based techniques that can provide either global or regional lung functional readouts at multiple time-points.

Introduction: Aging can be associated with reduced muscle power, functional decline, and increased plasma concentrations of proinflammatory cytokines. Functional training (FT) can improve muscle power, functional fitness and reduce plasma cytokines. However, the functional training optimal volume required to produce these adaptations must be clarified. Our study analyzed the effects of multiple–set functional training (MSFT) and single–set functional training (SSFT) on postmenopausal women’s muscle power, functional fitness, and inflammatory profile.Methods: Forty–three women were randomly allocated into three groups: multiple–set functional training (n = 16, age 64.13 ± 5.17), single–set functional training (n = 14, age 63.79 ± 4.88), and control group (CG, n = 13, age 64.62 ± 5.44). The bench press and squat exercises evaluated upper and lower limb muscle power. The following tests assessed functional fitness: putting on and taking off a T–shirt, gallon–jug shelf–transfer, standing up and walking around the house, five times sit–to–stand, and 400–m walk. Plasma cytokine (TNF–α, IL–6, and IL 10) concentrations were measured by flow cytometry. Results: Single–set functional training and multiple–set functional training increased upper and lower limbs muscle power and improved functional fitness, except for the putting on and taking off a T–shirt test. Multiple–set functional training reduced TNF–α and IL–6, while single–set functional training reduced only TNF–α. IL–10 was unaffected by exercise.Discussion: Single–set functional training and multiple–set functional training, therefore, promoted similar muscle power and functional fitness improvements over 24 weeks. Multiple–set functional training was more effective than single–set functional training, reducing both TNF and IL–6, while single–set functional training only decreased TNF–α.

Editorial on the Research Topic Cellular Senescence in Physiology and Pathophysiology It has been known since Leonard Hayflick’s observations and brilliant designed experiments that cells have a limited replicative capacity and lifespan (Hayflick and Moorhead, 1961). Cells that reach a certain number of doubling times can no longer divide and subsequently these cells turn into a special cellular state called senescent (Özdemir et al., 2023). The heterogeneity of senescent cells has limited the knowledge of drivers and consequences of cellular senescence in tissues and organs (Roy et al., 2020). This cellular response, which is characterized by an irreversible cell cycle arrest after limited cell divisions is called replicative senescence. Sir Macfarlane Burnett called this phenomenon “the Hayflick limit” (Burnet, 1974). Subsequent studies have also shown that senescence is induced by various intrinsic and extrinsic stress factors such as oxidative stress, UV radiation, oncogenes and anticancer compounds or radiation used cancer therapy other than this replicative form (Özdemir et al., 2023). Although senescent cells are metabolically active, they differ morphologically and functionally from normal cells. Senescent cells are larger than normal cells and show multiple and large nuclei. These cells secrete a large number of biologically active molecules, mainly cytokines, growth factors, and matrix metalloproteinases, called SASP (Senescence associated secretory phenotype) into their microenvironment. SASP has been shown to cause deleterious effects such as inflammation, cancer cell proliferation, migration, invasion, and resistance to chemotherapeutics in the surrounding tissues (Coppé et al., 2010; Özdemir et al., 2023). All these features of senescent cells have been associated with many physiopathological events, especially age-related diseases and cancer. However, despite all these studies, there are many contradictory demonstrations that need to be clarified regarding the development of senescence, the morphological features of senescent cells, and the effects of SASP on other cells around. While it is generally accepted that senescent cells have an enlarged and flattened morphological structure, the 3D holographic measurements indicate that there was no difference in the thickness between senescent and normal cells (Şimay et al., 2018). An interesting study published in JCB revealed that senescent cancerous cells phagocytose both neighboring senescent and non-senescent tumor cells in their microenvironment (Tonnessen-Murray et al., 2019). However, this feature of senescent cancer cells could not be confirmed by other studies (Şimay Demir et al., 2021). Functionally, the effects of SASP on other surrounding cells vary depending on the cell types and senescence stimuli. It also differs on which type of cells it interacts with, and whether these cells are normal or cancerous (Basisty et al., 2020). Therefore, a comprehensive profiling of SASP is required in each senescence form to identify the effects of SASP and to take action against the detrimental consequences it triggers (Basisty et al., 2020; Jochems et al., 2021). The transcriptome signatures of the senescent cell shows heterogeneity depending on the cell type and the stress stimulant (Hernandez-Segura et al., 2017). After senescence induced in a panel of 13 cancer cell lines, transcriptome analysis of senescent cells was performed and these data were presented in an interactive online system called “CANCER SENESCopedia” (Jochems et al., 2021). These reports show that there is yet a long way to go in determining the characteristic features of senescent cells in general. Since these studies were performed in a range of cancer cell lines, information on senescence formation induced by different stimuli in both non-tumour cells and other cancer types is limited. On the other hand, studies on the discovery and development of senotherapeutic drugs that target the specific elimination of senescent cells (senolytic) and suppression of the activity of SASP (senomorphic) to inhibit the deleterious results of senescence in both aging and cancer chemotherapy, continue. This Research Topic of Frontiers in Physiology includes important studies on senescence and some of the various physiopathological events that play an important role in the process. The article by Zhang et al. points out that polo-like kinase 1 activity delays senescence formation of nucleus pulposus cells and mediates the reduction of intervertebral disc degeneration and thus the prevention of back pain (Zhang et al., 2022). Apart from this, senescence is also associated with parturition. Wan et al. explain the role of fetal lung-associated exosomes from the amniotic fluid in primary human amniotic epithelial cell senescence and apoptosis thereby inducing delivery (Wan et al.). Ren et al. contribute to this Research Topic by identifying a novel sulfur dioxide probe that inhibits high glucose-induced senescence in umbilical vascular endothelial cells by inducing the degradation of lipid droplets (Ren et al.). Senescence is also induced after adjuvant therapy (chemotherapy and radiotherapy) by inducing DNA damage. In their study, Jiang et al. demonstrated that the small GTPases RagC and Rheb are required for the activation of mTOR to promote chemoresistance in chemotherapy-induced senescence in HepG2 cells (Jiang et al.). Moreover, the regulatory role of E3 ubiquitin ligases is discussed in response to DNA damage, as reviewed by Lu et al.. In conclusion, recent reports of this Research Topic fill an important gap in the physiopathological events in which senescent takes place. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. This work was supported by the TUBITAK (grant number 215S998). The authors declare that the research...

The aims of the study were to analyze metabolic power (MP) and MP derived parameters for different positions in the German Soccer Bundesliga and to evaluate if classification of high-intensity is more suited using the metabolic power approach instead of using traditional speed-based methods. 1,345 video match analysis (25 Hz) datasets from 380 players in 96 matches of the German first Bundesliga were gathered by an automatic player tracking system. Displacement (speed, acceleration, distance) and energetic (MP, energy expenditure) variables were determined. Intensity was classified utilizing conventional thresholds. Metabolic and running profiles were compared among six positional groups and between the halves of the match respectively (one-way ANOVA). Further, time spent, distance covered and energy expended at high speed (>15.5 km h⁻¹) and high acceleration (>2 m s⁻²) were compared to those at high MP (>20 W kg⁻¹) (one-way ANOVA) for evaluating if metabolic power is more suited to describe intensity in team sports. Main findings are that central-attacking midfielders (CAM) and central midfielders (CM) expended more energy (CAM: 59.8 ± 4.2 kJ kg⁻¹; CM: 59.6 ± 3.6 kJ kg⁻¹) and covered more distance (CAM: 11,494 ± 765 m; CM: 11,445 ± 638 m) than all other positions (p < 0.001). In the whole group of players, less time (t) and less energy were expended (EE) in high speed (t: 302 ± 84 s; EE: 10.1 ± 2.9 kJ kg⁻¹) and at high acceleration zones (t: 147 ± 24 s; EE: 5.5 ± 1.2 kJ kg⁻¹) when compared to high MP zone (t: 617 ± 141 s; EE: 20.0 ± 4.4 kJ kg⁻¹) (p < 0.001). Furthermore, players covered more distance at high MP (2,464 ± 597 m) than at high speed (1,638 ± 458 m) and much less at high acceleration (359 ± 67 m) (p < 0.001). The higher activity profiles of CAM and CM compared to the other positions indicate the need for higher developed physiological performance in players of these positions. High intensity activities should be interpreted differently when using MP and displacement parameters as indicators of high intensity in soccer.

The gastrointestinal tract contains a complex microbial community. Peyer’s patches (PPs) play an important role in inducing mucosal immune responses in the gastrointestinal tract. However, little is known about the effect of commensal microbiota on the host’s PPs. Here, we analyzed the phenotypic-to-transcriptome changes in the intestine PPs of specific pathogen-free (SPF) and germ-free (GF) piglets (fed in an environment with and without commensal microbiota, respectively) to elucidate the role of commensal microbiota in host intestine mucosal immunity. Analyses of anatomical and histological characteristics showed that commensal microbiota deficiency led to PP hypoplasia, especially regarding B and T cells. A total of 12,444 mRNAs were expressed in 12 libraries; 2,156 and 425 differentially expressed (DE) mRNAs were detected in the jejunal PP (JPP) and ileal PP (IPP), respectively (SPF vs. GF). The shared DE mRNAs of the JPP and IPP were mainly involved in basic physiological and metabolic processes, while the specific DE mRNAs were enriched in regulating immune cells in the JPP and microbial responses and cellular immunity in the IPP. Commensal microbiota significantly modulated the expression of genes related to B-cell functions, including activation, proliferation, differentiation, apoptosis, receptor signaling, germinal center formation, and IgA isotype class switching, particularly in the JPP. TLR4 pathway-related genes were induced in response to microbial colonization and in LPS/SCFA-treated B cells. We also detected 69 and 21 DE lncRNAs in the JPP and IPP, respectively, and four one-to-one lncRNA-mRNA pairs were identified. These findings might represent key regulatory axes for host intestine mucosal immunity development during microbial colonization. Overall, the findings of this study revealed that commensal microbiota modulated phenotypic characteristics and gene expression in the piglet intestine PPs and underscored the importance of early microbial colonization for host mucosal immunity development.

Whole-Body Electromyostimulation (WB-EMS) is a training technology that enables simultaneous stimulation of all the main muscle groups with a specific impulse intensity for each electrode. The corresponding time-efficiency and joint-friendliness of WB-EMS may be particularly attractive for people unable or unmotivated to conduct (intense) conventional training protocols. However, due to the enormous metabolic and musculoskeletal impact of WB-EMS, particular attention must be paid to the application of this technology. In the past, several scientific and newspaper articles reported severe adverse effects of WB-EMS. To increase the safety of commercial non-medical WB-EMS application, recommendations “for safe and effective whole-body electromyostimulation” were launched in 2016. However, new developments and trends require an update of these recommendations to incorporate more international expertise with demonstrated experience in the application of WB-EMS. The new version of these consensus-based recommendations has been structured into 1) “general aspects of WB-EMS”, 2) “preparation for training”, recommendations for the 3) “WB-EMS application” itself and 4) “safety aspects during and after training”. Key topics particularly addressed are 1) consistent and close supervision of WB-EMS application, 2) mandatory qualification of WB-EMS trainers, 3) anamnesis and corresponding consideration of contraindications prior to WB-EMS, 4) the participant’s proper preparation for the session, 5) careful preparation of the WB-EMS novice, 6) appropriate regeneration periods between WB-EMS sessions and 7) continuous interaction between trainer and participant at a close physical distance. In summary, we are convinced that the present guideline will contribute to greater safety and effectiveness in the area of non-medical commercial WB-EMS application.

Well designed and formulated natural feed additives have the potential to provide many of the growth promoting and disease mitigating characteristics of in-feed antibiotics, particularly feed additives that elicit their effects on targeted areas of the gut. Here, we describe the mechanism of action of a microencapsulated feed additive containing organic acids and botanicals (AviPlus^®P) on the jejunum and ileum of 15-day-old broiler-type chickens. Day-of-hatch chicks were provided ad libitum access to feed containing either 0 or 500 g/MT of the feed additive for the duration of the study. Fifteen days post-hatch, birds were humanely euthanized and necropsied. Jejunum and ileum tissue samples were collected and either flash frozen or stored in RNA-later as appropriate for downstream applications. Chicken-specific kinome peptide array analysis was conducted on the jejunum and ileum tissues, comparing the tissues from the treated birds to those from their respective controls. Detailed analysis of peptides representing individual kinase target sites revealed that in the ileum there was a broad increase in the signal transduction pathways centering on activation of HIF-1α, AMPK, mTOR, PI3K-Akt and NFκB. These signaling responses were largely decreased in the jejunum relative to control birds. Gene expression analysis agrees with the kinome data showing strong immune gene expression in the ileum and reduced expression in the jejunum. The microencapsulated blend of organic acids and botanicals elicit a more anti-inflammatory phenotype and reduced signaling in the jejunum while resulting in enhanced immunometabolic responses in the ileum.

Insects often establish long-term relationships with intracellular symbiotic bacteria, i.e., endosymbionts, that provide them with essential nutrients such as amino acids and vitamins. Endosymbionts are typically confined within specialized host cells called bacteriocytes that may form an organ, the bacteriome. Compartmentalization within host cells is paramount for protecting the endosymbionts and also avoiding chronic activation of the host immune system. In the cereal weevil Sitophilus oryzae, bacteriomes are present as a single organ at the larval foregut-midgut junction, and in adults, at the apex of midgut mesenteric caeca and at the apex of the four ovarioles. While the adult midgut endosymbionts experience a drastic proliferation during early adulthood followed by complete elimination through apoptosis and autophagy, ovarian endosymbionts are maintained throughout the weevil lifetime by unknown mechanisms. Bacteria present in ovarian bacteriomes are thought to be involved in the maternal transmission of endosymbionts through infection of the female germline, but the exact mode of transmission is not fully understood. Here, we show that endosymbionts are able to colonize the germarium in one-week-old females, pinpointing a potential infection route of oocytes. To identify potential immune regulators of ovarian endosymbionts, we have analyzed the transcriptomes of the ovarian bacteriomes through young adult development, from one-day-old adults to sexually mature ones. In contrast with midgut bacteriomes, immune effectors are downregulated in ovarian bacteriomes at the onset of sexual maturation. We hypothesize that relaxation of endosymbiont control by antimicrobial peptides might allow bacterial migration and potential oocyte infection, ensuring endosymbiont transmission.

Bilateral index for upper limbs was determined for maximal force, speed and power in 18 male handball players. Variables were individually assessed with a functional electromechanical dynamometer during unilateral and bilateral bench press push-off for 40%, 60%, and 75% of the maximal isometric force. Limb dominance (symmetry indices) and load effects in the bilateral index were analysed. Bilateral index showed a bilateral deficit for power (range = −8.50 to −41.48) and velocity (range = −11.15 to −38.41), that increases with the load (p < 0.05). For maximum force, a bilateral facilitation (range = 2.26–5.57), which did not vary significantly as a function of load, was observed. Symmetry indices showed no association with the bilateral index (40% load: r = 0.45, 60% load: r = 0.05, 75% load: r = 0.39). These results contribute to understanding the phenomenon; however, individual-to-individual observation reflects that caution should be kept when assessing an individual athlete. In conclusion, bilateral deficit or facilitation for bench press depends on the variable considered, whereas its magnitude depends on the load. Moreover, limb dominance does not affect it. This finding must be regarded as a general trend, but a different situation may occur during the assessment of a particular athlete.

Introduction: Dynamic positron emission tomography (PET) and the application of kinetic models can provide important quantitative information based on its temporal information. This however requires arterial blood sampling, which can be challenging to acquire. Nowadays, state-of-the-art PET/CT systems offer fully automated, whole-body (WB) kinetic modelling protocols using image-derived input functions (IDIF) to replace arterial blood sampling. Here, we compared the validity of an automatic WB kinetic model protocol to the reference standard arterial input function (AIF) for both clinical and research settings.Methods: Sixteen healthy participants underwent dynamic WB [¹⁸F]FDG scans using a continuous bed motion PET/CT system with simultaneous arterial blood sampling. Multiple processing pipelines that included automatic and manually generated IDIFs derived from the aorta and left ventricle, with and without motion correction were compared to the AIF. Subsequently generated quantitative images of glucose metabolism were compared to evaluate performance of the different input functions.Results: We observed moderate to high correlations between IDIFs and the AIF regarding area under the curve (r = 0.49–0.89) as well as for the cerebral metabolic rate of glucose (CMRGlu) (r = 0.68–0.95). Manual placing of IDIFs and motion correction further improved their similarity to the AIF.Discussion: In general, the automatic vendor protocol is a feasible approach for the quantification of CMRGlu for both, clinical and research settings where expertise or time is not available. However, we advise on a rigorous inspection of the placement of the volume of interest, the resulting IDIF, and the quantitative values to ensure valid interpretations. In protocols requiring longer scan times or where cohorts are prone to involuntary movement, manual IDIF definition with additional motion correction is recommended, as this has greater accuracy and reliability.

Introduction: The microbiota–gut–brain axis plays an important role in the pathophysiology of autism spectrum disorder, but its specific mechanisms remain unclear. This study aimed to explore the associations of changes in neurotransmitters and short-chain fatty acids with alterations in gut microbiota in valproic acid model rats.Methods: The autism model rats were established by prenatal exposure to valproic acid (VPA). The Morris water maze test, open field test, and three-chamber test were conducted to assess the behaviors of rats. 16S rRNA gene sequences extracted from fecal samples were used to assess the gut microbial composition. Gas and liquid chromatography–mass spectroscopy was used to identify short-chain fatty acids in fecal samples and neurotransmitters in the prefrontal cortex (PFC).Results: The results showed that 28 bacterial taxa between valproic acid model rats and control rats were identified, and the most differential bacterial taxa in valproic acid model rats and control rats belonged to metagenomic species and Lactobacillus intestinalis. Acetic acid, butyric acid, valeric acid, isobutyric acid, and isovaleric acid were significantly decreased in the valproic acid model rats compared to those in control rats. Five neurotransmitters (threonine, kynurenine, tryptophan, 5-hydroxyindoleacetic acid, denoted as 5-HIAA, and betaine aldehyde chloride, denoted as BAC) were significantly decreased, whereas betaine was increased in the prefrontal cortex of valproic acid model rats compared to control rats. A variety of neurotransmitters (≥4) were correlated with Pseudomonas, Collisella, and Streptococcus at the genus level, and they were also related to the decrease of short-chain fatty acids.Discussion: According to this study, we can preliminarily infer that gut microbiota or their metabolic productions (such as SCFAs) may influence central neurotransmitter metabolism through related pathways of the gut-brain axis. These results provide microbial and short-chain fatty acid (SCFA) frameworks for understanding the role of the microbiota–gut–brain axis in autism spectrum disorder and shed new light on autism spectrum disorder treatment.

Use of smart patches by athletes: A concise SWOT analysis

In the last century broiler chicken lines have undergone an extensive breeding regime aimed primarily at growth and high meat yield. It is not known if breeding has also resulted in a change to the broiler breeder’s associated gut microbiota. Here we compared the gut microbiota of 37-week-old commercial Cobb breeding dams with dams from a broiler Legacy line which has not undergone selection since 1986. The dams from both lines were kept together in the same shed under the same management protocol from day of hatch to avoid additional confounders. We chose this age to allow significant bacterial exchange, thus avoiding exposure dependent artifacts and so that we could compare dams at the same developmental state of adulthood and peak laying performance. Significant differences in the composition of the cecum bacterial communities were found. Bacteria of the genus Akkermansia, implicated in mucin degradation and associated with host metabolic health, accounted for 4.98% ± 5.04% of the Cobb cecum community, but were mostly absent from the ceca of the Legacy line dams. Inversely, Legacy dams had higher levels of Clostridiales, Lactobacillales and Aeromonadales. These results show that breeding has resulted in a change in the gut microbiota composition, likely by changing the physiological conditions in the mucosa. It remains unclear if changes in gut microbiota composition are a part of the mechanism affecting growth or are a secondary result of other physiological changes accelerating growth. Therefore, the identification of these changes opens the door to further targeted research.

Background: Field potential (FP) signals from human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) spheroid which are used for drug safety tests in the preclinical stage are different from action potential (AP) signals and require working knowledge of the multi-electrode array (MEA) system. In this study, we developed in silico three-dimensional (3-D) models of hiPSC-CM spheroids for the simulation of field potential measurement. We compared our model simulation results against in vitro experimental data under the effect of drugs E-4031 and nifedipine.Methods:In silico 3-D models of hiPSC-CM spheroids were constructed in spherical and discoidal shapes. Tetrahedral meshes were generated inside the models, and the propagation of the action potential in the model was obtained by numerically solving the monodomain reaction-diffusion equation. An electrical model of electrode was constructed and FPs were calculated using the extracellular potentials from the AP propagations. The effects of drugs were simulated by matching the simulation results with in vitro experimental data.Results: The simulated FPs from the 3-D models of hiPSC-CM spheroids exhibited highly variable shapes depending on the stimulation and measurement locations. The values of the IC₅₀ of E-4031 and nifedipine calculated by matching the simulated FP durations with in vitro experimental data were in line with the experimentally measured ones reported in the literature.Conclusion: The 3-D in silico models of hiPSC-CM spheroids generated highly variable FPs similar to those observed in in vitro experiments. The in silico model has the potential to complement the interpretation of the FP signals obtained from in vitro experiments.

Background: We investigated the impact of moderate muscle cooling induced by single and intermittent/prolonged cold-water immersions (CWI) on muscle force and contractility in unfatigued state and during the development of fatigue resulting from electrically induced contractions.Methods: Twelve young males participated in this study consisting of two phases [single phase (SP) followed by intermittent/prolonged phase (IPP)], with both phases including two conditions (i.e., four trials in total) performed randomly: control passive sitting (CON) and cold-water immersions (10°C). SP-CWI included one 45 min-bath (from 15 to 60 min). IPP-CWI included three baths (45 min-bath from 15 to 60 min, and 15 min-baths from 165 to 180 min and from 255 to 270 min), with participants sitting at room temperature the rest of the time until 300 min. Blood pressure and intramuscular (Tmu) temperature were assessed, and neuromuscular testing was performed at baseline and 60 min after baseline during SP, and at baseline, 60, 90, 150 and 300 min after baseline during IPP. A fatiguing protocol (100 electrical stimulations) was performed after the last neuromuscular testing of each trial.Results: In unfatigued state, SP-CWI and IPP-CWI reduced electrically induced torque at 100 Hz (P100) but not at 20 Hz (P20), and increased P20/P100 ratio. The changes from baseline for P100 and P20/P100 ratio were lower in IPP-CWI than SP-CWI. Both cold-water immersion conditions slowed down muscle contraction and relaxation, and reduced maximal isokinetic contraction torque, but the changes from baseline were lower after IPP-CWI than SP-CWI. cold-water immersions did not impair maximal voluntary isometric contraction. During the fatiguing protocol, torque fatigue index and the changes in muscle contractile properties were larger after IPP-CWI than SP-CWI, but were in the same range as after CON conditions. The differences of muscle contractile function between SP-CWI and IPP-CWI were accompanied by a lower reduction of superficial Tmu and a smaller increase in systolic blood pressure after IPP-CWI than SP-CWI.Conclusion: IPP-CWI induces a less pronounced fast-to-slow contractile transition compared to SP-CWI, and this may result from the reduced vasoconstriction response and enhanced blood perfusion of the superficial muscle vessels, which could ultimately limit the reduction of superficial Tmu.

Hypertensive pregnancy disorders put the maternal-fetal dyad at risk and are one of the leading causes of morbidity and mortality during pregnancy. Multiple efforts have been made to understand the physiological mechanisms behind changes in blood pressure. Still, to date, no study has focused on analyzing the dynamics of the interactions between the systems involved in blood pressure control. In this work, we aim to address this question by evaluating the phase coherence between different signals using wavelet phase coherence. Electrocardiogram, continuous blood pressure, electrocardiogram-derived respiration, and muscle sympathetic nerve activity signals were obtained from ten normotensive pregnant women, ten normotensive non-pregnant women, and ten pregnant women with preeclampsia during rest and cold pressor test. At rest, normotensive pregnant women showed higher phase coherence in the high-frequency band (0.15-0.4 Hz) between muscle sympathetic nerve activity and the RR interval, blood pressure, and respiration compared to non-pregnant normotensive women. Although normotensive pregnant women showed no phase coherence differences with respect to hypertensive pregnant women at rest, higher phase coherence between the same pairs of variables was found during the cold pressor test. These results suggest that, in addition to the increased sympathetic tone of normotensive pregnant women widely described in the existing literature, there is an increase in cardiac parasympathetic modulation and respiratory-driven modulation of muscle sympathetic nerve activity and blood pressure that could compensate sympathetic increase and make blood pressure control more efficient to maintain it in normal ranges. Moreover, blunted modulation could prevent its buffer effect and produce an increase in blood pressure levels, as observed in the hypertensive women in this study. This initial exploration of cardiorespiratory coupling in pregnancy opens the opportunity to follow up on more in-depth analyses and determine causal influences.

Ca²⁺ plays a crucial role in excitation-contraction coupling in cardiac myocytes. Dysfunctional Ca²⁺ regulation alters the force of contraction and causes cardiac arrhythmias. Ca²⁺ entry into cardiomyocytes is mediated mainly through L-type Ca²⁺ channels, leading to the subsequent Ca²⁺ release from the sarcoplasmic reticulum. L-type Ca²⁺ channels are composed of the conventional Ca_v1.2, ubiquitously expressed in all heart chambers, and the developmentally regulated Ca_v1.3, exclusively expressed in the atria, sinoatrial node, and atrioventricular node in the adult heart. As such, Ca_v1.3 is implicated in the pathogenesis of sinoatrial and atrioventricular node dysfunction as well as atrial fibrillation. More recently, Ca_v1.3 de novo expression was suggested in heart failure. Here, we review the functional role, expression levels, and regulation of Ca_v1.3 in the heart, including in the context of cardiac diseases. We believe that the elucidation of the functional and molecular pathways regulating Ca_v1.3 in the heart will assist in developing novel targeted therapeutic interventions for the aforementioned arrhythmias.

Background and Objective: Cardiovascular disease is a high-fatality health issue. Accurate measurement of cardiovascular function depends on precise segmentation of physiological structure and accurate evaluation of functional parameters. Structural segmentation of heart images and calculation of the volume of different ventricular activity cycles form the basis for quantitative analysis of physiological function and can provide the necessary support for clinical physiological diagnosis, as well as the analysis of various cardiac diseases. Therefore, it is important to develop an efficient heart segmentation algorithm.Methods: A total of 275 nuclear magnetic resonance imaging (MRI) heart scans were collected, analyzed, and preprocessed from Huaqiao University Affiliated Strait Hospital, and the data were used in our improved deep learning model, which was designed based on the U-net network. The training set included 80% of the images, and the remaining 20% was the test set. Based on five time phases from end-diastole (ED) to end-systole (ES), the segmentation findings showed that it is possible to achieve improved segmentation accuracy and computational complexity by segmenting the left ventricle (LV), right ventricle (RV), and myocardium (myo).Results: We improved the Dice index of the LV to 0.965 and 0.921, and the Hausdorff index decreased to 5.4 and 6.9 in the ED and ES phases, respectively; RV Dice increased to 0.938 and 0.860, and the Hausdorff index decreased to 11.7 and 12.6 in the ED and ES, respectively; myo Dice increased to 0.889 and 0.901, and the Hausdorff index decreased to 8.3 and 9.2 in the ED and ES, respectively.Conclusion: The model obtained in the final experiment provided more accurate segmentation of the left and right ventricles, as well as the myocardium, from cardiac MRI. The data from this model facilitate the prediction of cardiovascular disease in real-time, thereby providing potential clinical utility.

Within the pulmonary acini ventilation and blood perfusion are brought together on a huge surface area separated by a very thin blood-gas barrier of tissue components to allow efficient gas exchange. During ventilation pulmonary acini are cyclically subjected to deformations which become manifest in changes of the dimensions of both alveolar and ductal airspaces as well as the interalveolar septa, composed of a dense capillary network and the delicate tissue layer forming the blood-gas barrier. These ventilation-related changes are referred to as micromechanics. In lung diseases, abnormalities in acinar micromechanics can be linked with injurious stresses and strains acting on the blood-gas barrier. The mechanisms by which interalveolar septa and the blood-gas barrier adapt to an increase in alveolar volume have been suggested to include unfolding, stretching, or changes in shape other than stretching and unfolding. Folding results in the formation of pleats in which alveolar epithelium is not exposed to air and parts of the blood-gas barrier are folded on each other. The opening of a collapsed alveolus (recruitment) can be considered as an extreme variant of septal wall unfolding. Alveolar recruitment can be detected with imaging techniques which achieve light microscopic resolution. Unfolding of pleats and stretching of the blood-gas barrier, however, require electron microscopic resolution to identify the basement membrane. While stretching results in an increase of the area of the basement membrane, unfolding of pleats and shape changes do not. Real time visualization of these processes, however, is currently not possible. In this review we provide an overview of septal wall micromechanics with focus on unfolding/folding as well as stretching. At the same time we provide a state-of-the-art design-based stereology methodology to quantify microarchitecture of alveoli and interalveolar septa based on different imaging techniques and design-based stereology.

Introduction: The striped ambrosia beetle Trypodendron lineatum (Coleoptera, Curculionidae, Scolytinae) is a major forest pest in the Holarctic region. It uses an aggregation pheromone and host and non-host volatiles to locate suitable host trees, primarily stressed or dying conifer trees. The beetles bore into the xylem and inoculate spores of their obligate fungal mutualist Phialophoropsis ferruginea inside their excavated egg galleries, with the fungus serving as the main food source for the developing larvae. Olfactory sensory neuron (OSN) responses to pheromones and host volatiles are poorly understood in T. lineatum and other ambrosia beetles, and nothing is known about potential responses to fungal volatiles.Methods: We screened responses of OSNs present in 170 antennal olfactory sensilla using single sensillum recordings (SSR) and 57 odor stimuli, including pheromones, host and non-host compounds, as well as volatiles produced by P. ferruginea and fungal symbionts of other scolytine beetles.Results and Discussion: Thirteen OSN classes were characterized based on their characteristic response profiles. An OSN class responding to the aggregation pheromone lineatin was clearly the most abundant on the antennae. In addition, four OSN classes responded specifically to volatile compounds originating from the obligate fungal mutualist and three responded to non-host plant volatiles. Our data also show that T. lineatum has OSN classes tuned to pheromones of other bark beetles. Several OSN classes showed similar response profiles to those previously described in the sympatric bark beetle Ips typographus, which may reflect their shared ancestry.

Stress is an integral part of life. While acute responses to stress are generally regarded as beneficial in dealing with immediate threats, chronic exposure to threatening stimuli exerts deleterious effects and can be either a contributing or an aggravating factor for many chronic diseases including cancer. Chronic psychological stress has been identified as a significant factor contributing to the development and progression of cancer, but the mechanisms that link chronic stress to cancer remain incompletely understood. Psychological stressors initiate multiple physiological responses that result in the activation of the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system, and the subsequent changes in immune function. Chronic stress exposure disrupts the homeostatic communication between the neuroendocrine and immune systems, shifting immune signaling toward a proinflammatory state. Stress-induced chronic low-grade inflammation and a decline in immune surveillance are both implicated in cancer development and progression. Conversely, tumor-induced inflammatory cytokines, apart from driving a tumor-supportive inflammatory microenvironment, can also exert their biological actions distantly via circulation and therefore adversely affect the stress response. In this minireview, we summarize the current findings on the relationship between stress and cancer, focusing on the role of inflammation in stress-induced neuroendocrine-immune crosstalk. We also discuss the underlying mechanisms and their potential for cancer treatment and prevention.

Background: The pathogenesis of COVID-19, including thrombocytopenia, has not been fully clarified. The lungs are a major organ of platelet production and thrombocytopenia induced by severe COVID-19 was proposed.Methods: the change of platelet level was analysed with clinical parameters in 95 hospitalized COVID-19 patients in Wuhan Third Hospital. The production of platelets in the lungs was explored in an ARDS rat model.Results: The level of platelets was negatively correlated with disease severity and was recovered with disease improvement. The non-survivors were accompanied by lower levels of platelet. The odds ratio (OR) of the valley level of the platelet count (PLTlow) was greater than 1, suggesting that PLTlow could be a death exposure factor. The platelet/lymphocyte ratio (PLR) was positively associated with severity of COVID-19, and the platelet/lymphocyte ratio threshold of 248.5 was best correlated with death risk (sensitivity 0.641 and specificity 0.815). To demonstrate the possible biogenesis aberration of platelet in lungs, an LPS-induced ARDS rat model was applied. Lower level of platelet in peripheral and less production of platelet from lungs in ARDS were demonstrated. Though megakaryocyte (MK) number in ARDS lungs is higher than controls, the immature platelet fraction (IPF) in postpulmonary blood is still at the same level as prepulmonary in ARDS rat, indicating that ARDS rats generated fewer platelets in lungs.Conclusion: Our data suggested that COVID-19-induced severe lung inflammation may impair platelet production in the lung. Thrombocytopenia may be mainly caused by platelet consumption for multiorgan thrombosis; however, biogenesis aberration of platelet in the lung induced by diffuse interstitial pulmonary damage cannot be ruled out.