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Adenosine A2A receptors (A2AR) and dopamine D2 receptors (D2R) are known to be involved in the physiological response to hypoxia, and their expression/activity may be modulated by chronic sustained or intermittent hypoxia. To date, A2AR and D2R can form transient physical receptor–receptor interactions (RRIs) giving rise to a dynamic equilibrium able to influence ligand binding and signaling, as demonstrated in different native tissues and transfected mammalian cell systems. Given the presence of A2AR and D2R in type I cells, type II cells, and afferent nerve terminals of the carotid body (CB), the aim of this work was to demonstrate here, for the first time, the existence of A2AR–D2R heterodimers by in situ proximity ligation assay (PLA). Our data by PLA analysis and tyrosine hydroxylase/S100 colocalization indicated the formation of A2AR–D2R heterodimers in type I and II cells of the CB; the presence of A2AR–D2R heterodimers also in afferent terminals is also suggested by PLA signal distribution. RRIs could play a role in CB dynamic modifications and plasticity in response to development/aging and environmental stimuli, including chronic intermittent/sustained hypoxia. Exploring other RRIs will allow for a broad comprehension of the regulative mechanisms these interactions preside over, with also possible clinical implications.

Mechanical trauma can (MT) cause secondary injury, such as cardiomyocyte apoptosis and cardiac dysfunction has been reported. However, the effects of mechanical trauma on gastrointestinal tract is unclear. This study aims to observe the main location and time of gastrointestinal tract injury caused by non-directional trauma and explain the reason of the increase of LPS in blood caused by mechanical injury. Morphological changes in the stomach, ileum and cecum at different time points after MT were observed in this experiment. The results reveal that the injury to the cecal mucosa in the rats was more obvious than that in the ileum and the stomach. The cecal epithelial cell junction was significantly widened at 20 min after MT, and the plasma LPS and D-lactic acid concentrations increased significantly at the same time point. In addition, some bacterial structures in the widened intercellular space and near the capillary wall of the cecal mucosa were detected at 12 h after MT. This finding suggests that the main reason for the increase in LPS in plasma after MT is cecal mucosal injury. This study is important for the early intervention of the gastrointestinal tract to prevent secondary injury after MT.

Vitamin D is an essential nutrient for the maintenance of skeletal muscle and bone health. The vitamin D receptor (VDR) is present in muscle, as is CYP27B1, the enzyme that hydroxylates 25(OH)D to its active form, 1,25(OH)D. Furthermore, mounting evidence suggests that vitamin D may play an important role during muscle damage and regeneration. Muscle damage is characterized by compromised muscle fiber architecture, disruption of contractile protein integrity, and mitochondrial dysfunction. Muscle regeneration is a complex process that involves restoration of mitochondrial function and activation of satellite cells (SC), the resident skeletal muscle stem cells. VDR expression is strongly upregulated following injury, particularly in central nuclei and SCs in animal models of muscle injury. Mechanistic studies provide some insight into the possible role of vitamin D activity in injured muscle. In vitro and in vivo rodent studies show that vitamin D mitigates reactive oxygen species (ROS) production, augments antioxidant capacity, and prevents oxidative stress, a common antagonist in muscle damage. Additionally, VDR knockdown results in decreased mitochondrial oxidative capacity and ATP production, suggesting that vitamin D is crucial for mitochondrial oxidative phosphorylation capacity; an important driver of muscle regeneration. Vitamin D regulation of mitochondrial health may also have implications for SC activity and self-renewal capacity, which could further affect muscle regeneration. However, the optimal timing, form and dose of vitamin D, as well as the mechanism by which vitamin D contributes to maintenance and restoration of muscle strength following injury, have not been determined. More research is needed to determine mechanistic action of 1,25(OH)D on mitochondria and SCs, as well as how this action manifests following muscle injury in vivo. Moreover, standardization in vitamin D sufficiency cut-points, time-course study of the efficacy of vitamin D administration, and comparison of multiple analogs of vitamin D are necessary to elucidate the potential of vitamin D as a significant contributor to muscle regeneration following injury. Here we will review the contribution of vitamin D to skeletal muscle regeneration following injury.

The pre-Bötzinger complex (preBötC) of the ventral medulla generates the mammalian inspiratory breathing rhythm. When isolated in explants and deprived of synaptic inhibition, the preBötC continues to generate inspiratory-related rhythm. Mechanisms underlying burst generation have been investigated for decades, but cellular and synaptic mechanisms responsible for burst termination have received less attention. KCNQ-mediated K+ currents contribute to burst termination in other systems, and their transcripts are expressed in preBötC neurons. Therefore, we tested the hypothesis that KCNQ channels also contribute to burst termination in the preBötC. We recorded KCNQ-like currents in preBötC inspiratory neurons in neonatal rat slices that retain respiratory rhythmicity. Blocking KCNQ channels with XE991 or linopirdine (applied via superfusion or locally) increased inspiratory burst duration by 2- to 3-fold. By contrast, activation of KCNQ with retigabine decreased inspiratory burst duration by ~35%. These data from reduced preparations suggest that the KCNQ current in preBötC neurons contributes to inspiratory burst termination.

Whiteflies are Hemipterans that typically feed on the undersides of plant leaves. They cause severe damage by direct feeding as well as transmitting plant viruses to a wide range of plants. However, it remains largely unknown which genes play a key role in development and host selection. In this study, weighted gene co-expression network analysis was applied to construct gene co-expression networks in whitefly. Nineteen gene co-expression modules were detected from 15560 expressed genes of whitefly. Combined with the transcriptome data of salivary glands and midgut, we identified three gene co-expression modules related to host plant selection. These three modules contain genes related to host-plant recognition, such as detoxification genes, chemosensory genes and some salivary gland-associated genes. Results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses elucidated the following pathways involved in these modules: lysosome, metabolic and detoxification pathways. The modules related to the development contain two co-expression modules; moreover, the genes were annotated to the development of chitin-based cuticle. This analysis provides a basis for future functional analysis of genes involved in host-plant recognition.

Emerging evidence suggests that type 2 diabetes (T2D) may impair the ability to properly adjust the circulation during exercise with augmented blood pressure (BP) and an attenuated contracting skeletal muscle blood flow (BF) response being reported. This review provides a brief overview of the current understanding of these altered exercise responses in T2D and the potential underlying mechanisms, with an emphasis on the sympathetic nervous system and its regulation during exercise. The research presented support augmented sympathetic activation, heightened BP, reduced skeletal muscle BF, and impairment in the ability to attenuate sympathetically mediated vasoconstriction (i.e., functional sympatholysis) as potential drivers of neurovascular dysregulation during exercise in T2D. Furthermore, emerging evidence supporting a contribution of the exercise pressor reflex and central command is discussed along with proposed future directions for studies in this important area of research.

Cerebrovascular reactivity (CVR) is used as an outcome measure of brain health. Traditionally, lower CVR is associated with ageing, poor fitness and brain-related conditions (e.g. stroke, dementia). Indeed, CVR is suggested as a biomarker for disease risk. However, recent findings report conflicting associations between ageing or fitness and CVR measures. Inconsistent findings may relate to different neuroimaging modalities used, which include transcranial Doppler (TCD) and blood-oxygen-level-dependant (BOLD) contrast magnetic resonance imaging (MRI). We assessed the relationship between CVR metrics derived from two common imaging modalities, TCD and BOLD MRI, within the same individuals and with expected significant differences (i.e., younger vs. older) to maximise the expected spread in measures. We conducted two serial studies using TCD- and MRI-derived measures of CVR (via inspired 5% CO2 in air). Study 1 compared 20 younger (24 ± 7 years) with 15 older (66 ± 7 years) participants, Study 2 compared 10 younger (22 ± 2 years) with 10 older (72 ± 4 years) participants. Combining the main measures across studies, no significant correlation (r = 0.15, p = 0.36) was observed between individual participant TCD- and BOLD-CVR measures. Further, these measures showed differential effects between age groups; with TCD-CVR higher in the older compared to younger group (4 ± 1 vs. 3 ± 1 %MCAv/mmHg PETCO2; p < 0.05, Hedges’ g = 0.75), whereas BOLD-CVR showed no difference (p = 0.104, Hedges’ g = 0.38). In Study 2 additional measures were obtained to understand the origin of the discrepancy: phase contrast angiography (PCA) MRI of the middle cerebral artery, showed a significantly lower blood flow (but not velocity) CVR response in older compared with younger participants (p > 0.05, Hedges’ g = 1.08). The PCA CVR metrics did not significantly correlate with the BOLD- or TCD-CVR measures. The differing CVR observations between imaging modalities were despite expected, correlated (r = 0.62–0.82), age-related differences in resting CBF measures across modalities. Taken together, findings across both studies show no clear relationship between TCD- and BOLD-CVR measures. We hypothesize that CVR differences between imaging modalities are in part due to the aspects of the vascular tree that are assessed (TCD:arteries; BOLD:venules/veins). Further work is needed to understand the between-modality CVR response differences, but caution is needed when comparing CVR metrics derived from different imaging modalities.

Avalanches are major natural hazards in snow-covered mountains, threatening people and infrastructure. With ongoing climate change, the frequency and types of snow avalanches may change, affecting the rates of avalanche burial and survival. With a wetter and warmer snow climate, consequences of burial may become more severe. In this review, we assess the potential effects of climate change on the frequency and characteristics of avalanches. We then discuss how these changes might affect the survival rates of subjects buried by avalanches and might influence the responses of search and rescue (SAR) teams and health care providers. While climate change is inevitable, the effects on avalanches remain elusive. The frequency of human triggered avalanches may not change, because this depends largely on the number and behavior of winter recreationists. Blunt trauma and secondary injuries will likely become more frequent as terrain roughness is expected to rise and snow cover to become thinner. Higher snow densities in avalanche debris will likely interfere with the respiration of completely buried victims. Asphyxia and trauma, as causes of avalanche death, may increase. It is unlikely that SAR and health care providers involved in avalanche rescue will have to change their strategies in areas where they are already established. The effects of climate change might foster the expansion of mitigation strategies and the establishment of mountain rescue services in areas subject to increased avalanche hazards caused by changes in snow cover and land use.

Traditional enhanced external counterpulsation (EECP) used for the clinical treatment of patients with coronary heart disease only assesses diastolic/systolic blood pressure (Q = D/S > 1.2). However, improvement of the hemodynamic environment surrounding vascular endothelial cells of coronary arteries after long-term application of EECP is the basis of the treatment. Currently, the quantitative hemodynamic mechanism is not well understood. In this study, a standard 0D/3D geometric multi-scale model of the coronary artery was established to simulate the hemodynamic effects of different counterpulsation modes on the vascular endothelium. In this model, the neural regulation caused by counterpulsation was thoroughly considered. Two clinical trials were carried out to verify the numerical calculation model. The results demonstrated that the increase in counterpulsation pressure amplitude and pressurization duration increased coronary blood perfusion and wall shear stress (WSS) and reduced the oscillatory shear index (OSI) of the vascular wall. However, the impact of pressurization duration was the predominant factor. The results of the standard model and the two real individual models indicated that a long pressurization duration would cause more hemodynamic risk areas by resulting in excessive WSS, which could not be reflected by the change in the Q value. Therefore, long-term pressurization during each cardiac cycle therapy is not recommended for patients with coronary heart disease and clinical treatment should not just pay attention to the change in the Q value. Additional physiological indicators can be used to evaluate the effects of counterpulsation treatment.

Rationale: Reducing the respiratory rate during extracorporeal membrane oxygenation (ECMO) decreases the mechanical power, but it might induce alveolar de-recruitment. Dissecting de-recruitment due to lung edema vs. the fraction due to hypoventilation may be challenging in injured lungs.Objectives: We characterized changes in lung physiology (primary endpoint: development of atelectasis) associated with progressive reduction of the respiratory rate in healthy animals on ECMO.Methods: Six female pigs underwent general anesthesia and volume control ventilation (Baseline: PEEP 5 cmH2O, Vt 10 ml/kg, I:E = 1:2, FiO2 0.5, rate 24 bpm). Veno-venous ECMO was started and respiratory rate was progressively reduced to 18, 12, and 6 breaths per minute (6-h steps), while all other settings remained unchanged. ECMO blood flow was kept constant while gas flow was increased to maintain stable PaCO2.Measurements and Main Results: At Baseline (without ECMO) and toward the end of each step, data from quantitative CT scan, electrical impedance tomography, and gas exchange were collected. Increasing ECMO gas flow while lowering the respiratory rate was associated with an increase in the fraction of non-aerated tissue (i.e., atelectasis) and with a decrease of tidal ventilation reaching the gravitationally dependent lung regions (p = 0.009 and p = 0.018). Intrapulmonary shunt increased (p < 0.001) and arterial PaO2 decreased (p < 0.001) at lower rates. The fraction of non-aerated lung was correlated with longer expiratory time spent at zero flow (r = 0.555, p = 0.011).Conclusions: Progressive decrease of respiratory rate coupled with increasing CO2 removal in mechanically ventilated healthy pigs is associated with development of lung atelectasis, higher shunt, and poorer oxygenation.

Action potential (AP) firing rate and rhythm of sinoatrial nodal cells (SANC) are controlled by synergy between intracellular rhythmic local Ca2+ releases (LCRs) (“Ca2+ clock”) and sarcolemmal electrogenic mechanisms (“membrane clock”). However, some SANC do not fire APs (dormant SANC). Prior studies have shown that β-adrenoceptor stimulation can restore AP firing in these cells. Here we tested whether this relates to improvement of synchronization of clock coupling. We characterized membrane potential, ion currents, Ca2+ dynamics, and phospholamban (PLB) phosphorylation, regulating Ca2+ pump in enzymatically isolated single guinea pig SANC prior to, during, and following β-adrenoceptor stimulation (isoproterenol) or application of cell-permeant cAMP (CPT-cAMP). Phosphorylation of PLB (Serine 16) was quantified in the same cells following Ca2+ measurement. In dormant SANC LCRs were small and disorganized at baseline, membrane potential was depolarized (−38 ± 1 mV, n = 46), and ICaL, If, and IK densities were smaller vs SANC firing APs. β-adrenoceptor stimulation or application of CPT-cAMP led to de novo spontaneous AP generation in 44 and 46% of dormant SANC, respectively. The initial response was an increase in size, rhythmicity and synchronization of LCRs, paralleled with membrane hyperpolarization and small amplitude APs (rate ∼1 Hz). During the transition to steady-state AP firing, LCR size further increased, while LCR period shortened. LCRs became more synchronized resulting in the growth of an ensemble LCR signal peaked in late diastole, culminating in AP ignition; the rate of diastolic depolarization, AP amplitude, and AP firing rate increased. ICaL, IK, and If amplitudes in dormant SANC increased in response to β-adrenoceptor stimulation. During washout, all changes reversed in order. Total PLB was higher, but the ratio of phosphorylated PLB (Serine 16) to total PLB was lower in dormant SANC. β-adrenoceptor stimulation increased this ratio in AP-firing cells. Thus, transition of dormant SANC to AP firing is linked to the increased functional coupling of membrane and Ca2+ clock proteins. The transition occurs via (i) an increase in cAMP-mediated phosphorylation of PLB accelerating Ca2+ pumping, (ii) increased spatiotemporal LCR synchronization, yielding a larger diastolic LCR ensemble signal resulting in an earlier increase in diastolic INCX; and (iii) increased current densities of If, ICaL, and IK.

Objective: We evaluated substrate utilization during submaximal exercise, together with glycemic responses and hormonal counter-regulation to exercise, in children with type 1 diabetes mellitus (T1DM).Methods: Twelve pre-pubescent children with T1DM and 12 healthy children were matched by sex and age. Participants completed a submaximal incremental exercise test to determine their fat and carbohydrate oxidation rates by indirect calorimetry. Levels of glycemia, glucagon, cortisol, growth hormone, noradrenaline, adrenaline, and insulin were monitored until 120 min post-exercise.Results: Absolute peak oxygen uptake (VO2 peak) was significantly lower in the children with T1DM than in the healthy controls (1131.4 ± 102.5 vs. 1383.0 ± 316.6 ml.min−1, p = 0.03). Overall carbohydrate and lipid oxidation rates were the same in the two groups, but for exercise intensities, higher than 50% of VO2 peak, fat oxidation rate was significantly lower in the children with T1DM. The absolute maximal lipid oxidation rate was significantly lower in the T1DM children (158.1 ± 31.6 vs. 205.4 ± 42.1 mg.min−1, p = 0.005), and they reached a significantly lower exercise power than the healthy controls (26.4 ± 1.2 vs. 35.4 ± 3.3 W, p = 0.03). Blood glucose responses to exercise were negatively correlated with pre-exercise blood glucose concentrations (r = −0.67; p = 0.03).Conclusion: Metabolic and hormonal responses during sub-maximal exercise are impaired in young children with T1DM.

Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by the loss of dystrophin. DMD is associated with muscle degeneration, necrosis, inflammation, fatty replacement, and fibrosis, resulting in muscle weakness, respiratory and cardiac failure, and premature death. There is no curative treatment. Investigations on disease-causing mechanisms offer an opportunity to identify new therapeutic targets to treat DMD. An abnormal elevation of the intracellular calcium (Cai2+) concentration in the dystrophin-deficient muscle is a major secondary event, which contributes to disease progression in DMD. Emerging studies have suggested that targeting Ca2+-handling proteins and/or mechanisms could be a promising therapeutic strategy for DMD. Here, we provide an updated overview of the mechanistic roles the sarcolemma, sarcoplasmic/endoplasmic reticulum, and mitochondria play in the abnormal and sustained elevation ofCai2+levels and their involvement in DMD pathogenesis. We also discuss current approaches aimed at restoring Ca2+homeostasis as potential therapies for DMD.

A 6-week feeding strategy experiment was conducted to investigate the effects of time-dependent protein restriction and subsequent recovery on shrimp. Diets with protein levels of 43 and 36% were used as adequate and restricted diets, respectively. Shrimp with an initial body weight of 6.52 ± 0.46 g were given four feeding strategies: feeding on an adequate diet for six weeks (T1, the control), having protein-restricted diet in weeks 1 and 4 (T2), being given a protein-restricted diet in weeks 1, 3, and 5 (T3), and having protein-restricted diet in weeks 1, 2, 4, and 5 (T4). WG, SGR, FE, and PER of shrimp in T1–T3 showed no significant difference (P > 0.05), these indicators of T4 were significantly reduced (P < 0.05). No significant differences were found in digestive enzyme activities of shrimp among all treatments (P > 0.05). Crude protein content of shrimp muscle in T4 was lower than that of T1–T3. The expression level of tor in T4 was lower than that in other treatments, while 4e-bp was higher than that of other treatments. To balance saving on feeding cost and growth performance, giving the shrimp a protein-restricted diet for 1 week with subsequent refeeding (T2 and T3) is suitable for shrimp under high-density conditions.

Short-chain fatty acids (SCFAs) are the main metabolites produced by the bacterial fermentation of dietary fiber, and they play a critical role in the maintenance of intestinal health. SCFAs are also essential for modulating different processes, and they have anti-inflammatory properties and immunomodulatory effects. As the inflammatory process predisposes the development of cancer and promotes all stages of tumorigenesis, an antitumor effect has also been associated with SCFAs. This is strongly supported by epidemiological studies showing that a diet rich in fiber is linked to a reduced risk of colon cancer and has significant clinical benefits in patients with inflammatory bowel disease (IBD). SCFAs may signal through the metabolite-sensing G protein-coupled receptors free fatty acid receptor 3 [FFAR3 or G protein-coupled receptor 41 (GPR41)], FFAR2 (GPR43), and GPR109A (also known as hydroxycarboxylic acid receptor 2 or HCAR2) expressed in the gut epithelium and immune cells. This review summarizes the existing knowledge regarding the SCFA-mediated suppression of inflammation and carcinogenesis in IBD and colon cancer.

Pulmonary hypertension (PH) is a critical and dangerous disease in cardiovascular system. Pulmonary vascular remodeling is an important pathophysiological mechanism for the development of pulmonary arterial hypertension. Pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy, and enhancing secretory activity are the main causes of pulmonary vascular remodeling. Previous studies have proven that various active substances and inflammatory factors, such as interleukin 6 (IL-6), IL-8, chemotactic factor for monocyte 1, etc., are involved in pulmonary vascular remodeling in PH. However, the underlying mechanisms of these active substances to promote the PASMC proliferation remain to be elucidated. In our study, we demonstrated that PASMC senescence, as a physiopathologic mechanism, played an essential role in hypoxia-induced PASMC proliferation. In the progression of PH, senescence PASMCs could contribute to PASMC proliferation via increasing the expression of paracrine IL-6 (senescence-associated secretory phenotype). In addition, we found that activated mTOR/S6K1 pathway can promote PASMC senescence and elevate hypoxia-induced PASMC proliferation. Further study revealed that the activation of mTOR/S6K1 pathway was responsible for senescence PASMCs inducing PASMC proliferation via paracrine IL-6. Targeted inhibition of PASMC senescence could effectively suppress PASMC proliferation and relieve pulmonary vascular remodeling in PH, indicating a potential for the exploration of novel anti-PH strategies.

Full functioning of the airway physical barrier depends on cellular integrity, which is coordinated by a series of tight junction (TJ) proteins. Due to airway spasm, edema, and mucus obstruction, positive end-expiratory alveolar pressure (also termed auto-PEEP) is a common pathophysiological phenomenon, especially in acute asthma attack. However, the influence of auto-PEEP on small airway epithelial TJs is currently unclear. We performed studies to investigate the effect of extra pressure on small airway epithelial TJs and its mechanism. The results first confirmed that a novel mechanosensitive receptor, piezo-1, was highly expressed in the airway epithelium of asthmatic mice. Extra pressure induced the degradation of occludin, ZO-1 and claudin-18 in primary human small airway epithelial cells (HSAECs), resulting in a decrease in transepithelial electrical resistance (TER) and an increase in cell layer permeability. Through in vitro investigations, we observed that exogenous pressure stimulation could elevate the intracellular calcium concentration ([Ca2+]i) in HSAECs. Downregulation of piezo-1 with siRNA and pretreatment with BAPTA-AM or ALLN reduced the degradation of TJs and attenuated the impairment of TJ function induced by exogenous pressure. These findings indicate the critical role of piezo-1/[Ca2+]i/calpain signaling in the regulation of small airway TJs under extra pressure stimulation.

Doxorubicin (DOX) cardiotoxicity is a life-threatening side effect that leads to a poor prognosis in patients receiving chemotherapy. We investigated the role of miR-22 in doxorubicin-induced cardiomyopathy and the underlying mechanism in vivo and in vitro. Specifically, we designed loss-of-function and gain-of-function experiments to identify the role of miR-22 in doxorubicin-induced cardiomyopathy. Our data suggested that inhibiting miR-22 alleviated cardiac fibrosis and cardiac dysfunction induced by doxorubicin. In addition, inhibiting miR-22 mitigated mitochondrial dysfunction through the sirt1/PGC-1α pathway. Knocking out miR-22 enhanced mitochondrial biogenesis, as evidenced by increased PGC-1α, TFAM, and NRF-1 expression in vivo. Furthermore, knocking out miR-22 rescued mitophagy, which was confirmed by increased expression of PINK1 and parkin and by the colocalization of LC3 and mitochondria. These protective effects were abolished by overexpressing miR-22. In conclusion, miR-22 may represent a new target to alleviate cardiac dysfunction in doxorubicin-induced cardiomyopathy and improve prognosis in patients receiving chemotherapy.

Background:In individuals with a spinal cord injury thermoregulatory mechanisms are fully or partially interrupted. This could lead to exercise-induced hyperthermia in temperate conditions which can be even more distinct in hot conditions. Hyperthermia has been suggested to impair physiological mechanisms in athletes, which could negatively influence physical performance and subjective well-being or cause mild to severe health issues.Objective:The aim was to evaluate the literature on the thermoregulatory and thermal responses of individuals with a spinal cord injury during exercise in temperate and hot conditions taking the effects of cooling techniques and heat acclimation into account.Data sources:Two electronic databases, PubMed and Web of Science were searched. Studies were eligible if they observed the influence of exercise on various thermoregulatory parameters (e.g., core and skin temperature, sweat rate, thermal sensation) in individuals with a spinal cord injury.Results:In total 32 articles were included of which 26 were of strong, 3 of moderate and 3 of weak quality. Individuals with a high lesion level, especially those with a tetraplegia, reached a higher core and skin temperature with a lower sweat rate. The use of cooling techniques before and during exercise can positively affect the burden of the impaired thermoregulatory system in all individuals with a spinal cord injury.Conclusion:Due to the absence of normal thermoregulatory abilities, individuals with a high-level spinal cord injury need special attention when they are exercising in temperate and hot conditions to prevent them from potential heat related issues. The use of cooling techniques can reduce this risk.

The brain is a neurovascular organ. A stimulus-response approach is effective in interrogating the physiology of its vasculature. Ideally, the stimulus is standardized across patients, and in a single patient over time. We developed a standard stimulus and attempted to measure, classify, and interpret the many forms of responses. Over the past 20 years, our work has delivered nuanced insights into normal cerebral vascular physiology, as well as adaptive physiological responses in the presence of disease. The trajectory of our understanding did not follow a logical linear progression; rather, it emerged as a coalescence of new, old, and previously dismissed, ideas that had accumulated over time. In this essay, we review what we believe were our most valuable – and sometimes controversial insights during our two decades-long journey.

Background: Despite decades of intense research, the pathophysiology and pathogenesis of acute respiratory distress syndrome (ARDS) are not adequately elucidated, which hamper the improvement of effective and convincing therapies for ARDS patients. Mechanical ventilation remains to be one of the primary supportive approaches for managing ARDS cases. Nevertheless, mechanical ventilation leads to the induction of further aggravating lung injury which is known as leading to ventilator-induced lung injury (VILI). It has been reported that lncRNAs play important roles in various cellular process through transcriptional, posttranscriptional, translational, and epigenetic regulations. However, to our knowledge, there is no investigation of the expression profile and functions of transcriptome-level endothelium-related lncRNAs in VILI yet.Methods: To screen the differential expression of lncRNAs and mRNAs in Human pulmonary microvascular endothelial cells (HPMECs) subjected to cyclic stretch, we constructed a cellular model of VILI, followed by transcriptome profiling using Affymetrix Human Transcriptome Array 2.0. Bioinformatics analyses, including functional and pathway enrichment analysis, protein–protein interaction network, lncRNA-mRNA coexpression network, and cis-analyses, were performed to reveal the potential functions and underlying mechanisms of differentially expressed lncRNAs.Results: In total, 199 differentially expressed lncRNAs (DELs) and 97 differential expressed mRNAs were screened in HPMECs subjected to 20% cyclic stretch for 2 h. The lncRNA-mRNA coexpression network suggested that DELs mainly enriched in response to hypoxia, response to oxidative stress, inflammatory response, cellular response to hypoxia, and NF-kappa B signaling pathway. LncRNA n335470, n406639, n333984, and n337322 might regulate inflammation and fibrosis induced by cyclic stretch through cis- or trans-acting mechanisms.Conclusion: This study provides the first transcriptomic landscape of differentially expressed lncRNAs in HPMECs subjected to cyclic stretch, which provides novel insights into the molecular mechanisms and potential directions for future basic and clinical research of VILI.

In recent years, coronary heart disease (CHD) has become one of the main diseases that endanger human health, with a high mortality and disability rate. Myocardial ischemia (MI) is the main symptom in the development of CHD. Continuous and severe myocardial ischemia will lead to myocardial infarction. The clinical manifestations of MI are mainly the changes of ST-T segment of ECG, that is, ST segment and T wave. Nearly one third of patients with CHD, however, has no obvious ECG changes. In this paper, a new method for detecting MI based on the T-wave area curve (TWAC) was proposed. Through observation and analysis of clinical data, it was found that there exist significant correlation between the morphology of TWAC and MI. The TWAC morphology of normal subject is smooth and gentle, while the TWAC morphology of patients with coronary stenosis is mostly jagged, and the curve becomes more severe with more severe stenosis. The preliminary test results show that the sensitivity, specificity, and accuracy of the proposed method for detecting MI are 84.3, 83.6, and 84%, respectively. This study shows that the TWAC based approach may be an effective method for detecting MI, especially for the CHD patients with no obvious ECG changes.

Obesity is an important risk factor for metabolic syndrome and obstructive sleep apnea (OSA). Bariatric surgery has been shown to effectively reduce weight and obesity-related comorbidities. However, the prevalence and severity of OSA in obese patients with different baseline metabolic states and the improvements of OSA after bariatric surgery remain unknown. The main aims of this study were to ascertain the prevalence of OSA in young Chinese obese patients with different metabolic states and to evaluate their respective OSA remission after laparoscopic sleeve gastrectomy. We first performed a cross-sectional study involving 123 metabolically healthy obese patients and 200 metabolically unhealthy obese patients (who had the same age and BMI ranges) to estimate the prevalence of OSA at baseline. Then we performed a retrospective study, which was registered at ClinicalTrials.gov (ref. NCT02653430) of 67 patients who underwent laparoscopic sleeve gastrectomy to evaluate the remission of OSA. Metabolically healthy and unhealthy obese patients had similar apnea-hypopnea index levels (16.6 ± 22.0 vs. 16.7 ± 18.7 events/h, P = 0.512) and prevalence of OSA (66.7% vs. 69.0%, P = 0.662). Male sex, age, waist circumference and lower liver-to-spleen ratio were independent risk factors for OSA. After laparoscopic sleeve gastrectomy, no difference was found in the decrease in body mass index (BMI) change (10.8 ± 4.8 vs. 10.8 ± 3.0 kg/m2, P = 0.996) or the decrease in the apnea-hypopnea index (18.9 ± 24.6 vs. 17.0 ± 24.0 events/h, P = 0.800). The remission of moderate-to-severe OSA was observed in the MHO (36.3%; 54.5–18.2%, P = 0.125) and MUO (32.2%; 66.1–33.9%, P = 0.001) patients. These results suggest that, in patients with obesity, metabolic syndrome does not add extra risk for the prevalence or severity of OSA. Both metabolically healthy and unhealthy obese patients could benefit equally from laparoscopic sleeve gastrectomy in terms of weight loss and obstructive sleep apnea remission.

Ultra-endurance running (UER) has seen an important increase in participation over the last few decades. Long hours of UER can lead to excessive stress on the body, resulting in musculoskeletal injuries (MSKI). UER is not a uniform sport and events can differ considerably in distance (over 42.195 km), time (e.g., events over 6 h) and multi-day or multi-stage events on various surfaces (e.g., track, on-road, off-road). The aims of this scoping review were therefore: (1) to examine the current evidence of MSKI, providing a synthesis of the most common MSKI by anatomical region and specific diagnosis; (2) categorize MSKI by type of UER activity (competition: time-limited; multi-stage; continuous UER events and training); (3) describe knowledge gaps in the literature and provide advice on potential further research. Our electronic literature search (PubMed, SPORTDiscus, Web of Science) identified a total of 13 studies (9 in competition, and 4 in training). Anatomical site, diagnosis and rate of injuries differ between competition and training as well as between different UER types. MSKI are observed in 18% of multi-stage events (0.7–1.8 injuries/runner and 7.2 injuries/1000 h). Most MSKI involve the lower leg (35.0%), ankle (16.8%), knee (13.1%) and foot (12.6%), with main diagnosis of medial tibial stress syndrome (30.1%) and patella femoral pain syndrome (PFPS; 7.2%). Single, continuous UER events differ between a 1005 km road race with almost all of the injuries due to overuse, with the main anatomical site of the knee (31%), ankle (28%) and lower leg (14%) and main diagnosis of PFPS (15.6%), compared to a 65 km trail race, with 32.8% of MSKI, mainly on the foot [plantar fasciitis (28.6%)], ankle [sprain (28.6%)] and knee. Timed-UER events (injury rate of 2.1 injuries/athlete) observed most injuries on the ankle (36%) and knee (19%), with the main diagnosis of tendinitis of the foot dorsiflexors (30%). Injuries during training most commonly affect, the back (42%), and knee (40%) and bone stress injuries (22%). Main diagnoses include ankle sprain (18%), iliotibial band injury (16%) and Achilles tendinopathy (11%). Future considerations include examining MSKI in different UER events, environments and surfaces, and on larger study populations. Establishing risk factors, examining sex differences and using a standard reporting system of MSKI in UER are also important.

In mobile healthcare, heart rate variability (HRV) is increasingly being used in dynamic patient states. In this situation, shortening of the measurement time is required. This study aimed to validate ultra-short-term HRV in non-static conditions. We conducted electrocardiogram (ECG) measurements at rest, during exercise, and in the post-exercise recovery period in 30 subjects and analyzed ultra-short-term HRV in time and frequency domains by ECG in 10, 30, 60, 120, 180, and 240-s intervals, and compared the values to the 5-min HRV. For statistical analysis, null hypothesis testing, Cohen’s d statistics, Pearson’s correlation coefficient, and Bland-Altman analysis were used, with a statistical significance level of P < 0.05. The feasibility of ultra-short-term HRV and the minimum time required for analysis showed differences in each condition and for each analysis method. If the strict criteria satisfying all the statistical methods were followed, the ultra-short-term HRV could be derived from a from 30 to 240-s length of ECG. However, at least 120 s was required in the post-exercise recovery or exercise conditions, and even ultra-short-term HRV was not measurable in some variables. In contrast, according to the lenient criteria needed to satisfy only one of the statistical criteria, the minimum time required for ultra-short-term HRV analysis was 10–60 s in the resting condition, 10–180 s in the exercise condition, and 10–120 s in the post-exercise recovery condition. In conclusion, the results of this study showed that a longer measurement time was required for ultra-short-term HRV analysis in dynamic conditions. This suggests that the existing ultra-short-term HRV research results derived from the static condition cannot applied to the non-static conditions of daily life and that a criterion specific to the non-static conditions are necessary.

Introduction: The purpose of this study was to clarify whether blood-flow restriction during resting intervals [resting blood-flow restriction (rBFR)] is comparable to a continuous BFR (cBFR) training regarding its effects on maximum strength, hypertrophy, fatigue resistance, and perceived discomfort.Materials and Methods: Nineteen recreationally trained participants performed four sets (30-15-15-15 repetitions) with 20% 1RM on a 45° leg press twice a week for 6 weeks (cBFR, n = 10; rBFR, n = 9). Maximum strength, fatigue resistance, muscle thickness, and girth were assessed at three timepoints (pre, mid, and post). Subjective pain and perceived exertion were determined immediately after training at two timepoints (mid and post).Results: Maximum strength (p < 0.001), fatigue resistance (p < 0.001), muscle thickness (p < 0.001), and girth (p = 0.008) increased in both groups over time with no differences between groups (p > 0.05). During the intervention, the rBFR group exposed significantly lower perceived pain and exertion values compared to cBFR (p < 0.05).Discussion: Resting blood-flow restriction training led to similar gains in strength, fatigue resistance, and muscle hypertrophy as cBFR training while provoking less discomfort and perceived exertion in participants. In summary, rBFR training could provide a meaningful alternative to cBFR as this study showed similar functional and structural changes as well as less discomfort.

Background: Cystic fibrosis (CF) affects the autonomic nervous system (ANS) and exercise in healthy children modulates the interaction between sympathetic and parasympathetic activity. This study aimed to evaluate the effects of a short-term resistance exercise program on heart rate variability (HRV) in children and adolescents with CF.Methods: A randomized controlled trial was carried out in children diagnosed with CF aged 6–18 years. Individuals were divided into two groups: control (CON) and resistance-training (EX). Individuals in the EX group completed an individualized guided resistance program (5-RM—60–80%) for 8 weeks (3 sessions of 60 min/week). Upper and lower limbs exercises (seated bench press, seated lateral row, and leg press) were used. HRV was measured using a Suunto watch with subjects in lying position.Results: Nineteen subjects (13 boys) were included (CON = 11; and EX = 8). Mean age was 12.2 ± 3.3, FEV1 (forced expiratory volume in the first second) z-score was 1.72 ± 1.54 and peak oxygen consumption (VO2peak) 42.7 ± 7.4 mL.Kg–1.min–1. Exercise induced significant changes in the frequency-domain variables, including a decrease in LF power (p = 0.001, d = 0.98) and LF/HF ratio (p = 0.020, d = 0.92), and an increase in HF power (p = 0.001, d = −0.97), compared to the CON group. No significant changes were found for time-domain variables, although increases with a moderate effect size were seen for SDNN (p = 0.152, d = −0.41) and RMSSD (p = 0.059, d = −0.49) compared to the CON group.Conclusion: A short-term resistance exercise-training program was able to modulate HRV in children and adolescents with CF presenting mild to moderate lung function impairment and good physical condition.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT04293926.

Stomoxys calcitrans (stable fly) is a cosmopolitan biting fly of both medical and veterinary importance. Unlike blood-feeding-related behavior of stable fly, its plant feeding, the fitness value, and the S. calcitrans–plant interaction are less understood. Here we show based on two chloroplast DNA genes, ribulose bisphosphate carboxylase large chain (rbcL) and the intergenic spacer gene trnH-psbA, that field-collected male and female stable flies fed on various plant species. We investigated the fitness cost of plant feeding using Parthenium hysterophorus, one of the plant species identified to have been fed on by the field-collected flies. Supplementation of blood feeding with a flowering P. hysterophorus plant as nectar source enhanced egg hatchability significantly as compared to blood alone, showing the fitness value of nectar supplementation. However, nectar supplementation did not affect the number of eggs laid or longevity of S. calcitrans as compared to flies that fed on blood alone. S. calcitrans maintained on sugar alone failed to lay eggs. The various plants stable flies fed on demonstrated chemodiversity with their own signature scent. The behavioral response of S. calcitrans to these signature compounds varied from strong attraction (γ-terpinene) to neutral (linalool oxide and myrcene) to repellency (butanoic acid). Our study demonstrated that stable flies feed on nectar, and plant nectar supplementation of blood feeding enhanced larval emergence. Thus, our result has implication in stable fly reproduction, survival, disease transmission, boosting laboratory colony, and the possibility of using plant-derived odors for mass trapping of stable fly, for instance, using γ-terpinene.

Cleft palate is one of the most common craniofacial birth defects, however, little is known about how changes in the DNA damage response (DDR) cause cleft palate. To determine the role of DDR during palatogenesis, the DDR process was altered using a pharmacological intervention approach. A compromised DDR caused by a poly (ADP-ribose) polymerase (PARP) enzyme inhibitor resulted in cleft palate in wild-type mouse embryos, with increased DNA damage and apoptosis. In addition, a mouse genetic approach was employed to disrupt breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2), known as key players in DDR. An ectomesenchymal-specific deletion ofBrca1orBrca2resulted in cleft palate due to attenuation of cell survival. This was supported by the phenotypes of the ectomesenchymal-specificBrca1/Brca2double-knockout mice. The cleft palate phenotype was rescued by superimposing p53 null alleles, demonstrating that the BRCA1/2–p53 DDR pathway is critical for palatogenesis. Our study highlights the importance of DDR in palatogenesis.

The sliding filament–swinging cross bridge theory of skeletal muscle contraction provides a reasonable description of muscle properties during isometric contractions at or near maximum isometric force. However, it fails to predict muscle force during dynamic length changes, implying that the model is not complete. Mounting evidence suggests that, along with cross bridges, a Ca2+-sensitive viscoelastic element, likely the titin protein, contributes to muscle force and work. The purpose of this study was to develop a multi-level approach deploying stretch-shortening cycles (SSCs) to test the hypothesis that, along with cross bridges, Ca2+-sensitive viscoelastic elements in sarcomeres contribute to force and work. Using whole soleus muscles from wild type andmdmmice, which carry a small deletion in the N2A region of titin, we measured the activation- and phase-dependence of enhanced force and work during SSCs with and without doublet stimuli. In wild type muscles, a doublet stimulus led to an increase in peak force and work per cycle, with the largest effects occurring for stimulation during the lengthening phase of SSCs. In contrast,mdmmuscles showed neither doublet potentiation features, nor phase-dependence of activation. To further distinguish the contributions of cross bridge and non-cross bridge elements, we performed SSCs on permeabilized psoas fiber bundles activated to different levels using either [Ca2+] or [Ca2+] plus the myosin inhibitor 2,3-butanedione monoxime (BDM). Across activation levels ranging from 15 to 100% of maximum isometric force, peak force, and work per cycle were enhanced for fibers in [Ca2+] plus BDM compared to [Ca2+] alone at a corresponding activation level, suggesting a contribution from Ca2+-sensitive, non-cross bridge, viscoelastic elements. Taken together, our results suggest that a tunable viscoelastic element such as titin contributes to: (1) persistence of force at low [Ca2+] in doublet potentiation; (2) phase- and length-dependence of doublet potentiation observed in wild type muscles and the absence of these effects inmdmmuscles; and (3) increased peak force and work per cycle in SSCs. We conclude that non-cross bridge viscoelastic elements, likely titin, contribute substantially to muscle force and work, as well as the phase-dependence of these quantities, during dynamic length changes.

Muscle-tendon unit length plays a crucial role in quadriceps femoris muscle (QF) physiological adaptation, but the influence of hip and knee angles during QF neuromuscular electrical stimulation (NMES) is poorly investigated. We investigated the effect of muscle length on maximum electrically induced contraction (MEIC) and current efficiency. We secondarily assessed the architecture of all QF constituents and their tendon-aponeurosis complex (TAC) displacement to calculate a stiffness index. This study was a randomized, repeated measure, blinded design with a sample of twenty healthy men aged 24.0 ± 4.6. The MEIC was assessed in four different positions: supine with knee flexion of 60° (SUP60); seated with knee flexion of 60° (SIT60); supine with knee flexion of 20° (SUP20), and seated with knee flexion of 20° (SIT20). The current efficiency (MEIC/maximum tolerated current amplitude) was calculated. Ultrasonography of the QF was performed at rest and during NMES to measure pennation angle (θp) and fascicle length (Lf), and the TAC stiffness index. MEIC and current efficiency were greater for SUP60 and SIT60 compared to SUP20 and SIT20. The vastus lateralis and medialis showed lower θp and higher Lf at SUP60 and SIT60, while for the rectus femoris, in SUP60 there were lower θp and higher Lf than in all positions. The vastus intermedius had a similar pattern to the other vastii, except for lack of difference in θp between SIT60 compared to SUP20 and SIT20. The TAC stiffness index was greater for SUP60. We concluded that NMES generate greater torque and current efficiency at 60° of knee flexion, compared to 20°. For these knee angles, lengthening the QF at the hip did not promote significant change. Each QF constituent demonstrated muscle physiology patterns according to hip and/or knee angles, even though a greater Lf and lower θp were predominant in SUP60 and SIT60. QF TAC index stiffened in more elongated positions, which probably contributed to enhanced force transmission and slightly higher torque in SUP60. Our findings may help exercise physiologist better understand the impact of hip and knee angles on designing more rational NMES stimulation strategies.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT03822221.

Background: Inhomogeneous intra-atrial conduction facilitates both initiation and perpetuation of atrial fibrillation (AF) and is reflected in electrogram (EGM) morphology. Objective: The primary objective of this study is to investigate regional differences in features of different EGM types during SR and to design a patient-specific signal fingerprint, which quantifies the severity and extensiveness of inhomogeneity in conduction. Methods: Patients (N=189, 86% male; mean age 65±9 years) undergoing coronary artery bypass grafting underwent high resolution mapping of the right atrium (RA), left atrium (LA), pulmonary vein area (PVA) including Bachmans bundle (BB). EGMs during 5 seconds of sinus rhythm (SR) were classified as single potentials (SP), short double potentials (SDP, interval between deflections 15 ms) or fractionated potentials (FP, ≥3 deflections). Of all SPs, differences in relative R- and S-wave amplitude of all SPs were calculated (R/S ratios). Time difference between first and last deflection were determined (fractionation duration, FD) and potentials with amplitudes

Background: Kinetics, moderators and reference limits for exercise-induced cardiac troponin T (cTnT) elevations are still unclear.Methods: A systematic review of published literature was conducted adhering to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Studies reporting high-sensitivity cardiac troponin T (hs-cTnT) concentrations before and after a bout of exercise in athletes were included and analyzed. The final dataset consisted of 62 estimates from 16 bouts in 13 studies of 5–1,002 athletes (1,421 in total). Meta-analysis was performed using general linear mixed modeling and Bayesian inferences about effect magnitudes. Modifying fixed-effect moderators of gender, age, baseline level, exercise duration, intensity and modalities were investigated. Simulation was used to derive 99th percentile with 95% limits of upper reference ranges for hs-cTnT of athletic populations.Results: The mean and upper reference limits of hs-cTnT before exercise were 4.4 and 19 ng.L−1. Clear increases in hs-cTnT ranging from large to very large (factor changes of 2.1–7.5, 90% compatibility limits, ×/÷1.3) were evident from 0.7 through 25 h, peaking at 2.9 h after the midpoint of a 2.5-h bout of running, when the mean and upper reference limit for hs-cTnT were 33 and 390 ng L−1. A four-fold increase in exercise duration produced a large clear increase (2.4, ×/÷1.7) in post-exercise hs-cTnT. Rowing exercise demonstrated an extremely large clear reduction (0.1 ×/÷2.4).Conclusions: The kinetics of cTnT elevation following exercise, the positive effect of exercise duration, the impact of exercise modality and 99th upper reference limits for athletic populations were reasonably well defined by this meta-analysis.

Genetic selection for earlier sexual maturation and extended production cycles in laying hens has significantly improved reproductive efficiency. While limited emphasis has been placed on the underlying physiological changes, we hypothesize that modifications in the control of the hypothalamic-pituitary gonadal (HPG) axis have occurred. Thus, three strains of White leghorn derivatives were followed from hatch to 100 weeks of age (woa), including Lohmann LSL-lite (n = 120) as current commercial hens, heritage Shaver White leghorns (n = 100) as 2000s commercial equivalents, and Smoky Joe hens (n = 68) as 1960s commercial equivalents. Body weight (BW) and egg production were monitored, and blood samples were collected throughout to monitor estradiol (E2) concentrations. Tissue samples were collected at 12, 17, 20, 25, 45, 60, 75, and 100 woa to capture changes in mRNA levels of key genes involved in the HPG axis and monitor ovarian follicular pools. All hens, regardless of strain, age or photoperiod laid their first egg within a 64-gram BW window and, as E2 levels increased prior to photostimulation (PS) in Lohmann and Shaver hens, a metabolic trigger likely induced sexual maturation. However, increased levels of Opsin 5 (OPN5) were observed during the maturation period. Although an elevation in gonadotrophin-releasing hormone I (GnRH-I) mRNA levels was associated with early maturation, no changes in gonadotrophin-inhibitory hormone (GnIH) mRNA levels were observed. Nonetheless, a significant shift in pituitary sensitivity to GnRH was associated with maturation. Throughout the trial, Lohmann, Shaver, and Smoky Joe hens laid 515, 417, and 257 eggs, respectively (p < 0.0001). Results show that the extended laying persistency in Lohmann hens was supported by sustained pituitary sensitivity to GnRH-I, recurrent elevations in follicle-stimulating hormone (FSH) mRNA levels, and five cyclical elevations in E2 levels. This was also associated with a consistently higher pool of small white ovarian follicles. In summary, our results demonstrate first that, regardless of photoperiodic cues, meeting a specific narrow body weight threshold is sufficient to initiate sexual maturation in Leghorn chicken derivatives. Furthermore, recurrent increases in E2 and FSH may be the key to sustain extended laying period, allowing modern layers to double their reproductive capacity compared to their 1960s-counterparts.

Hereditary spherocytosis (HS) is the most common form of hereditary chronic hemolytic anemia. It is caused by mutations in red blood cell (RBC) membrane and cytoskeletal proteins, which compromise membrane integrity, leading to vesiculation. Eventually, this leads to entrapment of poorly deformable spherocytes in the spleen. Splenectomy is a procedure often performed in HS. The clinical benefit results from removing the primary site of destruction, thereby improving RBC survival. But whether changes in RBC properties contribute to the clinical benefit of splenectomy is unknown. In this study we used ektacytometry to investigate the longitudinal effects of splenectomy on RBC properties in five well-characterized HS patients at four different time points and in a case-control cohort of 26 HS patients. Osmotic gradient ektacytometry showed that splenectomy resulted in improved intracellular viscosity (hydration state) whereas total surface area and surface-to-volume ratio remained essentially unchanged. The cell membrane stability test (CMST), which assesses the in vitro response to shear stress, showed that after splenectomy, HS RBCs had partly regained the ability to shed membrane, a property of healthy RBCs, which was confirmed in the case-control cohort. In particular the CMST holds promise as a novel biomarker in HS that reflects RBC membrane health and may be used to asses treatment response in HS.

Mathematical biology and pharmacology models have a long and rich history in the fields of medicine and physiology, impacting our understanding of disease mechanisms and the development of novel therapeutics. With an increased focus on the pharmacology application of system models and the advances in data science spanning mechanistic and empirical approaches, there is a significant opportunity and promise to leverage these advancements to enhance the development and application of the systems pharmacology field. In this paper, we will review milestones in the evolution of mathematical biology and pharmacology models, highlight some of the gaps and challenges in developing and applying systems pharmacology models, and provide a vision for an integrated strategy that leverages advances in adjacent fields to overcome these challenges.

Background Autism spectrum disorder (ASD), a neurodevelopmental disorder, has been reported with an altered brain connectivity pattern in the sensory network using resting-state functional magnetic imaging (rs-fMRI) compared to typical developing participants (TDs). However, there is still no consistent conclusion. In the current study, we investigated the alterations of the intra-network and inter-network connectivity pattern relating to sensory in children with ASD compared with TDs, and further assessed whether these alterations are associated with autistic behavioral symptoms. Methods rs-fMRI was used to assess young boys with ASD (N=29) and TD (N=29), aged 3-7-years. Groups were matched for age and handiness. Spatial patterns of the sensory rest state networks (RSNs) were obtained using group Independent component analysis (ICA) method, and between-groups differences were evaluated within each sensory network. Then, the time series of each RSN were extracted from each participant preprocessed data. Correlation analysis was assessed among intra- and inter-network functional connectivity (FC) and symptom severity in children with ASD. Results Four sensory components were identified, including auditory network (AN), higher visual network (HVN), primary visual network (PVN) and sensorimotor network (SMN). Functional images revealed two sensory networks exhibiting significant increased FCs in ASD group, located within AN and SMN. Higher positive connectivity between PVN and HVN in ASD group is associated with symptom severity. Conclusion Current study might shed light that the abnormal connectivity patterns of sensory network regions may underlie impaired higher-order multisensory integration in ASD children, and social impairment of ASD are caused probably by aberrant FCs involving inter/intra- sensory network.

ObjectiveThe aim of the present study was to characterize the cyclic sleep processes of sleep-stage dynamics, cortical activity, and heart rate variability during sleep in the adaptation night in healthy young adults.MethodsSeventy-four healthy adults participated in polysomnographic recordings on two consecutive nights. Conventional sleep variables were assessed according to standard criteria. Sleep-stage continuity and dynamics were evaluated by sleep runs and transitions, respectively. These variables were compared between the two nights. Electroencephalographic and cardiac activities were subjected to frequency domain analyses. Cycle-by-cycle analysis was performed for the above variables in 34 subjects with four sleep cycles and compared between the two nights.ResultsConventional sleep variables reflected lower sleep quality in the adaptation night than in the experimental night. Bouts of stage N1 and stage N2 were shorter, and bouts of stage Wake were longer in the adaptation night than in the experimental night, but there was no difference in stage N3 or stage REM. The normalized transition probability from stage N2 to stage N1 was higher and that from stage N2 to N3 was lower in the adaptation night, whereas that from stage N3 to other stages did not differ between the nights. Cycle-by-cycle analysis revealed that sleep-stage distribution and cortical beta EEG power differed between the two nights in the first sleep cycle. However, the HF amplitude of the heart rate variability was lower over the four sleep cycles in the adaptation night than in the experimental night.ConclusionThe results suggest the distinct vulnerability of the autonomic adaptation processes within the central nervous system in young healthy subjects while sleeping in a sleep laboratory for the first time.

BackgroundFew data are available about the role of herbal extract loaded nanoparticles as an alternative safe medicine for the management of a gastric ulcer.AimThis work is targeted at exploring the physiological effects of pomegranate loaded nanoparticles (PLN) against an indomethacin IND-induced gastric ulcer and comparing the results with traditional pomegranate peel extract (PPE).MethodsTwenty-four rats were equally distributed into four groups: control, IND-treated, PLN-treated, and PPE-treated groups. Gross examination of gastric mucosa, and the calculation of ulcer and inhibition indices were done. Serum malondialdehyde (MDA), total antioxidant capacity (TAC), interleukin 2 (IL-2), IL-6, IL-10, gastric homogenate prostaglandin E2 (PGE2), and nitric oxide (NO) were estimated. Mucosal endothelial nitric oxide synthase (eNOS mRNA) expression was identified by qPCR. Histological and immuno-histochemical staining of Tumor necrosis factor-α (TNF-α) and eNOS of stomach mucosa were performed.ResultsIn comparison with the control group, IND-treated rats showed visible multiple ulcers with ulcer index, serum MDA, IL-2 and IL-6 were elevated while IL-10, PGE2, NO, and eNOS mRNA expression were significantly reduced. Damaged surface epithelium with disrupted glandular architecture and heavy leucocyte infiltration of lamina propria was noticed. Immunohistochemical staining of stomach mucosa revealed marked increased TNF-α and reduced eNOS. Oral administration of PLN and PPE succeeded in improving the gross mucosal picture, and all biochemical, histological, and immunohistochemical alterations.ConclusionBoth PLN and PPE potently alleviated IND-induced gastric ulceration via increasing TAC, PGE2, NO, eNOS mRNA, and protein expression. However, the healing effect of PLN was obviously greater than PPE-treated rats.

In order to explore the synergistic control effect of crude extracts of Artemisia sieversiana and Metarhizium anisopliae on Oedaleus asiaticus, we used different doses of M. anisopliae and crude extracts of A. sieversiana singly and in combination, to determine their toxicities to fourth instar O. asiaticus. The results showed that the combination of 10% crude extract of A. sieversiana with 107 and 108 spores/g M. anisopliae concentrations and the combination of 20% crude extract of A. sieversiana with 107 and 108 spores/g M. anisopliae concentrations had significant effects on the mortality, body weight gain, body length gain, growth rate, and overall performance of O. asiaticus than those of the crude extract of A. sieversiana and M. anisopliae alone. Among them, the 20% A. sieversiana crude extract mixed with 108 spores/g M. anisopliae and 10% A. sieversiana crude extract combined with 107 spores/g M. anisopliae, had the best control efficacy. In order to clarify the biochemical mechanism underlying the immune responses of O. asiaticus to the pesticide treatments, we monitored the activities of four enzymes: superoxidase dismutase (SOD), peroxidase (POD), catalase (CAT), and polyphenol oxidase (PPO). The results showed that the activities of three enzymes (SOD, CAT, and PPO) were significantly increased from the treatment with the combination of M. anisopliae mixed with crude extract of A. sieversiana. Interestingly, compared to the crude extract, the combination treatment did not significantly induce the expression of POD enzyme activity, which may be a biochemical factor for increasing the control effect of the combination treatment. Our results showed that the combination treatment had synergistic and antagonistic effects on host mortality, growth, development, and enzyme activities in O. asiaticus.

Vascular aging plays a pivotal role in the morbidity and mortality of elderly people. Decrease in autophagy leads to acceleration of vascular aging, while increase in autophagy leads to deceleration of vascular aging. And emerging evidence indicates that acetylation plays an important role in autophagy regulation; therefore, recent research has focused on an in-depth analysis of the mechanisms underlying this regulation. In this review, current knowledge on the role of acetylation of autophagy-related proteins and the mechanisms by which acetylation including non-autophagy-related acetylation and autophagy related acetylation regulate vascular aging have been discussed. We conclude that the occurrence of acetylation modification during autophagy is a fundamental mechanism underlying autophagy regulation and provides promising targets to retard vascular aging.

AimsThis study investigated the contribution of the regulator of G-protein signaling 5 (Rgs5) knockout to the alteration of the action potential duration (APD) restitution and repolarizing dispersion in ventricle.Methods and ResultsThe effects of Rgs5–/– were investigated by QT variance (QTv) and heart rate variability analysis of Rgs5–/– mice. Monophasic action potential analysis was investigated in isolated Rgs5–/– heart. Rgs5–/– did not promote ventricular remodeling. The 24-h QTv and QT variability index (QTVI) of the Rgs5–/– mice were higher than those of wild-type (WT) mice (P < 0.01). In WT mice, a positive correlation was found between QTv and the standard deviation of all NN intervals (r = 0.62; P < 0.01), but not in Rgs5–/– mice (R = 0.01; P > 0.05). The absence of Rgs5 resulted in a significant prolongation of effective refractory period and APD in isolated ventricle. In addition, compared with WT mice, the knockout of Rgs5 significantly deepened the slope of the APD recovery curve at all 10 sites of the heart (P < 0.01) and increased the spatial dispersions of Smax (COV-Smax) (WT: 0.28 ± 0.03, Rgs5–/–: 0.53 ± 0.08, P < 0.01). Compared with WT heart, Rgs5–/– increased the induced S1–S2 interval at all sites of heart and widened the window of vulnerability of ventricular tachyarrhythmia (P < 0.05).ConclusionOur findings indicate that Rgs5–/– is an important regulator of ventricular tachyarrhythmia in mice by prolonging ventricular repolarization and increasing spatial dispersion in ventricle.

BackgroundAcute high altitude (HA) exposure elicits blood pressure (BP) responses in most subjects, and some of them suffer from acute mountain sickness (AMS). However, a 24-h ambulatory BP (ABP) change and the correlation with the occurrence of AMS in different sexes are still unclear.ObjectivesThis prospective study aimed to investigate HA induced BP responses in males and females and the relationship between AMS and 24-h ABP.MethodsForty-six subjects were matched according to demographic parameters by propensity score matching with a ratio of 1:1. All the subjects were monitored by a 24-h ABP device; the measurement was one period of 24 h BP. 2018 Lake Louise questionnaire was used to evaluate AMS.ResultsBoth the incidence of AMS (14 [60.9%] vs. 5 [21.7%], P = 0.007) and headache (18 [78.3%] vs. 8 [34.8%], P = 0.003) were higher in females than in males. All subjects showed an elevated BP in the early morning [morning systolic BP (SBP), 114.72 ± 13.57 vs. 120.67 ± 11.10, P = 0.013]. The elevation of morning SBP variation was more significant in females than in males (11.95 ± 13.19 vs. −0.05 ± 14.49, P = 0.005), and a higher morning BP surge increase (4.69 ± 18.09 vs. −9.66 ± 16.96, P = 0.005) was observed after acute HA exposure in the female group. The increase of morning SBP was associated with AMS occurrence (R = 0.662, P < 0.001) and AMS score (R = 0.664, P = 0.001). Among the AMS symptoms, we further revealed that the incidence (R = 0.786, P < 0.001) and the severity of headache (R = 0.864, P < 0.001) are closely correlated to morning SBP.ConclusionsOur study demonstrates that females are more likely to suffer from AMS than males. AMS is closely associated with elevated BP in the early morning period, which may be correlated to higher headache incidence in subjects with higher morning SBP.

Nearly 2 decades since its discovery as one of the genes responsible for the Wolf-Hirschhorn Syndrome (WHS), the primary function of the leucine-zipper EF-hand containing transmembrane 1 (LETM1) protein in the inner mitochondrial membrane (IMM) or the mechanism by which it regulates mitochondrial Ca2+ handling is unresolved. Meanwhile, LETM1 has been associated with the regulation of fundamental cellular processes, such as development, cellular respiration and metabolism, and apoptosis. This mini-review summarizes the diversity of cellular functions impacted by LETM1 and highlights the multiple roles of LETM1 in health and disease.

Trunk muscle strength and control is an important prerequisite for everyday activities among elderly people decreasing the predisposition to falls. High levels of physical exercise performed by older athletes could offer benefits to core/trunk muscle strength and postural control compared with recreational physical activities and among elderly people with lower levels of physical activity. The present study aimed to compare trunk muscle strength and postural control of older running athletes vs. older physically active adults. Participants were master road runners (RUN, n = 15, six women, 64.3 ± 3.6 years) and physically active elderly (control group, CON, n = 15, six women, 65.4 ± 5.0 years) people that were submitted to the evaluations: esthesiometer, posturography (force plate), and isokinetic test (Biodex dynamometer) of trunk muscle extension and flexion. RUN presented higher values for relative peak torque of trunk extensor muscles at 60°/s (p = 0.046) and 180°/s (p = 0.007) and relative average power during trunk extension at 60°/s (p = 0.008) and 180°/s (p = 0.004) compared to CON. CON had a higher medial-lateral oscillation speed of the center of pressure in the stable condition with eyes closed (p = 0.004) compared to RUN. RUN presented higher isokinetic torque of extensor trunk muscles and better postural control than CON. This supposedly could help with postural control and balance and contribute to the prevention of falls among the elderly. The practice of running systematically by master athletes may partially explained our findings.

Several shortcomings on cardiopulmonary exercise testing (CPET) interpretation have shed a negative light on the test as a clinically useful tool. For instance, the reader should recognize patterns of dysfunction based on clusters of variables rather than relying on rigid interpretative algorithms. Correct display of key graphical data is of foremost relevance: prolixity and redundancy should be avoided. Submaximal dyspnea ratings should be plotted as a function of work rate (WR) and ventilatory demand. Increased work of breathing and/or obesity may normalize peak oxygen uptake (V̇O2) despite a low peak WR. Among the determinants of V̇O2, only heart rate is measured during non-invasive CPET. It follows that in the absence of findings suggestive of severe impairment in O2delivery, the boundaries between inactivity and early cardiovascular disease are blurred in individual subjects. A preserved breathing reserve should not be viewed as evidence that “the lungs” are not limiting the subject. In this context, measurements of dynamic inspiratory capacity are key to uncover abnormalities germane to exertional dyspnea. A low end-tidal partial pressure for carbon dioxide may indicate either increased “wasted” ventilation or alveolar hyperventilation; thus, direct measurements of arterial (or arterialized) PO2might be warranted. Differentiating a chaotic breathing pattern from the normal breath-by-breath noise might be complex if the plotted data are not adequately smoothed. A sober recognition of these limitations, associated with an interpretation report free from technicalities and convoluted terminology, is crucial to enhance the credibility of CPET in the eyes of the practicing physician.

The wide-spread culture of transgenic Bt cotton resisting the infamous cotton bollworms has reduced the adoption of broad-spectrum insecticides to a large extent. Consequently, the non-targeted insect Adelphocoris suturalis Jakovlev has become a major cotton pest in China. Entomopathogenic microbes show promising results for controlling this pest in the future, but A. suturalis innate immune responses to these pathogens are poorly understood. Here, we used the entomopathogenic fungus Beauveria bassiana and the Gram-negative pathogenic bacteria Enterobactor cloacae to infect A. suturalis nymphs, followed by high throughput RNA-seq to analyze the immune transcriptomes of A. suturalis in response to the two pathogens. A total of 150 immunity-related genes were identified, including pattern recognition receptors, extracellular signal modulators, signal pathways (Toll, IMD, JNK, and JAK/STAT), and response effectors. Further quantitative real-time PCR analysis demonstrated that B. bassiana and E. cloacae were recognized by different receptors (GNBP and PGRP, respectively); activated Toll pathway and IMD pathway respectively; and both induced expression of the effector gene Defensin. However, melanization is suppressed in B. bassiana-infected nymphs. Collectively, this study provides a transcriptomic snapshot of the A. suturalis immune system, and at the genetic level, gains multifaceted insights of the immune response to fungal and Gram-negative bacterial pathogens. Ultimately this work pioneers the study of molecular mechanisms underlying immune interactions between A. suturalis and its pathogens and assists in the development of novel mitigation strategies to control this pest.

In the mild subtype of inherited carnitine palmitoyltransferase II (CPTII) deficiency, muscular mitochondrial fatty acid β-oxidation is impaired. In this condition, interventions involve daily dietary restriction of fats and increase of carbohydrates, whereas physical exercise is commonly contraindicated due to the risk of muscle pain and rhabdomyolysis. We present the case of a 14-year-old female with CPTII deficiency who underwent a 1-h session of unsupervised exercise training for 6 months, 3 days per week, including interval and resistance exercises, after diet assessment and correction. Before and after intervention, the resting metabolic rate (RMR) and respiratory quotient (RQ) were measured by indirect calorimetry, and a cardiopulmonary exercise test (CPET, 10 W/30 s to exhaustion) was performed. Interval training consisted of a 1 min run and a 5 min walk (for 15 min progressively increased to 30 min). During these efforts, the heart rate was maintained over 70% HR max corresponding to respiratory exchange ratio (RER) of 0.98. Resistance training included upper/lower split workouts (3 sets of 8 repetitions each, with 2 min rest between sets). Blood CK was checked before and 36 h after two training sessions chosen randomly without significant difference. After training, RMR increased (+8.1%) and RQ lowered into the physiological range (from 1.0 to 0.85). CPET highlighted an increase of peak power output (+16.7%), aerobic performance (VO2 peak, 8.3%) and anaerobic threshold (+5.7%), oxygen pulse (+4.5%) and a much longer isocapnic buffering duration (+335%). No muscle pain or rhabdomyolysis was reported. Results from our study highlight that training based on short-duration high-intensity exercise improves overall metabolism and aerobic fitness, thus being feasible, at least in a case of CPTII deficiency.

Vascular endothelial growth factor (VEGF) plays a pivotal role in regulating cerebral angiogenesis after stroke. Meanwhile, excessive VEGF expression induces increased microvascular permeability in brain, probably leading to neurological deterioration. Therefore, the appropriate level of VEGF expression is significant to the recovery of brain exposed to stroke. In this work, we demonstrate that microRNA-150 (miR-150) and its predicted target MYB form a negative feedback loop to control the level of post-stroke VEGF expression. Repression of MYB leads to decreased expression of miR-150 in brain microvascular endothelial cells (BMVECs) exposed to oxygen glucose deprivation (OGD), thus miR-150 was predicted to be down-regulated by MYB. Moreover, MYB was confirmed to be a direct target of miR-150 by using dual luciferase reporter assay. In our previous work, we have validated VEGF as another direct target of miR-150. Therefore, MYB participates in regulation of VEGF via miR-150 under OGD, forming a feedback loop with miR-150. We also find that high levels of miR-150 inhibitors combined with MYB silence contribute to further enhancement of VEGF expression in BMVECs in response to OGD. These observations suggest that the feedback loop comprised of miR-150 and MYB, which is a pivotal endogenous epigenetic regulation to control the expression levels of VEGF in BMVECs subjected to OGD.