ABSTRACT
Blood-borne myeloid cells, neutrophils and monocytes, play a central role in the development of indirect acute lung injury (ALI) during sepsis and noninfectious systemic inflammatory response syndrome. By contrast, the contribution of circulating myeloid cell-derived extracellular vesicles (EVs) to ALI is unknown, despite acute increases in their numbers during sepsis and systemic inflammatory response syndrome. Here, we investigated the direct role of circulating myeloid-EVs in ALI using a mouse isolated perfused lung system and a human cell coculture model of pulmonary vascular inflammation consisting of lung microvascular endothelial cells and peripheral blood mononuclear cells. Total and immunoaffinity-isolated myeloid (CD11b+) and platelet (CD41+) EVs were prepared from the plasma of intravenous LPS-injected endotoxemic donor mice and transferred directly into recipient lungs. Two-hour perfusion of lungs with unfractionated EVs from a single donor induced pulmonary edema formation and increased perfusate concentrations of RAGE (receptor for advanced glycation end products), consistent with lung injury. These responses were abolished in the lungs of monocyte-depleted mice. The isolated myeloid- but not platelet-EVs produced a similar injury response and the acute intravascular release of proinflammatory cytokines and endothelial injury markers. In the in vitro human coculture model, human myeloid- (CD11b+) but not platelet- (CD61+) EVs isolated from LPS-stimulated whole blood induced acute proinflammatory cytokine production and endothelial activation. These findings implicate circulating myeloid-EVs as acute mediators of pulmonary vascular inflammation and edema, suggesting an alternative therapeutic target for attenuation of indirect ALI.
Subject(s)
Acute Lung Injury , Extracellular Vesicles , Pneumonia , Sepsis , Humans , Lipopolysaccharides/pharmacology , Leukocytes, Mononuclear , Endothelial Cells , Lung , Acute Lung Injury/therapy , Inflammation , Monocytes , Systemic Inflammatory Response SyndromeABSTRACT
Rationale: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator-induced lung injury. eCypA (extracellular CypA [cyclophilin A]) is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to coronavirus disease (COVID-19). Objectives: To explore the involvement of eCypA in the pathophysiology of ventilator-induced lung injury. Methods: Mice were ventilated with a low or high Vt for up to 3 hours, with or without blockade of eCypA signaling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretching to explore the cellular source of eCypA, and CypA concentrations were measured in BAL fluid from patients with acute respiratory distress syndrome to evaluate the clinical relevance. Measurements and Main Results: High-Vt ventilation in mice provoked a rapid increase in soluble CypA concentration in the alveolar space but not in plasma. In vivo ventilation and in vitro stretching experiments indicated the alveolar epithelium as the likely major source. In vivo blockade of eCypA signaling substantially attenuated physiological dysfunction, macrophage activation, and MMPs (matrix metalloproteinases). Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated concentrations of eCypA within BAL fluid. Conclusions: CypA is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. eCypA represents an exciting novel target for pharmacological intervention.
Subject(s)
Anti-Inflammatory Agents/immunology , Cyclophilin A/immunology , Inflammation/immunology , Respiration, Artificial/adverse effects , Respiratory Distress Syndrome/immunology , Respiratory Mucosa/immunology , Ventilator-Induced Lung Injury/immunology , Ventilator-Induced Lung Injury/physiopathology , Animals , COVID-19/genetics , COVID-19/physiopathology , Cells, Cultured/drug effects , Cyclophilin A/pharmacology , Humans , Inflammation/physiopathology , Male , Mice , Models, Animal , Respiratory Distress Syndrome/physiopathology , SARS-CoV-2 , Ventilator-Induced Lung Injury/geneticsABSTRACT
Cellular stress or injury induces release of endogenous danger signals such as ATP, which plays a central role in activating immune cells. ATP is essential for the release of nonclassically secreted cytokines such as IL-1ß but, paradoxically, has been reported to inhibit the release of classically secreted cytokines such as TNF. Here, we reveal that ATP does switch off soluble TNF (17 kDa) release from LPS-treated macrophages, but rather than inhibiting the entire TNF secretion, ATP packages membrane TNF (26 kDa) within microvesicles (MVs). Secretion of membrane TNF within MVs bypasses the conventional endoplasmic reticulum- and Golgi transport-dependent pathway and is mediated by acid sphingomyelinase. These membrane TNF-carrying MVs are biologically more potent than soluble TNF in vivo, producing significant lung inflammation in mice. Thus, ATP critically alters TNF trafficking and secretion from macrophages, inducing novel unconventional membrane TNF signaling via MVs without direct cell-to-cell contact. These data have crucial implications for this key cytokine, particularly when therapeutically targeting TNF in acute inflammatory diseases.-Soni, S., O'Dea, K. P., Tan, Y. Y., Cho, K., Abe, E., Romano, R., Cui, J., Ma, D., Sarathchandra, P., Wilson, M. R., Takata, M. ATP redirects cytokine trafficking and promotes novel membrane TNF signaling via microvesicles.
Subject(s)
Adenosine Triphosphate/immunology , Cell Membrane/immunology , Extracellular Vesicles/immunology , Macrophages/immunology , Pneumonia/immunology , Signal Transduction/immunology , Tumor Necrosis Factor-alpha/immunology , Acute Disease , Adenosine Triphosphate/genetics , Animals , Cell Communication/genetics , Cell Communication/immunology , Cell Membrane/genetics , Endoplasmic Reticulum/genetics , Endoplasmic Reticulum/immunology , Extracellular Vesicles/genetics , Golgi Apparatus/genetics , Golgi Apparatus/immunology , Inflammation/chemically induced , Inflammation/genetics , Inflammation/immunology , Lipopolysaccharides/toxicity , Male , Mice , Mice, Knockout , Pneumonia/chemically induced , Pneumonia/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Electroacupuncture (EA) has been reported to benefit hypertension, but the underlying mechanisms are still unclear. We hypothesized that EA attenuates hypertension, in part, through modulation of γ-aminobutyric acid (GABA) receptor function in the nucleus tractus solitarii (NTS). In the present study, the long-term effect of EA on GABA receptor function and expression was examined in the NTS of two-kidney, one-clip (2K1C) renovascular hypertensive rats. EA (0.1-0.4 mA, 2 and 15 Hz) was applied at Zusanli (ST36) acupoints overlying the deep fibular nerve for 30 min once a day for two weeks. The results showed that long-term EA treatment improved blood pressure (BP) and markedly restored the baroreflex response in 2K1C hypertensive rats. The increased pressor and depressor responses to microinjection of GABAB receptor agonist and antagonist into the NTS in the hypertensive rats were blunted by the EA treatment. Moreover, EA treatment attenuated the increased GABAB receptor expression in the NTS of hypertensive rats. In contrast, EA had no significant effect on the GABAA receptor function and expression in the NTS of 2K1C hypertensive rats. These findings suggest that the beneficial effects of EA on renovascular hypertension may be through modulation of functional GABAB receptors in the NTS.
Subject(s)
Baroreflex/physiology , Electroacupuncture/methods , Hypertension/physiopathology , Hypertension/therapy , Receptors, GABA-B/physiology , Solitary Nucleus/physiology , Animals , Male , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Currently, the viability of cryostored blastocysts that are subsequently re-warmed is determined via the percentage of cell survival. However, the large number of cells that forms the blastocyst can make this estimate difficult and unreliable. Studies have shown that fast re-expanding blastocysts have superior pregnancy rates. AIM: To determine whether the degree and speed of blastocoele re-expansion following cryopreservation and warming correlate with rates of live birth. MATERIALS AND METHODS: A retrospective cohort study of 757 frozen embryo transfer cycles over a 4-year period at Royal Prince Alfred Hospital, Sydney. Clinical and embryology notes were retrieved. Details regarding patient demographics, stimulation cycle from which embryos were derived, frozen embryo transfer cycles, embryology and pregnancy outcomes were recorded. RESULTS: Female (P = 0.01) and male age (P = 0.02) at the time of embryo creation were inversely associated with live birth. Fertilisation method (P = 0.03), embryo type at cryopreservation (P = 0.009), embryo grade at cryopreservation (P < 0.0001), percentage of cell survival post-thaw (P < 0.0001) and the degree of re-expansion (P = 0.003) were the IVF and embryology factors significantly associated with live birth. A predictive model (CryoPredict) was created in order to individualise the probability that the transfer of a given embryo would result in live birth. CONCLUSIONS: The degree and speed of blastocoele re-expansion postcryopreservation and subsequent warming can be used in conjunction with other parameters to predict live birth.
Subject(s)
Algorithms , Blastocyst , Cryopreservation , Live Birth , Adult , Age Factors , Cell Survival , Embryo Transfer , Female , Fertilization in Vitro/methods , Forecasting/methods , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
In a public health crisis, communication plays a vital role in making sure policies and recommendations from the government level get disseminated accurately to its people and is only considered as effective when the public accepts, supports, complies to, and engages in policies or behaves as per governments' recommendations. Adopting the multivariate audience segmentation strategy for health communication, this study uses a data-driven analytical method to (1) identify audience segments of public health crisis communication in Singapore based on knowledge, risk perception, emotional responses, and preventive behaviors; and (2) characterize each audience segment according to demographic factors, personality traits, information processing styles, and health information preferences. Results (N = 2033) from a web-based questionnaire executed in August 2021 have identified three audience segments: the less-concerned (n = 650), the risk-anxious (n = 142), and the risk-majority (n = 1,241). This study offers insights to how audiences of public health crisis communication perceive, process, and respond to information directed to them during the pandemic, thereby informing policy makers to tailor more targeted public health communication interventions in promoting positive attitude and behavior change.
ABSTRACT
For elite performers, psychomotor behavior's success or failure can be traced to differences in brain dynamics. The psychomotor efficiency hypothesis suggests refined cortical activity through 1) selective activation of task-relevant processes and 2) inhibition of non-essential processes. The use of electroencephalography (EEG) has been applied to investigate psychomotor performance's neural processes. The EEG markers that reflect an elevation of psychomotor efficiency include left temporal alpha (T3 alpha), frontal midline theta (Fm theta), sensorimotor rhythm (SMR), and the coherence between frontal and left temporal regions. However, the relationship between elite performers' task-relevant and non-essential neural processes is still not well understood. Therefore, this study aimed to explore how each task-relevant and inhibition of non-essential processes contribute to superior psychomotor behavior. Thirty-five highly skilled marksmen were recruited to perform 30 shots in the shooting task while the EEG was recorded. The marksmen were divided into two groups (superior & inferior) based on a median split of shooting performance. The superior group exhibited higher accuracy and precision, with a reduction in movement jerk. EEG measures revealed that the superior group exhibited higher SMR before the trigger pull than the inferior group. In addition, the superior group demonstrated reduced Fz-T3 coherence in their bull's eye shots than the missed shots. These results suggest that the superior group exhibited less effortful engagement of task-relevant processes and lower interference from non-essential cortical regions than the inferior group. The study's overall findings support the psychomotor efficiency hypothesis. When comparing highly skilled performers, the slight differences in brain dynamics ultimately contribute to the success or failure of psychomotor performance.
Subject(s)
Brain , Gastropoda , Animals , Electroencephalography , Inhibition, Psychological , MovementABSTRACT
Extracellular microvesicles (MVs) are released into the circulation in large numbers during acute systemic inflammation, yet little is known of their intravascular cell/tissue-specific interactions under these conditions. We recently described a dramatic increase in the uptake of intravenously injected MVs by monocytes marginated within the pulmonary vasculature, in a mouse model of low-dose lipopolysaccharide-induced systemic inflammation. To investigate the mechanisms of enhanced MV uptake by monocytes, we developed an in vitro model using in vivo derived monocytes. Although mouse blood is a convenient source, monocyte numbers are too low for in vitro experimentation. In contrast, differentiated bone marrow monocytes are abundant, but they are rapidly mobilized during systemic inflammation, and thus no longer available. Instead, we developed a protocol using marginated monocytes from the pulmonary vasculature as an anatomically relevant and abundant source. Mice are sacrificed by terminal anesthesia, the lungs inflated and perfused via the pulmonary artery. Perfusate cell populations are evaluated by flow cytometry, combined with in vitro generated fluorescently labelled MVs, and incubated in suspension for up to one hour. Washed cells are analyzed by flow cytometry to quantify MV uptake and confocal microscopy to localize MVs within cells (O'Dea et al., 2020). Using this perfusion-based method, substantial numbers of marginated pulmonary vascular monocytes are recovered, allowing multiple in vitro tests to be performed from a single mouse donor. As MV uptake profiles were comparable to those observed in vivo, this method is suitable for physiologically relevant high throughput mechanistic studies on mouse monocytes under in vitro conditions. Graphic abstract: Figure 1. Schematic of lung perfusate cell harvest and co-incubation with in vitro generated MVs. Created with BioRender.com.
ABSTRACT
Past research on Singapore English (SgE) has shown that there are specific segmental and prosodic patterns that are unique to the three major ethnic groups, Chinese, Malay, and Indian in Singapore. These features have been highlighted as the "stereotypical" ethnic markers of SgE speakers, assuming substrate influence from the speakers' "ethnic" languages (Mandarin, Malay, and Tamil). However, recent research suggests that Singaporeans are becoming increasingly English dominant and has challenged the position of the ethnic languages as true "mother tongues" of Singaporeans. Hence, this study seeks to question if such "stereotypical" ethnic features exist, and if so, the extent to which a less dominant ethnic language would affect the phonology of speakers' English. This study looks specifically at the production of consonants /f/, /θ/, /t/, /v/, and /w/ as salient segmental features in SgE. Participants' phonetic behavior of /θ/, which was produced similarly across the three ethnic groups, disputed substrate influence. Tamil speakers were the most disparate, particularly with the /v/-/w/ contrast production. However, these deviations were often sporadic phonetic changes, which scarcely reflect robust speech patterns in the community. As a result, consonantal production in SgE is found to be largely independent of substrate influence and relatively uniform across the three ethnicities. The homogeneity observed in this study sheds light on bilinguals' acquisition of sounds, and it also provides phonological evidence toward the understanding of the evolutionary process of postcolonial Englishes.
Subject(s)
Asian People/ethnology , Multilingualism , Phonetics , Speech , Verbal Behavior , Adult , Female , Humans , Language , Male , Singapore , Speech Production MeasurementABSTRACT
OBJECTIVE: To investigate the effect of electroacupuncture (EA) at "Taichong"(LR3) on blood pressure, sympathetic nerve activity, baroreflex sensitivity, and α 2-adrenergic receptor (α2AR) expression in nucleus tractus solitarii (NTS) in hypertensive rats, so as to reveal its mechanisms underlying improvement of hypertension. METHODS: Male Sprague Dawley rats were randomly divided into 4 groups: sham-operation, model, EA, and sham-EA (non-acupoint) groups, with 12 rats in each group. The hypertension model was established by occlusion of the right renal aorta (two-kidney-one clip method). Rats of the sham-operation group received the same surgery but without occlusion of the renal artery. EA (2 Hz/15 Hz, 2 mA) was applied to bilateral LR3 for 30 min, once a day for 28 days, and sham EA was applied to the skin of the rat tail near the buttock on both sides. The mean arterial pressure (MAP) of the abdominal aorta and heart rate (HR) were recorded. The autonomic nerve function was assessed by using frequency domain analysis of heart rate variability (HRV), and the baroreflex sensitivity detected by sequential method. Plasma norepinephrine (NE) level was measured by ELISA, and the α2AR positive neurons and α2AR protein expression in NTS were detected by using fluorescence immunohistochemistry and Western blot, respectively. The functions of α2AR within the NTS in modulating MBP and HR were verified by microinjection of its agonist (clonidine) and antagonist (yohimbine) separately. RESULTS: Compared to the sham operation rats, the hypertension rats displayed significant increases in the MAP (P<0.01), plasma norepinephrine content (P<0.01), ratios of low frequency/total power (LF/TP) and low frequency/high frequency (LF/HF) (P<0.01), and significant reduction in the overall gain, uplink sequence gain and downlink sequence gain of baroreflex (P<0.01), the number α2AR positive neurons and α2AR protein expression level in NTS (P<0.01). The rats in the EA group (rather than in the sham-EA group) showed significant reduction in MAP at the 3rd and 4th week, plasma NE content, LF/TP and LF/HF (P<0.01), and obvious increase in the overall gain, uplink sequence gain and downlink sequence gain of baroreflex (P<0.01), and the number of α2AR positive neurons and α2AR protein expression in comparison (P<0.05) with those of the model group. Microinjection of clonidine into NTS induced an evident decrease in both MAP and HR in the model group relevant to the sham operation group (P<0.01), while the MAP and HR changes of the EA (not sham EA) group were considerably bigger than those of the model group (P<0.05), being similar to those of the sham-operation group (P>0.05), which suggested an elimination of the BP-lowering effect of clonidine after EA. CONCLUSION: EA at LR3 can reduce MBP, sympathetic activities, improve baroreflex sensitivity in renovascular hypertensive rats, which may be associated with its effects in up-regulating the decreased NTS α2AR expression and functional activities.
Subject(s)
Electroacupuncture , Hypertension , Animals , Baroreflex , Hypertension/genetics , Hypertension/therapy , Male , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic , Solitary NucleusABSTRACT
BACKGROUND: Compound kushen injection (CKI), a Chinese patent drug, is widely used in the treatment of various cancers, especially neoplasms of the digestive system. However, the underlying mechanism of CKI in pancreatic cancer (PC) treatment has not been totally elucidated. METHODS: Here, to overcome the limitation of conventional network pharmacology methods with a weak combination with clinical information, this study proposes a network pharmacology approach of integrated bioinformatics that applies a weighted gene co-expression network analysis (WGCNA) to conventional network pharmacology, and then integrates molecular docking technology and biological experiments to verify the results of this network pharmacology analysis. RESULTS: The WGCNA analysis revealed 2 gene modules closely associated with classification, staging and survival status of PC. Further CytoHubba analysis revealed 10 hub genes (NCAPG, BUB1, CDK1, TPX2, DLGAP5, INAVA, MST1R, TMPRSS4, TMEM92 and SFN) associated with the development of PC, and survival analysis found 5 genes (TSPOAP1, ADGRG6, GPR87, FAM111B and MMP28) associated with the prognosis and survival of PC. By integrating these results into the conventional network pharmacology study of CKI treating PC, we found that the mechanism of CKI for PC treatment was related to cell cycle, JAK-STAT, ErbB, PI3K-Akt and mTOR signalling pathways. Finally, we found that CDK1, JAK1, EGFR, MAPK1 and MAPK3 served as core genes regulated by CKI in PC treatment, and were further verified by molecular docking, cell proliferation assay, RT-qPCR and western blot analysis. CONCLUSIONS: Overall, this study suggests that the optimized network pharmacology approach is suitable to explore the molecular mechanism of CKI in the treatment of PC, which provides a reference for further investigating biomarkers for diagnosis and prognosis of PC and even the clinical rational application of CKI.
ABSTRACT
BACKGROUND: Diabetic cardiomyopathy is a main cause of the increased morbidity in diabetic patients, no effective treatment is available so far. Polydatin, a resveratrol glucoside isolated from the Polygonum cuspidatum, was found by our and others have antioxidant and cardioprotective activities. Therapeutic effects of polydatin on diabetic cardiomyopathy and the possible mechanisms remains unclear. This study aimed to investigate the cardioprotective effects and underlying mechanisms of polydatin on myocardial injury induced by hyperglycemia. METHODS: Diabetes in rats was made by high-fat diet combined with multiple low doses of streptozotocin, and then treated with polydatin (100 mg·kg-1·day-1, by gavage) for 8 weeks. Cardiac function was examined by echocardiography. Myocardial tissue and blood samples were collected for histology, protein and metabolic characteristics analysis. In cultured H9c2 cells with 30 mM of glucose, the direct effects of polydatin on myocyte injury were also observed. RESULTS: In diabetic rats, polydatin administration significantly improved myocardial dysfunction and attenuated histological abnormalities, as evidenced by elevating left ventricular shortening fraction and ejection fraction, as well as reducing cardiac hypertrophy and interstitial fibrosis. In cultured H9c2 cells, pretreatment of polydatin dose-dependently inhibited high glucose-induced cardiomyocyte injury. Further observation evidenced that polydatin suppressed the increase in the reactive oxygen species levels, NADPH oxidase activity and inflammatory cytokines production induced by hyperglycemia in vivo and in vitro. Polydatin also prevented the increase expression of NOX4, NOX2 and NF-κB in the high glucose -stimulated H9c2 cells and diabetic hearts. CONCLUSIONS: Our results demonstrate that the cardioprotective effect of polydatin against hyperglycemia-induced myocardial injury is mediated by inhibition of NADPH oxidase and NF-κB activity. The findings may provide a novel understanding the mechanisms of the polydatin to be a potential treatment of diabetic cardiomyopathy.
Subject(s)
Cardiomyopathies/prevention & control , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 2/complications , Drugs, Chinese Herbal/therapeutic use , Glucosides/therapeutic use , Stilbenes/therapeutic use , Animals , Cardiomyopathies/etiology , Cell Line , Drug Evaluation, Preclinical , Drugs, Chinese Herbal/pharmacology , Fallopia japonica , Glucosides/pharmacology , Heart/drug effects , Male , Myocardium/metabolism , NADPH Oxidases/antagonists & inhibitors , NF-kappa B/antagonists & inhibitors , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Stilbenes/pharmacologyABSTRACT
Microvesicles (MVs), a plasma membrane-derived subclass of extracellular vesicles, are produced and released into the circulation during systemic inflammation, yet little is known of cell/tissue-specific uptake of MVs under these conditions. We hypothesized that monocytes contribute to uptake of circulating MVs and that their increased margination to the pulmonary circulation and functional priming during systemic inflammation produces substantive changes to the systemic MV homing profile. Cellular uptake of i.v.-injected, fluorescently labelled MVs (J774.1 macrophage-derived) in vivo was quantified by flow cytometry in vascular cell populations of the lungs, liver and spleen of C57BL6 mice. Under normal conditions, both Ly6Chigh and Ly6Clow monocytes contributed to MV uptake but liver Kupffer cells were the dominant target cell population. Following induction of sub-clinical endotoxemia with low-dose i.v. LPS, MV uptake by lung-marginated Ly6Chigh monocytes increased markedly, both at the individual cell level (~2.5-fold) and through substantive expansion of their numbers (~8-fold), whereas uptake by splenic macrophages was unchanged and uptake by Kupffer cells actually decreased (~50%). Further analysis of MV uptake within the pulmonary vasculature using a combined model approach of in vivo macrophage depletion, ex vivo isolated perfused lungs and in vitro lung perfusate cell-based assays, indicated that Ly6Chigh monocytes possess a high MV uptake capacity (equivalent to Kupffer cells), that is enhanced directly by endotoxemia and ablated in the presence of phosphatidylserine (PS)-enriched liposomes and ß3 integrin receptor blocking peptide. Accordingly, i.v.-injected PS-enriched liposomes underwent a redistribution of cellular uptake during endotoxemia similar to MVs, with enhanced uptake by Ly6Chigh monocytes and reduced uptake by Kupffer cells. These findings indicate that monocytes, particularly lung-marginated Ly6Chigh subset monocytes, become a dominant target cell population for MVs during systemic inflammation, with significant implications for the function and targeting of endogenous and therapeutically administered MVs, lending novel insights into the pathophysiology of pulmonary vascular inflammation.
ABSTRACT
Electroacupuncture (EA) has been used to treat numerous diseases, including hypertension. This study aimed to investigate the long-term effect and underlying mechanisms of EA stimulation at the LI11 point on the hypertension and sympathetic nerve activity in two-kidney, one-clip (2K1C) hypertensive rats. EA (0.1-0.4 mA, 2 and 15 Hz) was applied to the acupoints LI11 overlying the deep radial nerve once a day for 6 weeks. The mean arterial pressure (MAP) and heart rate (HR) were determined by radiotelemetry, and the sympathetic nerve activity was evaluated by telemetric analyses of the low-frequency component of blood pressure (BP) and by plasma epinephrine and norepinephrine levels. The results showed 6 weeks of EA significantly lowered the increased BP effectively, inhibited the enhanced sympathetic nerve activities and attenuated cardiac hypertrophy in 2K1C hypertensive rats. The level of orexin receptor-1 (OX1R) in the rostral ventrolateral medulla (RVLM) after EA treatment was markedly reduced in 2K1C rats, while there was no difference in the RVLM expression of orexin receptor-2 (OX2R) in 2K1C and 2K1C+EA rats. Moreover, the increased pressor and depressor responses to microinjection of orexin A or OX1R antagonist SB408124 into the RVLM of 2K1C rats were significantly blunted by the EA treatment. These findings suggest that BP-lowering effect of EA on renovascular hypertension may be through inhibition of central sympathetic activities and modulation of functional orexin receptors in the RVLM.
ABSTRACT
The allocation of mental workload is critical to maintain cognitive-motor performance under various demands. While mental workload has been investigated during performance, limited efforts have examined it during cognitive-motor learning, while none have concurrently manipulated task difficulty. It is reasonable to surmise that the difficulty level at which a skill is practiced would impact the rate of skill acquisition and also the rate at which mental workload is reduced during learning (relatively slowed for challenging compared to easier tasks). This study aimed to monitor mental workload by assessing cortical dynamics during a task practiced under two difficulty levels over four days while perceived task demand, performance, and electroencephalography (EEG) were collected. As expected, self-reported mental workload was reduced, greater working memory engagement via EEG theta synchrony was observed, and reduced cortical activation, as indexed by progressive EEG alpha synchrony was detected during practice. Task difficulty was positively related to the magnitude of alpha desynchrony and accompanied by elevations in the theta-alpha ratio. Counter to expectation, the absence of an interaction between task difficulty and practice days for both theta and alpha power indicates that the refinement of mental processes throughout learning occurred at a comparable rate for both levels of difficulty. Thus, the assessment of brain dynamics was sensitive to the rate of change of cognitive workload with practice, but not to the degree of difficulty. Future work should consider a broader range of task demands and additional measures of brain processes to further assess this phenomenon.
Subject(s)
Attention/physiology , Cognition/physiology , Psychomotor Performance/physiology , Task Performance and Analysis , Workload , Adult , Electroencephalography/methods , Female , Humans , Learning/physiology , Male , Reaction Time/physiology , Workload/psychology , Young AdultABSTRACT
A novel ERP approach was proposed to index variations in mental workload, particularly in attentional reserve, which is complementary to EEG spectral content thought to reflect mental effort. To our knowledge, no study has assessed mental effort and attentional reserve simultaneously in EEG gel-based and, importantly, dry systems, which are particularly well suited for real-world settings. Therefore, by systematically considering ERP, EEG spectral, and importantly the combination of both, this study examined if a small set of dry EEG electrodes could detect changes in both spectral and ERP metrics to assess the mental workload under various challenges with a similar fidelity to their gel-based counterparts in a laboratory setting. By employing both EEG gel-based and dry systems, the ERP and spectral markers were computed while participants executed a visuomotor task under three levels of challenge. For both EEG systems, more challenging levels of difficulty were associated with concomitant changes in ERP amplitude, and spectral power reflected a reduction of the attentional reserve and an increase in cognitive-motor effort, respectively. Those variations in attentional reserve and cognitive-motor effort collectively indexed mental workload with nearly identical fidelity for both gel-based and dry EEG systems. These findings promise to assess the mental workload in situations where the use of dry EEG systems could be advantageously employed to examine human cognitive-motor performance.
Subject(s)
Attention/physiology , Cerebral Cortex/physiology , Electroencephalography/methods , Evoked Potentials/physiology , Psychomotor Performance/physiology , Adult , Electroencephalography/instrumentation , Female , Humans , Male , Young AdultABSTRACT
While the concepts of cognitive workload and attentional reserve have been thought to have an inverse relationship for some time, such a relationship has never been empirically tested. This was the purpose of the present study. Aspects of the electroencephalogram were used to assess both cognitive workload and attentional reserve. Specifically, spectral measures of cortical activation were used to assess cognitive workload, while amplitudes of the event-related potential from the presentation of unattended "novel" sounds were used to assess attentional reserve. The relationship between these two families of measures was assessed using canonical correlation. Twenty-seven participants performed a flight simulator task under three levels of challenge. Verification of manipulation was performed using self-report measures of task demand, objective task performance, and heart rate variability using electrocardiography. Results revealed a strong, negative relationship between the spectral measures of cortical activation, believed to be representative of cognitive workload, and ERP amplitudes, believed to be representative of attentional reserve. This finding provides support for the theoretical and intuitive notion that cognitive workload and attentional reserve are inversely related. The practical implications of this result include improved state classification using advanced machine learning techniques, enhanced personnel selection/recruitment/placement, and augmented learning/training.
Subject(s)
Attention/physiology , Brain Waves/physiology , Evoked Potentials/physiology , Psychomotor Performance/physiology , Adult , Electrocardiography , Female , Humans , Male , Young AdultABSTRACT
OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Quchi" (LI 11) on arterial blood pressure (BP), sympathetic nerve activity, barorefiex sensitivity (BRS) and expression of brain derived neurotrophic factor (BDNF) and nicotinamide adenine dinucleotide phosphate (NADPH) enzyme subunit p 47 phox in the rostral ventrolateral medulla (RVML) in hypertension rats. METHODS: A total of 45 male SD rats were randomly divided into sham operation, artificial cerebro-spinal fluid (aCSF) , model, "Quchi"(LI 11), and Jianyu (LI 15) groups (n = 9 in each group). The hypertension model was established by microinjection of Ang II (200 pg x kg(-1) x day(-1)) into the lateral ventricle (A-C: 1.0 mm, L: 1.4 mm, H: 4.5 mm) for 2 weeks (aCSF for aCSF group). After 1 week's Ang II perfusion, EA (2 Hz/15 Hz, 1 mA) was applied to bilateral "Quchi" (LI 11)or "Jianyu" (LI 15) for 20 min, once daily for two weeks. The mean arterial pressure (MAP) and heart rate (HR) were detected by using a Non-Invasive Blood Pressure System (tail cuff method). The BRS (BP-to-HR transfer function) was determined by calculating the ratio of HR fluctuation (HR : HR, between post- and pre-intravenous injection of phenylephrine)/MAP fluctuation (MAP : MAP, between post- and pre-phenylephrine injection) , the urinary norepinephrine (NE) level in 24 h was assayed by ELISA. Real-time PCR and Western blot were used to detect the mRNA and protein expression of BDNF and p 47phox in the RVML region tissue. RESULTS: Following modeling, the MAP, HR and 24 h-urinary NE levels and p 47phox mRNA and protein expression levels in the RVML were significantly increased (P<0.01), and the BRS was decreased significantly (P<0.01). After EA intervention, the MAP, HR and 24 h-urinary NE levels and p 47 phox mRNA and protein expression levels in the RVML were considerably lower in the LI 11 group than in the model group (P<0.05), while the BRS level was markedly increased in the LI 11 group compared with the model group (P<0.05). The expression levels of BDNF mRNA and protein in the RVLM region were obviously up-regulated in the LI 11 group compared with the model group (P<0.05). No significant differences were found between the LI 15 group and the model group in the MAP, HR, 24 h-urinary NE, BRS, BDNF mRNA and protein and p 47 phox mRNA and protein expression levels (P>0.05). CONCLUSION: EA stimulation of "Quchi" (LI 11) can down-regulate arterial blood pressure, sympathetic nerve activity, and increase the baroreflex sensitivity in hypertension rats, which may be related to its effects in down-regulating p 47 phox mRNA and protein expression in the RVML.
Subject(s)
Acupuncture Points , Arterial Pressure , Electroacupuncture , Hypertension/therapy , Sympathetic Nervous System/physiopathology , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Humans , Hypertension/genetics , Hypertension/metabolism , Hypertension/physiopathology , Male , Rats , Rats, Sprague-Dawley , Sympathetic Nervous System/metabolismABSTRACT
Cognitive workload is an important element of cognitive-motor performance such as that exhibited during the piloting of an aircraft. Namely, an increase in task demands on the pilot can elevate cognitive information processing and, thus, the risk of human error. As such, there is a need to develop methods that reliably assess mental workload in pilots within operational settings. The present study contributes to this research goal by identifying physiological and brain biomarkers of cognitive workload and attentional reserve during a simulated aircraft piloting task under three progressive levels of challenge. A newly developed experimental method was employed by which electroencephalography (EEG) was acquired via a dry (i.e., gel-free sensors) system using few scalp sites. Self-reported responses to surveys and piloting performance indicators were analyzed. The findings revealed that as the challenge (task demands) increased, the perceived mental load increased, attentional reserve was attenuated, and task performance decreased. Such an increase in task demands was also reflected by changes in heart rate variability (HRV), as well as in the amplitude of the P300 component of event-related potentials to auditory probes, and in the spectral power of specific EEG frequency bands. This work provides a first step towards a long-term goal to develop a composite system of biomarkers for real-time cognitive workload assessment and state assessment of pilots in operational settings.
Subject(s)
Brain/physiology , Cognition , Event-Related Potentials, P300 , Aircraft , Attention/physiology , Biomarkers , Computer Simulation , Electroencephalography , Heart Rate , Humans , Task Performance and Analysis , Work Performance , Workload , Young AdultABSTRACT
Osteogenesis and angiogenesis are two closely correlated processes during bone growth, development, remodelling and repair.Vascular endothelial growth factor (VEGF) is an essential mediator during the process of angiogenesis. Based on an extensive literature search, which was carried out using the PubMed database and the keywords of osteogenesis, VEGF, endochondral ossification and intramembranous ossification, this manuscript reviews the role of VEGF in ossification, with emphasis on its effect in endochondral and intramembranous ossification. Osteogenesis and angiogenesis are closely correlated processes. VEGF acts as an essential mediator during these processes. It not only functions in bone angiogenesis but also in various aspects of bone development.