Effect of acute gastric dilatation on gastric myoelectic and motor activity in dogs.

PubMed

Hall, J A; Solie, T N; Seim, H B; Twedt, D C

1999-05-01

To investigate the effects of experimentally induced acute gastric dilatation on electrical and mechanical activities of the stomach in dogs. 7 healthy dogs. Electrodes and strain-gauge force transducers were implanted on the serosal surface of the antrum and pylorus. Eight days later, baseline gastric electrical and contractile activities were recorded. The dogs were anesthetized and mechanically ventilated to maintain normocapnia while the stomach was distended (intragastric pressure, 30 mm Hg) for 180 minutes, using a thin compliant bag. Gastric electrical and contractile activities were recorded again on days 1 and 10 after dilatation. Recordings were analyzed to determine gastric slow-wave frequency, slow-wave dysrhythmia, propagation velocity of slow-waves, coupling of contractions to slow waves, motility index on the basis of relative contractile amplitudes, and onset of contractions after a standardized meal. Electrical or contractile activities were not significantly different 18 hours after acute gastric dilatation (day 1). Arrhythmias were evident before and after gastric dilatation in dogs from which food was withheld and in dogs after consumption of a meal. Variables for assessing gastric electrical and contractile activities were unaffected 18 hours after acute gastric dilatation. Analysis of results of this study indicated that altered electrical and contractile activities in dogs with short-term gastric dilatation are not likely to be secondary to the process of acute gastric dilatation.

Synthesis and contractile activity of the C-terminal heptapeptide of substance P with N5-dimethyl glutamine in the 6-position. Active site studies.

PubMed

Poulos, C P; Pinas, N; Theodoropoulos, D

1980-09-15

The synthesis and testing of [N5-dimethyl-Gln6]-SP5-11 showed 37 +/- 12% contractile activity relative to SP, and intrinsic efficacy 98 +/- 4%. This finding indicates that the carboxamide groups of the dual Gln5-Cln6 moiety are not equally related with the contractile response of the C-terminal heptapeptide of SP.

Plasticity of TOM complex assembly in skeletal muscle mitochondria in response to chronic contractile activity.

PubMed

Joseph, Anna-Maria; Hood, David A

2012-03-01

We investigated the assembly of the TOM complex within skeletal muscle under conditions of chronic contractile activity-induced mitochondrial biogenesis. Tom40 import into mitochondria was increased by chronic contractile activity, as was its time-dependent assembly into the TOM complex. These changes coincided with contractile activity-induced augmentations in the expression of key protein import machinery components Tim17, Tim23, and Tom22, as well as the cytosolic chaperone Hsp90. These data indicate the adaptability of the TOM protein import complex and suggest a regulatory role for the assembly of this complex in exercise-induced mitochondrial biogenesis. Copyright © 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.

Rapid Feedforward Inhibition and Asynchronous Excitation Regulate Granule Cell Activity in the Mammalian Main Olfactory Bulb

PubMed Central

Burton, Shawn D.

2015-01-01

Granule cell-mediated inhibition is critical to patterning principal neuron activity in the olfactory bulb, and perturbation of synaptic input to granule cells significantly alters olfactory-guided behavior. Despite the critical role of granule cells in olfaction, little is known about how sensory input recruits granule cells. Here, we combined whole-cell patch-clamp electrophysiology in acute mouse olfactory bulb slices with biophysical multicompartmental modeling to investigate the synaptic basis of granule cell recruitment. Physiological activation of sensory afferents within single glomeruli evoked diverse modes of granule cell activity, including subthreshold depolarization, spikelets, and suprathreshold responses with widely distributed spike latencies. The generation of these diverse activity modes depended, in part, on the asynchronous time course of synaptic excitation onto granule cells, which lasted several hundred milliseconds. In addition to asynchronous excitation, each granule cell also received synchronous feedforward inhibition. This inhibition targeted both proximal somatodendritic and distal apical dendritic domains of granule cells, was reliably recruited across sniff rhythms, and scaled in strength with excitation as more glomeruli were activated. Feedforward inhibition onto granule cells originated from deep short-axon cells, which responded to glomerular activation with highly reliable, short-latency firing consistent with tufted cell-mediated excitation. Simulations showed that feedforward inhibition interacts with asynchronous excitation to broaden granule cell spike latency distributions and significantly attenuates granule cell depolarization within local subcellular compartments. Collectively, our results thus identify feedforward inhibition onto granule cells as a core feature of olfactory bulb circuitry and establish asynchronous excitation and feedforward inhibition as critical regulators of granule cell activity. SIGNIFICANCE STATEMENT Inhibitory granule cells are involved critically in shaping odor-evoked principal neuron activity in the mammalian olfactory bulb, yet little is known about how sensory input activates granule cells. Here, we show that sensory input to the olfactory bulb evokes a barrage of asynchronous synaptic excitation and highly reliable, short-latency synaptic inhibition onto granule cells via a disynaptic feedforward inhibitory circuit involving deep short-axon cells. Feedforward inhibition attenuates local depolarization within granule cell dendritic branches, interacts with asynchronous excitation to suppress granule cell spike-timing precision, and scales in strength with excitation across different levels of sensory input to normalize granule cell firing rates. PMID:26490853

Contractile-Ring Assembly in Fission Yeast Cytokinesis: Recent Advances and New Perspectives

PubMed Central

Lee, I-Ju; Coffman, Valerie C.; Wu, Jian-Qiu

2017-01-01

The fission yeast Schizosaccharomyces pombe is an excellent model organism to study cytokinesis. Here, we review recent advances on contractile-ring assembly in fission yeast. First, we summarize the assembly of cytokinesis nodes, the precursors of a normal contractile ring. IQGAP Rng2 and myosin essential light chain Cdc4 are recruited by the anillin-like protein Mid1, followed by the addition of other cytokinesis node proteins. Mid1 localization on the plasma membrane is stabilized by interphase node proteins. Second, we discuss proteins and processes that contribute to the search, capture, pull, and release mechanism of contractile-ring assembly. Actin filaments nucleated by formin Cdc12, the motor activity of myosin-II, the stiffness of the actin network, and severing of actin filaments by cofilin all play essential roles in contractile-ring assembly. Finally, we discuss the Mid1-independent pathway for ring assembly, and the possible mechanisms underlying the ring maturation and constriction. Collectively, we provide an overview of the current understanding of contractile-ring assembly and uncover future directions in studying cytokinesis in fission yeast. PMID:22887981

Contractile-ring assembly in fission yeast cytokinesis: Recent advances and new perspectives.

PubMed

Lee, I-Ju; Coffman, Valerie C; Wu, Jian-Qiu

2012-10-01

The fission yeast Schizosaccharomyces pombe is an excellent model organism to study cytokinesis. Here, we review recent advances on contractile-ring assembly in fission yeast. First, we summarize the assembly of cytokinesis nodes, the precursors of a normal contractile ring. IQGAP Rng2 and myosin essential light chain Cdc4 are recruited by the anillin-like protein Mid1, followed by the addition of other cytokinesis node proteins. Mid1 localization on the plasma membrane is stabilized by interphase node proteins. Second, we discuss proteins and processes that contribute to the search, capture, pull, and release mechanism of contractile-ring assembly. Actin filaments nucleated by formin Cdc12, the motor activity of myosin-II, the stiffness of the actin network, and severing of actin filaments by cofilin all play essential roles in contractile-ring assembly. Finally, we discuss the Mid1-independent pathway for ring assembly, and the possible mechanisms underlying the ring maturation and constriction. Collectively, we provide an overview of the current understanding of contractile-ring assembly and uncover future directions in studying cytokinesis in fission yeast. Copyright © 2012 Wiley Periodicals, Inc.

Activity-induced regulation of myosin isoform distribution - Comparison of two contractile activity programs

NASA Technical Reports Server (NTRS)

Diffee, Gary M.; Caiozzo, Vince J.; Mccue, Samuel A.; Herrick, Robert E.; Baldwin, Kenneth M.

1993-01-01

This study examined the role of specific types of contractile activity in regulating myosin heavy chain (MHC) isoform expression in rodent soleus. A combination of hindlimb suspension (SN) and two programmed contractile training activity paradigms, either isometric contractile activity (ST-IM) or high-load slowly shortening isovelocity activity, were utilized. Both training paradigms increased muscle mass compared with SN alone. However, only ST-IM resulted in a partial prevention of the suspension-induced decrease in type I MHC. With the use of a fluorescently labeled antibody to type IIa MHC, the distribution of MHCs among fibers was examined immunohistochemically. In SN, the percentage of cells staining positive for type IIa MHC was increased but the staining intensity of the positively staining cells was unchanged compared with control cells. In the ST-IM soleus, the percentage of positively staining fibers was unchanged but the intensity of the positively staining cells was decreased compared with SN values. These results suggest that 1) isometric contractile activity is more effective than isovelocity activity in preventing suspension-induced shifts in soleus MHC distribution and 2) changes associated with both suspension and training occur in only a small number of fibers, with the majority of fibers apparently unresponsive to these interventions.

A massively asynchronous, parallel brain.

PubMed

Zeki, Semir

2015-05-19

Whether the visual brain uses a parallel or a serial, hierarchical, strategy to process visual signals, the end result appears to be that different attributes of the visual scene are perceived asynchronously--with colour leading form (orientation) by 40 ms and direction of motion by about 80 ms. Whatever the neural root of this asynchrony, it creates a problem that has not been properly addressed, namely how visual attributes that are perceived asynchronously over brief time windows after stimulus onset are bound together in the longer term to give us a unified experience of the visual world, in which all attributes are apparently seen in perfect registration. In this review, I suggest that there is no central neural clock in the (visual) brain that synchronizes the activity of different processing systems. More likely, activity in each of the parallel processing-perceptual systems of the visual brain is reset independently, making of the brain a massively asynchronous organ, just like the new generation of more efficient computers promise to be. Given the asynchronous operations of the brain, it is likely that the results of activities in the different processing-perceptual systems are not bound by physiological interactions between cells in the specialized visual areas, but post-perceptually, outside the visual brain.

Roles of Formin Nodes and Myosin Motor Activity in Mid1p-dependent Contractile-Ring Assembly during Fission Yeast Cytokinesis

PubMed Central

Coffman, Valerie C.; Nile, Aaron H.; Lee, I-Ju; Liu, Huayang

2009-01-01

Two prevailing models have emerged to explain the mechanism of contractile-ring assembly during cytokinesis in the fission yeast Schizosaccharomyces pombe: the spot/leading cable model and the search, capture, pull, and release (SCPR) model. We tested some of the basic assumptions of the two models. Monte Carlo simulations of the SCPR model require that the formin Cdc12p is present in >30 nodes from which actin filaments are nucleated and captured by myosin-II in neighboring nodes. The force produced by myosin motors pulls the nodes together to form a compact contractile ring. Live microscopy of cells expressing Cdc12p fluorescent fusion proteins shows for the first time that Cdc12p localizes to a broad band of 30–50 dynamic nodes, where actin filaments are nucleated in random directions. The proposed progenitor spot, essential for the spot/leading cable model, usually disappears without nucleating actin filaments. α-Actinin ain1 deletion cells form a normal contractile ring through nodes in the absence of the spot. Myosin motor activity is required to condense the nodes into a contractile ring, based on slower or absent node condensation in myo2-E1 and UCS rng3-65 mutants. Taken together, these data provide strong support for the SCPR model of contractile-ring formation in cytokinesis. PMID:19864459

TRPA1-dependent regulation of bladder detrusor smooth muscle contractility in normal and type I diabetic rats

PubMed Central

Philyppov, Igor B.; Paduraru, Oksana N.; Gulak, Kseniya L.; Skryma, Roman; Prevarskaya, Natalia; Shuba, Yaroslav M.

2016-01-01

TRPA1 is a Ca2+-permeable cation channel that is activated by painful low temperatures (˂17 °C), irritating chemicals, reactive metabolites and mediators of inflammation. In the bladder TRPA1 is predominantly expressed in sensory afferent nerve endings, where it mediates sensory transduction. The contractile effect of its activation on detrusor smooth muscle (DSM) is explained by the release from sensory afferents of inflammatory factors – tachykinins and prostaglandins, which cause smooth muscle cell contraction. Diabetes is a systemic disease, with common complications being diabetic cystopathies and urinary incontinence. However, data on how diabetes affects bladder contractility associated with TRPA1 activation are not available. In this study, by using a rat model with streptozotocin-induced type I diabetes, contractility measurements of DSM strips in response to TRPA1-activating and modulating pharmacological agents and assessment of TRPA1 mRNA expression in bladder-innervating dorsal root ganglia, we have shown that diabetes enhances the TRPA1-dependent mechanism involved in bladder DSM contractility. This is not due to changes in TRPA1 expression, but mainly due to the general inflammatory reaction caused by diabetes. The latter leads to an increase in cyclooxygenase-2-dependent prostaglandin synthesis through the mechanisms associated with substance P activity. This results in the enhanced functional coupling between the tachykinin and prostanoid systems, and the concomitant increase of their impact on DSM contractility in response to TRPA1 activation. PMID:26935999

TRPA1-dependent regulation of bladder detrusor smooth muscle contractility in normal and type I diabetic rats.

PubMed

Philyppov, Igor B; Paduraru, Oksana N; Gulak, Kseniya L; Skryma, Roman; Prevarskaya, Natalia; Shuba, Yaroslav M

2016-01-01

TRPA1 is a Ca(2+)-permeable cation channel that is activated by painful low temperatures (<17°C), irritating chemicals, reactive metabolites and mediators of inflammation. In the bladder TRPA1 is predominantly expressed in sensory afferent nerve endings, where it mediates sensory transduction. The contractile effect of its activation on detrusor smooth muscle (DSM) is explained by the release from sensory afferents of inflammatory factors - tachykinins and prostaglandins, which cause smooth muscle cell contraction. Diabetes is a systemic disease, with common complications being diabetic cystopathies and urinary incontinence. However, data on how diabetes affects bladder contractility associated with TRPA1 activation are not available. In this study, by using a rat model with streptozotocin-induced type I diabetes, contractility measurements of DSM strips in response to TRPA1-activating and modulating pharmacological agents and assessment of TRPA1 mRNA expression in bladder-innervating dorsal root ganglia, we have shown that diabetes enhances the TRPA1-dependent mechanism involved in bladder DSM contractility. This is not due to changes in TRPA1 expression, but mainly due to the general inflammatory reaction caused by diabetes. The latter leads to an increase in cyclooxygenase-2-dependent prostaglandin synthesis through the mechanisms associated with substance P activity. This results in the enhanced functional coupling between the tachykinin and prostanoid systems, and the concomitant increase of their impact on DSM contractility in response to TRPA1 activation.

Activation of Toll-like receptor 3 increases mouse aortic vascular smooth muscle cell contractility through ERK1/2 pathway.

PubMed

Hardigan, Trevor; Spitler, Kathryn; Matsumoto, Takayuki; Carrillo-Sepulveda, Maria Alicia

2015-11-01

Activation of Toll-like receptor 3 (TLR3), a pattern recognition receptor of the innate immune system, is associated with vascular complications. However, whether activation of TLR3 alters vascular contractility is unknown. We, therefore, hypothesized that TLR3 activation augments vascular contractility and activates vascular smooth muscle cell (VSMC) contractile apparatus proteins. Male mice were treated with polyinosinic-polycytidylic acid (Poly I:C group, 14 days), a TLR3 agonist; control mice received saline (vehicle, 14 days). At the end of protocol, blood pressure was measured by tail cuff method. Aortas were isolated and assessed for contractility experiments using a wire myograph. Aortic protein content was used to determine phosphorylated/total interferon regulatory factor 3 (IRF3), a downstream target of TLR3 signaling, and ERK1/2 using Western blot. We investigated the TLR3/IRF3/ERK1/2 signaling pathway and contractile-related proteins such as phosphorylated/total myosin light chain (MLC) and caldesmon (CaD) in aortic VSMC primary cultures. Poly I:C-treated mice exhibited (vs. vehicle-treated mice) (1) elevated systolic blood pressure. Moreover, Poly I:C treatment (2) enhanced aortic phenylephrine-induced maximum contraction, which was suppressed by PD98059 (ERK1/2 inhibitor), and (3) increased aortic levels of phosphorylated IRF3 and ERK1/2. Stimulation of mouse aortic VSMCs with Poly I:C resulted in increased phosphorylation of IRF3, ERK1/2, MLC, and CaD. Inhibition of ERK1/2 abolished Poly I:C-mediated phosphorylation of MLC and CaD. Our data provide functional evidence for the role of TLR3 in vascular contractile events, suggesting TLR3 as a potential new therapeutic target in vascular dysfunction and regulation of blood pressure.

Regulation of adult cardiocyte growth: effects of active and passive mechanical loading

NASA Technical Reports Server (NTRS)

Decker, M. L.; Janes, D. M.; Barclay, M. M.; Harger, L.; Decker, R. S.

1997-01-01

Fluctuations in hemodynamic load have been documented to modulate contractile protein turnover and myofibrillar structure in the heart; however, the relative importance of active and passive loading in regulating adult cardiocyte growth remains unresolved. To address this issue at the cellular level, adult feline cardiocytes were cultured either on Silastic membranes or plastic surfaces. Cardiocyte-laden membranes were stretched 10% of their rest length to enhance passive loading, whereas heart cells cultured on plastic or Silastic were field stimulated at 1 Hz to mimic active loading. Turnover of contractile proteins and structural integrity of the contractile-cytoskeletal apparatus were monitored for periods ranging from 4 to 72 h. Active and passive loading elevated contractile protein synthesis nearly equally (approximately 50%) and promoted the attachment of remodeled myofibrils to vinculin-positive focal contacts and/or costameres during the first 24 h of loading. Thereafter, rates of contractile protein synthesis returned to control values in passively stretched heart cells but remained elevated in field-stimulated cultures. The fractional rate of growth was increased significantly (approximately 8%/day) in electrically paced cells, whereas in passively stretched cardiocytes the growth rate rose only modestly (approximately 2%/day). Changes in the rate of myocyte growth appeared more closely correlated with the development of focal contacts and myofibril remodeling than with changes in myofibrillar protein turnover per se. 2,3-Butanedione monoxime, nifedipine, and, to a lesser extent, ryanodine blocked field-stimulated contractile protein synthesis and myofibrillar remodeling but had no impact on protein turnover or myofibril reassembly in passively loaded cardiocytes. The results of these experiments imply that both active and passive loading stimulate contractile protein turnover and myofibril remodeling, but the generation of active tension accelerates cardiocyte growth to a greater extent than passive loading. Furthermore, pharmacological interventions suggest that unique pathways may mediate these cellular events in actively and passively loaded adult cardiocytes.

Regulation of adult cardiocyte growth: effects of active and passive mechanical loading.

PubMed

Decker, M L; Janes, D M; Barclay, M M; Harger, L; Decker, R S

1997-06-01

Fluctuations in hemodynamic load have been documented to modulate contractile protein turnover and myofibrillar structure in the heart; however, the relative importance of active and passive loading in regulating adult cardiocyte growth remains unresolved. To address this issue at the cellular level, adult feline cardiocytes were cultured either on Silastic membranes or plastic surfaces. Cardiocyte-laden membranes were stretched 10% of their rest length to enhance passive loading, whereas heart cells cultured on plastic or Silastic were field stimulated at 1 Hz to mimic active loading. Turnover of contractile proteins and structural integrity of the contractile-cytoskeletal apparatus were monitored for periods ranging from 4 to 72 h. Active and passive loading elevated contractile protein synthesis nearly equally (approximately 50%) and promoted the attachment of remodeled myofibrils to vinculin-positive focal contacts and/or costameres during the first 24 h of loading. Thereafter, rates of contractile protein synthesis returned to control values in passively stretched heart cells but remained elevated in field-stimulated cultures. The fractional rate of growth was increased significantly (approximately 8%/day) in electrically paced cells, whereas in passively stretched cardiocytes the growth rate rose only modestly (approximately 2%/day). Changes in the rate of myocyte growth appeared more closely correlated with the development of focal contacts and myofibril remodeling than with changes in myofibrillar protein turnover per se. 2,3-Butanedione monoxime, nifedipine, and, to a lesser extent, ryanodine blocked field-stimulated contractile protein synthesis and myofibrillar remodeling but had no impact on protein turnover or myofibril reassembly in passively loaded cardiocytes. The results of these experiments imply that both active and passive loading stimulate contractile protein turnover and myofibril remodeling, but the generation of active tension accelerates cardiocyte growth to a greater extent than passive loading. Furthermore, pharmacological interventions suggest that unique pathways may mediate these cellular events in actively and passively loaded adult cardiocytes.

[Effect of dopamine and its antagonists on contractile activity of the lower esophageal sphincter and the stomach (author's transl)].

PubMed

Itoh, Z; Aizawa, I; Nakamura, T

1980-06-01

Effect of dopamine and its antagonists, domperidone and metoclopramide (MCP), on contractile activity of the lower esophageal sphincter (LES) and the stomach was studied in 5 healthy conscious dogs. Contractile activity was measured by means of chronically implanted force transducers. Contractile activity of the LES and the stomach was completely inhibited by an intravenous infusion of dopamine (10, 20 and 40 micrograms/kg-min) during the digestive and interdigestive state. Domperidone, when administered alone (0.5, 1.0 and 2.0 mg/kg), had no effect on contractile activity of the LES and the stomach during the both periods. Though deprived of any noticeable effect on the digestive contractions, MCP (0.25, 0.5 and 1.0 mg/kg) abolished the interdigestive contractions and produced characteristic contractions. Domperidone restored postprandial and interdigestive contractions to their initial stage before dopamine administration in a dose-related fashion. Dopamine-induced inhibition was antagonized by MCP during the digestive state, however, MCP had no effect on the interdigestive contractions that had been inhibited by dopamine. Since domperidone has no activity upon normal contractions of the gastrointestinal tract, it may be assumed that if domperidone alone has some influence upon gut motor activity or any improvement in clinical symptoms is seen after domperidone, a disorder of the dopaminergic system could be strongly suggested.

Identification of biochemical adaptations in hyper- or hypocontractile hearts from phospholamban mutant mice by expression proteomics.

PubMed

Pan, Yan; Kislinger, Thomas; Gramolini, Anthony O; Zvaritch, Elena; Kranias, Evangelia G; MacLennan, David H; Emili, Andrew

2004-02-24

Phospholamban (PLN) is a critical regulator of cardiac contractility through its binding to and regulation of the activity of the sarco(endo)plasmic reticulum Ca2+ ATPase. To uncover biochemical adaptations associated with extremes of cardiac muscle contractility, we used high-throughput gel-free tandem MS to monitor differences in the relative abundance of membrane proteins in standard microsomal fractions isolated from the hearts of PLN-null mice (PLN-KO) with high contractility and from transgenic mice overexpressing a superinhibitory PLN mutant in a PLN-null background (I40A-KO) with diminished contractility. Significant differential expression was detected for a subset of the 782 proteins identified, including known membrane-associated biomarkers, components of signaling pathways, and previously uninvestigated proteins. Proteins involved in fat and carbohydrate metabolism and proteins linked to G protein-signaling pathways activating protein kinase C were enriched in I40A-KO cardiac muscle, whereas proteins linked to enhanced contractile function were enriched in PLN-KO mutant hearts. These data demonstrate that Ca2+ dysregulation, leading to elevated or depressed cardiac contractility, induces compensatory biochemical responses.

Apelin Increases Cardiac Contractility via Protein Kinase Cε- and Extracellular Signal-Regulated Kinase-Dependent Mechanisms

PubMed Central

Perjés, Ábel; Skoumal, Réka; Tenhunen, Olli; Kónyi, Attila; Simon, Mihály; Horváth, Iván G.; Kerkelä, Risto; Ruskoaho, Heikki; Szokodi, István

2014-01-01

Background Apelin, the endogenous ligand for the G protein-coupled apelin receptor, is an important regulator of the cardiovascular homoeostasis. We previously demonstrated that apelin is one of the most potent endogenous stimulators of cardiac contractility; however, its underlying signaling mechanisms remain largely elusive. In this study we characterized the contribution of protein kinase C (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2) and myosin light chain kinase (MLCK) to the positive inotropic effect of apelin. Methods and Results In isolated perfused rat hearts, apelin increased contractility in association with activation of prosurvival kinases PKC and ERK1/2. Apelin induced a transient increase in the translocation of PKCε, but not PKCα, from the cytosol to the particulate fraction, and a sustained increase in the phosphorylation of ERK1/2 in the left ventricle. Suppression of ERK1/2 activation diminished the apelin-induced increase in contractility. Although pharmacological inhibition of PKC attenuated the inotropic response to apelin, it had no effect on ERK1/2 phosphorylation. Moreover, the apelin-induced positive inotropic effect was significantly decreased by inhibition of MLCK, a kinase that increases myofilament Ca2+ sensitivity. Conclusions Apelin increases cardiac contractility through parallel and independent activation of PKCε and ERK1/2 signaling in the adult rat heart. Additionally MLCK activation represents a downstream mechanism in apelin signaling. Our data suggest that, in addition to their role in cytoprotection, modest activation of PKCε and ERK1/2 signaling improve contractile function, therefore these pathways represent attractive possible targets in the treatment of heart failure. PMID:24695532

Gene transfer of heterologous G protein-coupled receptors to cardiomyocytes: differential effects on contractility.

PubMed

Laugwitz, K L; Weig, H J; Moretti, A; Hoffmann, E; Ueblacker, P; Pragst, I; Rosport, K; Schömig, A; Ungerer, M

2001-04-13

In heart failure, reduced cardiac contractility is accompanied by blunted cAMP responses to beta-adrenergic stimulation. Parathyroid hormone (PTH)-related peptide and arginine vasopressin are released from the myocardium in response to increased wall stress but do not stimulate contractility or adenylyl cyclase at physiological concentrations. To bypass the defective beta-adrenergic signaling cascade, recombinant P1 PTH/PTH-related peptide receptors (rPTH1-Rs) and V(2) vasopressin receptors (rV(2)-Rs), which are normally not expressed in the myocardium and which are both strongly coupled to adenylyl cyclase, and recombinant beta(2)-adrenergic receptors (rbeta(2)-ARs) were overexpressed in cardiomyocytes by viral gene transfer. The capacity of endogenous hormones to increase contractility via the heterologous, recombinant receptors was compared. Whereas V(2)-Rs are uniquely coupled to Gs, PTH1-Rs and beta(2)-ARs are also coupled to other G proteins. Gene transfer of rPTH1-Rs or rbeta(2)-ARs to adult cardiomyocytes resulted in maximally increased basal contractility, which could not be further stimulated by adding receptor agonists. Agonists at rPTH1-Rs induced increased cAMP formation and phospholipase C activity. In contrast, healthy or failing rV(2)-R-expressing cardiomyocytes showed unaltered basal contractility. Their contractility and cAMP formation increased only at agonist exposure, which did not activate phospholipase C. In summary, we found that gene transfer of PTH1-Rs to cardiomyocytes results in constitutive activity of the transgene, as does that of beta(2)-ARS: In the absence of receptor agonists, rPTH1-Rs and rbeta(2)-ARs increase basal contractility, coupling to 2 G proteins simultaneously. In contrast, rV(2)-Rs are uniquely coupled to Gs and are not constitutively active, retaining their property to be activated exclusively on agonist stimulation. Therefore, gene transfer of V(2)-Rs might be more suited to test the effects of cAMP-stimulating receptors in heart failure than that of PTH1-Rs or beta(2)-ARS:

An Examination of Undergraduates' Metacognitive Strategies in Pre-Class Asynchronous Activity in a Flipped Classroom

ERIC Educational Resources Information Center

Yilmaz, Rabia M.; Baydas, Ozlem

2017-01-01

The aim of the study is to examine undergraduate students' awareness of metacognition, the metacognitive strategies they use in their learning and their learning performance in pre-class asynchronous activity in a flipped classroom. The sample consisted of 47 undergraduate students. Eleven students were not included in this study since they did…

Activation of Akt rescues endoplasmic reticulum stress-impaired murine cardiac contractile function via glycogen synthase kinase-3β-mediated suppression of mitochondrial permeation pore opening.

PubMed

Zhang, Yingmei; Xia, Zhi; La Cour, Karissa H; Ren, Jun

2011-11-01

The present study was designed to examine the impact of chronic Akt activation on endoplasmic reticulum (ER) stress-induced cardiac mechanical anomalies, if any, and the underlying mechanism involved. Wild-type and transgenic mice with cardiac-specific overexpression of the active mutant of Akt (Myr-Akt) were subjected to the ER stress inducer tunicamycin (1 or 3 mg/kg). ER stress led to compromised echocardiographic (elevated left ventricular end-systolic diameter and reduced fractional shortening) and cardiomyocyte contractile function, intracellular Ca(2+) mishandling, and cell survival in wild-type mice associated with mitochondrial damage. In vitro ER stress induction in murine cardiomyocytes upregulated the ER stress proteins Gadd153, GRP78, and phospho-eIF2α, and promoted reactive oxygen species production, carbonyl formation, apoptosis, mitochondrial membrane potential loss, and mitochondrial permeation pore (mPTP) opening associated with overtly impaired cardiomyocyte contractile and intracellular Ca(2+) properties. Interestingly, these anomalies were mitigated by chronic Akt activation or the ER chaperon tauroursodeoxycholic acid (TUDCA). Treatment with tunicamycin also dephosphorylated Akt and its downstream signal glycogen synthase kinase 3β (GSK3β) (leading to activation of GSK3β), the effect of which was abrogated by Akt activation and TUDCA. The ER stress-induced cardiomyocyte contractile and mitochondrial anomalies were obliterated by the mPTP inhibitor cyclosporin A, GSK3β inhibitor SB216763, and ER stress inhibitor TUDCA. This research reported the direct relationship between ER stress and cardiomyocyte contractile and mitochondrial anomalies for the first time. Taken together, these data suggest that ER stress may compromise cardiac contractile and intracellular Ca(2+) properties, possibly through the Akt/GSK3β-dependent impairment of mitochondrial integrity.

RhoA GTPase inhibition organizes contraction during epithelial morphogenesis

PubMed Central

Mason, Frank M.; Xie, Shicong; Vasquez, Claudia G.; Tworoger, Michael

2016-01-01

During morphogenesis, contraction of the actomyosin cytoskeleton within individual cells drives cell shape changes that fold tissues. Coordination of cytoskeletal contractility is mediated by regulating RhoA GTPase activity. Guanine nucleotide exchange factors (GEFs) activate and GTPase-activating proteins (GAPs) inhibit RhoA activity. Most studies of tissue folding, including apical constriction, have focused on how RhoA is activated by GEFs to promote cell contractility, with little investigation as to how GAPs may be important. Here, we identify a critical role for a RhoA GAP, Cumberland GAP (C-GAP), which coordinates with a RhoA GEF, RhoGEF2, to organize spatiotemporal contractility during Drosophila melanogaster apical constriction. C-GAP spatially restricts RhoA pathway activity to a central position in the apical cortex. RhoGEF2 pulses precede myosin, and C-GAP is required for pulsation, suggesting that contractile pulses result from RhoA activity cycling. Finally, C-GAP expression level influences the transition from reversible to irreversible cell shape change, which defines the onset of tissue shape change. Our data demonstrate that RhoA activity cycling and modulating the ratio of RhoGEF2 to C-GAP are required for tissue folding. PMID:27551058

Tamsulosin modulates, but does not abolish the spontaneous activity in the guinea pig prostate gland.

PubMed

Chakrabarty, Basu; Dey, Anupa; Lam, Michelle; Ventura, Sabatino; Exintaris, Betty

2015-06-01

To examine the effects of the α1A -adrenoceptor antagonist, tamsulosin, on spontaneous contractile and electrical activity in the guinea-pig prostate gland. The effects of tamsulosin (0.1 and 0.3 nM) were investigated in adult and ageing male guinea pig prostate glands using conventional tension recording and electrophysiological intracellular microelectrode recording techniques. Tamsulosin reduced spontaneous activity, and had different age-dependent effects on adult and ageing guinea pigs at different concentrations. 0.1 nM tamsulosin caused a significantly greater reduction of spontaneous contractile and electrical activity in ageing guinea pigs in comparison to adult guinea pigs. In contrast, 0.3 nM tamsulosin had a significantly greater reduction of spontaneous contractile and electrical activity in adult guinea pigs in comparison to ageing guinea pigs. This study demonstrates that tamsulosin can modulate spontaneous myogenic stromal contractility and the underlying spontaneous electrical activity; tamsulosin does not block spontaneous activity. This reduction in spontaneous activity suggests that downstream cellular mechanisms underlying smooth muscle tone are being targeted, and these may represent novel therapeutic targets to better treat benign prostatic hyperplasia. © 2014 Wiley Periodicals, Inc.

An Apical MRCK-driven Morphogenetic Pathway Controls Epithelial Polarity

PubMed Central

Zihni, Ceniz; Vlassaks, Evi; Terry, Stephen; Carlton, Jeremy; Leung, Thomas King Chor; Olson, Michael; Pichaud, Franck; Balda, Maria Susana; Matter, Karl

2017-01-01

Polarized epithelia develop distinct cell surface domains, with the apical membrane acquiring characteristic morphological features such as microvilli. Cell polarization is driven by polarity determinants including the evolutionarily conserved partitioning defective (PAR) proteins that are separated into distinct cortical domains. PAR protein segregation is thought to be a consequence of asymmetric actomyosin contractions. The mechanism of activation of apically polarized actomyosin contractility is unknown. Here we show that the Cdc42 effector MRCK activates Myosin-II at the apical pole to segregate aPKC-Par6 from junctional Par3, defining the apical domain. Apically polarized MRCK-activated actomyosin contractility is reinforced by cooperation with aPKC-Par6 downregulating antagonistic RhoA-driven junctional actomyosin contractility, and drives polarization of cytosolic brush border determinants and apical morphogenesis. MRCK-activated polarized actomyosin contractility is required for apical differentiation and morphogenesis in vertebrate epithelia and Drosophila photoreceptors. Our results identify an apical origin of actomyosin-driven morphogenesis that couples cytoskeletal reorganization to PAR polarity signalling. PMID:28825699

Distributed Consensus of Stochastic Delayed Multi-agent Systems Under Asynchronous Switching.

PubMed

Wu, Xiaotai; Tang, Yang; Cao, Jinde; Zhang, Wenbing

2016-08-01

In this paper, the distributed exponential consensus of stochastic delayed multi-agent systems with nonlinear dynamics is investigated under asynchronous switching. The asynchronous switching considered here is to account for the time of identifying the active modes of multi-agent systems. After receipt of confirmation of mode's switching, the matched controller can be applied, which means that the switching time of the matched controller in each node usually lags behind that of system switching. In order to handle the coexistence of switched signals and stochastic disturbances, a comparison principle of stochastic switched delayed systems is first proved. By means of this extended comparison principle, several easy to verified conditions for the existence of an asynchronously switched distributed controller are derived such that stochastic delayed multi-agent systems with asynchronous switching and nonlinear dynamics can achieve global exponential consensus. Two examples are given to illustrate the effectiveness of the proposed method.

Long-term effects of extrinsic denervation on VIP and substance P innervation in circular muscle of rat jejunum.

PubMed

Kasparek, Michael S; Fatima, Javairiah; Iqbal, Corey W; Duenes, Judith A; Sarr, Michael G

2007-10-01

Intestinal denervation contributes to enteric motor dysfunction after small bowel transplantation (SBT). Our aim was to determine long-term effects of extrinsic denervation on function of nonadrenergic, noncholinergic innervation with substance P and vasoactive intestinal polypeptide (VIP). Contractile activity of jejunal circular muscle strips from six age-matched, naive control rats (NC) and eight rats 1 year after syngeneic SBT was studied in tissue chambers. Spontaneous contractile activity did not differ between groups. Exogenous VIP inhibited contractile activity dose-dependently to a comparable degree in both groups. The VIP antagonist ([D-p-Cl-Phe(6),Leu(17)]-VIP) and the nitric oxide synthase inhibitor L-NG-nitro-arginine did not affect VIP-induced inhibition but increased contractile activity during electrical field stimulation (EFS) in both groups. Exogenous substance P increased contractile activity dose-dependently, greater in NC than SBT. The substance P antagonist ([D-Pro(2),D-Trp(7,9)]-substance P) inhibited effects of exogenous substance P and decreased the excitatory EFS response. Immunohistofluorescence showed tyrosine hydroxylase staining after SBT indicating sympathetic reinnervation. In jejunal circular muscle after chronic denervation, response to exogenous substance P, but not VIP, is decreased, whereas endogenous release of both neurotransmitters is preserved. Alterations in balance of excitatory and inhibitory pathways occur despite extrinsic reinnervation and might contribute to enteric motor dysfunction after SBT.

Muscular tissues of the squid Doryteuthis pealeii express identical myosin heavy chain isoforms: an alternative mechanism for tuning contractile speed

PubMed Central

Shaffer, Justin F.; Kier, William M.

2012-01-01

SUMMARY The speed of muscle contraction is largely controlled at the sarcomere level by the ATPase activity of the motor protein myosin. Differences in amino acid sequence in catalytically important regions of myosin yield different myosin isoforms with varying ATPase activities and resulting differences in cross-bridge cycling rates and interfilamentary sliding velocities. Modulation of whole-muscle performance by changes in myosin isoform ATPase activity is regarded as a universal mechanism to tune contractile properties, especially in vertebrate muscles. Invertebrates such as squid, however, may exhibit an alternative mechanism to tune contractile properties that is based on differences in muscle ultrastructure, including variable myofilament and sarcomere lengths. To determine definitively whether contractile properties of squid muscles are regulated via different myosin isoforms (i.e. different ATPase activities), the nucleotide and amino acid sequences of the myosin heavy chain from the squid Doryteuthis pealeii were determined from the mantle, arm, tentacle, fin and funnel retractor musculature. We identified three myosin heavy chain isoforms in squid muscular tissues, with differences arising at surface loop 1 and the carboxy terminus. All three isoforms were detected in all five tissues studied. These results suggest that the muscular tissues of D. pealeii express identical myosin isoforms, and it is likely that differences in muscle ultrastructure, not myosin ATPase activity, represent the most important mechanism for tuning contractile speeds. PMID:22189767

Network evolution induced by asynchronous stimuli through spike-timing-dependent plasticity.

PubMed

Yuan, Wu-Jie; Zhou, Jian-Fang; Zhou, Changsong

2013-01-01

In sensory neural system, external asynchronous stimuli play an important role in perceptual learning, associative memory and map development. However, the organization of structure and dynamics of neural networks induced by external asynchronous stimuli are not well understood. Spike-timing-dependent plasticity (STDP) is a typical synaptic plasticity that has been extensively found in the sensory systems and that has received much theoretical attention. This synaptic plasticity is highly sensitive to correlations between pre- and postsynaptic firings. Thus, STDP is expected to play an important role in response to external asynchronous stimuli, which can induce segregative pre- and postsynaptic firings. In this paper, we study the impact of external asynchronous stimuli on the organization of structure and dynamics of neural networks through STDP. We construct a two-dimensional spatial neural network model with local connectivity and sparseness, and use external currents to stimulate alternately on different spatial layers. The adopted external currents imposed alternately on spatial layers can be here regarded as external asynchronous stimuli. Through extensive numerical simulations, we focus on the effects of stimulus number and inter-stimulus timing on synaptic connecting weights and the property of propagation dynamics in the resulting network structure. Interestingly, the resulting feedforward structure induced by stimulus-dependent asynchronous firings and its propagation dynamics reflect both the underlying property of STDP. The results imply a possible important role of STDP in generating feedforward structure and collective propagation activity required for experience-dependent map plasticity in developing in vivo sensory pathways and cortices. The relevance of the results to cue-triggered recall of learned temporal sequences, an important cognitive function, is briefly discussed as well. Furthermore, this finding suggests a potential application for examining STDP by measuring neural population activity in a cultured neural network.

TRPM4 Is a Novel Component of the Adhesome Required for Focal Adhesion Disassembly, Migration and Contractility

PubMed Central

Cáceres, Mónica; Ortiz, Liliana; Recabarren, Tatiana; Romero, Anibal; Colombo, Alicia; Leiva-Salcedo, Elías; Varela, Diego; Rivas, José; Silva, Ian; Morales, Diego; Campusano, Camilo; Almarza, Oscar; Simon, Felipe; Toledo, Hector; Park, Kang-Sik; Trimmer, James S.; Cerda, Oscar

2015-01-01

Cellular migration and contractility are fundamental processes that are regulated by a variety of concerted mechanisms such as cytoskeleton rearrangements, focal adhesion turnover, and Ca2+ oscillations. TRPM4 is a Ca2+-activated non-selective cationic channel (Ca2+-NSCC) that conducts monovalent but not divalent cations. Here, we used a mass spectrometry-based proteomics approach to identify putative TRPM4-associated proteins. Interestingly, the largest group of these proteins has actin cytoskeleton-related functions, and among these nine are specifically annotated as focal adhesion-related proteins. Consistent with these results, we found that TRPM4 localizes to focal adhesions in cells from different cellular lineages. We show that suppression of TRPM4 in MEFs impacts turnover of focal adhesions, serum-induced Ca2+ influx, focal adhesion kinase (FAK) and Rac activities, and results in reduced cellular spreading, migration and contractile behavior. Finally, we demonstrate that the inhibition of TRPM4 activity alters cellular contractility in vivo, affecting cutaneous wound healing. Together, these findings provide the first evidence, to our knowledge, for a TRP channel specifically localized to focal adhesions, where it performs a central role in modulating cellular migration and contractility. PMID:26110647

Functional, structural, and chemical changes in myosin associated with hydrogen peroxide treatment of skeletal muscle fibers.

PubMed

Prochniewicz, Ewa; Lowe, Dawn A; Spakowicz, Daniel J; Higgins, LeeAnn; O'Conor, Kate; Thompson, LaDora V; Ferrington, Deborah A; Thomas, David D

2008-02-01

To understand the molecular mechanism of oxidation-induced inhibition of muscle contractility, we have studied the effects of hydrogen peroxide on permeabilized rabbit psoas muscle fibers, focusing on changes in myosin purified from these fibers. Oxidation by 5 mM peroxide decreased fiber contractility (isometric force and shortening velocity) without significant changes in the enzymatic activity of myofibrils and isolated myosin. The inhibitory effects were reversed by treating fibers with dithiothreitol. Oxidation by 50 mM peroxide had a more pronounced and irreversible inhibitory effect on fiber contractility and also affected enzymatic activity of myofibrils, myosin, and actomyosin. Peroxide treatment also affected regulation of contractility, resulting in fiber activation in the absence of calcium. Electron paramagnetic resonance of spin-labeled myosin in muscle fibers showed that oxidation increased the fraction of myosin heads in the strong-binding structural state under relaxing conditions (low calcium) but had no effect under activating conditions (high calcium). This change in the distribution of structural states of myosin provides a plausible explanation for the observed changes in both contractile and regulatory functions. Mass spectroscopy analysis showed that 50 mM but not 5 mM peroxide induced oxidative modifications in both isoforms of the essential light chains and in the heavy chain of myosin subfragment 1 by targeting multiple methionine residues. We conclude that 1) inhibition of muscle fiber contractility via oxidation of myosin occurs at high but not low concentrations of peroxide and 2) the inhibitory effects of oxidation suggest a critical and previously unknown role of methionines in myosin function.

Thrombopoietin modulates cardiac contractility in vitro and contributes to myocardial depressing activity of septic shock serum.

PubMed

Lupia, Enrico; Spatola, Tiziana; Cuccurullo, Alessandra; Bosco, Ornella; Mariano, Filippo; Pucci, Angela; Ramella, Roberta; Alloatti, Giuseppe; Montrucchio, Giuseppe

2010-09-01

Thrombopoietin (TPO) is a humoral growth factor that has been shown to increase platelet activation in response to several agonists. Patients with sepsis have increased circulating TPO levels, which may enhance platelet activation, potentially participating to the pathogenesis of multi-organ failure. Aim of this study was to investigate whether TPO affects myocardial contractility and participates to depress cardiac function during sepsis. We showed the expression of the TPO receptor c-Mpl on myocardial cells and tissue by RT-PCR, immunofluorescence and western blotting. We then evaluated the effect of TPO on the contractile function of rat papillary muscle and isolated heart. TPO did not change myocardial contractility in basal conditions, but, when followed by epinephrine (EPI) stimulation, it blunted the enhancement of contractile force induced by EPI both in papillary muscle and isolated heart. An inhibitor of TPO prevented TPO effect on cardiac inotropy. Treatment of papillary muscle with pharmacological inhibitors of phosphatidylinositol 3-kinase, NO synthase, and guanilyl cyclase abolished TPO effect, indicating NO as the final mediator. We finally studied the role of TPO in the negative inotropic effect exerted by human septic shock (HSS) serum and TPO cooperation with TNF-alpha and IL-1beta. Pre-treatment with the TPO inhibitor prevented the decrease in contractile force induced by HSS serum. Moreover, TPO significantly amplified the negative inotropic effect induced by TNF-alpha and IL-1beta in papillary muscle. In conclusion, TPO negatively modulates cardiac inotropy in vitro and contributes to the myocardial depressing activity of septic shock serum.

Omecamtiv mercabil and blebbistatin modulate cardiac contractility by perturbing the regulatory state of the myosin filament.

PubMed

Kampourakis, Thomas; Zhang, Xuemeng; Sun, Yin-Biao; Irving, Malcolm

2018-01-01

Omecamtiv mecarbil and blebbistatin perturb the regulatory state of the thick filament in heart muscle. Omecamtiv mecarbil increases contractility at low levels of activation by stabilizing the ON state of the thick filament. Omecamtiv mecarbil decreases contractility at high levels of activation by disrupting the acto-myosin ATPase cycle. Blebbistatin reduces contractility by stabilizing the thick filament OFF state and inhibiting acto-myosin ATPase. Thick filament regulation is a promising target for novel therapeutics in heart disease. Contraction of heart muscle is triggered by a transient rise in intracellular free calcium concentration linked to a change in the structure of the actin-containing thin filaments that allows the head or motor domains of myosin from the thick filaments to bind to them and induce filament sliding. It is becoming increasingly clear that cardiac contractility is also regulated through structural changes in the thick filaments, although the molecular mechanisms underlying thick filament regulation are still relatively poorly understood. Here we investigated those mechanisms using small molecules - omecamtiv mecarbil (OM) and blebbistatin (BS) - that bind specifically to myosin and respectively activate or inhibit contractility in demembranated cardiac muscle cells. We measured isometric force and ATP utilization at different calcium and small-molecule concentrations in parallel with in situ structural changes determined using fluorescent probes on the myosin regulatory light chain in the thick filaments and on troponin C in the thin filaments. The results show that BS inhibits contractility and actin-myosin ATPase by stabilizing the OFF state of the thick filament in which myosin head domains are more parallel to the filament axis. In contrast, OM stabilizes the ON state of the thick filament, but inhibits contractility at high intracellular calcium concentration by disrupting the actin-myosin ATPase pathway. The effects of BS and OM on the calcium sensitivity of isometric force and filament structural changes suggest that the co-operativity of calcium activation in physiological conditions is due to positive coupling between the regulatory states of the thin and thick filaments. © 2017 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Omecamtiv mercabil and blebbistatin modulate cardiac contractility by perturbing the regulatory state of the myosin filament

PubMed Central

Kampourakis, Thomas; Zhang, Xuemeng; Sun, Yin‐Biao

2017-01-01

Key points Omecamtiv mecarbil and blebbistatin perturb the regulatory state of the thick filament in heart muscle.Omecamtiv mecarbil increases contractility at low levels of activation by stabilizing the ON state of the thick filament.Omecamtiv mecarbil decreases contractility at high levels of activation by disrupting the acto‐myosin ATPase cycle.Blebbistatin reduces contractility by stabilizing the thick filament OFF state and inhibiting acto‐myosin ATPase.Thick filament regulation is a promising target for novel therapeutics in heart disease. Abstract Contraction of heart muscle is triggered by a transient rise in intracellular free calcium concentration linked to a change in the structure of the actin‐containing thin filaments that allows the head or motor domains of myosin from the thick filaments to bind to them and induce filament sliding. It is becoming increasingly clear that cardiac contractility is also regulated through structural changes in the thick filaments, although the molecular mechanisms underlying thick filament regulation are still relatively poorly understood. Here we investigated those mechanisms using small molecules – omecamtiv mecarbil (OM) and blebbistatin (BS) – that bind specifically to myosin and respectively activate or inhibit contractility in demembranated cardiac muscle cells. We measured isometric force and ATP utilization at different calcium and small‐molecule concentrations in parallel with in situ structural changes determined using fluorescent probes on the myosin regulatory light chain in the thick filaments and on troponin C in the thin filaments. The results show that BS inhibits contractility and actin‐myosin ATPase by stabilizing the OFF state of the thick filament in which myosin head domains are more parallel to the filament axis. In contrast, OM stabilizes the ON state of the thick filament, but inhibits contractility at high intracellular calcium concentration by disrupting the actin‐myosin ATPase pathway. The effects of BS and OM on the calcium sensitivity of isometric force and filament structural changes suggest that the co‐operativity of calcium activation in physiological conditions is due to positive coupling between the regulatory states of the thin and thick filaments. PMID:29052230

Upregulation of contractile endothelin type B receptors by lipid-soluble cigarette smoking particles in rat cerebral arteries via activation of MAPK

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sandhu, Hardip, E-mail: sandhu.hardip@gmail.co; Xu, Cang Bao; Edvinsson, Lars

2010-11-15

Cigarette smoke exposure increases the risk of stroke. However, the underlying molecular mechanisms are poorly understood. Endothelin system plays key roles in the pathogenesis of stroke. The present study was designed to examine if lipid-soluble (dimethyl sulfoxide-soluble) cigarette smoke particles (DSP) induces upregulation of contractile endothelin type B (ET{sub B}) receptors in rat cerebral arteries and if activation of mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-{kappa}B) mediate the upregulation of contractile endothelin receptors in the cerebral arteries. Rat middle cerebral arteries were isolated and organ cultured in serum free medium for 24 h in the presence of DSPmore » with or without specific inhibitors: MEK specific (U0126), p38 specific (SB202190), JNK specific (SP600125), NF-{kappa}B specific (BMS-345541) or (IMD-0354), transcription inhibitor (actinomycin D), or translation blocker (cycloheximide). Contractile responses to the ET{sub B} receptor agonist sarafotoxin 6c were investigated by a sensitive myograph. The expression of the ET{sub B} receptors were studied at mRNA and protein levels using quantitative real time PCR and immunohistochemistry, respectively. Results show that organ culture per se induced transcriptional upregulation of contractile ET{sub B} receptors in the cerebral vascular smooth muscle cells. This upregulation was further increased at the translational level by addition of DSP to the organ culture, but this increase was not seen by addition of nicotine or water-soluble cigarette smoke particles to the organ culture. The increased upregulation of contractile ET{sub B} receptors by DSP was abrogated by U0126, SP600125, actinomycin D, and cycloheximide, suggesting that the underlying molecular mechanisms involved in this process include activation of MEK and JNK MAPK-mediated transcription and translation of new contractile ET{sub B} receptors. Thus, the MAPK-mediated upregulation of contractile ET{sub B} receptors in cerebral arteries might be a pharmacological target for the treatment of smoke-associated cerebral vascular disease like stroke.« less

Mechanically Induced Chromatin Condensation Requires Cellular Contractility in Mesenchymal Stem Cells.

PubMed

Heo, Su-Jin; Han, Woojin M; Szczesny, Spencer E; Cosgrove, Brian D; Elliott, Dawn M; Lee, David A; Duncan, Randall L; Mauck, Robert L

2016-08-23

Mechanical cues play important roles in directing the lineage commitment of mesenchymal stem cells (MSCs). In this study, we explored the molecular mechanisms by which dynamic tensile loading (DL) regulates chromatin organization in this cell type. Our previous findings indicated that the application of DL elicited a rapid increase in chromatin condensation through purinergic signaling mediated by ATP. Here, we show that the rate and degree of condensation depends on the frequency and duration of mechanical loading, and that ATP release requires actomyosin-based cellular contractility. Increases in baseline cellular contractility via the addition of an activator of G-protein coupled receptors (lysophosphatidic acid) induced rapid ATP release, resulting in chromatin condensation independent of loading. Conversely, inhibition of contractility through pretreatment with either a RhoA/Rock inhibitor (Y27632) or MLCK inhibitor (ML7) abrogated ATP release in response to DL, blocking load-induced chromatin condensation. With loading, ATP release occurred very rapidly (within the first 10-20 s), whereas changes in chromatin occurred at a later time point (∼10 min), suggesting a downstream biochemical pathway mediating this process. When cells were pretreated with blockers of the transforming growth factor (TGF) superfamily, purinergic signaling in response to DL was also eliminated. Further analysis showed that this pretreatment decreased contractility, implicating activity in the TGF pathway in the establishment of the baseline contractile state of MSCs (in the absence of exogenous ligands). These data indicate that chromatin condensation in response to DL is regulated through the interplay between purinergic and RhoA/Rock signaling, and that ligandless activity in the TGF/bone morphogenetic proteins signaling pathway contributes to the establishment of baseline contractility in MSCs. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The Effects of Ibogaine on Uterine Smooth Muscle Contractions: Relation to the Activity of Antioxidant Enzymes.

PubMed

Oreščanin-Dušić, Zorana; Tatalović, Nikola; Vidonja-Uzelac, Teodora; Nestorov, Jelena; Nikolić-Kokić, Aleksandra; Mijušković, Ana; Spasić, Mihajlo; Paškulin, Roman; Bresjanac, Mara; Blagojević, Duško

2018-01-01

Ibogaine is an indole alkaloid originally extracted from the root bark of the African rainforest shrub Tabernanthe iboga . It has been explored as a treatment for substance abuse because it interrupts drug addiction and relieves withdrawal symptoms. However, it has been shown that ibogaine treatment leads to a sharp and transient fall in cellular ATP level followed by an increase of cellular respiration and ROS production. Since contractile tissues are sensitive to changes in the levels of ATP and ROS, here we investigated an ibogaine-mediated link between altered redox homeostasis and uterine contractile activity. We found that low concentrations of ibogaine stimulated contractile activity in spontaneously active uteri, but incremental increase of doses inhibited it. Inhibitory concentrations of ibogaine led to decreased SOD1 and elevated GSH-Px activity, but doses that completely inhibited contractions increased CAT activity. Western blot analyses showed that changes in enzyme activities were not due to elevated enzyme protein concentrations but posttranslational modifications. Changes in antioxidant enzyme activities point to a vast concentration-dependent increase in H 2 O 2 level. Knowing that extracellular ATP stimulates isolated uterus contractility, while H 2 O 2 has an inhibitory effect, this concentration-dependent stimulation/inhibition could be linked to ibogaine-related alterations in ATP level and redox homeostasis.

The Effects of Ibogaine on Uterine Smooth Muscle Contractions: Relation to the Activity of Antioxidant Enzymes

PubMed Central

Paškulin, Roman

2018-01-01

Ibogaine is an indole alkaloid originally extracted from the root bark of the African rainforest shrub Tabernanthe iboga. It has been explored as a treatment for substance abuse because it interrupts drug addiction and relieves withdrawal symptoms. However, it has been shown that ibogaine treatment leads to a sharp and transient fall in cellular ATP level followed by an increase of cellular respiration and ROS production. Since contractile tissues are sensitive to changes in the levels of ATP and ROS, here we investigated an ibogaine-mediated link between altered redox homeostasis and uterine contractile activity. We found that low concentrations of ibogaine stimulated contractile activity in spontaneously active uteri, but incremental increase of doses inhibited it. Inhibitory concentrations of ibogaine led to decreased SOD1 and elevated GSH-Px activity, but doses that completely inhibited contractions increased CAT activity. Western blot analyses showed that changes in enzyme activities were not due to elevated enzyme protein concentrations but posttranslational modifications. Changes in antioxidant enzyme activities point to a vast concentration-dependent increase in H2O2 level. Knowing that extracellular ATP stimulates isolated uterus contractility, while H2O2 has an inhibitory effect, this concentration-dependent stimulation/inhibition could be linked to ibogaine-related alterations in ATP level and redox homeostasis. PMID:29599898

Store-Operated Ca2+ Entry (SOCE) Contributes to Normal Skeletal Muscle Contractility in young but not in aged skeletal muscle

PubMed Central

Brotto, Leticia S.; Bougoin, Sylvain; Nosek, Thomas M.; Reid, Michael; Hardin, Brian; Pan, Zui; Ma, Jianjie; Parness, Jerome

2011-01-01

Muscle atrophy alone is insufficient to explain the significant decline in contractile force of skeletal muscle during normal aging. One contributing factor to decreased contractile force in aging skeletal muscle could be compromised excitation-contraction (E-C) coupling, without sufficient available Ca2+ to allow for repetitive muscle contractility, skeletal muscles naturally become weaker. Using biophysical approaches, we previously showed that store-operated Ca2+ entry (SOCE) is compromised in aged skeletal muscle but not in young ones. While important, a missing component from previous studies is whether or not SOCE function correlates with contractile function during aging. Here we test the contribution of extracellular Ca2+ to contractile function of skeletal muscle during aging. First, we demonstrate graded coupling between SR Ca2+ release channel-mediated Ca2+ release and activation of SOCE. Inhibition of SOCE produced significant reduction of contractile force in young skeletal muscle, particularly at high frequency stimulation, and such effects were completely absent in aged skeletal muscle. Our data indicate that SOCE contributes to the normal physiological contractile response of young healthy skeletal muscle and that defective extracellular Ca2+ entry through SOCE contributes to the reduced contractile force characteristic of aged skeletal muscle. PMID:21666285

Store-operated Ca(2+) entry (SOCE) contributes to normal skeletal muscle contractility in young but not in aged skeletal muscle.

PubMed

Thornton, Angela M; Zhao, Xiaoli; Weisleder, Noah; Brotto, Leticia S; Bougoin, Sylvain; Nosek, Thomas M; Reid, Michael; Hardin, Brian; Pan, Zui; Ma, Jianjie; Parness, Jerome; Brotto, Marco

2011-06-01

Muscle atrophy alone is insufficient to explain the significant decline in contractile force of skeletal muscle during normal aging. One contributing factor to decreased contractile force in aging skeletal muscle could be compromised excitation-contraction (E-C) coupling, without sufficient available Ca(2+) to allow for repetitive muscle contractility, skeletal muscles naturally become weaker. Using biophysical approaches, we previously showed that store-operated Ca(2+) entry (SOCE) is compromised in aged skeletal muscle but not in young ones. While important, a missing component from previous studies is whether or not SOCE function correlates with contractile function during aging. Here we test the contribution of extracellular Ca(2+) to contractile function of skeletal muscle during aging. First, we demonstrate graded coupling between SR Ca(2+) release channel-mediated Ca(2+) release and activation of SOCE. Inhibition of SOCE produced significant reduction of contractile force in young skeletal muscle, particularly at high frequency stimulation, and such effects were completely absent in aged skeletal muscle. Our data indicate that SOCE contributes to the normal physiological contractile response of young healthy skeletal muscle and that defective extracellular Ca(2+) entry through SOCE contributes to the reduced contractile force characteristic of aged skeletal muscle.

Novel approaches to determine contractile function of the isolated adult zebrafish ventricular cardiac myocyte.

PubMed

Dvornikov, Alexey V; Dewan, Sukriti; Alekhina, Olga V; Pickett, F Bryan; de Tombe, Pieter P

2014-05-01

The zebrafish (Danio rerio) has been used extensively in cardiovascular biology, but mainly in the study of heart development. The relative ease of its genetic manipulation may indicate the suitability of this species as a cost-effective model system for the study of cardiac contractile biology. However, whether the zebrafish heart is an appropriate model system for investigations pertaining to mammalian cardiac contractile structure-function relationships remains to be resolved. Myocytes were isolated from adult zebrafish hearts by enzymatic digestion, attached to carbon rods, and twitch force and intracellular Ca(2+) were measured. We observed the modulation of twitch force, but not of intracellular Ca(2+), by both extracellular [Ca(2+)] and sarcomere length. In permeabilized cells/myofibrils, we found robust myofilament length-dependent activation. Moreover, modulation of myofilament activation-relaxation and force redevelopment kinetics by varied Ca(2+) activation levels resembled that found previously in mammalian myofilaments. We conclude that the zebrafish is a valid model system for the study of cardiac contractile structure-function relationships.

[Effect of acetylcholine and acetylcholinesterase on the activity of contractile vacuole of Amoeba proteus].

PubMed

Bagrov, Ia Iu; Manusova, N B

2011-01-01

Acetylcholine (ACh, 1 microM) stimulates activity of the contractile vacuole of proteus. The effect of ACh is not mimicked by its analogs which are not hydrolyzed by acetylcholinesterase (AChE), i. e., carbacholine and 5-methylfurmethide. The effect of ACh is not sensitive to the blocking action of M-cholinolytics, atropine and mytolone, but is suppressed by N-cholinolytic, tubocurarine. The inhibitors of AChE, eserine (0.01 microM) and armine (0.1 microM), suppress the effect of ACh on amoeba contractile vacuole. ACh does not affect activation of contractile vacuole induced by arginine-vasopressin (1 microM), but it blocks such effect of opiate receptors agonist, dynorphin A1-13 (0.01 microM). This effect of ACh is also suppressed by the inhibitors of AChE. These results suggest that, in the above-described effects of ACh, AChE acts not as an antagonist, but rather as a synergist.

Positioning (Mis)Aligned: The (Un)Making of Intercultural Asynchronous Computer-Mediated Communication

ERIC Educational Resources Information Center

Wu, Zhiwei

2018-01-01

Framed from positioning theory and dynamic systems theory, the paper reports on a naturalistic study involving four Chinese participants and their American peers in an intercultural asynchronous computer-mediated communication (ACMC) activity. Based on the moment-by-moment analysis and triangulation of forum posts, reflective essays, and…

A Group Intelligence-Based Asynchronous Argumentation Learning-Assistance Platform

ERIC Educational Resources Information Center

Huang, Chenn-Jung; Chang, Shun-Chih; Chen, Heng-Ming; Tseng, Jhe-Hao; Chien, Sheng-Yuan

2016-01-01

Structured argumentation support environments have been built and used in scientific discourse in the literature. However, to the best our knowledge, there is no research work in the literature examining whether student's knowledge has grown during learning activities with asynchronous argumentation. In this work, an intelligent computer-supported…

Adding the Human Touch to Asynchronous Online Learning

ERIC Educational Resources Information Center

Glenn, Cynthia Wheatley

2018-01-01

For learners to actively accept responsibility in a virtual classroom platform, it is necessary to provide special motivation extending across the traditional classroom setting into asynchronous online learning. This article explores specific ways to do this that bridge the gap between ground and online students' learning experiences, and how…

Endocrine regulation of airway contractility is overlooked.

PubMed

Bossé, Ynuk

2014-08-01

Asthma is a prevalent respiratory disorder triggered by a variety of inhaled environmental factors, such as allergens, viruses, and pollutants. Asthma is characterized by an elevated activation of the smooth muscle surrounding the airways, as well as a propensity of the airways to narrow excessively in response to a spasmogen (i.e. contractile agonist), a feature called airway hyperresponsiveness. The level of airway smooth muscle (ASM) activation is putatively controlled by mediators released in its vicinity. In asthma, many mediators that affect ASM contractility originate from inflammatory cells that are mobilized into the airways, such as eosinophils. However, mounting evidence indicates that mediators released by remote organs can also influence the level of activation of ASM, as well as its level of responsiveness to spasmogens and relaxant agonists. These remote mediators are transported through circulating blood to act either directly on ASM or indirectly via the nervous system by tuning the level of cholinergic activation of ASM. Indeed, mediators generated from diverse organs, including the adrenals, pancreas, adipose tissue, gonads, heart, intestines, and stomach, affect the contractility of ASM. Together, these results suggest that, apart from a paracrine mode of regulation, ASM is subjected to an endocrine mode of regulation. The results also imply that defects in organs other than the lungs can contribute to asthma symptoms and severity. In this review, I suggest that the endocrine mode of regulation of ASM contractility is overlooked. © 2014 Society for Endocrinology.

Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity

PubMed Central

Eisner, Verónica; Gao, Erhe; Csordás, György; Slovinsky, William S.; Paillard, Melanie; Cheng, Lan; Ibetti, Jessica; Chen, S. R. Wayne; Chuprun, J. Kurt; Hoek, Jan B.; Koch, Walter J.; Hajnóczky, György

2017-01-01

Mitochondrial fusion is thought to be important for supporting cardiac contractility, but is hardly detectable in cultured cardiomyocytes and is difficult to directly evaluate in the heart. We overcame this obstacle through in vivo adenoviral transduction with matrix-targeted photoactivatable GFP and confocal microscopy. Imaging in whole rat hearts indicated mitochondrial network formation and fusion activity in ventricular cardiomyocytes. Promptly after isolation, cardiomyocytes showed extensive mitochondrial connectivity and fusion, which decayed in culture (at 24–48 h). Fusion manifested both as rapid content mixing events between adjacent organelles and slower events between both neighboring and distant mitochondria. Loss of fusion in culture likely results from the decline in calcium oscillations/contractile activity and mitofusin 1 (Mfn1), because (i) verapamil suppressed both contraction and mitochondrial fusion, (ii) after spontaneous contraction or short-term field stimulation fusion activity increased in cardiomyocytes, and (iii) ryanodine receptor-2–mediated calcium oscillations increased fusion activity in HEK293 cells and complementing changes occurred in Mfn1. Weakened cardiac contractility in vivo in alcoholic animals is also associated with depressed mitochondrial fusion. Thus, attenuated mitochondrial fusion might contribute to the pathogenesis of cardiomyopathy. PMID:28096338

Low concentrations of niflumic acid enhance basal spontaneous and carbachol-induced contractions of the detrusor.

PubMed

Lam, Wai Ping; Tang, Hong Chai; Zhang, Xin; Leung, Ping Chung; Yew, David Tai Wai; Liang, Willmann

2014-02-01

The urinary bladder expresses Ca(2+)-activated Cl(-) channels (CACC), but its physiological role in governing contractility remains to be defined. The CACC modulator niflumic acid (NFA) is widely used despite the variable results arisen from different drug concentrations used. This study was designed to examine the effects of NFA at low concentrations on detrusor strip contractility. Rat detrusor strips with mucosa-intact (+MU) and mucosa-denuded (-MU) were prepared in transverse (Tr) and longitudinal (Lg) with respect to the bladder orientation. Isometric force measurements were made at baseline (for spontaneous phasic contractile activity) and during drug stimulation (by carbachol, CCh) with and without NFA. NFA (1 and 10 μmol/L) pretreatment enhanced CCh-induced contractions more in +MU than -MU strips with no selectivity on contractile direction. For spontaneous phasic contractions, NFA-treated strips in the Tr direction showed increased phasic amplitude, while phasic frequency was unchanged. The findings suggest low concentrations of NFA having a potentiating effect on detrusor contractions that was sensitive to the MU and contractile direction.

Increasing O-GlcNAcylation level on organ culture of soleus modulates the calcium activation parameters of muscle fibers.

PubMed

Cieniewski-Bernard, Caroline; Montel, Valerie; Berthoin, Serge; Bastide, Bruno

2012-01-01

O-N-acetylglucosaminylation is a reversible post-translational modification which presents a dynamic and highly regulated interplay with phosphorylation. New insights suggest that O-GlcNAcylation might be involved in striated muscle physiology, in particular in contractile properties such as the calcium activation parameters. By the inhibition of O-GlcNAcase, we investigated the effect of the increase of soleus O-GlcNAcylation level on the contractile properties by establishing T/pCa relationships. We increased the O-GlcNAcylation level on soleus biopsies performing an organ culture of soleus treated or not with PUGNAc or Thiamet-G, two O-GlcNAcase inhibitors. The enhancement of O-GlcNAcylation pattern was associated with an increase of calcium affinity on slow soleus skinned fibers. Analysis of the glycoproteins pattern showed that this effect is solely due to O-GlcNAcylation of proteins extracted from skinned biopsies. We also characterized the O-GlcNAcylated contractile proteins using a proteomic approach, and identified among others troponin T and I as being O-GlcNAc modified. We quantified the variation of O-GlcNAc level on all these identified proteins, and showed that several regulatory contractile proteins, predominantly fast isoforms, presented a drastic increase in their O-GlcNAc level. Since the only slow isoform of contractile protein presenting an increase of O-GlcNAc level was MLC2, the effect of enhanced O-GlcNAcylation pattern on calcium activation parameters could involve the O-GlcNAcylation of sMLC2, without excluding that an unidentified O-GlcNAc proteins, such as TnC, could be potentially involved in this mechanism. All these data strongly linked O-GlcNAcylation to the modulation of contractile activity of skeletal muscle.

AMP-Activated Protein Kinase Deficiency Rescues Paraquat-Induced Cardiac Contractile Dysfunction Through an Autophagy-Dependent Mechanism

PubMed Central

Wang, Qiurong; Yang, Lifang; Hua, Yinan; Nair, Sreejayan; Xu, Xihui; Ren, Jun

2014-01-01

Aim: Paraquat, a quaternary nitrogen herbicide, is a highly toxic prooxidant resulting in multi-organ failure including the heart although the underlying mechanism still remains elusive. This study was designed to examine the role of the cellular fuel sensor AMP-activated protein kinase (AMPK) in paraquat-induced cardiac contractile and mitochondrial injury. Results: Wild-type and transgenic mice with overexpression of a mutant AMPK α2 subunit (kinase dead, KD), with reduced activity in both α1 and α2 subunits, were administered with paraquat (45 mg/kg) for 48 h. Paraquat elicited cardiac mechanical anomalies including compromised echocardiographic parameters (elevated left ventricular end-systolic diameter and reduced factional shortening), suppressed cardiomyocyte contractile function, intracellular Ca2+ handling, reduced cell survival, and overt mitochondrial damage (loss in mitochondrial membrane potential). In addition, paraquat treatment promoted phosphorylation of AMPK and autophagy. Interestingly, deficiency in AMPK attenuated paraquat-induced cardiac contractile and intracellular Ca2+ derangement. The beneficial effect of AMPK inhibition was associated with inhibition of the AMPK-TSC-mTOR-ULK1 signaling cascade. In vitro study revealed that inhibitors for AMPK and autophagy attenuated paraquat-induced cardiomyocyte contractile dysfunction. Conclusion: Taken together, our findings revealed that AMPK may mediate paraquat-induced myocardial anomalies possibly by regulating the AMPK/mTOR-dependent autophagy. PMID:25092649

The comparative morphology of the muscle tissues and changes in constituents in the pig types.

PubMed

Fehér, G; Fazekas, S; Sándor, I; Kollár, N

1990-09-01

The authors have revealed the main value characteristics of pork production by testing in five different types of pig the volume of contractile and collagen proteins, that of proteoglycans, the constituents of blood and the enzymes of the blood plasma. The contractile proteins of the muscle tissues basically determine the quality of pork. The same applies to the water retention capacity, colloidal characteristics and glycogen content of meat. The amount of contractile proteins has decreased in the best meat producing types of pig. Parallel with the decrease of white meat, and with the increase in the volume of ham, chop and chuck the contractile protein content of muscles decreased. The scientific fact according to which there is a certain correlation among the changes in the volume of contractile proteins, blood sugar level, blood serum CPK and the intensity of activity of the LDH enzymes promotes the qualifying of live animals and the work of the geneticists aiming at the increasing of the contractile protein content of the muscle tissues of pigs by selection. According to tests carried out by us the primary cause of PSE changes is a decreased volume of contractile proteins. Increased stress sensitivity and all the other factors have but a secondary importance and are all consequential. The decrease in the quantity of contractile proteins or--it is better to put it this way--the lack of the proper amount of such proteins characterizing a fully developed pig's organism is caused by the nowadays usual breeding technologies and can be well explained by those selection activities which aim at a one-sided kind of pork production.

Extracellular UDP enhances P2X-mediated bladder smooth muscle contractility via P2Y6 activation of the phospholipase C/inositol trisphosphate pathway

PubMed Central

Yu, Weiqun; Sun, Xiaofeng; Robson, Simon C.; Hill, Warren G.

2013-01-01

Bladder dysfunction characterized by abnormal bladder smooth muscle (BSM) contractions is pivotal to the disease process in overactive bladder, urge incontinence, and spinal cord injury. Purinergic signaling comprises one key pathway in modulating BSM contractility, but molecular mechanisms remain unclear. Here we demonstrate, using myography, that activation of P2Y6 by either UDP or a specific agonist (MRS 2693) induced a sustained increase in BSM tone (up to 2 mN) in a concentration-dependent manner. Notably, activation of P2Y6 enhanced ATP-mediated BSM contractile force by up to 45%, indicating synergistic interactions between P2X and P2Y signaling. P2Y6-activated responses were abolished by phospholipase C (PLC) and inositol trisphosphate (IP3) receptor antagonists U73122 and xestospongin C, demonstrating involvement of the PLC/IP3 signal pathway. Mice null for Entpd1, an ectonucleotidase on BSM, demonstrated increased force generation on P2Y6 activation (150%). Thus, in vivo perturbations to purinergic signaling resulted in altered P2Y6 activity and bladder contractility. We conclude that UDP, acting on P2Y6, regulates BSM tone and in doing so selectively maximizes P2X1-mediated contraction forces. This novel neurotransmitter pathway may play an important role in urinary voiding disorders characterized by abnormal bladder motility.—Yu, W., Sun, X., Robson, S. C., Hill, W. G. Extracellular UDP enhances P2X-mediated bladder smooth muscle contractility via P2Y6 activation of the phospholipase C/inositol trisphosphate pathway. PMID:23362118

Asynchronous Online Peer Assistance: Telephone Messages of Encouragement in Post Licensure Nursing Programs

ERIC Educational Resources Information Center

Melrose, Sherri; Swettenham, Steve

2012-01-01

Peer assistance activities can strengthen online learning environments. And yet, like other professional adult learners, working post licensure nurses attending university part time to upgrade their credentials may have limited interest in student-to-student interaction. Some intentionally choose asynchronous self-paced courses so they can work on…

PTP1B triggers integrin-mediated repression of myosin activity and modulates cell contractility

PubMed Central

González Wusener, Ana E.; González, Ángela; Nakamura, Fumihiko; Arregui, Carlos O.

2016-01-01

ABSTRACT Cell contractility and migration by integrins depends on precise regulation of protein tyrosine kinase and Rho-family GTPase activities in specific spatiotemporal patterns. Here we show that protein tyrosine phosphatase PTP1B cooperates with β3 integrin to activate the Src/FAK signalling pathway which represses RhoA-myosin-dependent contractility. Using PTP1B null (KO) cells and PTP1B reconstituted (WT) cells, we determined that some early steps following cell adhesion to fibronectin and vitronectin occurred robustly in WT cells, including aggregation of β3 integrins and adaptor proteins, and activation of Src/FAK-dependent signalling at small puncta in a lamellipodium. However, these events were significantly impaired in KO cells. We established that cytoskeletal strain and cell contractility was highly enhanced at the periphery of KO cells compared to WT cells. Inhibition of the Src/FAK signalling pathway or expression of constitutive active RhoA in WT cells induced a KO cell phenotype. Conversely, expression of constitutive active Src or myosin inhibition in KO cells restored the WT phenotype. We propose that this novel function of PTP1B stimulates permissive conditions for adhesion and lamellipodium assembly at the protruding edge during cell spreading and migration. PMID:26700725

Catecholamines and myocardial contractile function during hypodynamia and with an altered thyroid hormone balance

NASA Technical Reports Server (NTRS)

Pruss, G. M.; Kuznetsov, V. I.; Zhilinskaya, A. A.

1980-01-01

The dynamics of catecholamine content and myocardial contractile function during hypodynamia were studied in 109 white rats whose motor activity was severely restricted for up to 30 days. During the first five days myocardial catecholamine content, contractile function, and physical load tolerance decreased. Small doses of thyroidin counteracted this tendency. After 15 days, noradrenalin content and other indices approached normal levels and, after 30 days, were the same as control levels, although cardiac functional reserve was decreased. Thyroidin administration after 15 days had no noticeable effect. A detailed table shows changes in 17 indices of myocardial contractile function during hypodynamia.

PKA catalytic subunit compartmentation regulates contractile and hypertrophic responses to β-adrenergic signaling

PubMed Central

Yang, Jason H.; Polanowska-Grabowska, Renata K.; Smith, Jeffrey S.; Shields, Charles W.; Saucerman, Jeffrey J.

2014-01-01

β-adrenergic signaling is spatiotemporally heterogeneous in the cardiac myocyte, conferring exquisite control to sympathetic stimulation. Such heterogeneity drives the formation of protein kinase A (PKA) signaling microdomains, which regulate Ca2+ handling and contractility. Here, we test the hypothesis that the nucleus independently comprises a PKA signaling microdomain regulating myocyte hypertrophy. Spatially-targeted FRET reporters for PKA activity identified slower PKA activation and lower isoproterenol sensitivity in the nucleus (t50 = 10.60±0.68 min; EC50 = 89.00 nmol/L) than in the cytosol (t50 = 3.71±0.25 min; EC50 = 1.22 nmol/L). These differences were not explained by cAMP or AKAP-based compartmentation. A computational model of cytosolic and nuclear PKA activity was developed and predicted that differences in nuclear PKA dynamics and magnitude are regulated by slow PKA catalytic subunit diffusion, while differences in isoproterenol sensitivity are regulated by nuclear expression of protein kinase inhibitor (PKI). These were validated by FRET and immunofluorescence. The model also predicted differential phosphorylation of PKA substrates regulating cell contractility and hypertrophy. Ca2+ and cell hypertrophy measurements validated these predictions and identified higher isoproterenol sensitivity for contractile enhancements (EC50 = 1.84 nmol/L) over cell hypertrophy (EC50 = 85.88 nmol/L). Over-expression of spatially targeted PKA catalytic subunit to the cytosol or nucleus enhanced contractile and hypertrophic responses, respectively. We conclude that restricted PKA catalytic subunit diffusion is an important PKA compartmentation mechanism and the nucleus comprises a novel PKA signaling microdomain, insulating hypertrophic from contractile β-adrenergic signaling responses. PMID:24225179

Cell division requires a direct link between microtubule-bound RacGAP and Anillin in the contractile ring.

PubMed

Gregory, Stephen L; Ebrahimi, Saman; Milverton, Joanne; Jones, Whitney M; Bejsovec, Amy; Saint, Robert

2008-01-08

The mitotic microtubule array plays two primary roles in cell division. It acts as a scaffold for the congression and separation of chromosomes, and it specifies and maintains the contractile-ring position. The current model for initiation of Drosophila and mammalian cytokinesis [1-5] postulates that equatorial localization of a RhoGEF (Pbl/Ect2) by a microtubule-associated motor protein complex creates a band of activated RhoA [6], which subsequently recruits contractile-ring components such as actin, myosin, and Anillin [1-3]. Equatorial microtubules are essential for continued constriction, but how they interact with the contractile apparatus is unknown. Here, we report the first direct molecular link between the microtubule spindle and the actomyosin contractile ring. We find that the spindle-associated component, RacGAP50C, which specifies the site of cleavage [1-5], interacts directly with Anillin, an actin and myosin binding protein found in the contractile ring [7-10]. Both proteins depend on this interaction for their localization. In the absence of Anillin, the spindle-associated RacGAP loses its association with the equatorial cortex, and cytokinesis fails. These results account for the long-observed dependence of cytokinesis on the continual presence of microtubules at the cortex.

Variations in carbachol- and ATP-induced contractions of the rat detrusor: effects of gender, mucosa and contractile direction.

PubMed

Liang, Willmann; Leung, Ping Chung

2012-12-01

Contractile characteristics of the bladder may depend on variables such as gender, mucosa (MU) and direction of the contractions. However, definitive information is not yet available despite earlier studies on the effects of one variable or another. Here, we explored the differences in the rat detrusor attributable to gender, mucosa and contractile direction. K+, carbachol (CCh) and ATP were used as contractile stimuli on rat detrusor strips with and without MU. Contractility was monitored using a myograph system. Both tonic and phasic contractile activities were analyzed. MU-independent contractions induced by CCh were more potent in females, an effect specific to the longitudinal direction only. The maximal CCh response was larger also in females when MU was removed, suggesting a stronger MU-independent component in the contraction. The larger area under curves of the females under ATP stimulation showed dependence on MU and contractile direction as well. ATP-induced contractions in the males were affected more by MU in the transverse direction than in the females. Direction- and MU-dependent variability of ATP responses was also observed in the males but not in females. Findings here added new information to the understanding of bladder contractile physiology, providing insights into the quest for better drugs in managing bladder disorders.

Stochastic Ratcheting on a Funneled Energy Landscape Is Necessary for Highly Efficient Contractility of Actomyosin Force Dipoles

NASA Astrophysics Data System (ADS)

Komianos, James E.; Papoian, Garegin A.

2018-04-01

Current understanding of how contractility emerges in disordered actomyosin networks of nonmuscle cells is still largely based on the intuition derived from earlier works on muscle contractility. In addition, in disordered networks, passive cross-linkers have been hypothesized to percolate force chains in the network, hence, establishing large-scale connectivity between local contractile clusters. This view, however, largely overlooks the free energy of cross-linker binding at the microscale, which, even in the absence of active fluctuations, provides a thermodynamic drive towards highly overlapping filamentous states. In this work, we use stochastic simulations and mean-field theory to shed light on the dynamics of a single actomyosin force dipole—a pair of antiparallel actin filaments interacting with active myosin II motors and passive cross-linkers. We first show that while passive cross-linking without motor activity can produce significant contraction between a pair of actin filaments, driven by thermodynamic favorability of cross-linker binding, a sharp onset of kinetic arrest exists at large cross-link binding energies, greatly diminishing the effectiveness of this contractility mechanism. Then, when considering an active force dipole containing nonmuscle myosin II, we find that cross-linkers can also serve as a structural ratchet when the motor dissociates stochastically from the actin filaments, resulting in significant force amplification when both molecules are present. Our results provide predictions of how actomyosin force dipoles behave at the molecular level with respect to filament boundary conditions, passive cross-linking, and motor activity, which can explicitly be tested using an optical trapping experiment.

Smooth muscle-protein translocation and tissue function.

PubMed

Eddinger, Thomas J

2014-09-01

Smooth muscle (SM) tissue is a complex organization of multiple cell types and is regulated by numerous signaling molecules (neurotransmitters, hormones, cytokines, etc.). SM contractile function can be regulated via expression and distribution of the contractile and cytoskeletal proteins, and activation of any of the second messenger pathways that regulate them. Spatial-temporal changes in the contractile, cytoskeletal or regulatory components of SM cells (SMCs) have been proposed to alter SM contractile activity. Ca(2+) sensitization/desensitization can occur as a result of changes at any of these levels, and specific pathways have been identified at all of these levels. Understanding when and how proteins can translocate within the cytoplasm, or to-and-from the plasmalemma and the cytoplasm to alter contractile activity is critical. Numerous studies have reported translocation of proteins associated with the adherens junction and G protein-coupled receptor activation pathways in isolated SMC systems. Specific examples of translocation of vinculin to and from the adherens junction and protein kinase C (PKC) and 17 kDa PKC-potentiated inhibitor of myosin light chain phosphatase (CPI-17) to and from the plasmalemma in isolated SMC systems but not in intact SM tissues are discussed. Using both isolated SMC systems and SM tissues in parallel to pursue these studies will advance our understanding of both the role and mechanism of these pathways as well as their possible significance for Ca(2+) sensitization in intact SM tissues and organ systems. © 2014 Wiley Periodicals, Inc.

A massively asynchronous, parallel brain

PubMed Central

Zeki, Semir

2015-01-01

Whether the visual brain uses a parallel or a serial, hierarchical, strategy to process visual signals, the end result appears to be that different attributes of the visual scene are perceived asynchronously—with colour leading form (orientation) by 40 ms and direction of motion by about 80 ms. Whatever the neural root of this asynchrony, it creates a problem that has not been properly addressed, namely how visual attributes that are perceived asynchronously over brief time windows after stimulus onset are bound together in the longer term to give us a unified experience of the visual world, in which all attributes are apparently seen in perfect registration. In this review, I suggest that there is no central neural clock in the (visual) brain that synchronizes the activity of different processing systems. More likely, activity in each of the parallel processing-perceptual systems of the visual brain is reset independently, making of the brain a massively asynchronous organ, just like the new generation of more efficient computers promise to be. Given the asynchronous operations of the brain, it is likely that the results of activities in the different processing-perceptual systems are not bound by physiological interactions between cells in the specialized visual areas, but post-perceptually, outside the visual brain. PMID:25823871

Vitamin K3 inhibits mouse uterine contraction in vitro via interference with the calcium transfer and the potassium channels.

PubMed

Zhang, Xian-Xia; Lu, Li-Min; Wang, Li

2016-08-05

Previous studies have demonstrated vitamin K3 had a great relief to smooth muscle spastic disorders, but no researches have yet pinpointed its possible anti-contractile activity in the uterus. Here, we evaluated the effect of vitamin K3 on myometrial contractility and explored the possible mechanisms of vitamin K3 action. Myograph apparatus were used to record the changes in contractility of isolated mouse uterine strips in a tissue bath. Uterine strips were exposed to vitamin K3 or vehicle. Vitamin K3 suppressed spontaneous contractions in a concentration dependent manner. It significantly decreased the contractile frequency induced by PGF2ɑ but not their amplitude (expect 58.0 μM). Prior incubation with vitamin K3 reduced the effectiveness of PGF2ɑ-induced contraction. The antispasmodic effect of vitamin K3 was also sensitive to potassium channel blockers, such as tetraethylammonium, 4-aminopyridine, iberiotoxin) but not to the nitric oxide related pathway blockers. High concentrations (29.0, 58.0 μM) of vitamin K3 weakened the Ca(2+) dose response and inhibited phase 1 contraction (intracellular stored calcium release). These dates suggest that vitamin K3 specifically suppresses myometrial contractility by affecting calcium and potassium channels; thus, this approach has potential therapy for uterine contractile activity related disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

An internal regulatory element controls troponin I gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yutzey, K.E.; Kline, R.L.; Konieczmy, S.F.

1989-04-01

During skeletal myogenesis, approximately 20 contractile proteins and related gene products temporally accumulate as the cells fuse to form multinucleated muscle fibers. In most instances, the contractile protein genes are regulated transcriptionally, which suggests that a common molecular mechanism may coordinate the expression of this diverse and evolutionarily unrelated gene set. Recent studies have examined the muscle-specific cis-acting elements associated with numerous contractile protein genes. All of the identified regulatory elements are positioned in the 5'-flanking regions, usually within 1,500 base pairs of the transcription start site. Surprisingly, a DNA consensus sequence that is common to each contractile protein genemore » has not been identified. In contrast to the results of these earlier studies, the authors have found that the 5'-flanking region of the quail troponin I (TnI) gene is not sufficient to permit the normal myofiber transcriptional activation of the gene. Instead, the TnI gene utilizes a unique internal regulatory element that is responsible for the correct myofiber-specific expression pattern associated with the TnI gene. This is the first example in which a contractile protein gene has been shown to rely primarily on an internal regulatory element to elicit transcriptional activation during myogenesis. The diversity of regulatory elements associated with the contractile protein genes suggests that the temporal expression of the genes may involve individual cis-trans regulatory components specific for each gene.« less

An internal regulatory element controls troponin I gene expression.

PubMed Central

Yutzey, K E; Kline, R L; Konieczny, S F

1989-01-01

During skeletal myogenesis, approximately 20 contractile proteins and related gene products temporally accumulate as the cells fuse to form multinucleated muscle fibers. In most instances, the contractile protein genes are regulated transcriptionally, which suggests that a common molecular mechanism may coordinate the expression of this diverse and evolutionarily unrelated gene set. Recent studies have examined the muscle-specific cis-acting elements associated with numerous contractile protein genes. All of the identified regulatory elements are positioned in the 5'-flanking regions, usually within 1,500 base pairs of the transcription start site. Surprisingly, a DNA consensus sequence that is common to each contractile protein gene has not been identified. In contrast to the results of these earlier studies, we have found that the 5'-flanking region of the quail troponin I (TnI) gene is not sufficient to permit the normal myofiber transcriptional activation of the gene. Instead, the TnI gene utilizes a unique internal regulatory element that is responsible for the correct myofiber-specific expression pattern associated with the TnI gene. This is the first example in which a contractile protein gene has been shown to rely primarily on an internal regulatory element to elicit transcriptional activation during myogenesis. The diversity of regulatory elements associated with the contractile protein genes suggests that the temporal expression of the genes may involve individual cis-trans regulatory components specific for each gene. Images PMID:2725509

Glucose Regulation of Load‐Induced mTOR Signaling and ER Stress in Mammalian Heart

PubMed Central

Sen, Shiraj; Kundu, Bijoy K.; Wu, Henry Cheng‐Ju; Hashmi, S. Shahrukh; Guthrie, Patrick; Locke, Landon W.; Roy, R. Jack; Matherne, G. Paul; Berr, Stuart S.; Terwelp, Matthew; Scott, Brian; Carranza, Sylvia; Frazier, O. Howard; Glover, David K.; Dillmann, Wolfgang H.; Gambello, Michael J.; Entman, Mark L.; Taegtmeyer, Heinrich

2013-01-01

Background Changes in energy substrate metabolism are first responders to hemodynamic stress in the heart. We have previously shown that hexose‐6‐phosphate levels regulate mammalian target of rapamycin (mTOR) activation in response to insulin. We now tested the hypothesis that inotropic stimulation and increased afterload also regulate mTOR activation via glucose 6‐phosphate (G6P) accumulation. Methods and Results We subjected the working rat heart ex vivo to a high workload in the presence of different energy‐providing substrates including glucose, glucose analogues, and noncarbohydrate substrates. We observed an association between G6P accumulation, mTOR activation, endoplasmic reticulum (ER) stress, and impaired contractile function, all of which were prevented by pretreating animals with rapamycin (mTOR inhibition) or metformin (AMPK activation). The histone deacetylase inhibitor 4‐phenylbutyrate, which relieves ER stress, also improved contractile function. In contrast, adding the glucose analogue 2‐deoxy‐d‐glucose, which is phosphorylated but not further metabolized, to the perfusate resulted in mTOR activation and contractile dysfunction. Next we tested our hypothesis in vivo by transverse aortic constriction in mice. Using a micro‐PET system, we observed enhanced glucose tracer analog uptake and contractile dysfunction preceding dilatation of the left ventricle. In contrast, in hearts overexpressing SERCA2a, ER stress was reduced and contractile function was preserved with hypertrophy. Finally, we examined failing human hearts and found that mechanical unloading decreased G6P levels and ER stress markers. Conclusions We propose that glucose metabolic changes precede and regulate functional (and possibly also structural) remodeling of the heart. We implicate a critical role for G6P in load‐induced mTOR activation and ER stress. PMID:23686371

Role of VIP and substance P in NANC innervation in the longitudinal smooth muscle of the rat jejunum - influence of extrinsic denervation.

PubMed

Kasparek, Michael S; Fatima, Javairiah; Iqbal, Corey W; Duenes, Judith A; Sarr, Michael G

2007-07-01

This study was designed to determine changes in nonadrenergic, noncholinergic (NANC) neurotransmission mediated by Vasoactive Intestinal Polypeptide (VIP) and Substance P after small bowel transplantation (SBT). Six groups of rats (n > or = 6 per group) were studied: naïve controls (NC); 1 wk after anesthesia/sham celiotomy (SC-1); 1 or 8 wk after jejunal and ileal transection/reanastomosis (TA-1, TA-8), or syngeneic, orthotopic SBT (SBT-1, SBT-8). Jejunal longitudinal muscle strips were studied under NANC-conditions for spontaneous contractile activity, response to exogenous VIP and Substance P, and electrical field stimulation (EFS). Spontaneous activity did not differ between the six groups. VIP inhibited contractile activity in all groups 1 wk postoperatively (P < 0.05), which was prevented by the NO synthase inhibitor L-N(G)-nitro arginine (L-NNA). In contrast, VIP had no effect in the other groups. Precontraction with Substance P exposed an inhibitory effect of VIP in all groups (P < 0.05 each). Substance P increased contractile activity in all groups, but to a lesser extent in SBT-8 compared with NC, TA-8, and SBT-1 (P < 0.05). The inhibitory effect of EFS at 6 Hz was prevented by L-NNA in NC and TA-8; addition of the VIP antagonist ([D-p-Cl-Phe(6), Leu(17)]-VIP) increased contractile activity in NC, but not in TA-8 and SBT-8. The Substance P antagonist ([D-Pro(2), D-Trp(7,9)]-Substance P) decreased contractile activity during EFS at 50 Hz in NC and SBT-8. SBT decreased response to exogenous Substance P, although release of endogenous Substance P (EFS) is preserved. Changes in VIP signaling are acute and reversible and not caused by effects of SBT.

Actomyosin-based tissue folding requires a multicellular myosin gradient

PubMed Central

Miller, Pearson W.; Chanet, Soline; Stoop, Norbert; Dunkel, Jörn

2017-01-01

Tissue folding promotes three-dimensional (3D) form during development. In many cases, folding is associated with myosin accumulation at the apical surface of epithelial cells, as seen in the vertebrate neural tube and the Drosophila ventral furrow. This type of folding is characterized by constriction of apical cell surfaces, and the resulting cell shape change is thought to cause tissue folding. Here, we use quantitative microscopy to measure the pattern of transcription, signaling, myosin activation and cell shape in the Drosophila mesoderm. We found that cells within the ventral domain accumulate different amounts of active apical non-muscle myosin 2 depending on the distance from the ventral midline. This gradient in active myosin depends on a newly quantified gradient in upstream signaling proteins. A 3D continuum model of the embryo with induced contractility demonstrates that contractility gradients, but not contractility per se, promote changes to surface curvature and folding. As predicted by the model, experimental broadening of the myosin domain in vivo disrupts tissue curvature where myosin is uniform. Our data argue that apical contractility gradients are important for tissue folding. PMID:28432215

Analysis of an Asynchronous Online Discussion as a Supportive Model for Peer Collaboration and Reflection in Teacher Education

ERIC Educational Resources Information Center

Plešec Gasparic, Romina; Pecar, Mojca

2016-01-01

Professional development of future teachers is based on connecting theory and practice with the aim of supporting and developing critical, independent, responsible decision-making and active teaching. With this aim we designed a blended learning environment with an asynchronous online discussion, enabling collaboration and reflection even when…

Toward Personal and Emotional Connectivity in Mobile Higher Education through Asynchronous Formative Audio Feedback

ERIC Educational Resources Information Center

Rasi, Päivi; Vuojärvi, Hanna

2018-01-01

This study aims to develop asynchronous formative audio feedback practices for mobile learning in higher education settings. The development was conducted in keeping with the principles of design-based research. The research activities focused on an inter-university online course, within which the use of instructor audio feedback was tested,…

Students' Perceptions of Online Discussions, Participation and E-Moderation Behaviours in Peer-Moderated Asynchronous Online Discussions

ERIC Educational Resources Information Center

Ghadirian, Hajar; Fauzi Mohd Ayub, Ahmad; Salehi, Keyvan

2018-01-01

The aim of this study was to investigate the relationships between students' perceptions of online discussions, participation and e-moderation behaviours in peer-moderated asynchronous online discussions. Using survey data, the learning system's activity log and discussion transcripts, the authors analysed how 84 learners' perceptions of online…

Synchronous and Asynchronous E-Language Learning: A Case Study of Virtual University of Pakistan

ERIC Educational Resources Information Center

Perveen, Ayesha

2016-01-01

This case study evaluated the impact of synchronous and asynchronous E-Language Learning activities (ELL-ivities) in an E-Language Learning Environment (ELLE) at Virtual University of Pakistan. The purpose of the study was to assess e-language learning analytics based on the constructivist approach of collaborative construction of knowledge. The…

Disordered Actomyosin Is Sufficient to Promote Cooperative and Telescopic Contractility

NASA Astrophysics Data System (ADS)

Murrell, Michael; Linsmeier, Ian; Banerjee, Shiladitya; Kim, Tae Yoon; Jung, Wonyeong; Oakes, Patrick

While the molecular interactions between myosin motors and F-actin are well known, the relationship between F-actin organization and myosin-mediated force generation remains poorly understood. Here, we explore the accumulation of myosin-induced stresses within a 2D biomimetic model of the actomyosin cortex, where myosin activity is controlled spatially and temporally using light. By controlling the geometry and the duration of myosin activation, we show that contraction of disordered actomyosin is highly cooperative, telescopic with the activation area and generates a pattern of mechanical stresses consistent with those observed in contractile cells. We quantitatively reproduce these properties using an in vitro isotropic model of the actomyosin cytoskeleton, and explore the physical origins of telescopic contractility in disordered networks using agent-based simulations. NSF CMMI-1525316.

Effect of hindlimb immobilization on the fatigability of skeletal muscle

NASA Technical Reports Server (NTRS)

Witzmann, F. A.; Kim, D. H.; Fitts, R. H.

1983-01-01

The effect of 6 weeks of disuse atrophy produced by hindlimb immobilization was studied in situ (33.5 C) in the soleus and extensor digitorum longus muscles of rats. The results indicate that disuse causes preferential alterations in the isometric contractile properties of slow-twitch, as opposed to fast-twitch, skeletal muscles. During continuous contractile activity, atrophied muscles were found to have lower ATP levels and an apparent increase in their dependence on anaerobic metabolism, as reflected by the more extensive depletion of glycogen and enhanced lactate formation. Although the atrophied muscles were determined to have fewer cross bridges and thus generated lower tension, the pattern of decline in active cross-bridge formation and tetanic tension during contractile activity was found to proceed in a manner similar to controls.

Universal filtered multi-carrier system for asynchronous uplink transmission in optical access network

NASA Astrophysics Data System (ADS)

Kang, Soo-Min; Kim, Chang-Hun; Han, Sang-Kook

2016-02-01

In passive optical network (PON), orthogonal frequency division multiplexing (OFDM) has been studied actively due to its advantages such as high spectra efficiency (SE), dynamic resource allocation in time or frequency domain, and dispersion robustness. However, orthogonal frequency division multiple access (OFDMA)-PON requires tight synchronization among multiple access signals. If not, frequency orthogonality could not be maintained. Also its sidelobe causes inter-channel interference (ICI) to adjacent channel. To prevent ICI caused by high sidelobes, guard band (GB) is usually used which degrades SE. Thus, OFDMA-PON is not suitable for asynchronous uplink transmission in optical access network. In this paper, we propose intensity modulation/direct detection (IM/DD) based universal filtered multi-carrier (UFMC) PON for asynchronous multiple access. The UFMC uses subband filtering to subsets of subcarriers. Since it reduces sidelobe of each subband by applying subband filtering, it could achieve better performance compared to OFDM. For the experimental demonstration, different sample delay was applied to subbands to implement asynchronous transmission condition. As a result, time synchronization robustness of UFMC was verified in asynchronous multiple access system.

[Subcellular basis of disorders of the contractile capacity of the heart in L-thyroxine-induced thyrotoxicosis].

PubMed

Karsanov, N V; Melashvili, N O; Khugashvili, Z G; Mamulashvili, L D; Azrumelashvili, M I; Khaindrava, G K; Kapanadze, R V

1990-02-01

In experiments on dogs, the authors examined the functional activity of three cardiomyocyte systems responsible for contraction-relaxation (the systems of contractile proteins, calcium transport and energy supply) in the dynamics of L-thyroxine-induced toxicosis. A fall in the capacity of the contractile protein system to generate energy and to perform was shown to play the leading role in decrease of myocardial reserve forces and reduction in cardiac contractility. There was a drop in the intensity of calcium transport through the membranes of the sarcoplasmic reticulum and mitochondria and a deficiency of the direct energy source for contraction only in the late period of the disease.

Boundaries steer the contraction of active gels

NASA Astrophysics Data System (ADS)

Schuppler, Matthias; Keber, Felix C.; Kröger, Martin; Bausch, Andreas R.

2016-10-01

Cells set up contractile actin arrays to drive various shape changes and to exert forces to their environment. To understand their assembly process, we present here a reconstituted contractile system, comprising F-actin and myosin II filaments, where we can control the local activation of myosin by light. By stimulating different symmetries, we show that the force balancing at the boundaries determine the shape changes as well as the dynamics of the global contraction. Spatially anisotropic attachment of initially isotropic networks leads to a self-organization of highly aligned contractile fibres, being reminiscent of the order formation in muscles or stress fibres. The observed shape changes and dynamics are fully recovered by a minimal physical model.

Extracellular signal-regulated kinase (ERK) activation preserves cardiac function in pressure overload induced hypertrophy.

PubMed

Mutlak, Michael; Schlesinger-Laufer, Michal; Haas, Tali; Shofti, Rona; Ballan, Nimer; Lewis, Yair E; Zuler, Mor; Zohar, Yaniv; Caspi, Lilac H; Kehat, Izhak

2018-05-24

Chronic pressure overload and a variety of mediators induce concentric cardiac hypertrophy. When prolonged, cardiac hypertrophy culminates in decreased myocardial function and heart failure. Activation of the extracellular signal-regulated kinase (ERK) is consistently observed in animal models of hypertrophy and in human patients, but its role in the process is controversial. We generated transgenic mouse lines with cardiomyocyte restricted overexpression of intrinsically active ERK1, which similar to the observations in hypertrophy is phosphorylated on both the TEY and the Thr207 motifs and is overexpressed at pathophysiological levels. The activated ERK1 transgenic mice developed a modest adaptive hypertrophy with increased contractile function and without fibrosis. Following induction of pressure-overload, where multiple pathways are stimulated, this activation did not further increase the degree of hypertrophy but protected the heart through a decrease in the degree of fibrosis and maintenance of ventricular contractile function. The ERK pathway acts to promote a compensated hypertrophic response, with enhanced contractile function and reduced fibrosis. The activation of this pathway may be a therapeutic strategy to preserve contractile function when the pressure overload cannot be easily alleviated. The inhibition of this pathway, which is increasingly being used for cancer therapy on the other hand, should be used with caution in the presence of pressure-overload. Copyright © 2017. Published by Elsevier B.V.

Predicting changes in cardiac myocyte contractility during early drug discovery with in vitro assays

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morton, M.J., E-mail: michael.morton@astrazeneca.com; Armstrong, D.; Abi Gerges, N.

2014-09-01

Cardiovascular-related adverse drug effects are a major concern for the pharmaceutical industry. Activity of an investigational drug at the L-type calcium channel could manifest in a number of ways, including changes in cardiac contractility. The aim of this study was to define which of the two assay technologies – radioligand-binding or automated electrophysiology – was most predictive of contractility effects in an in vitro myocyte contractility assay. The activity of reference and proprietary compounds at the L-type calcium channel was measured by radioligand-binding assays, conventional patch-clamp, automated electrophysiology, and by measurement of contractility in canine isolated cardiac myocytes. Activity inmore » the radioligand-binding assay at the L-type Ca channel phenylalkylamine binding site was most predictive of an inotropic effect in the canine cardiac myocyte assay. The sensitivity was 73%, specificity 83% and predictivity 78%. The radioligand-binding assay may be run at a single test concentration and potency estimated. The least predictive assay was automated electrophysiology which showed a significant bias when compared with other assay formats. Given the importance of the L-type calcium channel, not just in cardiac function, but also in other organ systems, a screening strategy emerges whereby single concentration ligand-binding can be performed early in the discovery process with sufficient predictivity, throughput and turnaround time to influence chemical design and address a significant safety-related liability, at relatively low cost. - Highlights: • The L-type calcium channel is a significant safety liability during drug discovery. • Radioligand-binding to the L-type calcium channel can be measured in vitro. • The assay can be run at a single test concentration as part of a screening cascade. • This measurement is highly predictive of changes in cardiac myocyte contractility.« less

Changes in contractile activation characteristics of rat fast and slow skeletal muscle fibres during regeneration.

PubMed

Gregorevic, Paul; Plant, David R; Stupka, Nicole; Lynch, Gordon S

2004-07-15

Damaged skeletal muscle fibres are replaced with new contractile units via muscle regeneration. Regenerating muscle fibres synthesize functionally distinct isoforms of contractile and regulatory proteins but little is known of their functional properties during the regeneration process. An advantage of utilizing single muscle fibre preparations is that assessment of their function is based on the overall characteristics of the contractile apparatus and regulatory system and as such, these preparations are sensitive in revealing not only coarse, but also subtle functional differences between muscle fibres. We examined the Ca(2+)- and Sr(2+)-activated contractile characteristics of permeabilized fibres from rat fast-twitch (extensor digitorum longus) and slow-twitch (soleus) muscles at 7, 14 and 21 days following myotoxic injury, to test the hypothesis that fibres from regenerating fast and slow muscles have different functional characteristics to fibres from uninjured muscles. Regenerating muscle fibres had approximately 10% of the maximal force producing capacity (P(o)) of control (uninjured) fibres, and an altered sensitivity to Ca(2+) and Sr(2+) at 7 days post-injury. Increased force production and a shift in Ca(2+) sensitivity consistent with fibre maturation were observed during regeneration such that P(o) was restored to 36-45% of that in control fibres by 21 days, and sensitivity to Ca(2+) and Sr(2+) was similar to that of control (uninjured) fibres. The findings support the hypothesis that regenerating muscle fibres have different contractile activation characteristics compared with mature fibres, and that they adopt properties of mature fast- or slow-twitch muscle fibres in a progressive manner as the regeneration process is completed.

Electrical engineering unit for the reactive power control of the load bus at the voltage instability

NASA Astrophysics Data System (ADS)

Kotenev, A. V.; Kotenev, V. I.; Kochetkov, V. V.; Elkin, D. A.

2018-01-01

For the purpose of reactive power control error reduction and decrease of the voltage sags in the electric power system caused by the asynchronous motors started the mathematical model of the load bus was developed. The model was built up of the sub-models of the following elements: a transformer, a transmission line, a synchronous and an asynchronous loads and a capacitor bank load, and represents the automatic reactive power control system taking into account electromagnetic processes of the asynchronous motors started and reactive power changing of the electric power system elements caused by the voltage fluctuation. The active power/time and reactive power/time characteristics based on the recommended procedure of the equivalent electric circuit parameters calculation were obtained. The derived automatic reactive power control system was shown to eliminate the voltage sags in the electric power system caused by the asynchronous motors started.

Alterations in serotonin receptor-induced contractility of bovine lateral saphenous vein in cattle grazing endophyte-infected tall fescue.

PubMed

Klotz, J L; Brown, K R; Xue, Y; Matthews, J C; Boling, J A; Burris, W R; Bush, L P; Strickland, J R

2012-02-01

As part of a 2-yr study documenting the physiologic impact of grazing endophyte-infected tall fescue on growing cattle, 2 experiments were conducted to characterize and evaluate effects of grazing 2 levels of toxic endophyte-infected tall fescue pastures on vascular contractility and serotonin receptors. Experiment 1 examined vasoconstrictive activities of 5-hydroxytryptamine (5HT), α-methylserotonin (ME5HT; a 5HT(2) receptor agonist), d-lysergic acid (LSA), and ergovaline (ERV) on lateral saphenous veins collected from steers immediately removed from a high-endophyte-infected tall fescue pasture (HE) or a low-endophyte-infected mixed-grass (LE) pasture. Using the same pastures, Exp. 2 evaluated effects of grazing 2 levels of toxic endophyte-infected tall fescue on vasoconstrictive activities of (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), BW 723C86 (BW7), CGS-12066A (CGS), and 5-carboxamidotryptamine hemiethanolate maleate (5CT), agonists for 5HT(2A),( 2B), 5HT(1B), and 5HT(7) receptors, respectively. One-half of the steers in Exp. 2 were slaughtered immediately after removal from pasture, and the other one-half were fed finishing diets for >91 d before slaughter. For Exp. 1, maximal contractile intensities were greater (P < 0.05) for steers grazing LE pastures than HE pastures for 5HT (73.3 vs. 48.9 ± 2.1%), ME5HT (52.7 vs. 24.9 ± 1.5%), and ERV (65.7 vs. 49.1 ± 2.6%). Onset of contractile response did not differ for 5HT (P = 0.26) and ERV (P = 0.93), but onset of ME5HT contraction was not initiated (P < 0.05) in HE steers until 10(-4) compared with 10(-5) M in LE-grazing steers. For Exp. 2, maximal contractile intensities achieved with DOI were 35% less (P < 0.05), whereas those achieved with 5CT were 37% greater (P < 0.05), in steers grazing HE pastures. Contractile response to CGS did not differ between pasture groups, and there was an absence of contractile response to BW7 in both groups. There were no differences between endophyte content in contractile responses after animals were finished for >91 d. Experiment 1 demonstrated that grazing of HE pastures for 89 to 105 d induces functional alterations in blood vessels, as evidenced by reduced contractile capacity and altered serotonergic receptor activity. Experiment 2 demonstrated that grazing HE pastures alters vascular responses, which may be mediated through altered serotonin receptor activities, and these alterations may be ameliorated by the removal of ergot alkaloid exposure as demonstrated by the absence of differences in finished steers.

Local 3D matrix microenvironment regulates cell migration through spatiotemporal dynamics of contractility-dependent adhesions

NASA Astrophysics Data System (ADS)

Doyle, Andrew D.; Carvajal, Nicole; Jin, Albert; Matsumoto, Kazue; Yamada, Kenneth M.

2015-11-01

The physical properties of two-dimensional (2D) extracellular matrices (ECMs) modulate cell adhesion dynamics and motility, but little is known about the roles of local microenvironmental differences in three-dimensional (3D) ECMs. Here we generate 3D collagen gels of varying matrix microarchitectures to characterize their regulation of 3D adhesion dynamics and cell migration. ECMs containing bundled fibrils demonstrate enhanced local adhesion-scale stiffness and increased adhesion stability through balanced ECM/adhesion coupling, whereas highly pliable reticular matrices promote adhesion retraction. 3D adhesion dynamics are locally regulated by ECM rigidity together with integrin/ECM association and myosin II contractility. Unlike 2D migration, abrogating contractility stalls 3D migration regardless of ECM pore size. We find force is not required for clustering of activated integrins on 3D native collagen fibrils. We propose that efficient 3D migration requires local balancing of contractility with ECM stiffness to stabilize adhesions, which facilitates the detachment of activated integrins from ECM fibrils.

Direct Proof of Endo-Epicardial Asynchrony of the Atrial Wall During Atrial Fibrillation in Humans.

PubMed

de Groot, Natasja; van der Does, Lisette; Yaksh, Ameeta; Lanters, Eva; Teuwen, Christophe; Knops, Paul; van de Woestijne, Pieter; Bekkers, Jos; Kik, Charles; Bogers, Ad; Allessie, Maurits

2016-05-01

The presence of focal fibrillation waves during atrial fibrillation (AF) can, besides ectopic activity, also be explained by asynchronous activation of the atrial endo- and epicardial layer and transmurally propagating fibrillation waves. To provide direct proof of endo-epicardial asynchrony, we performed simultaneous high-resolution mapping of the right atrial endo- and epicardial wall during AF in humans. Intraoperative mapping of the endo- and epicardial right atrial wall was performed during (induced) AF in 10 patients with AF (paroxysmal: n=3; persistent: n=4; and longstanding persistent: n=3) and 4 patients without a history of AF. A clamp made of 2 rectangular 8×16 electrode arrays (interelectrode distance 2 mm) was inserted into the incision in the right atrial appendage. Recordings of 10 seconds of AF were analyzed to determine the incidence of asynchronous endo-epicardial activation times (≥15 ms) of opposite electrodes. Asynchronous endo-epicardial activation ranged between 0.9 and 55.9% without preference for either side. Focal waves appeared equally frequent at endocardium and epicardium (11% versus 13%; ITALIC! P=0.18). Using strict criteria for breakthrough (presence of an opposite wave within 4 mm and ≤14 ms before the origin of the focal wave), the majority (65%) of all focal fibrillation waves could be attributed to endo-epicardial excitation. We provided the first evidence for asynchronous activation of the endo-epicardial wall during AF in humans. Endo-epicardial asynchrony may play a major role in the pathophysiology of AF and may offer an explanation why in some patients therapy fails. © 2016 American Heart Association, Inc.

A novel asynchronous access method with binary interfaces

PubMed Central

2008-01-01

Background Traditionally synchronous access strategies require users to comply with one or more time constraints in order to communicate intent with a binary human-machine interface (e.g., mechanical, gestural or neural switches). Asynchronous access methods are preferable, but have not been used with binary interfaces in the control of devices that require more than two commands to be successfully operated. Methods We present the mathematical development and evaluation of a novel asynchronous access method that may be used to translate sporadic activations of binary interfaces into distinct outcomes for the control of devices requiring an arbitrary number of commands to be controlled. With this method, users are required to activate their interfaces only when the device under control behaves erroneously. Then, a recursive algorithm, incorporating contextual assumptions relevant to all possible outcomes, is used to obtain an informed estimate of user intention. We evaluate this method by simulating a control task requiring a series of target commands to be tracked by a model user. Results When compared to a random selection, the proposed asynchronous access method offers a significant reduction in the number of interface activations required from the user. Conclusion This novel access method offers a variety of advantages over traditionally synchronous access strategies and may be adapted to a wide variety of contexts, with primary relevance to applications involving direct object manipulation. PMID:18959797

Contractile function of the myocardium with prolonged hypokinesia in patients with surgical tuberculosis

NASA Technical Reports Server (NTRS)

Zakutayeva, V. P.; Matiks, N. I.

1978-01-01

The changes in the myocardial contractile function with hypokinesia in surgical tuberculosis patients are discussed. The phase nature of the changes is noted, specifically the changes in the various systoles, diastole, and other parts of the cardiac cycle. The data compare these changes during confinement in bed with no motor activity to and with a return to motor activity after leaving the in-bed regimen.

Asynchronous P300-based brain-computer interface to control a virtual environment: initial tests on end users.

PubMed

Aloise, Fabio; Schettini, Francesca; Aricò, Pietro; Salinari, Serenella; Guger, Christoph; Rinsma, Johanna; Aiello, Marco; Mattia, Donatella; Cincotti, Febo

2011-10-01

Motor disability and/or ageing can prevent individuals from fully enjoying home facilities, thus worsening their quality of life. Advances in the field of accessible user interfaces for domotic appliances can represent a valuable way to improve the independence of these persons. An asynchronous P300-based Brain-Computer Interface (BCI) system was recently validated with the participation of healthy young volunteers for environmental control. In this study, the asynchronous P300-based BCI for the interaction with a virtual home environment was tested with the participation of potential end-users (clients of a Frisian home care organization) with limited autonomy due to ageing and/or motor disabilities. System testing revealed that the minimum number of stimulation sequences needed to achieve correct classification had a higher intra-subject variability in potential end-users with respect to what was previously observed in young controls. Here we show that the asynchronous modality performed significantly better as compared to the synchronous mode in continuously adapting its speed to the users' state. Furthermore, the asynchronous system modality confirmed its reliability in avoiding misclassifications and false positives, as previously shown in young healthy subjects. The asynchronous modality may contribute to filling the usability gap between BCI systems and traditional input devices, representing an important step towards their use in the activities of daily living.

Student participation and interactivity using asynchronous computer-mediated communication for resolution of an undergraduate capstone management case study.

PubMed

Miller, Paulette J

2012-01-01

Online discussion activities are designed for computer-mediated learning activities in face-to-face, hybrid, and totally online courses. The use of asynchronous computer-mediated communication (A-CMC) coupled with authentic workplace case studies provides students in the protected learning environment with opportunities to practice workplace decision making and communication. In this study, communication behaviors of transmitter and receiver were analyzed to determine participation and interactivity in communication among small-group participants in a health information management capstone management course.

Teaching Writing within the Common European Framework of Reference (CEFR): A Supplement Asynchronous Blended Learning Approach in an EFL Undergraduate Course in Egypt

ERIC Educational Resources Information Center

Shaarawy, Hanaa Youssef; Lotfy, Nohayer Esmat

2013-01-01

Based on the Common European Framework of Reference (CEFR) and following a blended learning approach (a supplement model), this article reports on a quasi-experiment where writing was taught evenly with other language skills in everyday language contexts and where asynchronous online activities were required from students to extend learning beyond…

Diabetes attenuates urothelial modulation of detrusor contractility and spontaneous activity.

PubMed

Wang, Yi; Tar, Moses T; Fu, Shibo; Melman, Arnold; Davies, Kelvin P

2014-10-01

To investigate the effect of diabetes on urothelial modulation of bladder contractility. Bladder strips (urothelium intact or denuded) were prepared from 8-week-old streptozotocin-induced diabetic (n = 19) and non-diabetic control rats (n = 10). The effect of modulators of MaxiK (iberiotoxin and tetraethylammonium) and Kv7 (XE991 and retigabine) potassium channel activity were investigated for their effects on both carbachol-induced force generation and spontaneous contractile activity. In bladder strips from non-diabetic animals, the presence of the urothelium resulted in marked sensitivity to carbachol-induced force generation by modulators of MaxiK and Kv7 channel activity, whereas in the diabetic animal urothelial sensitivity to these agents was significantly diminished. Urothelial-intact bladder strips from non-diabetic animals were more sensitive to modulators of Kv7 activity in reducing the amplitude of spontaneous phasic contractions than urothelial-denuded bladder strips, whereas in diabetic animals the presence or absence of the urothelium did not alter the sensitivity to modulators of Kv7 activity. Spontaneous activity in the presence of tetraethylammonium was not affected by the urothelium in bladder strips from either diabetic or non-diabetic animals. The presence of the urothelium in bladders from non-diabetic animals modulates the activity of potassium blockers to affect bladder contractility, whereas in the diabetic bladder this effect is attenuated. These findings could help to explain the lack of success of pharmaceutical treatments targeting potassium channels to treat bladder pathology in patients with diseases imparing urothelial function. © 2014 The Japanese Urological Association.

Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

PubMed Central

Cittadini, A; Monti, MG; Iaccarino, G; Di Rella, F; Tsichlis, PN; Di Gianni, A; Strömer, H; Sorriento, D; Peschle, C; Trimarco, B; Saccà, L; Condorelli, G

2010-01-01

The serine-threonine kinase Akt/PKB mediates stimuli from different classes of cardiomyocyte receptors, including the growth hormone/insulin like growth factor and the β-adrenergic receptors. Whereas the growth-promoting and antiapoptotic properties of Akt activation are well established, little is known about the effects of Akt on myocardial contractility, intracellular calcium (Ca2+) handling, oxygen consumption, and β-adrenergic pathway. To this aim, Sprague–Dawley rats were subjected to a wild-type Akt in vivo adenoviral gene transfer using a catheter-based technique combined with aortopulmonary crossclamping. Left ventricular (LV) contractility and intracellular Ca2+ handling were evaluated in an isolated isovolumic buffer-perfused, aequorin-loaded whole heart preparations 10 days after the surgery. The Ca2+–force relationship was obtained under steady-state conditions in tetanized muscles. No significant hypertrophy was detected in adenovirus with wild-type Akt (Ad.Akt) versus controls rats (LV-to-body weight ratio 2.6±0.2 versus 2.7±0.1 mg/g, controls versus Ad.Akt, P, NS). LV contractility, measured as developed pressure, increased by 41% in Ad.Akt. This was accounted for by both more systolic Ca2+ available to the contractile machinery (+19% versus controls) and by enhanced myofilament Ca2+ responsiveness, documented by an increased maximal Ca2+-activated pressure (+19% versus controls) and a shift to the left of the Ca2+–force relationship. Such increased contractility was paralleled by a slight increase of myocardial oxygen consumption (14%), while titrated dose of dobutamine providing similar inotropic effect augmented oxygen consumption by 39% (P<0.01). Phospholamban, calsequestrin, and ryanodine receptor LV mRNA and protein content were not different among the study groups, while sarcoplasmic reticulum Ca2+ ATPase protein levels were significantly increased in Ad.Akt rats. β-Adrenergic receptor density, affinity, kinase-1 levels, and adenylyl cyclase activity were similar in the three animal groups. In conclusion, our results support an important role for Akt/PKB in the regulation of myocardial contractility and mechanoenergetics. PMID:16094411

Nitrergic signalling via interstitial cells of Cajal regulates motor activity in murine colon.

PubMed

Lies, Barbara; Beck, Katharina; Keppler, Jonas; Saur, Dieter; Groneberg, Dieter; Friebe, Andreas

2015-10-15

In the enteric nervous systems, NO is released from nitrergic neurons as a major inhibitory neurotransmitter. NO acts via NO-sensitive guanylyl cyclase (NO-GC), which is found in different gastrointestinal (GI) cell types including smooth muscle cells (SMCs) and interstitial cells of Cajal (ICC). The precise mechanism of nitrergic signalling through these two cell types to regulate colonic spontaneous contractions is not fully understood yet. In the present study we investigated the impact of endogenous and exogenous NO on colonic contractile motor activity using mice lacking nitric oxide-sensitive guanylyl cyclase (NO-GC) globally and specifically in SMCs and ICC. Longitudinal smooth muscle of proximal colon from wild-type (WT) and knockout (KO) mouse strains exhibited spontaneous contractile activity ex vivo. WT and smooth muscle-specific guanylyl cyclase knockout (SMC-GCKO) colon showed an arrhythmic contractile activity with varying amplitudes and frequencies. In contrast, colon from global and ICC-specific guanylyl cyclase knockout (ICC-GCKO) animals showed a regular contractile rhythm with constant duration and amplitude of the rhythmic contractions. Nerve blockade (tetrodotoxin) or specific blockade of NO signalling (L-NAME, ODQ) did not significantly affect contractions of GCKO and ICC-GCKO colon whereas the arrhythmic contractile patterns of WT and SMC-GCKO colon were transformed into uniform motor patterns. In contrast, the response to electric field-stimulated neuronal NO release was similar in SMC-GCKO and global GCKO. In conclusion, our results indicate that basal enteric NO release acts via myenteric ICC to influence the generation of spontaneous contractions whereas the effects of elevated endogenous NO are mediated by SMCs in the murine proximal colon. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Urothelial/lamina propria spontaneous activity and the role of M3 muscarinic receptors in mediating rate responses to stretch and carbachol.

PubMed

Moro, Christian; Uchiyama, Jumpei; Chess-Williams, Russ

2011-12-01

To investigate the effects of tissue stretch and muscarinic receptor stimulation on the spontaneous activity of the urothelium/lamina propria and identify the specific receptor subtype mediating these responses. Isolated strips of porcine urothelium with lamina propria were set up for in vitro recording of contractile activity. Muscarinic receptor subtype-selective antagonists were used to identify the receptors influencing the contractile rate responses to stretch and stimulation with carbachol. Isolated strips of urothelium with lamina propria developed spontaneous contractions (3.7 cycles/min) that were unaffected by tetrodotoxin, Nω-nitro-L-arginine, or indomethacin. Carbachol (1 μM) increased the spontaneous contractile rate of these tissue strips by 122% ± 27% (P < .001). These responses were significantly depressed in the presence of the M3-selective muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (10-30 nM) but were not affected by the M1-selective antagonist pirenzepine (30-100 nM) or the M2-selective antagonist methoctramine (0.1-1 μM). Stretching of the tissue also caused an increase in the spontaneous contractile rate, and these responses were abolished by atropine (1 μM) and low concentrations of 4-diphenylacetoxy-N-methylpiperidine methiodide (10 nM). Darifenacin, oxybutynin, tolterodine, and solifenacin (1 μM) all significantly depressed the frequency responses to carbachol (1 μM). The urothelium with the lamina propria exhibits a spontaneous contractile activity that is increased during stretch. The mechanism appears to involve endogenous acetylcholine release acting on M3 muscarinic receptors. Anticholinergic drugs used clinically depress the responses of these tissues, and this mechanism might represent an additional site of action for these drugs in the treatment of bladder overactivity. Copyright © 2011 Elsevier Inc. All rights reserved.

TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1

PubMed Central

Doleschal, Bernhard; Primessnig, Uwe; Wölkart, Gerald; Wolf, Stefan; Schernthaner, Michaela; Lichtenegger, Michaela; Glasnov, Toma N.; Kappe, C. Oliver; Mayer, Bernd; Antoons, Gudrun; Heinzel, Frank; Poteser, Michael; Groschner, Klaus

2015-01-01

Aim TRPC3 is a non-selective cation channel, which forms a Ca2+ entry pathway involved in cardiac remodelling. Our aim was to analyse acute electrophysiological and contractile consequences of TRPC3 activation in the heart. Methods and results We used a murine model of cardiac TRPC3 overexpression and a novel TRPC3 agonist, GSK1702934A, to uncover (patho)physiological functions of TRPC3. GSK1702934A induced a transient, non-selective conductance and prolonged action potentials in TRPC3-overexpressing myocytes but lacked significant electrophysiological effects in wild-type myocytes. GSK1702934A transiently enhanced contractility and evoked arrhythmias in isolated Langendorff hearts from TRPC3-overexpressing but not wild-type mice. Interestingly, pro-arrhythmic effects outlasted TRPC3 current activation, were prevented by enhanced intracellular Ca2+ buffering, and suppressed by the NCX inhibitor 3′,4′-dichlorobenzamil hydrochloride. GSK1702934A substantially promoted NCX currents in TRPC3-overexpressing myocytes. The TRPC3-dependent electrophysiologic, pro-arrhythmic, and inotropic actions of GSK1702934A were mimicked by angiotensin II (AngII). Immunocytochemistry demonstrated colocalization of TRPC3 with NCX1 and disruption of local interaction upon channel activation by either GSK1702934A or AngII. Conclusion Cardiac TRPC3 mediates Ca2+ and Na+ entry in proximity of NCX1, thereby elevating cellular Ca2+ levels and contractility. Excessive activation of TRPC3 is associated with transient cellular Ca2+ overload, spatial uncoupling between TRPC3 and NCX1, and arrhythmogenesis. We propose TRPC3-NCX micro/nanodomain communication as determinant of cardiac contractility and susceptibility to arrhythmogenic stimuli. PMID:25631581

Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability.

PubMed

Takaki, Tohru; Montagner, Marco; Serres, Murielle P; Le Berre, Maël; Russell, Matt; Collinson, Lucy; Szuhai, Karoly; Howell, Michael; Boulton, Simon J; Sahai, Erik; Petronczki, Mark

2017-07-24

Altered nuclear shape is a defining feature of cancer cells. The mechanisms underlying nuclear dysmorphia in cancer remain poorly understood. Here we identify PPP1R12A and PPP1CB, two subunits of the myosin phosphatase complex that antagonizes actomyosin contractility, as proteins safeguarding nuclear integrity. Loss of PPP1R12A or PPP1CB causes nuclear fragmentation, nuclear envelope rupture, nuclear compartment breakdown and genome instability. Pharmacological or genetic inhibition of actomyosin contractility restores nuclear architecture and genome integrity in cells lacking PPP1R12A or PPP1CB. We detect actin filaments at nuclear envelope rupture sites and define the Rho-ROCK pathway as the driver of nuclear damage. Lamin A protects nuclei from the impact of actomyosin activity. Blocking contractility increases nuclear circularity in cultured cancer cells and suppresses deformations of xenograft nuclei in vivo. We conclude that actomyosin contractility is a major determinant of nuclear shape and that unrestrained contractility causes nuclear dysmorphia, nuclear envelope rupture and genome instability.

Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability

PubMed Central

Takaki, Tohru; Montagner, Marco; Serres, Murielle P.; Le Berre, Maël; Russell, Matt; Collinson, Lucy; Szuhai, Karoly; Howell, Michael; Boulton, Simon J.; Sahai, Erik; Petronczki, Mark

2017-01-01

Altered nuclear shape is a defining feature of cancer cells. The mechanisms underlying nuclear dysmorphia in cancer remain poorly understood. Here we identify PPP1R12A and PPP1CB, two subunits of the myosin phosphatase complex that antagonizes actomyosin contractility, as proteins safeguarding nuclear integrity. Loss of PPP1R12A or PPP1CB causes nuclear fragmentation, nuclear envelope rupture, nuclear compartment breakdown and genome instability. Pharmacological or genetic inhibition of actomyosin contractility restores nuclear architecture and genome integrity in cells lacking PPP1R12A or PPP1CB. We detect actin filaments at nuclear envelope rupture sites and define the Rho-ROCK pathway as the driver of nuclear damage. Lamin A protects nuclei from the impact of actomyosin activity. Blocking contractility increases nuclear circularity in cultured cancer cells and suppresses deformations of xenograft nuclei in vivo. We conclude that actomyosin contractility is a major determinant of nuclear shape and that unrestrained contractility causes nuclear dysmorphia, nuclear envelope rupture and genome instability. PMID:28737169

p21-Activated kinase (Pak) regulates airway smooth muscle contraction by regulating paxillin complexes that mediate actin polymerization.

PubMed

Zhang, Wenwu; Huang, Youliang; Gunst, Susan J

2016-09-01

In airway smooth muscle, tension development caused by a contractile stimulus requires phosphorylation of the 20 kDa myosin light chain (MLC), which activates crossbridge cycling and the polymerization of a pool of submembraneous actin. The p21-activated kinases (Paks) can regulate the contractility of smooth muscle and non-muscle cells, and there is evidence that this occurs through the regulation of MLC phosphorylation. We show that Pak has no effect on MLC phosphorylation during the contraction of airway smooth muscle, and that it regulates contraction by mediating actin polymerization. We find that Pak phosphorylates the adhesion junction protein, paxillin, on Ser273, which promotes the formation of a signalling complex that activates the small GTPase, cdc42, and the actin polymerization catalyst, neuronal Wiskott-Aldrich syndrome protein (N-WASP). These studies demonstrate a novel role for Pak in regulating the contractility of smooth muscle by regulating actin polymerization. The p21-activated kinases (Pak) can regulate contractility in smooth muscle and other cell and tissue types, but the mechanisms by which Paks regulate cell contractility are unclear. In airway smooth muscle, stimulus-induced contraction requires phosphorylation of the 20 kDa light chain of myosin, which activates crossbridge cycling, as well as the polymerization of a small pool of actin. The role of Pak in airway smooth muscle contraction was evaluated by inhibiting acetylcholine (ACh)-induced Pak activation through the expression of a kinase inactive mutant, Pak1 K299R, or by treating tissues with the Pak inhibitor, IPA3. Pak inhibition suppressed actin polymerization and contraction in response to ACh, but it did not affect myosin light chain phosphorylation. Pak activation induced paxillin phosphorylation on Ser273; the paxillin mutant, paxillin S273A, inhibited paxillin Ser273 phosphorylation and inhibited actin polymerization and contraction. Immunoprecipitation analysis of tissue extracts and proximity ligation assays in dissociated cells showed that Pak activation and paxillin Ser273 phosphorylation triggered the formation of an adhesion junction signalling complex with paxillin that included G-protein-coupled receptor kinase-interacting protein (GIT1) and the cdc42 guanine exchange factor, βPIX (Pak interactive exchange factor). Assembly of the Pak-GIT1-βPIX-paxillin complex was necessary for cdc42 and neuronal Wiskott-Aldrich syndrome protein (N-WASP) activation, actin polymerization and contraction in response to ACh. RhoA activation was also required for the recruitment of Pak to adhesion junctions, Pak activation, paxillin Ser273 phosphorylation and paxillin complex assembly. These studies demonstrate a novel role for Pak in the regulation of N-WASP activation, actin dynamics and cell contractility. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

p21‐Activated kinase (Pak) regulates airway smooth muscle contraction by regulating paxillin complexes that mediate actin polymerization

PubMed Central

Zhang, Wenwu; Huang, Youliang

2016-01-01

Key points In airway smooth muscle, tension development caused by a contractile stimulus requires phosphorylation of the 20 kDa myosin light chain (MLC), which activates crossbridge cycling and the polymerization of a pool of submembraneous actin.The p21‐activated kinases (Paks) can regulate the contractility of smooth muscle and non‐muscle cells, and there is evidence that this occurs through the regulation of MLC phosphorylation.We show that Pak has no effect on MLC phosphorylation during the contraction of airway smooth muscle, and that it regulates contraction by mediating actin polymerization.We find that Pak phosphorylates the adhesion junction protein, paxillin, on Ser273, which promotes the formation of a signalling complex that activates the small GTPase, cdc42, and the actin polymerization catalyst, neuronal Wiskott–Aldrich syndrome protein (N‐WASP).These studies demonstrate a novel role for Pak in regulating the contractility of smooth muscle by regulating actin polymerization. Abstract The p21‐activated kinases (Pak) can regulate contractility in smooth muscle and other cell and tissue types, but the mechanisms by which Paks regulate cell contractility are unclear. In airway smooth muscle, stimulus‐induced contraction requires phosphorylation of the 20 kDa light chain of myosin, which activates crossbridge cycling, as well as the polymerization of a small pool of actin. The role of Pak in airway smooth muscle contraction was evaluated by inhibiting acetylcholine (ACh)‐induced Pak activation through the expression of a kinase inactive mutant, Pak1 K299R, or by treating tissues with the Pak inhibitor, IPA3. Pak inhibition suppressed actin polymerization and contraction in response to ACh, but it did not affect myosin light chain phosphorylation. Pak activation induced paxillin phosphorylation on Ser273; the paxillin mutant, paxillin S273A, inhibited paxillin Ser273 phosphorylation and inhibited actin polymerization and contraction. Immunoprecipitation analysis of tissue extracts and proximity ligation assays in dissociated cells showed that Pak activation and paxillin Ser273 phosphorylation triggered the formation of an adhesion junction signalling complex with paxillin that included G‐protein‐coupled receptor kinase‐interacting protein (GIT1) and the cdc42 guanine exchange factor, βPIX (Pak interactive exchange factor). Assembly of the Pak–GIT1–βPIX–paxillin complex was necessary for cdc42 and neuronal Wiskott–Aldrich syndrome protein (N‐WASP) activation, actin polymerization and contraction in response to ACh. RhoA activation was also required for the recruitment of Pak to adhesion junctions, Pak activation, paxillin Ser273 phosphorylation and paxillin complex assembly. These studies demonstrate a novel role for Pak in the regulation of N‐WASP activation, actin dynamics and cell contractility. PMID:27038336

Effects of minoxidil and nitroprusside on reflex increases in myocardial contractility.

PubMed Central

Robie, N W

1978-01-01

1 The effects of nitroprusside and minoxidil on increases in myocardial contractility resulting from carotid artery occlusion were investigated in anaesthetized dogs. The results were compared with those produced by intravenous influsion of noradrenaline. 2 Nitroprusside and minoxidil attenuated the pressor responses produced by carotid artery occlusion. 3 Nitroprusside, but not minoxidil, attenuated the maximal myocardial contractility resulting from carotid occlusion. 4 The pressor and contractility responses to noradrenaline infusion were unaffected by either agent. 5 Nitroprusside failed to alter the myocardial responses produced by dimethylphenylpiperazinium. 6 These results, in conjunction with those of other investigators who have demonstrated that nitroprusside does not affect the release of noradrenaline from adrenergic neurons, suggest that nitroprusside may inhibit sympathetic nervous system reflex activity via an afferent and/or central component. PMID:620094

Contractile ring stability in S. pombe depends on F-BAR protein Cdc15p and Bgs1p transport from the Golgi complex.

PubMed

Arasada, Rajesh; Pollard, Thomas D

2014-09-11

Cdc15p is known to contribute to cytokinesis in fission yeast; however, the protein is not required to assemble the contractile ring of actin and myosin, but it helps to anchor the ring to the plasma membrane. Cdc15p has a lipid-binding F-BAR domain, suggesting that it provides a physical link between the plasma membrane and contractile ring proteins. However, we find that a more important function of Cdc15p during cytokinesis is to help deliver a transmembrane enzyme, Bgs1p (also called Cps1p), from the Golgi apparatus to the plasma membrane, where it appears to anchor the contractile ring. Bgs1p synthesizes the cell wall in the cleavage furrow, but its enzyme activity is not required to anchor the contractile ring. We estimate that ∼ 2,000 Bgs1p molecules are required to anchor the ring. Without Bgs1p anchors, contractile rings slide along the plasma membrane, a phenomenon that depends on an unconventional type II myosin called Myp2p. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

FAST: A fully asynchronous and status-tracking pattern for geoprocessing services orchestration

NASA Astrophysics Data System (ADS)

Wu, Huayi; You, Lan; Gui, Zhipeng; Gao, Shuang; Li, Zhenqiang; Yu, Jingmin

2014-09-01

Geoprocessing service orchestration (GSO) provides a unified and flexible way to implement cross-application, long-lived, and multi-step geoprocessing service workflows by coordinating geoprocessing services collaboratively. Usually, geoprocessing services and geoprocessing service workflows are data and/or computing intensive. The intensity feature may make the execution process of a workflow time-consuming. Since it initials an execution request without blocking other interactions on the client side, an asynchronous mechanism is especially appropriate for GSO workflows. Many critical problems remain to be solved in existing asynchronous patterns for GSO including difficulties in improving performance, status tracking, and clarifying the workflow structure. These problems are a challenge when orchestrating performance efficiency, making statuses instantly available, and constructing clearly structured GSO workflows. A Fully Asynchronous and Status-Tracking (FAST) pattern that adopts asynchronous interactions throughout the whole communication tier of a workflow is proposed for GSO. The proposed FAST pattern includes a mechanism that actively pushes the latest status to clients instantly and economically. An independent proxy was designed to isolate the status tracking logic from the geoprocessing business logic, which assists the formation of a clear GSO workflow structure. A workflow was implemented in the FAST pattern to simulate the flooding process in the Poyang Lake region. Experimental results show that the proposed FAST pattern can efficiently tackle data/computing intensive geoprocessing tasks. The performance of all collaborative partners was improved due to the asynchronous mechanism throughout communication tier. A status-tracking mechanism helps users retrieve the latest running status of a GSO workflow in an efficient and instant way. The clear structure of the GSO workflow lowers the barriers for geospatial domain experts and model designers to compose asynchronous GSO workflows. Most importantly, it provides better support for locating and diagnosing potential exceptions.

Developing asynchronous online interprofessional education.

PubMed

Sanborn, Heidi

2016-09-01

For many health programmes, developing interprofessional education (IPE) has been a challenge. Evidence on the best method for design and implementation of IPE has been slow to emerge, with little research on how to best incorporate IPE in the asynchronous online learning environment. This leaves online programmes with no clear guidance when embarking upon an initiative to integrate IPE into the curriculum. One tool that can be effective at guiding the incorporation of IPE across all learning platforms is the Interprofessional Education Collaborative (IPEC) competencies. A project was designed to integrate the nationally defined IPEC competencies throughout an asynchronous, online baccalaureate nursing completion programme. A programme-wide review led to targeted revision of course and unit-level objectives, learning experiences, and assessments based on the IPEC framework. As a result of this effort, the programme curriculum now provides interprofessional learning activities across all courses. This report provides a method for using the IPEC competencies to incorporate IPE within various asynchronous learning assessments, assuring students learn about, with, and from other professions.

Nitric oxide and CaMKII: Critical steps in the cardiac contractile response To IGF-1 and swim training.

PubMed

Burgos, Juan I; Yeves, Alejandra M; Barrena, Jorge P; Portiansky, Enrique L; Vila-Petroff, Martín G; Ennis, Irene L

2017-11-01

Cardiac adaptation to endurance training includes improved contractility by a non-yet clarified mechanism. Since IGF-1 is the main mediator of the physiological response to exercise, we explored its effect on cardiac contractility and the putative involvement of nitric oxide (NO) and CaMKII in control and swim-trained mice. IGF-1 increased cardiomyocyte shortening (128.1±4.6% vs. basal; p˂0.05) and accelerated relaxation (time to 50% relengthening: 49.2±2.0% vs. basal; p˂0.05), effects abrogated by inhibition of: AKT with MK-2206, NO production with the NO synthase (NOS) inhibitor L-NAME and the specific NOS1 inhibitor nitroguanidine (NG), and CaMKII with KN-93. In agreement, an increase in NO in response to IGF-1 (133.8±2.2%) was detected and prevented by both L-NAME and NG but not KN-93, suggesting that CaMKII activation was downstream NO. In addition, we determined CaMKII activity (P-CaMKII) and phosphorylation of its target, Thr17-PLN. IGF-1, by a NO-dependent mechanism, significantly increased both (227.2±29.4% and 145.3±5.4%, respectively) while no changes in the CaMKII phosphorylation site of ryanodine receptor were evident. The improvement in contractility induced by IGF-1 was associated with increased Ca 2+ transient amplitude, rate of decay and SR content. Interestingly, this response was absent in cardiomyocytes from transgenic mice that express a CaMKII inhibitory peptide (AC3-I strain). Moreover, AC3-I mice subjected to swim training did develop physiological cardiac hypertrophy but not the contractile adaptation. Therefore, we conclude that NO-dependent CaMKII activation plays a critical role in the improvement in contractility induced by IGF-1 and exercise training. Interestingly, this pathway would not contribute to the adaptive hypertrophy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mechanisms of TNFalpha-induced cardiac dysfunction in cholestatic bile duct-ligated mice: interaction between TNFalpha and endocannabinoids.

PubMed

Yang, Ying-Ying; Liu, Hongqun; Nam, Soon Woo; Kunos, George; Lee, Samuel S

2010-08-01

Chronic liver disease is associated with endotoxemia, oxidative stress, increased endocannabinoids and decreased cardiac responsiveness. Endocannabinoids activate the tumor necrosis factor-alpha (TNFalpha)-nuclear factor kappaB (NFkappaB) pathway. However, how they interact with each other remains obscure. We therefore aimed to clarify the relationship between the TNFalpha-NFkappaB pathway and endocannabinoids in the pathogenesis of cardiodepression of cholestatic bile duct ligated (BDL) mice. BDL mice with TNFalpha knockout (TNFalpha-/-) and infusion of anti-TNFalpha antibody were used. Cardiac mRNA and protein expression of NFkappaBp65, c-Jun-N-terminal kinases (JNK), p38 mitogen-activated protein kinase (p38MAPK), extracelullar-signal- regulated kinase (ERK), inducible nitric oxide synthase (iNOS), Copper/Zinc and Magnesium-superoxide dismutase (Cu/ Zn- and Mn-SOD), cardiac anandamide, 2-arachidonoylglycerol (2-AG), nitric oxide (NOx) and glutathione, and plasma TNFalpha were measured. The effects of TNFalpha, cannabinoid receptor (CB1) antagonist AM251 and the endocannabinoid reuptake inhibitor UCM707, on the contractility of isolated cardiomyocytes, were assessed. In BDL mice, cardiac mRNA and protein expression of NFkappaBp65, p38MAPK, iNOS, NOx, anandamide, and plasma TNFa were increased, whereas glutathione, Cu/Zn-SOD, and Mn-SOD were decreased. Cardiac contractility was blunted in BDL mice. Anti-TNFa treatment in BDL mice decreased cardiac anandamide and NOx, reduced expression of NFkappaBp65, p38MAPK, and iNOS, enhanced expression of Cu/Zn-SOD and Mn-SOD, increased reductive glutathione and restored cardiomyocyte contractility. TNFa-depressed contractility was worsened by UCM707, whereas AM251 improved contractility. Increased TNFalpha, acting via NFkappaB-iNOS and p38MAPK signaling pathways, plays an important role in the pathogenesis of cardiodepression in BDL mice. TNFalpha also suppressed contractility by increasing oxidative stress and endocannabinoid activity.

BK Channel-Mediated Relaxation of Urinary Bladder Smooth Muscle: A Novel Paradigm for Phosphodiesterase Type 4 Regulation of Bladder Function

PubMed Central

Xin, Wenkuan; Li, Ning; Cheng, Qiuping

2014-01-01

Elevation of intracellular cAMP and activation of protein kinase A (PKA) lead to activation of large conductance voltage- and Ca2+-activated K+ (BK) channels, thus attenuation of detrusor smooth muscle (DSM) contractility. In this study, we investigated the mechanism by which pharmacological inhibition of cAMP-specific phosphodiesterase 4 (PDE4) with rolipram or Ro-20-1724 (C15H22N2O3) suppresses guinea pig DSM excitability and contractility. We used high-speed line-scanning confocal microscopy, ratiometric fluorescence Ca2+ imaging, and perforated whole-cell patch-clamp techniques on freshly isolated DSM cells, along with isometric tension recordings of DSM isolated strips. Rolipram caused an increase in the frequency of Ca2+ sparks and the spontaneous transient BK currents (TBKCs), hyperpolarized the cell membrane potential (MP), and decreased the intracellular Ca2+ levels. Blocking BK channels with paxilline reversed the hyperpolarizing effect of rolipram and depolarized the MP back to the control levels. In the presence of H-89 [N-[2-[[3-(4-bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulfonamide dihydrochloride], a PKA inhibitor, rolipram did not cause MP hyperpolarization. Rolipram or Ro-20-1724 reduced DSM spontaneous and carbachol-induced phasic contraction amplitude, muscle force, duration, and frequency, and electrical field stimulation-induced contraction amplitude, muscle force, and tone. Paxilline recovered DSM contractility, which was suppressed by pretreatment with PDE4 inhibitors. Rolipram had reduced inhibitory effects on DSM contractility in DSM strips pretreated with paxilline. This study revealed a novel cellular mechanism whereby pharmacological inhibition of PDE4 leads to suppression of guinea pig DSM contractility by increasing the frequency of Ca2+ sparks and the functionally coupled TBKCs, consequently hyperpolarizing DSM cell MP. Collectively, this decreases the global intracellular Ca2+ levels and DSM contractility in a BK channel-dependent manner. PMID:24459245

Stimulatory action of itopride hydrochloride on colonic motor activity in vitro and in vivo.

PubMed

Tsubouchi, Tadashi; Saito, Takaharu; Mizutani, Fujie; Yamauchi, Toshie; Iwanaga, Yuji

2003-08-01

We investigated the effects of itopride hydrochloride (itopride, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride), a gastroprokinetic agent, on the colonic motor activity in vitro and in vivo, in comparison with benzamides, cisapride hydrate (cisapride), and mosapride citrate (mosapride). Itopride stimulated both peristaltic and segmental motility induced by applying intraluminal pressure to the isolated guinea pig colon. Although cisapride and mosapride enhanced the segmental motility, they markedly reduced the peristaltic motility. In conscious dogs with implanted strain gauge force transducers, itopride stimulated contractile activity in the gastrointestinal tract from the stomach to the colon. Cisapride stimulated contractile activity in the gastric antrum, ileum, and ascending colon. Mosapride stimulated contractile activity only in the gastric antrum and ileum. In guinea pigs and rats, itopride accelerated colonic luminal transit. On the other hand, cisapride and mosapride failed to enhance colonic transit. These results demonstrate that itopride has a stimulatory action on colonic peristalsis, propelling colonic luminal contents, different from that of cisapride and mosapride. Therefore, itopride may be a useful drug for the treatment of functional bowel disorders such as functional constipation.

Why eicosanoids could represent a new class of tocolytics on uterine activity in pregnant women.

PubMed

Corriveau, Stéphanie; Berthiaume, Maryse; Rousseau, Eric; Pasquier, Jean-Charles

2009-10-01

The purpose of this study was to assess the effects of exogenous eicosanoids on spontaneous uterine contractile activity. Eight uterine biopsies were performed from women who were undergoing elective cesarean delivery. Tension measurements were performed in vitro on myometrial strips. Contractile activities were quantified by the calculation of the area under the curve. The effects of eicosanoids and specific enzyme inhibitors were assessed. Fractions from various uterine tissues were analyzed by Western blot. Data demonstrate the presence, in some tested tissues, of cytochrome P-450 epoxygenase and soluble epoxide hydrolase, which respectively produce and degrade epoxyeicosatrienoic acid regioisomers. Inhibition of soluble epoxide hydrolase with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid or omega-hydroxylase with N-methylsulfonyl-12,12-dibromododec-11-enamide resulted in a tocolytic effect; N-methylsulfonyl-6-[2-propargyloxyphenyl] hexanamide, which is an epoxygenase inhibitor, had no effect. Exogenous epoxyeicosatrienoic acids displayed significant tocolytic effects on spontaneous contractile activities. Epoxy- and hydroxyeicosanoids represent new bioactive, arachidonic acid by-products with in vitro tocolytic activities. These findings suggest that cytochrome P-450 isozymes may represent relevant pharmacologic targets under physiopathologic conditions.

Contractile properties of skinned muscle fibres from young and adult normal and dystrophic (mdx) mice.

PubMed Central

Williams, D A; Head, S I; Lynch, G S; Stephenson, D G

1993-01-01

1. Single muscle fibres were enzymatically isolated from the soleus and extensor digitorum longus (EDL) muscles of genetically dystrophic mdx and normal (C57BL/10) mice aged 3-6 or 17-23 weeks. 2. Fibres of both muscles were chemically skinned with the non-ionic detergent Triton X-100 (2% v/v). Ca(2+)- and Sr(2+)-activated contractile responses were recorded and comparisons were made between several contractile parameters of various fibre types of normal and dystrophic mice of similar age. 3. There were no significant differences in the following contractile parameters of skinned fibres of normal and mdx mice of the same age: sensitivity to activating Ca2+ (pCa50) or Sr2+ (pSr50) and differential sensitivity to the activating ions (pCa50-pSr50). However the maximum isometric tension (Po) and the frequency of myofibrillar force oscillations in EDL fast-twitch fibres of young mdx mice were significantly lower than those of soleus fast-twitch fibres of the same animals, or fast-twitch fibres (EDL or soleus) of normal mice. 4. Age-related differences were apparent in some contractile parameters of both normal and mdx mice. In particular the steepness of force-pCa and force-pSr curves increased with age in normal mice, yet decreased with age in fibres of mdx mice. 5. A fluorescent probe, ethidium bromide, which interchelates with DNA, was used with laser-scanning confocal microscopy to determine the distribution of myonuclei in fibres. Fibres isolated from either muscle type of normal animals displayed a characteristic peripheral spiral of myonuclei. Fibres from muscles of mdx mice displayed three major patterns of nuclear distribution; the normal peripheral spiral, long central strands of nuclei, and a mixture of these two patterns. 6. The contractile characteristics of mdx fibres were not markedly influenced by the nuclear distribution pattern in that there were no discernible differences in the major contractile parameters (the Hill coefficients nCa and nSr, which are associated with the steepness of the Ca2+ and Sr2+ activation curves, pCa50, pSr50, pCa50-pSr50) of skinned fibres possessing peripheral or central nuclei. However, except for nSr, these values were all lower in individual fibres which displayed similar proportions of central and peripheral nuclei. The presence of mixed nucleation and absence of fibres with embryonic contractile characteristics in mdx mice suggest that the dystrophin-negative fibres can repair locally occurring muscle damage. Images Fig. 1 Fig. 1(Contd.) Fig. 4 Fig. 5 PMID:8487206

Role of mechanics in the appearance of oscillatory instability and standing waves of the mechanochemical activity in the Physarum polycephalum plasmodium

NASA Astrophysics Data System (ADS)

Teplov, Vladimir A.

2017-06-01

The modes of continuously distributed mechanochemical self-sustained oscillations (autowaves) exhibited by the Physarum plasmodium under different experimental conditions are reviewed. The role of the stretch-induced activation of contractile oscillations in the spatiotemporal self-organization of the plasmodium is elucidated. Different mathematical models describing contractile autowaves in ectoplasm and the streaming of the endoplasm are considered. Our mathematical models, which are based on the hypothesis of local positive feedback between the deformation and contraction of the contractile apparatus, are also presented. The feedback is mediated through a chemical regulatory system, whose kinetics involves the coupling to the mechanical strain. The mathematical analysis and computer simulations have demonstrated that the solutions of the models agree quantitatively with the experimental data. In particular, the only hydrodynamic interactions between the different parts of the plasmodium via the streaming endoplasm can lead to globally coordinated ectoplasmic contractions and vigorous shuttle endoplasmic streaming. These models, with empirically determined values of the viscoelastic parameters, well simulate the form and duration of the transient contractile processes observed after the isolation of the strands as well as the subsequent excitation of auto-oscillations and their stretch-induced activation under isotonic and isometric conditions.

Increased CCT-eta expression is a marker of latent and active disease and a modulator of fibroblast contractility in Dupuytren's contracture.

PubMed

Satish, Latha; O'Gorman, David B; Johnson, Sandra; Raykha, Christina; Gan, Bing Siang; Wang, James H-C; Kathju, Sandeep

2013-07-01

Dupuytren's contracture (DC) is a fibroproliferative disorder of unknown etiology characterized by a scar-like contracture that develops in the palm and/or digits. We have previously reported that the eta subunit of the chaperonin containing T-complex polypeptide (CCT-eta) is increased in fibrotic wound healing, and is essential for the accumulation of α-smooth muscle actin (α-SMA) in fibroblasts. The purpose of this study was to determine if CCT-eta is similarly implicated in the aberrant fibrosis seen in DC and to investigate the role of CCT-eta in the behavior of myo/fibroblasts in DC. Fibroblasts were obtained from DC-affected palmar fascia, from adjacent phenotypically normal palmar fascia in the same DC patients (PF), and from non-DC palmar fascial tissues in patients undergoing carpal tunnel (CT) release. Inherent contractility in these three populations was examined using fibroblast-populated collagen lattices (FPCLs) and by cell traction force microscopy. Expression of CCT-eta and α-SMA protein was determined by Western blot. The effect of CCT-eta inhibition on the contractility of DC cells was determined by deploying an siRNA versus CCT-eta. DC cells were significantly more contractile than both matching palmar fascial (PF) cells and CT cells in both assays, with PF cells demonstrating an intermediate contractility in the FPCL assay. Whereas α-SMA protein was significantly increased only in DC cells compared to PF and CT cells, CCT-eta protein was significantly increased in both PF and DC cells compared to CT cells. siRNA-mediated depletion of CCT-eta inhibited the accumulation of both CCT-eta and α-SMA protein in DC cells, and also significantly decreased the contractility of treated DC cells. These observations suggest that increased expression of CCT-eta appears to be a marker for latent and active disease in these patients and to be essential for the increased contractility exhibited by these fibroblasts.

Nitric oxide signaling pathways involved in the inhibition of spontaneous activity in the guinea pig prostate.

PubMed

Dey, Anupa; Lang, Richard J; Exintaris, Betty

2012-06-01

We investigated nitric oxide mediated inhibition of spontaneous activity recorded in young and aging guinea pig prostates. Conventional intracellular microelectrode and tension recording techniques were used. The nitric oxide donor sodium nitroprusside (10 μM) abolished spontaneous contractions and slow wave activity in 5 young and 5 aging prostates. Upon adding the nitric oxide synthase inhibitor L-NAME (10 μM) the frequency of spontaneous contractile and electrical activity was significantly increased in each age group. This increase was significantly larger in 4 to 8 preparations of younger vs aging prostates (about 40% to 50% vs about 10% to 20%, 2-way ANOVA p<0.01). Other measured parameters, including the duration, amplitude and membrane potential of spontaneous electrical and contractile activity, were not altered from control values. The guanylate cyclase inhibitor ODQ (10 μM) significantly increased the frequency of spontaneous activity by 10% to 30% in 6 young guinea pig prostates (Student paired t test p<0.05). However, it had no effect on aging prostates. The cGMP analogue 8-Br-GMP (1 μM) and the PDE5 inhibitor dipyridamole (1 μM) significantly decreased the frequency of contractile activity by about 70% in 4 to 9 young and older prostates (Student paired t test p<0.05). The decrease in the response to L-NAME in spontaneous contractile and slow wave activity in aging prostate tissue compared to that in young prostates suggests that with age there is a decrease in nitric oxide production. This may further explain the increase in prostatic smooth muscle tone observed in age related prostate specific conditions, such as benign prostatic hyperplasia. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Pharmacological characterisation of extracts of coffee dusts.

PubMed Central

Zuskin, E; Duncan, P G; Douglas, J S

1983-01-01

The contractile or relaxant activities or both of aqueous extracts of green and roasted coffees were assayed on isolated guinea pig tracheal spirals. Contractile and relaxant activities were compared with histamine and theophylline, respectively. Green coffee extracts induced concentration dependent contraction, but the maximal tension never exceeded 76.3% +/- 5.2 of a maximal histamine contraction (0.69 +/- 0.07 g/mm2 v 0.52 +/- 0.05 g/mm2; p (0.01). One gram of green coffee dust had a biological activity equivalent to 1.23 +/- 0.1 mg of histamine. The pD2 value of histamine was -5.17 +/- 0.05. The potency of green coffee was unaffected by mepyramine maleate (1 micrograms/ml, final bath concentration) while that of histamine was reduced 500 fold. Tissues contracted with histamine were not significantly relaxed by green coffee extracts. By contrast, roasted coffee extracts induced concentration dependent relaxation of uncontracted and histamine contracted tissues. Tissues contracted with green coffee extracts were also completely relaxed by roasted coffee extracts. The pD2 value of theophylline was -4.10 +/- 0.03. The relaxant activity of 1 g of roasted coffee was equivalent to 1.95 +/- 0.16 mg of theophylline. The potency of these extracts was significantly reduced after propranolol (1 micrograms/ml; dose ratio 1.56). Our results show that coffee dust extracts have considerable biological activity which changes from a contractile to a relaxant action as a consequence of processing. The greater incidence of adverse reactions to green coffee dust(s) in coffee workers may be related to the contractile activity present in green coffee dust. PMID:6830717

An exploration of teaching presence in online interprofessional education facilitation.

PubMed

Evans, Sherryn Maree; Ward, Catherine; Reeves, Scott

2017-07-01

Although the prevalence of online asynchronous interprofessional education (IPE) has increased in the last decade, little is known about the processes of facilitation in this environment. The teaching presence element of the Community of Inquiry Framework offers an approach to analyze the contributions of online facilitators, however, to date it has only been used on a limited basis in health professions education literature. Using an exploratory case study design, we explored the types of contributions made by IPE facilitators to asynchronous interprofessional team discussions by applying the notion of teaching presence. Using a purposeful sampling approach, we analyzed 14 facilitators' contributions to asynchronous team discussion boards in an online IPE course. We analyzed data using directed content analysis based on the key indicators of teaching presence. The online IPE facilitators undertook the three critical pedagogical functions identified in teaching presence: facilitating discourse, direct instruction, and instructional design and organization. While our data fitted well with a number of key activities embedded in these three functions, further modification of the teaching presence concept was needed to describe our facilitators' teaching presence. This study provides an initial insight into the key elements of online asynchronous IPE facilitation. Further research is required to continue to illuminate the complexity of online asynchronous IPE facilitation.

Asynchronous P300 classification in a reactive brain-computer interface during an outlier detection task

NASA Astrophysics Data System (ADS)

Krumpe, Tanja; Walter, Carina; Rosenstiel, Wolfgang; Spüler, Martin

2016-08-01

Objective. In this study, the feasibility of detecting a P300 via an asynchronous classification mode in a reactive EEG-based brain-computer interface (BCI) was evaluated. The P300 is one of the most popular BCI control signals and therefore used in many applications, mostly for active communication purposes (e.g. P300 speller). As the majority of all systems work with a stimulus-locked mode of classification (synchronous), the field of applications is limited. A new approach needs to be applied in a setting in which a stimulus-locked classification cannot be used due to the fact that the presented stimuli cannot be controlled or predicted by the system. Approach. A continuous observation task requiring the detection of outliers was implemented to test such an approach. The study was divided into an offline and an online part. Main results. Both parts of the study revealed that an asynchronous detection of the P300 can successfully be used to detect single events with high specificity. It also revealed that no significant difference in performance was found between the synchronous and the asynchronous approach. Significance. The results encourage the use of an asynchronous classification approach in suitable applications without a potential loss in performance.

Actomyosin contractility rotates the cell nucleus

PubMed Central

Kumar, Abhishek; Maitra, Ananyo; Sumit, Madhuresh; Ramaswamy, Sriram; Shivashankar, G. V.

2014-01-01

The cell nucleus functions amidst active cytoskeletal filaments, but its response to their contractile stresses is largely unexplored. We study the dynamics of the nuclei of single fibroblasts, with cell migration suppressed by plating onto micro-fabricated patterns. We find the nucleus undergoes noisy but coherent rotational motion. We account for this observation through a hydrodynamic approach, treating the nucleus as a highly viscous inclusion residing in a less viscous fluid of orientable filaments endowed with active stresses. Lowering actin contractility selectively by introducing blebbistatin at low concentrations drastically reduced the speed and coherence of the angular motion of the nucleus. Time-lapse imaging of actin revealed a correlated hydrodynamic flow around the nucleus, with profile and magnitude consistent with the results of our theoretical approach. Coherent intracellular flows and consequent nuclear rotation thus appear to be an intrinsic property of cells. PMID:24445418

Actomyosin contractility rotates the cell nucleus.

PubMed

Kumar, Abhishek; Maitra, Ananyo; Sumit, Madhuresh; Ramaswamy, Sriram; Shivashankar, G V

2014-01-21

The cell nucleus functions amidst active cytoskeletal filaments, but its response to their contractile stresses is largely unexplored. We study the dynamics of the nuclei of single fibroblasts, with cell migration suppressed by plating onto micro-fabricated patterns. We find the nucleus undergoes noisy but coherent rotational motion. We account for this observation through a hydrodynamic approach, treating the nucleus as a highly viscous inclusion residing in a less viscous fluid of orientable filaments endowed with active stresses. Lowering actin contractility selectively by introducing blebbistatin at low concentrations drastically reduced the speed and coherence of the angular motion of the nucleus. Time-lapse imaging of actin revealed a correlated hydrodynamic flow around the nucleus, with profile and magnitude consistent with the results of our theoretical approach. Coherent intracellular flows and consequent nuclear rotation thus appear to be an intrinsic property of cells.

Superoxide anion stress attenuates the contractile response of the Guinea pig vas deferens to ATP and diadenosine tetraphosphate. Possible effect on calcium dysregulation.

PubMed

Al-Rawi, Mahmood B; Aleisa, Abdulaziz M; Khattab, Mahmoud M

2008-01-01

Induction of endogenous superoxide anion stress by the use of the superoxide dismutase inhibitor diethylthiocarbamate (DETCA; 10 mmol/l) produced a potent inhibition of the ATP (0.3-10 mmol/l) and diadenosine tetraphosphate (AP(4)A) contractile activity in the isolated vas deferens by 29-92 and 24-90%, respectively. Pyrogallol (0.1 mmol/l), the exogenous superoxide anion generator, produced a significant inhibition on the contractile activity of the vas deferens induced by ATP and AP(4)A by 33-89 and 25-82%, respectively. DETCA (10 mmol/l) and pyrogallol (0.1 mmol/l) attenuated the contractile response of isolated guinea pig vas deferens strips to the selective P2X agonist alpha,beta-methyleneATP (alpha,beta-meATP; 50 micromol/l) by 25 and 47%, respectively. In Ca(2+)-free high-K(+) (80 mmol/l) Krebs solution, pyrogallol and DETCA produced inhibition of the contractile response to alpha,beta-meATP (50 micromol/l) in similar way to that in normal Krebs solution. The further addition of CaCl(2) (1 mmol/l) abolished the inhibitory effects exerted by pyrogallol and DETCA. The control contractile response to alpha,beta-meATP (50 micromol/l) was not affected in Ca(2+)-free high-K(+) (80 mmol/l) Krebs solution. It may be concluded that superoxide anion stress produces a significant inhibitory effect on both mono- and di-nucleotide purinergic contraction of the vas deferens. Superoxide anion appears to interrupt the P2X(1)-mediated transduction cascade at some step(s) of intracellular calcium handling. Copyright 2008 S. Karger AG, Basel.

Pulvinar thalamic nucleus allows for asynchronous spike propagation through the cortex

PubMed Central

Cortes, Nelson; van Vreeswijk, Carl

2015-01-01

We create two multilayered feedforward networks composed of excitatory and inhibitory integrate-and-fire neurons in the balanced state to investigate the role of cortico-pulvino-cortical connections. The first network consists of ten feedforward levels where a Poisson spike train with varying firing rate is applied as an input in layer one. Although the balanced state partially avoids spike synchronization during the transmission, the average firing-rate in the last layer either decays or saturates depending on the feedforward pathway gain. The last layer activity is almost independent of the input even for a carefully chosen intermediate gain. Adding connections to the feedforward pathway by a nine areas Pulvinar structure improves the firing-rate propagation to become almost linear among layers. Incoming strong pulvinar spikes balance the low feedforward gain to have a unit input-output relation in the last layer. Pulvinar neurons evoke a bimodal activity depending on the magnitude input: synchronized spike bursts between 20 and 80 Hz and an asynchronous activity for very both low and high frequency inputs. In the first regime, spikes of last feedforward layer neurons are asynchronous with weak, low frequency, oscillations in the rate. Here, the uncorrelated incoming feedforward pathway washes out the synchronized thalamic bursts. In the second regime, spikes in the whole network are asynchronous. As the number of cortical layers increases, long-range pulvinar connections can link directly two or more cortical stages avoiding their either saturation or gradual activity falling. The Pulvinar acts as a shortcut that supplies the input-output firing-rate relationship of two separated cortical areas without changing the strength of connections in the feedforward pathway. PMID:26042026

Calcium handling precedes cardiac differentiation to initiate the first heartbeat

PubMed Central

Tyser, Richard CV; Miranda, Antonio MA; Chen, Chiann-mun; Davidson, Sean M

2016-01-01

The mammalian heartbeat is thought to begin just prior to the linear heart tube stage of development. How the initial contractions are established and the downstream consequences of the earliest contractile function on cardiac differentiation and morphogenesis have not been described. Using high-resolution live imaging of mouse embryos, we observed randomly distributed spontaneous asynchronous Ca2+-oscillations (SACOs) in the forming cardiac crescent (stage E7.75) prior to overt beating. Nascent contraction initiated at around E8.0 and was associated with sarcomeric assembly and rapid Ca2+ transients, underpinned by sequential expression of the Na+-Ca2+ exchanger (NCX1) and L-type Ca2+ channel (LTCC). Pharmacological inhibition of NCX1 and LTCC revealed rapid development of Ca2+ handling in the early heart and an essential early role for NCX1 in establishing SACOs through to the initiation of beating. NCX1 blockade impacted on CaMKII signalling to down-regulate cardiac gene expression, leading to impaired differentiation and failed crescent maturation. DOI: http://dx.doi.org/10.7554/eLife.17113.001 PMID:27725084

Contractile activity of the bladder urothelium/lamina propria and its regulation by nitric oxide.

PubMed

Moro, Christian; Leeds, Charlotte; Chess-Williams, Russ

2012-01-15

In the bladder, nitric oxide (NO) is released from neuronal and non-neuronal sources, but its actions are unclear. Strips of urothelium plus lamina propria contract in response to agonists and develop spontaneous phasic contractions, and the aim of this study was to investigate the influence of NO on this activity. Isolated strips of urothelium/lamina propria from porcine bladder developed spontaneous contractions (3.5 ± 0.3 cycles/min) and contracted in response to carbachol and electrical field stimulation (EFS). The NO synthase inhibitor N(ω)-nitro-l-arginine (L-NNA, 100 μM) had no effects on the tissues, but the NO donors diethylamine NONOate (DEANO, 100 μM) and nitroprusside (10 μM) caused relaxation, slowed the spontaneous rate of contractions and inhibited responses to carbachol. Maximum tonic contractions to carbachol were reduced by 17 ± 4% (P<0.001) and 35 ± 5% (P<0.001) by DEANO and nitroprusside respectively and the potency of carbachol was also reduced. Carbachol also increased the spontaneous frequency of contraction and these rate responses were again inhibited by DEANO and nitroprusside, but unaffected by L-NNA. Similarly, responses to EFS were significantly depressed (52-70%) by DEANO (P<0.05), but were unaffected by L-NNA. These data demonstrate spontaneous contractile activity and also nerve and agonist-induced tonic contractile activity within the urothelium and lamina propria. This activity is sensitive to depression by NO, but NO does not appear to be spontaneously released to influence this activity, nor does it appear to be released by muscarinic receptor stimulation. However the results suggest that in situations where NO production is increased, NO can influence the contractile activity of this tissue. Copyright © 2011 Elsevier B.V. All rights reserved.

Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization

PubMed Central

Mao, Lan; Pierce, Stephanie L.; Swamy, Geeta K.; Heine, R. Phillips; Murtha, Amy P.

2016-01-01

Oxytocin is a potent uterotonic agent and is used clinically for induction and augmentation of labor, as well as for prevention and treatment of postpartum hemorrhage. Oxytocin increases uterine contractility by activating the oxytocin receptor (OXTR), a member of the G protein-coupled receptor family, which is prone to molecular desensitization. After oxytocin binding, the OXTR is phosphorylated by a member of the G protein-coupled receptor kinase (GRK) family, which allows for recruitment of β-arrestin, receptor internalization, and desensitization. According to previous in vitro analyses, desensitization of calcium signaling by the OXTR is mediated by GRK6. The objective of this study was to determine the role of GRK6 in mediating uterine contractility. Here, we demonstrate that uterine GRK6 levels increase in pregnancy and using a telemetry device to measure changes in uterine contractility in live mice during labor, show that mice lacking GRK6 produce a phenotype of enhanced uterine contractility during both spontaneous and oxytocin-induced labor compared with wild-type or GRK5 knockout mice. In addition, the observed enhanced contractility was associated with high rates of term stillbirth. Lastly, using a heterologous in vitro model, we show that β-arrestin recruitment to the OXTR, which is necessary for homologous OXTR desensitization, is dependent on GRK6. Our findings suggest that GRK6-mediated OXTR desensitization in labor is necessary for normal uterine contractile patterns and optimal fetal outcome. PMID:26886170

Coupled expression of troponin T and troponin I isoforms in single skeletal muscle fibers correlates with contractility.

PubMed

Brotto, Marco A; Biesiadecki, Brandon J; Brotto, Leticia S; Nosek, Thomas M; Jin, Jian-Ping

2006-02-01

Striated muscle contraction is powered by actin-activated myosin ATPase. This process is regulated by Ca(2+) via the troponin complex. Slow- and fast-twitch fibers of vertebrate skeletal muscle express type I and type II myosin, respectively, and these myosin isoenzymes confer different ATPase activities, contractile velocities, and force. Skeletal muscle troponin has also diverged into fast and slow isoforms, but their functional significance is not fully understood. To investigate the expression of troponin isoforms in mammalian skeletal muscle and their functional relationship to that of the myosin isoforms, we concomitantly studied myosin, troponin T (TnT), and troponin I (TnI) isoform contents and isometric contractile properties in single fibers of rat skeletal muscle. We characterized a large number of Triton X-100-skinned single fibers from soleus, diaphragm, gastrocnemius, and extensor digitorum longus muscles and selected fibers with combinations of a single myosin isoform and a single class (slow or fast) of the TnT and TnI isoforms to investigate their role in determining contractility. Types IIa, IIx, and IIb myosin fibers produced higher isometric force than that of type I fibers. Despite the polyploidy of adult skeletal muscle fibers, the expression of fast or slow isoforms of TnT and TnI is tightly coupled. Fibers containing slow troponin had higher Ca(2+) sensitivity than that of the fast troponin fibers, whereas fibers containing fast troponin showed a higher cooperativity of Ca(2+) activation than that of the slow troponin fibers. These results demonstrate distinct but coordinated regulation of troponin and myosin isoform expression in skeletal muscle and their contribution to the contractile properties of muscle.

Coupled expression of troponin T and troponin I isoforms in single skeletal muscle fibers correlates with contractility

PubMed Central

BROTTO, MARCO A.; BIESIADECKI, BRANDON J.; BROTTO, LETICIA S.; NOSEK, THOMAS M; JIN, J.-P.

2005-01-01

(Summary) Brotto, Marco A., Brandon J. Biesiadecki, Leticia S. Brotto, Thomas M. Nosek, and J.-P. Jin. Striated muscle contraction is powered by actin-activated myosin ATPase. This process is regulated by Ca2+ via the troponin complex. Slow and fast twitch fibers of vertebrate skeletal muscle express type I and type II myosin, respectively, and these myosin isoenzymes confer different ATPase activities, contractile velocities and force. Skeletal muscle troponin has also diverged into fast and slow isoforms, but their functional significance is not fully understood. To investigate the expression of troponin isoforms in mammalian skeletal muscle and their functional relationship to that of the myosin isoforms, we concomitantly studied myosin and troponin T (TnT) and troponin I (TnI) isoform contents and isometric contractile properties in single fibers of rat skeletal muscle. We characterized a large number of Triton skinned single fibers from soleus, diaphragm, gastrocnemius and extensor digitorum longus muscles and selected fibers with combinations of a single myosin isoform and a single class (slow or fast) of TnT and TnI isoform to investigate their role in determining contractility. Type IIa, IIx and IIb myosin fibers produced higher isometric force than that of type I fibers. Despite the polyploidy of adult skeletal muscle fibers, the expression of fast or slow isoforms of TnT and TnI is tightly coupled. Fibers containing slow troponin had higher Ca2+ sensitivity than that of the fast troponin fibers, while fibers containing fast troponin showed a higher cooperativity of Ca2+ activation than that of the slow troponin fibers. The results demonstrate distinctive, but coordinated, regulation of troponin and myosin isoform expression in skeletal muscle and their contribution to the contractile properties. PMID:16192301

Diadenosine tetra- and pentaphosphates affect contractility and bioelectrical activity in the rat heart via P2 purinergic receptors.

PubMed

Pustovit, Ksenia B; Kuzmin, Vladislav S; Abramochkin, Denis V

2016-03-01

Diadenosine polyphosphates (Ap(n)As) are endogenously produced molecules which have been identified in various tissues of mammalian organism, including myocardium. Ap(n)As contribute to the blood clotting and are also widely accepted as regulators of blood vascular tone. Physiological role of Ap(n)As in cardiac muscle has not been completely elucidated. The present study aimed to investigate the effects of diadenosine tetra- (Ap4A) and penta- (Ap5A) polyphosphates on contractile function and action potential (AP) waveform in rat supraventricular and ventricular myocardium. We have also demonstrated the effects of A4pA and Ap5A in myocardial sleeves of pulmonary veins (PVs), which play a crucial role in genesis of atrial fibrillation. APs were recorded with glass microelectrodes in multicellular myocardial preparations. Contractile activity was measured in isolated Langendorff-perfused rat hearts. Both Ap4A and Ap5A significantly reduced contractility of isolated Langendorff-perfused heart and produced significant reduction of AP duration in left and right auricle, interatrial septum, and especially in right ventricular wall myocardium. Ap(n)As also shortened APs in rat pulmonary veins and therefore may be considered as potential proarrhythmic factors. Cardiotropic effects of Ap4A and Ap5A were strongly antagonized by selective blockers of P2 purine receptors suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), while P1 blocker DPCPX was not effective. We conclude that Ap(n)As may be considered as new class of endogenous cardioinhibitory compounds. P2 purine receptors play the central role in mediation of Ap4A and Ap5A inhibitory effects on electrical and contractile activity in different regions of the rat heart.

Effect of chronic, extrinsic denervation on functional NANC innervation with vasoactive intestinal polypeptide and substance P in longitudinal muscle of rat jejunum.

PubMed

Kasparek, M S; Fatima, J; Iqbal, C W; Duenes, J A; Sarr, M G

2008-03-01

Intestinal denervation contributes to enteric motor dysfunction after intestinal transplantation [small bowel transplantation (SBT)]. Our aim was to determine long-term effects of extrinsic denervation on functional non-adrenergic, non-cholinergic innervation with vasoactive intestinal polypeptide (VIP) and substance P. Contractile activity of jejunal longitudinal muscle from six age-matched, naïve control rats (NC) and eight rats 1 year after syngeneic SBT were studied in tissue chambers. Spontaneous contractile activity did not differ between groups. Exogenous VIP inhibited contractile activity dose-dependently in both groups, greater in NC than in SBT. The VIP antagonist ([D-p-Cl-Phe(6),Leu(17)]-VIP) and the nitric oxide synthase inhibitor l-N(G)-nitro arginine prevented inhibition by exogenous VIP and electrical field stimulation (EFS) in both groups. Exogenous substance P increased contractile activity dose-dependently, greater in NC than in SBT. The substance P antagonist ([D-Pro(2),D-Trp(7,9)]-substance P) inhibited effects of exogenous substance P and increased the EFS-induced inhibitory response. Immunohistofluorescence showed staining for tyrosine hydroxylase in the jejunoileum 1 year after SBT suggesting sympathetic reinnervation. In rat jejunal longitudinal muscle after chronic denervation, response to exogenous VIP and substance P is decreased, while endogenous release of both neurotransmitters is preserved. These alterations in excitatory and inhibitory pathways occur despite extrinsic reinnervation and might contribute to enteric motor dysfunction after SBT.

Effect of chronic, extrinsic denervation on functional NANC innervation with vasoactive intestinal polypeptide and substance P in longitudinal muscle of rat jejunum1

PubMed Central

KASPAREK, M. S.; FATIMA, J.; IQBAL, C. W.; DUENES, J. A.; SARR, M. G.

2008-01-01

Intestinal denervation contributes to enteric motor dysfunction after intestinal transplantation [small bowel transplantation (SBT)]. Our aim was to determine long-term effects of extrinsic denervation on functional non-adrenergic, non-cholinergic innervation with vasoactive intestinal polypeptide (VIP) and substance P. Contractile activity of jejunal longitudinal muscle from six age-matched, naïve control rats (NC) and eight rats 1 year after syngeneic SBT were studied in tissue chambers. Spontaneous contractile activity did not differ between groups. Exogenous VIP inhibited contractile activity dose-dependently in both groups, greater in NC than in SBT. The VIP antagonist ([D-p-Cl-Phe6,Leu17]-VIP) and the nitric oxide synthase inhibitor L-NG-nitro arginine prevented inhibition by exogenous VIP and electrical field stimulation (EFS) in both groups. Exogenous substance P increased contractile activity dose-dependently, greater in NC than in SBT. The substance P antagonist ([D-Pro2,D-Trp7,9]-substance P) inhibited effects of exogenous substance P and increased the EFS-induced inhibitory response. Immunohistofluorescence showed staining for tyrosine hydroxylase in the jejunoileum 1 year after SBT suggesting sympathetic reinnervation. In rat jejunal longitudinal muscle after chronic denervation, response to exogenous VIP and substance P is decreased, while endogenous release of both neurotransmitters is preserved. These alterations in excitatory and inhibitory pathways occur despite extrinsic reinnervation and might contribute to enteric motor dysfunction after SBT. PMID:17971029

Assessment of the Contractile Properties of Permeabilized Skeletal Muscle Fibers.

PubMed

Claflin, Dennis R; Roche, Stuart M; Gumucio, Jonathan P; Mendias, Christopher L; Brooks, Susan V

2016-01-01

Permeabilized individual skeletal muscle fibers offer the opportunity to evaluate contractile behavior in a system that is greatly simplified, yet physiologically relevant. Here we describe the steps required to prepare, permeabilize and preserve small samples of skeletal muscle. We then detail the procedures used to isolate individual fiber segments and attach them to an experimental apparatus for the purpose of controlling activation and measuring force generation. We also describe our technique for estimating the cross-sectional area of fiber segments. The area measurement is necessary for normalizing the absolute force to obtain specific force, a measure of the intrinsic force-generating capability of the contractile system.

First report on an inotropic peptide activating tetrodotoxin-sensitive, "neuronal" sodium currents in the heart.

PubMed

Kirchhof, Paulus; Tal, Tzachy; Fabritz, Larissa; Klimas, Jan; Nesher, Nir; Schulte, Jan S; Ehling, Petra; Kanyshkova, Tatayana; Budde, Thomas; Nikol, Sigrid; Fortmueller, Lisa; Stallmeyer, Birgit; Müller, Frank U; Schulze-Bahr, Eric; Schmitz, Wilhelm; Zlotkin, Eliahu; Kirchhefer, Uwe

2015-01-01

New therapeutic approaches to improve cardiac contractility without severe risk would improve the management of acute heart failure. Increasing systolic sodium influx can increase cardiac contractility, but most sodium channel activators have proarrhythmic effects that limit their clinical use. Here, we report the cardiac effects of a novel positive inotropic peptide isolated from the toxin of the Black Judean scorpion that activates neuronal tetrodotoxin-sensitive sodium channels. All venoms and peptides were isolated from Black Judean Scorpions (Buthotus Hottentotta) caught in the Judean Desert. The full scorpion venom increased left ventricular function in sedated mice in vivo, prolonged ventricular repolarization, and provoked ventricular arrhythmias. An inotropic peptide (BjIP) isolated from the full venom by chromatography increased cardiac contractility but did neither provoke ventricular arrhythmias nor prolong cardiac repolarization. BjIP increased intracellular calcium in ventricular cardiomyocytes and prolonged inactivation of the cardiac sodium current. Low concentrations of tetrodotoxin (200 nmol/L) abolished the effect of BjIP on calcium transients and sodium current. BjIP did not alter the function of Nav1.5, but selectively activated the brain-type sodium channels Nav1.6 or Nav1.3 in cellular electrophysiological recordings obtained from rodent thalamic slices. Nav1.3 (SCN3A) mRNA was detected in human and mouse heart tissue. Our pilot experiments suggest that selective activation of tetrodotoxin-sensitive neuronal sodium channels can safely increase cardiac contractility. As such, the peptide described here may become a lead compound for a new class of positive inotropic agents. © 2014 American Heart Association, Inc.

Calcium-responsive contractility during fertilization in sea urchin eggs.

PubMed

Stack, Christianna; Lucero, Amy J; Shuster, Charles B

2006-04-01

Fertilization triggers a reorganization of oocyte cytoskeleton, and in sea urchins, there is a dramatic increase in cortical F-actin. However, the role that myosin II plays during fertilization remains largely unexplored. Myosin II is localized to the cortical cytoskeleton both before and after fertilization and to examine myosin II contractility in living cells, Lytechinus pictus eggs were observed by time-lapse microscopy. Upon sperm binding, a cell surface deflection traversed the egg that was followed by and dependent on the calcium wave. The calcium-dependence of surface contractility could be reproduced in unfertilized eggs, where mobilization of intracellular calcium in unfertilized eggs under compression resulted in a marked contractile response. Lastly, inhibition of myosin II delayed absorption of the fertilization cone, suggesting that myosin II not only responds to the same signals that activate eggs but also participates in the remodeling of the cortical actomyosin cytoskeleton during the first zygotic cell cycle. (c) 2006 Wiley-Liss, Inc.

Calcium-Responsive Contractility During Fertilization in Sea Urchin Eggs

PubMed Central

Stack, Christianna; Lucero, Amy J.; Shuster, Charles B.

2008-01-01

Fertilization triggers a reorganization of oocyte cytoskeleton, and in sea urchins there is a dramatic increase in cortical F-actin. However, the role that myosin II plays during fertilization remains largely unexplored. Myosin II is localized to the cortical cytoskeleton both prior to- and following fertilization, and to examine myosin II contractility in living cells, Lytechinus pictus eggs were observed by time-lapse microscopy. Upon sperm binding, a cell surface deflection traversed the egg that was followed- and dependent on the calcium wave. The calcium-dependence of surface contractility could be reproduced in unfertilized eggs, where mobilization of intracellular calcium in unfertilized eggs under compression resulted in a marked contractile response. Lastly, inhibition of myosin II delayed absorption of the fertilization cone, suggesting that myosin II not only responds to the same signals that activate eggs, but also participates in the remodeling of the cortical actomyosin cytoskeleton during the first zygotic cell cycle. PMID:16470603

Effects of Mechanical Coupling Between Cardiomyocytes and Cardiac Fibroblasts on Myocardium

NASA Astrophysics Data System (ADS)

Zorlutuna, Pinar; Nguyen, Trung Dung; Nagarajan, Neerajha

Cardiomyocytes show excitatory responses to stimulation solely by mechanical forces through their stretch-activated ion channels, and can fire action potentials upon mechanical stimulation through a pathway known as mechano-electric feedback. Furthermore, cardiomyocyte (CM) - cardiac fibroblasts (CF) can couple mechanically through cell-cell junctions. Here we investigated the effects of CM and CF mechanical coupling on myocardial physiology and pathology using a bio-nanoindentered coupled with fast calcium imaging and microelectrode arrays. In order to study mechanical signal transmission, we measured the contractile forces generated by CMs, as well as by CFs that were coupled to the CMs. We observed that CFs were beating with the same frequency but at smaller magnitude compared to CMs, and their contractility was dependent on the substrate stiffness. Our results showed that beating CMs actively stretched neighbouring CFs through the deformation of the substrate the cells were seeded on, which promoted the myocardial contractility through mechanical coupling. The results also revealed that CM contractility was propagated greater on soft substrates than stiff ones. Results of this study could help identify the role of the infarcted tissue stiffness and size on heart failure. This study is supported by NSF Grant No: 1530884.

Ultraslow myosin molecular motors of placental contractile stem villi in humans.

PubMed

Lecarpentier, Yves; Claes, Victor; Lecarpentier, Edouard; Guerin, Catherine; Hébert, Jean-Louis; Arsalane, Abdelilah; Moumen, Abdelouahab; Krokidis, Xénophon; Michel, Francine; Timbely, Oumar

2014-01-01

Human placental stem villi (PSV) present contractile properties. In vitro mechanics were investigated in 40 human PSV. Contraction of PSV was induced by both KCl exposure (n = 20) and electrical tetanic stimulation (n = 20). Isotonic contractions were registered at several load levels ranging from zero-load up to isometric load. The tension-velocity relationship was found to be hyperbolic. This made it possible to apply the A. Huxley formalism for determining the rate constants for myosin cross-bridge (CB) attachment and detachment, CB single force, catalytic constant, myosin content, and maximum myosin ATPase activity. These molecular characteristics of myosin CBs did not differ under either KCl exposure or tetanus. A comparative approach was established from studies previously published in the literature and driven by mean of a similar method. As compared to that described in mammalian striated muscles, we showed that in human PSV, myosin CB rate constants for attachment and detachment were about 103 times lower whereas myosin ATPase activity was 105 times lower. Up to now, CB kinetics of contractile cells arranged along the long axis of the placental sheath appeared to be the slowest ever observed in any mammalian contractile tissue.

Probing the contractile vacuole as Achilles' heel of the biotrophic grapevine pathogen Plasmopara viticola.

PubMed

Tröster, Viktoria; Setzer, Tabea; Hirth, Thomas; Pecina, Anna; Kortekamp, Andreas; Nick, Peter

2017-09-01

The causative agent of Grapevine Downy Mildew, the oomycete Plasmopara viticola, poses a serious threat to viticulture. In the current work, the contractile vacuole of the zoospore is analysed as potential target for novel plant protection strategies. Using a combination of electron microscopy, spinning disc confocal microscopy, and video differential interference contrast microscopy, we have followed the genesis and dynamics of this vacuole required during the search for the stomata, when the non-walled zoospore is exposed to hypotonic conditions. This subcellular description was combined with a pharmacological study, where the functionality of the contractile vacuole was blocked by manipulation of actin, by Na, Cu, and Al ions or by inhibition of the NADPH oxidase. We further observe that RGD peptides (mimicking binding sites for integrins at the extracellular matrix) can inhibit the function of the contractile vacuole as well. Finally, we show that an extract from Chinese liquorice (Glycyrrhiza uralensis) proposed as biocontrol for Downy Mildews can efficiently induce zoospore burst and that this activity depends on the activity of NADPH oxidase. The effect of the extract can be phenocopied by its major compound, glycyrrhizin, suggesting a mode of action for this biologically safe alternative to copper products.

Osmolality- and Na+ -dependent effects of hyperosmotic NaCl solution on contractile activity and Ca2+ cycling in rat ventricular myocytes.

PubMed

Ricardo, Rafael A; Bassani, Rosana A; Bassani, José W M

2008-01-01

Hypertonic NaCl solutions have been used for small-volume resuscitation from hypovolemic shock. We sought to identify osmolality- and Na(+)-dependent components of the effects of the hyperosmotic NaCl solution (85 mOsm/kg increment) on contraction and cytosolic Ca(2+) concentration ([Ca(2+)](i)) in isolated rat ventricular myocytes. The biphasic change in contraction and Ca(2+) transient amplitude (decrease followed by recovery) was accompanied by qualitatively similar changes in sarcoplasmic reticulum (SR) Ca(2+) content and fractional release and was mimicked by isosmotic, equimolar increase in extracellular [Na(+)] ([Na(+)](o)). Raising osmolality with sucrose, however, augmented systolic [Ca(2+)](i) monotonically without change in SR parameters and markedly decreased contraction amplitude and diastolic cell length. Functional SR inhibition with thapsigargin abolished hyperosmolality effects on [Ca(2+)](i). After 15-min perfusion, both hyperosmotic solutions slowed mechanical relaxation during twitches and [Ca(2+)](i) decline during caffeine-evoked transients, raised diastolic and systolic [Ca(2+)](i), and depressed systolic contractile activity. These effects were greater with sucrose solution, and were not observed after isosmotic [Na(+)](o) increase. We conclude that under the present experimental conditions, transmembrane Na(+) redistribution apparently plays an important role in determining changes in SR Ca(2+) mobilization, which markedly affect contractile response to hyperosmotic NaCl solutions and attenuate the osmotically induced depression of contractile activity.

Substance P activates both contractile and inflammatory pathways in lymphatics through the neurokinin receptors NK1R and NK3R.

PubMed

Chakraborty, Sanjukta; Nepiyushchikh, Zhanna; Davis, Michael J; Zawieja, David C; Muthuchamy, Mariappan

2011-01-01

The aim of this study was to elucidate the molecular signaling mechanisms by which substance P (SP) modulates lymphatic muscle contraction and to determine whether SP stimulates both contractile as well as inflammatory pathways in the lymphatics. A rat mesenteric lymphatic muscle cell culture model (RMLMCs) and known specific pharmacological inhibitors were utilized to delineate SP-mediated signaling pathways in lymphatics. We detected expression of neurokinin receptor 1 (NK1R) and neurokinin receptor 3 (NK3R) in RMLMCs. SP stimulation increased phosphorylation of myosin light chain 20 (MLC₂₀) as well as p38 mitogen associated protein kinase (p38-MAPK) and extracellular signal regulated kinase (ERK1/2) indicating activation of both a contractile and a pro-inflammatory MAPK pathway. Pharmacological inhibition of both NK1R and NK3R significantly affected the downstream SP signaling. We further examined whether there was any crosstalk between the two pathways upon SP stimulation. Inhibition of ERK1/2 decreased levels of p-MLC₂₀ after SP activation, in a PKC dependent manner, indicating a potential crosstalk between these two pathways. These data provide the first evidence that SP-mediated crosstalk between pro-inflammatory and contractile signaling mechanisms exists in the lymphatic system and may be an important bridge between lymphatic function modulation and inflammation. © 2010 John Wiley & Sons Ltd.

Substance P activates both contractile and inflammatory pathways in lymphatics through the neurokinin receptors NK1R and NK3R

PubMed Central

Chakraborty, Sanjukta; Nepiyushchikh, Zhanna; Davis, Michael J.; Zawieja, David C.; Muthuchamy, Mariappan

2010-01-01

Objective The aim of this study was to elucidate the molecular signaling mechanisms by which substance P (SP) modulates lymphatic muscle contraction and to determine whether SP stimulates both contractile as well as inflammatory pathways in the lymphatics. Methods A rat mesenteric lymphatic muscle cell culture model (RMLMCs) and known specific pharmacological inhibitors were utilized to delineate SP mediated signaling pathways in lymphatics. Results We detected expression of neurokinin receptor 1 (NK1R) and neurokinin receptor 3 (NK3R) in RMLMCs. SP stimulation increased phosphorylation of myosin light chain 20 (MLC20) as well as p38 mitogen associated protein kinase (p38-MAPK) and extracellular signal regulated kinase (ERK1/2) indicating activation of both a contractile and a pro-inflammatory MAPK pathway. Pharmacological inhibition of both NK1R and NK3R significantly affected the downstream SP signaling. We further examined whether there was any crosstalk between the two pathways upon SP stimulation. Inhibition of ERK1/2 decreased levels of p-MLC20 after SP activation, in a PKC dependent manner, indicating a potential crosstalk between these two pathways. Conclusions These data provide the first evidence that SP mediated crosstalk between pro-inflammatory and contractile signaling mechanisms exists in the lymphatic system and may be an important bridge between lymphatic function modulation and inflammation. PMID:21166923

Rho Kinase (ROCK) collaborates with Pak to Regulate Actin Polymerization and Contraction in Airway Smooth Muscle.

PubMed

Zhang, Wenwu; Bhetwal, Bhupal P; Gunst, Susan J

2018-05-10

The mechanisms by which Rho kinase (ROCK) regulates airway smooth muscle contraction were determined in tracheal smooth muscle tissues. ROCK may mediate smooth muscle contraction by inhibiting myosin regulatory light chain (RLC) phosphatase. ROCK can also regulate F-actin dynamics during cell migration, and actin polymerization is critical for airway smooth muscle contraction. Our results show that ROCK does not regulate airway smooth muscle contraction by inhibiting myosin RLC phosphatase or by stimulating myosin RLC phosphorylation. We find that ROCK regulates airway smooth muscle contraction by activating the serine-threonine kinase Pak, which mediates the activation of Cdc42 and Neuronal-Wiskott-Aldrich Syndrome protein (N-WASp). N-WASP transmits signals from cdc42 to the Arp2/3 complex for the nucleation of actin filaments. These results demonstrate a novel molecular function for ROCK in the regulation of Pak and cdc42 activation that is critical for the processes of actin polymerization and contractility in airway smooth muscle. Rho kinase (ROCK), a RhoA GTPase effector, can regulate the contraction of airway and other smooth muscle tissues. In some tissues, ROCK can inhibit myosin regulatory light chain (RLC) phosphatase, which increases the phosphorylation of myosin RLC and promotes smooth muscle contraction. ROCK can also regulate cell motility and migration by affecting F-actin dynamics. Actin polymerization is stimulated by contractile agonists in airway smooth muscle tissues and is required for contractile tension development in addition to myosin RLC phosphorylation. We investigated the mechanisms by which ROCK regulates the contractility of tracheal smooth muscle tissues by expressing a kinase inactive mutant of ROCK, ROCK-K121G, in the tissues or by treating them with the ROCK inhibitor, H-1152P. Our results show no role for ROCK in the regulation of non-muscle or smooth muscle myosin RLC phosphorylation during contractile stimulation in this tissue. We find that ROCK regulates airway smooth muscle contraction by mediating activation of the serine-threonine kinase, Pak, to promote actin polymerization. Pak catalyzes paxillin phosphorylation on Ser273 and coupling of the GIT1-βPIX-Pak signaling module to paxillin, which activates the GEF activity βPIX towards cdc42. Cdc42 is required for the activation of Neuronal Wiskott-Aldrich Syndrome protein (N-WASp), which transmits signals from cdc42 to the Arp2/3 complex for the nucleation of actin filaments. Our results demonstrate a novel molecular function for ROCK in the regulation of Pak and cdc42 activation that is critical for the processes of actin polymerization and contractility in airway smooth muscle. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Effects of divalent cations and La3+ on contractility and ecto-ATPase activity in the guinea-pig urinary bladder.

PubMed Central

Ziganshin, A U; Ziganshina, L E; Hoyle, C H; Burnstock, G

1995-01-01

1. Several cations (Ba2+, Cd2+, Co2+, Cu2+, Mn2+, Ni2+, Zn2+ and La3+, all as chloride salts, 1-1000 microM) were tested in the guinea-pig urinary bladder for their ability to: (i) modify contractile responses to electrical field stimulation (EFS), ATP, alpha,beta-methylene ATP (alpha,beta-meATP), carbachol (CCh), and KCl; (ii) affect ecto-ATPase activity. 2. Ba2+ (10-1000 microM) concentration-dependently potentiated contractile responses evoked by EFS (4-16 Hz), ATP (100 microM), alpha,beta-meATP (1 microM), CCh (0.5 microM), and KCl (30 mM). Ni2+ at concentrations of 1-100 microM also potentiated contractility of the urinary bladder, but at concentrations tested its effect was not concentration-dependent. Cu2+ at a concentration of 10 microM and Cd2+ at a concentration of 1 microM potentiated responses to all stimuli, except KCl. Ni2+ at a concentration of 1000 microM and Cd2+ at a concentration of 100 microM inhibited contractions evoked by all stimuli, and at a concentration of 1000 microM Cd2+ abolished any contractions. Responses to ATP and alpha,beta-meATP were selectively inhibited by Cu2+, Zn2+ or La3+, each at a concentration of 1 mM. 3. Cu2+, Ni2+, Zn2+ and La3+ (100-1000 microM) concentration-dependently inhibited ecto-ATPase activity in the urinary bladder smooth muscle preparations, while Ba2+ and Mn2+ were without effect, and Cd2+ and Co2+ caused significant inhibition only at a concentration of 1000 microM. 4. There was no correlation between the extent of ecto-ATPase inhibition and the effect on contractile activity of any of the cations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7735690

Mitochondrial matrix metalloproteinase activation decreases myocyte contractility in hyperhomocysteinemia.

PubMed

Moshal, Karni S; Tipparaju, Srinivas M; Vacek, Thomas P; Kumar, Munish; Singh, Mahavir; Frank, Iluiana E; Patibandla, Phani K; Tyagi, Neetu; Rai, Jayesh; Metreveli, Naira; Rodriguez, Walter E; Tseng, Michael T; Tyagi, Suresh C

2008-08-01

Cardiomyocyte N-methyl-d-aspartate receptor-1 (NMDA-R1) activation induces mitochondrial dysfunction. Matrix metalloproteinase protease (MMP) induction is a negative regulator of mitochondrial function. Elevated levels of homocysteine [hyperhomocysteinemia (HHCY)] activate latent MMPs and causes myocardial contractile abnormalities. HHCY is associated with mitochondrial dysfunction. We tested the hypothesis that HHCY activates myocyte mitochondrial MMP (mtMMP), induces mitochondrial permeability transition (MPT), and causes contractile dysfunction by agonizing NMDA-R1. The C57BL/6J mice were administered homocystinemia (1.8 g/l) in drinking water to induce HHCY. NMDA-R1 expression was detected by Western blot and confocal microscopy. Localization of MMP-9 in the mitochondria was determined using confocal microscopy. Ultrastructural analysis of the isolated myocyte was determined by electron microscopy. Mitochondrial permeability was measured by a decrease in light absorbance at 540 nm using the spectrophotometer. The effect of MK-801 (NMDA-R1 inhibitor), GM-6001 (MMP inhibitor), and cyclosporine A (MPT inhibitor) on myocyte contractility and calcium transients was evaluated using the IonOptix video edge track detection system and fura 2-AM. Our results demonstrate that HHCY activated the mtMMP-9 and caused MPT by agonizing NMDA-R1. A significant decrease in percent cell shortening, maximal rate of contraction (-dL/dt), and maximal rate of relaxation (+dL/dt) was observed in HHCY. The decay of calcium transient amplitude was faster in the wild type compared with HHCY. Furthermore, the HHCY-induced decrease in percent cell shortening, -dL/dt, and +dL/dt was attenuated in the mice treated with MK-801, GM-6001, and cyclosporin A. We conclude that HHCY activates mtMMP-9 and induces MPT, leading to myocyte mechanical dysfunction by agonizing NMDA-R1.

Effects of Hange-shashin-to (TJ-14) and Keishi-ka-shakuyaku-to (TJ-60) on contractile activity of circular smooth muscle of the rat distal colon.

PubMed

Kito, Yoshihiko; Teramoto, Noriyoshi

2012-11-01

The Japanese Kampo medicines Hange-shashin-to (TJ-14) and Keishi-ka-shakuyaku-to (TJ-60) have been used to treat symptoms of human diarrhea on an empirical basis as Japanese traditional medicines. However, it remains unclear how these drugs affect smooth muscle tissues in the distal colon. The aim of the present study was to investigate the effects of TJ-14 and TJ-60 on the contractile activity of circular smooth muscle from the rat distal colon. TJ-14 and TJ-60 (both 1 mg/ml) inhibited spontaneous contractions of circumferentially cut preparations with the mucosa intact. Blockade of nitric oxide (NO) synthase or soluble guanylate cyclase activity abolished the inhibitory effects of TJ-60 but only attenuated the inhibitory effects of TJ-14. Apamin (1 μM), a blocker of small-conductance Ca(2+)-activated K(+) channels (SK channels), attenuated the inhibitory effects of 5 mg/ml TJ-60 but not those of 5 mg/ml TJ-14. TJ-14 suppressed contractile responses (phasic contractions and off-contractions) evoked by transmural nerve stimulation and increased basal tone, whereas TJ-60 had little effect on these parameters. These results suggest that 1 mg/ml TJ-14 or TJ-60 likely inhibits spontaneous contractions of the rat distal colon through the production of NO. Activation of SK channels seems to be involved in the inhibitory effects of 5 mg/ml TJ-60. Since TJ-14 has potent inhibitory effects on myogenic and neurogenic contractile activity, TJ-14 may be useful in suppressing gastrointestinal motility.

Spontaneous flow in polar active fluids: the effect of a phenomenological self propulsion-like term.

PubMed

Bonelli, Francesco; Gonnella, Giuseppe; Tiribocchi, Adriano; Marenduzzo, Davide

2016-01-01

We present hybrid lattice Boltzmann simulations of extensile and contractile active fluids where we incorporate phenomenologically the tendency of active particles such as cell and bacteria, to move, or swim, along the local orientation. Quite surprisingly, we show that the interplay between alignment and activity can lead to completely different results, according to geometry (periodic boundary conditions or confinement between flat walls) and nature of the activity (extensile or contractile). An interesting generic outcome is that the alignment interaction can transform stationary active patterns into continuously moving ones: the dynamics of these evolving patterns can be oscillatory or chaotic according to the strength of the alignment term. Our results suggest that flow-polarisation alignment can have important consequences on the collective dynamics of active fluids and active gel.

DAI-CLIPS: Distributed, Asynchronous, Interacting CLIPS

NASA Technical Reports Server (NTRS)

Gagne, Denis; Garant, Alain

1994-01-01

DAI-CLIPS is a distributed computational environment within which each CLIPS is an active independent computational entity with the ability to communicate freely with other CLIPS. Furthermore, new CLIPS can be created, others can be deleted or modify their expertise, all dynamically in an asynchronous and independent fashion during execution. The participating CLIPS are distributed over a network of heterogeneous processors taking full advantage of the available processing power. We present the general framework encompassing DAI-CLIPS and discuss some of its advantages and potential applications.

LncRNA ZFAS1 as a SERCA2a Inhibitor to Cause Intracellular Ca2+ Overload and Contractile Dysfunction in a Mouse Model of Myocardial Infarction.

PubMed

Zhang, Ying; Jiao, Lei; Sun, Lihua; Li, Yanru; Gao, Yuqiu; Xu, Chaoqian; Shao, Yingchun; Li, Mengmeng; Li, Chunyan; Lu, Yanjie; Pan, Zhenwei; Xuan, Lina; Zhang, Yiyuan; Li, Qingqi; Yang, Rui; Zhuang, Yuting; Zhang, Yong; Yang, Baofeng

2018-05-11

Ca 2+ homeostasis-a critical determinant of cardiac contractile function-is critically regulated by SERCA2a (sarcoplasmic reticulum Ca 2+ -ATPase 2a). Our previous study has identified ZFAS1 as a new lncRNA biomarker of acute myocardial infarction (MI). To evaluate the effects of ZFAS1 on SERCA2a and the associated Ca 2+ homeostasis and cardiac contractile function in the setting of MI. ZFAS1 expression was robustly increased in cytoplasm and sarcoplasmic reticulum in a mouse model of MI and a cellular model of hypoxia. Knockdown of endogenous ZFAS1 by virus-mediated silencing shRNA partially abrogated the ischemia-induced contractile dysfunction. Overexpression of ZFAS1 in otherwise normal mice created similar impairment of cardiac function as that observed in MI mice. Moreover, at the cellular level, ZFAS1 overexpression weakened the contractility of cardiac muscles. At the subcellular level, ZFAS1 deleteriously altered the Ca 2+ transient leading to intracellular Ca 2+ overload in cardiomyocytes. At the molecular level, ZFAS1 was found to directly bind SERCA2a protein and to limit its activity, as well as to repress its expression. The effects of ZFAS1 were readily reversible on knockdown of this lncRNA. Notably, a sequence domain of ZFAS1 gene that is conserved across species mimicked the effects of the full-length ZFAS1 . Mutation of this domain or application of an antisense fragment to this conserved region efficiently canceled out the deleterious actions of ZFAS1 . ZFAS1 had no significant effects on other Ca 2+ -handling regulatory proteins. ZFAS1 is an endogenous SERCA2a inhibitor, acting by binding to SERCA2a protein to limit its intracellular level and inhibit its activity, and a contributor to the impairment of cardiac contractile function in MI. Therefore, anti- ZFAS1 might be considered as a new therapeutic strategy for preserving SERCA2a activity and cardiac function under pathological conditions of the heart. © 2018 The Authors.

Repeated high-intensity exercise modulates Ca(2+) sensitivity of human skeletal muscle fibers.

PubMed

Gejl, K D; Hvid, L G; Willis, S J; Andersson, E; Holmberg, H-C; Jensen, R; Frandsen, U; Hansen, J; Plomgaard, P; Ørtenblad, N

2016-05-01

The effects of short-term high-intensity exercise on single fiber contractile function in humans are unknown. Therefore, the purposes of this study were: (a) to access the acute effects of repeated high-intensity exercise on human single muscle fiber contractile function; and (b) to examine whether contractile function was affected by alterations in the redox balance. Eleven elite cross-country skiers performed four maximal bouts of 1300 m treadmill skiing with 45 min recovery. Contractile function of chemically skinned single fibers from triceps brachii was examined before the first and following the fourth sprint with respect to Ca(2+) sensitivity and maximal Ca(2+) -activated force. To investigate the oxidative effects of exercise on single fiber contractile function, a subset of fibers was incubated with dithiothreitol (DTT) before analysis. Ca(2+) sensitivity was enhanced by exercise in both MHC I (17%, P < 0.05) and MHC II (15%, P < 0.05) fibers. This potentiation was not present after incubation of fibers with DTT. Specific force of both MHC I and MHC II fibers was unaffected by exercise. In conclusion, repeated high-intensity exercise increased Ca(2+) sensitivity in both MHC I and MHC II fibers. This effect was not observed in a reducing environment indicative of an exercise-induced oxidation of the human contractile apparatus. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Thrombin-induced contraction in alveolar epithelial cells probed by traction microscopy.

PubMed

Gavara, Núria; Sunyer, Raimon; Roca-Cusachs, Pere; Farré, Ramon; Rotger, Mar; Navajas, Daniel

2006-08-01

Contractile tension of alveolar epithelial cells plays a major role in the force balance that regulates the structural integrity of the alveolar barrier. The aim of this work was to study thrombin-induced contractile forces of alveolar epithelial cells. A549 alveolar epithelial cells were challenged with thrombin, and time course of contractile forces was measured by traction microscopy. The cells exhibited basal contraction with total force magnitude 55.0 +/- 12.0 nN (mean +/- SE, n = 12). Traction forces were exerted predominantly at the cell periphery and pointed to the cell center. Thrombin (1 U/ml) induced a fast and sustained 2.5-fold increase in traction forces, which maintained peripheral and centripetal distribution. Actin fluorescent staining revealed F-actin polymerization and enhancement of peripheral actin rim. Disruption of actin cytoskeleton with cytochalasin D (5 microM, 30 min) and inhibition of myosin light chain kinase with ML-7 (10 microM, 30 min) and Rho kinase with Y-27632 (10 microM, 30 min) markedly depressed basal contractile tone and abolished thrombin-induced cell contraction. Therefore, the contractile response of alveolar epithelial cells to the inflammatory agonist thrombin was mediated by actin cytoskeleton remodeling and actomyosin activation through myosin light chain kinase and Rho kinase signaling pathways. Thrombin-induced contractile tension might further impair alveolar epithelial barrier integrity in the injured lung.

Skeletal muscle contractile properties in a novel murine model for limb girdle muscular dystrophy 2i.

PubMed

Rehwaldt, Jordan D; Rodgers, Buel D; Lin, David C

2017-12-01

Limb-girdle muscular dystrophy (LGMD) 2i results from mutations in fukutin-related protein and aberrant α-dystroglycan glycosylation. Although this significantly compromises muscle function and ambulation, the comprehensive characteristics of contractile dysfunction are unknown. Therefore, we quantified the in situ contractile properties of the medial gastrocnemius in young adult P448L mice, an affected muscle of a novel model of LGMD2i. Normalized maximal twitch force, tetanic force, and power were significantly smaller in P448L mice, compared with sex-matched, wild-type mice. These differences were consistent with the replacement of contractile fibers by passive tissue. The shape of the active force-length relationships were similar in both groups, regardless of sex, consistent with an intact sarcomeric structure in P448L mice. Passive force-length curves normalized to maximal isometric force were steeper in P448L mice, and passive elements contribute disproportionately more to total contractile force in P448L mice. Sex differences were mostly noted in the force-velocity curves, as normalized values for maximal and optimal velocities were significantly slower in P448L males, compared with wild-type, but not in P448L females. This suggests that the dystrophic phenotype, which may include possible changes in cross-bridge kinetics and fiber-type proportions, progresses more quickly in P448L males. These results together indicate that active force and power generation are compromised in both sexes of P448L mice, while passive forces increase. More importantly, the results identified several functional markers of disease pathophysiology that could aid in developing and assessment of novel therapeutics for LGMD2i and possibly other dystroglycanopathies as well. NEW & NOTEWORTHY Comprehensive assessments of muscle contractile function have, until now, never been performed in an animal model for any dystroglycanopathy. This study suggests that skeletal muscle contractile properties are significantly compromised in a recently developed model for limb-girdle muscular dystrophy 2i, the P448L mouse. It further identifies novel pathological markers of muscle function that are suitable for developing therapeutics and for better understanding of disease pathogenesis.

Sirtuin 1 protects the aging heart from contractile dysfunction mediated through the inhibition of endoplasmic reticulum stress-mediated apoptosis in cardiac-specific Sirtuin 1 knockout mouse model.

PubMed

Hsu, Yu-Juei; Hsu, Shih-Che; Hsu, Chiao-Po; Chen, Yen-Hui; Chang, Yung-Lung; Sadoshima, Junichi; Huang, Shih-Ming; Tsai, Chien-Sung; Lin, Chih-Yuan

2017-02-01

The longevity regulator Sirtuin 1 is an NAD + -dependent histone deacetylase that regulates endoplasmic reticulum stress and influences cardiomyocyte apoptosis during cardiac contractile dysfunction induced by aging. The mechanism underlying Sirtuin 1 function in cardiac contractile dysfunction related to aging has not been completely elucidated. We evaluated cardiac contractile function, endoplasmic reticulum stress, apoptosis, and oxidative stress in 6- and 12month-old cardiac-specific Sirtuin 1 knockout (Sirt1 -/- ) and control (Sirt1 f/f ) mice using western blotting and immunohistochemistry. Mice were injected with a protein disulphide isomerase inhibitor. For in vitro analysis, cultured H9c2 cardiomyocytes were exposed to either a Sirtuin 1 inhibitor or activator, with or without a mitochondrial inhibitor, to evaluate the effects of Sirtuin 1 on endoplasmic reticulum stress, nitric oxide synthase expression, and apoptosis. The effects of protein disulphide isomerase inhibition on oxidative stress and ER stress-related apoptosis were also investigated. Compared with 6-month-old Sirt1 f/f mice, marked impaired contractility was observed in 12-month-old Sirt1 -/- mice. These findings were consistent with increased endoplasmic reticulum stress and apoptosis in the myocardium. Measures of oxidative stress and nitric oxide synthase expression were significantly higher in Sirt1 -/- mice compared with those in Sirt1 f/f mice at 6months. In vitro experiments revealed increased endoplasmic reticulum stress-mediated apoptosis in H9c2 cardiomyocytes treated with a Sirtuin 1 inhibitor; the effects were ameliorated by a Sirtuin 1 activator. Moreover, consistent with the in vitro findings, impaired cardiac contractility was demonstrated in Sirt1 -/- mice injected with a protein disulphide isomerase inhibitor. The present study demonstrates that the aging heart is characterized by contractile dysfunction associated with increased oxidative stress and endoplasmic reticulum stress and Sirtuin 1 might have the ability to protect the aging hearts from the inhibition of endoplasmic reticulum-mediated apoptosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Continuous EEG signal analysis for asynchronous BCI application.

PubMed

Hsu, Wei-Yen

2011-08-01

In this study, we propose a two-stage recognition system for continuous analysis of electroencephalogram (EEG) signals. An independent component analysis (ICA) and correlation coefficient are used to automatically eliminate the electrooculography (EOG) artifacts. Based on the continuous wavelet transform (CWT) and Student's two-sample t-statistics, active segment selection then detects the location of active segment in the time-frequency domain. Next, multiresolution fractal feature vectors (MFFVs) are extracted with the proposed modified fractal dimension from wavelet data. Finally, the support vector machine (SVM) is adopted for the robust classification of MFFVs. The EEG signals are continuously analyzed in 1-s segments, and every 0.5 second moves forward to simulate asynchronous BCI works in the two-stage recognition architecture. The segment is first recognized as lifted or not in the first stage, and then is classified as left or right finger lifting at stage two if the segment is recognized as lifting in the first stage. Several statistical analyses are used to evaluate the performance of the proposed system. The results indicate that it is a promising system in the applications of asynchronous BCI work.

Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel

PubMed Central

Goldschen-Ohm, Marcel P.; Capes, Deborah L.; Oelstrom, Kevin M.; Chanda, Baron

2013-01-01

Voltage-dependent Na+ channels are crucial for electrical signalling in excitable cells. Membrane depolarization initiates asynchronous movements in four non-identical voltage-sensing domains of the Na+ channel. It remains unclear to what extent this structural asymmetry influences pore gating as compared with outwardly rectifying K+ channels, where channel opening results from a final concerted transition of symmetric pore gates. Here we combine single channel recordings, cysteine accessibility and voltage clamp fluorimetry to probe the relationships between voltage sensors and pore conformations in an inactivation deficient Nav1.4 channel. We observe three distinct conductance levels such that DI-III voltage sensor activation is kinetically correlated with formation of a fully open pore, whereas DIV voltage sensor movement underlies formation of a distinct subconducting pore conformation preceding inactivation in wild-type channels. Our experiments reveal that pore gating in sodium channels involves multiple transitions driven by asynchronous movements of voltage sensors. These findings shed new light on the mechanism of coupling between activation and fast inactivation in voltage-gated sodium channels. PMID:23322038

Asynchronous Gossip for Averaging and Spectral Ranking

NASA Astrophysics Data System (ADS)

Borkar, Vivek S.; Makhijani, Rahul; Sundaresan, Rajesh

2014-08-01

We consider two variants of the classical gossip algorithm. The first variant is a version of asynchronous stochastic approximation. We highlight a fundamental difficulty associated with the classical asynchronous gossip scheme, viz., that it may not converge to a desired average, and suggest an alternative scheme based on reinforcement learning that has guaranteed convergence to the desired average. We then discuss a potential application to a wireless network setting with simultaneous link activation constraints. The second variant is a gossip algorithm for distributed computation of the Perron-Frobenius eigenvector of a nonnegative matrix. While the first variant draws upon a reinforcement learning algorithm for an average cost controlled Markov decision problem, the second variant draws upon a reinforcement learning algorithm for risk-sensitive control. We then discuss potential applications of the second variant to ranking schemes, reputation networks, and principal component analysis.

A comparison of classroom and online asynchronous problem-based learning for students undertaking statistics training as part of a Public Health Masters degree.

PubMed

de Jong, N; Verstegen, D M L; Tan, F E S; O'Connor, S J

2013-05-01

This case-study compared traditional, face-to-face classroom-based teaching with asynchronous online learning and teaching methods in two sets of students undertaking a problem-based learning module in the multilevel and exploratory factor analysis of longitudinal data as part of a Masters degree in Public Health at Maastricht University. Students were allocated to one of the two study variants on the basis of their enrolment status as full-time or part-time students. Full-time students (n = 11) followed the classroom-based variant and part-time students (n = 12) followed the online asynchronous variant which included video recorded lectures and a series of asynchronous online group or individual SPSS activities with synchronous tutor feedback. A validated student motivation questionnaire was administered to both groups of students at the start of the study and a second questionnaire was administered at the end of the module. This elicited data about student satisfaction with the module content, teaching and learning methods, and tutor feedback. The module coordinator and problem-based learning tutor were also interviewed about their experience of delivering the experimental online variant and asked to evaluate its success in relation to student attainment of the module's learning outcomes. Student examination results were also compared between the two groups. Asynchronous online teaching and learning methods proved to be an acceptable alternative to classroom-based teaching for both students and staff. Educational outcomes were similar for both groups, but importantly, there was no evidence that the asynchronous online delivery of module content disadvantaged part-time students in comparison to their full-time counterparts.

Expansion and concatenation of nonmuscle myosin IIA filaments drive cellular contractile system formation during interphase and mitosis

PubMed Central

Fenix, Aidan M.; Taneja, Nilay; Buttler, Carmen A.; Lewis, John; Van Engelenburg, Schuyler B.; Ohi, Ryoma; Burnette, Dylan T.

2016-01-01

Cell movement and cytokinesis are facilitated by contractile forces generated by the molecular motor, nonmuscle myosin II (NMII). NMII molecules form a filament (NMII-F) through interactions of their C-terminal rod domains, positioning groups of N-terminal motor domains on opposite sides. The NMII motors then bind and pull actin filaments toward the NMII-F, thus driving contraction. Inside of crawling cells, NMIIA-Fs form large macromolecular ensembles (i.e., NMIIA-F stacks), but how this occurs is unknown. Here we show NMIIA-F stacks are formed through two non–mutually exclusive mechanisms: expansion and concatenation. During expansion, NMIIA molecules within the NMIIA-F spread out concurrent with addition of new NMIIA molecules. Concatenation occurs when multiple NMIIA-Fs/NMIIA-F stacks move together and align. We found that NMIIA-F stack formation was regulated by both motor activity and the availability of surrounding actin filaments. Furthermore, our data showed expansion and concatenation also formed the contractile ring in dividing cells. Thus interphase and mitotic cells share similar mechanisms for creating large contractile units, and these are likely to underlie how other myosin II–based contractile systems are assembled. PMID:26960797

Maintaining High Assurance in Asynchronous Messaging

DTIC Science & Technology

2015-10-24

Assurance in Asynchronous Messaging Kevin E. Foltz and William R. Simpson Abstract—Asynchronous messaging is the delivery of a message without... integrity , and confidentiality guarantees. End-to-end security for asynchronous messaging must be provided by the asynchronous messaging layer itself... continuing its processing. At the completion of message transmission, the sender does not know when or whether the receiver received it. The message

Non-adrenergic, non-cholinergic neural activation in guinea-pig bronchi: powerful and frequency-dependent stabilizing effect on tone.

PubMed Central

Lindén, A.; Ullman, A.; Löfdahl, C. G.; Skoogh, B. E.

1993-01-01

1. We examined non-adrenergic, non-cholinergic (NANC) stimulation for its stabilizing effect on bronchial smooth-muscle tone with respect to its regulatory power and the effect of variations in neural impulse frequency. 2. The guinea-pig isolated main bronchus (n = 4-12) was pretreated with indomethacin (10 microM) and incubated with atropine (1 microM) and guanethidine (10 microM). Electrical field stimulation (EFS: 1200 mA, 0.5 ms, 240 s) was applied at various levels of tone prior to EFS: first without tone, then at a moderate tone induced by histamine (0.3 microM) and, finally, at a high tone induced by histamine (6 microM). Three different stimulation frequencies (1, 3 or 10 Hz) were used in order to produce moderate to near-maximum contractile and relaxant NANC neural responses. Both the contractile and the relaxant NANC responses were tetrodotoxin-sensitive in the guinea-pig isolated main bronchus (3 Hz). 3. Without tone prior to EFS, NANC activation (1, 3 or 10 Hz) induced a pronounced contractile response. At a moderate level of tone prior to EFS, NANC activation induced a less pronounced contractile response. At the highest level of tone prior to EFS, NANC activation induced a relaxant response. All these NANC responses adjusted the tone towards a similar level and this 'stabilization level' was 56(6)% at 1 Hz, 65(3)% at 3 Hz and 56(5)% at 10 Hz, expressed as a percentage of the maximum histamine-induced (0.1 mM) tone in each airway preparation. 4. There was a difference of approximately 90% of maximum between the highest and the lowest tone level prior to NANC activation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8358575

Cardiac-Specific Overexpression of Catalase Attenuates Lipopolysaccharide-Induced Myocardial Contractile Dysfunction: Role of Autophagy

PubMed Central

Turdi, Subat; Han, Xuefeng; Huff, Anna F.; Roe, Nathan D.; Hu, Nan; Gao, Feng; Ren, Jun

2012-01-01

Lipopolysaccharide (LPS) from Gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complication in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity and carbonyl formation. Kaplan-Meier curve was constructed for survival following LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice following LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O2−, and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury following LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by antioxidant NAC and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. PMID:22902401

Effects of the Tibetan herbal formula Padma Lax on visceral nociception and contractility of longitudinal smooth muscle in a rat model.

PubMed

Gschossmann, J M; Krayer, M; Flogerzi, B; Balsiger, B M

2010-09-01

The high prevalence of functional bowel disorders among the general population contrasts with the limited number of pharmacological treatment options for this condition. This has led to an interest for alternative therapeutic approaches. Padma Lax is an herbal laxative on the basis of Tibetan formulas. Our aim is to examine the effect of Padma Lax on visceral nociception in vivo and (B) on contractile activity of longitudinal smooth muscle of the lower gut in vitro and ex vivo. (A) Visceral sensory function in response to colorectal distension was assessed by abdominal wall electromyography in male Wistar rats pretreated with Padma Lax. (B) Effects of Padma Lax on contractility of gut smooth muscles were studied both in vitro with superfusion of the agent and ex vivo following oral administration of the preparation. Activities were measured as area under the curve. (A) For visceral sensitivity, no differences were observed between the Padma Lax and the control group. (B) Proximal colon muscle strips of the Padma Lax pretreated group showed significantly lower spontaneous contractility ex vivo than controls. Cholinergic procontractile stimulation was reduced in Padma Lax pretreated group and in colon strips of naive rats when Padma Lax was superfused in vitro (all P < 0.05). Cholinergic mechanisms appear to be important in the modulation of rat proximal colon contractility of orally and directly applied Padma Lax. These findings help elucidate a potential mechanism of action of this herbal remedy which has undergone clinical testing in patients with constipation predominant irritable bowel syndrome.

Defect Proliferation in Active Nematic Suspensions

NASA Astrophysics Data System (ADS)

Mishra, Prashant; Bowick, Mark J.; Giomi, Luca; Marchetti, M. Cristina

2014-03-01

The rich structure of equilibrium nematic suspensions, with their characteristic disclination defects, is modified when active forces come into play. The uniform nematic state is known to be unstable to splay (extensile) or bend (contractile) deformations above a critical activity. At even higher activity the flow becomes oscillatory and eventually turbulent. Using hydrodynamics, we classify the active flow regimes as functions of activity and order parameter friction for both contractile and extensile systems. The turbulent regime is marked by a non-zero steady state density of mobile defect pairs. The defect density itself scales with an ``active Ericksen number,'' defined as the ratio of the rate at which activity is injected into the system to the relaxation rate of orientational deformations. The work at Syracuse University was supported by the NSF on grant DMR-1004789 and by the Syracuse Soft Matter Program.

Platelets as Contractile Nanomachines for Targeting Drug Delivery in Hemostasis and Thrombosis

DTIC Science & Technology

2015-12-01

capsules were suspended in platelet - rich plasma , which was subsequently exposed to 1 U/mL of thrombin, the capsules successfully targeted target...activated platelets . As thrombi in myocardial infarctions and strokes are platelet - rich , this is an ideal system to achieve high concentrations of...AWARD NUMBER: W81XWH-13-1-0495 TITLE: Platelets as Contractile Nanomachines for Targeting Drug Delivery in Hemostasis and Thrombosis PRINCIPAL

The complex field of interplay between vasoactive agents.

PubMed

Hansen, Pernille B

2009-11-01

Lai et al. provide important new information regarding the interaction between the sympathetic and renin-angiotensin systems in the regulation of glomerular afferent arteriolar contractility. Their study demonstrates a calcium-independent enhanced contractile response to angiotensin II following norepinephrine administration. The interplay between the norepinephrine- and angiotensin II-stimulated pathways could potentially be important in physiological as well as pathophysiological situations with increased sympathetic nervous system activity, such as hypertension.

Contractility of the cell rear drives invasion of breast tumor cells in 3D Matrigel

PubMed Central

Poincloux, Renaud; Collin, Olivier; Lizárraga, Floria; Romao, Maryse; Debray, Marcel; Piel, Matthieu; Chavrier, Philippe

2011-01-01

Cancer cells use different modes of migration, including integrin-dependent mesenchymal migration of elongated cells along elements of the 3D matrix as opposed to low-adhesion-, contraction-based amoeboid motility of rounded cells. We report that MDA-MB-231 human breast adenocarcinoma cells invade 3D Matrigel with a characteristic rounded morphology and with F-actin and myosin-IIa accumulating at the cell rear in a uropod-like structure. MDA-MB-231 cells display neither lamellipodia nor bleb extensions at the leading edge and do not require Arp2/3 complex activity for 3D invasion in Matrigel. Accumulation of phospho-MLC and blebbing activity were restricted to the uropod as reporters of actomyosin contractility, and velocimetric analysis of fluorescent beads embedded within the 3D matrix showed that pulling forces exerted to the matrix are restricted to the side and rear of cells. Inhibition of actomyosin contractility or β1 integrin function interferes with uropod formation, matrix deformation, and invasion through Matrigel. These findings support a model whereby actomyosin-based uropod contractility generates traction forces on the β1 integrin adhesion system to drive cell propulsion within the 3D matrix, with no contribution of lamellipodia extension or blebbing to movement. PMID:21245302

Initial diameter of the polar body contractile ring is minimized by the centralspindlin complex.

PubMed

Fabritius, Amy S; Flynn, Jonathan R; McNally, Francis J

2011-11-01

Polar body formation is an essential step in forming haploid eggs from diploid oocytes. This process involves completion of a highly asymmetric cytokinesis that results in a large egg and two small polar bodies. Unlike mitotic contractile rings, polar body contractile rings assemble over one spindle pole so that the spindle must move through the contractile ring before cytokinesis. During time-lapse imaging of C. elegans meiosis, the contractile ring moved downward along the length of the spindle and completed scission at the midpoint of the spindle, even when spindle length or rate of ring movement was increased. Patches of myosin heavy chain and dynamic furrowing of the plasma membrane over the entire embryo suggested that global cortical contraction forces the meiotic spindle and overlying membrane out through the contractile ring center. Consistent with this model, depletion of myosin phosphatase increased the velocity of ring movement along the length of the spindle. Global dynamic furrowing, which was restricted to anaphase I and II, was dependent on myosin II, the anaphase promoting complex and separase, but did not require cortical contact by the spindle. Large cortical patches of myosin during metaphase I and II indicated that myosin was already in the active form before activation of separase. To identify the signal at the midpoint of the anaphase spindle that induces scission, we depleted two proteins that mark the exact midpoint of the spindle during late anaphase, CYK-4 and ZEN-4. Depletion of either protein resulted in the unexpected phenotype of initial ingression of a polar body ring with twice the diameter of wild type. This phenotype revealed a novel mechanism for minimizing polar body size. Proteins at the spindle midpoint are required for initial ring ingression to occur close to the membrane-proximal spindle pole. 2011 Elsevier Inc. All rights reserved.

Temporal processing of audiovisual stimuli is enhanced in musicians: evidence from magnetoencephalography (MEG).

PubMed

Lu, Yao; Paraskevopoulos, Evangelos; Herholz, Sibylle C; Kuchenbuch, Anja; Pantev, Christo

2014-01-01

Numerous studies have demonstrated that the structural and functional differences between professional musicians and non-musicians are not only found within a single modality, but also with regard to multisensory integration. In this study we have combined psychophysical with neurophysiological measurements investigating the processing of non-musical, synchronous or various levels of asynchronous audiovisual events. We hypothesize that long-term multisensory experience alters temporal audiovisual processing already at a non-musical stage. Behaviorally, musicians scored significantly better than non-musicians in judging whether the auditory and visual stimuli were synchronous or asynchronous. At the neural level, the statistical analysis for the audiovisual asynchronous response revealed three clusters of activations including the ACC and the SFG and two bilaterally located activations in IFG and STG in both groups. Musicians, in comparison to the non-musicians, responded to synchronous audiovisual events with enhanced neuronal activity in a broad left posterior temporal region that covers the STG, the insula and the Postcentral Gyrus. Musicians also showed significantly greater activation in the left Cerebellum, when confronted with an audiovisual asynchrony. Taken together, our MEG results form a strong indication that long-term musical training alters the basic audiovisual temporal processing already in an early stage (direct after the auditory N1 wave), while the psychophysical results indicate that musical training may also provide behavioral benefits in the accuracy of the estimates regarding the timing of audiovisual events.

Cadmium translocation by contractile roots differs from that in regular, non-contractile roots

PubMed Central

Lux, Alexander; Lackovič, Andrej; Van Staden, Johannes; Lišková, Desana; Kohanová, Jana; Martinka, Michal

2015-01-01

Background and Aims Contractile roots are known and studied mainly in connection with the process of shrinkage of their basal parts, which acts to pull the shoot of the plant deeper into the ground. Previous studies have shown that the specific structure of these roots results in more intensive water uptake at the base, which is in contrast to regular root types. The purpose of this study was to find out whether the basal parts of contractile roots are also more active in translocation of cadmium to the shoot. Methods Plants of the South African ornamental species Tritonia gladiolaris were cultivated in vitro for 2 months, at which point they possessed well-developed contractile roots. They were then transferred to Petri dishes with horizontally separated compartments of agar containing 50 µmol Cd(NO3)2 in the region of the root base or the root apex. Seedlings of 4-d-old maize (Zea mays) plants, which do not possess contractile roots, were also transferred to similar Petri dishes. The concentrations of Cd in the leaves of the plants were compared after 10 d of cultivation. Anatomical analyses of Tritonia roots were performed using appropriately stained freehand cross-sections. Key Results The process of contraction required specific anatomical adaptation of the root base in Tritonia, with less lignified and less suberized tissues in comparison with the subapical part of the root. These unusual developmental characteristics were accompanied by more intensive translocation of Cd ions from the basal part of contractile roots to the leaves than from the apical–subapical root parts. The opposite effects were seen in the non-contractile roots of maize, with higher uptake and transport by the apical parts of the root and lower uptake and transport by the basal part. Conclusions The specific characteristics of contractile roots may have a significant impact on the uptake of ions, including toxic metals from the soil surface layers. This may be important for plant nutrition, for example in the uptake of nutrients from upper soil layers, which are richer in humus in otherwise nutrient-poor soils, and also has implications for the uptake of surface-soil pollutants. PMID:25939652

Effects of intra-aortic balloon pump counterpulsation on left ventricular mechanoenergetics in a porcine model of acute ischemic heart failure.

PubMed

Malliaras, Konstantinos; Charitos, Efstratios; Diakos, Nikolaos; Pozios, Iraklis; Papalois, Apostolos; Terrovitis, John; Nanas, John

2014-12-01

We investigated the effects of intra-aortic balloon pump (IABP) counterpulsation on left ventricular (LV) contractility, relaxation, and energy consumption and probed the underlying physiologic mechanisms in 12 farm pigs, using an ischemia-reperfusion model of acute heart failure. During both ischemia and reperfusion, IABP support unloaded the LV, decreased LV energy consumption (pressure-volume area, stroke work), and concurrently improved LV mechanical performance (ejection fraction, stroke volume, cardiac output). During reperfusion exclusively, IABP also improved LV relaxation (tau) and contractility (Emax, PRSW). The beneficial effects of IABP support on LV relaxation and contractility correlated with IABP-induced augmentation of coronary blood flow. In conclusion, we find that during both ischemia and reperfusion, IABP support optimizes LV energetic performance (decreases energy consumption and concurrently improves mechanical performance) by LV unloading. During reperfusion exclusively, IABP support also improves LV contractility and active relaxation, possibly due to a synergistic effect of unloading and augmentation of coronary blood flow.

Wrinkling of a spherical lipid interface induced by actomyosin cortex

NASA Astrophysics Data System (ADS)

Ito, Hiroaki; Nishigami, Yukinori; Sonobe, Seiji; Ichikawa, Masatoshi

2015-12-01

Actomyosin actively generates contractile forces that provide the plasma membrane with the deformation stresses essential to carry out biological processes. Although the contractile property of purified actomyosin has been extensively studied, to understand the physical contribution of the actomyosin contractile force on a deformable membrane is still a challenging problem and of great interest in the field of biophysics. Here, we reconstitute a model system with a cell-sized deformable interface that exhibits anomalous curvature-dependent wrinkling caused by the actomyosin cortex underneath the spherical closed interface. Through a shape analysis of the wrinkling deformation, we find that the dominant contributor to the wrinkled shape changes from bending elasticity to stretching elasticity of the reconstituted cortex upon increasing the droplet curvature radius of the order of the cell size, i.e., tens of micrometers. The observed curvature dependence is explained by the theoretical description of the cortex elasticity and contractility. Our present results provide a fundamental insight into the deformation of a curved membrane induced by the actomyosin cortex.

A disassembly-driven mechanism explains F-actin-mediated chromosome transport in starfish oocytes

PubMed Central

Bun, Philippe; Dmitrieff, Serge; Belmonte, Julio M

2018-01-01

While contraction of sarcomeric actomyosin assemblies is well understood, this is not the case for disordered networks of actin filaments (F-actin) driving diverse essential processes in animal cells. For example, at the onset of meiosis in starfish oocytes a contractile F-actin network forms in the nuclear region transporting embedded chromosomes to the assembling microtubule spindle. Here, we addressed the mechanism driving contraction of this 3D disordered F-actin network by comparing quantitative observations to computational models. We analyzed 3D chromosome trajectories and imaged filament dynamics to monitor network behavior under various physical and chemical perturbations. We found no evidence of myosin activity driving network contractility. Instead, our observations are well explained by models based on a disassembly-driven contractile mechanism. We reconstitute this disassembly-based contractile system in silico revealing a simple architecture that robustly drives chromosome transport to prevent aneuploidy in the large oocyte, a prerequisite for normal embryonic development. PMID:29350616

Mechanics of epithelial closure over non-adherent environments

NASA Astrophysics Data System (ADS)

Vedula, Sri Ram Krishna; Peyret, Grégoire; Cheddadi, Ibrahim; Chen, Tianchi; Brugués, Agustí; Hirata, Hiroaki; Lopez-Menendez, Horacio; Toyama, Yusuke; Neves de Almeida, Luís; Trepat, Xavier; Lim, Chwee Teck; Ladoux, Benoit

2015-01-01

The closure of gaps within epithelia is crucial to maintain its integrity during biological processes such as wound healing and gastrulation. Depending on the distribution of extracellular matrix, gap closure occurs through assembly of multicellular actin-based contractile cables or protrusive activity of border cells into the gap. Here we show that the supracellular actomyosin contractility of cells near the gap edge exerts sufficient tension on the surrounding tissue to promote closure of non-adherent gaps. Using traction force microscopy, we observe that cell-generated forces on the substrate at the gap edge first point away from the centre of the gap and then increase in the radial direction pointing into the gap as closure proceeds. Combining with numerical simulations, we show that the increase in force relies less on localized purse-string contractility and more on large-scale remodelling of the suspended tissue around the gap. Our results provide a framework for understanding the assembly and the mechanics of cellular contractility at the tissue level.

The inverted pendulum model of bipedal standing cannot be stabilized through direct feedback of force and contractile element length and velocity at realistic series elastic element stiffness.

PubMed

van Soest, A J Knoek; Rozendaal, Leonard A

2008-07-01

Control of bipedal standing is typically analyzed in the context of a single-segment inverted pendulum model. The stiffness K (SE) of the series elastic element that transmits the force generated by the contractile elements of the ankle plantarflexors to the skeletal system has been reported to be smaller in magnitude than the destabilizing gravitational stiffness K ( g ). In this study, we assess, in case K (SE) + K ( g ) < 0, if bipedal standing can be locally stable under direct feedback of contractile element length, contractile element velocity (both sensed by muscle spindles) and muscle force (sensed by Golgi tendon organs) to alpha-motoneuron activity. A theoretical analysis reveals that even though positive feedback of force may increase the stiffness of the muscle-tendon complex to values well over the destabilizing gravitational stiffness, dynamic instability makes it impossible to obtain locally stable standing under the conditions assumed.

Mechanics of epithelial closure over non-adherent environments

PubMed Central

Vedula, Sri Ram Krishna; Peyret, Grégoire; Cheddadi, Ibrahim; Chen, Tianchi; Brugués, Agustí; Hirata, Hiroaki; Lopez-Menendez, Horacio; Toyama, Yusuke; Neves de Almeida, Luís; Trepat, Xavier; Lim, Chwee Teck; Ladoux, Benoit

2015-01-01

The closure of gaps within epithelia is crucial to maintain its integrity during biological processes such as wound healing and gastrulation. Depending on the distribution of extracellular matrix, gap closure occurs through assembly of multicellular actin-based contractile cables or protrusive activity of border cells into the gap. Here we show that the supracellular actomyosin contractility of cells near the gap edge exerts sufficient tension on the surrounding tissue to promote closure of non-adherent gaps. Using traction force microscopy, we observe that cell-generated forces on the substrate at the gap edge first point away from the centre of the gap and then increase in the radial direction pointing into the gap as closure proceeds. Combining with numerical simulations, we show that the increase in force relies less on localized purse-string contractility and more on large-scale remodelling of the suspended tissue around the gap. Our results provide a framework for understanding the assembly and the mechanics of cellular contractility at the tissue level. PMID:25608921

Ginseng Is Useful to Enhance Cardiac Contractility in Animals

PubMed Central

Cherng, Yih-Giun; Chen, Li-Jen; Niu, Ho-Shan; Chang, Chen Kuei; Niu, Chiang-Shan

2014-01-01

Ginseng has been shown to be effective on cardiac dysfunction. Recent evidence has highlighted the mediation of peroxisome proliferator-activated receptors (PPARs) in cardiac function. Thus, we are interested to investigate the role of PPARδ in ginseng-induced modification of cardiac contractility. The isolated hearts in Langendorff apparatus and hemodynamic analysis in catheterized rats were applied to measure the actions of ginseng ex vivo and in vivo. In normal rats, ginseng enhanced cardiac contractility and hemodynamic dP/dt max significantly. Both actions were diminished by GSK0660 at a dose enough to block PPARδ. However, ginseng failed to modify heart rate at the same dose, although it did produce a mild increase in blood pressure. Data of intracellular calcium level and Western blotting analysis showed that both the PPARδ expression and troponin I phosphorylation were raised by ginseng in neonatal rat cardiomyocyte. Thus, we suggest that ginseng could enhance cardiac contractility through increased PPARδ expression in cardiac cells. PMID:24689053

Global interrupt and barrier networks

DOEpatents

Blumrich, Matthias A.; Chen, Dong; Coteus, Paul W.; Gara, Alan G.; Giampapa, Mark E; Heidelberger, Philip; Kopcsay, Gerard V.; Steinmacher-Burow, Burkhard D.; Takken, Todd E.

2008-10-28

A system and method for generating global asynchronous signals in a computing structure. Particularly, a global interrupt and barrier network is implemented that implements logic for generating global interrupt and barrier signals for controlling global asynchronous operations performed by processing elements at selected processing nodes of a computing structure in accordance with a processing algorithm; and includes the physical interconnecting of the processing nodes for communicating the global interrupt and barrier signals to the elements via low-latency paths. The global asynchronous signals respectively initiate interrupt and barrier operations at the processing nodes at times selected for optimizing performance of the processing algorithms. In one embodiment, the global interrupt and barrier network is implemented in a scalable, massively parallel supercomputing device structure comprising a plurality of processing nodes interconnected by multiple independent networks, with each node including one or more processing elements for performing computation or communication activity as required when performing parallel algorithm operations. One multiple independent network includes a global tree network for enabling high-speed global tree communications among global tree network nodes or sub-trees thereof. The global interrupt and barrier network may operate in parallel with the global tree network for providing global asynchronous sideband signals.

Blood pressure and the contractility of a human leg muscle.

PubMed

Luu, Billy L; Fitzpatrick, Richard C

2013-11-01

These studies investigate the relationships between perfusion pressure, force output and pressor responses for the contracting human tibialis anterior muscle. Eight healthy adults were studied. Changing the height of tibialis anterior relative to the heart was used to control local perfusion pressure. Electrically stimulated tetanic force output was highly sensitive to physiological variations in perfusion pressure showing a proportionate change in force output of 6.5% per 10 mmHg. This perfusion-dependent change in contractility begins within seconds and is reversible with a 53 s time constant, demonstrating a steady-state equilibrium between contractility and perfusion pressure. These stimulated contractions did not produce significant cardiovascular responses, indicating that the muscle pressor response does not play a major role in cardiovascular regulation at these workloads. Voluntary contractions at forces that would require constant motor drive if perfusion pressure had remained constant generated a central pressor response when perfusion pressure was lowered. This is consistent with a larger cortical drive being required to compensate for the lost contractility with lower perfusion pressure. The relationship between contractility and perfusion for this large postural muscle was not different from that of a small hand muscle (adductor pollicis) and it responded similarly to passive peripheral and active central changes in arterial pressure, but extended over a wider operating range of pressures. If we consider that, in a goal-oriented motor task, muscle contractility determines central motor output and the central pressor response, these results indicate that muscle would fatigue twice as fast without a pressor response. From its extent, timing and reversibility we propose a testable hypothesis that this change in contractility arises through contraction- and perfusion-dependent changes in interstitial K(+) concentration.

Blood pressure and the contractility of a human leg muscle

PubMed Central

Luu, Billy L; Fitzpatrick, Richard C

2013-01-01

These studies investigate the relationships between perfusion pressure, force output and pressor responses for the contracting human tibialis anterior muscle. Eight healthy adults were studied. Changing the height of tibialis anterior relative to the heart was used to control local perfusion pressure. Electrically stimulated tetanic force output was highly sensitive to physiological variations in perfusion pressure showing a proportionate change in force output of 6.5% per 10 mmHg. This perfusion-dependent change in contractility begins within seconds and is reversible with a 53 s time constant, demonstrating a steady-state equilibrium between contractility and perfusion pressure. These stimulated contractions did not produce significant cardiovascular responses, indicating that the muscle pressor response does not play a major role in cardiovascular regulation at these workloads. Voluntary contractions at forces that would require constant motor drive if perfusion pressure had remained constant generated a central pressor response when perfusion pressure was lowered. This is consistent with a larger cortical drive being required to compensate for the lost contractility with lower perfusion pressure. The relationship between contractility and perfusion for this large postural muscle was not different from that of a small hand muscle (adductor pollicis) and it responded similarly to passive peripheral and active central changes in arterial pressure, but extended over a wider operating range of pressures. If we consider that, in a goal-oriented motor task, muscle contractility determines central motor output and the central pressor response, these results indicate that muscle would fatigue twice as fast without a pressor response. From its extent, timing and reversibility we propose a testable hypothesis that this change in contractility arises through contraction- and perfusion-dependent changes in interstitial K+ concentration. PMID:24018946

Vascular smooth muscle cell contractile protein expression is increased through protein kinase G-dependent and -independent pathways by glucose-6-phosphate dehydrogenase inhibition and deficiency.

PubMed

Chettimada, Sukrutha; Joshi, Sachindra Raj; Dhagia, Vidhi; Aiezza, Alessandro; Lincoln, Thomas M; Gupte, Rakhee; Miano, Joseph M; Gupte, Sachin A

2016-10-01

Homeostatic control of vascular smooth muscle cell (VSMC) differentiation is critical for contractile activity and regulation of blood flow. Recently, we reported that precontracted blood vessels are relaxed and the phenotype of VSMC is regulated from a synthetic to contractile state by glucose-6-phosphate dehydrogenase (G6PD) inhibition. In the current study, we investigated whether the increase in the expression of VSMC contractile proteins by inhibition and knockdown of G6PD is mediated through a protein kinase G (PKG)-dependent pathway and whether it regulates blood pressure. We found that the expression of VSMC-restricted contractile proteins, myocardin (MYOCD), and miR-1 and miR-143 are increased by G6PD inhibition or knockdown. Importantly, RNA-sequence analysis of aortic tissue from G6PD-deficient mice revealed uniform increases in VSMC-restricted genes, particularly those regulated by the MYOCD-serum response factor (SRF) switch. Conversely, expression of Krüppel-like factor 4 (KLF4) is decreased by G6PD inhibition. Interestingly, the G6PD inhibition-induced expression of miR-1 and contractile proteins was blocked by Rp-β-phenyl-1,N 2 -etheno-8-bromo-guanosine-3',5'-cyclic monophosphorothioate, a PKG inhibitor. On the other hand, MYOCD and miR-143 levels are increased by G6PD inhibition through a PKG-independent manner. Furthermore, blood pressure was lower in the G6PD-deficient compared with wild-type mice. Therefore, our results suggest that the expression of VSMC contractile proteins induced by G6PD inhibition occurs via PKG1α-dependent and -independent pathways. Copyright © 2016 the American Physiological Society.

Skeletal muscle morphology and contractile function in relation to muscle denervation in diabetic neuropathy

PubMed Central

Major, Brendan; Kimpinski, Kurt; Doherty, Timothy J.; Rice, Charles L.

2013-01-01

The objective of the study was to assess the effects of diabetic polyneuropathy (DPN) on muscle contractile properties in humans, and how these changes are related to alterations in muscle morphology and denervation. Patients with DPN (n = 12) were compared with age- and sex-matched controls (n = 12). Evoked and voluntary contractile properties, including stimulated twitch responses and maximal voluntary contractions, of the dorsiflexor muscles were assessed using an isometric ankle dynamometer. Motor unit number estimates (MUNE) of the tibialis anterior (TA) were performed via quantitative electromyography and decomposition-enhanced spike-triggered averaging. Peak tibialis anterior (TA) cross-sectional area (CSA; cm2), and relative proportion of contractile to noncontractile tissue (%) was determined from magnetic resonance images. Patients with DPN demonstrated decreased strength (−35%) and slower (−45%) dorsiflexion contractile properties for both evoked and voluntary contractions (P < 0.05). These findings were not accounted for by differences in voluntary activation (P > 0.05) or antagonist coactivation (P > 0.05). Additionally, patients with DPN were weaker when strength was normalized to TA total CSA (−30%; P < 0.05) or contractile tissue CSA (−26%; P < 0.05). In the DPN patient group, TA MUNEs were negatively related to both % noncontractile tissue (P < 0.05; r = 0.72) and twitch half-relaxation time (P < 0.05; r = 0.60), whereas no relationships were found between these variables in controls (P > 0.05). We conclude that patients with DPN demonstrated reduced strength and muscle quality as well as contractile slowing. This process may contribute to muscle power loss and functional impairments reported in patients with DPN, beyond the loss of strength commonly observed. PMID:24356519

Relationship between individual neuron and network spontaneous activity in developing mouse cortex.

PubMed

Barnett, Heather M; Gjorgjieva, Julijana; Weir, Keiko; Comfort, Cara; Fairhall, Adrienne L; Moody, William J

2014-12-15

Spontaneous synchronous activity (SSA) that propagates as electrical waves is found in numerous central nervous system structures and is critical for normal development, but the mechanisms of generation of such activity are not clear. In previous work, we showed that the ventrolateral piriform cortex is uniquely able to initiate SSA in contrast to the dorsal neocortex, which participates in, but does not initiate, SSA (Lischalk JW, Easton CR, Moody WJ. Dev Neurobiol 69: 407-414, 2009). In this study, we used Ca(2+) imaging of cultured embryonic day 18 to postnatal day 2 coronal slices (embryonic day 17 + 1-4 days in culture) of the mouse cortex to investigate the different activity patterns of individual neurons in these regions. In the piriform cortex where SSA is initiated, a higher proportion of neurons was active asynchronously between waves, and a larger number of groups of coactive cells was present compared with the dorsal cortex. When we applied GABA and glutamate synaptic antagonists, asynchronous activity and cellular clusters remained, while synchronous activity was eliminated, indicating that asynchronous activity is a result of cell-intrinsic properties that differ between these regions. To test the hypothesis that higher levels of cell-autonomous activity in the piriform cortex underlie its ability to initiate waves, we constructed a conductance-based network model in which three layers differed only in the proportion of neurons able to intrinsically generate bursting behavior. Simulations using this model demonstrated that a gradient of intrinsic excitability was sufficient to produce directionally propagating waves that replicated key experimental features, indicating that the higher level of cell-intrinsic activity in the piriform cortex may provide a substrate for SSA generation. Copyright © 2014 the American Physiological Society.

Drifting States and Synchronization Induced Chaos in Autonomous Networks of Excitable Neurons.

PubMed

Echeveste, Rodrigo; Gros, Claudius

2016-01-01

The study of balanced networks of excitatory and inhibitory neurons has led to several open questions. On the one hand it is yet unclear whether the asynchronous state observed in the brain is autonomously generated, or if it results from the interplay between external drivings and internal dynamics. It is also not known, which kind of network variabilities will lead to irregular spiking and which to synchronous firing states. Here we show how isolated networks of purely excitatory neurons generically show asynchronous firing whenever a minimal level of structural variability is present together with a refractory period. Our autonomous networks are composed of excitable units, in the form of leaky integrators spiking only in response to driving currents, remaining otherwise quiet. For a non-uniform network, composed exclusively of excitatory neurons, we find a rich repertoire of self-induced dynamical states. We show in particular that asynchronous drifting states may be stabilized in purely excitatory networks whenever a refractory period is present. Other states found are either fully synchronized or mixed, containing both drifting and synchronized components. The individual neurons considered are excitable and hence do not dispose of intrinsic natural firing frequencies. An effective network-wide distribution of natural frequencies is however generated autonomously through self-consistent feedback loops. The asynchronous drifting state is, additionally, amenable to an analytic solution. We find two types of asynchronous activity, with the individual neurons spiking regularly in the pure drifting state, albeit with a continuous distribution of firing frequencies. The activity of the drifting component, however, becomes irregular in the mixed state, due to the periodic driving of the synchronized component. We propose a new tool for the study of chaos in spiking neural networks, which consists of an analysis of the time series of pairs of consecutive interspike intervals. In this space, we show that a strange attractor with a fractal dimension of about 1.8 is formed in the mentioned mixed state.

Drifting States and Synchronization Induced Chaos in Autonomous Networks of Excitable Neurons

PubMed Central

Echeveste, Rodrigo; Gros, Claudius

2016-01-01

The study of balanced networks of excitatory and inhibitory neurons has led to several open questions. On the one hand it is yet unclear whether the asynchronous state observed in the brain is autonomously generated, or if it results from the interplay between external drivings and internal dynamics. It is also not known, which kind of network variabilities will lead to irregular spiking and which to synchronous firing states. Here we show how isolated networks of purely excitatory neurons generically show asynchronous firing whenever a minimal level of structural variability is present together with a refractory period. Our autonomous networks are composed of excitable units, in the form of leaky integrators spiking only in response to driving currents, remaining otherwise quiet. For a non-uniform network, composed exclusively of excitatory neurons, we find a rich repertoire of self-induced dynamical states. We show in particular that asynchronous drifting states may be stabilized in purely excitatory networks whenever a refractory period is present. Other states found are either fully synchronized or mixed, containing both drifting and synchronized components. The individual neurons considered are excitable and hence do not dispose of intrinsic natural firing frequencies. An effective network-wide distribution of natural frequencies is however generated autonomously through self-consistent feedback loops. The asynchronous drifting state is, additionally, amenable to an analytic solution. We find two types of asynchronous activity, with the individual neurons spiking regularly in the pure drifting state, albeit with a continuous distribution of firing frequencies. The activity of the drifting component, however, becomes irregular in the mixed state, due to the periodic driving of the synchronized component. We propose a new tool for the study of chaos in spiking neural networks, which consists of an analysis of the time series of pairs of consecutive interspike intervals. In this space, we show that a strange attractor with a fractal dimension of about 1.8 is formed in the mentioned mixed state. PMID:27708572

On the asynchronization of hemispheric high-latitude solar activity

NASA Astrophysics Data System (ADS)

Li, K. J.; Gao, P. X.; Zhan, L. S.; Shi, X. J.; Zhu, W. W.

2008-11-01

The monthly mean numbers of polar faculae in the time interval of 1951 August to 1998 December, from observations of the National Astronomical Observatory of Japan are used to investigate the reasons which mathematically result in the asynchronization of high-latitude solar activity between the northern and southern hemispheres. It is found that the monthly mean numbers of polar faculae in the northern hemisphere three months lead those in the southern one, which should mathematically lead to phase asynchrony of the hemispheric polar-facula activity but with a slight effect. The Schwabe period length for the polar-facula activity in one hemisphere obviously differs from that in the other, which should also lead to phase asynchrony of the hemispheric polar-facula activity. It is the low-frequency components of the hemispheric polar-facula activity in period scales around the Schwabe cycle that are responsible for its strong phase synchronization. In the high-frequency components, there is a strong phase mixing, which should also lead to phase asynchrony of the hemispheric polar-facula activity.

Surface-distributed low-frequency asynchronous stimulation delays fatigue of stimulated muscles.

PubMed

Maneski, Lana Z Popović; Malešević, Nebojša M; Savić, Andrej M; Keller, Thierry; Popović, Dejan B

2013-12-01

One important reason why functional electrical stimulation (FES) has not gained widespread clinical use is the limitation imposed by rapid muscle fatigue due to non-physiological activation of the stimulated muscles. We aimed to show that asynchronous low-pulse-rate (LPR) electrical stimulation applied by multipad surface electrodes greatly postpones the occurrence of muscle fatigue compared with conventional stimulation (high pulse rate, HPR). We compared the produced force vs. time of the forearm muscles responsible for finger flexion in 2 stimulation protocols, LPR (fL = 10 Hz) and HPR (fH = 40 Hz). Surface-distributed low-frequency asynchronous stimulation (sDLFAS) doubles the time interval before the onset of fatigue (104 ± 80%) compared with conventional synchronous stimulation. Combining the performance of multipad electrodes (increased selectivity and facilitated positioning) with sDLFAS (decreased fatigue) can improve many FES applications in both the lower and upper extremities. Copyright © 2013 Wiley Periodicals, Inc.

Cardiac Dysfunction in HIV-1 Transgenic Mouse: Role of Stress and BAG3.

PubMed

Cheung, Joseph Y; Gordon, Jennifer; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Tilley, Douglas G; Gao, Erhe; Koch, Walter J; Rabinowitz, Joseph; Klotman, Paul E; Khalili, Kamel; Feldman, Arthur M

2015-08-01

Since highly active antiretroviral therapy improved long-term survival of acquired immunodeficiency syndrome (AIDS) patients, AIDS cardiomyopathy has become an increasingly relevant clinical problem. We used human immunodeficiency virus (HIV)-1 transgenic (Tg26) mouse to explore molecular mechanisms of AIDS cardiomyopathy. Tg26 mice had significantly lower left ventricular (LV) mass and smaller end-diastolic and end-systolic LV volumes. Under basal conditions, cardiac contractility and relaxation and single myocyte contraction dynamics were not different between wild-type (WT) and Tg26 mice. Ten days after open heart surgery, contractility and relaxation remained significantly depressed in Tg26 hearts, suggesting that Tg26 mice did not tolerate surgical stress well. To simulate heart failure in which expression of Bcl2-associated athanogene 3 (BAG3) is reduced, we down-regulated BAG3 by small hairpin ribonucleic acid in WT and Tg26 hearts. BAG3 down-regulation significantly reduced contractility in Tg26 hearts. BAG3 overexpression rescued contractile abnormalities in myocytes expressing the HIV-1 protein Tat. We conclude: (i) Tg26 mice exhibit normal contractile function at baseline; (ii) Tg26 mice do not tolerate surgical stress well; (iii) BAG3 down-regulation exacerbated cardiac dysfunction in Tg26 mice; (iv) BAG3 overexpression rescued contractile abnormalities in myocytes expressing HIV-1 protein Tat; and (v) BAG3 may occupy a role in pathogenesis of AIDS cardiomyopathy. © 2015 Wiley Periodicals, Inc.

Adenosine triphosphate as a molecular mediator of the vascular response to injury.

PubMed

Guth, Christy M; Luo, Weifung; Jolayemi, Olukemi; Chadalavada, Kalyan S; Komalavilas, Padmini; Cheung-Flynn, Joyce; Brophy, Colleen M

2017-08-01

Human saphenous veins used for arterial bypass undergo stretch injury at the time of harvest and preimplant preparation. Vascular injury promotes intimal hyperplasia, the leading cause of graft failure, but the molecular events leading to this response are largely unknown. This study investigated adenosine triphosphate (ATP) as a potential molecular mediator in the vascular response to stretch injury, and the downstream effects of the purinergic receptor, P2X7R, and p38 MAPK activation. A subfailure stretch rat aorta model was used to determine the effect of stretch injury on release of ATP and vasomotor responses. Stretch-injured tissues were treated with apyrase, the P2X7R antagonist, A438079, or the p38 MAPK inhibitor, SB203580, and subsequent contractile forces were measured using a muscle bath. An exogenous ATP (eATP) injury model was developed and the experiment repeated. Change in p38 MAPK phosphorylation after stretch and eATP tissue injury was determined using Western blotting. Noninjured tissue was incubated in the p38 MAPK activator, anisomycin, and subsequent contractile function and p38 MAPK phosphorylation were analyzed. Stretch injury was associated with release of ATP. Contractile function was decreased in tissue subjected to subfailure stretch, eATP, and anisomycin. Contractile function was restored by apyrase, P2X7R antagonism, and p38-MAPK inhibition. Stretch, eATP, and anisomycin-injured tissue demonstrated increased phosphorylation of p38 MAPK. Taken together, these data suggest that the vascular response to stretch injury is associated with release of ATP and activation of the P2X7R/P38 MAPK pathway, resulting in contractile dysfunction. Modulation of this pathway in vein grafts after harvest and before implantation may reduce the vascular response to injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Phosphoinositide 3-Kinase p110β Regulates Integrin αIIbβ3 Avidity and the Cellular Transmission of Contractile Forces*

PubMed Central

Schoenwaelder, Simone M.; Ono, Akiko; Nesbitt, Warwick S.; Lim, Joanna; Jarman, Kate; Jackson, Shaun P.

2010-01-01

Phosphoinositide (PI) 3-kinase (PI3K) signaling processes play an important role in regulating the adhesive function of integrin αIIbβ3, necessary for platelet spreading and sustained platelet aggregation. PI3K inhibitors are effective at reducing platelet aggregation and thrombus formation in vivo and as a consequence are currently being evaluated as novel antithrombotic agents. PI3K regulation of integrin αIIbβ3 activation (affinity modulation) primarily occurs downstream of Gi-coupled and tyrosine kinase-linked receptors linked to the activation of Rap1b, AKT, and phospholipase C. In the present study, we demonstrate an important role for PI3Ks in regulating the avidity (strength of adhesion) of high affinity integrin αIIbβ3 bonds, necessary for the cellular transmission of contractile forces. Using knock-out mouse models and isoform-selective PI3K inhibitors, we demonstrate that the Type Ia p110β isoform plays a major role in regulating thrombin-stimulated fibrin clot retraction in vitro. Reduced clot retraction induced by PI3K inhibitors was not associated with defects in integrin αIIbβ3 activation, actin polymerization, or actomyosin contractility but was associated with a defect in integrin αIIbβ3 association with the contractile cytoskeleton. Analysis of integrin αIIbβ3 adhesion contacts using total internal reflection fluorescence microscopy revealed an important role for PI3Ks in regulating the stability of high affinity integrin αIIbβ3 bonds. These studies demonstrate an important role for PI3K p110β in regulating the avidity of high affinity integrin αIIbβ3 receptors, necessary for the cellular transmission of contractile forces. These findings may provide new insight into the potential antithrombotic properties of PI3K p110β inhibitors. PMID:19940148

Single-Cell Functional Analysis of Stem-Cell Derived Cardiomyocytes on Micropatterned Flexible Substrates.

PubMed

Kijlstra, Jan David; Hu, Dongjian; van der Meer, Peter; Domian, Ibrahim J

2017-11-15

Human pluripotent stem-cell derived cardiomyocytes (hPSC-CMs) hold great promise for applications in human disease modeling, drug discovery, cardiotoxicity screening, and, ultimately, regenerative medicine. The ability to study multiple parameters of hPSC-CM function, such as contractile and electrical activity, calcium cycling, and force generation, is therefore of paramount importance. hPSC-CMs cultured on stiff substrates like glass or polystyrene do not have the ability to shorten during contraction, making them less suitable for the study of hPSC-CM contractile function. Other approaches require highly specialized hardware and are difficult to reproduce. Here we describe a protocol for the preparation of hPSC-CMs on soft substrates that enable shortening, and subsequently the simultaneous quantitative analysis of their contractile and electrical activity, calcium cycling, and force generation at single-cell resolution. This protocol requires only affordable and readily available materials and works with standard imaging hardware. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

A biomechanical model of agonist-initiated contraction in the asthmatic airway.

PubMed

Brook, B S; Peel, S E; Hall, I P; Politi, A Z; Sneyd, J; Bai, Y; Sanderson, M J; Jensen, O E

2010-01-31

This paper presents a modelling framework in which the local stress environment of airway smooth muscle (ASM) cells may be predicted and cellular responses to local stress may be investigated. We consider an elastic axisymmetric model of a layer of connective tissue and circumferential ASM fibres embedded in parenchymal tissue and model the active contractile force generated by ASM via a stress acting along the fibres. A constitutive law is proposed that accounts for active and passive material properties as well as the proportion of muscle to connective tissue. The model predicts significantly different contractile responses depending on the proportion of muscle to connective tissue in the remodelled airway. We find that radial and hoop-stress distributions in remodelled muscle layers are highly heterogenous with distinct regions of compression and tension. Such patterns of stress are likely to have important implications, from a mechano-transduction perspective, on contractility, short-term cytoskeletal adaptation and long-term airway remodelling in asthma. Copyright 2009 Elsevier B.V. All rights reserved.

Substrate stiffness regulates cadherin-dependent collective migration through myosin-II contractility

PubMed Central

Ng, Mei Rosa; Besser, Achim

2012-01-01

The mechanical microenvironment is known to influence single-cell migration; however, the extent to which mechanical cues affect collective migration of adherent cells is not well understood. We measured the effects of varying substrate compliance on individual cell migratory properties in an epithelial wound-healing assay. Increasing substrate stiffness increased collective cell migration speed, persistence, and directionality as well as the coordination of cell movements. Dynamic analysis revealed that wounding initiated a wave of motion coordination from the wound edge into the sheet. This was accompanied by a front-to-back gradient of myosin-II activation and establishment of cell polarity. The propagation was faster and farther reaching on stiff substrates, indicating that substrate stiffness affects the transmission of directional cues. Manipulation of myosin-II activity and cadherin–catenin complexes revealed that this transmission is mediated by coupling of contractile forces between neighboring cells. Thus, our findings suggest that the mechanical environment integrates in a feedback with cell contractility and cell–cell adhesion to regulate collective migration. PMID:23091067

Effect of oxytocin on contraction of rabbit proximal colon in vitro

PubMed Central

Xie, Dong-Ping; Chen, Lian-Bi; Liu, Chuan-Yong; Liu, Jing-Zhang; Liu, Ke-Jing

2003-01-01

AIM: To investigate the effects of oxytocin (OT) on isolated rabbit proximal colon and its mechanism. METHODS: Both longitudinal muscle (LM) and circular muscle (CM) were suspended in a tissue chamber containing 5 mL Krebs solution (37 °C), bubbled continuously with 950 mL·L-1 O2 and 50 mL·L-1 CO2. Isometric spontaneous contractile responses to oxytocin or other drugs were recorded in circular and longitudinal muscle strips. RESULTS: OT (0.1 U·L-1) failed to elicit significant effects on the contractile activity of proximal colonic smooth muscle strips (P > 0.05). OT (1 to 10 U·L-1) decreased the mean contractile amplitude and the contractile frequency of CM and LM. Hexamethonium (10 μmol·L-1) partly blocked the inhibition of oxytocin (1 U·L-1) on the contractile frenquency of CM. Nω-nitro-L-arginine-methylester (L-NAME, 1 μmol·L-1), progesterone (32 μmol·L-1) and estrogen (2.6 μmol·L-1) had no effects on OT-induced responses. CONCLUSION: OT inhibits the motility of proximal colon in rabbits. The action is partly relevant with N receptor, but irrelevant with that of NO, progesterone or estrogen. PMID:12508375

A cdk1 gradient guides surface contraction waves in oocytes.

PubMed

Bischof, Johanna; Brand, Christoph A; Somogyi, Kálmán; Májer, Imre; Thome, Sarah; Mori, Masashi; Schwarz, Ulrich S; Lénárt, Péter

2017-10-11

Surface contraction waves (SCWs) in oocytes and embryos lead to large-scale shape changes coupled to cell cycle transitions and are spatially coordinated with the cell axis. Here, we show that SCWs in the starfish oocyte are generated by a traveling band of myosin II-driven cortical contractility. At the front of the band, contractility is activated by removal of cdk1 inhibition of the RhoA/RhoA kinase/myosin II signaling module, while at the rear, contractility is switched off by negative feedback originating downstream of RhoA kinase. The SCW's directionality and speed are controlled by a spatiotemporal gradient of cdk1-cyclinB. This gradient is formed by the release of cdk1-cyclinB from the asymmetrically located nucleus, and progressive degradation of cyclinB. By combining quantitative imaging, biochemical and mechanical perturbations with mathematical modeling, we demonstrate that the SCWs result from the spatiotemporal integration of two conserved regulatory modules, cdk1-cyclinB for cell cycle regulation and RhoA/Rok/NMYII for actomyosin contractility.Surface contraction waves (SCWs) are prominent shape changes coupled to cell cycle transitions in oocytes. Here the authors show that SCWs are patterned by the spatiotemporal integration of two conserved modules, cdk1-cyclinB for cell cycle regulation and RhoA/Rok/NMYII for actomyosin contractility.

[A basis for application of cardiac contractility variability in the Evaluation and assessment of exercise and fitness].

PubMed

Bu, Bin; Wang, Aihua; Han, Haijun; Xiao, Shouzhong

2010-06-01

Cardiac contractility variability (CCV) is a new concept which is introduced in the research field of cardiac contractility in recent years, that is to say, there are some disparities between cardiac contractilities when heart contracts. The changing signals of cardiac contractility contain a plenty of information on the cardiovascular function and disorder. In order to collect and analyze the message, we could quantitatively evaluate the tonicity and equilibrium of cardiac sympathetic nerve and parasympathetic nerve, and the effects of bio-molecular mechanism on the cardiovascular activities. By analyzing CCV, we could further understand the background of human being's heritage characteristics, nerve types, the adjusting mechanism, the molecular biology, and the adjustment of cardiac automatic nerve. With the development of the computing techniques, the digital signal processing method and its application in medical field, this analysis has been progressing greatly. By now, the assessment of CCV, just like the analysis of heart rate variability, is mainly via time domain and frequency domain analysis. CCV is one of the latest research fields in human cardiac signals being scarcely reported in the field of sports medicine; however, its research progresses are of important value for cardiac physiology and pathology in sports medicine and rehabilitation medicine.

Fatigability and Blood Flow in the Rat Gastrocnemius-Plantaris-Soleus after Hindlimb Suspension

NASA Technical Reports Server (NTRS)

McDonald, K. S.; Delp, M. D.; Fitts, R. H.

1992-01-01

The purpose of this study was to test the hypothesis that hindlimb suspension increases the fatigability of the soleus during intense contractile activity and determine whether the increased fatigue is associated with a reduced muscle blood flow. Cage-control (C) and 15-day hindlimb-suspended (HS) rats were anesthetized, and either the gastrocnemius-plantaris-soleus (G-P-S) muscle group or the soleus was stimulated (100 Hz, 100-ms trains at 120/min) for 10 min in situ. In the G-P-S preparation, blood flow was measured with radiolabeled microspheres before and at 2 and 10 min of contractile activity. The G-P-S fatigued markedly at this stimulation frequency, and the differences between C and HS animals were not significant until the 9th min of contractile activity. In contrast, the stimulation resulted in faster rates and significantly larger amounts of fatigue in the soleus from HS than from C animals. The atrophied soleus showed significant differences by I min of stimulation (C = 70 +/- 1% vs. HS = 57 +/- 2% of peak train force) and remained different at 10 min (C = 64 +/- 4% vs. HS = 45 +/- 2% peak train force). Relative blood flow to the soleus was similar between groups before and during contractile activity (rest: C = 20 +/- 3 vs. HS= 12 +/- 3; 2 min: C= 128 +/- 6 vs. HS = 118 +/- 4; 10 min: C = 123 +/- 11 vs. HS = 105 +/- 11 ml min(exp -1) 100 g(exp -1)). In conclusion, these results established that 15 days of HS increased the fatigability of the soleus, but the effect was not caused by a reduced muscle blood flow.

GSNOR Deficiency Enhances In Situ Skeletal Muscle Strength, Fatigue Resistance, and RyR1 S-Nitrosylation Without Impacting Mitochondrial Content and Activity

PubMed Central

Moon, Younghye; Cao, Yenong; Zhu, Jingjing; Xu, Yuanyuan; Balkan, Wayne; Buys, Emmanuel S.; Diaz, Francisca; Kerrick, W. Glenn; Hare, Joshua M.

2017-01-01

Abstract Aim: Nitric oxide (NO) plays important, but incompletely defined roles in skeletal muscle. NO exerts its regulatory effects partly though S-nitrosylation, which is balanced by denitrosylation by enzymes such as S-nitrosoglutathione reductase (GSNOR), whose functions in skeletal muscle remain to be fully deciphered. Results: GSNOR null (GSNOR−/−) tibialis anterior (TA) muscles showed normal growth and were stronger and more fatigue resistant than controls in situ. However, GSNOR−/− lumbrical muscles showed normal contractility and Ca2+ handling in vitro, suggesting important differences in GSNOR function between muscles or between in vitro and in situ environments. GSNOR−/− TA muscles exhibited normal mitochondrial content, and capillary densities, but reduced type IIA fiber content. GSNOR inhibition did not impact mitochondrial respiratory complex I, III, or IV activities. These findings argue that enhanced GSNOR−/− TA contractility is not driven by changes in mitochondrial content or activity, fiber type, or blood vessel density. However, loss of GSNOR led to RyR1 hypernitrosylation, which is believed to increase muscle force output under physiological conditions. cGMP synthesis by soluble guanylate cyclase (sGC) was decreased in resting GSNOR−/− muscle and was more responsive to agonist (DETANO, BAY 41, and BAY 58) stimulation, suggesting that GSNOR modulates cGMP production in skeletal muscle. Innovation: GSNOR may act as a “brake” on skeletal muscle contractile performance under physiological conditions by modulating nitrosylation/denitrosylation balance. Conclusions: GSNOR may play important roles in skeletal muscle contractility, RyR1 S-nitrosylation, fiber type specification, and sGC activity. Antioxid. Redox Signal. 26, 165–181. PMID:27412893

High-definition spatiotemporal mapping of contractile activity in the isolated proximal colon of the rabbit.

PubMed

Lentle, Roger G; Janssen, Patrick W M; Asvarujanon, Patchana; Chambers, Paul; Stafford, Kevin J; Hemar, Yacine

2008-03-01

Four types of contractile activity were identified and characterised in the isolated triple haustrated proximal colon of the rabbit using high-definition spatiotemporal mapping techniques. Mass peristalses were hexamethonium-sensitive deep circular contractions with associated taenial longitudinal contractile activity that occurred irregularly and propagated rapidly aborad, preceded by a zone of local lumen distension. They were sufficiently sustained for each event to occupy the length of the isolated colonic segment and the contraction persisted longer orally than aborally, the difference being more pronounced when lumen contents were viscous. Haustra were bounded by deep even-spaced ring contractions that progressed slowly aborad (haustral progression). Haustral formation and progression were hexamethonium-sensitive and coordinated across intertaenial domains. Ripples were hexamethonium-resistant phasic circular contractions that propagated predominantly orad at varying rates. In the presence of haustra, they were uncoordinated across intertaenial domains but were more coordinated when haustra were absent. Fast phasic contractions were relatively shallow hexamethonium-resistant contractions that propagated rapidly in a predominantly aborad direction. Fast phasic circular contractions were accompanied by taenial longitudinal muscle contractions which increased in amplitude prior to a mass peristaltic event and following the administration of hexamethonium. On the basis of the concurrence and interaction of these contractile activities, we hypothesise that dual pacemakers are present with fast phasic contractions being modulated by the interstitial cells of Cajal in the Auerbach's plexus (ICC-MY) while ripples are due to the submucosal ICC (ICC-SM). Further, that ICC-SM mediate the enteric motor neurons that generate haustral progression, while the intramuscular ICC (ICC-IM) mediate mass peristalsis. The orad movement of watery fluid was possibly due to ripples in the absence of haustra.

Characterizing the Propagation of Uterine Electrophysiological Signals Recorded with a Multi-Sensor Abdominal Array in Term Pregnancies.

PubMed

Escalona-Vargas, Diana; Govindan, Rathinaswamy B; Furdea, Adrian; Murphy, Pam; Lowery, Curtis L; Eswaran, Hari

2015-01-01

The objective of this study was to quantify the number of segments that have contractile activity and determine the propagation speed from uterine electrophysiological signals recorded over the abdomen. The uterine magnetomyographic (MMG) signals were recorded with a 151 channel SARA (SQUID Array for Reproductive Assessment) system from 36 pregnant women between 37 and 40 weeks of gestational age. The MMG signals were scored and segments were classified based on presence of uterine contractile burst activity. The sensor space was then split into four quadrants and in each quadrant signal strength at each sample was calculated using center-of-gravity (COG). To this end, the cross-correlation analysis of the COG was performed to calculate the delay between pairwise combinations of quadrants. The relationship in propagation across the quadrants was quantified and propagation speeds were calculated from the delays. MMG recordings were successfully processed from 25 subjects and the average values of propagation speeds ranged from 1.3-9.5 cm/s, which was within the physiological range. The propagation was observed between both vertical and horizontal quadrants confirming multidirectional propagation. After the multiple pairwise test (99% CI), significant differences in speeds can be observed between certain vertical or horizontal combinations and the crossed pair combinations. The number of segments containing contractile activity in any given quadrant pair with a detectable delay was significantly higher in the lower abdominal pairwise combination as compared to all others. The quadrant-based approach using MMG signals provided us with high spatial-temporal information of the uterine contractile activity and will help us in the future to optimize abdominal electromyographic (EMG) recordings that are practical in a clinical setting.

Characterizing the Propagation of Uterine Electrophysiological Signals Recorded with a Multi-Sensor Abdominal Array in Term Pregnancies

PubMed Central

Escalona-Vargas, Diana; Govindan, Rathinaswamy B.; Furdea, Adrian; Murphy, Pam; Lowery, Curtis L.; Eswaran, Hari

2015-01-01

The objective of this study was to quantify the number of segments that have contractile activity and determine the propagation speed from uterine electrophysiological signals recorded over the abdomen. The uterine magnetomyographic (MMG) signals were recorded with a 151 channel SARA (SQUID Array for Reproductive Assessment) system from 36 pregnant women between 37 and 40 weeks of gestational age. The MMG signals were scored and segments were classified based on presence of uterine contractile burst activity. The sensor space was then split into four quadrants and in each quadrant signal strength at each sample was calculated using center-of-gravity (COG). To this end, the cross-correlation analysis of the COG was performed to calculate the delay between pairwise combinations of quadrants. The relationship in propagation across the quadrants was quantified and propagation speeds were calculated from the delays. MMG recordings were successfully processed from 25 subjects and the average values of propagation speeds ranged from 1.3–9.5 cm/s, which was within the physiological range. The propagation was observed between both vertical and horizontal quadrants confirming multidirectional propagation. After the multiple pairwise test (99% CI), significant differences in speeds can be observed between certain vertical or horizontal combinations and the crossed pair combinations. The number of segments containing contractile activity in any given quadrant pair with a detectable delay was significantly higher in the lower abdominal pairwise combination as compared to all others. The quadrant-based approach using MMG signals provided us with high spatial-temporal information of the uterine contractile activity and will help us in the future to optimize abdominal electromyographic (EMG) recordings that are practical in a clinical setting. PMID:26505624

2-Deoxyadenosine triphosphate restores the contractile function of cardiac myofibril from adult dogs with naturally occurring dilated cardiomyopathy

PubMed Central

Cheng, Yuanhua; Hogarth, Kaley A.; O'Sullivan, M. Lynne; Regnier, Michael

2015-01-01

Dilated cardiomyopathy (DCM) is a major type of heart failure resulting from loss of systolic function. Naturally occurring canine DCM is a widely accepted experimental paradigm for studying human DCM. 2-Deoxyadenosine triphosphate (dATP) can be used by myosin and is a superior energy substrate over ATP for cross-bridge formation and increased systolic function. The objective of this study was to evaluate the beneficial effect of dATP on contractile function of cardiac myofibrils from dogs with naturally occurring DCM. We measured actomyosin NTPase activity and contraction/relaxation properties of isolated myofibrils from nonfailing (NF) and DCM canine hearts. NTPase assays indicated replacement of ATP with dATP significantly increased myofilament activity in both NF and DCM samples. dATP significantly improved maximal tension of DCM myofibrils to the NF sample level. dATP also restored Ca2+ sensitivity of tension that was reduced in DCM samples. Similarly, dATP increased the kinetics of contractile activation (kACT), with no impact on the rate of cross-bridge tension redevelopment (kTR). Thus, the activation kinetics (kACT/kTR) that were reduced in DCM samples were restored for dATP to NF sample levels. dATP had little effect on relaxation. The rate of early slow-phase relaxation was slightly reduced with dATP, but its duration was not, nor was the fast-phase relaxation or times to 50 and 90% relaxation. Our findings suggest that myosin utilization of dATP improves cardiac myofibril contractile properties of naturally occurring DCM canine samples, restoring them to NF levels, without compromising relaxation. This suggests elevation of cardiac dATP is a promising approach for the treatment of DCM. PMID:26497964

2-Deoxyadenosine triphosphate restores the contractile function of cardiac myofibril from adult dogs with naturally occurring dilated cardiomyopathy.

PubMed

Cheng, Yuanhua; Hogarth, Kaley A; O'Sullivan, M Lynne; Regnier, Michael; Pyle, W Glen

2016-01-01

Dilated cardiomyopathy (DCM) is a major type of heart failure resulting from loss of systolic function. Naturally occurring canine DCM is a widely accepted experimental paradigm for studying human DCM. 2-Deoxyadenosine triphosphate (dATP) can be used by myosin and is a superior energy substrate over ATP for cross-bridge formation and increased systolic function. The objective of this study was to evaluate the beneficial effect of dATP on contractile function of cardiac myofibrils from dogs with naturally occurring DCM. We measured actomyosin NTPase activity and contraction/relaxation properties of isolated myofibrils from nonfailing (NF) and DCM canine hearts. NTPase assays indicated replacement of ATP with dATP significantly increased myofilament activity in both NF and DCM samples. dATP significantly improved maximal tension of DCM myofibrils to the NF sample level. dATP also restored Ca(2+) sensitivity of tension that was reduced in DCM samples. Similarly, dATP increased the kinetics of contractile activation (kACT), with no impact on the rate of cross-bridge tension redevelopment (kTR). Thus, the activation kinetics (kACT/kTR) that were reduced in DCM samples were restored for dATP to NF sample levels. dATP had little effect on relaxation. The rate of early slow-phase relaxation was slightly reduced with dATP, but its duration was not, nor was the fast-phase relaxation or times to 50 and 90% relaxation. Our findings suggest that myosin utilization of dATP improves cardiac myofibril contractile properties of naturally occurring DCM canine samples, restoring them to NF levels, without compromising relaxation. This suggests elevation of cardiac dATP is a promising approach for the treatment of DCM. Copyright © 2016 the American Physiological Society.

Myotropic Effects of Cholinergic Muscarinic Agonists and Antagonists in the Beetle Tenebrio molitor L.

PubMed

Chowanski, Szymon; Rosinski, Grzegorz

2017-01-01

In mammals, the cholinergic nervous system plays a crucial role in neuronal regulation of physiological processes. It acts on cells by two types of receptors - nicotinic and muscarinic receptors. Both signal transmission pathways also operate in the central and peripheral cholinergic nervous system of insects. In our pharmacological experiments, we studied the effects of two muscarinic agonists (carbachol, pilocarpine) and two muscarinic antagonists (atropine, scopolamine) on the muscle contractile activity of visceral organs in the beetle, Tenebrio molitor. Both antagonists, when injected to haemolymph at concentration 10-5 M, caused delayed and prolonged cardioinhibitory effects on heart contractility in ortho- and antidromic phases of heart activity in T. molitor pupa what was observed as negative chrono- and inotropic effects. Agonist of muscarinic receptors - carbachol evoked opposite effect and increased contraction rate but only in antidromic phase. Pilocarpine, the second agonist induced weak negative chronotropic effects in the antiand orthodromic phases of heart activity. However, neither agonists had an effect on semi-isolated beetle heart in vitro. Only atropine at the highest tested concentrations slightly decreased the frequency of myocardial contractions. These suggest the regulation of heart activity by muscarinic system indirectly. The tested compounds also affected the contractility of the oviduct and hindgut, but the responses of these organs were varied and depended on the concentration of the applied compounds. These pharmacological experiments suggest the possible modulation of insect visceral muscle contractility by the cholinergic nervous system and indirectly indicate the presence of muscarinic receptor(s) in the visceral organs of the beetle T. molitor. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Active fantasy sports: rationale and feasibility of leveraging online fantasy sports to promote physical activity.

PubMed

Moller, Arlen C; Majewski, Sara; Standish, Melanie; Agarwal, Pooja; Podowski, Aleksandra; Carson, Rebecca; Eyesus, Biruk; Shah, Aakash; Schneider, Kristin L

2014-11-25

The popularity of active video games (AVGs) has skyrocketed over the last decade. However, research suggests that the most popular AVGs, which rely on synchronous integration between players' activity and game features, fail to promote physical activity outside of the game or for extended periods of engagement. This limitation has led researchers to consider AVGs that involve asynchronous integration of players' ongoing physical activity with game features. Rather than build an AVG de novo, we selected an established sedentary video game uniquely well suited for the incorporation of asynchronous activity: online fantasy sports. The primary aim of this study was to explore the feasibility of a new asynchronous AVG-active fantasy sports-designed to promote physical activity. We conducted two pilot studies of an active fantasy sports game designed to promote physical activity. Participants wore a low cost triaxial accelerometer and participated in an online fantasy baseball (Study 1, n=9, 13-weeks) or fantasy basketball (Study 2, n=10, 17-weeks) league. Privileges within the game were made contingent on meeting weekly physical activity goals (eg, averaging 10,000 steps/day). Across the two studies, the feasibility of integrating physical activity contingent features and privileges into online fantasy sports games was supported. Participants found the active fantasy sports game enjoyable, as or more enjoyable than traditional (sedentary) online fantasy sports (Study 1: t8=4.43, P<.01; Study 2: t9=2.09, P=.07). Participants in Study 1 increased their average steps/day, t8=2.63, P<.05, while participants in Study 2 maintained (ie, did not change) their activity, t9=1.57, P=.15). In postassessment interviews, social support within the game was cited as a key motivating factor for increasing physical activity. Preliminary evidence supports potential for the active fantasy sports system as a sustainable and scalable intervention for promoting adult physical activity.

Active Fantasy Sports: Rationale and Feasibility of Leveraging Online Fantasy Sports to Promote Physical Activity

PubMed Central

Majewski, Sara; Standish, Melanie; Agarwal, Pooja; Podowski, Aleksandra; Carson, Rebecca; Eyesus, Biruk; Shah, Aakash; Schneider, Kristin L

2014-01-01

Background The popularity of active video games (AVGs) has skyrocketed over the last decade. However, research suggests that the most popular AVGs, which rely on synchronous integration between players’ activity and game features, fail to promote physical activity outside of the game or for extended periods of engagement. This limitation has led researchers to consider AVGs that involve asynchronous integration of players’ ongoing physical activity with game features. Rather than build an AVG de novo, we selected an established sedentary video game uniquely well suited for the incorporation of asynchronous activity: online fantasy sports. Objective The primary aim of this study was to explore the feasibility of a new asynchronous AVG—active fantasy sports—designed to promote physical activity. Methods We conducted two pilot studies of an active fantasy sports game designed to promote physical activity. Participants wore a low cost triaxial accelerometer and participated in an online fantasy baseball (Study 1, n=9, 13-weeks) or fantasy basketball (Study 2, n=10, 17-weeks) league. Privileges within the game were made contingent on meeting weekly physical activity goals (eg, averaging 10,000 steps/day). Results Across the two studies, the feasibility of integrating physical activity contingent features and privileges into online fantasy sports games was supported. Participants found the active fantasy sports game enjoyable, as or more enjoyable than traditional (sedentary) online fantasy sports (Study 1: t 8=4.43, P<.01; Study 2: t 9=2.09, P=.07). Participants in Study 1 increased their average steps/day, t 8=2.63, P<.05, while participants in Study 2 maintained (ie, did not change) their activity, t 9=1.57, P=.15). In postassessment interviews, social support within the game was cited as a key motivating factor for increasing physical activity. Conclusions Preliminary evidence supports potential for the active fantasy sports system as a sustainable and scalable intervention for promoting adult physical activity. PMID:25654304

Acceptability of an Asynchronous Learning Forum on Mobile Devices

ERIC Educational Resources Information Center

Chang, Chih-Kai

2010-01-01

Mobile learning has recently become noteworthy because mobile devices have become popular. To construct an asynchronous learning forum on mobile devices is important because an asynchronous learning forum is always an essential part of networked asynchronous distance learning. However, the input interface in handheld learning devices, which is…

The Influence of Asynchronous Video Communication on Learner Social Presence: A Narrative Analysis of Four Cases

ERIC Educational Resources Information Center

Borup, Jered; West, Richard E.; Graham, Charles R.

2013-01-01

Online courses are increasingly using asynchronous video communication. However, little is known about how asynchronous video communication influences students' communication patterns. This study presents four narratives of students with varying characteristics who engaged in asynchronous video communication. The extrovert valued the efficiency of…

Endoplasmic reticulum Chaperon Tauroursodeoxycholic Acid Alleviates Obesity-Induced Myocardial Contractile Dysfunction

PubMed Central

Ceylan-Isik, Asli F.; Sreejayan, Nair; Ren, Jun

2010-01-01

ER stress is involved in the pathophysiology of obesity although little is known about the role of ER stress on obesity-associated cardiac dysfunction. This study was designed to examine the effect of ER chaperone tauroursodeoxycholic acid (TUDCA) on obesity-induced myocardial dysfunction. Adult lean and ob/ob obese mice were treated TUDCA (50 mg/kg/d, p.o.) or vehicle for 5 wks. Oral glucose tolerance test (OGTT) was performed. Echocardiography, cardiomyocyte contractile and intracellular Ca2+ properties were assessed. Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity and protein expression of intracellular Ca2+ regulatory proteins were measured using 45Ca2+ uptake and Western blot analysis, respectively. Insulin signaling, ER stress markers and HSP90 were evaluated. Our results revealed that chronic TUDCA treatment lower systolic blood pressure and lessened glucose intolerance in obese mice. Obesity led to increased diastolic diameter, cardiac hypertrophy, compromised fractional shortening, cardiomyocyte contractile (peak shortening, maximal velocity of shortening/relengthening, and duration of contraction/relaxation) and intracellular Ca2+ properties, all of which were significantly attenuated by TUDCA. TUDCA reconciled obesity-associated decreased in SERCA activity and expression, and increase in serine phosphorylation of IRS, total and phosphorylated cJun, ER stress markers Bip, peIF2α and pPERK. Obesity-induced changes in phospholamban and HSP90 were unaffected by TUDCA. In vitro finding revealed that TUDCA ablated palmitic acid-induced cardiomyocyte contractile dysfunction. In summary, these data depicted a pivotal role of ER stress in obesity-associated cardiac contractile dysfunction, suggesting the therapeutic potential of ER stress as a target in the management of cardiac dysfunction in obesity. PMID:21035453

Activation of neurokinin NK(2) receptors by tachykinin peptides causes contraction of uterus in pregnant women near term.

PubMed

Patak, E N; Ziccone, S; Story, M E; Fleming, A J; Lilley, A; Pennefather, J N

2000-06-01

The aim of this study was firstly to elucidate whether the mammalian tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB)-regulated contractility of myometrium obtained from near-term pregnant women, and secondly to investigate the receptor subtype(s) responsible. In the presence of peptidase inhibitors, i.e. thiorphan (3 micromol/l; endopeptidase 24.11 inhibitor), captopril (10 micromol/l; angiotensin converting enzyme inhibitor) and bestatin (10 micromol/l; aminopeptidase inhibitor); all three mammalian tachykinins elicited concentration-related contractions of isolated myometrial preparations. The rank order of agonist potency of the mammalian tachykinins in the presence of the peptidase inhibitors was NKA > SP = NKB, indicating that the contractile effects were mediated by activation of an NK(2) receptor. The NK(2) receptor-selective agonist, [Lys(5), MeLeu(9), Nle(10)]NKA(4-10), produced concentration-related contractile responses, while the respective NK(1) and NK(3) receptor-selective agonists, [Sar(9), Met(O(2))(11)]SP and [N-MePhe(7)]NKB, had no effect either in the absence or presence of the peptidase inhibitors. The NK(2) receptor-selective antagonist, SR48968, produced concentration-related rightward shift in the log concentration curve to [Lys(5), MeLeu(9), Nle(10)]NKA(4-10). This study shows that tachykinins elicit contractile effects on human myometrium obtained from pregnant women near term, and that these effects are mediated by an NK(2) receptor. An excitatory effect of the tachykinins on these preparations could indicate a physiological role for these peptides in enhancing contractility of the uterus in women at term.

Esophageal Epithelial Resistance and Lower Esophageal Sphincter Muscle Contraction Increase in a Chronic Diabetic Rabbit Model.

PubMed

Capanoglu, Doga; Coskunsever, Deniz; Olukman, Murat; Ülker, Sibel; Bor, Serhat

2016-07-01

Esophageal motility disorders and possibly gastroesophageal reflux disease are common in patients with diabetes mellitus. We aimed to investigate both the electrophysiological characteristics of the esophageal epithelium and the contractility of the lower esophageal sphincter (LES) muscle in alloxane-induced diabetic rabbits. Electrophysiological properties were measured using an Ussing chamber method. An acid-pepsin model was employed with pH 1.7 or weakly acidic (pH 4) Ringer and/or pepsin. Smooth muscle strips of the LES were mounted in an isolated organ bath. Contractile responses to an electrical field stimulation and cumulative concentrations of acetylcholine were recorded. Contractility of the muscle strips were tested in the presence of Rho-kinase inhibitor (Y-27632) and nonspecific nitric oxide inhibitor (L-NAME). The resistance of diabetic tissue perfused in the pH 1.7 Ringer decreased 17 %; pepsin addition decreased it by 49 %. The same concentrations caused a more distinct loss of resistance in the control tissues (22 and 76 %, p < 0.05). The perfusion of tissues in increased concentrations of luminal and serosal glucose did not change the tissue resistance and voltage. Diabetes significantly increased both the electrical field stimulation and acetylcholine-induced contractions in the LES muscle strips (p < 0.01). Incubation with Y-27632 significantly decreased the acetylcholine-induced contractions in a concentration-dependent manner (p < 0.01). The acid-pepsin model in the diabetic rabbit esophageal tissue had less injury compared with the control. The diabetic rabbit LES muscle had higher contractility, possibly because of the activation of the Rho-Rhokinase pathway. Our results show that in a chronic diabetic rabbit model the esophagus resists reflux by activating mechanisms of mucosal defense and increasing the contractility of the LES.

Pericyte contractility controls endothelial cell cycle progression and sprouting: insights into angiogenic switch mechanics.

PubMed

Durham, Jennifer T; Surks, Howard K; Dulmovits, Brian M; Herman, Ira M

2014-11-01

Microvascular stability and regulation of capillary tonus are regulated by pericytes and their interactions with endothelial cells (EC). While the RhoA/Rho kinase (ROCK) pathway has been implicated in modulation of pericyte contractility, in part via regulation of the myosin light chain phosphatase (MLCP), the mechanisms linking Rho GTPase activity with actomyosin-based contraction and the cytoskeleton are equivocal. Recently, the myosin phosphatase-RhoA-interacting protein (MRIP) was shown to mediate the RhoA/ROCK-directed MLCP inactivation in vascular smooth muscle. Here we report that MRIP directly interacts with the β-actin-specific capping protein βcap73. Furthermore, manipulation of MRIP expression influences pericyte contractility, with MRIP silencing inducing cytoskeletal remodeling and cellular hypertrophy. MRIP knockdown induces a repositioning of βcap73 from the leading edge to stress fibers; thus MRIP-silenced pericytes increase F-actin-driven cell spreading twofold. These hypertrophied and cytoskeleton-enriched pericytes demonstrate a 2.2-fold increase in contractility upon MRIP knockdown when cells are plated on a deformable substrate. In turn, silencing pericyte MRIP significantly affects EC cycle progression and angiogenic activation. When MRIP-silenced pericytes are cocultured with capillary EC, there is a 2.0-fold increase in EC cycle entry. Furthermore, in three-dimensional models of injury and repair, silencing pericyte MRIP results in a 1.6-fold elevation of total tube area due to EC network formation and increased angiogenic sprouting. The pivotal role of MRIP expression in governing pericyte contractile phenotype and endothelial growth should lend important new insights into how chemomechanical signaling pathways control the "angiogenic switch" and pathological angiogenic induction. Copyright © 2014 the American Physiological Society.

Nonequilibrium phase transitions, fluctuations and correlations in an active contractile polar fluid.

PubMed

Gowrishankar, Kripa; Rao, Madan

2016-02-21

We study the patterning, fluctuations and correlations of an active polar fluid consisting of contractile polar filaments on a two-dimensional substrate, using a hydrodynamic description. The steady states generically consist of arrays of inward pointing asters and show a continuous transition from a moving lamellar phase, a moving aster street, to a stationary aster lattice with no net polar order. We next study the effect of spatio-temporal athermal noise, parametrized by an active temperature TA, on the stability of the ordered phases. In contrast to its equilibrium counterpart, we find that the active crystal shows true long range order at low TA. On increasing TA, the asters dynamically remodel, concomitantly we find novel phase transitions characterized by bond-orientational and polar order upon "heating".

Pharmacists' perception of synchronous versus asynchronous distance learning for continuing education programs.

PubMed

Buxton, Eric C

2014-02-12

To evaluate and compare pharmacists' satisfaction with the content and learning environment of a continuing education program series offered as either synchronous or asynchronous webinars. An 8-lecture series of online presentations on the topic of new drug therapies was offered to pharmacists in synchronous and asynchronous webinar formats. Participants completed a 50-question online survey at the end of the program series to evaluate their perceptions of the distance learning experience. Eighty-two participants completed the survey instrument (41 participants from the live webinar series and 41 participants from the asynchronous webinar series.) Responses indicated that while both groups were satisfied with the program content, the asynchronous group showed greater satisfaction with many aspects of the learning environment. The synchronous and asynchronous webinar participants responded positively regarding the quality of the programming and the method of delivery, but asynchronous participants rated their experience more positively overall.

Pharmacists’ Perception of Synchronous Versus Asynchronous Distance Learning for Continuing Education Programs

PubMed Central

2014-01-01

Objective. To evaluate and compare pharmacists’ satisfaction with the content and learning environment of a continuing education program series offered as either synchronous or asynchronous webinars. Methods. An 8-lecture series of online presentations on the topic of new drug therapies was offered to pharmacists in synchronous and asynchronous webinar formats. Participants completed a 50-question online survey at the end of the program series to evaluate their perceptions of the distance learning experience. Results. Eighty-two participants completed the survey instrument (41 participants from the live webinar series and 41 participants from the asynchronous webinar series.) Responses indicated that while both groups were satisfied with the program content, the asynchronous group showed greater satisfaction with many aspects of the learning environment. Conclusion. The synchronous and asynchronous webinar participants responded positively regarding the quality of the programming and the method of delivery, but asynchronous participants rated their experience more positively overall. PMID:24558276

Comparing the force ripple during asynchronous and conventional stimulation.

PubMed

Downey, Ryan J; Tate, Mark; Kawai, Hiroyuki; Dixon, Warren E

2014-10-01

Asynchronous stimulation has been shown to reduce fatigue during electrical stimulation; however, it may also exhibit a force ripple. We quantified the ripple during asynchronous and conventional single-channel transcutaneous stimulation across a range of stimulation frequencies. The ripple was measured during 5 asynchronous stimulation protocols, 2 conventional stimulation protocols, and 3 volitional contractions in 12 healthy individuals. Conventional 40 Hz and asynchronous 16 Hz stimulation were found to induce contractions that were as smooth as volitional contractions. Asynchronous 8, 10, and 12 Hz stimulation induced contractions with significant ripple. Lower stimulation frequencies can reduce fatigue; however, they may also lead to increased ripple. Future efforts should study the relationship between force ripple and the smoothness of the evoked movements in addition to the relationship between stimulation frequency and NMES-induced fatigue to elucidate an optimal stimulation frequency for asynchronous stimulation. © 2014 Wiley Periodicals, Inc.

Changes of contractile responses due to simulated weightlessness in rat soleus muscle

NASA Astrophysics Data System (ADS)

Elkhammari, A.; Noireaud, J.; Léoty, C.

1994-08-01

Some contractile and electrophysiological properties of muscle fibers isolated from the slow-twitch soleus (SOL) and fast-twitch extensor digitorum longus (EDL) muscles of rats were compared with those measured in SOL muscles from suspended rats. In suspendede SOL (21 days of tail-suspension) membrane potential (Em), intracellular sodium activity (aiNa) and the slope of the relationship between Em and log [K]o were typical of fast-twitch muscles. The relation between the maximal amplitude of K-contractures vs Em was steeper for control SOL than for EDL and suspended SOL muscles. After suspension, in SOL muscles the contractile threshold and the inactivation curves for K-contractures were shifted to more positive Em. Repriming of K-contractures was unaffected by suspencion. The exposure of isolated fibers to perchlorate (ClO4-)-containing (6-40 mM) solutions resulted ina similar concentration-dependent shift to more negative Em of activation curves for EDL and suspended SOL muscles. On exposure to a Na-free TEA solution, SOL from control and suspended rats, in contrast to EDL muscles, generated slow contractile responses. Suspended SOL showed a reduced sensitivity to the contracture-producing effect of caffeine compared to control muscles. These results suggested that the modification observed due to suspension could be encounted by changes in the characteristics of muscle fibers from slow to fast-twitch type.

Urothelium-dependent and urothelium-independent detrusor contractility mediated by nitric oxide synthase and cyclooxygenase inhibition.

PubMed

Santoso, Aneira Gracia Hidayat; Lo, Wan Ning; Liang, Willmann

2011-04-01

The urothelium has been implicated in regulating detrusor smooth muscle contractility but the identity of the putative urothelium-derived inhibitory factor remains unconfirmed. There was inconclusive evidence on the role of nitric oxide synthase (NOS) and cyclooxygenase (COX) in mediating detrusor contractions. This study examined varying regulation by NOS and COX in transverse and longitudinal carbachol (CCh)-induced and unstimulated phasic contractions. Rat detrusor strips with the urothelium-intact (+UE) and urothelium-denuded (-UE) were isolated in both transverse and longitudinal directions. Isometric tension of the detrusor strips was recorded both during stimulation with CCh and at the unstimulated state. In the unstimulated state, phasic contractile activity was measured. Tension recordings were made with and without the NOS inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) and COX inhibitor indomethacin (Indo). Only transverse +UE strips responded convincingly to L-NAME and Indo treatment, generating larger CCh-induced contractions. In unstimulated tissues, L-NAME treatment increased phasic amplitude in -UE strips only. Indo treatment failed to elicit any change in the amplitude but suppressed frequency of the phasic activity in transverse +UE strips. There was no significant Indo-mediated change in other strips. The data suggested heterogeneity in the regulation of directional detrusor contractility via NOS- and COX-associated mechanisms. Copyright © 2011 Wiley-Liss, Inc.

Cerebral Artery Alpha-1 AR Subtypes: High Altitude Long-Term Acclimatization Responses

PubMed Central

Goyal, Ravi; Goyal, Dipali; Chu, Nina; Van Wickle, Jonathan; Longo, Lawrence D.

2014-01-01

In response to hypoxia and other stress, the sympathetic (adrenergic) nervous system regulates arterial contractility and blood flow, partly through differential activities of the alpha1 (α1) - adrenergic receptor (AR) subtypes (α1A-, α1B-, and α1D-AR). Thus, we tested the hypothesis that with acclimatization to long-term hypoxia (LTH), contractility of middle cerebral arteries (MCA) is regulated by changes in expression and activation of the specific α1-AR subtypes. We conducted experiments in MCA from adult normoxic sheep maintained near sea level (300 m) and those exposed to LTH (110 days at 3801 m). Following acclimatization to LTH, ovine MCA showed a 20% reduction (n = 5; P<0.05) in the maximum tension achieved by 10−5 M phenylephrine (PHE). LTH-acclimatized cerebral arteries also demonstrated a statistically significant (P<0.05) inhibition of PHE-induced contractility in the presence of specific α1-AR subtype antagonists. Importantly, compared to normoxic vessels, there was significantly greater (P<0.05) α1B-AR subtype mRNA and protein levels in LTH acclimatized MCA. Also, our results demonstrate that extracellular regulated kinase 1 and 2 (ERK1/2)-mediated negative feedback regulation of PHE-induced contractility is modulated by α1B-AR subtype. Overall, in ovine MCA, LTH produces profound effects on α1-AR subtype expression and function. PMID:25393740

Bone Morphogenetic Protein 4 Promotes Vascular Smooth Muscle Contractility by Activating MicroRNA-21 (miR-21), which Down-regulates Expression of Family of Dedicator of Cytokinesis (DOCK) Proteins*

PubMed Central

Kang, Hara; Davis-Dusenbery, Brandi N.; Nguyen, Peter H.; Lal, Ashish; Lieberman, Judy; Van Aelst, Linda; Lagna, Giorgio; Hata, Akiko

2012-01-01

The bone morphogenetic protein 4 (BMP4) signaling pathway plays a critical role in the promotion and maintenance of the contractile phenotype in vascular smooth muscle cell (vSMC). Misexpression or inactivating mutations of the BMP receptor gene can lead to dedifferentiation of vSMC characterized by increased migration and proliferation that is linked to vascular proliferative disorders. Previously we demonstrated that vSMCs increase microRNA-21 (miR-21) biogenesis upon BMP4 treatment, which induces contractile gene expression by targeting programmed cell death 4 (PDCD4). To identify novel targets of miR-21 that are critical for induction of the contractile phenotype by BMP4, biotinylated miR-21 was expressed in vSMCs followed by an affinity purification of mRNAs associated with miR-21. Nearly all members of the dedicator of cytokinesis (DOCK) 180-related protein superfamily were identified as targets of miR-21. Down-regulation of DOCK4, -5, and -7 by miR-21 inhibited cell migration and promoted cytoskeletal organization by modulating an activity of small GTPase. Thus, this study uncovers a regulatory mechanism of the vSMC phenotype by the BMP4-miR-21 axis through DOCK family proteins. PMID:22158624

Cerebral artery alpha-1 AR subtypes: high altitude long-term acclimatization responses.

PubMed

Goyal, Ravi; Goyal, Dipali; Chu, Nina; Van Wickle, Jonathan; Longo, Lawrence D

2014-01-01

In response to hypoxia and other stress, the sympathetic (adrenergic) nervous system regulates arterial contractility and blood flow, partly through differential activities of the alpha1 (α1) - adrenergic receptor (AR) subtypes (α1A-, α1B-, and α1D-AR). Thus, we tested the hypothesis that with acclimatization to long-term hypoxia (LTH), contractility of middle cerebral arteries (MCA) is regulated by changes in expression and activation of the specific α1-AR subtypes. We conducted experiments in MCA from adult normoxic sheep maintained near sea level (300 m) and those exposed to LTH (110 days at 3801 m). Following acclimatization to LTH, ovine MCA showed a 20% reduction (n = 5; P<0.05) in the maximum tension achieved by 10-5 M phenylephrine (PHE). LTH-acclimatized cerebral arteries also demonstrated a statistically significant (P<0.05) inhibition of PHE-induced contractility in the presence of specific α1-AR subtype antagonists. Importantly, compared to normoxic vessels, there was significantly greater (P<0.05) α1B-AR subtype mRNA and protein levels in LTH acclimatized MCA. Also, our results demonstrate that extracellular regulated kinase 1 and 2 (ERK1/2)-mediated negative feedback regulation of PHE-induced contractility is modulated by α1B-AR subtype. Overall, in ovine MCA, LTH produces profound effects on α1-AR subtype expression and function.

Synchronous Office Hours in an Asynchronous Course: Making the Connection

ERIC Educational Resources Information Center

Gibbons-Kunka, Beatrice

2017-01-01

The notion of synchronous office hours in an asynchronous course seems counterintuitive. After all, one of the tenets of asynchronous education is to not require students to be online and participating at any time during the course. Having taught higher education online asynchronous courses for twenty years, the researcher experimented with online…

Power output of skinned skeletal muscle fibres from the cheetah (Acinonyx jubatus)

PubMed Central

West, T.G.; Toepfer, Christopher N.; Woledge, Roger C.; Curtin, N.A.; Rowlerson, Anthea; Kalakoutis, Michaeljohn; Hudson, Penny; Wilson, Alan M.

2015-01-01

SUMMARY Muscle samples were taken from the gluteus, semitendinosus and longissimus muscles of a captive cheetah immediately after euthanasia. Fibres were “skinned” to remove all membranes leaving the contractile filament array intact and functional. Segments of skinned fibres from these cheetah muscles and from rabbit psoas muscle were activated at 20°C by a temperature jump protocol. Step and ramp length changes were imposed after active stress had developed. The stiffness of the non-contractile ends of the fibres (series elastic component) was measured at two different stress values in each fibre; stiffness was strongly dependent on stress. Using these stiffness values, the speed of shortening of the contractile component was evaluated, and hence the power it was producing. Fibres were analysed for myosin heavy chain content using gel electrophoresis, and identified as either slow (Type I) or fast (Type II). The power output of cheetah Type II fibre segments was 92.5 ± 4.3 W kg−1 (mean ±s.e., 14 fibres) during shortening at relative stress 0.15 (=stress during shortening/isometric stress). For rabbit psoas fibre segments (presumably Type IIX) the corresponding value was significantly higher (P<0.001), 119.7 ± 6.2 W kg−1 (mean ±s.e.,7 fibres). These values are our best estimates of the maximum power output under the conditions used here. Thus the contractile filament power from cheetah was less than that of rabbit when maximally activated at 20°C, and does not account for the superior locomotor performance of the cheetah. PMID:23580727

Power output of skinned skeletal muscle fibres from the cheetah (Acinonyx jubatus).

PubMed

West, Timothy G; Toepfer, Christopher N; Woledge, Roger C; Curtin, Nancy A; Rowlerson, Anthea; Kalakoutis, Michaeljohn; Hudson, Penny; Wilson, Alan M

2013-08-01

Muscle samples were taken from the gluteus, semitendinosus and longissimus muscles of a captive cheetah immediately after euthanasia. Fibres were 'skinned' to remove all membranes, leaving the contractile filament array intact and functional. Segments of skinned fibres from these cheetah muscles and from rabbit psoas muscle were activated at 20°C by a temperature-jump protocol. Step and ramp length changes were imposed after active stress had developed. The stiffness of the non-contractile ends of the fibres (series elastic component) was measured at two different stress values in each fibre; stiffness was strongly dependent on stress. Using these stiffness values, the speed of shortening of the contractile component was evaluated, and hence the power it was producing. Fibres were analysed for myosin heavy chain content using gel electrophoresis, and identified as either slow (type I) or fast (type II). The power output of cheetah type II fibre segments was 92.5±4.3 W kg(-1) (mean ± s.e., 14 fibres) during shortening at relative stress 0.15 (the stress during shortening/isometric stress). For rabbit psoas fibre segments (presumably type IIX) the corresponding value was significantly higher (P<0.001), 119.7±6.2 W kg(-1) (mean ± s.e., 7 fibres). These values are our best estimates of the maximum power output under the conditions used here. Thus, the contractile filament power from cheetah was less than that of rabbit when maximally activated at 20°C, and does not account for the superior locomotor performance of the cheetah.

Pharmacological characterization and chemical fractionation of a liposterolic extract of saw palmetto (Serenoa repens): effects on rat prostate contractility.

PubMed

Chua, Thiam; Eise, Nicole T; Simpson, Jamie S; Ventura, Sabatino

2014-03-14

Saw palmetto (Serenoa repens) was first used medicinally by native American Indians to treat urological disorders. Nowadays, saw palmetto extracts are widely used in Europe and North America to treat the urinary symptoms associated with benign prostatic hyperplasia even though its mechanisms of action are poorly understood. This study aimed to characterize the bioactive constituents of a lipid extract of saw palmetto that are able to affect contractility of the rat prostate gland. The mechanism of action will also be investigated. A commercially available lipid extract of saw palmetto was subjected to fractionation using normal phase column chromatography. Composition of fractions was assessed by proton nuclear magnetic resonance spectroscopy ((1)H NMR) and mass spectrometry (MS). Contractile activities of these fractions were evaluated pharmacologically using isolated preparations of rat prostate gland and compared to the activity of the crude extract. Saw palmetto extract inhibited contractions of the rat prostate gland which were consistent with smooth muscle relaxant activity. Only the ethyl acetate fraction resulting from chromatography inhibited contractions of isolated rat prostates similarly to the inhibition produced by the crude lipid extract. Comparison with authentic samples and analysis of NMR data revealed that this bioactivity was due to the fatty acid components present in the ethyl acetate fraction. Bioassay using various pharmacological tools identified multiple contractile mechanisms which were affected by the bioactive constituents. A fatty acid component of saw palmetto extract causes inhibition of prostatic smooth muscle contractions via a non-specific mechanism. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

[Role of sialic acid loss in the myocardium in depressing the contractile function of the heart muscle during stress].

PubMed

Meerson, F Z; Saulia, A I; Gudumak, V S

1985-01-01

Under conditions of stress a time-dependent decrease in content of sialic acids was found in adult rats; within 9 hrs of the animal immobilization the sialic acid content was decreased by 40% as compared with controls. At the same time, activities of trypsin and LDHI were increased in blood serum. The data obtained suggest that activation of proteases occurring during the stress led to increased hydrolysis of base components of glycocalyx and to impairment of the cardiomyocyte sarcolemma. These phenomena appear to be responsible for the post-stress deterioration of heart muscle contractile functions.

Modulation of cardiac contractility by the phospholamban/SERCA2a regulatome.

PubMed

Kranias, Evangelia G; Hajjar, Roger J

2012-06-08

Heart disease remains the leading cause of death and disability in the Western world. Current therapies aim at treating the symptoms rather than the subcellular mechanisms, underlying the etiology and pathological remodeling in heart failure. A universal characteristic, contributing to the decreased contractile performance in human and experimental failing hearts, is impaired calcium sequestration into the sarcoplasmic reticulum (SR). SR calcium uptake is mediated by a Ca(2+)-ATPase (SERCA2), whose activity is reversibly regulated by phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA and phosphorylation of PLN relieves this inhibition. However, the initial simple view of a PLN/SERCA regulatory complex has been modified by our recent identification of SUMO, S100 and the histidine-rich Ca-binding protein as regulators of SERCA activity. In addition, PLN activity is regulated by 2 phosphoproteins, the inhibitor-1 of protein phosphatase 1 and the small heat shock protein 20, which affect the overall SERCA-mediated Ca-transport. This review will highlight the regulatory mechanisms of cardiac contractility by the multimeric SERCA/PLN-ensemble and the potential for new therapeutic avenues targeting this complex by using small molecules and gene transfer methods.

Influence of Upper-Body Exercise on the Fatigability of Human Respiratory Muscles

PubMed Central

TILLER, NICHOLAS B.; CAMPBELL, IAN G.; ROMER, LEE M.

2017-01-01

ABSTRACT Purpose Diaphragm and abdominal muscles are susceptible to contractile fatigue in response to high-intensity, whole-body exercise. This study assessed whether the ventilatory and mechanical loads imposed by high-intensity, upper-body exercise would be sufficient to elicit respiratory muscle fatigue. Methods Seven healthy men (mean ± SD; age = 24 ± 4 yr, peak O2 uptake [V˙O2peak] = 31.9 ± 5.3 mL·kg−1·min−1) performed asynchronous arm-crank exercise to exhaustion at work rates equivalent to 30% (heavy) and 60% (severe) of the difference between gas exchange threshold and V˙O2peak. Contractile fatigue of the diaphragm and abdominal muscles was assessed by measuring pre- to postexercise changes in potentiated transdiaphragmatic and gastric twitch pressures (Pdi,tw and Pga,tw) evoked by supramaximal magnetic stimulation of the cervical and thoracic nerves, respectively. Results Exercise time was 24.5 ± 5.8 min for heavy exercise and 9.8 ± 1.8 min for severe exercise. Ventilation over the final minute of heavy exercise was 73 ± 20 L·min−1 (39% ± 11% maximum voluntary ventilation) and 99 ± 19 L·min−1 (53% ± 11% maximum voluntary ventilation) for severe exercise. Mean Pdi,tw did not differ pre- to postexercise at either intensity (P > 0.05). Immediately (5–15 min) after severe exercise, mean Pga,tw was significantly lower than pre-exercise values (41 ± 13 vs 53 ± 15 cm H2O, P < 0.05), with the difference no longer significant after 25–35 min. Abdominal muscle fatigue (defined as ≥15% reduction in Pga,tw) occurred in 1/7 subjects after heavy exercise and 5/7 subjects after severe exercise. Conclusions High-intensity, upper-body exercise elicits significant abdominal, but not diaphragm, muscle fatigue in healthy men. The increased magnitude and prevalence of fatigue during severe-intensity exercise is likely due to additional (nonrespiratory) loading of the thorax. PMID:28288012

Influence of Upper-Body Exercise on the Fatigability of Human Respiratory Muscles.

PubMed

Tiller, Nicholas B; Campbell, Ian G; Romer, Lee M

2017-07-01

Diaphragm and abdominal muscles are susceptible to contractile fatigue in response to high-intensity, whole-body exercise. This study assessed whether the ventilatory and mechanical loads imposed by high-intensity, upper-body exercise would be sufficient to elicit respiratory muscle fatigue. Seven healthy men (mean ± SD; age = 24 ± 4 yr, peak O2 uptake [V˙O2peak] = 31.9 ± 5.3 mL·kg·min) performed asynchronous arm-crank exercise to exhaustion at work rates equivalent to 30% (heavy) and 60% (severe) of the difference between gas exchange threshold and V˙O2peak. Contractile fatigue of the diaphragm and abdominal muscles was assessed by measuring pre- to postexercise changes in potentiated transdiaphragmatic and gastric twitch pressures (Pdi,tw and Pga,tw) evoked by supramaximal magnetic stimulation of the cervical and thoracic nerves, respectively. Exercise time was 24.5 ± 5.8 min for heavy exercise and 9.8 ± 1.8 min for severe exercise. Ventilation over the final minute of heavy exercise was 73 ± 20 L·min (39% ± 11% maximum voluntary ventilation) and 99 ± 19 L·min (53% ± 11% maximum voluntary ventilation) for severe exercise. Mean Pdi,tw did not differ pre- to postexercise at either intensity (P > 0.05). Immediately (5-15 min) after severe exercise, mean Pga,tw was significantly lower than pre-exercise values (41 ± 13 vs 53 ± 15 cm H2O, P < 0.05), with the difference no longer significant after 25-35 min. Abdominal muscle fatigue (defined as ≥15% reduction in Pga,tw) occurred in 1/7 subjects after heavy exercise and 5/7 subjects after severe exercise. High-intensity, upper-body exercise elicits significant abdominal, but not diaphragm, muscle fatigue in healthy men. The increased magnitude and prevalence of fatigue during severe-intensity exercise is likely due to additional (nonrespiratory) loading of the thorax.

Effect of hypokinesia on contractile function of cardiac muscle

NASA Technical Reports Server (NTRS)

Meyerson, F. Z.; Kapelko, V. I.; Trikhpoyeva, A. M.; Gorina, M. S.

1980-01-01

Rats were subjected to hypokinesia for two months and the contractile function of isolated papillary muscle was studied. Hypokinesia reduced significantly the isotonic contraction rate which depended on the ATPase activity of the myofibrils; it also reduced the rate and index of relaxation which depended on the functional capacity of the Ca(++) pump of the sarcoplasmic reticulum. The maximum force of isometric contraction determined by the quantity of actomyosin bridges in the myofibrils did not change after hypokinesia. This complex of changes is contrary to that observed in adaptation to exercise when the rate of isotonic contraction and relaxation increases while the force of isometric contraction does not change. The possible mechanism of this stability of the contractile force during adaptation and readaptation of the heart is discussed.

Psychophysiological effects of synchronous versus asynchronous music during cycling.

PubMed

Lim, Harry B T; Karageorghis, Costas I; Romer, Lee M; Bishop, Daniel T

2014-02-01

Synchronizing movement to a musical beat may reduce the metabolic cost of exercise, but findings to date have been equivocal. Our aim was to examine the degree to which the synchronous application of music moderates the metabolic demands of a cycle ergometer task. Twenty-three recreationally active men made two laboratory visits. During the first visit, participants completed a maximal incremental ramp test on a cycle ergometer. At the second visit, they completed four randomized 6-min cycling bouts at 90% of ventilatory threshold (control, metronome, synchronous music, and asynchronous music). Main outcome variables were oxygen uptake, HR, ratings of dyspnea and limb discomfort, affective valence, and arousal. No significant differences were evident for oxygen uptake. HR was lower under the metronome condition (122 ± 15 bpm) compared to asynchronous music (124 ± 17 bpm) and control (125 ± 16 bpm). Limb discomfort was lower while listening to the metronome (2.5 ± 1.2) and synchronous music (2.3 ± 1.1) compared to control (3.0 ± 1.5). Both music conditions, synchronous (1.9 ± 1.2) and asynchronous (2.1 ± 1.3), elicited more positive affective valence compared to metronome (1.2 ± 1.4) and control (1.2 ± 1.2), while arousal was higher with synchronous music (3.4 ± 0.9) compared to metronome (2.8 ± 1.0) and control (2.8 ± 0.9). Synchronizing movement to a rhythmic stimulus does not reduce metabolic cost but may lower limb discomfort. Moreover, synchronous music has a stronger effect on limb discomfort and arousal when compared to asynchronous music.

Bladder smooth muscle organ culture preparation maintains the contractile phenotype

PubMed Central

Wang, Tanchun; Kendig, Derek M.; Chang, Shaohua; Trappanese, Danielle M.; Chacko, Samuel

2012-01-01

Smooth muscle cells, when subjected to culture, modulate from a contractile to a secretory phenotype. This has hampered the use of cell culture for molecular techniques to study the regulation of smooth muscle biology. The goal of this study was to develop a new organ culture model of bladder smooth muscle (BSM) that would maintain the contractile phenotype and aid in the study of BSM biology. Our results showed that strips of BSM subjected to up to 9 days of organ culture maintained their contractile phenotype, including the ability to achieve near-control levels of force with a temporal profile similar to that of noncultured tissues. The technical aspects of our organ culture preparation that were responsible, in part, for the maintenance of the contractile phenotype were a slight longitudinal stretch during culture and subjection of the strips to daily contraction-relaxation. The tissues contained viable cells throughout the cross section of the strips. There was an increase in extracellular collagenous matrix, resulting in a leftward shift in the passive length-tension relationship. There were no significant changes in the content of smooth muscle-specific α-actin, calponin, h-caldesmon, total myosin heavy chain, protein kinase G, Rho kinase-I, or the ratio of SM1 to SM2 myosin isoforms. Moreover the organ cultured tissues maintained functional voltage-gated calcium channels and large-conductance calcium-activated potassium channels. Therefore, we propose that this novel BSM organ culture model maintains the contractile phenotype and will be a valuable tool for the use in cellular/molecular biology studies of bladder myocytes. PMID:22896042

The Inhibitory Effect of Botulinum Toxin Type A on Rat Pyloric Smooth Muscle Contractile Response to Substance P In Vitro

PubMed Central

Shao, Yu-Feng; Xie, Jun-Fan; Ren, Yin-Xiang; Wang, Can; Kong, Xiang-Pan; Zong, Xiao-Jian; Fan, Lin-Lan; Hou, Yi-Ping

2015-01-01

A decrease in pyloric myoelectrical activity and pyloric substance P (SP) content following intrasphincteric injection of botulinum toxin type A (BTX-A) in free move rats have been demonstrated in our previous studies. The aim of the present study was to investigate the inhibitory effect of BTX-A on rat pyloric muscle contractile response to SP in vitro and the distributions of SP and neurokinin 1 receptor (NK1R) immunoreactive (IR) cells and fibers within pylorus. After treatment with atropine, BTX-A (10 U/mL), similar to [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-SP (APTL-SP, 1 μmol/L) which is an NK1R antagonist, decreased electric field stimulation (EFS)-induced contractile tension and frequency, whereas, subsequent administration of APTL-SP did not act on contractility. Incubation with BTX-A at 4 and 10 U/mL for 4 h respectively decreased SP (1 μmol/L)-induced contractions by 26.64% ± 5.12% and 74.92% ± 3.62%. SP-IR fibers and NK1R-IR cells both located within pylorus including mucosa and circular muscle layer. However, fewer SP-fibers were observed in pylorus treated with BTX-A (10 U/mL). In conclusion, BTX-A inhibits SP release from enteric terminals in pylorus and EFS-induced contractile responses when muscarinic cholinergic receptors are blocked by atropine. In addition, BTX-A concentration- and time-dependently directly inhibits SP-induced pyloric smooth muscle contractility. PMID:26501321

The Inhibitory Effect of Botulinum Toxin Type A on Rat Pyloric Smooth Muscle Contractile Response to Substance P In Vitro.

PubMed

Shao, Yu-Feng; Xie, Jun-Fan; Ren, Yin-Xiang; Wang, Can; Kong, Xiang-Pan; Zong, Xiao-Jian; Fan, Lin-Lan; Hou, Yi-Ping

2015-10-15

A decrease in pyloric myoelectrical activity and pyloric substance P (SP) content following intrasphincteric injection of botulinum toxin type A (BTX-A) in free move rats have been demonstrated in our previous studies. The aim of the present study was to investigate the inhibitory effect of BTX-A on rat pyloric muscle contractile response to SP in vitro and the distributions of SP and neurokinin 1 receptor (NK1R) immunoreactive (IR) cells and fibers within pylorus. After treatment with atropine, BTX-A (10 U/mL), similar to [D-Arg¹, D-Phe⁵, D-Trp(7,9), Leu(11)]-SP (APTL-SP, 1 μmol/L) which is an NK1R antagonist, decreased electric field stimulation (EFS)-induced contractile tension and frequency, whereas, subsequent administration of APTL-SP did not act on contractility. Incubation with BTX-A at 4 and 10 U/mL for 4 h respectively decreased SP (1 μmol/L)-induced contractions by 26.64% ± 5.12% and 74.92% ± 3.62%. SP-IR fibers and NK1R-IR cells both located within pylorus including mucosa and circular muscle layer. However, fewer SP-fibers were observed in pylorus treated with BTX-A (10 U/mL). In conclusion, BTX-A inhibits SP release from enteric terminals in pylorus and EFS-induced contractile responses when muscarinic cholinergic receptors are blocked by atropine. In addition, BTX-A concentration- and time-dependently directly inhibits SP-induced pyloric smooth muscle contractility.

Pharmacological action of DA-9701 on the motility of feline stomach circular smooth muscle.

PubMed

Nguyen, Thanh Thao; Song, Hyun Ju; Ko, Sung Kwon; Sohn, Uy Dong

2015-03-01

DA-9701, a new prokinetic agent for the treatment of functional dyspepsia, is formulated with Pharbitis semen and Corydalis tuber. This study wasconducted to determine the pharmacological action of DA-9701 and to identify the receptors involved in DA-9701 -induced contractile responsesin the feline gastric corporal, fundic and antral circular smooth muscle. Concentration-response curve to DA-9701 was established. The tissue trips were exposed to methylsergide, ketanserin, ondansetron, GR 113808, atropine and dopamine before administration of DA-9701. The contractile force was determined before and after administration of drugs by a polygraph.DA-9701 enhanced the spontaneous contractile amplitude of antrum, corpus and fundus. However, it did not change the spontaneous contractile frequency of antrum and corpus, but concentration-dependently reduced that of fundus. In the fundus, DA-9701 -induced tonic contractions were inhibited by dopamine, methylsergide, ketanserine, ondansetron or GR 113808 respectively, but not by atropine, indicating that the contractile responses are mediated by multiple receptors: 5-HT2, 5-HT3, 5-HT4, and dopamine receptors. In the corpus, DA-9701-induced contractions were blocked by atropine, dopamine or GR 113808, but not by methysergide, ketanserin or ondansetron, indicating that they are involved in receptors on both, smooth muscles and neurons: 5-HT4 and dopamine receptors. However, contractile responses to DA-9701 are mainly mediated by dopamine receptors in the antrum. These results suggest that DA-9701 has important roles in gastric accommodation by enhancing tonic activity of fundus, and in gastric emptying and gastrointestinal transit by phasic contractions of corpus and antrum mediated by multiple receptors.

Temporal Processing of Audiovisual Stimuli Is Enhanced in Musicians: Evidence from Magnetoencephalography (MEG)

PubMed Central

Lu, Yao; Paraskevopoulos, Evangelos; Herholz, Sibylle C.; Kuchenbuch, Anja; Pantev, Christo

2014-01-01

Numerous studies have demonstrated that the structural and functional differences between professional musicians and non-musicians are not only found within a single modality, but also with regard to multisensory integration. In this study we have combined psychophysical with neurophysiological measurements investigating the processing of non-musical, synchronous or various levels of asynchronous audiovisual events. We hypothesize that long-term multisensory experience alters temporal audiovisual processing already at a non-musical stage. Behaviorally, musicians scored significantly better than non-musicians in judging whether the auditory and visual stimuli were synchronous or asynchronous. At the neural level, the statistical analysis for the audiovisual asynchronous response revealed three clusters of activations including the ACC and the SFG and two bilaterally located activations in IFG and STG in both groups. Musicians, in comparison to the non-musicians, responded to synchronous audiovisual events with enhanced neuronal activity in a broad left posterior temporal region that covers the STG, the insula and the Postcentral Gyrus. Musicians also showed significantly greater activation in the left Cerebellum, when confronted with an audiovisual asynchrony. Taken together, our MEG results form a strong indication that long-term musical training alters the basic audiovisual temporal processing already in an early stage (direct after the auditory N1 wave), while the psychophysical results indicate that musical training may also provide behavioral benefits in the accuracy of the estimates regarding the timing of audiovisual events. PMID:24595014

Pseudo Asynchronous Level Crossing adc for ecg Signal Acquisition.

PubMed

Marisa, T; Niederhauser, T; Haeberlin, A; Wildhaber, R A; Vogel, R; Goette, J; Jacomet, M

2017-02-07

A new pseudo asynchronous level crossing analogue-to-digital converter (adc) architecture targeted for low-power, implantable, long-term biomedical sensing applications is presented. In contrast to most of the existing asynchronous level crossing adc designs, the proposed design has no digital-to-analogue converter (dac) and no continuous time comparators. Instead, the proposed architecture uses an analogue memory cell and dynamic comparators. The architecture retains the signal activity dependent sampling operation by generating events only when the input signal is changing. The architecture offers the advantages of smaller chip area, energy saving and fewer analogue system components. Beside lower energy consumption the use of dynamic comparators results in a more robust performance in noise conditions. Moreover, dynamic comparators make interfacing the asynchronous level crossing system to synchronous processing blocks simpler. The proposed adc was implemented in [Formula: see text] complementary metal-oxide-semiconductor (cmos) technology, the hardware occupies a chip area of 0.0372 mm 2 and operates from a supply voltage of [Formula: see text] to [Formula: see text]. The adc's power consumption is as low as 0.6 μW with signal bandwidth from [Formula: see text] to [Formula: see text] and achieves an equivalent number of bits (enob) of up to 8 bits.

The effect of N-acetylcysteine on cardiac contractility to dobutamine in rats with streptozotocin-induced diabetes.

PubMed

Cheng, Xing; Xia, Zhengyuan; Leo, Joyce M; Pang, Catherine C Y

2005-09-05

We examined if myocardial depression at the acute phase of diabetes (3 weeks after injection of streptozotocin, 60 mg/kg i.v.) is due to activation of inducible nitric oxide synthase and production of peroxynitrite, and if treatment with N-acetylcysteine (1.2 g/day/kg for 3 weeks, antioxidant) improves cardiac function. Four groups of rats were used: control, N-acetylcysteine-treated control, diabetic and N-acetylcysteine-treated diabetic. Pentobarbital-anaesthetized diabetic rats, relative to the controls, had reduced left ventricular contractility to dobutamine (1-57 microg/min/kg). The diabetic rats also had increased myocardial levels of thiobarbituric acid reactive substances, immunostaining of inducible nitric oxide synthase and nitrotyrosine, and similar baseline 15-F2t-isoprostane. N-acetylcysteine did not affect responses in the control rats; but increased cardiac contractility to dobutamine, reduced myocardial immunostaining of inducible nitric oxide synthase and nitrotyrosine and level of 15-F2t-isoprostane, and increased cardiac contractility to dobutamine in the diabetic rats. Antioxidant supplementation in diabetes reduces oxidative stress and improves cardiac function.

Bistable front dynamics in a contractile medium: travelling wave and cortical advection define stable zones of RhoA signaling at epithelial adherens junctions

NASA Astrophysics Data System (ADS)

Neufeld, Zoltan

Recent studies have demonstrated that mechanical forces can lead to novel mechanisms of pattern formation such as clustering and oscillations in contractile systems. We investigate how contractile forces in mechanically active media can affect bistable front propagation. We found that contraction regulates the front speed or can fully suppress its propagation in space to create a static localized zone. We demonstrate how the interplay between biochemical signaling through positive feedback, combined with diffusion on the cell membrane and mechanical forces generated in the actomyosin cortex, can determine the spatial distribution of RhoA signaling at cell-cell junctions. The dynamical mechanism relies on the balance between a propagating bistable signal that is opposed by an advective flow generated by an actomyosin stress gradient. Experimental observations on the behaviour of the system when contractility is inhibited are in qualitative agreement with the predictions of the model. In collaboration with: Zoltan Neufeld, Guillermo A. Gomez, and Alpha S. Yap, University of Queensland, Brisbane, Australia

An epigenetic state associated with areas of gene duplication

PubMed Central

Gimelbrant, Alexander A.; Chess, Andrew

2006-01-01

Asynchronous DNA replication is an epigenetically determined feature found in all cases of monoallelic expression, including genomic imprinting, X-inactivation, and random monoallelic expression of autosomal genes such as immunoglobulins and olfactory receptor genes. Most genes of the latter class were identified in experiments focused on genes functioning in the chemosensory and immune systems. We performed an unbiased survey of asynchronous replication in the mouse genome, excluding known asynchronously replicated genes. Fully 10% (eight of 80) of the genes tested exhibited asynchronous replication. A common feature of the newly identified asynchronously replicated areas is their proximity to areas of tandem gene duplication. Testing of other clustered areas supported the idea that such regions are enriched with asynchronously replicated genes. PMID:16687731

How well do mean field theories of spiking quadratic-integrate-and-fire networks work in realistic parameter regimes?

PubMed

Grabska-Barwińska, Agnieszka; Latham, Peter E

2014-06-01

We use mean field techniques to compute the distribution of excitatory and inhibitory firing rates in large networks of randomly connected spiking quadratic integrate and fire neurons. These techniques are based on the assumption that activity is asynchronous and Poisson. For most parameter settings these assumptions are strongly violated; nevertheless, so long as the networks are not too synchronous, we find good agreement between mean field prediction and network simulations. Thus, much of the intuition developed for randomly connected networks in the asynchronous regime applies to mildly synchronous networks.

Acute dynamin inhibition dissects synaptic vesicle recycling pathways that drive spontaneous and evoked neurotransmission

PubMed Central

Chung, ChiHye; Barlyko, Barbara; Leitz, Jeremy; Liu, Xinran; Kavalali, Ege T.

2010-01-01

Synapses maintain synchronous, asynchronous and spontaneous forms of neurotransmission that are distinguished by their Ca2+-dependence and time course. Despite recent advances in our understanding of the mechanisms that underlie these three forms of release, it remains unclear whether they originate from the same vesicle population or arise from distinct vesicle pools with diverse propensities for release. Here, we used a reversible inhibitor of dynamin, dynasore, to dissect the vesicle pool dynamics underlying the three forms of neurotransmitter release in hippocampal GABAergic inhibitory synapses. In dynasore, evoked synchronous release and asynchronous neurotransmission detected after activity showed marked and unrecoverable depression within seconds. In contrast, spontaneous release remained intact after intense stimulation in dynasore or during prolonged (~1 hour) application of dynasore at rest, suggesting that separate recycling pathways maintain evoked and spontaneous synaptic vesicle trafficking. In addition, simultaneous imaging of spectrally separable styryl dyes revealed that in a given synapse vesicles that recycle spontaneously and in response to activity do not mix. These findings suggest that evoked synchronous and asynchronous release originate from the same vesicle pool that recycles rapidly in a dynamin-dependent manner, while a distinct vesicle pool sustains spontaneous release independent of dynamin activation. This result lends further support to the notion that synapses harbor distinct vesicle populations with divergent release properties that maintain independent forms of neurotransmission. PMID:20107062

CALIX[4]ARENE C-99 INHIBITS MYOSIN ATPase ACTIVITY AND CHANGES THE ORGANIZATION OF CONTRACTILE FILAMENTS OF MYOMETRIUM.

PubMed

Labyntseva, R D; Bevza, A A; Lul'ko, A O; Cherenok, S O; Kalchenko, V I; Kosterin, S O

2015-01-01

Calix[4]arenes are cup-like macrocyclic (polyphenolic) compounds, they are regarded as promising molecular "platforms" for the design of new physiologically active compounds. We have earlier found that calix[4]arene C-99 inhibits the ATPase activity of actomyosin and myosin subfragment-1 of pig uterus in vitro. The aim of this study was to investigate the interaction of calix[4]arene C-99 with myosin from rat uterine myocytes. It was found that the ATPase activity of myosin prepared from pre-incubated with 100 mM of calix[4]arene C-99 myocytes was almost 50% lower than in control. Additionally, we have revealed the effect of calix[4]arene C-99 on the subcellular distribution of actin and myosin in uterus myocytes by the method of confocal microscopy. This effect can be caused by reorganization of the structure of the contractile smooth muscle cell proteins due to their interaction with calix[4]arene. The obtained results demonstrate the ability of calix[4]arene C-99 to penetrate into the uterus muscle cells and affect not only the myosin ATPase activity, but also the structure of the actin and myosin filaments in the myometrial cells. Demonstrated ability of calix[4]arene C-99 can be used for development of new pharmacological agents for efficient normalization of myometrial contractile hyperfunction.

Impact of pregnancy and vaginal delivery on the passive and active mechanics of the rat vagina.

PubMed

Feola, Andrew; Moalli, Pamela; Alperin, Marianna; Duerr, Robbie; Gandley, Robin E; Abramowitch, Steven

2011-01-01

Remodeling of vaginal extracellular matrix and smooth muscle likely plays a critical role in reducing the risk of maternal injury during vaginal delivery by altering the mechanical properties to increase distension and reduce stress. Long-Evans rats were divided into five groups to examine the passive mechanical and active contractile properties throughout pregnancy and postpartum: virgin (n=17), mid-pregnant (Day 14-16, n=12), late-pregnant (Day 20-22, n=14), immediate postpartum (0-2 h after delivery, n=14), and 4 week postpartum (n=15). Longitudinal sections of vaginal tissue were loaded to failure uniaxially for passive mechanical or active contractile properties were examined. For passive mechanics, the tangent modulus decreased 45% by mid-pregnancy and immediately postpartum (p<0.001). The ultimate strain continuously increased up to 43% higher than virgin animals (p=0.007) in the immediate postpartum group. For active mechanics, the maximal contractile force was 36-56% lower through immediate postpartum animals, and was significantly more sensitive to K+ throughout pregnancy and postpartum (p=0.003). The changes observed in the passive and active properties of the rat vagina are consistent with what would be expected from a tissue that is remodeling to maximize its ability to distend at the time of vaginal delivery to facilitate passage of the fetus with minimal injury.

Glucose-6-phosphate dehydrogenase and NADPH redox regulates cardiac myocyte L-type calcium channel activity and myocardial contractile function.

PubMed

Rawat, Dhwajbahadur K; Hecker, Peter; Watanabe, Makino; Chettimada, Sukrutha; Levy, Richard J; Okada, Takao; Edwards, John G; Gupte, Sachin A

2012-01-01

We recently demonstrated that a 17-ketosteroid, epiandrosterone, attenuates L-type Ca(2+) currents (I(Ca-L)) in cardiac myocytes and inhibits myocardial contractility. Because 17-ketosteroids are known to inhibit glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, and to reduce intracellular NADPH levels, we hypothesized that inhibition of G6PD could be a novel signaling mechanism which inhibit I(Ca-L) and, therefore, cardiac contractile function. We tested this idea by examining myocardial function in isolated hearts and Ca(2+) channel activity in isolated cardiac myocytes. Myocardial function was tested in Langendorff perfused hearts and I(Ca-L) were recorded in the whole-cell patch configuration by applying double pulses from a holding potential of -80 mV and then normalized to the peak amplitudes of control currents. 6-Aminonicotinamide, a competitive inhibitor of G6PD, increased pCO(2) and decreased pH. Additionally, 6-aminonicotinamide inhibited G6PD activity, reduced NADPH levels, attenuated peak I(Ca-L) amplitudes, and decreased left ventricular developed pressure and ±dp/dt. Finally, dialyzing NADPH into cells from the patch pipette solution attenuated the suppression of I(Ca-L) by 6-aminonicotinamide. Likewise, in G6PD-deficient mice, G6PD insufficiency in the heart decreased GSH-to-GSSG ratio, superoxide, cholesterol and acetyl CoA. In these mice, M-mode echocardiographic findings showed increased diastolic volume and end-diastolic diameter without changes in the fraction shortening. Taken together, these findings suggest that inhibiting G6PD activity and reducing NADPH levels alters metabolism and leads to inhibition of L-type Ca(2+) channel activity. Notably, this pathway may be involved in modulating myocardial contractility under physiological and pathophysiological conditions during which the pentose phosphate pathway-derived NADPH redox is modulated (e.g., ischemia-reperfusion and heart failure).

Large-conductance voltage- and Ca2+-activated K+ channel regulation by protein kinase C in guinea pig urinary bladder smooth muscle

PubMed Central

Hristov, Kiril L.; Smith, Amy C.; Parajuli, Shankar P.; Malysz, John

2013-01-01

Large-conductance voltage- and Ca2+-activated K+ (BK) channels are critical regulators of detrusor smooth muscle (DSM) excitability and contractility. PKC modulates the contraction of DSM and BK channel activity in non-DSM cells; however, the cellular mechanism regulating the PKC-BK channel interaction in DSM remains unknown. We provide a novel mechanistic insight into BK channel regulation by PKC in DSM. We used patch-clamp electrophysiology, live-cell Ca2+ imaging, and functional studies of DSM contractility to elucidate BK channel regulation by PKC at cellular and tissue levels. Voltage-clamp experiments showed that pharmacological activation of PKC with PMA inhibited the spontaneous transient BK currents in native freshly isolated guinea pig DSM cells. Current-clamp recordings revealed that PMA significantly depolarized DSM membrane potential and inhibited the spontaneous transient hyperpolarizations in DSM cells. The PMA inhibitory effects on DSM membrane potential were completely abolished by the selective BK channel inhibitor paxilline. Activation of PKC with PMA did not affect the amplitude of the voltage-step-induced whole cell steady-state BK current or the single BK channel open probability (recorded in cell-attached mode) upon inhibition of all major Ca2+ sources for BK channel activation with thapsigargin, ryanodine, and nifedipine. PKC activation with PMA elevated intracellular Ca2+ levels in DSM cells and increased spontaneous phasic and nerve-evoked contractions of DSM isolated strips. Our results support the concept that PKC activation leads to a reduction of BK channel activity in DSM via a Ca2+-dependent mechanism, thus increasing DSM contractility. PMID:24352333

The slow inward calcium current is responsible for a part of the contraction of patch-clamped rat myoballs.

PubMed

Rivet, M; Cognard, C; Raymond, G

1989-01-01

The slow inward calcium current and the contractile response were simultaneously recorded in voltage clamped (whole cell patch clamp recording) rat myoballs in primary culture. The shape of the contraction(T)/potential(V) relationship and the application of the inorganic calcium channel blocker cadmium (1.5 mM), which suppresses a part of the contractile activity, demonstrate the existence of two components of contraction. One of them is related to the slow calcium current.

Effect of noni (Morinda citrifolia Linn.) fruit and its bioactive principles scopoletin and rutin on rat vas deferens contractility: an ex vivo study.

PubMed

Pandy, Vijayapandi; Narasingam, Megala; Kunasegaran, Thubasni; Murugan, Dharmani Devi; Mohamed, Zahurin

2014-01-01

This study examined the effect of methanolic extract of Morinda citrifolia Linn. (MMC) and its bioactive principles, scopoletin and rutin, on dopamine- and noradrenaline-evoked contractility in isolated rat vas deferens preparations. MMC (1-40 mg/mL), scopoletin (1-200 μg/mL), and rutin hydrate (0.6-312.6 μg/mL) dose-dependently inhibited the contractility evoked by submaximal concentrations of both dopamine and noradrenaline, respectively. Haloperidol and prazosin, reference dopamine D2, and α 1-adrenoceptors antagonists significantly reversed the dopamine- and noradrenaline-induced contractions, respectively, in a dose-dependent manner. Interestingly, MMC per se at higher doses (60-100 mg/mL) showed dose-dependent contractile response in rat vas deferens which was partially inhibited by high doses of haloperidol but not by prazosin. These results demonstrated the biphasic effects of MMC on dopaminergic system; that is, antidopaminergic effect at lower concentrations (<40 mg/mL) and dopaminergic agonistic effect at higher concentrations (>60 mg/mL). However, similar contractile response at high doses of scopoletin (0.5-5 mg/mL) and rutin hydrate (0.5-5 mg/mL) per se was not observed. Therefore, it can be concluded that the bioactive principles of MMC, scopoletin, and rutin might be responsible for the antidopaminergic and antiadrenergic activities of MMC.

Use of arginine-glycine-aspartic acid adhesion peptides coupled with a new collagen scaffold to engineer a myocardium-like tissue graft.

PubMed

Schussler, O; Coirault, C; Louis-Tisserand, M; Al-Chare, W; Oliviero, P; Menard, C; Michelot, R; Bochet, P; Salomon, D R; Chachques, J C; Carpentier, A; Lecarpentier, Y

2009-03-01

Cardiac tissue engineering might be useful in treatment of diseased myocardium or cardiac malformations. The creation of functional, biocompatible contractile tissues, however, remains challenging. We hypothesized that coupling of arginine-glycine-aspartic acid-serine (RGD+) adhesion peptides would improve cardiomyocyte viability and differentiation and contractile performance of collagen-cell scaffolds. Clinically approved collagen scaffolds were functionalized with RGD+ cells and seeded with cardiomyocytes. Contractile performance, cardiomyocyte viability and differentiation were analyzed at days 1 and 8 and/or after culture for 1 month. The method used for the RGD+ cell-collagen scaffold coupling enabled the following features: high coupling yields and complete washout of excess reagent and by-products with no need for chromatography; spectroscopic quantification of RGD+ coupling; a spacer arm of 36 A, a length reported as optimal for RGD+-peptide presentation and favorable for integrin-receptor clustering and subsequent activation. Isotonic and isometric mechanical parameters, either spontaneous or electrostimulated, exhibited good performance in RGD+ constructs. Cell number and viability was increased in RGD+ scaffolds, and we saw good organization of cell contractile apparatus with occurrence of cross-striation. We report a novel method of engineering a highly effective collagen-cell scaffold based on RGD+ peptides cross-linked to a clinically approved collagen matrix. The main advantages were cell contractile performance, cardiomyocyte viability and differentiation.

Contractile activity of ATP and diadenosine tetraphosphate on urinary bladder in the rats: role of superoxide anion and urothelium.

PubMed

Khattab, M M; Al-Hrasen, M N

2006-04-01

Both ATP and diadenosine tetraphosphate (AP(4)A) produced a dose-dependent contraction of rat isolated urinary bladder rings. The AP(4)A dose-response curve was to the left of that of ATP, and the maximum response was greater than that produced by ATP. Mechanical removal of the urothelium increased the contractile response to ATP by between 53% and 71%, and that to AP(4)A by 42% (at highest AP(4)A concentration) to 68% at lower concentration. Inhibition of Cu/Zn superoxide dismutase with diethylthiocarbamate (DETCA, 5 mm) significantly reduced the ATP-evoked contraction by 31% (at high ATP concentration) to 40% at low ATP concentration. Similarly, the AP(4)A-induced contractions were significantly decreased by 27% at low AP(4)A level to 38% at higher concentrations. Induction of exogenous superoxide anion stress by the use of the superoxide anion generator, pyrogallol (0.5 mm), significantly decreased both ATP- and AP(4)A-induced contractions of the rat urinary bladder over the whole dose range. Contractile responses to ATP decreased by 36-40%, and those to AP(4)A by 44-49%. In conclusion, the urinary bladder urothelium exerts an inhibitory control over the purinergic contractility produced by adenine mononucleotides and dinucleotides. Superoxide anion stress, whether endogenous or exogenous, attenuates the ATP-induced as well as AP(4)A-induced contractility.

Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide

NASA Technical Reports Server (NTRS)

Nyhan, Daniel; Kim, Soonyul; Dunbar, Stacey; Li, Dechun; Shoukas, Artin; Berkowitz, Dan E.

2002-01-01

Vascular contractile hyporesponsiveness is an important mechanism underlying orthostatic intolerance after microgravity. Baroreceptor reflexes can modulate both pulmonary resistance and capacitance function and thus cardiac output. We hypothesized, therefore, that pulmonary vasoreactivity is impaired in the hindlimb-unweighted (HLU) rat model of microgravity. Pulmonary artery (PA) contractile responses to phenylephrine (PE) and U-46619 (U4) were significantly decreased in the PAs from HLU vs. control (C) animals. N(G)-nitro-L-arginine methyl ester (10(-5) M) enhanced the contractile responses in the PA rings from both C and HLU animals and completely abolished the differential responses to PE and U4 in HLU vs. C animals. Vasorelaxant responses to ACh were significantly enhanced in PA rings from HLU rats compared with C. Moreover, vasorelaxant responses to sodium nitroprusside were also significantly enhanced. Endothelial nitric oxide synthase (eNOS) and soluble guanlyl cyclase expression were significantly enhanced in PA and lung tissue from HLU rats. In marked contrast, the expression of inducible nitric oxide synthase was unchanged in lung tissue. These data support the hypothesis that vascular contractile responsiveness is attenuated in PAs from HLU rats and that this hyporesponsiveness is due at least in part to increased nitric oxide synthase activity resulting from enhanced eNOS expression. These findings may have important implications for blood volume distribution and attenuated stroke volume responses to orthostatic stress after microgravity exposure.

Effects of epidermal growth factor, interleukin 1 and nitric oxide on prostaglandin production by guinea-pig uterus.

PubMed

Keeble, J E; Poyser, N L

2002-08-01

Initial experiments in the present study investigated the effects of epidermal growth factor (EGF), interleukin 1beta (IL-1beta) and sodium nitroprusside (a nitric oxide donor) on the output of prostaglandins from guinea-pig uterus on day 7 of the oestrous cycle. Superfusion of day 7 guinea-pig uterus in vitro with either EGF or sodium nitroprusside increased the output of PGF(2alpha) and 6-keto-PGF(1alpha), but not of PGE(2). IL-1beta had no effect on the output of these three prostaglandins. EGF still increased the output of PGF(2alpha), but did not increase the output of 6-keto-PGF(1alpha) in a calcium-depleted superfusate. Subsequent experiments investigated the effect of sodium nitroprusside on contractile activity of day 7 guinea-pig uterus. Basal spontaneous activity of both the intact uterus and isolated myometrium superfused in vitro was low. Sodium nitroprusside increased the contractile activity of these tissues two- to fourfold. EGF did not affect the contractile activity of the uterus, indicating that sodium nitroprusside-induced contractions are not due to increased prostaglandin production. Overall, the findings indicate that EGF and nitric oxide may act as mediators in the mechanism by which oestradiol acting on a progesterone-primed uterus stimulates the increase in PGF(2alpha) production by the guinea-pig uterus necessary for luteolysis. Nitric oxide may increase the spontaneous activity of the uterus when this activity is low.

Weakly sheared active suspensions: hydrodynamics, stability, and rheology.

PubMed

Cui, Zhenlu

2011-03-01

We present a kinetic model for flowing active suspensions and analyze the behavior of a suspension subjected to a weak steady shear. Asymptotic solutions are sought in Deborah number expansions. At the leading order, we explore the steady states and perform their stability analysis. We predict the rheology of active systems including an activity thickening or thinning behavior of the apparent viscosity and a negative apparent viscosity depending on the particle type, flow alignment, and the anchoring conditions, which can be tested on bacterial suspensions. We find remarkable dualities that show that flow-aligning rodlike contractile (extensile) particles are dynamically and rheologically equivalent to flow-aligning discoid extensile (contractile) particles for both tangential and homeotropic anchoring conditions. Another key prediction of this work is the role of the concentration of active suspensions in controlling the rheological behavior: the apparent viscosity may decrease with the increase of the concentration.

The role of skeletal muscle contractile duration throughout the whole day: reducing sedentary time and promoting universal physical activity in all people

PubMed Central

2017-01-01

Abstract A shared goal of many researchers has been to discover how to improve health and prevent disease, through safely replacing a large amount of daily sedentary time with physical activity in everyone, regardless of age and current health status. This involves contrasting how different muscle contractile activity patterns regulate the underlying molecular and physiological responses impacting health‐related processes. It also requires an equal attention to behavioural feasibility studies in extremely unfit and sedentary people. A sound scientific principle is that the body is constantly sensing and responding to changes in skeletal muscle metabolism induced by contractile activity. Because of that, the rapid time course of health‐related responses to physical inactivity/activity patterns are caused in large part directly because of the variable amounts of muscle inactivity/activity throughout the day. However, traditional modes and doses of exercise fall far short of replacing most of the sedentary time in the modern lifestyle, because both the weekly frequency and the weekly duration of exercise time are an order of magnitude less than those for people sitting inactive. This can explain why high amounts of sedentary time produce distinct metabolic and cardiovascular responses through inactivity physiology that are not sufficiently prevented by low doses of exercise. For these reasons, we hypothesize that maintaining a high metabolic rate over the majority of the day, through safe and sustainable types of muscular activity, will be the optimal way to create a healthy active lifestyle over the whole lifespan. PMID:28657123

Recovery of skeletal muscle mass after extensive injury: positive effects of increased contractile activity.

PubMed

Richard-Bulteau, Hélène; Serrurier, Bernard; Crassous, Brigitte; Banzet, Sébastien; Peinnequin, André; Bigard, Xavier; Koulmann, Nathalie

2008-02-01

The present study was designed to test the hypothesis that increasing physical activity by running exercise could favor the recovery of muscle mass after extensive injury and to determine the main molecular mechanisms involved. Left soleus muscles of female Wistar rats were degenerated by notexin injection before animals were assigned to either a sedentary group or an exercised group. Both regenerating and contralateral intact muscles from active and sedentary rats were removed 5, 7, 14, 21, 28 and 42 days after injury (n = 8 rats/group). Increasing contractile activity through running exercise during muscle regeneration ensured the full recovery of muscle mass and muscle cross-sectional area as soon as 21 days after injury, whereas muscle weight remained lower even 42 days postinjury in sedentary rats. Proliferator cell nuclear antigen and MyoD protein expression went on longer in active rats than in sedentary rats. Myogenin protein expression was higher in active animals than in sedentary animals 21 days postinjury. The Akt-mammalian target of rapamycin (mTOR) pathway was activated early during the regeneration process, with further increases of mTOR phosphorylation and its downstream effectors, eukaryotic initiation factor-4E-binding protein-1 and p70(s6k), in active rats compared with sedentary rats (days 7-14). The exercise-induced increase in mTOR phosphorylation, independently of Akt, was associated with decreased levels of phosphorylated AMP-activated protein kinase. Taken together, these results provided evidence that increasing contractile activity during muscle regeneration ensured early and full recovery of muscle mass and suggested that these beneficial effects may be due to a longer proliferative step of myogenic cells and activation of mTOR signaling, independently of Akt, during the maturation step of muscle regeneration.

Physical exercise during muscle regeneration improves recovery of the slow/oxidative phenotype.

PubMed

Koulmann, Nathalie; Richard-Bulteau, Hélène; Crassous, Brigitte; Serrurier, Bernard; Pasdeloup, Marielle; Bigard, Xavier; Banzet, Sébastien

2017-01-01

As skeletal muscle mass recovery after extensive injury is improved by contractile activity, we explored whether concomitant exercise accelerates recovery of the contractile and metabolic phenotypes after muscle injury. After notexin-induced degeneration of a soleus muscle, Wistar rats were assigned to active (running exercise) or sedentary groups. Myosin heavy chains (MHC), metabolic enzymes, and calcineurin were studied during muscle regeneration at different time points. The mature MHC profile recovered earlier in active rats (21 days after injury) than in sedentary rats (42 days). Calcineurin was higher in the active degenerated than in the sedentary degenerated muscles at day 14. Citrate synthase and total lactate dehydrogenase (LDH) activity decreased after injury and were similarly recovered in both active and sedentary groups at 14 or 42 days, respectively. H-LDH isozyme activity recovered earlier in the active rats. Exercise improved recovery of the slow/oxidative phenotype after soleus muscle injury. Muscle Nerve 55: 91-100, 2017. © 2016 Wiley Periodicals, Inc.

Evidence that simulated microgravity may alter the vascular nonreceptor tyrosine kinase second messenger pathway

NASA Technical Reports Server (NTRS)

Kahwaji, C. I.; Sheibani, S.; Han, S.; Siu, W. O.; Kaka, A. H.; Fathy, T. M.; el-Abbadi, N. H.; Purdy, R. E.

2000-01-01

Simulated microgravity (hind limb unweighting; HU) reduces maximal contractile capacity to norepinephrine (NE) but not 5-hydroxytryptamine (5-HT) in the rat abdominal aorta of male Wistar rats. Our earlier study showed that voltage-operated calcium channels, the MAPK pathway [1], and vasoconstrictive prostaglandins contribute to the NE-induced contraction of control (C) but not HU, aorta rings. Genistein, a general tyrosine kinase inhibitor, caused a significant reduction in vascular contractility in C but not HU arteries. The present study explored the role of protein kinase C (PKC) and extracellular receptor-activated kinase 1 and 2 (ERK1/2) in the HU-induced vascular hyporesponsiveness to NE. Microgravity was simulated in Wistar rats by 20 day HU. The abdominal aorta was removed from control and HU rats, cut into 3 mm rings, and mounted in tissue baths to measure isometric contraction. Protein levels were determined using Western blot analysis. PD98059, a selective MAPKK inhibitor, caused a marked inhibition of NE-induced contraction in both C and HU arteries. Calphostin C, a PKC inhibitor, completely abolished the contractile response to NE in both C and HU tissues. Phosphorylated (activated) ERK1/2 protein mass was greater in C, compared to HU, aortas, and was reduced by genistein only in C tissues. MAPK total protein levels in the rat aorta were increased in the HU-treated, compared to C, animals. These results indicate that PKC represents an early transduction step in the contractile response to NE in the rat abdominal aorta. That inhibition of the step immediately before activation of MAPK reduced contraction in both C and HU tissues, while general tyrosine kinase inhibition with genistein blocked only the control responses, suggests that a nonreceptor tyrosine kinase may be involved in HU-induced vascular hyporesponsiveness to NE.

G protein-coupled estrogen receptor 1-mediated effects in the rat myometrium.

PubMed

Tica, Andrei A; Dun, Erica C; Tica, Oana S; Gao, Xin; Arterburn, Jeffrey B; Brailoiu, G Cristina; Oprea, Tudor I; Brailoiu, Eugen

2011-11-01

G protein-coupled estrogen receptor 1 (GPER), also named GPR30, has been previously identified in the female reproductive system. In this study, GPER expression was found in the female rat myometrium by reverse transcriptase-polymerase chain reaction and immunocytochemistry. Using GPER-selective ligands, we assessed the effects of the GPER activation on resting membrane potential and cytosolic Ca(2+) concentration ([Ca(2+)](i)) in rat myometrial cells, as well as on contractility of rat uterine strips. G-1, a specific GPER agonist, induced a concentration-dependent depolarization and increase in [Ca(2+)](i) in myometrial cells. The depolarization was abolished in Na(+)-free saline. G-1-induced [Ca(2+)](i) increase was markedly decreased by nifedipine, a L-type Ca(2+) channel blocker, by Ca(2+)-free or Na(+)-free saline. Intracellular administration of G-1 produced a faster and transitory increase in [Ca(2+)](i), with a higher amplitude than that induced by extracellular application, supporting an intracellular localization of the functional GPER in myometrial cells. Depletion of internal Ca(2+) stores with thapsigargin produced a robust store-activated Ca(2+) entry; the Ca(2+) response to G-1 was similar to the constitutive Ca(2+) entry and did not seem to involve store-operated Ca(2+) entry. In rat uterine strips, administration of G-1 increased the frequency and amplitude of contractions and the area under the contractility curve. The effects of G-1 on membrane potential, [Ca(2+)](i), and uterine contractility were prevented by pretreatment with G-15, a GPER antagonist, further supporting the involvement of GPER in these responses. Taken together, our results indicate that GPER is expressed and functional in rat myometrium. GPER activation produces depolarization, elevates [Ca(2+)](i) and increases contractility in myometrial cells.

Changes in force and calcium sensitivity in the developing avian heart.

PubMed

Godt, R E; Fogaça, R T; Nosek, T M

1991-11-01

The aim of this study was to characterize the development of the contractile properties of intact and chemically skinned muscle from chicken heart and to compare these characteristics with those of developing mammalian heart reported by others. Small trabeculae were dissected from left ventricles of Arbor Acre chickens between embryonic day 7 and young adulthood (7 weeks post-hatching). At all ages, increasing extracellular calcium (0.45-3.6 mM) progressively increased twitch force of electrically stimulated trabeculae. Twitch force at 1.8 mM extracellular calcium, normalized to cross-sectional area, increased to a maximum at 1 day post-hatching, remained constant through 3 weeks post-hatching, but then decreased at 7 weeks post-hatching. The maximal calcium-activated force of trabeculae chemically skinned with Triton X-100 detergent increased to a maximum 2 days before the time of hatching and was not significantly changed up to 7 weeks post-hatching. Over the ages studied, average twitch force in 1.8 mM calcium was between 26 and 66% of maximal calcium-activated force after skinning, suggesting that the contractile apparatus is not fully activated during the twitch in normal Ringer. In skinned trabeculae, the calcium sensitivity of the contractile apparatus was higher in the embryo than in the young adult. These age-dependent changes in calcium sensitivity are correlated with isoform switching in troponin T. A decrease in pH from 7.0 to 6.5 decreased the calcium sensitivity of the contractile apparatus to a greater degree in skinned trabeculae from young adult hearts than in those from embryonic hearts. This change in susceptibility to acidosis is temporally associated with isoform switching in troponin I.(ABSTRACT TRUNCATED AT 250 WORDS)

Retosiban Prevents Stretch-Induced Human Myometrial Contractility and Delays Labor in Cynomolgus Monkeys.

PubMed

Aye, Irving L M H; Moraitis, Alexandros A; Stanislaus, Dinesh; Charnock-Jones, D Stephen; Smith, Gordon C S

2018-03-01

Stretch of the myometrium promotes its contractility and is believed to contribute to the control of parturition at term and to the increased risk of preterm birth in multiple pregnancies. To determine the effects of the putative oxytocin receptor (OTR) inverse agonist retosiban on (1) the contractility of human myometrial explants and (2) labor in nonhuman primates. Human myometrial biopsies were obtained at planned term cesarean, and explants were exposed to stretch in the presence and absence of a range of drugs, including retosiban. The in vivo effects of retosiban were determined in cynomolgus monkeys. Prolonged mechanical stretch promoted myometrial extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Moreover, stretch-induced stimulation of myometrial contractility was prevented by ERK1/2 inhibitors. Retosiban (10 nM) prevented stretch-induced stimulation of myometrial contractility and phosphorylation of ERK1/2. Moreover, the inhibitory effect of retosiban on stretch-induced ERK1/2 phosphorylation was prevented by coincubation with a 100-fold excess of a peptide OTR antagonist, atosiban. Compared with vehicle-treated cynomolgus monkeys, treatment with oral retosiban (100 to 150 days of gestational age) reduced the risk of spontaneous delivery (hazard ratio = 0.07, 95% confidence interval 0.01 to 0.60, P = 0.015). The OTR acts as a uterine mechanosensor, whereby stretch increases myometrial contractility through agonist-free activation of the OTR. Retosiban prevents this through inverse agonism of the OTR and, in vivo, reduced the likelihood of spontaneous labor in nonhuman primates. We hypothesize that retosiban may be an effective preventative treatment of preterm birth in high-risk multiple pregnancies, an area of unmet clinical need.

Lack of miR-133a Decreases Contractility of Diabetic Hearts: A Role for Novel Cross Talk Between Tyrosine Aminotransferase and Tyrosine Hydroxylase

PubMed Central

Nandi, Shyam Sundar; Zheng, Hong; Sharma, Neeru M.; Shahshahan, Hamid R.; Patel, Kaushik P.

2016-01-01

MicroRNAs (miRNAs) have a fundamental role in diabetic heart failure. The cardioprotective miRNA-133a (miR-133a) is downregulated, and contractility is decreased in diabetic hearts. Norepinephrine (NE) is a key catecholamine that stimulates contractility by activating β-adrenergic receptors (β-AR). NE is synthesized from tyrosine by the rate-limiting enzyme, tyrosine hydroxylase (TH), and tyrosine is catabolized by tyrosine aminotransferase (TAT). However, the cross talk/link between TAT and TH in the heart is unclear. To determine whether miR-133a plays a role in the cross talk between TH and TAT and regulates contractility by influencing NE biosynthesis and/or β-AR levels in diabetic hearts, Sprague-Dawley rats and miR-133a transgenic (miR-133aTg) mice were injected with streptozotocin to induce diabetes. The diabetic rats were then treated with miR-133a mimic or scrambled miRNA. Our results revealed that miR-133a mimic treatment improved the contractility of the diabetic rat’s heart concomitant with upregulation of TH, cardiac NE, β-AR, and downregulation of TAT and plasma levels of NE. In miR-133aTg mice, cardiac-specific miR-133a overexpression prevented upregulation of TAT and suppression of TH in the heart after streptozotocin was administered. Moreover, miR-133a overexpression in CATH.a neuronal cells suppressed TAT with concomitant upregulation of TH, whereas knockdown and overexpression of TAT demonstrated that TAT inhibited TH. Luciferase reporter assay confirmed that miR-133a targets TAT. In conclusion, miR-133a controls the contractility of diabetic hearts by targeting TAT, regulating NE biosynthesis, and consequently, β-AR and cardiac function. PMID:27411382

Asynchronous Video Streaming vs. Synchronous Videoconferencing for Teaching a Pharmacogenetic Pharmacotherapy Course

PubMed Central

2007-01-01

Objectives To compare students' performance and course evaluations for a pharmacogenetic pharmacotherapy course taught by synchronous videoconferencing method via the Internet and for the same course taught via asynchronous video streaming via the Internet. Methods In spring 2005, a pharmacogenetic therapy course was taught to 73 students located on Amarillo, Lubbock, and Dallas campuses using synchronous videoconferencing, and in spring 2006, to 78 students located on the same 3 campuses using asynchronous video streaming. A course evaluation was administered to each group at the end of the courses. Results Students in the asynchronous setting had final course grades of 89% ± 7% compared to the mean final course grade of 87% ± 7% in the synchronous group (p = 0.05). Regardless of which technology was used, average course grades did not differ significantly among the 3 campus sites. Significantly more of the students in the asynchronous setting agreed (57%) with the statement that they could read the lecture notes and absorb the content on their own without attending the class than students in the synchronous class (23%; chi-square test; p < 0.001). Conclusions Students in both asynchronous and synchronous settings performed well. However, students taught using asynchronous videotaped lectures had lower satisfaction with the method of content delivery, and preferred live interactive sessions or a mix of interactive sessions and asynchronous videos over delivery of content using the synchronous or asynchronous method alone. PMID:17429516

Adiponectin downregulation is associated with volume overload-induced myocyte dysfunction in rats

PubMed Central

Wang, Li-li; Miller, Dori; Wanders, Desiree; Nanayakkara, Gayani; Amin, Rajesh; Judd, Robert; Morrison, Edward E; Zhong, Ju-ming

2016-01-01

Aim: Adiponectin has been reported to exert protective effects during pathological ventricular remodeling, but the role of adiponectin in volume overload-induced heart failure remains unclear. In this study we investigated the effect of adiponectin on cardiac myocyte contractile dysfunction following volume overload in rats. Methods: Volume overload was surgically induced in rats by infrarenal aorta-vena cava fistula. The rats were intravenously administered adenoviral adiponectin at 2-, 6- and 9-weeks following fistula. The protein expression of adiponectin, adiponectin receptors (AdipoR1/R2 and T-cadherin) and AMPK activity were measured using Western blot analyses. Isolated ventricular myocytes were prepared at 12 weeks post-fistula to examine the contractile performance of myocytes and intracellular Ca2+ transient. Results: A-V fistula resulted in significant reductions in serum and myocardial adiponectin levels, myocardial adiponectin receptor (AdipoR1/R2 and T-cadherin) levels, as well as myocardial AMPK activity. Consistent with these changes, the isolated myocytes exhibited significant depression in cell shortening and intracellular Ca2+ transient. Administration of adenoviral adiponectin significantly increased serum adiponectin levels and prevented myocyte contractile dysfunction in fistula rats. Furthermore, pretreatment of isolated myocytes with recombinant adiponectin (2.5 μg/mL) significantly improved their contractile performance in fistula rats, but had no effects in control or adenoviral adiponectin-administered rats. Conclusion: These results demonstrate a positive correlation between adiponectin downregulation and volume overload-induced ventricular remodeling. Adiponectin plays a protective role in volume overload-induced heart failure. PMID:26616727

Increased longitudinal contractility and diastolic function at rest in well-trained amateur Marathon runners: a speckle tracking echocardiography study

PubMed Central

2014-01-01

Background Regular physical activity reduces cardiovascular risk. There is concern that Marathon running might acutely damage the heart. It is unknown to what extent intensive physical endurance activity influences the cardiac mechanics at resting condition. Methods Eighty-four amateur marathon runners (43 women and 41 men) from Berlin-Brandenburg area who had completed at least one marathon previously underwent clinical examination and echocardiography at least 10 days before the Berlin Marathon at rest. Standard transthoracic echocardiography and 2D strain and strain rate analysis were performed. The 2D Strain and strain rate values were compared to previous published data of healthy untrained individuals. Results The average global longitudinal peak systolic strain of the left ventricle was -23 +/- 2% with peak systolic strain rate -1.39 +/- 0.21/s, early diastolic strain rate 2.0 +/- 0.40/s and late diastolic strain rate 1.21 +/- 0.31/s. These values are significantly higher compared to the previous published values of normal age-adjusted individuals. In addition, no age-related decline of longitudinal contractility in well-trained athletes was observed. Conclusions There is increased overall longitudinal myocardial contractility at rest in experienced endurance athletes compared to the published normal values in the literature indicating a preserved and even supra-normal contractility in the athletes. There is no age dependent decline of the longitudinal 2D Strain values. This underlines the beneficial effects of regular physical exercise even in advanced age. PMID:24571726

Formation of contractile networks and fibers in the medial cell cortex through myosin-II turnover, contraction, and stress-stabilization

PubMed Central

Nie, Wei; Wei, Ming-Tzo; Ou-Yang, Daniel H.; Jedlicka, Sabrina S.; Vavylonis, Dimitrios

2015-01-01

The morphology of adhered cells depends crucially on the formation of a contractile meshwork of parallel and cross-linked fibers along the contacting surface. The motor activity and minifilament assembly of non-muscle myosin-II is an important component of cortical cytoskeletal remodeling during mechanosensing. We used experiments and computational modeling to study cortical myosin-II dynamics in adhered cells. Confocal microscopy was used to image the medial cell cortex of HeLa cells stably expressing myosin regulatory light chain tagged with GFP (MRLC-GFP). The distribution of MRLC-GFP fibers and focal adhesions was classified into three types of network morphologies. Time-lapse movies show: myosin foci appearance and disappearance; aligning and contraction; stabilization upon alignment. Addition of blebbistatin, which perturbs myosin motor activity, leads to a reorganization of the cortical networks and to a reduction of contractile motions. We quantified the kinetics of contraction, disassembly and reassembly of myosin networks using spatio-temporal image correlation spectroscopy (STICS). Coarse-grained numerical simulations include bipolar minifilaments that contract and align through specified interactions as basic elements. After assuming that minifilament turnover decreases with increasing contractile stress, the simulations reproduce stress-dependent fiber formation in between focal adhesions above a threshold myosin concentration. The STICS correlation function in simulations matches the function measured in experiments. This study provides a framework to help interpret how different cortical myosin remodeling kinetics may contribute to different cell shape and rigidity depending on substrate stiffness. PMID:25641802

Involvement of connexin 43 phosphorylation and gap junctional communication between smooth muscle cells in vasopressin-induced ROCK-dependent vasoconstriction after hemorrhagic shock.

PubMed

Yang, Guangming; Peng, Xiaoyong; Wu, Yue; Li, Tao; Liu, Liangming

2017-10-01

We examined the roles played by gap junctions (GJs) and the GJ channel protein connexin 43 (Cx43) in arginine vasopressin (AVP)-induced vasoconstriction after hemorrhagic shock and their relationship to Rho kinase (ROCK) and protein kinase C (PKC). The results showed that AVP induced an endothelium-independent contraction in rat superior mesenteric arteries (SMAs). Blocking the GJs significantly decreased the contractile response of SMAs and vascular smooth muscle cells (VSMCs) to AVP after shock and hypoxia. The selective Cx43-mimetic peptide inhibited the vascular contractile effect of AVP after shock and hypoxia. AVP restored hypoxia-induced decrease of Cx43 phosphorylation at Ser 262 and gap junctional communication in VSMCs. Activation of RhoA with U-46619 increased the contractile effect of AVP. This effect was antagonized by the ROCK inhibitor Y27632 and the Cx43-mimetic peptide. In contrast, neither an agonist nor an inhibitor of PKC had significant effects on AVP-induced contraction after hemorrhagic shock. In addition, silencing of Cx43 with siRNA blocked the AVP-induced increase of ROCK activity in hypoxic VSMCs. In conclusion, AVP-mediated vascular contractile effects are endothelium and myoendothelial gap junction independent. Gap junctions between VSMCs, gap junctional communication, and Cx43 phosphorylation at Ser 262 play important roles in the vascular effects of AVP. RhoA/ROCK, but not PKC, is involved in this process. Copyright © 2017 the American Physiological Society.

Atorvastatin calcium inhibits phenotypic modulation of PDGF-BB-induced VSMCs via down-regulation the Akt signaling pathway.

PubMed

Chen, Shuang; Liu, Baoqin; Kong, Dehui; Li, Si; Li, Chao; Wang, Huaqin; Sun, Yingxian

2015-01-01

Plasticity of vascular smooth muscle cells (VSMCs) plays a central role in the onset and progression of proliferative vascular diseases. In adult tissue, VSMCs exist in a physiological contractile-quiescent phenotype, which is defined by lack of the ability of proliferation and migration, while high expression of contractile marker proteins. After injury to the vessel, VSMC shifts from a contractile phenotype to a pathological synthetic phenotype, associated with increased proliferation, migration and matrix secretion. It has been demonstrated that PDGF-BB is a critical mediator of VSMCs phenotypic switch. Atorvastatin calcium, a selective inhibitor of 3-hydroxy-3-methyl-glutaryl l coenzyme A (HMG-CoA) reductase, exhibits various protective effects against VSMCs. In this study, we investigated the effects of atorvastatin calcium on phenotype modulation of PDGF-BB-induced VSMCs and the related intracellular signal transduction pathways. Treatment of VSMCs with atorvastatin calcium showed dose-dependent inhibition of PDGF-BB-induced proliferation. Atorvastatin calcium co-treatment inhibited the phenotype modulation and cytoskeleton rearrangements and improved the expression of contractile phenotype marker proteins such as α-SM actin, SM22α and calponin in comparison with PDGF-BB alone stimulated VSMCs. Although Akt phosphorylation was strongly elicited by PDGF-BB, Akt activation was attenuated when PDGF-BB was co-administrated with atorvastatin calcium. In conclusion, atorvastatin calcium inhibits phenotype modulation of PDGF-BB-induced VSMCs and activation of the Akt signaling pathway, indicating that Akt might play a vital role in the modulation of phenotype.

Spontaneous Activity Drives Local Synaptic Plasticity In Vivo.

PubMed

Winnubst, Johan; Cheyne, Juliette E; Niculescu, Dragos; Lohmann, Christian

2015-07-15

Spontaneous activity fine-tunes neuronal connections in the developing brain. To explore the underlying synaptic plasticity mechanisms, we monitored naturally occurring changes in spontaneous activity at individual synapses with whole-cell patch-clamp recordings and simultaneous calcium imaging in the mouse visual cortex in vivo. Analyzing activity changes across large populations of synapses revealed a simple and efficient local plasticity rule: synapses that exhibit low synchronicity with nearby neighbors (<12 μm) become depressed in their transmission frequency. Asynchronous electrical stimulation of individual synapses in hippocampal slices showed that this is due to a decrease in synaptic transmission efficiency. Accordingly, experimentally increasing local synchronicity, by stimulating synapses in response to spontaneous activity at neighboring synapses, stabilized synaptic transmission. Finally, blockade of the high-affinity proBDNF receptor p75(NTR) prevented the depression of asynchronously stimulated synapses. Thus, spontaneous activity drives local synaptic plasticity at individual synapses in an "out-of-sync, lose-your-link" fashion through proBDNF/p75(NTR) signaling to refine neuronal connectivity. VIDEO ABSTRACT. Copyright © 2015 Elsevier Inc. All rights reserved.

Building asynchronous geospatial processing workflows with web services

NASA Astrophysics Data System (ADS)

Zhao, Peisheng; Di, Liping; Yu, Genong

2012-02-01

Geoscience research and applications often involve a geospatial processing workflow. This workflow includes a sequence of operations that use a variety of tools to collect, translate, and analyze distributed heterogeneous geospatial data. Asynchronous mechanisms, by which clients initiate a request and then resume their processing without waiting for a response, are very useful for complicated workflows that take a long time to run. Geospatial contents and capabilities are increasingly becoming available online as interoperable Web services. This online availability significantly enhances the ability to use Web service chains to build distributed geospatial processing workflows. This paper focuses on how to orchestrate Web services for implementing asynchronous geospatial processing workflows. The theoretical bases for asynchronous Web services and workflows, including asynchrony patterns and message transmission, are examined to explore different asynchronous approaches to and architecture of workflow code for the support of asynchronous behavior. A sample geospatial processing workflow, issued by the Open Geospatial Consortium (OGC) Web Service, Phase 6 (OWS-6), is provided to illustrate the implementation of asynchronous geospatial processing workflows and the challenges in using Web Services Business Process Execution Language (WS-BPEL) to develop them.

Passive and active ventricular elastances of the left ventricle

PubMed Central

Zhong, Liang; Ghista, Dhanjoo N; Ng, Eddie YK; Lim, Soo T

2005-01-01

Background Description of the heart as a pump has been dominated by models based on elastance and compliance. Here, we are presenting a somewhat new concept of time-varying passive and active elastance. The mathematical basis of time-varying elastance of the ventricle is presented. We have defined elastance in terms of the relationship between ventricular pressure and volume, as: dP = EdV + VdE, where E includes passive (Ep) and active (Ea) elastance. By incorporating this concept in left ventricular (LV) models to simulate filling and systolic phases, we have obtained the time-varying expression for Ea and the LV-volume dependent expression for Ep. Methods and Results Using the patient's catheterization-ventriculogram data, the values of passive and active elastance are computed. Ea is expressed as: ; Epis represented as: . Ea is deemed to represent a measure of LV contractility. Hence, Peak dP/dt and ejection fraction (EF) are computed from the monitored data and used as the traditional measures of LV contractility. When our computed peak active elastance (Ea,max) is compared against these traditional indices by linear regression, a high degree of correlation is obtained. As regards Ep, it constitutes a volume-dependent stiffness property of the LV, and is deemed to represent resistance-to-filling. Conclusions Passive and active ventricular elastance formulae can be evaluated from a single-beat P-V data by means of a simple-to-apply LV model. The active elastance (Ea) can be used to characterize the ventricle's contractile state, while passive elastance (Ep) can represent a measure of resistance-to-filling. PMID:15707494

Decoding illusory self-location from activity in the human hippocampus.

PubMed

Guterstam, Arvid; Björnsdotter, Malin; Bergouignan, Loretxu; Gentile, Giovanni; Li, Tie-Qiang; Ehrsson, H Henrik

2015-01-01

Decades of research have demonstrated a role for the hippocampus in spatial navigation and episodic and spatial memory. However, empirical evidence linking hippocampal activity to the perceptual experience of being physically located at a particular place in the environment is lacking. In this study, we used a multisensory out-of-body illusion to perceptually 'teleport' six healthy participants between two different locations in the scanner room during high-resolution functional magnetic resonance imaging (fMRI). The participants were fitted with MRI-compatible head-mounted displays that changed their first-person visual perspective to that of a pair of cameras placed in one of two corners of the scanner room. To elicit the illusion of being physically located in this position, we delivered synchronous visuo-tactile stimulation in the form of an object moving toward the cameras coupled with touches applied to the participant's chest. Asynchronous visuo-tactile stimulation did not induce the illusion and served as a control condition. We found that illusory self-location could be successfully decoded from patterns of activity in the hippocampus in all of the participants in the synchronous (P < 0.05) but not in the asynchronous condition (P > 0.05). At the group-level, the decoding accuracy was significantly higher in the synchronous than in the asynchronous condition (P = 0.012). These findings associate hippocampal activity with the perceived location of the bodily self in space, which suggests that the human hippocampus is involved not only in spatial navigation and memory but also in the construction of our sense of bodily self-location.

Decoding illusory self-location from activity in the human hippocampus

PubMed Central

Guterstam, Arvid; Björnsdotter, Malin; Bergouignan, Loretxu; Gentile, Giovanni; Li, Tie-Qiang; Ehrsson, H. Henrik

2015-01-01

Decades of research have demonstrated a role for the hippocampus in spatial navigation and episodic and spatial memory. However, empirical evidence linking hippocampal activity to the perceptual experience of being physically located at a particular place in the environment is lacking. In this study, we used a multisensory out-of-body illusion to perceptually ‘teleport’ six healthy participants between two different locations in the scanner room during high-resolution functional magnetic resonance imaging (fMRI). The participants were fitted with MRI-compatible head-mounted displays that changed their first-person visual perspective to that of a pair of cameras placed in one of two corners of the scanner room. To elicit the illusion of being physically located in this position, we delivered synchronous visuo-tactile stimulation in the form of an object moving toward the cameras coupled with touches applied to the participant’s chest. Asynchronous visuo-tactile stimulation did not induce the illusion and served as a control condition. We found that illusory self-location could be successfully decoded from patterns of activity in the hippocampus in all of the participants in the synchronous (P < 0.05) but not in the asynchronous condition (P > 0.05). At the group-level, the decoding accuracy was significantly higher in the synchronous than in the asynchronous condition (P = 0.012). These findings associate hippocampal activity with the perceived location of the bodily self in space, which suggests that the human hippocampus is involved not only in spatial navigation and memory but also in the construction of our sense of bodily self-location. PMID:26236222

Effects of St John's wort and its active constituents, hypericin and hyperforin, on isolated rat urinary bladder.

PubMed

Valeri, Aurora; Capasso, Raffaele; Valoti, Massimo; Pessina, Federica

2012-12-01

To investigate the effect of St John's wort (SJW) and its active constituents hypericin and hyperforin on detrusor smooth muscle contractility and their possible neuroprotective role against ischaemic-like conditions, which could arise during overactive bladder disease. In whole bladders, intrinsic nerves underwent electrical field stimulation (EFS). The effect of drugs on the contractile response and its recovery in reperfusion phase (R) was monitored at different concentrations during 1 or 2 h of anoxia-glucopenia (A-G) and the first 30 min of R. The effects of the drugs were also investigated on rat detrusor muscle strips contracted with carbachol, KCl and electrically. SJW has spasmolytic activity, which increases with increasing concentration and it worsens the damage induced by A-G/R on rat urinary bladder. Hypericin and hyperforin had no effect during ischemic-like conditions but they both exert a dual modulation of rat detrusor strips contraction. At high micromolar concentrations they showed a relaxing effect, but at submicromolar range hypericin increased the plasma membrane depolarisation and hyperforin showed a stimulatory effect on the cholinergic system. The results of our study showed that SJW and its constituents could modulate urinary bladder contractility and even worsen A-G/R injury. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction

PubMed Central

Richart, Adèle; Vilar, Jose; Lemitre, Mathilde; Marck, Pauline; Branchereau, Maxime; Guerin, Coralie; Gautier, Gregory; Blank, Ulrich; Heymes, Christophe; Luche, Elodie; Cousin, Béatrice; Rodewald, Hans-Reimer

2016-01-01

Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles for mast cells (MCs) in postischemic cardiac remodeling. Because c-Kit mutations affect multiple cell types of both immune and nonimmune origin, we addressed the impact of MCs on cardiac function after MI, using the c-Kit–independent MC-deficient (Cpa3Cre/+) mice. In response to MI, MC progenitors originated primarily from white adipose tissue, infiltrated the heart, and differentiated into mature MCs. MC deficiency led to reduced postischemic cardiac function and depressed cardiomyocyte contractility caused by myofilament Ca2+ desensitization. This effect correlated with increased protein kinase A (PKA) activity and hyperphosphorylation of its targets, troponin I and myosin-binding protein C. MC-specific tryptase was identified to regulate PKA activity in cardiomyocytes via protease-activated receptor 2 proteolysis. This work reveals a novel function for cardiac MCs modulating cardiomyocyte contractility via alteration of PKA-regulated force–Ca2+ interactions in response to MI. Identification of this MC-cardiomyocyte cross-talk provides new insights on the cellular and molecular mechanisms regulating the cardiac contractile machinery and a novel platform for therapeutically addressable regulators. PMID:27353089

Magnetic Resonance Assessment of Hypertrophic and Pseudo-Hypertrophic Changes in Lower Leg Muscles of Boys with Duchenne Muscular Dystrophy and Their Relationship to Functional Measurements.

PubMed

Vohra, Ravneet S; Lott, Donovan; Mathur, Sunita; Senesac, Claudia; Deol, Jasjit; Germain, Sean; Bendixen, Roxanna; Forbes, Sean C; Sweeney, H Lee; Walter, Glenn A; Vandenborne, Krista

2015-01-01

The primary objectives of this study were to evaluate contractile and non-contractile content of lower leg muscles of boys with Duchenne muscular dystrophy (DMD) and determine the relationships between non-contractile content and functional abilities. Lower leg muscles of thirty-two boys with DMD and sixteen age matched unaffected controls were imaged. Non-contractile content, contractile cross sectional area and non-contractile cross sectional area of lower leg muscles (tibialis anterior, extensor digitorum longus, peroneal, medial gastrocnemius and soleus) were assessed by magnetic resonance imaging (MRI). Muscle strength, timed functional tests and the Brooke lower extremity score were also assessed. Non-contractile content of lower leg muscles (peroneal, medial gastrocnemius, and soleus) was significantly greater than control group (p<0.05). Non-contractile content of lower leg muscles correlated with Brooke score (rs = 0.64-0.84) and 30 feet walk (rs = 0.66-0.80). Dorsiflexor (DF) and plantarflexor (PF) specific torque was significantly different between the groups. Overall, non-contractile content of the lower leg muscles was greater in DMD than controls. Furthermore, there was an age dependent increase in contractile content in the medial gastrocnemius of boys with DMD. The findings of this study suggest that T1 weighted MR images can be used to monitor disease progression and provide a quantitative estimate of contractile and non-contractile content of tissue in children with DMD.

Magnetic Resonance Assessment of Hypertrophic and Pseudo-Hypertrophic Changes in Lower Leg Muscles of Boys with Duchenne Muscular Dystrophy and Their Relationship to Functional Measurements

PubMed Central

Vohra, Ravneet S.; Lott, Donovan; Mathur, Sunita; Senesac, Claudia; Deol, Jasjit; Germain, Sean; Bendixen, Roxanna; Forbes, Sean C.; Sweeney, H. Lee; Walter, Glenn A.; Vandenborne, Krista

2015-01-01

Introduction The primary objectives of this study were to evaluate contractile and non-contractile content of lower leg muscles of boys with Duchenne muscular dystrophy (DMD) and determine the relationships between non-contractile content and functional abilities. Methods Lower leg muscles of thirty-two boys with DMD and sixteen age matched unaffected controls were imaged. Non-contractile content, contractile cross sectional area and non-contractile cross sectional area of lower leg muscles (tibialis anterior, extensor digitorum longus, peroneal, medial gastrocnemius and soleus) were assessed by magnetic resonance imaging (MRI). Muscle strength, timed functional tests and the Brooke lower extremity score were also assessed. Results Non-contractile content of lower leg muscles (peroneal, medial gastrocnemius, and soleus) was significantly greater than control group (p<0.05). Non-contractile content of lower leg muscles correlated with Brooke score (rs = 0.64-0.84) and 30 feet walk (rs = 0.66-0.80). Dorsiflexor (DF) and plantarflexor (PF) specific torque was significantly different between the groups. Discussion Overall, non-contractile content of the lower leg muscles was greater in DMD than controls. Furthermore, there was an age dependent increase in contractile content in the medial gastrocnemius of boys with DMD. The findings of this study suggest that T1 weighted MR images can be used to monitor disease progression and provide a quantitative estimate of contractile and non-contractile content of tissue in children with DMD. PMID:26103164

Izalpinin from fruits of Alpinia oxyphylla with antagonistic activity against the rat bladder contractility.

PubMed

Yuan, Yuan; Tan, Yin-Feng; Xu, Peng; Li, Hailong; Li, Yong-Hui; Chen, Wen-Ya; Zhang, Jun-Qing; Chen, Feng; Huang, Guo-Jun

2014-01-01

Alpinia oxyphylla (Zingiberaceae), an herbaceous perennial plant, its capsular fruit is commonly used in traditional Chinese medicine for the treatment of different urinary incontinence symptoms including frequency, urgency and nocturia. These symptoms are similar to the overactive bladder syndrome. In our lab, we found that the 95% ethanol extract of the capsular fruits exhibited significant anti-muscarinic activity. Some constituents in capsular fruits including flavonoids (e.g., izalpinin and tectochrysin), diarylheptanoids (e.g., yakuchinone A and yakuchinone B) and sesquiterpenes (e.g., nootkatone), are regarded as representative chemicals with putative pharmacological activities. This study aimed to evaluate the in vitro antagonistic actions of izalpinin on carbachol-induced contraction of the rat detrusor muscle. In vitro inhibition of rat detrusor contractile response to carbachol was used to study the functional activity of izalpinin. The isolated detrusor strips of rats were mounted in organ baths containing oxygenated Krebs' solution. The cumulative consecutive concentration-response curves to carbachol-evoked contractions in strips of rat bladder were obtained. Carbachol induced concentration-dependent contractions of isolated rat bladder detrusor strips. The vehicle DMSO had no impact on the contraction response. The contraction effects were concentration-dependently antagonized by izalpinin, with a mean EC50 value of 0.35 µM. The corresponding cumulative agonist concentration-response curves shifted right-ward. Izalpinin exhibits inhibitory role of muscarinic receptor-related detrusor contractile activity, and it may be a promising lead compound to treat overactive bladder.

Fropofol decreases force development in cardiac muscle.

PubMed

Ren, Xianfeng; Schmidt, William; Huang, Yiyuan; Lu, Haisong; Liu, Wenjie; Bu, Weiming; Eckenhoff, Roderic; Cammarato, Anthony; Gao, Wei Dong

2018-03-09

Supranormal contractile properties are frequently associated with cardiac diseases. Anesthetic agents, including propofol, can depress myocardial contraction. We tested the hypothesis that fropofol, a propofol derivative, reduces force development in cardiac muscles via inhibition of cross-bridge cycling and may therefore have therapeutic potential. Force and intracellular Ca 2+ ([Ca 2+ ] i ) transients of rat trabecular muscles were determined. Myofilament ATPase, actin-activated myosin ATPase, and velocity of actin filaments propelled by myosin were also measured. Fropofol dose dependently decreased force without altering [Ca 2+ ] i in normal and pressure-induced hypertrophied-hypercontractile muscles. Similarly, fropofol depressed maximum Ca 2+ -activated force ( F max ) and increased the [Ca 2+ ] i required for 50% activation at steady-state (Ca 50 ) without affecting the Hill coefficient in both intact and skinned cardiac fibers. The drug also depressed cardiac myofibrillar and actin-activated myosin ATPase activity. In vitro actin sliding velocity was significantly reduced when fropofol was introduced during rigor binding of cross-bridges. The data suggest that the depressing effects of fropofol on cardiac contractility are likely to be related to direct targeting of actomyosin interactions. From a clinical standpoint, these findings are particularly significant, given that fropofol is a nonanesthetic small molecule that decreases myocardial contractility specifically and thus may be useful in the treatment of hypercontractile cardiac disorders.-Ren, X., Schmidt, W., Huang, Y., Lu, H., Liu, W., Bu, W., Eckenhoff, R., Cammarato, A., Gao, W. D. Fropofol decreases force development in cardiac muscle.

Focal Contacts as Mechanosensors

PubMed Central

Riveline, Daniel; Zamir, Eli; Balaban, Nathalie Q.; Schwarz, Ulrich S.; Ishizaki, Toshimasa; Narumiya, Shuh; Kam, Zvi; Geiger, Benjamin; Bershadsky, Alexander D.

2001-01-01

The transition of cell–matrix adhesions from the initial punctate focal complexes into the mature elongated form, known as focal contacts, requires GTPase Rho activity. In particular, activation of myosin II–driven contractility by a Rho target known as Rho-associated kinase (ROCK) was shown to be essential for focal contact formation. To dissect the mechanism of Rho-dependent induction of focal contacts and to elucidate the role of cell contractility, we applied mechanical force to vinculin-containing dot-like adhesions at the cell edge using a micropipette. Local centripetal pulling led to local assembly and elongation of these structures and to their development into streak-like focal contacts, as revealed by the dynamics of green fluorescent protein–tagged vinculin or paxillin and interference reflection microscopy. Inhibition of Rho activity by C3 transferase suppressed this force-induced focal contact formation. However, constitutively active mutants of another Rho target, the formin homology protein mDia1 (Watanabe, N., T. Kato, A. Fujita, T. Ishizaki, and S. Narumiya. 1999. Nat. Cell Biol. 1:136–143), were sufficient to restore force-induced focal contact formation in C3 transferase-treated cells. Force-induced formation of the focal contacts still occurred in cells subjected to myosin II and ROCK inhibition. Thus, as long as mDia1 is active, external tension force bypasses the requirement for ROCK-mediated myosin II contractility in the induction of focal contacts. Our experiments show that integrin-containing focal complexes behave as individual mechanosensors exhibiting directional assembly in response to local force. PMID:11402062

Single cell active force generation under dynamic loading - Part I: AFM experiments.

PubMed

Weafer, P P; Reynolds, N H; Jarvis, S P; McGarry, J P

2015-11-01

A novel series of experiments are performed on single cells using a bespoke AFM system where the response of cells to dynamic loading at physiologically relevant frequencies is uncovered. Measured forces for the untreated cells are dramatically different to cytochalasin-D (cyto-D) treated cells, indicating that the contractile actin cytoskeleton plays a critical role in the response of cells to dynamic loading. Following a change in applied strain magnitude, while maintaining a constant applied strain rate, the compression force for contractile cells recovers to 88.9±7.8% of the steady state force. In contrast, cyto-D cell compression forces recover to only 38.0±6.7% of the steady state force. Additionally, untreated cells exhibit strongly negative (pulling) forces during unloading half-cycles when the probe is retracted. In comparison, negligible pulling forces are measured for cyto-D cells during probe retraction. The current study demonstrates that active contractile forces, generated by actin-myosin cross-bridge cycling, dominate the response of single cells to dynamic loading. Such active force generation is shown to be independent of applied strain magnitude. Passive forces generated by the applied deformation are shown to be of secondary importance, exhibiting a high dependence on applied strain magnitude, in contrast to the active forces in untreated cells. A novel series of experiments are performed on single cells using a bespoke AFM system where the response of cells to dynamic loading at physiologically relevant frequencies is uncovered. Contractile cells, which contain the active force generation machinery of the actin cytoskeleton, are shown to be insensitive to applied strain magnitude, exhibiting high resistance to dynamic compression and stretching. Such trends are not observed for cells in which the actin cytoskeleton has been chemically disrupted. These biomechanical insights have not been previously reported. This detailed characterisation of single cell active and passive stress during dynamic loading has important implications for tissue engineering strategies, where applied deformation has been reported to significantly affect cell mechanotransduction and matrix synthesis. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Antioxidant Phytochemicals of Opuntia ficus-indica (L.) Mill. Cladodes with Potential Anti-spasmodic Activity.

PubMed

Lanuzza, Francesco; Occhiuto, Francesco; Monforte, Maria Teresa; Tripodo, Maria Marcella; D'Angelo, Valeria; Galati, Enza Maria

2017-10-01

Opuntia ficus-indica (OFI) (L.) Mill. (Cactaceae), a plant widespread in dry regions of the world, shows interesting biological activities (cicatrizant, antiulcer, anti-inflammatory, and hypolipidemic) and is widely used in traditional medicine. Phytochemical analysis and antispasmodic effect of wild OFI cladodes were carried out. Polyphenols and Vitamin E occurrence, in antioxidant pool of OFI cladodes, were quantified by high-performance liquid chromatography. The antispasmodic effect of OFI cladodes was assessed in isolated rabbit smooth muscle tissues. The experiments were carried out with preparations of rabbit jejunum and uterus with the spontaneous contractile activity, to evaluate the effect of cumulative concentrations of the extract on basal tone, amplitude, and frequency of contractions. Catechin, quercetin, kaempferol, isorhamnetin and chlorogenic, ferulic, and p-coumaric acid were identified. α-, β-, and γ-tocopherols have been highlighted and α-tocopherol is the major component. OFI cladodes contain significant amount of polyphenols and tocopherols that are effective radical scavengers and inhibited ethanol 1,1-diphenyl-2-picrylhydrazyl formation by 50%. OFI cladodes caused a light inhibition of amplitude and frequency of spontaneous contractions and a marked decrease in muscle basal tone of rabbit jejunum preparations. On spontaneously contracting uterus preparations, the addition of increasing concentrations of cladode extract caused uterine muscle relaxation. The contraction of smooth muscle preparations depends on an increase in cytoplasmic free calcium ion concentration, which activates the contractile elements. The flavonoids may suppress the contractility of smooth myocytes, by an inhibition of availability of Ca 2+ for muscle contraction. Opuntia ficus-indica (OFI) cladodes contain significant amount of polyphenols and tocopherols that are effective radical scavengers and inhibited ethanol 1,1-diphenyl-2-picrylhydrazyl formation by 50%Polyphenols and Vitamin E complex occurrence in OFI cladodes were characterized by high-performance liquid chromatographyOFI cladodes exhibited significative antispasmodic activity. The antispasmodic effect was assessed in isolated rabbit smooth muscle tissues. The experiments were carried out with preparations of rabbit jejunum and uterus with the spontaneous contractile activity, to evaluate the effect of cumulative concentrations of the extract on basal tone, amplitude, and frequency of contractions. Abbreviations used: OFI: Opuntia ficus-indica , DPPH: Ethanol 1,1-diphenyl-2-picrylhydrazyl.

Comparison of speckle-tracking echocardiography with invasive hemodynamics for the detection of characteristic cardiac dysfunction in type-1 and type-2 diabetic rat models.

PubMed

Mátyás, Csaba; Kovács, Attila; Németh, Balázs Tamás; Oláh, Attila; Braun, Szilveszter; Tokodi, Márton; Barta, Bálint András; Benke, Kálmán; Ruppert, Mihály; Lakatos, Bálint Károly; Merkely, Béla; Radovits, Tamás

2018-01-16

Measurement of systolic and diastolic function in animal models is challenging by conventional non-invasive methods. Therefore, we aimed at comparing speckle-tracking echocardiography (STE)-derived parameters to the indices of left ventricular (LV) pressure-volume (PV) analysis to detect cardiac dysfunction in rat models of type-1 (T1DM) and type-2 (T2DM) diabetes mellitus. Rat models of T1DM (induced by 60 mg/kg streptozotocin, n = 8) and T2DM (32-week-old Zucker Diabetic Fatty rats, n = 7) and corresponding control animals (n = 5 and n = 8, respectively) were compared. Echocardiography and LV PV analysis were performed. LV short-axis recordings were used for STE analysis. Global circumferential strain, peak strain rate values in systole (SrS), isovolumic relaxation (SrIVR) and early diastole (SrE) were measured. LV contractility, active relaxation and stiffness were measured by PV analysis. In T1DM, contractility and active relaxation were deteriorated to a greater extent compared to T2DM. In contrast, diastolic stiffness was impaired in T2DM. Correspondingly, STE described more severe systolic dysfunction in T1DM. Among diastolic STE parameters, SrIVR was more decreased in T1DM, however, SrE was more reduced in T2DM. In T1DM, SrS correlated with contractility, SrIVR with active relaxation, while in T2DM SrE was related to cardiac stiffness, cardiomyocyte diameter and fibrosis. Strain and strain rate parameters can be valuable and feasible measures to describe the dynamic changes in contractility, active relaxation and LV stiffness in animal models of T1DM and T2DM. STE corresponds to PV analysis and also correlates with markers of histological myocardial remodeling.

Effects of hindlimb unweighting on the mechanical and structure properties of the rat abdominal aorta

NASA Technical Reports Server (NTRS)

Papadopoulos, Anthony; Delp, Michael D.

2003-01-01

Previous studies have shown that hindlimb unweighting of rats, a model of microgravity, reduces evoked contractile tension of peripheral conduit arteries. It has been hypothesized that this diminished contractile tension is the result of alterations in the mechanical properties of these arteries (e.g., active and passive mechanics). Therefore, the purpose of this study was to determine whether the reduced contractile force of the abdominal aorta from 2-wk hindlimb-unweighted (HU) rats results from a mechanical function deficit resulting from structural vascular alterations or material property changes. Aortas were isolated from control (C) and HU rats, and vasoconstrictor responses to norepinephrine (10(-9)-10(-4) M) and AVP (10(-9)-10(-5) M) were tested in vitro. In a second series of tests, the active and passive Cauchy stress-stretch relations were determined by incrementally increasing the uniaxial displacement of the aortic rings. Maximal Cauchy stress in response to norepinephrine and AVP were less in aortic rings from HU rats. The active Cauchy stress-stretch response indicated that, although maximum stress was lower in aortas from HU rats (C, 8.1 +/- 0.2 kPa; HU, 7.0 +/- 0.4 kPa), it was achieved at a similar hoop stretch. There were also no differences in the passive Cauchy stress-stretch response or the gross vascular morphology (e.g., medial cross-sectional area: C, 0.30 +/- 0.02 mm(2); HU, 0.32 +/- 0.01 mm(2)) between groups and no differences in resting or basal vascular tone at the displacement that elicits peak developed tension between groups (resting tension: C, 1.71 +/- 0.06 g; HU, 1.78 +/- 0.14 g). These results indicate that HU does not alter the functional mechanical properties of conduit arteries. However, the significantly lower active Cauchy stress of aortas from HU rats demonstrates a true contractile deficit in these arteries.

Changes in muscle fiber contractility and extracellular matrix production during skeletal muscle hypertrophy.

PubMed

Mendias, Christopher L; Schwartz, Andrew J; Grekin, Jeremy A; Gumucio, Jonathan P; Sugg, Kristoffer B

2017-03-01

Skeletal muscle can adapt to increased mechanical loads by undergoing hypertrophy. Transient reductions in whole muscle force production have been reported during the onset of hypertrophy, but contractile changes in individual muscle fibers have not been previously studied. Additionally, the extracellular matrix (ECM) stores and transmits forces from muscle fibers to tendons and bones, and determining how the ECM changes during hypertrophy is important in understanding the adaptation of muscle tissue to mechanical loading. Using the synergist ablation model, we sought to measure changes in muscle fiber contractility, collagen content, and cross-linking, and in the expression of several genes and activation of signaling proteins that regulate critical components of myogenesis and ECM synthesis and remodeling during muscle hypertrophy. Tissues were harvested 3, 7, and 28 days after induction of hypertrophy, and nonoverloaded rats served as controls. Muscle fiber specific force (sF o ), which is the maximum isometric force normalized to cross-sectional area, was reduced 3 and 7 days after the onset of mechanical overload, but returned to control levels by 28 days. Collagen abundance displayed a similar pattern of change. Nearly a quarter of the transcriptome changed over the course of overload, as well as the activation of signaling pathways related to hypertrophy and atrophy. Overall, this study provides insight into fundamental mechanisms of muscle and ECM growth, and indicates that although muscle fibers appear to have completed remodeling and regeneration 1 mo after synergist ablation, the ECM continues to be actively remodeling at this time point. NEW & NOTEWORTHY This study utilized a rat synergist ablation model to integrate changes in single muscle fiber contractility, extracellular matrix composition, activation of important signaling pathways in muscle adaption, and corresponding changes in the muscle transcriptome to provide novel insight into the basic biological mechanisms of muscle fiber hypertrophy. Copyright © 2017 the American Physiological Society.

Changes in muscle fiber contractility and extracellular matrix production during skeletal muscle hypertrophy

PubMed Central

Schwartz, Andrew J.; Grekin, Jeremy A.; Gumucio, Jonathan P.; Sugg, Kristoffer B.

2017-01-01

Skeletal muscle can adapt to increased mechanical loads by undergoing hypertrophy. Transient reductions in whole muscle force production have been reported during the onset of hypertrophy, but contractile changes in individual muscle fibers have not been previously studied. Additionally, the extracellular matrix (ECM) stores and transmits forces from muscle fibers to tendons and bones, and determining how the ECM changes during hypertrophy is important in understanding the adaptation of muscle tissue to mechanical loading. Using the synergist ablation model, we sought to measure changes in muscle fiber contractility, collagen content, and cross-linking, and in the expression of several genes and activation of signaling proteins that regulate critical components of myogenesis and ECM synthesis and remodeling during muscle hypertrophy. Tissues were harvested 3, 7, and 28 days after induction of hypertrophy, and nonoverloaded rats served as controls. Muscle fiber specific force (sFo), which is the maximum isometric force normalized to cross-sectional area, was reduced 3 and 7 days after the onset of mechanical overload, but returned to control levels by 28 days. Collagen abundance displayed a similar pattern of change. Nearly a quarter of the transcriptome changed over the course of overload, as well as the activation of signaling pathways related to hypertrophy and atrophy. Overall, this study provides insight into fundamental mechanisms of muscle and ECM growth, and indicates that although muscle fibers appear to have completed remodeling and regeneration 1 mo after synergist ablation, the ECM continues to be actively remodeling at this time point. NEW & NOTEWORTHY This study utilized a rat synergist ablation model to integrate changes in single muscle fiber contractility, extracellular matrix composition, activation of important signaling pathways in muscle adaption, and corresponding changes in the muscle transcriptome to provide novel insight into the basic biological mechanisms of muscle fiber hypertrophy. PMID:27979985

SYSTEMATIC REGULARITY OF HEMISPHERIC SUNSPOT AREAS OVER THE PAST 140 YEARS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deng, L. H.; Xiang, Y. Y.; Qu, Z. N.

2016-03-15

Solar magnetic activity varies with time in the two hemispheres in different ways. The hemispheric interconnection of solar activity phenomena provides an important clue to understanding the dynamical behavior of solar dynamo actions. In this paper, several analysis approaches are proposed to analyze the systematic regularity of hemispheric asynchronism and amplitude asymmetry of long-term sunspot areas during solar cycles 9–24. It is found that, (1) both the hemispheric asynchronism and the amplitude asymmetry of sunspot areas are prevalent behaviors and are not anomalous, but the hemispheric asynchronism exhibits a much more regular behavior than the amplitude asymmetry; (2) the phase-leadingmore » hemisphere returns back to the identical hemisphere every 8 solar cycles, and the secular periodic pattern of hemispheric phase differences follows 3 (south leading) + 5 (north leading) solar cycles, which probably corresponds to the Gleissberg cycle; and (3) the pronounced periodicities of (absolute and normalized) asymmetry indices and lines of synchronization (LOSs) are not identical: the significant periodic oscillations are 80.65 ± 6.31, 20.91 ± 0.40, and 13.45 ± 0.16 years for the LOS values, and 51.34 ± 2.48, 8.83/8.69 ± 0.07, and 3.77 ± 0.02 years for the (absolute and normalized) asymmetry indices. The analysis results improve our knowledge on the hemispheric interrelation of solar magnetic activity and may provide valuable constraints for solar dynamo models.« less

The effects of space flight on the contractile apparatus of antigravity muscles: implications for aging and deconditioning.

PubMed

Baldwin, K M; Caiozzo, V J; Haddad, F; Baker, M J; Herrick, R E

1994-05-01

Previous studies have shown that the unloading of skeletal muscle, as occurring during exposure to space flight, exerts a profound effect on both the mass (cross sectional area) of skeletal muscle fibers and the relative expression of protein isoforms comprising the contractile system. Available information suggests that slow (type I) fibers, comprising chiefly the antigravity muscles of experimental animals, in addition to atrophying, undergo alterations in the type of myosin heavy chain (MHC) expressed such that faster isoforms become concomitantly expressed in a sub-population of slow fibers when insufficient force-bearing activity is maintained on the muscle. Consequently, these transformations in both mass and myosin heavy chain phenotype could exert a significant impact on the functional properties of skeletal muscle as manifest in the strength, contractile speed, and endurance scope of the muscle. To further explore these issues, a study was performed in which young adult male rats were exposed to zero gravity for six days, following which, the antigravity soleus muscle was examined for a) contractile properties, determined in situ and b) isomyosin expression, as studied using biochemical, molecular biology, and histochemical/immunohistochemical techniques.

The effects of space flight on the contractile apparatus of antigravity muscles: implications for aging and deconditioning

NASA Technical Reports Server (NTRS)

Baldwin, K. M.; Caiozzo, V. J.; Haddad, F.; Baker, M. J.; Herrick, R. E.

1994-01-01

Previous studies have shown that the unloading of skeletal muscle, as occurring during exposure to space flight, exerts a profound effect on both the mass (cross sectional area) of skeletal muscle fibers and the relative expression of protein isoforms comprising the contractile system. Available information suggests that slow (type I) fibers, comprising chiefly the antigravity muscles of experimental animals, in addition to atrophying, undergo alterations in the type of myosin heavy chain (MHC) expressed such that faster isoforms become concomitantly expressed in a sub-population of slow fibers when insufficient force-bearing activity is maintained on the muscle. Consequently, these transformations in both mass and myosin heavy chain phenotype could exert a significant impact on the functional properties of skeletal muscle as manifest in the strength, contractile speed, and endurance scope of the muscle. To further explore these issues, a study was performed in which young adult male rats were exposed to zero gravity for six days, following which, the antigravity soleus muscle was examined for a) contractile properties, determined in situ and b) isomyosin expression, as studied using biochemical, molecular biology, and histochemical/immunohistochemical techniques.

Molecular Regulation of Parturition: A Myometrial Perspective

PubMed Central

Renthal, Nora E.; Williams, Koriand’r C.; Montalbano, Alina P.; Chen, Chien-Cheng; Gao, Lu; Mendelson, Carole R.

2015-01-01

The molecular mechanisms that maintain quiescence of the myometrium throughout most of pregnancy and promote its transformation to a highly coordinated contractile unit culminating in labor are complex and intertwined. During pregnancy, progesterone (P4) produced by the placenta and/or ovary serves a dominant role in maintaining myometrial quiescence by blocking proinflammatory response pathways and expression of so-called “contractile” genes. In the majority of placental mammals, increased uterine contractility near term is heralded by an increase in circulating estradiol-17β (E2) and/or increased estrogen receptor α (ERα) activity and a sharp decline in circulating P4 levels. However, in women, circulating levels of P4 and progesterone receptors (PR) in myometrium remain elevated throughout pregnancy and into labor. This has led to the concept that increased uterine contractility leading to term and preterm labor is mediated, in part, by a decline in PR function. The biochemical mechanisms for this decrease in PR function are also multifaceted and interwoven. In this paper, we focus on the molecular mechanisms that mediate myometrial quiescence and contractility and their regulation by the two central hormones of pregnancy, P4 and estradiol-17β. The integrative roles of microRNAs also are considered. PMID:26337112

Development and maintenance of force and stiffness in airway smooth muscle.

PubMed

Lan, Bo; Norris, Brandon A; Liu, Jeffrey C-Y; Paré, Peter D; Seow, Chun Y; Deng, Linhong

2015-03-01

Airway smooth muscle (ASM) plays a central role in the excessive narrowing of the airway that characterizes the primary functional impairment in asthma. This phenomenon is known as airway hyper-responsiveness (AHR). Emerging evidence suggests that the development and maintenance of ASM force involves dynamic reorganization of the subcellular filament network in both the cytoskeleton and the contractile apparatus. In this review, evidence is presented to support the view that regulation of ASM contraction extends beyond the classical actomyosin interaction and involves processes within the cytoskeleton and at the interfaces between the cytoskeleton, the contractile apparatus, and the extracellular matrix. These processes are initiated when the muscle is activated, and collectively they cause the cytoskeleton and the contractile apparatus to undergo structural transformation, resulting in a more connected and solid state that allows force generated by the contractile apparatus to be transmitted to the extracellular domain. Solidification of the cytoskeleton also serves to stiffen the muscle and hence the airway. Oscillatory strain from tidal breathing and deep inspiration is believed to be the counter balance that prevents hypercontraction and stiffening of ASM in vivo. Dysregulation of this balance could lead to AHR seen in asthma.

Electrical and contractile activities of the human rectosigmoid.

PubMed Central

Sarna, S; Latimer, P; Campbell, D; Waterfall, W E

1982-01-01

Electrical and mechanical activities were recorded from the rectosigmoid of normal subjects using an intraluminal recording tube with two sets of bipolar electrodes and strain gauges. Four distinct types of electrical activities were recorded. (1) Electrical control activity (ECA). This activity varied in amplitude and frequency over time and the control waves were not phase-locked. The means of dominant frequency components in the lower and higher frequency ranges were 3.86 +/- 0.18 SD and 10.41 +/- 0.46 SD c/min, respectively. The overall dominant frequency component was mostly in the lower frequency range of 2.0-9.0 c/min. (2) Discrete electrical response activity (DERA). This activity appeared as short duration bursts (less than 10 s) of response potentials whose repetition rate was in the total colonic electrical control activity frequency range of 2.0-13.0 c/min. The mean duration of this activity was 2.24 +/- 1.30 SD s. (3) Continuous electrical response activity (CERA). This activity appeared as long duration bursts (greater than 10 s) of response potentials which were not related to electrical control activity. Its mean duration was 14.78 +/- 3.68 SD s. This activity generally did not propagate. (4) Contractile electrical complex (CEC). This activity appeared as oscillations in the frequency range of 25-40 c/min and was also not related to electrical control activity. This activity propagated, sometimes proximally and sometimes distally. Its mean duration was 18.87 +/- 9.22 SD s. The latter three types of electrical activities were all associated with different types of contractions. These contractions, however, did not always occlude the lumen. Colonic electrical control activity controls the appearance of discrete electrical response activity in time and space. The mechanism of generation of continuous electrical response activity and contractile electrical complex is not yet known. PMID:7095566

Chronic clenbuterol treatment compromises force production without directly altering skeletal muscle contractile machinery

PubMed Central

Py, G; Ramonatxo, C; Sirvent, P; Sanchez, A M J; Philippe, A G; Douillard, A; Galbès, O; Lionne, C; Bonnieu, A; Chopard, A; Cazorla, O; Lacampagne, A; Candau, R B

2015-01-01

Clenbuterol is a β2-adrenergic receptor agonist known to induce skeletal muscle hypertrophy and a slow-to-fast phenotypic shift. The aim of the present study was to test the effects of chronic clenbuterol treatment on contractile efficiency and explore the underlying mechanisms, i.e. the muscle contractile machinery and calcium-handling ability. Forty-three 6-week-old male Wistar rats were randomly allocated to one of six groups that were treated with either subcutaneous equimolar doses of clenbuterol (4 mg kg−1 day−1) or saline solution for 9, 14 or 21 days. In addition to the muscle hypertrophy, although an 89% increase in absolute maximal tetanic force (Po) was noted, specific maximal tetanic force (sPo) was unchanged or even depressed in the slow twitch muscle of the clenbuterol-treated rats (P < 0.05). The fit of muscle contraction and relaxation force kinetics indicated that clenbuterol treatment significantly reduced the rate constant of force development and the slow and fast rate constants of relaxation in extensor digitorum longus muscle (P < 0.05), and only the fast rate constant of relaxation in soleus muscle (P < 0.05). Myofibrillar ATPase activity increased in both relaxed and activated conditions in soleus (P < 0.001), suggesting that the depressed specific tension was not due to the myosin head alteration itself. Moreover, action potential-elicited Ca2+ transients in flexor digitorum brevis fibres (fast twitch fibres) from clenbuterol-treated animals demonstrated decreased amplitude after 14 days (−19%, P < 0.01) and 21 days (−25%, P < 0.01). In conclusion, we showed that chronic clenbuterol treatment reduces contractile efficiency, with altered contraction and relaxation kinetics, but without directly altering the contractile machinery. Lower Ca2+ release during contraction could partially explain these deleterious effects. PMID:25656230

Moderate ethanol administration accentuates cardiomyocyte contractile dysfunction and mitochondrial injury in high fat diet-induced obesity.

PubMed

Yuan, Fang; Lei, Yonghong; Wang, Qiurong; Esberg, Lucy B; Huang, Zaixing; Scott, Glenda I; Li, Xue; Ren, Jun

2015-03-18

Light to moderate drinking confers cardioprotection although it remains unclear with regards to the role of moderate drinking on cardiac function in obesity. This study was designed to examine the impact of moderate ethanol intake on myocardial function in high fat diet intake-induced obesity and the mechanism(s) involved with a focus on mitochondrial integrity. C57BL/6 mice were fed low or high fat diet for 16 weeks prior to ethanol challenge (1g/kg/d for 3 days). Cardiac contractile function, intracellular Ca(2+) homeostasis, myocardial histology, and mitochondrial integrity [aconitase activity and the mitochondrial proteins SOD1, UCP-2 and PPARγ coactivator 1α (PGC-1α)] were assessed 24h after the final ethanol challenge. Fat diet intake compromised cardiomyocyte contractile and intracellular Ca(2+) properties (depressed peak shortening and maximal velocities of shortening/relengthening, prolonged duration of relengthening, dampened intracellular Ca(2+) rise and clearance without affecting duration of shortening). Although moderate ethanol challenge failed to alter cardiomyocyte mechanical property under low fat diet intake, it accentuated high fat diet intake-induced changes in cardiomyocyte contractile function and intracellular Ca(2+) handling. Moderate ethanol challenge failed to affect fat diet intake-induced cardiac hypertrophy as evidenced by H&E staining. High fat diet intake reduced myocardial aconitase activity, downregulated levels of mitochondrial protein UCP-2, PGC-1α, SOD1 and interrupted intracellular Ca(2+) regulatory proteins, the effect of which was augmented by moderate ethanol challenge. Neither high fat diet intake nor moderate ethanol challenge affected protein or mRNA levels as well as phosphorylation of Akt and GSK3β in mouse hearts. Taken together, our data revealed that moderate ethanol challenge accentuated high fat diet-induced cardiac contractile and intracellular Ca(2+) anomalies as well as mitochondrial injury. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Mediation by SRIF1 receptors of the contractile action of somatostatin in rat isolated distal colon; studies using some novel SRIF analogues.

PubMed Central

McKeen, E S; Feniuk, W; Humphrey, P P

1994-01-01

1. The motor effects of somatostatin-14 (SRIF), and several SRIF peptide analogues were investigated on the rat isolated distal colon. The objective of these studies was to characterize the receptor mediating the contractile action of SRIF by comparing the relative agonist potencies of a range of SRIF analogues. 2. SRIF (1 nM-1 microM) produced concentration-dependent contractions with an EC50 value of approximately 10 nM. Contractile responses induced by SRIF were insensitive to atropine (1 microM) or naloxone (1 microM) but abolished by tetrodotoxin (1 microM). Somatostatin-28 (SRIF28), also induced concentration-dependent contractions and was equipotent with SRIF. Phosphoramidon (1 microM) and amastatin (10 microM) did not increase the potency of either SRIF or SRIF28. 3. The SRIF peptide analogues, octreotide, SRIF25, seglitide, angiopeptin and CGP23996 (1 nM-1 microM) produced contractile responses in the rat distal colon, each having similar potency and maximal activity relative to SRIF. The SSTR2 receptor-selective hexapeptide, BIM23027 (0.1 nM-1 microM), and the SRIF stereoisomer, D-Trp8-SRIF (0.1 nM-1 microM), were the most potent agonists examined being approximately 12 and 7 times more potent than SRIF, respectively. In contrast, the SSTR5 receptor-selective analogue, L362,855, was approximately 120 times weaker than SRIF, whilst the SSTR3 receptor-selective analogue, BIM23056, was inactive at concentrations up to 3 microM. 4. The putative SRIF receptor antagonist, (cyclo(7-aminoheptanoyl Phe-D-Trp-Lys-Thr[Bzl]))(CPP) (1 microM), had no agonist activity and had no effect on contractions induced by SRIF. 5. The contractile actions of BIM23027 and seglitide were subject to pronounced desensitization.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7834217

Regulation of contractile protein gene expression in unloaded mouse skeletal muscle

NASA Technical Reports Server (NTRS)

Criswell, D. S.; Carson, J. A.; Booth, F. W.

1996-01-01

Hindlimb unloading was performed on mice in an effort to study the regulation of contractile protein genes. In particular, the regulation of myosin heavy chain IIb was examined. During unloading, muscle fibers undergo a type conversion. Preliminary data from this study does not support the hypothesis that the fiber type conversion is due to an increase in promoter activity of fast isoform genes, such as myosin heavy chain IIb. The consequences of this finding are examined, with particular focus on other factors controlling gene regulation.

Effect of Noni (Morinda citrifolia Linn.) Fruit and Its Bioactive Principles Scopoletin and Rutin on Rat Vas Deferens Contractility: An Ex Vivo Study

PubMed Central

Narasingam, Megala; Murugan, Dharmani Devi; Mohamed, Zahurin

2014-01-01

This study examined the effect of methanolic extract of Morinda citrifolia Linn. (MMC) and its bioactive principles, scopoletin and rutin, on dopamine- and noradrenaline-evoked contractility in isolated rat vas deferens preparations. MMC (1–40 mg/mL), scopoletin (1–200 μg/mL), and rutin hydrate (0.6–312.6 μg/mL) dose-dependently inhibited the contractility evoked by submaximal concentrations of both dopamine and noradrenaline, respectively. Haloperidol and prazosin, reference dopamine D2, and α 1-adrenoceptors antagonists significantly reversed the dopamine- and noradrenaline-induced contractions, respectively, in a dose-dependent manner. Interestingly, MMC per se at higher doses (60–100 mg/mL) showed dose-dependent contractile response in rat vas deferens which was partially inhibited by high doses of haloperidol but not by prazosin. These results demonstrated the biphasic effects of MMC on dopaminergic system; that is, antidopaminergic effect at lower concentrations (<40 mg/mL) and dopaminergic agonistic effect at higher concentrations (>60 mg/mL). However, similar contractile response at high doses of scopoletin (0.5–5 mg/mL) and rutin hydrate (0.5–5 mg/mL) per se was not observed. Therefore, it can be concluded that the bioactive principles of MMC, scopoletin, and rutin might be responsible for the antidopaminergic and antiadrenergic activities of MMC. PMID:25045753

Molecular organization of cytokinesis nodes and contractile rings by super-resolution fluorescence microscopy of live fission yeast

PubMed Central

Laplante, Caroline; Huang, Fang; Tebbs, Irene R.; Bewersdorf, Joerg; Pollard, Thomas D.

2016-01-01

Cytokinesis in animals, fungi, and amoebas depends on the constriction of a contractile ring built from a common set of conserved proteins. Many fundamental questions remain about how these proteins organize to generate the necessary tension for cytokinesis. Using quantitative high-speed fluorescence photoactivation localization microscopy (FPALM), we probed this question in live fission yeast cells at unprecedented resolution. We show that nodes, protein assembly precursors to the contractile ring, are discrete structural units with stoichiometric ratios and distinct distributions of constituent proteins. Anillin Mid1p, Fes/CIP4 homology-Bin/amphiphysin/Rvs (F-BAR) Cdc15p, IQ motif containing GTPase-activating protein (IQGAP) Rng2p, and formin Cdc12p form the base of the node that anchors the ends of myosin II tails to the plasma membrane, with myosin II heads extending into the cytoplasm. This general node organization persists in the contractile ring where nodes move bidirectionally during constriction. We observed the dynamics of the actin network during cytokinesis, starting with the extension of short actin strands from nodes, which sometimes connected neighboring nodes. Later in cytokinesis, a broad network of thick bundles coalesced into a tight ring around the equator of the cell. The actin ring was ∼125 nm wide and ∼125 nm thick. These observations establish the organization of the proteins in the functional units of a cytokinetic contractile ring. PMID:27647921

A device for rapid and quantitative measurement of cardiac myocyte contractility

NASA Astrophysics Data System (ADS)

Gaitas, Angelo; Malhotra, Ricky; Li, Tao; Herron, Todd; Jalife, José

2015-03-01

Cardiac contractility is the hallmark of cardiac function and is a predictor of healthy or diseased cardiac muscle. Despite advancements over the last two decades, the techniques and tools available to cardiovascular scientists are limited in their utility to accurately and reliably measure the amplitude and frequency of cardiomyocyte contractions. Isometric force measurements in the past have entailed cumbersome attachment of isolated and permeabilized cardiomyocytes to a force transducer followed by measurements of sarcomere lengths under conditions of submaximal and maximal Ca2+ activation. These techniques have the inherent disadvantages of being labor intensive and costly. We have engineered a micro-machined cantilever sensor with an embedded deflection-sensing element that, in preliminary experiments, has demonstrated to reliably measure cardiac cell contractions in real-time. Here, we describe this new bioengineering tool with applicability in the cardiovascular research field to effectively and reliably measure cardiac cell contractility in a quantitative manner. We measured contractility in both primary neonatal rat heart cardiomyocyte monolayers that demonstrated a beat frequency of 3 Hz as well as human embryonic stem cell-derived cardiomyocytes with a contractile frequency of about 1 Hz. We also employed the β-adrenergic agonist isoproterenol (100 nmol l-1) and observed that our cantilever demonstrated high sensitivity in detecting subtle changes in both chronotropic and inotropic responses of monolayers. This report describes the utility of our micro-device in both basic cardiovascular research as well as in small molecule drug discovery to monitor cardiac cell contractions.

Macrophage migration inhibitory factor plays a permissive role in the maintenance of cardiac contractile function under starvation through regulation of autophagy.

PubMed

Xu, Xihui; Pacheco, Benjamin D; Leng, Lin; Bucala, Richard; Ren, Jun

2013-08-01

The cytokine macrophage migration inhibitory factor (MIF) protects the heart through AMPK activation. Autophagy, a conserved pathway for bulk degradation of intracellular proteins and organelles, helps preserve and recycle energy and nutrients for cells to survive under starvation. This study was designed to examine the role of MIF in cardiac homeostasis and autophagy regulation following an acute starvation challenge. Wild-type (WT) and MIF knockout mice were starved for 48 h. Echocardiographic data revealed little effect of starvation on cardiac geometry, contractile and intracellular Ca²⁺ properties. MIF deficiency unmasked an increase in left ventricular end-systolic diameter, a drop in fractional shortening associated with cardiomyocyte contractile and intracellular Ca²⁺ anomalies following starvation. Interestingly, the unfavourable effect of MIF deficiency was associated with interruption of starvation-induced autophagy. Furthermore, restoration of autophagy using rapamycin partially protected against starvation-induced cardiomyocyte contractile defects. In our in vitro model of starvation, neonatal mouse cardiomyocytes from WT and MIF-/- mice and H9C2 cells were treated with serum free-glucose free DMEM for 2 h. MIF depletion dramatically attenuated starvation-induced autophagic vacuole formation in neonatal mouse cardiomyocytes and exacerbated starvation-induced cell death in H9C2 cells. In summary, these results indicate that MIF plays a permissive role in the maintenance of cardiac contractile function under starvation by regulation of autophagy.

Understanding Cognitive Engagement in Online Discussion: Use of a Scaffolded, Audio-Based Argumentation Activity

ERIC Educational Resources Information Center

Oh, Eunjung Grace; Kim, Hyun Song

2016-01-01

The purpose of this paper is to explore how adult learners engage in asynchronous online discussion through the implementation of an audio-based argumentation activity. The study designed scaffolded audio-based argumentation activities to promote students' cognitive engagement. The research was conducted in an online graduate course at a liberal…

Activation of calcineurin in human failing heart ventricle by endothelin-1, angiotensin II and urotensin II

PubMed Central

Li, Joan; Wang, Jianchun; Russell, Fraser D; Molenaar, Peter

2005-01-01

The calcineurin (CaN) enzyme–transcriptional pathway is critically involved in hypertrophy of heart muscle in some animal models. Currently there is no information concerning the regulation of CaN activation by endogenous agonists in human heart. Human right ventricular trabeculae from explanted human (14 male/2 female) failing hearts were set up in a tissue bath and electrically paced at 1 Hz and incubated with or without 100 nM endothelin-1 (ET-1), 10 μM, angiotensin-II (Ang II) or 20 nM human urotensin-II (hUII) for 30 min. Tissues from four patients were incubated with 200 nM tacrolimus (FK506) for 30 min and then incubated in the presence or absence of ET-1 for a further 30 min. ET-1 increased contractile force in all 13 patients (P<0.001). Ang II and hUII increased contractile force in three out of eight and four out of 10 patients but overall nonsignificantly (P>0.1). FK506 had no effect on contractile force (P=0.12). ET-1, Ang II and hUII increased calcineurin activity by 32, 71 and 15%, respectively, while FK506 reduced activity by 34%. ET-1 in the presence of FK506 did not restore calcineurin activity (P=0.1). There was no relationship between basal CaN activity and expression levels in the right ventricle. Increased levels of free phosphate were detected in ventricular homogenates that were incubated with PKCɛ compared to samples incubated without PKCɛ. Endogenous cardiostimulants which activate Gαq-coupled receptors increase the activity of calcineurin in human heart following acute (30 min) exposure. PKC may contribute to this effect by increasing levels of phosphorylated calcineurin substrate. PMID:15821752

The role of skeletal muscle contractile duration throughout the whole day: reducing sedentary time and promoting universal physical activity in all people.

PubMed

Hamilton, Marc T

2018-04-15

A shared goal of many researchers has been to discover how to improve health and prevent disease, through safely replacing a large amount of daily sedentary time with physical activity in everyone, regardless of age and current health status. This involves contrasting how different muscle contractile activity patterns regulate the underlying molecular and physiological responses impacting health-related processes. It also requires an equal attention to behavioural feasibility studies in extremely unfit and sedentary people. A sound scientific principle is that the body is constantly sensing and responding to changes in skeletal muscle metabolism induced by contractile activity. Because of that, the rapid time course of health-related responses to physical inactivity/activity patterns are caused in large part directly because of the variable amounts of muscle inactivity/activity throughout the day. However, traditional modes and doses of exercise fall far short of replacing most of the sedentary time in the modern lifestyle, because both the weekly frequency and the weekly duration of exercise time are an order of magnitude less than those for people sitting inactive. This can explain why high amounts of sedentary time produce distinct metabolic and cardiovascular responses through inactivity physiology that are not sufficiently prevented by low doses of exercise. For these reasons, we hypothesize that maintaining a high metabolic rate over the majority of the day, through safe and sustainable types of muscular activity, will be the optimal way to create a healthy active lifestyle over the whole lifespan. © 2017 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Contractile activity of human skeletal muscle cells prevents insulin resistance by inhibiting pro-inflammatory signalling pathways.

PubMed

Lambernd, S; Taube, A; Schober, A; Platzbecker, B; Görgens, S W; Schlich, R; Jeruschke, K; Weiss, J; Eckardt, K; Eckel, J

2012-04-01

Obesity is closely associated with muscle insulin resistance and is a major risk factor for the pathogenesis of type 2 diabetes. Regular physical activity not only prevents obesity, but also considerably improves insulin sensitivity and skeletal muscle metabolism. We sought to establish and characterise an in vitro model of human skeletal muscle contraction, with a view to directly studying the signalling pathways and mechanisms that are involved in the beneficial effects of muscle activity. Contracting human skeletal muscle cell cultures were established by applying electrical pulse stimulation. To induce insulin resistance, skeletal muscle cells were incubated with human adipocyte-derived conditioned medium, monocyte chemotactic protein (MCP)-1 and chemerin. Similarly to in exercising skeletal muscle in vivo, electrical pulse stimulation induced contractile activity in human skeletal muscle cells, combined with the formation of sarcomeres, activation of AMP-activated protein kinase (AMPK) and increased IL-6 secretion. Insulin-stimulated glucose uptake was substantially elevated in contracting cells compared with control. The incubation of skeletal muscle cells with adipocyte-conditioned media, chemerin and MCP-1 significantly reduced the insulin-stimulated phosphorylation of Akt. This effect was abrogated by concomitant pulse stimulation of the cells. Additionally, pro-inflammatory signalling by adipocyte-derived factors was completely prevented by electrical pulse stimulation of the myotubes. We showed that the effects of electrical pulse stimulation on skeletal muscle cells were similar to the effect of exercise on skeletal muscle in vivo in terms of enhanced AMPK activation and IL-6 secretion. In our model, muscle contractile activity eliminates insulin resistance by blocking pro-inflammatory signalling pathways. This novel model therefore provides a unique tool for investigating the molecular mechanisms that mediate the beneficial effects of muscle contraction.

Role of the adapter protein Abi1 in actin-associated signaling and smooth muscle contraction.

PubMed

Wang, Tao; Cleary, Rachel A; Wang, Ruping; Tang, Dale D

2013-07-12

Actin filament polymerization plays a critical role in the regulation of smooth muscle contraction. However, our knowledge regarding modulation of the actin cytoskeleton in smooth muscle just begins to accumulate. In this study, stimulation with acetylcholine (ACh) induced an increase in the association of the adapter protein c-Abl interactor 1 (Abi1) with neuronal Wiskott-Aldrich syndrome protein (N-WASP) (an actin-regulatory protein) in smooth muscle cells/tissues. Furthermore, contractile stimulation activated N-WASP in live smooth muscle cells as evidenced by changes in fluorescence resonance energy transfer efficiency of an N-WASP sensor. Abi1 knockdown by lentivirus-mediated RNAi inhibited N-WASP activation, actin polymerization, and contraction in smooth muscle. However, Abi1 silencing did not affect myosin regulatory light chain phosphorylation at Ser-19 in smooth muscle. In addition, c-Abl tyrosine kinase and Crk-associated substrate (CAS) have been shown to regulate smooth muscle contraction. The interaction of Abi1 with c-Abl and CAS has not been investigated. Here, contractile activation induced formation of a multiprotein complex including c-Abl, CAS, and Abi1. Knockdown of c-Abl and CAS attenuated the activation of Abi1 during contractile activation. More importantly, Abi1 knockdown inhibited c-Abl phosphorylation at Tyr-412 and the interaction of c-Abl with CAS. These results suggest that Abi1 is an important component of the cellular process that regulates N-WASP activation, actin dynamics, and contraction in smooth muscle. Abi1 is activated by the c-Abl-CAS pathway, and Abi1 reciprocally controls the activation of its upstream regulator c-Abl.

Role of the Adapter Protein Abi1 in Actin-associated Signaling and Smooth Muscle Contraction*

PubMed Central

Wang, Tao; Cleary, Rachel A.; Wang, Ruping; Tang, Dale D.

2013-01-01

Actin filament polymerization plays a critical role in the regulation of smooth muscle contraction. However, our knowledge regarding modulation of the actin cytoskeleton in smooth muscle just begins to accumulate. In this study, stimulation with acetylcholine (ACh) induced an increase in the association of the adapter protein c-Abl interactor 1 (Abi1) with neuronal Wiskott-Aldrich syndrome protein (N-WASP) (an actin-regulatory protein) in smooth muscle cells/tissues. Furthermore, contractile stimulation activated N-WASP in live smooth muscle cells as evidenced by changes in fluorescence resonance energy transfer efficiency of an N-WASP sensor. Abi1 knockdown by lentivirus-mediated RNAi inhibited N-WASP activation, actin polymerization, and contraction in smooth muscle. However, Abi1 silencing did not affect myosin regulatory light chain phosphorylation at Ser-19 in smooth muscle. In addition, c-Abl tyrosine kinase and Crk-associated substrate (CAS) have been shown to regulate smooth muscle contraction. The interaction of Abi1 with c-Abl and CAS has not been investigated. Here, contractile activation induced formation of a multiprotein complex including c-Abl, CAS, and Abi1. Knockdown of c-Abl and CAS attenuated the activation of Abi1 during contractile activation. More importantly, Abi1 knockdown inhibited c-Abl phosphorylation at Tyr-412 and the interaction of c-Abl with CAS. These results suggest that Abi1 is an important component of the cellular process that regulates N-WASP activation, actin dynamics, and contraction in smooth muscle. Abi1 is activated by the c-Abl-CAS pathway, and Abi1 reciprocally controls the activation of its upstream regulator c-Abl. PMID:23740246

Synchronization of Hierarchical Time-Varying Neural Networks Based on Asynchronous and Intermittent Sampled-Data Control.

PubMed

Xiong, Wenjun; Patel, Ragini; Cao, Jinde; Zheng, Wei Xing

In this brief, our purpose is to apply asynchronous and intermittent sampled-data control methods to achieve the synchronization of hierarchical time-varying neural networks. The asynchronous and intermittent sampled-data controllers are proposed for two reasons: 1) the controllers may not transmit the control information simultaneously and 2) the controllers cannot always exist at any time . The synchronization is then discussed for a kind of hierarchical time-varying neural networks based on the asynchronous and intermittent sampled-data controllers. Finally, the simulation results are given to illustrate the usefulness of the developed criteria.In this brief, our purpose is to apply asynchronous and intermittent sampled-data control methods to achieve the synchronization of hierarchical time-varying neural networks. The asynchronous and intermittent sampled-data controllers are proposed for two reasons: 1) the controllers may not transmit the control information simultaneously and 2) the controllers cannot always exist at any time . The synchronization is then discussed for a kind of hierarchical time-varying neural networks based on the asynchronous and intermittent sampled-data controllers. Finally, the simulation results are given to illustrate the usefulness of the developed criteria.

Digital Synchronizer without Metastability

NASA Technical Reports Server (NTRS)

Simle, Robert M.; Cavazos, Jose A.

2009-01-01

A proposed design for a digital synchronizing circuit would eliminate metastability that plagues flip-flop circuits in digital input/output interfaces. This metastability is associated with sampling, by use of flip-flops, of an external signal that is asynchronous with a clock signal that drives the flip-flops: it is a temporary flip-flop failure that can occur when a rising or falling edge of an asynchronous signal occurs during the setup and/or hold time of a flip-flop. The proposed design calls for (1) use of a clock frequency greater than the frequency of the asynchronous signal, (2) use of flip-flop asynchronous preset or clear signals for the asynchronous input, (3) use of a clock asynchronous recovery delay with pulse width discriminator, and (4) tying the data inputs to constant logic levels to obtain (5) two half-rate synchronous partial signals - one for the falling and one for the rising edge. Inasmuch as the flip-flop data inputs would be permanently tied to constant logic levels, setup and hold times would not be violated. The half-rate partial signals would be recombined to construct a signal that would replicate the original asynchronous signal at its original rate but would be synchronous with the clock signal.

Cortical Flow-Driven Shapes of Nonadherent Cells.

PubMed

Callan-Jones, A C; Ruprecht, V; Wieser, S; Heisenberg, C P; Voituriez, R

2016-01-15

Nonadherent polarized cells have been observed to have a pearlike, elongated shape. Using a minimal model that describes the cell cortex as a thin layer of contractile active gel, we show that the anisotropy of active stresses, controlled by cortical viscosity and filament ordering, can account for this morphology. The predicted shapes can be determined from the flow pattern only; they prove to be independent of the mechanism at the origin of the cortical flow, and are only weakly sensitive to the cytoplasmic rheology. In the case of actin flows resulting from a contractile instability, we propose a phase diagram of three-dimensional cell shapes that encompasses nonpolarized spherical, elongated, as well as oblate shapes, all of which have been observed in experiment.

The Effects of Asynchronous Visual Delays on Simulator Flight Performance and the Development of Simulator Sickness Symptomatology

DTIC Science & Technology

1986-12-26

NAVAL TRAINING SYSTEMS CENTER ORLANDO. FLORIDA IT FILE COPY THE EFFECTS OF ASYNCHRONOUS VISUAL DELAYS ON SIMULATOR FLIGHT PERFORMANCE AND THE...ASYNCHRONOUS VISUAL. DELAYS ON SI.WLATOR FLIGHT PERF OMANCE AND THE DEVELOPMENT OF SIMLATOR SICKNESS SYMPTOMATOLOGY K. C. Uliano, E. Y. Lambert, R. S. Kennedy...ACCESSION NO. N63733N SP-01 0785-7P6 I. 4780 11. TITLE (Include Security Classification) The Effects of Asynchronous Visual Delays on Simulator Flight

Transversal stiffness of fibers and desmin content in leg muscles of rats under gravitational unloading of various durations.

PubMed

Ogneva, I V

2010-12-01

The aim of this research was the analysis of structural changes in various parts of the sarcolemma and contractile apparatus of muscle fibers by measuring their transversal stiffness by atomic force microscopy under gravitational unloading. Soleus, medial gastrocnemius, and tibialis anterior muscles of Wistar rats were the objects of the study. Gravitational unloading was carried out by antiorthostatic suspension of hindlimbs for 1, 3, 7, and 12 days. It was shown that the transversal stiffness of different parts of the contractile apparatus of soleus muscle fibers decreases during gravitational unloading in the relaxed, calcium-activated, and rigor states, the fibers of the medial gastrocnemius show no changes, whereas the transversal stiffness of tibialis anterior muscle increases. Thus the transversal stiffness of the sarcolemma in the relaxed state is reduced in all muscles, which may be due to the direct action of gravity as an external mechanical factor that can influence the tension on a membrane. The change of sarcolemma stiffness in activated fibers, which is due probably to the transfer of tension from the contractile apparatus, correlates with the dynamics of changes in the content of desmin.

Modeling and Analysis of Mixed Synchronous/Asynchronous Systems

NASA Technical Reports Server (NTRS)

Driscoll, Kevin R.; Madl. Gabor; Hall, Brendan

2012-01-01

Practical safety-critical distributed systems must integrate safety critical and non-critical data in a common platform. Safety critical systems almost always consist of isochronous components that have synchronous or asynchronous interface with other components. Many of these systems also support a mix of synchronous and asynchronous interfaces. This report presents a study on the modeling and analysis of asynchronous, synchronous, and mixed synchronous/asynchronous systems. We build on the SAE Architecture Analysis and Design Language (AADL) to capture architectures for analysis. We present preliminary work targeted to capture mixed low- and high-criticality data, as well as real-time properties in a common Model of Computation (MoC). An abstract, but representative, test specimen system was created as the system to be modeled.

A novel comparator featured with input data characteristic

NASA Astrophysics Data System (ADS)

Jiang, Xiaobo; Ye, Desheng; Xu, Xiangmin; Zheng, Shuai

2016-03-01

Two types of low-power asynchronous comparators featured with input data statistical characteristic are proposed in this article. The asynchronous ripple comparator stops comparing at the first unequal bit but delivers the result to the least significant bit. The pre-stop asynchronous comparator can completely stop comparing and obtain results immediately. The proposed and contrastive comparators were implemented in SMIC 0.18 μm process with different bit widths. Simulation shows that the proposed pre-stop asynchronous comparator features the lowest power consumption, shortest average propagation delay and highest area efficiency among the comparators. Data path of low-density parity check decoder using the proposed pre-stop asynchronous comparators are most power efficient compared with other data paths with synthesised, clock gating and bitwise competition logic comparators.

Overexpression of soluble ADAM33 promotes a hypercontractile phenotype of the airway smooth muscle cell in rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duan, Yiyuan; Long, Jiaoyue; Chen, Jun

A disintegrin and metalloproteinase 33 (ADAM33) has been identified as a susceptibility gene for asthma, but details of the causality are not fully understood. We hypothesize that soluble ADAM33 (sADAM33) overexpression can alter the mechanical behaviors of airway smooth muscle cells (ASMCs) via regulation of the cell's contractile phenotype, and thus contributes to airway hyperresponsiveness (AHR) in asthma. To test this hypothesis, we either overexpressed or knocked down the sADAM33 in rat ASMCs by transfecting the cells with sADAM33 coding sequence or a small interfering RNA (siRNA) that specifically targets the ADAM33 disintegrin domain, and subsequently assessed the cells formore » stiffness, contractility and traction force, together with the expression level of contractile and proliferative phenotype markers. We also investigated whether these changes were dependent on Rho/ROCK pathway by culturing the ASMCs either in the absence or presence of ROCK inhibitor (H1152). The results showed that the ASMCs with sADAM33 overexpression were stiffer and more contractile, generated greater traction force, exhibited increased expression levels of contractile phenotype markers and markedly enhanced Rho activation. Furthermore these changes were largely attenuated when the cells were cultured in the presence of H-1152. However, the knock-down of ADAM33 seemed insufficient to influence majority of the mechanical behaviors of the ASMCs. Taken together, we demonstrated that sADAM33 overexpression altered the mechanical behaviors of ASMCs in vitro, which was most likely by promoting a hypercontractile phenotype transition of ASMCs through Rho/ROCK pathway. This revelation may establish the previously missing link between ADAM33 expression and AHR, and also provide useful insight for targeting sADAM33 in asthma prevention and therapy. - Highlights: • sADAM33 overexpression enhances the stiffness, traction force and contractility of ASMCs. • sADAM33 overexpression promotes a hypercontractile phenotype of ASMCs. • The hypercontractile phenotype transition was largely mediated via Rho/ROCK pathway. • ADAM33 knock-down had little effect on the stiffness, traction force and contractility of ASMCs.« less

Traction force dynamics predict gap formation in activated endothelium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valent, Erik T.; Nieuw Amerongen, Geerten P. van; Hinsbergh, Victor W.M. van

In many pathological conditions the endothelium becomes activated and dysfunctional, resulting in hyperpermeability and plasma leakage. No specific therapies are available yet to control endothelial barrier function, which is regulated by inter-endothelial junctions and the generation of acto-myosin-based contractile forces in the context of cell-cell and cell-matrix interactions. However, the spatiotemporal distribution and stimulus-induced reorganization of these integral forces remain largely unknown. Traction force microscopy of human endothelial monolayers was used to visualize contractile forces in resting cells and during thrombin-induced hyperpermeability. Simultaneously, information about endothelial monolayer integrity, adherens junctions and cytoskeletal proteins (F-actin) were captured. This revealed a heterogeneousmore » distribution of traction forces, with nuclear areas showing lower and cell-cell junctions higher traction forces than the whole-monolayer average. Moreover, junctional forces were asymmetrically distributed among neighboring cells. Force vector orientation analysis showed a good correlation with the alignment of F-actin and revealed contractile forces in newly formed filopodia and lamellipodia-like protrusions within the monolayer. Finally, unstable areas, showing high force fluctuations within the monolayer were prone to form inter-endothelial gaps upon stimulation with thrombin. To conclude, contractile traction forces are heterogeneously distributed within endothelial monolayers and force instability, rather than force magnitude, predicts the stimulus-induced formation of intercellular gaps. - Highlights: • Endothelial monolayers exert dynamic- and heterogeneous traction forces. • High traction forces correlate with junctional areas and the F-actin cytoskeleton. • Newly formed inter-endothelial gaps are characterized by opposing traction forces. • Force stability is a key feature controlling endothelial permeability.« less

Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease.

PubMed

Höllmer, M; Willesen, J L; Tolver, A; Koch, J

2017-02-01

Myxomatous mitral valve disease (MMVD) induces progressive left atrial (LA) enlargement. The LA modulates left ventricular filling and performance through its reservoir, conduit, and contractile function. Assessment of LA size and function may provide valuable information on the level of cardiac compensation. Left atrial function in dogs with naturally occurring MMVD remains largely unexplored. The objective of this study was to evaluate LA volume and function in dogs with naturally occurring MMVD. This prospective study included 205 client-owned dogs of different breeds, 114 healthy dogs, and 91 dogs with MMVD of different disease severities. Using two-dimensional echocardiography, the biplane area-length method was applied to assess LA volume and calculate volumetric indices of LA reservoir, conduit, and contractile function. Left atrial volume and LA stroke volume increased, whereas LA reservoir and contractile function decreased with increasing disease severity. A maximal LA volume <2.25mL/kg was the optimal cut off identified for excluding congestive heart failure in dogs with chronic MMVD with a sensitivity of 96% and a specificity of 100%. An active LA emptying fraction <24% and/or a LA expansion index <126% were suggestive of congestive heart failure in dogs with chronic MMVD with a sensitivity of 77% and a specificity of 89% and a sensitivity of 82% and a specificity of 82%, respectively. Dogs with MMVD appear to have larger LA volumes with poorer LA function. Deteriorating LA function, characterized by a decreasing reservoir and active contractile function, was evident in dogs with MMVD with increasing disease severity. Copyright © 2016 Elsevier B.V. All rights reserved.

Atorvastatin Calcium Inhibits Phenotypic Modulation of PDGF-BB-Induced VSMCs via Down-Regulation the Akt Signaling Pathway

PubMed Central

Chen, Shuang; Liu, Baoqin; Kong, Dehui; Li, Si; Li, Chao; Wang, Huaqin; Sun, Yingxian

2015-01-01

Plasticity of vascular smooth muscle cells (VSMCs) plays a central role in the onset and progression of proliferative vascular diseases. In adult tissue, VSMCs exist in a physiological contractile-quiescent phenotype, which is defined by lack of the ability of proliferation and migration, while high expression of contractile marker proteins. After injury to the vessel, VSMC shifts from a contractile phenotype to a pathological synthetic phenotype, associated with increased proliferation, migration and matrix secretion. It has been demonstrated that PDGF-BB is a critical mediator of VSMCs phenotypic switch. Atorvastatin calcium, a selective inhibitor of 3-hydroxy-3-methyl-glutaryl l coenzyme A (HMG-CoA) reductase, exhibits various protective effects against VSMCs. In this study, we investigated the effects of atorvastatin calcium on phenotype modulation of PDGF-BB-induced VSMCs and the related intracellular signal transduction pathways. Treatment of VSMCs with atorvastatin calcium showed dose-dependent inhibition of PDGF-BB-induced proliferation. Atorvastatin calcium co-treatment inhibited the phenotype modulation and cytoskeleton rearrangements and improved the expression of contractile phenotype marker proteins such as α-SM actin, SM22α and calponin in comparison with PDGF-BB alone stimulated VSMCs. Although Akt phosphorylation was strongly elicited by PDGF-BB, Akt activation was attenuated when PDGF-BB was co-administrated with atorvastatin calcium. In conclusion, atorvastatin calcium inhibits phenotype modulation of PDGF-BB-induced VSMCs and activation of the Akt signaling pathway, indicating that Akt might play a vital role in the modulation of phenotype. PMID:25874930

Calcineurin Regulates Myocardial Function during Acute Endotoxemia

PubMed Central

Joshi, Mandar S.; Julian, Mark W.; Huff, Jennifer E.; Bauer, John A.; Xia, Yong; Crouser, Elliott D.

2006-01-01

Rationale: Cyclosporin A (CsA) is known to preserve cardiac contractile function during endotoxemia, but the mechanism is unclear. Increased nitric oxide (NO) production and altered mitochondrial function are implicated as mechanisms contributing to sepsis-induced cardiac dysfunction, and CsA has the capacity to reduce NO production and inhibit mitochondrial dysfunction relating to the mitochondrial permeability transition (MPT). Objectives: We hypothesized that CsA would protect against endotoxin-mediated cardiac contractile dysfunction by attenuating NO production and preserving mitochondrial function. Methods: Left ventricular function was measured continuously over 4 h in cats assigned as follows: control animals (n = 7); LPS alone (3 mg/kg, n = 8); and CsA (6 mg/kg, n = 7), a calcineurin inhibitor that blocks the MPT, or tacrolimus (FK506, 0.1 mg/kg, n = 7), a calcineurin inhibitor lacking MPT activity, followed in 30 min by LPS. Myocardial tissue was then analyzed for NO synthase-2 expression, tissue nitration, protein carbonylation, and mitochondrial morphology and function. Measurements and Main Results: LPS treatment resulted in impaired left ventricular contractility, altered mitochondrial morphology and function, and increased protein nitration. As hypothesized, CsA pretreatment normalized cardiac performance and mitochondrial respiration and reduced myocardial protein nitration. Unexpectedly, FK506 pretreatment had similar effects, normalizing both cardiac and mitochondrial parameters. However, CsA and FK506 pretreatments markedly increased protein carbonylation in the myocardium despite elevated manganese superoxide dismutase activity during endotoxemia. Conclusions: Our data indicate that calcineurin is a critical regulator of mitochondrial respiration, tissue nitration, protein carbonylation, and contractile function in the heart during acute endotoxemia. PMID:16424445

Facilitating preemptive hardware system design using partial reconfiguration techniques.

PubMed

Dondo Gazzano, Julio; Rincon, Fernando; Vaderrama, Carlos; Villanueva, Felix; Caba, Julian; Lopez, Juan Carlos

2014-01-01

In FPGA-based control system design, partial reconfiguration is especially well suited to implement preemptive systems. In real-time systems, the deadline for critical task can compel the preemption of noncritical one. Besides, an asynchronous event can demand immediate attention and, then, force launching a reconfiguration process for high-priority task implementation. If the asynchronous event is previously scheduled, an explicit activation of the reconfiguration process is performed. If the event cannot be previously programmed, such as in dynamically scheduled systems, an implicit activation to the reconfiguration process is demanded. This paper provides a hardware-based approach to explicit and implicit activation of the partial reconfiguration process in dynamically reconfigurable SoCs and includes all the necessary tasks to cope with this issue. Furthermore, the reconfiguration service introduced in this work allows remote invocation of the reconfiguration process and then the remote integration of off-chip components. A model that offers component location transparency is also presented to enhance and facilitate system integration.

Facilitating Preemptive Hardware System Design Using Partial Reconfiguration Techniques

PubMed Central

Rincon, Fernando; Vaderrama, Carlos; Villanueva, Felix; Caba, Julian; Lopez, Juan Carlos

2014-01-01

In FPGA-based control system design, partial reconfiguration is especially well suited to implement preemptive systems. In real-time systems, the deadline for critical task can compel the preemption of noncritical one. Besides, an asynchronous event can demand immediate attention and, then, force launching a reconfiguration process for high-priority task implementation. If the asynchronous event is previously scheduled, an explicit activation of the reconfiguration process is performed. If the event cannot be previously programmed, such as in dynamically scheduled systems, an implicit activation to the reconfiguration process is demanded. This paper provides a hardware-based approach to explicit and implicit activation of the partial reconfiguration process in dynamically reconfigurable SoCs and includes all the necessary tasks to cope with this issue. Furthermore, the reconfiguration service introduced in this work allows remote invocation of the reconfiguration process and then the remote integration of off-chip components. A model that offers component location transparency is also presented to enhance and facilitate system integration. PMID:24672292

Interactional Coherence in Asynchronous Learning Networks: A Rhetorical Approach

ERIC Educational Resources Information Center

Potter, Andrew

2008-01-01

Numerous studies have affirmed the value of asynchronous online communication as a learning resource. Several investigations, however, have indicated that discussions in asynchronous environments are often neither interactive nor coherent. The research reported sought to develop an enhanced understanding of interactional coherence, argumentation,…

An asynchronous learning approach for the instructional component of a dual-campus pharmacy resident teaching program.

PubMed

Garrison, Gina Daubney; Baia, Patricia; Canning, Jacquelyn E; Strang, Aimee F

2015-03-25

To describe the shift to an asynchronous online approach for pedagogy instruction within a pharmacy resident teaching program offered by a dual-campus college. The pedagogy instruction component of the teaching program (Part I) was redesigned with a focus on the content, delivery, and coordination of the learning environment. Asynchronous online learning replaced distance technology or lecture capture. Using a pedagogical content knowledge framework, residents participated in self-paced online learning using faculty recordings, readings, and discussion board activities. A learning management system was used to assess achievement of learning objectives and participation prior to progressing to the teaching experiences component of the teaching program (Part II). Evaluation of resident pedagogical knowledge development and participation in Part I of the teaching program was achieved through the learning management system. Participant surveys and written reflections showed general satisfaction with the online learning environment. Future considerations include addition of a live orientation session and increased faculty presence in the online learning environment. An online approach framed by educational theory can be an effective way to provide pedagogy instruction within a teaching program.

An Asynchronous Recurrent Network of Cellular Automaton-Based Neurons and Its Reproduction of Spiking Neural Network Activities.

PubMed

Matsubara, Takashi; Torikai, Hiroyuki

2016-04-01

Modeling and implementation approaches for the reproduction of input-output relationships in biological nervous tissues contribute to the development of engineering and clinical applications. However, because of high nonlinearity, the traditional modeling and implementation approaches encounter difficulties in terms of generalization ability (i.e., performance when reproducing an unknown data set) and computational resources (i.e., computation time and circuit elements). To overcome these difficulties, asynchronous cellular automaton-based neuron (ACAN) models, which are described as special kinds of cellular automata that can be implemented as small asynchronous sequential logic circuits have been proposed. This paper presents a novel type of such ACAN and a theoretical analysis of its excitability. This paper also presents a novel network of such neurons, which can mimic input-output relationships of biological and nonlinear ordinary differential equation model neural networks. Numerical analyses confirm that the presented network has a higher generalization ability than other major modeling and implementation approaches. In addition, Field-Programmable Gate Array-implementations confirm that the presented network requires lower computational resources.

AhV_aPA-induced vasoconstriction involves the IP₃Rs-mediated Ca²⁺ releasing.

PubMed

Zeng, Fuxing; Zou, Zhisong; Niu, Liwen; Li, Xu; Teng, Maikun

2013-08-01

AhV_aPA, the acidic PLA₂ purified from Agkistrodon halys pallas venom, was previously reported to possess a strong enzymatic activity and can remarkably induce a further contractile response on the 60 mM K⁺-induced contraction with an EC₅₀ in 369 nM on mouse thoracic aorta rings. In the present study, we found that the p-bromo-phenacyl-bromide (pBPB), which can completely inhibit the enzymatic activity of AhV_aPA, did not significantly reduce the contractile response on vessel rings induced by AhV_aPA, indicating that the vasoconstrictor effects of AhV_aPA are independent of the enzymatic activity. The inhibitor experiments showed that the contractile response induced by AhV_aPA is mainly attributed to the Ca²⁺ releasing from Ca²⁺ store, especially sarcoplasmic reticulum (SR). Detailed studies showed that the Ca²⁺ release from SR is related to the activation of inositol trisphosphate receptors (IP₃Rs) rather than ryanodine receptors (RyRs). Furthermore, the vasoconstrictor effect could be strongly reduced by pre-incubation with heparin, indicating that the basic amino acid residues on the surface of AhV_aPA may be involved in the interaction between AhV_aPA and the molecular receptors. These findings offer new insights into the functions of snake PLA₂ and provide a novel pathogenesis of A. halys pallas venom. Copyright © 2013 Elsevier Ltd. All rights reserved.

Perfusion-induced changes in cardiac contractility depend on capillary perfusion.

PubMed

Dijkman, M A; Heslinga, J W; Sipkema, P; Westerhof, N

1998-02-01

The perfusion-induced increase in cardiac contractility (Gregg phenomenon) is especially found in heart preparations that lack adequate coronary autoregulation and thus protection of changes in capillary pressure. We determined in the isolated perfused papillary muscle of the rat whether cardiac muscle contractility is related to capillary perfusion. Oxygen availability of this muscle is independent of internal perfusion, and perfusion may be varied or even stopped without loss of function. Muscles contracted isometrically at 27 degrees C (n = 7). During the control state stepwise increases in perfusion pressure resulted in all muscles in a significant increase in active tension. Muscle diameter always increased with increased perfusion pressure, but muscle segment length was unaffected. Capillary perfusion was then obstructed by plastic microspheres (15 microns). Flow, at a perfusion pressure of 66.6 +/- 26.2 cmH2O, reduced from 17.6 +/- 5.4 microliters/min in the control state to 3.2 +/- 1.3 microliters/min after microspheres. Active tension developed by the muscle in the unperfused condition before microspheres and after microspheres did not differ significantly (-12.8 +/- 29.4% change). After microspheres similar perfusion pressure steps as in control never resulted in an increase in active tension. Even at the two highest perfusion pressures (89.1 +/- 28.4 and 106.5 +/- 31.7 cmH2O) that were applied a significant decrease in active tension was found. We conclude that the Gregg phenomenon is related to capillary perfusion.

Cold application for neuromuscular recovery following intense lower-body exercise.

PubMed

Pointon, Monique; Duffield, Rob; Cannon, Jack; Marino, Frank E

2011-12-01

This study examined the effects of cold therapy (COLD) on recovery of voluntary and evoked contractile properties following high-intensity, muscle-damaging and fatiguing exercise. Ten resistance-trained males performed 6 × 25 maximal concentric/eccentric muscle contractions of the dominant knee extensors (KE) followed by a 20-min recovery (COLD v control) in a randomized cross-over design. Voluntary and evoked neuromuscular properties of the right KE, ratings of perceived muscle soreness (MS) and pain, and blood markers for muscle damage were measured pre- and post-exercise, and immediately post-recovery, 2, 24 and 48-h post-recovery. Exercise resulted in decrements in voluntary and evoked torque, increased MS and elevated muscle damage markers (p < 0.05). Measures of maximal voluntary contraction (MVC) or voluntary activation (VA) were not significantly enhanced by COLD (p > 0.05). Activation of right KE decreased post-exercise with increased activation of biceps femoris (BF) (p < 0.05). However, no significant differences were evident between conditions of activation of KE and hamstrings at any time point (p > 0.05). No significant differences were observed between conditions for creatine kinase or asparate aminotransferase (p > 0.05). However, perceptual ratings of pain were significantly (p < 0.05) lower following COLD compared to control. In conclusion, following damage to the contractile apparatus, COLD did not significantly hasten the recovery of peripheral contractile trauma. Despite no beneficial effect of COLD on recovery of MVC, perceptions of pain were reduced following COLD.

Labeled Postings for Asynchronous Interaction

ERIC Educational Resources Information Center

ChanLin, Lih-Juan; Chen, Yong-Ting; Chan, Kung-Chi

2009-01-01

The Internet promotes computer-mediated communications, and so asynchronous learning network systems permit more flexibility in time, space, and interaction than synchronous mode of learning. The key point of asynchronous learning is the materials for web-aided teaching and the flow of knowledge. This research focuses on improving online…

An Asynchronous Augmentation to Traditional Course Delivery.

ERIC Educational Resources Information Center

Wolverton, Marvin L.; Wolverton, Mimi

Asynchronous augmentation facilitates distributed learning, which relies heavily on technology and self-learning. This paper reports the results of delivering a real estate principles course using an asynchronous course delivery format. It highlights one of many ways to enhance learning using technology, and it provides information concerning how…

A Taxonomy of Learning through Asynchronous Discussion

ERIC Educational Resources Information Center

Knowlton, Dave S.

2005-01-01

This article presents a five-tiered taxonomy that describes the nature of participation in, and learning through, asynchronous discussion. The taxonomy is framed by a constructivist view of asynchronous discussion. The five tiers of the taxonomy include the following: (a) passive participation, (b) developmental participation, (c) generative…

Designing Asynchronous Online Discussion Environments: Recent Progress and Possible Future Directions

ERIC Educational Resources Information Center

Gao, Fei; Zhang, Tianyi; Franklin, Teresa

2013-01-01

Asynchronous online discussion environments are important platforms to support learning. Research suggests, however, threaded forums, one of the most popular asynchronous discussion environments, do not often foster productive online discussions naturally. This paper explores how certain properties of threaded forums have affected or constrained…

Integrating Asynchronous Digital Design Into the Computer Engineering Curriculum

ERIC Educational Resources Information Center

Smith, S. C.; Al-Assadi, W. K.; Di, J.

2010-01-01

As demand increases for circuits with higher performance, higher complexity, and decreased feature size, asynchronous (clockless) paradigms will become more widely used in the semiconductor industry, as evidenced by the International Technology Roadmap for Semiconductors' (ITRS) prediction of a likely shift from synchronous to asynchronous design…

Interaction Analysis for Supporting Students' Self-Regulation during Blog-Based CSCL Activities

ERIC Educational Resources Information Center

Michailidis, Nikolaos; Kapravelos, Efstathios; Tsiatsos, Thrasyvoulos

2018-01-01

Self-regulated learning is an important means of supporting students' self-awareness and self-regulation level so as to enhance their motivation and engagement. Interaction Analysis (IA) contributes to this end, and its use in studying learning dynamics involved in asynchronous Computer-Supported Collaborative Learning (CSCL) activities has…

Encouraging Social Presence and a Sense of Community in a Virtual Residential School

ERIC Educational Resources Information Center

Robinson, Kathleen

2009-01-01

This study describes the theoretical rationale underpinning the design and implementation of a career-related activity as an optional element of a virtual residential school. The activity comprised an interview with a practising chartered psychologist recorded as an MP3 audio file, which was subsequently supported by an asynchronous discussion…

Time-resolved microrheology of actively remodeling actomyosin networks

NASA Astrophysics Data System (ADS)

Silva, Marina Soares e.; Stuhrmann, Björn; Betz, Timo; Koenderink, Gijsje H.

2014-07-01

Living cells constitute an extraordinary state of matter since they are inherently out of thermal equilibrium due to internal metabolic processes. Indeed, measurements of particle motion in the cytoplasm of animal cells have revealed clear signatures of nonthermal fluctuations superposed on passive thermal motion. However, it has been difficult to pinpoint the exact molecular origin of this activity. Here, we employ time-resolved microrheology based on particle tracking to measure nonequilibrium fluctuations produced by myosin motor proteins in a minimal model system composed of purified actin filaments and myosin motors. We show that the motors generate spatially heterogeneous contractile fluctuations, which become less frequent with time as a consequence of motor-driven network remodeling. We analyze the particle tracking data on different length scales, combining particle image velocimetry, an ensemble analysis of the particle trajectories, and finally a kymograph analysis of individual particle trajectories to quantify the length and time scales associated with active particle displacements. All analyses show clear signatures of nonequilibrium activity: the particles exhibit random motion with an enhanced amplitude compared to passive samples, and they exhibit sporadic contractile fluctuations with ballistic motion over large (up to 30 μm) distances. This nonequilibrium activity diminishes with sample age, even though the adenosine triphosphate level is held constant. We propose that network coarsening concentrates motors in large clusters and depletes them from the network, thus reducing the occurrence of contractile fluctuations. Our data provide valuable insight into the physical processes underlying stress generation within motor-driven actin networks and the analysis framework may prove useful for future microrheology studies in cells and model organisms.

Hyperglycemia- and hyperinsulinemia-induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle.

PubMed

Lee, Yang; Fluckey, James D; Chakraborty, Sanjukta; Muthuchamy, Mariappan

2017-07-01

Insulin resistance is a well-known risk factor for obesity, metabolic syndrome (MetSyn) and associated cardiovascular diseases, but its mechanisms are undefined in the lymphatics. Mesenteric lymphatic vessels from MetSyn or LPS-injected rats exhibited impaired intrinsic contractile activity and associated inflammatory changes. Hence, we hypothesized that insulin resistance in lymphatic muscle cells (LMCs) affects cell bioenergetics and signaling pathways that consequently alter contractility. LMCs were treated with different concentrations of insulin or glucose or both at various time points to determine insulin resistance. Onset of insulin resistance significantly impaired glucose uptake, mitochondrial function, oxygen consumption rates, glycolysis, lactic acid, and ATP production in LMCs. Hyperglycemia and hyperinsulinemia also impaired the PI3K/Akt while enhancing the ERK/p38MAPK/JNK pathways in LMCs. Increased NF-κB nuclear translocation and macrophage chemoattractant protein-1 and VCAM-1 levels in insulin-resistant LMCs indicated activation of inflammatory mechanisms. In addition, increased phosphorylation of myosin light chain-20, a key regulator of lymphatic muscle contraction, was observed in insulin-resistant LMCs. Therefore, our data elucidate the mechanisms of insulin resistance in LMCs and provide the first evidence that hyperglycemia and hyperinsulinemia promote insulin resistance and impair lymphatic contractile status by reducing glucose uptake, altering cellular metabolic pathways, and activating inflammatory signaling cascades.-Lee, Y., Fluckey, J. D., Chakraborty, S., Muthuchamy, M. Hyperglycemia- and hyperinsulinemia-induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle. © FASEB.

Alterations by glyburide of effects of BRL 34915 and P 1060 on contraction, 86Rb efflux and the maxi-K+ channel in rat portal vein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, S.L.; Kim, H.S.; Okolie, P.

1990-05-01

Effects of the K+ channel blocking agent, glyburide, on the actions of two K+ channel openers, BRL 34915 (cromakalim) and P 1060 (Leo), a potent pinacidil derivative (N-(t-butyl)-N{double prime}-cyano-N{prime}-3-pyridyl-guanidine), were ascertained. Tension responses and {sup 86}Rb fluxes in rat portal vein strips and single channel electrophysiological recordings in enzymatically dissociated rat portal vein cells were obtained. Glyburide (0.3 microM) increased spontaneous contractile activity and caused concentration-dependent shifts in the relaxation responses to BRL 34915 and P 1060. Increases in {sup 86}Rb efflux were obtained only at much higher concentrations of BRL 34915 or P 1060, and these increases were blockedmore » only at higher concentrations of glyburide (5.0 microM). BRL 34915 and P 1060 specifically increase the open-state probability of the Ca+(+)-activated K+ (maxi-K+) channel, and these actions are blocked by glyburide and also by charybdotoxin. Changes in single channel activity and contractile responsiveness occur at similar concentrations of agonists and antagonists. Thus, the membrane channel in rat portal vein affected by glyburide, BRL 34915 and P 1060 appears to be the Ca+(+)-activated maxi-K+ channel (that does not show ATP dependence under the conditions of these experiments). Concentrations of agonists and antagonists effective on maxi-K+ channel activity correspond to those affecting contractile responsiveness and are lower than those eliciting changes in {sup 86}Rb flux.« less

Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism.

PubMed

Riveline, D; Zamir, E; Balaban, N Q; Schwarz, U S; Ishizaki, T; Narumiya, S; Kam, Z; Geiger, B; Bershadsky, A D

2001-06-11

The transition of cell-matrix adhesions from the initial punctate focal complexes into the mature elongated form, known as focal contacts, requires GTPase Rho activity. In particular, activation of myosin II-driven contractility by a Rho target known as Rho-associated kinase (ROCK) was shown to be essential for focal contact formation. To dissect the mechanism of Rho-dependent induction of focal contacts and to elucidate the role of cell contractility, we applied mechanical force to vinculin-containing dot-like adhesions at the cell edge using a micropipette. Local centripetal pulling led to local assembly and elongation of these structures and to their development into streak-like focal contacts, as revealed by the dynamics of green fluorescent protein-tagged vinculin or paxillin and interference reflection microscopy. Inhibition of Rho activity by C3 transferase suppressed this force-induced focal contact formation. However, constitutively active mutants of another Rho target, the formin homology protein mDia1 (Watanabe, N., T. Kato, A. Fujita, T. Ishizaki, and S. Narumiya. 1999. Nat. Cell Biol. 1:136-143), were sufficient to restore force-induced focal contact formation in C3 transferase-treated cells. Force-induced formation of the focal contacts still occurred in cells subjected to myosin II and ROCK inhibition. Thus, as long as mDia1 is active, external tension force bypasses the requirement for ROCK-mediated myosin II contractility in the induction of focal contacts. Our experiments show that integrin-containing focal complexes behave as individual mechanosensors exhibiting directional assembly in response to local force.

Is depressed myocyte contractility centrally involved in heart failure?

PubMed

Houser, Steven R; Margulies, Kenneth B

2003-03-07

This review examines the evidence for and against the hypothesis that abnormalities in cardiac contractility initiate the heart failure syndrome and drive its progression. There is substantial evidence that the contractility of failing human hearts is depressed and that abnormalities of basal Ca2+ regulation and adrenergic regulation of Ca2+ signaling are responsible. The cellular and molecular defects that cause depressed myocyte contractility are not well established but seem to culminate in abnormal sarcoplasmic reticulum uptake, storage, and release. There are also strong links between Ca2+ regulation, Ca2+ signaling pathways, hypertrophy, and heart failure that need to be more clearly delineated. There is not substantial direct evidence for a causative role for depressed contractility in the initiation and progression of human heart failure, and some studies show that heart failure can occur without depressed myocyte contractility. Stronger support for a causal role for depressed contractility in the initiation of heart failure comes from animal studies where maintaining or improving contractility can prevent heart failure. Recent clinical studies in humans also support the idea that beneficial heart failure treatments, such as beta-adrenergic antagonists, involve improved contractility. Current or previously used heart failure treatments that increase contractility, primarily by increasing cAMP, have generally increased mortality. Novel heart failure therapies that increase or maintain contractility or adrenergic signaling by selectively modulating specific molecules have produced promising results in animal experiments. How to reliably implement these potentially beneficial inotropic therapies in humans without introducing negative side effects is the major unanswered question in this field.

Propylthiouracil, independent of its antithyroid effect, promotes vascular smooth muscle cells differentiation via PTEN induction.

PubMed

Chen, Wei-Jan; Pang, Jong-Hwei S; Lin, Kwang-Huei; Lee, Dany-Young; Hsu, Lung-An; Kuo, Chi-Tai

2010-01-01

Propylthiouracil (PTU), independent of its antithyroid effect, is recently found to have an antiatherosclerotic effect. The aim of this study is to determine the impact of PTU on phenotypic modulation of vascular smooth muscle cells (VSMCs), as phenotypic modulation may contribute to the growth of atherosclerotic lesions and neointimal formation after arterial injury. Propylthiouracil reduced neointimal formation in balloon-injured rat carotid arteries. In vitro, PTU may convert VSMCs from a serum-induced dedifferentiation state to a differentiated state, as indicated by a spindle-shaped morphology and an increase in the expression of SMC differentiation marker contractile proteins, including calponin and smooth muscle (SM)-myosin heavy chain (SM-MHC). Transient transfection studies in VSMCs demonstrated that PTU induced the activity of SMC marker genes (calponin and SM-MHC) promoters, indicating that PTU up-regulates these genes expression predominantly at the transcriptional level. Furthermore, PTU enhanced the expression of PTEN and inhibition of PTEN by siRNA knockdown blocked PTU-induced activation of contractile proteins expression and promoter activity. In the rat carotid injury model, PTU reversed the down-regulation of contractile proteins and up-regulated PTEN in the neointima induced by balloon injury. Propylthiouracil promotes VSMC differentiation, at lest in part, via induction of the PTEN-mediated pathway. These findings suggest a possible mechanism by which PTU may contribute to its beneficial effects on atherogenesis and neointimal formation after arterial injury.

Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction.

PubMed

Ngkelo, Anta; Richart, Adèle; Kirk, Jonathan A; Bonnin, Philippe; Vilar, Jose; Lemitre, Mathilde; Marck, Pauline; Branchereau, Maxime; Le Gall, Sylvain; Renault, Nisa; Guerin, Coralie; Ranek, Mark J; Kervadec, Anaïs; Danelli, Luca; Gautier, Gregory; Blank, Ulrich; Launay, Pierre; Camerer, Eric; Bruneval, Patrick; Menasche, Philippe; Heymes, Christophe; Luche, Elodie; Casteilla, Louis; Cousin, Béatrice; Rodewald, Hans-Reimer; Kass, David A; Silvestre, Jean-Sébastien

2016-06-27

Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles for mast cells (MCs) in postischemic cardiac remodeling. Because c-Kit mutations affect multiple cell types of both immune and nonimmune origin, we addressed the impact of MCs on cardiac function after MI, using the c-Kit-independent MC-deficient (Cpa3(Cre/+)) mice. In response to MI, MC progenitors originated primarily from white adipose tissue, infiltrated the heart, and differentiated into mature MCs. MC deficiency led to reduced postischemic cardiac function and depressed cardiomyocyte contractility caused by myofilament Ca(2+) desensitization. This effect correlated with increased protein kinase A (PKA) activity and hyperphosphorylation of its targets, troponin I and myosin-binding protein C. MC-specific tryptase was identified to regulate PKA activity in cardiomyocytes via protease-activated receptor 2 proteolysis. This work reveals a novel function for cardiac MCs modulating cardiomyocyte contractility via alteration of PKA-regulated force-Ca(2+) interactions in response to MI. Identification of this MC-cardiomyocyte cross-talk provides new insights on the cellular and molecular mechanisms regulating the cardiac contractile machinery and a novel platform for therapeutically addressable regulators. ©2016 Ngkelo et al.

Interleukin 1 and Tumor Necrosis Factor Inhibit Cardiac Myocyte β -adrenergic Responsiveness

NASA Astrophysics Data System (ADS)

Gulick, Tod; Chung, Mina K.; Pieper, Stephen J.; Lange, Louis G.; Schreiner, George F.

1989-09-01

Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured cardiac myocytes in the presence of culture supernatants from activated immune cells. We observed that these culture supernatants inhibit β -adrenergic agonist-mediated increases in cultured cardiac myocyte contractility and intracellular cAMP accumulation. The myocyte contractile response to increased extracellular Ca2+ concentration is unaltered by prior exposure to these culture supernatants, as is the increase in myocyte intracellular cAMP concentration in response to stimulation with forskolin, a direct adenyl cyclase activator. Inhibition occurs in the absence of alteration in β -adrenergic receptor density or ligand binding affinity. Suppressive activity is attributable to the macrophage-derived cytokines interleukin 1 and tumor necrosis factor. Thus, these observations describe a role for defined cytokines in regulating the hormonal responsiveness and function of contractile cells. The effects of interleukin 1 and tumor necrosis factor on intracellular cAMP accumulation may be a model for immune modulation of other cellular functions dependent upon cyclic nucleotide metabolism. The uncoupling of agonist-occupied receptors from adenyl cyclase suggests that β -receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.

The regulation of smooth muscle contractility by zipper-interacting protein kinase.

PubMed

Ihara, Eikichi; MacDonald, Justin A

2007-01-01

Smooth muscle contractility is mainly regulated by phosphorylation of the 20 kDa myosin light chains (LC20), a process that is controlled by the opposing activities of myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP). Recently, intensive research has revealed that various protein kinase networks including Rho-kinase, integrin-linked kinase, zipper-interacting protein kinase (ZIPK), and protein kinase C (PKC) are involved in the regulation of LC20 phosphorylation and have important roles in modulating smooth muscle contractile responses to Ca2+ (i.e., Ca2+ sensitization and Ca2+ desensitization). Here, we review the general background and structure of ZIPK and summarize our current understanding of its involvement in a number of cell processes including cell death (apoptosis), cell motility, and smooth muscle contraction. ZIPK has been found to induce the diphosphorylation of LC20 at Ser-19 and Thr-18 in a Ca2+-independent manner and to regulate MLCP activity directly through its phosphorylation of the myosin-targeting subunit of MLCP or indirectly through its phosphorylation of the PKC-potentiated inhibitory protein of MLCP. Future investigations of ZIPK function in smooth muscle will undoubtably focus on determining the mechanisms that regulate its cellular activity, including the identification of upstream signaling pathways, the characterization of autoinhibitory domains and regulatory phosphorylation sites, and the development of specific inhibitor compounds.

Exploring Asynchronous and Synchronous Tool Use in Online Courses

ERIC Educational Resources Information Center

Oztok, Murat; Zingaro, Daniel; Brett, Clare; Hewitt, Jim

2013-01-01

While the independent contributions of synchronous and asynchronous interaction in online learning are clear, comparatively less is known about the pedagogical consequences of using both modes in the same environment. In this study, we examine relationships between students' use of asynchronous discussion forums and synchronous private messages…

Teaching Presence and Communication Timeliness in Asynchronous Online Courses

ERIC Educational Resources Information Center

Skramstad, Erik; Schlosser, Charles; Orellana, Anymir

2012-01-01

This study examined student perceptions of teaching presence and communication timeliness in asynchronous online courses. Garrison, Anderson, and Archer's (2000) community of inquiry model provided the framework for the survey research methodology used. Participants were 59 student volunteers taking 1 or more asynchronous online graduate courses.…

Two Studies Examining Argumentation in Asynchronous Computer Mediated Communication

ERIC Educational Resources Information Center

Joiner, Richard; Jones, Sarah; Doherty, John

2008-01-01

Asynchronous computer mediated communication (CMC) would seem to be an ideal medium for supporting development in student argumentation. This paper investigates this assumption through two studies. The first study compared asynchronous CMC with face-to-face discussions. The transactional and strategic level of the argumentation (i.e. measures of…

Asynchronous Discussion Board Facilitation and Rubric Use in a Blended Learning Environment

ERIC Educational Resources Information Center

Giacumo, Lisa

2012-01-01

The purpose of this study was to investigate the effects of instructor response prompts and rubrics on students' performance in an asynchronous discussion-board assignment, their learning achievement on an objective-type posttest, and their reported satisfaction levels. Researchers who have studied asynchronous computer-mediated student…

Asynchronous Learning Forums for Business Acculturation

ERIC Educational Resources Information Center

Pence, Christine Cope; Wulf, Catharina

2009-01-01

The use of IT as a facilitator for student collaboration in higher business education has grown rapidly since 2000. Asynchronous discussion forums are used abundantly for collaborative training purposes and for teaching students business-relevant tools for their future careers. This article presents an analysis of the asynchronous discussion forum…

Comparing face-to-face, synchronous, and asynchronous learning: postgraduate dental resident preferences.

PubMed

Kunin, Marc; Julliard, Kell N; Rodriguez, Tobias E

2014-06-01

The Department of Dental Medicine of Lutheran Medical Center has developed an asynchronous online curriculum consisting of prerecorded PowerPoint presentations with audio explanations. The focus of this study was to evaluate if the new asynchronous format satisfied the educational needs of the residents compared to traditional lecture (face-to-face) and synchronous (distance learning) formats. Lectures were delivered to 219 dental residents employing face-to-face and synchronous formats, as well as the new asynchronous format; 169 (77 percent) participated in the study. Outcomes were assessed with pretests, posttests, and individual lecture surveys. Results found the residents preferred face-to-face and asynchronous formats to the synchronous format in terms of effectiveness and clarity of presentations. This preference was directly related to the residents' perception of how well the technology worked in each format. The residents also rated the quality of student-instructor and student-student interactions in the synchronous and asynchronous formats significantly higher after taking the lecture series than they did before taking it. However, they rated the face-to-face format as significantly more conducive to student-instructor and student-student interaction. While the study found technology had a major impact on the efficacy of this curricular model, the results suggest that the asynchronous format can be an effective way to teach a postgraduate course.

Asynchronous glimpsing of speech: Spread of masking and task set-size

PubMed Central

Ozmeral, Erol J.; Buss, Emily; Hall, Joseph W.

2012-01-01

Howard-Jones and Rosen [(1993). J. Acoust. Soc. Am. 93, 2915–2922] investigated the ability to integrate glimpses of speech that are separated in time and frequency using a “checkerboard” masker, with asynchronous amplitude modulation (AM) across frequency. Asynchronous glimpsing was demonstrated only for spectrally wide frequency bands. It is possible that the reduced evidence of spectro-temporal integration with narrower bands was due to spread of masking at the periphery. The present study tested this hypothesis with a dichotic condition, in which the even- and odd-numbered bands of the target speech and asynchronous AM masker were presented to opposite ears, minimizing the deleterious effects of masking spread. For closed-set consonant recognition, thresholds were 5.1–8.5 dB better for dichotic than for monotic asynchronous AM conditions. Results were similar for closed-set word recognition, but for open-set word recognition the benefit of dichotic presentation was more modest and level dependent, consistent with the effects of spread of masking being level dependent. There was greater evidence of asynchronous glimpsing in the open-set than closed-set tasks. Presenting stimuli dichotically supported asynchronous glimpsing with narrower frequency bands than previously shown, though the magnitude of glimpsing was reduced for narrower bandwidths even in some dichotic conditions. PMID:22894234

Asynchronous vs didactic education: it's too early to throw in the towel on tradition.

PubMed

Jordan, Jaime; Jalali, Azadeh; Clarke, Samuel; Dyne, Pamela; Spector, Tahlia; Coates, Wendy

2013-08-08

Asynchronous, computer based instruction is cost effective, allows self-directed pacing and review, and addresses preferences of millennial learners. Current research suggests there is no significant difference in learning compared to traditional classroom instruction. Data are limited for novice learners in emergency medicine. The objective of this study was to compare asynchronous, computer-based instruction with traditional didactics for senior medical students during a week-long intensive course in acute care. We hypothesized both modalities would be equivalent. This was a prospective observational quasi-experimental study of 4th year medical students who were novice learners with minimal prior exposure to curricular elements. We assessed baseline knowledge with an objective pre-test. The curriculum was delivered in either traditional lecture format (shock, acute abdomen, dyspnea, field trauma) or via asynchronous, computer-based modules (chest pain, EKG interpretation, pain management, trauma). An interactive review covering all topics was followed by a post-test. Knowledge retention was measured after 10 weeks. Pre and post-test items were written by a panel of medical educators and validated with a reference group of learners. Mean scores were analyzed using dependent t-test and attitudes were assessed by a 5-point Likert scale. 44 of 48 students completed the protocol. Students initially acquired more knowledge from didactic education as demonstrated by mean gain scores (didactic: 28.39% ± 18.06; asynchronous 9.93% ± 23.22). Mean difference between didactic and asynchronous = 18.45% with 95% CI [10.40 to 26.50]; p = 0.0001. Retention testing demonstrated similar knowledge attrition: mean gain scores -14.94% (didactic); -17.61% (asynchronous), which was not significantly different: 2.68% ± 20.85, 95% CI [-3.66 to 9.02], p = 0.399. The attitudinal survey revealed that 60.4% of students believed the asynchronous modules were educational and 95.8% enjoyed the flexibility of the method. 39.6% of students preferred asynchronous education for required didactics; 37.5% were neutral; 23% preferred traditional lectures. Asynchronous, computer-based instruction was not equivalent to traditional didactics for novice learners of acute care topics. Interactive, standard didactic education was valuable. Retention rates were similar between instructional methods. Students had mixed attitudes toward asynchronous learning but enjoyed the flexibility. We urge caution in trading in traditional didactic lectures in favor of asynchronous education for novice learners in acute care.

Yap1 Protein Regulates Vascular Smooth Muscle Cell Phenotypic Switch by Interaction with Myocardin*

PubMed Central

Xie, Changqing; Guo, Yanhong; Zhu, Tianqing; Zhang, Jifeng; Ma, Peter X.; Chen, Y. Eugene

2012-01-01

The Hippo-Yap (Yes-associated protein) signaling pathway has emerged as one of the critical pathways regulating cell proliferation, differentiation, and apoptosis in response to environmental and developmental cues. However, Yap1 roles in vascular smooth muscle cell (VSMC) biology have not been investigated. VSMCs undergo phenotypic switch, a process characterized by decreased gene expression of VSMC contractile markers and increased proliferation, migration, and matrix synthesis. The goals of the present studies were to investigate the relationship between Yap1 and VSMC phenotypic switch and to determine the molecular mechanisms by which Yap1 affects this essential process in VSMC biology. Results demonstrated that the expression of Yap1 was rapidly up-regulated by stimulation with PDGF-BB (a known inducer of phenotypic switch in VSMCs) and in the injured vessel wall. Knockdown of Yap1 impaired VSMC proliferation in vitro and enhanced the expression of VSMC contractile genes as well by increasing serum response factor binding to CArG-containing regions of VSMC-specific contractile genes within intact chromatin. Conversely, the interaction between serum response factor and its co-activator myocardin was reduced by overexpression of Yap1 in a dose-dependent manner. Taken together, these results indicate that down-regulation of Yap1 promotes VSMC contractile phenotype by both up-regulating myocardin expression and promoting the association of the serum response factor-myocardin complex with VSMC contractile gene promoters and suggest that the Yap1 signaling pathway is a central regulator of phenotypic switch of VSMCs. PMID:22411986

Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion

PubMed Central

Ahmadzadeh, Hossein; Webster, Marie R.; Behera, Reeti; Jimenez Valencia, Angela M.; Wirtz, Denis; Weeraratna, Ashani T.; Shenoy, Vivek B.

2017-01-01

Cancer cell invasion from primary tumors is mediated by a complex interplay between cellular adhesions, actomyosin-driven contractility, and the physical characteristics of the extracellular matrix (ECM). Here, we incorporate a mechanochemical free-energy–based approach to elucidate how the two-way feedback loop between cell contractility (induced by the activity of chemomechanical interactions such as Ca2+ and Rho signaling pathways) and matrix fiber realignment and strain stiffening enables the cells to polarize and develop contractile forces to break free from the tumor spheroids and invade into the ECM. Interestingly, through this computational model, we are able to identify a critical stiffness that is required by the matrix to break intercellular adhesions and initiate cell invasion. Also, by considering the kinetics of the cell movement, our model predicts a biphasic invasiveness with respect to the stiffness of the matrix. These predictions are validated by analyzing the invasion of melanoma cells in collagen matrices of varying concentration. Our model also predicts a positive correlation between the elongated morphology of the invading cells and the alignment of fibers in the matrix, suggesting that cell polarization is directly proportional to the stiffness and alignment of the matrix. In contrast, cells in nonfibrous matrices are found to be rounded and not polarized, underscoring the key role played by the nonlinear mechanics of fibrous matrices. Importantly, our model shows that mechanical principles mediated by the contractility of the cells and the nonlinearity of the ECM behavior play a crucial role in determining the phenotype of the cell invasion. PMID:28196892

Enkephalinase inhibitor potentiates mammalian tachykinin-induced contraction in ferret trachea.

PubMed

Sekizawa, K; Tamaoki, J; Graf, P D; Basbaum, C B; Borson, D B; Nadel, J A

1987-12-01

To determine the roles of endogenous enkephalinase (EC.3.4.24.11) in regulating tachykinin-induced contraction of airway smooth muscle, the authors studied the effects of the enkephalinase inhibitor leucine-thiorphan on the contractile responses to substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) in isolated ferret tracheal smooth muscle segments. Leucine-thiorphan shifted, in concentration-dependent fashions, the dose-response curves to all tachykinins to lower concentrations. Leucine-thiorphan changed the rank order of tachykinin potency from NKA greater than SP greater than NKB to NKA = NKB greater than SP. Removal of the epithelium slightly enhanced the contractile responses to SP and NKA but not to NKB. Atropine shifted the dose-response curves of all tachykinins to higher concentrations. Each tachykinin increased the contractile response to electrical field stimulation (5 Hz, 20 sec of duration, 20 V) in a dose-dependent fashion. This effect was not altered by hexamethonium, indomethacin, BW755C or naloxone but was potentiated by leucine-thiorphan and inhibited by the tachykinin receptor antagonist (D-Pro2, D-Trp7,9)-SP and by atropine. Because tachykinins did not affect contractile responses to acetylcholine significantly, their effects were probably on presynaptic postganglionic nerves. Captopril, bestatin and leupeptin did not alter contractile responses, suggesting that angiotensin converting enzyme, aminopeptidases and serine proteinases did not modulate tachykinin-induced effects. Enkephalinase immunofluorescence was found in the smooth muscle and epithelium and confirmed the authors' finding of enkephalinase-like activity in the muscle. The results suggest that tracheal enkephalinase is an important modulator of tachykinin-induced effects.

Cross-sectional area of human trunk paraspinal muscles before and after posterior lumbar surgery using magnetic resonance imaging.

PubMed

Ghiasi, Mohammad S; Arjmand, Navid; Shirazi-Adl, Aboulfazl; Farahmand, Farzam; Hashemi, Hassan; Bagheri, Sahar; Valizadeh, Mahsa

2016-03-01

Iatrogenic injuries to paraspinal muscles during the posterior lumbar surgery (PLS) cause a reduction in their cross-sectional areas (CSAs) and contractile densities over time post-surgery. This study aims to quantify such alterations. Pre- and postoperative CSAs (~6 months interval) of all paraspinal muscles were measured in six patients undergoing PLS using a 3-T magnetic resonance (MR) scanner to quantify the alterations in geometrical and tissue effective contractile (non-fatty) CSAs of these muscles at all lumbar levels. To examine the presence of any confounding effects on recorded changes within ~7-month period, measurements were also carried out on ten healthy volunteers. In the healthy population, an important (~22%) portion of CSA of the erector spinae (ES) was noncontractile at the lower lumbar levels. Negligible variations over time in both the total geometrical (<1.7% in average) and contractile (<1.2%) CSAs of muscles were observed in the healthy group (i.e., no confounding effect). Following PLS, significant reductions were observed in the geometrical CSA of only multifidus (MF) muscle by ~14 and 11% as well as in its contractile CSA by ~26 and 14% at the L5-S1 and L4-L5 levels, respectively. The total CSA of ES at lower lumbar levels shows substantial noncontractile contents in both healthy and patient populations. Biomechanical models of the spine should hence account for the noncontractile contents using only the effective contractile muscle CSAs. Postoperative variations in CSAs of paraspinal muscles may have profound effects on patterns of muscle activities, spinal loading, and stability.

Effects of sodium metabisulphite on guinea pig contractile airway smooth muscle responses in vitro.

PubMed

Sun, J; Sakamoto, T; Chung, K F

1995-08-01

Sodium metabisulphite (MBS) is known to induce bronchoconstriction in asthmatic patients. The effects of MBS on guinea pig airway smooth muscle and on neurally mediated contraction in vitro have been examined. Tracheal and bronchial airway segments were placed in oxygenated buffer solution and electrical field stimulation was performed in the presence of indomethacin (10(-5) M) and propranolol (10(-6) M) for the measurement of isometric tension. Atropine (10(-6) M) was added to bronchial tissues. Concentrations of MBS up to 10(-3) M had no direct effect on airway smooth muscle contraction and did not alter either tracheal smooth muscle contraction induced by electrical field stimulation at all frequencies or acetylcholine-induced tracheal smooth muscle contraction. There was a similar response in the absence of epithelium, except for potentiation of the response induced by electrical field stimulation at 0.5 Hz (24 (10)% increase). However, MBS (10(-5), 10(-6) and 10(-7) M) augmented neurally-mediated non-adrenergic non-cholinergic contractile responses in the bronchi (13.3 (3.2)%, 23.8 (9.6)%, and 6.4 (1.6)%, respectively). MBS had no effect on the contractile response induced by substance P, but at higher concentrations (10(-3) M and 10(-4) M) it caused a time-dependent attenuation of responses induced by either electrical field stimulation or exogenously applied acetylcholine or substance P. MBS had no direct contractile responses but enhanced bronchoconstriction induced by activation of non-cholinergic neural pathways in the bronchus, probably through increased release of neuropeptides. At high concentrations MBS inhibited contractile responses initiated by receptor or neural stimulation.

Scalability of Asynchronous Networks Is Limited by One-to-One Mapping between Effective Connectivity and Correlations

PubMed Central

van Albada, Sacha Jennifer; Helias, Moritz; Diesmann, Markus

2015-01-01

Network models are routinely downscaled compared to nature in terms of numbers of nodes or edges because of a lack of computational resources, often without explicit mention of the limitations this entails. While reliable methods have long existed to adjust parameters such that the first-order statistics of network dynamics are conserved, here we show that limitations already arise if also second-order statistics are to be maintained. The temporal structure of pairwise averaged correlations in the activity of recurrent networks is determined by the effective population-level connectivity. We first show that in general the converse is also true and explicitly mention degenerate cases when this one-to-one relationship does not hold. The one-to-one correspondence between effective connectivity and the temporal structure of pairwise averaged correlations implies that network scalings should preserve the effective connectivity if pairwise averaged correlations are to be held constant. Changes in effective connectivity can even push a network from a linearly stable to an unstable, oscillatory regime and vice versa. On this basis, we derive conditions for the preservation of both mean population-averaged activities and pairwise averaged correlations under a change in numbers of neurons or synapses in the asynchronous regime typical of cortical networks. We find that mean activities and correlation structure can be maintained by an appropriate scaling of the synaptic weights, but only over a range of numbers of synapses that is limited by the variance of external inputs to the network. Our results therefore show that the reducibility of asynchronous networks is fundamentally limited. PMID:26325661

The monophasic action potential upstroke: a means of characterizing local conduction.

PubMed

Levine, J H; Moore, E N; Kadish, A H; Guarnieri, T; Spear, J F

1986-11-01

The upstrokes of monophasic action potentials (MAPs) recorded with an extracellular pressure electrode were characterized in isolated canine tissue preparations in vitro. The characteristics of the MAP upstroke were compared with those of the local action potential foot as well as with the characteristics of approaching electrical activation during uniform and asynchronous conduction. The upstroke of the MAP was exponential during uniform conduction. The time constant of rise of the MAP upstroke (TMAP) correlated with that of the action potential foot (Tfoot): TMAP + 1.01 Tfoot + 0.50; r2 = .80. Furthermore, changes in Tfoot with alterations in cycle length were associated with similar changes in TMAP: Tfoot = 1.06 TMAP - 0.11; r2 = .78. In addition, TMAP and Tfoot both deviated from exponential during asynchronous activation; the inflections that developed in the MAP upstroke correlated in time with intracellular action potential upstrokes that were asynchronous in onset in these tissues. Finally, the field of view of the MAP was determined and was found to be dependent in part on tissue architecture and the space constant. Specifically, the field of view of the MAP was found to be greater parallel compared with transverse to fiber orientation (6.02 +/- 1.74 vs 3.03 +/- 1.10 mm; p less than .01). These data suggest that the MAP upstroke may be used to define and characterize local electrical activation. The relatively large field of view of the MAP suggests that this technique may be a sensitive means to record focal membrane phenomena in vivo.

Steroid Hormones and Uterine Vascular Adaptation to Pregnancy

PubMed Central

Chang, Katherine; Zhang, Lubo

2008-01-01

Pregnancy is a physiological state that involves a significant decrease in uterine vascular tone and an increase in uterine blood flow, which is mediated in part by steroid hormones, including estrogen, progesterone, and cortisol. Previous studies have demonstrated the involvement of these hormones in the regulation of uterine artery contractility through signaling pathways specific to the endothelium and the vascular smooth muscle. Alterations in endothelial nitric oxide synthase expression and activity, nitric oxide production, and expression of enzymes involved in PGI2 production contribute to the uterine artery endothelium-specific responses. Steroid hormones also have an effect on calcium-activated potassium channel activity, PKC signaling pathway and myogenic tone, and alterations in pharmacomechanical coupling in the uterine artery smooth muscle. This review addresses current understanding of the molecular mechanisms by which steroid hormones including estrogen, progesterone, and cortisol modulate uterine artery contractility to alter uterine blood flow during pregnancy with an emphasis on the pregnant ewe model. PMID:18497342

The β3 -adrenoceptor agonist mirabegron increases human atrial force through β1 -adrenoceptors: an indirect mechanism?

PubMed

Mo, Weilan; Michel, Martin C; Lee, Xiang Wen; Kaumann, Alberto J; Molenaar, Peter

2017-08-01

Mirabegron has been classified as a β 3 -adrenoceptor agonist approved for overactive bladder syndrome. We investigated possible cardiac effects of mirabegron in the absence or presence of β-adrenoceptor subtype antagonists. In view of its phenylethanolamine structure, we investigated whether mirabegron has indirect sympathomimetic activity by using neuronal uptake blockers. Right atrial trabeculae, from non-failing hearts, were paced and contractile force measured at 37°C. Single concentrations of mirabegron were added in the absence or presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), β 3 (L-748,337), β 1 (CGP 20712A), β 2 (ICI 118,551) -adrenoceptor antagonists, neuronal uptake inhibitors desipramine or phenoxybenzamine. Mirabegron significantly increased contractile force in human right atrium (1 μM, 7.6 ± 2.6%, n = 7; 10 μM, 10.2 ± 1.5%, n = 22 compared with (-)-isoprenaline P < 0.05). In the presence of IBMX, mirabegron (10 μM) caused a greater contraction. L-748,337 (100 nM) had no effect on the increase in contractile force caused by mirabegron (10 μM). In contrast, mirabegron (10 μM) reduced contractile force in the presence of CGP 20712A, which was not affected by L-748,337 (100 nM) or ICI 118,551 (50 nM). Mirabegron (10 μM) also reduced contractile force in the presence of desipramine or phenoxybenzamine. Mirabegron increases human atrial force through β 1 - but not β 3 -adrenoceptors. Desipramine and phenoxybenzamine block neuronal uptake and conceivably prevent mirabegron from releasing noradrenaline. A non-specific cardiodepressant effect is not mediated through β 3 (or β 2 )-adrenoceptors, consistent with lack of β 3 -adrenoceptor function on human atrial contractility. © 2017 The British Pharmacological Society.

Fasudil inhibits the proliferation and contractility and induces cell cycle arrest and apoptosis of human endometriotic stromal cells: a promising agent for the treatment of endometriosis.

PubMed

Tsuno, Akitoshi; Nasu, Kaei; Kawano, Yukie; Yuge, Akitoshi; Li, Haili; Abe, Wakana; Narahara, Hisashi

2011-12-01

During the development of endometriotic lesions, excess fibrosis may lead to scarring and to the alterations of tissue function that are the characteristic features of this disease. Enhanced extracellular matrix contractility of endometriotic stromal cells (ECSC) mediated by the mevalonate-Ras homology (Rho)/Rho-associated coiled-coil-forming protein kinase (ROCK) pathway has been shown to contribute to the pathogenesis of endometriosis. To assess the use of fasudil, a selective ROCK inhibitor, for the medical treatment of endometriosis-associated fibrosis, the effects of this agent on the cell proliferation, apoptosis, cell cycle, morphology, cell density, and contractility of ECSC were investigated. The effects of fasudil on the expression of contractility-related, apoptosis-related, and cell cycle-related molecules in ECSC were also evaluated. Fasudil significantly inhibited the proliferation and contractility of ECSC and induced the cell cycle arrest in the G2/M phase and apoptosis of these cells. Morphological observation revealed the suppression of ECSC attachment to collagen fibers and decrease of cell density by fasudil. The expression of α-smooth muscle actin, RhoA, ROCK-I, and ROCK-II proteins was inhibited by fasudil administration. The expression of the antiapoptotic factors, Bcl-2 and Bcl-X(L), in two-dimensional cultured ECSC were down-regulated by the addition of fasudil, whereas, the expression of p16(INK4a) and p21(Waf1/Cip1) was up-regulated by the addition of fasudil. The present findings suggest that fasudil is a promising agent for the treatment of endometriosis. The inhibition of cell proliferation, contractility, and myofibroblastic differentiation, the attenuation of attachment to collagen fibers, the decrease of cell density, and the induction of cell cycle arrest and apoptosis of ECSC are involved in the active mechanisms of fasudil.

Oxytocin plus antibiotics: A synergism of potentiation to enhance bovine uterine contractility.

PubMed

Piccinno, M; Rizzo, A; Cariello, G; Staffieri, F; Sciorsci, R L

2016-09-15

This in vitro study investigates the modulatory effect of three antibiotics (amoxicillin, enrofloxacin, and rifaximin) on contractility of the bovine uterine tissue, in follicular and luteal phases. The evaluation of the effects of these antibiotics (10(-4) M) was performed on oxytocin-induced contractility. The decision to test these antibiotics with the oxytocin (10(-6) M) comes from the reported ability of these combinations of hinder the antibiotic resistance and the formation of bacterial biofilms. The procedures were carried out in isolated organ bath, and the contractile functionality of the strip throughout the experiment was evaluated after a dose of carbachol (10(-5) M). The results demonstrate the different modulatory activity of these antibiotics, on the plateau of contraction induced by oxytocin, in both phases of the estrus cycle. The differing individual antibiotic effects of our testing made it possible to identify, only in some cases. Rifaximin in the follicular phase and enrofloxacin in both phases of the estrous cycle, induced a synergistic enhancement (potentiation) of uterine strip contraction induced by oxytocin. This result is thought important because these associations might enable, in vivo, a simultaneous increase of uterine cleaning and the antimicrobial action on bacteria in planktonic form and of those organized in biofilms. Copyright © 2016 Elsevier Inc. All rights reserved.

Pharmacology of RG W-2938: a cardiotonic agent with vasodilator activity.

PubMed

Barrett, J A; Woltmann, R F; Swillo, R S; Kasiewski, C; Faith, W C; Campbell, H F; Perrone, M H

1990-10-01

The cardiovascular effects of RG W-2938, 6-[6-(3,4-dihydro-3-methyl-2(1H)-2-oxoquinazolinyl)]-4,5-dihydro-3 (2H-pyridazinone, a new nonglycoside, noncatecholamine cardiotonic/vasodilator agent were examined in vivo in anesthetized and conscious dogs and in vitro in isolated guinea pig hearts; in the latter, RG W-2938 5 nmol-5 mumol increased contractility in a dose-related fashion. RG W-2938 30-300 micrograms/kg administered intravenously (i.v.) to anesthetized dogs increased contractile force while decreasing arterial pressure and total peripheral resistance (TPR) in a dose-related manner. Heart rate (HR) was only slightly increased, and aortic flow was not appreciably altered. A single oral dose of RG W-2938 0.3 mg/kg administered to conscious chronically instrumented dogs produced a marked and sustained increase in contractility 15-240 min after treatment while only slightly increasing HR. The effects of RG W-2938 30-300 micrograms/kg, i.v. were studied in a mecamylamine-propranolol-induced model of heart failure. RG W-2938 effectively reversed the drug-induced heart failure by increasing myocardial contractility and decreasing arterial pressure while only slightly affecting HR. These studies show that RG W-2938 is an orally effective positive inotropic/vasodilator agent.

Hydrogel tissue construct-based high-content compound screening.

PubMed

Lam, Vy; Wakatsuki, Tetsuro

2011-01-01

Current pharmaceutical compound screening systems rely on cell-based assays to identify therapeutic candidates and potential toxicities. However, cells grown on 2D substrata or in suspension do not exhibit the mechanical or physiological properties of cells in vivo. To address this limitation, the authors developed an in vitro, high-throughput, 3D hydrogel tissue construct (HTC)-based assay system to quantify cell and tissue mechanical properties and multiple parameters of physiology. HTC mechanics was quantified using an automated device, and physiological status was assessed using spectroscopy-based indicators that were read on microplate readers. To demonstrate the application of this system, the authors screened 4 test compounds--rotenone (ROT), cytochalasin D (CD), 2,4-dinitrophenol (DNP), and Rho kinase inhibitor (H-1152)--for their ability to modulate HTC contractility without affecting actin integrity, mitochondrial membrane potential (MMP), or viability. All 4 compounds dose-dependently reduced HTC contractility. However, ROT was toxic, DNP dissipated MMP, and CD reduced both intracellular F-actin and viability. H-1152 was found to be the best candidate compound since it reduced HTC contractility with minimal side effects. The authors propose that their HTC-based assay system can be used to screen for compounds that modulate HTC contractility and assess the underlying physiological mechanism(s) of compound activity and toxicity.

Impact of tamsulosin and nifedipine on contractility of pregnant rat ureters in vitro.

PubMed

Haddad, Lisette; Corriveau, Stéphanie; Rousseau, Eric; Blouin, Simon; Pasquier, Jean-Charles; Ponsot, Yves; Roy-Lacroix, Marie-Ève

2018-01-01

To evaluate the in vitro effect of tamsulosin and nifedipine on the contractility of pregnant rat ureters and to perform quantitative analysis of the pharmacological effects. Medical expulsive therapy (MET) is commonly used to treat urolithiasis. However, this treatment is seldom used in pregnant women since no studies support this practice. This was an in vitro study on animal tissue derived from pregnant Sprague-Dawley rats. A total of 124 ureteral segments were mounted in an organ bath system and contractile response to methacholine (MCh) was assessed. Tamsulosin or nifedipine were added at cumulative concentrations (0.001-1 μM). The area under the curve (AUC) from isometric tension measurements was calculated. The effect of pharmacological agents and the respective controls were assessed by calculating the AUC for each 5-min interval. Statistical analyses were performed using the Mann-Whitney-Wilcoxon nonparametric test. Both drugs displayed statistically significant inhibitory activity at concentrations of 0.1 and 1 μM for tamsulosin and 1 μM for nifedipine when calculated as the AUC as compared to DMSO controls. Tamsulosin and nifedipine directly inhibit MCh-induced contractility of pregnant rat ureters. Further work is needed to determine the clinical efficacy of these medications for MET in pregnancy.

Nerve-dependent factors regulating transcript levels of glycogen phosphorylase in skeletal muscle.

PubMed

Matthews, C C; Carlsen, R C; Froman, B; Tait, R; Gorin, F

1998-06-01

1. Muscle glycogen phosphorylase (MGP), the rate-limiting enzyme for glycogen metabolism in skeletal muscle, is neurally regulated. Steady-state transcript levels of the skeletal muscle isozyme of MGP decrease significantly following muscle denervation and after prolonged muscle inactivity with an intact motor nerve. These data suggest that muscle activity has an important influence on MGP gene expression. The evidence to this point, however, does not preclude the possibility that MGP is also regulated by motor neuron-derived trophic factors. This study attempts to distinguish between regulation provided by nerve-evoked muscle contractile activity and that provided by the delivery of neurotrophic factors. 2. Steady-state MGP transcript levels were determined in rat tibialis anterior (TA) muscles following controlled interventions aimed at separating the contributions of contractile activity from axonally transported trophic factors. The innervated TA was rendered inactive by daily epineural injections of tetrodotoxin (TTX) into the sciatic nerve. Sustained inhibition of axonal transport was accomplished by applying one of three different concentrations of the antimicrotubule agent, vinblastine (VIN), to the proximal sciatic nerve for 1 hr. The axonal transport of acetylcholinesterase (AChE) was assessed 7, 14, and 28 days after the single application of VIN. 3. MGP transcript levels normalized to total RNA were reduced by 67% in rat TA, 7 days after nerve section. Daily injection of 2 microg TTX into the sciatic nerve for 7 days eliminated muscle contractile activity and reduced MGP transcript levels by 60%. 4. A single, 1-hr application of 0.10% (w/v) VIN to the sciatic nerve reduced axonal transport but did not alter MGP transcript levels in the associated TA, 7 days after treatment. Application of 0.10% VIN to the sciatic nerve also did not affect IA sensory or motor nerve conduction velocities or TA contractile function. 5. Treatment of the sciatic nerve with 0.40% (w/v) VIN for 1 hr reduced axonal transport and decreased MGP transcript levels by 50% within 7 days, but also reduced sensory and motor nerve conduction velocities and depressed TA contractile function. 6. Myogenin, a member of a family of regulatory factors shown to influence the transcription of many muscle genes, including MGP, was used as a molecular marker for muscle inactivity. Myogenin transcript levels were increased following denervation and after treatment with TTX or 0.40% VIN but not after treatment with 0.10% VIN. 7. The results suggest that MGP transcript levels in TA are regulated predominantly by muscle activity, rather than by the delivery of neurotrophic factors. Intrinsic myogenic factors, however, also play a role in MGP expression, since denervation did not reduce MGP transcript levels below 30% of control TA. The dominant influence of activity in the regulation of MGP contrasts with the proposed regulation of oxidative enzyme expression, which appears to depend on both activity and trophic factor influences.

AMP-Activated Protein Kinase – A Ubiquitous Signalling Pathway with Key Roles in the Cardiovascular System

PubMed Central

Salt, Ian P.; Hardie, D. Grahame

2017-01-01

The AMP-activated protein kinase (AMPK) is a key regulator of cellular and whole body energy homeostasis, which acts to restore energy homoeostasis whenever cellular energy charge is depleted. Over the last two decades, it has become apparent that AMPK regulates a number of other cellular functions and has specific roles in cardiovascular tissues, acting to regulate cardiac metabolism and contractile function as well as promoting anti-contractile, anti-inflammatory and anti-atherogenic actions in blood vessels. In this review, we will discuss the role of AMPK in the cardiovascular system, including the molecular basis of mutations in AMPK that alter cardiac physiology and the proposed mechanisms by which AMPK regulates vascular function under physiological and pathophysiological conditions. PMID:28546359

Fatigability and blood flow in the rat gastrocnemius-plantaris-soleus after hindlimb suspension

NASA Technical Reports Server (NTRS)

Mcdonald, K. S.; Delp, M. D.; Fitts, R. H.

1992-01-01

The hypothesis that hindlimb suspension (HS) increases the fatigability of the soleus during intense contractile activity and that the increased fatigue is associated with a reduced muscle blood flow was tested using caged control rats and rats subjected to HS for 15 days. After 15 days, either the soleus or the gastrocnemius-plantaris-soleus (G-P-S) muscle group was stimulated in situ (10 min at 100 Hz, 100 ms trains at 120/min), and in the G-P-S preparation, blood flow was measured with radiolabeled microspheres before and at 2 min and 10 min after the start of contractile activity. The results indicate that 15 days of HS resulted in increased fatigability of the soleus, but the effect was not caused by a reduced muscle blood flow.

p21-Activated kinase-1 and its role in integrated regulation of cardiac contractility.

PubMed

Sheehan, Katherine A; Ke, Yunbo; Solaro, R John

2007-09-01

We review here a novel concept in the regulation of cardiac contractility involving variations in the activity of the multifunctional enzyme, p21-activated kinase 1 (Pak1), a member of a family of proteins in the small G protein-signaling pathway that is activated by Cdc42 and Rac1. There is a large body of evidence from studies in noncardiac tissue that Pak1 activity is key in regulation of a number of cellular functions, including cytoskeletal dynamics, cell motility, growth, and proliferation. Although of significant potential impact, the role of Pak1 in regulation of the heart has been investigated in only a few laboratories. In this review, we discuss the structure of Pak1 and its sites of posttranslational modification and molecular interactions. We assemble an overview of the current data on Pak1 signaling in noncardiac tissues relative to similar signaling pathways in the heart, and we identify potential roles of Pak1 in cardiac regulation. Finally, we discuss the current state of Pak1 research in the heart in regard to regulation of contractility through functional myofilament and Ca(2+)-flux modification. An important aspect of this regulation is the modulation of kinase and phosphatase activity. We have focused on Pak1 regulation of protein phosphatase 2A (PP2A), which is abundant in cardiac muscle, thereby mediating dephosphorylation of sarcomeric proteins and sensitizing the myofilaments to Ca(2+). We present a model for Pak1 signaling that provides a mechanism for specifically affecting cardiac cellular processes in which regulation of protein phosphorylation states by PP2A dephosphorylation predominates.

Fostering Critical Reflection in a Computer-Based, Asynchronously Delivered Diversity Training Course

ERIC Educational Resources Information Center

Givhan, Shawn T.

2013-01-01

This dissertation study chronicles the creation of a computer-based, asynchronously delivered diversity training course for a state agency. The course format enabled efficient delivery of a mandatory curriculum to the Massachusetts Department of State Police workforce. However, the asynchronous format posed a challenge to achieving the learning…

Anonymity and Motivation in Asynchronous Discussions and L2 Vocabulary Learning

ERIC Educational Resources Information Center

Polat, Nihat; Mancilla, Rae; Mahalingappa, Laura

2013-01-01

This study investigates L2 attainment in asynchronous online environments, specifically possible relationships among anonymity, L2 motivation, participation in discussions, quality of L2 production, and success in L2 vocabulary learning. It examines, in asynchronous discussions, (a) if participation and (b) motivation contribute to L2 vocabulary…

Exploring the Effect of Scripted Roles on Cognitive Presence in Asynchronous Online Discussions

ERIC Educational Resources Information Center

Olesova, Larisa; Slavin, Margaret; Lim, Jieun

2016-01-01

The purpose of this study was to identify the effect of scripted roles on students' level of cognitive presence in asynchronous online threaded discussions. A quantitative content analysis was used to investigate: (1) what level of cognitive presence is achieved by students' assigned roles in asynchronous online discussions; (2) differences…

The Negotiation Model in Asynchronous Computer-Mediated Communication (CMC): Negotiation in Task-Based Email Exchanges

ERIC Educational Resources Information Center

Kitade, Keiko

2006-01-01

Based on recent studies, computer-mediated communication (CMC) has been considered a tool to aid in language learning on account of its distinctive interactional features. However, most studies have referred to "synchronous" CMC and neglected to investigate how "asynchronous" CMC contributes to language learning. Asynchronous CMC possesses…

Integrating the Intangibles into Asynchronous Online Instruction: Strategies for Improving Interaction and Social Presence

ERIC Educational Resources Information Center

McGuire, Beverley Foulks

2016-01-01

This paper considers how instructors of asynchronous online courses in the Humanities might integrate intangibles associated with face-to-face instruction into their online environments. It presents a case study of asynchronous online instruction in a philosophy and religion department at a midsize public university in the southeastern United…

Postgraduate Students' Knowledge Construction during Asynchronous Computer Conferences in a Blended Learning Environment: A Malaysian Experience

ERIC Educational Resources Information Center

Kian-Sam, Hong; Lee, Julia Ai Cheng

2008-01-01

Blended learning, using e-learning tools to supplement existing on campus learning, often incorporates asynchronous computer conferencing as a means of augmenting knowledge construction among students. This case study reports findings about levels of knowledge construction amongst adult postgraduate students in six asynchronous computer…

Asynchronous Learning Sources in a High-Tech Organization

ERIC Educational Resources Information Center

Bouhnik, Dan; Giat, Yahel; Sanderovitch, Yafit

2009-01-01

Purpose: The purpose of this study is to characterize learning from asynchronous sources among research and development (R&D) personnel. It aims to examine four aspects of asynchronous source learning: employee preferences regarding self-learning; extent of source usage; employee satisfaction with these sources and the effect of the sources on the…

Asynchronous reference frame agreement in a quantum network

NASA Astrophysics Data System (ADS)

Islam, Tanvirul; Wehner, Stephanie

2016-03-01

An efficient implementation of many multiparty protocols for quantum networks requires that all the nodes in the network share a common reference frame. Establishing such a reference frame from scratch is especially challenging in an asynchronous network where network links might have arbitrary delays and the nodes do not share synchronised clocks. In this work, we study the problem of establishing a common reference frame in an asynchronous network of n nodes of which at most t are affected by arbitrary unknown error, and the identities of the faulty nodes are not known. We present a protocol that allows all the correctly functioning nodes to agree on a common reference frame as long as the network graph is complete and not more than t\\lt n/4 nodes are faulty. As the protocol is asynchronous, it can be used with some assumptions to synchronise clocks over a network. Also, the protocol has the appealing property that it allows any existing two-node asynchronous protocol for reference frame agreement to be lifted to a robust protocol for an asynchronous quantum network.

Recently active contractile deformation in the forearc of southern Peru

NASA Astrophysics Data System (ADS)

Hall, S. R.; Farber, D.; Audin, L.; Finkel, R. C.

2010-12-01

In the Precordillera and Western Cordillera of southern Peru (14°-18°S), vast pediment surfaces have been abandoned through drainage diversion and river incision, with the major drainages carving deep canyons. Within this region, we have identified range-sub-parallel contractile structures that accommodate significant distributed crustal deformation. Young geomorphic features document both the presence and youthfulness of these contractile structures. Here, we determine exposure ages on geomorphic features such as pediment surfaces and fluvial terraces using in situ produced cosmogenic radionuclides, in conjunction with field and remote mapping. This chronologic data reveals that ancient surfaces have been preserved as a result of very low erosion rates. We measure this rate to be <0.5m/Ma on genetically similar surfaces spanning over 4 degrees of latitude throughout this region. While many ancient surfaces are preserved in forearc localities, we also observe young (30ka-1Ma) low-relief pediment surfaces modified by recent processes. Specifically, active structures accommodating compressional stresses locally displace active drainages and offset river terraces leading to their abandonment. Based on our chronology and geomorphic mapping, we calculate a Pleistocene river incision rate of ~0.3mm/yr determined from data collected along exoreic rivers. This rate is consistent with longer-term incision rates measured in other localities along this margin. We suggest that, in this region of southern Peru, the steep western wedge of the Andean margin supports the high topography of the Altiplano through a combination of uplift along steeply dipping contractile west-vergent structures and isostatic responses to the focused removal of large amounts of crustal material through canyon incision. Further, that these range sub-parallel structures are related at depth to a thrust system that plays a role in not only the maintenance of the Andean margin, but potentially in its formation as well.

Health economic modeling of the potential cost saving effects of Neurally Adjusted Ventilator Assist.

PubMed

Hjelmgren, Jonas; Bruce Wirta, Sara; Huetson, Pernilla; Myrén, Karl-Johan; Göthberg, Sylvia

2016-02-01

Asynchrony between patient and ventilator breaths is associated with increased duration of mechanical ventilation (MV). Neurally Adjusted Ventilatory Assist (NAVA) controls MV through an esophageal reading of diaphragm electrical activity via a nasogastric tube mounted with electrode rings. NAVA has been shown to decrease asynchrony in comparison to pressure support ventilation (PSV). The objective of this study was to conduct a health economic evaluation of NAVA compared with PSV. We developed a model based on an indirect link between improved synchrony with NAVA versus PSV and fewer days spent on MV in synchronous patients. Unit costs for MV were obtained from the Swedish intensive care unit register, and used in the model along with NAVA-specific costs. The importance of each parameter (proportion of asynchronous patients, costs, and average MV duration) for the overall results was evaluated through sensitivity analyses. Base case results showed that 21% of patients ventilated with NAVA were asynchronous versus 52% of patients receiving PSV. This equals an absolute difference of 31% and an average of 1.7 days less on MV and a total cost saving of US$7886 (including NAVA catheter costs). A breakeven analysis suggested that NAVA was cost effective compared with PSV given an absolute difference in the proportion of asynchronous patients greater than 2.5% (49.5% versus 52% asynchronous patients with NAVA and PSV, respectively). The base case results were stable to changes in parameters, such as difference in asynchrony, duration of ventilation and daily intensive care unit costs. This study showed economically favorable results for NAVA versus PSV. Our results show that only a minor decrease in the proportion of asynchronous patients with NAVA is needed for investments to pay off and generate savings. Future studies need to confirm this result by directly relating improved synchrony to the number of days on MV. © The Author(s), 2015.

Dose-dependent inhibition of uterine contractility by nitric oxide: A potential mechanism underlying persistent breeding-induced endometritis in the mare.

PubMed

Khan, Firdous A; Chenier, Tracey S; Murrant, Coral L; Foster, Robert A; Hewson, Joanne; Scholtz, Elizabeth L

2017-03-01

Nitric oxide (NO) may have a role in persistent breeding-induced endometritis in mares through an inhibitory effect on uterine contractility. The objectives of this study were to test the effect of NO on spontaneous uterine contractility in-vitro and to evaluate whether this effect varied between the longitudinal and circular muscle layers of the uterus. Reproductive tracts were collected from eight euthanized non-pregnant mares (age 4-19 years; body weight 405-530 kg). Transrectal examination of the reproductive tract was performed before euthanasia to evaluate stage of the estrous cycle and presence of any apparent abnormality. After euthanasia, one uterine tissue sample was collected for histological evaluation and four full-thickness uterine tissue strips (10-12 mm × 2 mm), two parallel to each muscle layer, were excised for in-vitro contractility evaluation. Strips were suspended in tissue chambers containing Krebs-Henseleit solution, with continuous aeration (95% O 2 -5% CO 2 ; pH 7.4) at 37 °C. After equilibration, spontaneous contractility was recorded (pre-treatment) and strips excised in each direction were randomly allocated to each of two groups: 1) SNAP (S-nitroso-N-acetylpenicillamine, an NO donor); or 2) NAP (N-acetyl-d-penicillamine, vehicle and time-matched control). These were treated at 15 min intervals with increasing concentrations (10 -7  M to 10 -3  M) of SNAP and NAP, respectively. Contractility data was recorded throughout the experiment. An interaction effect of group-by-concentration was observed (P < 0.0001). The mean contractility after treatment with 10 -4  M and 10 -3  M SNAP were significantly lower than the pre-treatment contractility and the mean contractility after treatment with lower SNAP concentrations. In contrast, contractility did not change significantly in the NAP treated controls. The effect of treatment on uterine contractility was not influenced by age or weight of the mare, stage of estrous cycle, uterine histology grade, or muscle layer. Secondary findings included significant main effects of stage of estrous cycle (increased contractility in estrus compared to diestrus), uterine histology grade (decreased contractility in grade IIB compared to grade I) and age (decreased contractility in mares aged > 8 years compared to mares aged ≤ 8 years). In conclusion, results of this study indicate that NO has a dose-dependent inhibitory effect on spontaneous uterine contractility irrespective of the muscle layer in the mare. Copyright © 2017 Elsevier Inc. All rights reserved.

Pediatric emergency medicine asynchronous e-learning: a multicenter randomized controlled Solomon four-group study.

PubMed

Chang, Todd P; Pham, Phung K; Sobolewski, Brad; Doughty, Cara B; Jamal, Nazreen; Kwan, Karen Y; Little, Kim; Brenkert, Timothy E; Mathison, David J

2014-08-01

Asynchronous e-learning allows for targeted teaching, particularly advantageous when bedside and didactic education is insufficient. An asynchronous e-learning curriculum has not been studied across multiple centers in the context of a clinical rotation. We hypothesize that an asynchronous e-learning curriculum during the pediatric emergency medicine (EM) rotation improves medical knowledge among residents and students across multiple participating centers. Trainees on pediatric EM rotations at four large pediatric centers from 2012 to 2013 were randomized in a Solomon four-group design. The experimental arms received an asynchronous e-learning curriculum consisting of nine Web-based, interactive, peer-reviewed Flash/HTML5 modules. Postrotation testing and in-training examination (ITE) scores quantified improvements in knowledge. A 2 × 2 analysis of covariance (ANCOVA) tested interaction and main effects, and Pearson's correlation tested associations between module usage, scores, and ITE scores. A total of 256 of 458 participants completed all study elements; 104 had access to asynchronous e-learning modules, and 152 were controls who used the current education standards. No pretest sensitization was found (p = 0.75). Use of asynchronous e-learning modules was associated with an improvement in posttest scores (p < 0.001), from a mean score of 18.45 (95% confidence interval [CI] = 17.92 to 18.98) to 21.30 (95% CI = 20.69 to 21.91), a large effect (partial η(2) = 0.19). Posttest scores correlated with ITE scores (r(2) = 0.14, p < 0.001) among pediatric residents. Asynchronous e-learning is an effective educational tool to improve knowledge in a clinical rotation. Web-based asynchronous e-learning is a promising modality to standardize education among multiple institutions with common curricula, particularly in clinical rotations where scheduling difficulties, seasonality, and variable experiences limit in-hospital learning. © 2014 by the Society for Academic Emergency Medicine.

Antioxidant Phytochemicals of Opuntia ficus-indica (L.) Mill. Cladodes with Potential Anti-spasmodic Activity

PubMed Central

Lanuzza, Francesco; Occhiuto, Francesco; Monforte, Maria Teresa; Tripodo, Maria Marcella; D’Angelo, Valeria; Galati, Enza Maria

2017-01-01

Background: Opuntia ficus-indica (OFI) (L.) Mill. (Cactaceae), a plant widespread in dry regions of the world, shows interesting biological activities (cicatrizant, antiulcer, anti-inflammatory, and hypolipidemic) and is widely used in traditional medicine. Objectives: Phytochemical analysis and antispasmodic effect of wild OFI cladodes were carried out. Material and Methods: Polyphenols and Vitamin E occurrence, in antioxidant pool of OFI cladodes, were quantified by high-performance liquid chromatography. The antispasmodic effect of OFI cladodes was assessed in isolated rabbit smooth muscle tissues. The experiments were carried out with preparations of rabbit jejunum and uterus with the spontaneous contractile activity, to evaluate the effect of cumulative concentrations of the extract on basal tone, amplitude, and frequency of contractions. Results: Catechin, quercetin, kaempferol, isorhamnetin and chlorogenic, ferulic, and p-coumaric acid were identified. α-, β-, and γ-tocopherols have been highlighted and α-tocopherol is the major component. OFI cladodes contain significant amount of polyphenols and tocopherols that are effective radical scavengers and inhibited ethanol 1,1-diphenyl-2-picrylhydrazyl formation by 50%. OFI cladodes caused a light inhibition of amplitude and frequency of spontaneous contractions and a marked decrease in muscle basal tone of rabbit jejunum preparations. On spontaneously contracting uterus preparations, the addition of increasing concentrations of cladode extract caused uterine muscle relaxation. Conclusion: The contraction of smooth muscle preparations depends on an increase in cytoplasmic free calcium ion concentration, which activates the contractile elements. The flavonoids may suppress the contractility of smooth myocytes, by an inhibition of availability of Ca2+ for muscle contraction. SUMMARY Opuntia ficus-indica (OFI) cladodes contain significant amount of polyphenols and tocopherols that are effective radical scavengers and inhibited ethanol 1,1-diphenyl-2-picrylhydrazyl formation by 50%Polyphenols and Vitamin E complex occurrence in OFI cladodes were characterized by high-performance liquid chromatographyOFI cladodes exhibited significative antispasmodic activity. The antispasmodic effect was assessed in isolated rabbit smooth muscle tissues. The experiments were carried out with preparations of rabbit jejunum and uterus with the spontaneous contractile activity, to evaluate the effect of cumulative concentrations of the extract on basal tone, amplitude, and frequency of contractions. Abbreviations used: OFI: Opuntia ficus-indica, DPPH: Ethanol 1,1-diphenyl-2-picrylhydrazyl. PMID:29142394

Modeling and Analysis of Asynchronous Systems Using SAL and Hybrid SAL

NASA Technical Reports Server (NTRS)

Tiwari, Ashish; Dutertre, Bruno

2013-01-01

We present formal models and results of formal analysis of two different asynchronous systems. We first examine a mid-value select module that merges the signals coming from three different sensors that are each asynchronously sampling the same input signal. We then consider the phase locking protocol proposed by Daly, Hopkins, and McKenna. This protocol is designed to keep a set of non-faulty (asynchronous) clocks phase locked even in the presence of Byzantine-faulty clocks on the network. All models and verifications have been developed using the SAL model checking tools and the Hybrid SAL abstractor.

Detection of Failure in Asynchronous Motor Using Soft Computing Method

NASA Astrophysics Data System (ADS)

Vinoth Kumar, K.; Sony, Kevin; Achenkunju John, Alan; Kuriakose, Anto; John, Ano P.

2018-04-01

This paper investigates the stator short winding failure of asynchronous motor also their effects on motor current spectrums. A fuzzy logic approach i.e., model based technique possibly will help to detect the asynchronous motor failure. Actually, fuzzy logic similar to humanoid intelligent methods besides expected linguistic empowering inferences through vague statistics. The dynamic model is technologically advanced for asynchronous motor by means of fuzzy logic classifier towards investigate the stator inter turn failure in addition open phase failure. A hardware implementation was carried out with LabVIEW for the online-monitoring of faults.

Asynchronous discrete control of continuous processes

NASA Astrophysics Data System (ADS)

Kaliski, M. E.; Johnson, T. L.

1984-07-01

The research during this second contract year continued to deal with the development of sound theoretical models for asynchronous systems. Two criteria served to shape the research pursued: the first, that the developed models extend and generalize previously developed research for synchronous discrete control; the second, that the models explicitly address the question of how to incorporate system transition times into themselves. The following sections of this report concisely delineate this year's work. Our original proposal for this research identified four general tasks of investigation: (1.1) Analysis of Qualitative Properties of Asynchronous Hybrid Systems; (1.2) Acceptance and Control for Asynchronous Hybrid Systems.

Rigidity Sensing Explained by Active Matter Theory

PubMed Central

Marcq, Philippe; Yoshinaga, Natsuhiko; Prost, Jacques

2011-01-01

The magnitude of traction forces exerted by living animal cells on their environment is a monotonically increasing and approximately sigmoidal function of the stiffness of the external medium. We rationalize this observation using active matter theory, and propose that adaptation to substrate rigidity results from an interplay between passive elasticity and active contractility. PMID:21943439

Contractile effect of rifaximin on bovine uterus in the presence of steroid hormone antagonists.

PubMed

Sciorsci, R L; Piccinno, M; Rizzo, A

2018-04-01

This in vitro study investigated the modulatory effect of rifaximin on bovine uterus contractility, in both phases of the oestrous cycle, with and without the steroid hormones that are predominant in the respective phases: oestrogen in the follicular phase and progesterone in the luteal phase. The procedures were conducted in an isolated organ bath by using rifaximin alone (10 -4  M) and in association with the steroid hormone antagonists (10 -5  M) tamoxifen (oestrogen antagonist) in the follicular phase and mifepristone (progesterone antagonist) in the luteal phase. The results indicated that rifaximin can stimulate uterine contractility. Indeed, the administration of rifaximin in the presence of tamoxifen or mifepristone increased the tonic activity of the uterus in both phases of the cycle. This result is clinically significant because rifaximin might also enable, in vivo, a simultaneous increase in uterine cleaning and the antimicrobial action against bacteria during the first 14 days postpartum, during the development of acute metritis. Copyright © 2018 Elsevier Inc. All rights reserved.

Cortical PAR polarity proteins promote robust cytokinesis during asymmetric cell division

PubMed Central

Jordan, Shawn N.; Davies, Tim; Zhuravlev, Yelena; Dumont, Julien; Shirasu-Hiza, Mimi

2016-01-01

Cytokinesis, the physical division of one cell into two, is thought to be fundamentally similar in most animal cell divisions and driven by the constriction of a contractile ring positioned and controlled solely by the mitotic spindle. During asymmetric cell divisions, the core polarity machinery (partitioning defective [PAR] proteins) controls the unequal inheritance of key cell fate determinants. Here, we show that in asymmetrically dividing Caenorhabditis elegans embryos, the cortical PAR proteins (including the small guanosine triphosphatase CDC-42) have an active role in regulating recruitment of a critical component of the contractile ring, filamentous actin (F-actin). We found that the cortical PAR proteins are required for the retention of anillin and septin in the anterior pole, which are cytokinesis proteins that our genetic data suggest act as inhibitors of F-actin at the contractile ring. Collectively, our results suggest that the cortical PAR proteins coordinate the establishment of cell polarity with the physical process of cytokinesis during asymmetric cell division to ensure the fidelity of daughter cell formation. PMID:26728855

Effects of platelet activating factor on contractile force and 45Ca fluxes in guinea-pig isolated atria.

PubMed Central

Diez, J.; Delpón, E.; Tamargo, J.

1990-01-01

1. The effects of platelet activating factor (PAF) were studied on the electromechanical properties and 45Ca2+ fluxes of guinea-pig isolated atria. 2 Both in spontaneously beating and electrically driven atria, PAF (10(-12)-10(-7) M) increased atrial rate but produced a biphasic effect on contractile force. At low concentrations (up to 10(-10) M) it produced a positive inotropic effect, while at higher concentrations PAF exerted a negative inotropic effect. A similar biphasic effect was observed in the slow contractions elicited by isoprenaline in K(+)-depolarized atrial fibres. 3. The positive inotropic effect of PAF was prevented by verapamil, whereas pretreatment of atria with propranolol, phentolamine, indomethacin or atropine did not modify its positive and negative inotropic actions. BN 52021, a specific PAF antagonist, abolished both the positive and negative inotropic effects. 4. PAF had no effect on the characteristics of the action potentials recorded in either normally polarized or K(+)-depolarized (slow action potential) atrial fibres. 5. At concentrations at which it increased contractile force, PAF potentiated the contractile responses to Ca2+ (0.9-9 mM), whereas at negative inotropic concentrations it inhibited them. The negative inotropic effect of PAF was partially reversed in 70% Na+ medium. 6. At 10(-11) M, PAF increased 45Ca2+ uptake and reduced the rate coefficient (kcm) for the 45Ca2+ efflux. This increase in 45Ca2+ uptake was abolished in atria pretreated with verapamil or BN 52021. However, 10(-7) M PAF modified neither 45Ca2+ uptake nor efflux in atrial muscle.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2379035

Differential effects of peroxynitrite on contractile protein properties in fast- and slow-twitch skeletal muscle fibers of rat.

PubMed

Dutka, T L; Mollica, J P; Lamb, G D

2011-03-01

Oxidative modification of contractile proteins is thought to be a key factor in muscle weakness observed in many pathophysiological conditions. In particular, peroxynitrite (ONOO(-)), a potent short-lived oxidant, is a likely candidate responsible for this contractile dysfunction. In this study ONOO(-) or 3-morpholinosydnonimine (Sin-1, a ONOO(-) donor) was applied to rat skinned muscle fibers to characterize the effects on contractile properties. Both ONOO(-) and Sin-1 exposure markedly reduced maximum force in slow-twitch fibers but had much less effect in fast-twitch fibers. The rate of isometric force development was also reduced without change in the number of active cross bridges. Sin-1 exposure caused a disproportionately large decrease in Ca(2+) sensitivity, evidently due to coproduction of superoxide, as it was prevented by Tempol, a superoxide dismutase mimetic. The decline in maximum force with Sin-1 and ONOO(-) treatments could be partially reversed by DTT, provided it was applied before the fiber was activated. Reversal by DTT indicates that the decrease in maximum force was due at least in part to oxidation of cysteine residues. Ascorbate caused similar reversal, further suggesting that the cysteine residues had undergone S-nitrosylation. The reduction in Ca(2+) sensitivity, however, was not reversed by either DTT or ascorbate. Western blot analysis showed cross-linking of myosin heavy chain (MHC) I, appearing as larger protein complexes after ONOO(-) exposure. The findings suggest that ONOO(-) initially decreases maximum force primarily by oxidation of cysteine residues on the myosin heads, and that the accompanying decrease in Ca(2+) sensitivity is likely due to other, less reversible actions of hydroxyl or related radicals.

Contractile properties of muscle fibers from the deep and superficial digital flexors of horses.

PubMed

Butcher, M T; Chase, P B; Hermanson, J W; Clark, A N; Brunet, N M; Bertram, J E A

2010-10-01

Equine digital flexor muscles have independent tendons but a nearly identical mechanical relationship to the main joint they act upon. Yet these muscles have remarkable diversity in architecture, ranging from long, unipennate fibers ("short" compartment of DDF) to very short, multipennate fibers (SDF). To investigate the functional relevance of the form of the digital flexor muscles, fiber contractile properties were analyzed in the context of architecture differences and in vivo function during locomotion. Myosin heavy chain (MHC) isoform fiber type was studied, and in vitro motility assays were used to measure actin filament sliding velocity (V(f)). Skinned fiber contractile properties [isometric tension (P(0)/CSA), velocity of unloaded shortening (V(US)), and force-Ca(2+) relationships] at both 10 and 30°C were characterized. Contractile properties were correlated with MHC isoform and their respective V(f). The DDF contained a higher percentage of MHC-2A fibers with myosin (heavy meromyosin) and V(f) that was twofold faster than SDF. At 30°C, P(0)/CSA was higher for DDF (103.5 ± 8.75 mN/mm(2)) than SDF fibers (81.8 ± 7.71 mN/mm(2)). Similarly, V(US) (pCa 5, 30°C) was faster for DDF (2.43 ± 0.53 FL/s) than SDF fibers (1.20 ± 0.22 FL/s). Active isometric tension increased with increasing Ca(2+) concentration, with maximal Ca(2+) activation at pCa 5 at each temperature in fibers from each muscle. In general, the collective properties of DDF and SDF were consistent with fiber MHC isoform composition, muscle architecture, and the respective functional roles of the two muscles in locomotion.

Pericellular Versican Regulates the Fibroblast-Myofibroblast Transition

PubMed Central

Hattori, Noriko; Carrino, David A.; Lauer, Mark E.; Vasanji, Amit; Wylie, James D.; Nelson, Courtney M.; Apte, Suneel S.

2011-01-01

The cell and its glycosaminoglycan-rich pericellular matrix (PCM) comprise a functional unit. Because modification of PCM influences cell behavior, we investigated molecular mechanisms that regulate PCM volume and composition. In fibroblasts and other cells, aggregates of hyaluronan and versican are found in the PCM. Dermal fibroblasts from Adamts5−/− mice, which lack a versican-degrading protease, ADAMTS5, had reduced versican proteolysis, increased PCM, altered cell shape, enhanced α-smooth muscle actin (SMA) expression and increased contractility within three-dimensional collagen gels. The myofibroblast-like phenotype was associated with activation of TGFβ signaling. We tested the hypothesis that fibroblast-myofibroblast transition in Adamts5−/− cells resulted from versican accumulation in PCM. First, we noted that versican overexpression in human dermal fibroblasts led to increased SMA expression, enhanced contractility, and increased Smad2 phosphorylation. In contrast, dermal fibroblasts from Vcan haploinsufficient (Vcanhdf/+) mice had reduced contractility relative to wild type fibroblasts. Using a genetic approach to directly test if myofibroblast transition in Adamts5−/− cells resulted from increased PCM versican content, we generated Adamts5−/−;Vcanhdf/+ mice and isolated their dermal fibroblasts for comparison with dermal fibroblasts from Adamts5−/− mice. In Adamts5−/− fibroblasts, Vcan haploinsufficiency or exogenous ADAMTS5 restored normal fibroblast contractility. These findings demonstrate that altering PCM versican content through proteolytic activity of ADAMTS5 profoundly influenced the dermal fibroblast phenotype and may regulate a phenotypic continuum between the fibroblast and its alter ego, the myofibroblast. We propose that a physiological function of ADAMTS5 in dermal fibroblasts is to maintain optimal versican content and PCM volume by continually trimming versican in hyaluronan-versican aggregates. PMID:21828051

The Role of Rac1 on Carbachol-induced Contractile Activity in Detrusor Smooth Muscle from Streptozotocin-induced Diabetic Rats.

PubMed

Evcim, Atiye Sinem; Micili, Serap Cilaker; Karaman, Meral; Erbil, Guven; Guneli, Ensari; Gidener, Sedef; Gumustekin, Mukaddes

2015-06-01

This study was designed to determine the role of the small GTPase Rac1 on carbachol-induced contractile activity in detrusor smooth muscle using small inhibitor NSC 23766 in diabetic rats. Rac1 expression in bladder tissue was also evaluated. In the streptozotocin (STZ)-induced diabetic rat model, three study groups were composed of control, diabetic and insulin-treated diabetic subjects. The detrusor muscle strips were suspended in organ baths at the end of 8-12 weeks after STZ injection. Carbachol (CCh) (10(-9) -10(-4) M) concentration-response curves were obtained both in the absence and in the presence of Rac1 inhibitor NSC 23766 (0.1, 1 and 10 μM). Diabetes-related histopathological changes and Rac1 expressions were assessed by haematoxylin and eosin staining and immunohistochemical staining, respectively. CCh caused dose-dependent contractile responses in all the study groups. Rac1 inhibitor NSC 23766 inhibited CCh-induced contractile responses in all groups, but this inhibition seen in both diabetes groups was greater than in the control group. Histological examination revealed an increased bladder wall thickness both in the diabetes and in the insulin-treated diabetes groups compared to the control group. In immunohistochemical staining, expression of Rac1 was observed to be increased in all layers of bladder in both diabetic groups compared to the control group. In the diabetic bladders, increased expression of Rac1 and considerable inhibition of CCh-induced responses in the presence of NSC 23766 compared to those of the control group may indicate a specific role of Rac1 in diabetes-related bladder dysfunction, especially associated with cholinergic mediated detrusor overactivity. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Case-Based Learning in Virtual Groups--Collaborative Problem Solving Activities and Learning Outcomes in a Virtual Professional Training Course

ERIC Educational Resources Information Center

Kopp, Birgitta; Hasenbein, Melanie; Mandl, Heinz

2014-01-01

This article analyzes the collaborative problem solving activities and learning outcomes of five groups that worked on two different complex cases in a virtual professional training course. In this asynchronous virtual learning environment, all knowledge management content was delivered virtually and collaboration took place through forums. To…

A Journey on Refining Rules for Online Discussion: Implications for the Design of Learning Management Systems

ERIC Educational Resources Information Center

Chen, Der-Thanq; Wang, Yu-Mei; Hung, David

2009-01-01

Research on asynchronous online discussions has primarily focused on their efficacy in relation to learning outcomes. Rarely are there investigations on how the design of online learning activities or how discussions could be incorporated into student learning experience. We contend that successful online activities need careful and meticulous…

Using Electronic Communication Tools in Online Group Activities to Develop Collaborative Learning Skills

ERIC Educational Resources Information Center

Khalil, Hanan; Ebner, Martin

2017-01-01

The purpose of this study was to investigate the effect of using synchronous and asynchronous communication tools in online group activities to develop collaborative learning skills. An experimental study was implemented on a sample of faculty of education students in Mansoura University. The sample was divided into two groups, a group studied…

Combining Live Video and Audio Broadcasting, Synchronous Chat, and Asynchronous Open Forum Discussions in Distance Education

ERIC Educational Resources Information Center

Teng, Tian-Lih; Taveras, Marypat

2004-01-01

This article outlines the evolution of a unique distance education program that began as a hybrid--combining face-to-face instruction with asynchronous online teaching--and evolved to become an innovative combination of synchronous education using live streaming video, audio, and chat over the Internet, blended with asynchronous online discussions…

Utilizing Spectrum Efficiently (USE)

DTIC Science & Technology

2011-02-28

18 4.8 Space-Time Coded Asynchronous DS - CDMA with Decentralized MAI Suppression: Performance and...numerical results. 4.8 Space-Time Coded Asynchronous DS - CDMA with Decentralized MAI Suppression: Performance and Spectral Efficiency In [60] multiple...supported at a given signal-to-interference ratio in asynchronous direct-sequence code-division multiple-access ( DS - CDMA ) sys- tems was examined. It was

The Development, Validity, and Reliability of Communication Satisfaction in an Online Asynchronous Discussion Scale

ERIC Educational Resources Information Center

Hung, Min-Ling; Chou, Chien

2014-01-01

The purpose of this study was to identify dimensions of students' communication satisfaction in an asynchronous discussion forum. An asynchronous discussion may be defined as text-based human-to-human communication via computer networks that provides a platform for the participants to interact with one another to exchange ideas, insights, and…

Web-based Cases in Teaching and Learning - the Quality of Discussions and a Stage of Perspective Taking in Asynchronous Communication.

ERIC Educational Resources Information Center

Jarvela, Sanna; Hakkinen, Paivi

2002-01-01

Examines the quality of asynchronous interaction in Web-based conferencing among preservice teachers. The study combines asynchronous conferencing with peer and mentor collaboration to electronically apprentice student learning. Results point out different levels of Web-based discussion: higher-level, progressive, and lower-level discussion. A…

The effect of obesity on the contractile performance of isolated mouse soleus, EDL, and diaphragm muscles.

PubMed

Tallis, Jason; Hill, Cameron; James, Rob S; Cox, Val M; Seebacher, Frank

2017-01-01

Obesity affects the major metabolic and cellular processes involved in skeletal muscle contractility. Surprisingly, the effect of obesity on isolated skeletal muscle performance remains unresolved. The present study is the first to examine the muscle-specific changes in contractility following dietary-induced obesity using an isolated muscle work-loop (WL) model that more closely represents in vivo muscle performance. Following 16-wk high-calorific feeding, soleus (SOL), extensor digitorum longus (EDL), and diaphragm (DIA) were isolated from female (CD-1) mice, and contractile performance was compared against a lean control group. Obese SOL produced greater isometric force; however, isometric stress (force per unit muscle area), absolute WL power, and normalized WL power (watts per kilogram muscle mass) were unaffected. Maximal isometric force and absolute WL power of the EDL were similar between groups. For both EDL and DIA, isometric stress and normalized WL power were reduced in the obese groups. Obesity caused a significant reduction in fatigue resistance in all cases. Our findings demonstrate a muscle-specific reduction in contractile performance and muscle quality that is likely related to in vivo mechanical role, fiber type, and metabolic profile, which may in part be related to changes in myosin heavy chain expression and AMP-activated protein kinase activity. These results infer that, beyond the additional requirement of moving a larger body mass, functional performance and quality of life may be further limited by poor muscle function in obese individuals. As such, a reduction in muscle performance may be a substantial contributor to the negative cycle of obesity. The effect of obesity on isolated muscle function is surprisingly underresearched. The present study is the first to examine the effects of obesity on isolated muscle performance using a method that more closely represents real-world muscle function. This work uniquely establishes a muscle-specific profile of mechanical changes in relation to underpinning mechanisms. These findings may be important to understanding the negative cycle of obesity and in designing interventions for improving weight status. Copyright © 2017 the American Physiological Society.

Mechanisms of neurokinin A- and substance P-induced contractions in rat detrusor smooth muscle in vitro.

PubMed

Quinn, Teresa; Collins, Colm; Baird, Alan W

2004-09-01

To investigate the mechanisms of neurokinin A- and substance P-induced contractions of rat urinary bladder smooth muscle, and to compare them with those of the muscarinic agonist carbachol. Rat urinary bladder strips were suspended under 1 g of tension in a physiological buffer at 37 degrees C, gassed with 95% O(2)/5% CO(2). Mechanical activity was recorded isometrically during exposure to neurokinin A and substance P. Both agents produced concentration-dependent contractions of smooth muscle strips which were unaffected by tetrodotoxin (1 micro mol/L), peptidase inhibitors (captopril, thiorphan and bestatin; 1 micro mol/L each) or piroxicam (10 micro mol/L). The rank order of potency of agonists was neurokinin A > substance P > carbachol. Contractile responses to neurokinin A and substance P, like the contractile responses to carbachol, were abolished in a nominally Ca(2+)-free medium and significantly reduced by nifedipine (1 micro mol/L). SKF-96365 (60 micro mol/L), an inhibitor of receptor-mediated Ca(2+) entry, abolished the nifedipine-resistant response to substance P and carbachol, and significantly attenuated the response to neurokinin A. Depleting intracellular Ca(2+) stores with thapsigargin (1 micro mol/L) significantly attenuated neurokinin A-induced contractions but had no effect on substance P- or carbachol- induced contractions. The Rho-kinase inhibitor, Y-27632 (10 micro mol/L), significantly reduced both phasic and tonic components of the contractile responses to neurokinin A, substance P and carbachol. The contractile responses induced by tachykinins in rat urinary bladder smooth muscle strips involve a direct action on smooth muscle and are not modulated by peptidases or prostanoids. Neurokinin A and substance P, like carbachol-induced contractions, depend on extracellular Ca(2+) influx largely through voltage-operated and partly through receptor-operated Ca(2+) channels. Intracellular Ca(2+) release contributes to the contractile response to neurokinin A but appears to have no involvement in substance P- and carbachol-induced contractions. Rho-kinase activation contributes to contractions induced by substance P, neurokinin A and carbachol.

Purinergic modulation of adult guinea pig cardiomyocytes in long term cultures and co-cultures with extracardiac or intrinsic cardiac neurones.

PubMed

Horackova, M; Huang, M H; Armour, J A

1994-05-01

To determine the capacity of ATP to modify cardiomyocytes directly or indirectly via peripheral autonomic neurones, the effects of various purinergic agents were studied on long term cultures of adult guinea pig ventricular myocytes and their co-cultures with extracardiac (stellate ganglion) or intrinsic cardiac neurones. Ventricular myocytes and cardiac neurones were enzymatically dissociated and plated together or alone (myocytes only). Myocyte cultures were used for experiments after three to six weeks. The electrical and contractile properties of cultured myocytes and myocyte-neuronal networks were investigated. The spontaneous beating frequency of ventricular myocytes co-cultured with stellate ganglion neurones increased by approximately 140% (p < 0.001) following superfusion with 10(-5) M ATP. This effect was not modified significantly by tetrodotoxin or by beta adrenoceptor blockade (10(-5) M timolol), but was eliminated following application of the P2 antagonist suramin (10(-5) M). Basal spontaneous contractile rate was reduced by approximately 86% (p < 0.001) in the presence of suramin, indicating the existence of tonically active purinergic synaptic mechanisms in stellate ganglion neurone-myocyte cocultures. Suramin did not significantly affect non-innervated myocyte cultures. ATP increased myocyte contractile rate in intrinsic cardiac neurone-myocyte co-cultures by approximately 40% (p < 0.01) under control conditions, but when beta adrenergic receptors of tetrodotoxin sensitive neural responses were blocked, ATP induced greater augmentation (> 100%). In contrast, ATP induced much smaller effects in non-innervated myocyte cultures (approximately 26%, p < 0.01). Analogues of AT) showed the following order of potency: ATP > UTP > MSATP > beta gamma ATP > alpha beta ATP. Adenosine (10(-4) M) attenuated the beating frequency of myocytes in both types of co-culture, while not significantly affecting non-innervated myocyte cultures. The experimental model used in this study showed that extrinsic and intrinsic cardiac neurones which possess P2 receptors can greatly enhance cardiac myocyte contractile rate when activated by ATP. Since adenosine reduced contractile rate in both types of co-cultures while not affecting non-innervated myocytes, it is concluded that some of these neurones possess P1 receptors.

Asynchronous interaction, online technologies self-efficacy and self-regulated learning as predictors of academic achievement in an online class

NASA Astrophysics Data System (ADS)

McGhee, Rosie M. Hector

This research is a correlational study of the relationship among the independent variables: asynchronous interaction, online technologies self-efficacy, and self-regulated learning, and the dependent variable; academic achievement. This study involves an online computer literacy course at a local community college. Very little research exists on the relationship among asynchronous interaction, online technologies self-efficacy and self-regulated learning on predicting academic achievement in an online class. Liu (2008), in his study on student interaction in online courses, concluded that student interaction is a complex issue that needs more research to increase our understanding as it relates to distance education. The purpose of this study was to examine the relationships between asynchronous interaction, online technologies self-efficacy, self-regulated learning and academic achievement in an online computer literacy class at a community college. The researcher used quantitative methods to obtain and analyze data on the relationships among the variables during the summer 2010 semester. Forty-five community college students completed three web-based self-reporting instruments: (a) the GVU 10th WWW User Survey Questionnaire, (b) the Online Technologies Self-Efficacy Survey, and (c) selected items from the Motivated Strategies for Learning Questionnaire. Additional data was obtained from asynchronous discussions posted on Blackboard(TM) Learning Management System. The results of this study found that there were statistically significant relationships between asynchronous interaction and academic achievement (r = .55, p < .05) and between online technologies self-efficacy and academic achievement (r = .50, p < .05). However, there were low correlations between self-regulated learning and academic achievement ( r = -.02, p < .05). The results of this study reflect the constructivist tenants that the student is at the center of the learning experience. Driscoll (2005) said constructivist pedagogy sees the learner as an active participant in their learning experience rather than a passive vessel to be filled with information. This study is beneficial to theorists, administrators, leaders, online instructors, online course designers, faculty, students and others who are concerned about predictors for online students' success. Also, it serves as a foundation for future research and provides valuable information for educators interested in taking online teaching and learning to the next level.

Asynchronous vs didactic education: it’s too early to throw in the towel on tradition

PubMed Central

2013-01-01

Background Asynchronous, computer based instruction is cost effective, allows self-directed pacing and review, and addresses preferences of millennial learners. Current research suggests there is no significant difference in learning compared to traditional classroom instruction. Data are limited for novice learners in emergency medicine. The objective of this study was to compare asynchronous, computer-based instruction with traditional didactics for senior medical students during a week-long intensive course in acute care. We hypothesized both modalities would be equivalent. Methods This was a prospective observational quasi-experimental study of 4th year medical students who were novice learners with minimal prior exposure to curricular elements. We assessed baseline knowledge with an objective pre-test. The curriculum was delivered in either traditional lecture format (shock, acute abdomen, dyspnea, field trauma) or via asynchronous, computer-based modules (chest pain, EKG interpretation, pain management, trauma). An interactive review covering all topics was followed by a post-test. Knowledge retention was measured after 10 weeks. Pre and post-test items were written by a panel of medical educators and validated with a reference group of learners. Mean scores were analyzed using dependent t-test and attitudes were assessed by a 5-point Likert scale. Results 44 of 48 students completed the protocol. Students initially acquired more knowledge from didactic education as demonstrated by mean gain scores (didactic: 28.39% ± 18.06; asynchronous 9.93% ± 23.22). Mean difference between didactic and asynchronous = 18.45% with 95% CI [10.40 to 26.50]; p = 0.0001. Retention testing demonstrated similar knowledge attrition: mean gain scores −14.94% (didactic); -17.61% (asynchronous), which was not significantly different: 2.68% ± 20.85, 95% CI [−3.66 to 9.02], p = 0.399. The attitudinal survey revealed that 60.4% of students believed the asynchronous modules were educational and 95.8% enjoyed the flexibility of the method. 39.6% of students preferred asynchronous education for required didactics; 37.5% were neutral; 23% preferred traditional lectures. Conclusions Asynchronous, computer-based instruction was not equivalent to traditional didactics for novice learners of acute care topics. Interactive, standard didactic education was valuable. Retention rates were similar between instructional methods. Students had mixed attitudes toward asynchronous learning but enjoyed the flexibility. We urge caution in trading in traditional didactic lectures in favor of asynchronous education for novice learners in acute care. PMID:23927420

[A novel proposal explaining sleep disturbance of children in Japan--asynchronization].

PubMed

Kohyama, Jun

2008-07-01

It has been reported that more than half of the children in Japan suffer from daytime sleepiness. In contrast, about one quarter of junior high-school students in Japan complain of insomnia. According to the International Classification of Sleep Disorders (Second edition), these children could be diagnosed as having behaviorally-induced insufficient sleep syndrome due to inadequate sleeping habits. Getting on adequate amount of sleep should solve such problems;however, such a therapeutic approach often fails. Although social factors are involved in these sleep disturbances, I feel that a novel notion - asynchronization - leads to an understanding of the pathophysiology of disturbances in these children. Further, it could contribute to resolve their problems. The essence of asynchronization is a disturbance of various aspects (e.g., cycle, amplitude, phase, and interrelationship) of the biological rhythms that normally exhibits circadian oscillation. The main cause of asynchronization is hypothesized to be the combination of light exposure during night and the lack of light exposure in the morning. Asynchronization results in the disturbance of variable systems. Thus, symptoms of asynchronization include disturbances of the autonomic nervous system (sleepiness, insomnia, disturbance of hormonal excretion, gastrointestinal problems, etc.) and higher brain function (disorientation, loss of sociality, loss of will or motivation, impaired alertness and performance, etc.). Neurological (attention deficit, aggression, impulsiveness, hyperactivity, etc.), psychiatric (depressive disorders, personality disorders, anxiety disorders, etc.) and somatic (tiredness, fatigue, etc.) disturbances could also be symptoms of asynchronization. At the initial phase of asynchronization, disturbances are functional and can be resolved relatively easily, such as by the establishment of a regular sleep-wakefulness cycle;however, without adequate intervention the disturbances could gradually worsen and become hard to resolve.

Stand-Alone and Hybrid Positioning Using Asynchronous Pseudolites

PubMed Central

Gioia, Ciro; Borio, Daniele

2015-01-01

global navigation satellite system (GNSS) receivers are usually unable to achieve satisfactory performance in difficult environments, such as open-pit mines, urban canyons and indoors. Pseudolites have the potential to extend GNSS usage and significantly improve receiver performance in such environments by providing additional navigation signals. This also applies to asynchronous pseudolite systems, where different pseudolites operate in an independent way. Asynchronous pseudolite systems require, however, dedicated strategies in order to properly integrate GNSS and pseudolite measurements. In this paper, several asynchronous pseudolite/GNSS integration strategies are considered: loosely- and tightly-coupled approaches are developed and combined with pseudolite proximity and receiver signal strength (RSS)-based positioning. The performance of the approaches proposed has been tested in different scenarios, including static and kinematic conditions. The tests performed demonstrate that the methods developed are effective techniques for integrating heterogeneous measurements from different sources, such as asynchronous pseudolites and GNSS. PMID:25609041

Hydrodynamic advantages of swimming by salp chains.

PubMed

Sutherland, Kelly R; Weihs, Daniel

2017-08-01

Salps are marine invertebrates comprising multiple jet-propelled swimming units during a colonial life-cycle stage. Using theory, we show that asynchronous swimming with multiple pulsed jets yields substantial hydrodynamic benefit due to the production of steady swimming velocities, which limit drag. Laboratory comparisons of swimming kinematics of aggregate salps ( Salpa fusiformis and Weelia cylindrica ) using high-speed video supported that asynchronous swimming by aggregates results in a smoother velocity profile and showed that this smoother velocity profile is the result of uncoordinated, asynchronous swimming by individual zooids. In situ flow visualizations of W. cylindrica swimming wakes revealed that another consequence of asynchronous swimming is that fluid interactions between jet wakes are minimized. Although the advantages of multi-jet propulsion have been mentioned elsewhere, this is the first time that the theory has been quantified and the role of asynchronous swimming verified using experimental data from the laboratory and the field. © 2017 The Author(s).

Cell stiffness, contractile stress and the role of extracellular matrix

DOE Office of Scientific and Technical Information (OSTI.GOV)

An, Steven S., E-mail: san@jhsph.edu; Kim, Jina; Ahn, Kwangmi

Here we have assessed the effects of extracellular matrix (ECM) composition and rigidity on mechanical properties of the human airway smooth muscle (ASM) cell. Cell stiffness and contractile stress showed appreciable changes from the most relaxed state to the most contracted state: we refer to the maximal range of these changes as the cell contractile scope. The contractile scope was least when the cell was adherent upon collagen V, followed by collagen IV, laminin, and collagen I, and greatest for fibronectin. Regardless of ECM composition, upon adherence to increasingly rigid substrates, the ASM cell positively regulated expression of antioxidant genesmore » in the glutathione pathway and heme oxygenase, and disruption of a redox-sensitive transcription factor, nuclear erythroid 2 p45-related factor (Nrf2), culminated in greater contractile scope. These findings provide biophysical evidence that ECM differentially modulates muscle contractility and, for the first time, demonstrate a link between muscle contractility and Nrf2-directed responses.« less

Functional expression of KCNQ (Kv7) channels in guinea pig bladder smooth muscle and their contribution to spontaneous activity

PubMed Central

Anderson, U A; Carson, C; Johnston, L; Joshi, S; Gurney, A M; McCloskey, K D

2013-01-01

Background and Purpose The aim of the study was to determine whether KCNQ channels are functionally expressed in bladder smooth muscle cells (SMC) and to investigate their physiological significance in bladder contractility. Experimental Approach KCNQ channels were examined at the genetic, protein, cellular and tissue level in guinea pig bladder smooth muscle using RT-PCR, immunofluorescence, patch-clamp electrophysiology, calcium imaging, detrusor strip myography, and a panel of KCNQ activators and inhibitors. Key Results KCNQ subtypes 1–5 are expressed in bladder detrusor smooth muscle. Detrusor strips typically displayed TTX-insensitive myogenic spontaneous contractions that were increased in amplitude by the KCNQ channel inhibitors XE991, linopirdine or chromanol 293B. Contractility was inhibited by the KCNQ channel activators flupirtine or meclofenamic acid (MFA). The frequency of Ca2+-oscillations in SMC contained within bladder tissue sheets was increased by XE991. Outward currents in dispersed bladder SMC, recorded under conditions where BK and KATP currents were minimal, were significantly reduced by XE991, linopirdine, or chromanol, and enhanced by flupirtine or MFA. XE991 depolarized the cell membrane and could evoke transient depolarizations in quiescent cells. Flupirtine (20 μM) hyperpolarized the cell membrane with a simultaneous cessation of any spontaneous electrical activity. Conclusions and Implications These novel findings reveal the role of KCNQ currents in the regulation of the resting membrane potential of detrusor SMC and their important physiological function in the control of spontaneous contractility in the guinea pig bladder. PMID:23586426

Effects of load carrying on metabolic cost and hindlimb muscle dynamics in guinea fowl (Numida meleagris)

PubMed Central

McGowan, C. P.; Duarte, H. A.; Main, J. B.; Biewener, A. A.

2008-01-01

The goal of this study was to test whether the contractile patterns of two major hindlimb extensors of guinea fowl are altered by load-carrying exercise. We hypothesized that changes in contractile pattern, specifically a decrease in muscle shortening velocity or enhanced stretch activation, would result in a reduction in locomotor energy cost relative to the load carried. We also anticipated that changes in kinematics would reflect underlying changes in muscle strain. Oxygen consumption, muscle activation intensity, and fascicle strain rate were measured over a range of speeds while animals ran unloaded vs. when they carried a trunk load equal to 22% of their body mass. Our results showed that loading produced no significant (P > 0.05) changes in kinematic patterns at any speed. In vivo muscle contractile strain patterns in the iliotibialis lateralis pars postacetabularis and the medial head of the gastrocnemius showed a significant increase in active stretch early in stance (P < 0.01), but muscle fascicle shortening velocity was not significantly affected by load carrying. The rate of oxygen consumption increased by 17% (P < 0.01) during loaded conditions, equivalent to 77% of the relative increase in mass. Additionally, relative increases in EMG intensity (quantified as mean spike amplitude) indicated less than proportional recruitment, consistent with force enhancement via stretch activation, in the proximal iliotibialis lateralis pars postacetabularis; however, a greater than proportional increase in the medial gastrocnemius was observed. As a result, when averaged for the two muscles, EMG intensity increased in direct proportion to the fractional increase in load carried. PMID:16809624

Differences in Contractile Function of Myofibrils within Human Embryonic Stem Cell-Derived Cardiomyocytes vs. Adult Ventricular Myofibrils Are Related to Distinct Sarcomeric Protein Isoforms

PubMed Central

Iorga, Bogdan; Schwanke, Kristin; Weber, Natalie; Wendland, Meike; Greten, Stephan; Piep, Birgit; dos Remedios, Cristobal G.; Martin, Ulrich; Zweigerdt, Robert; Kraft, Theresia; Brenner, Bernhard

2018-01-01

Characterizing the contractile function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is key for advancing their utility for cellular disease models, promoting cell based heart repair, or developing novel pharmacological interventions targeting cardiac diseases. The aim of the present study was to understand whether steady-state and kinetic force parameters of β-myosin heavy chain (βMyHC) isoform-expressing myofibrils within human embryonic stem cell-derived cardiomyocytes (hESC-CMs) differentiated in vitro resemble those of human ventricular myofibrils (hvMFs) isolated from adult donor hearts. Contractile parameters were determined using the same micromechanical method and experimental conditions for both types of myofibrils. We identified isoforms and phosphorylation of main sarcomeric proteins involved in the modulation of force generation of both, chemically demembranated hESC-CMs (d-hESC-CMs) and hvMFs. Our results indicate that at saturating Ca2+ concentration, both human-derived contractile systems developed forces with similar rate constants (0.66 and 0.68 s−1), reaching maximum isometric force that was significantly smaller for d-hESC-CMs (42 kPa) than for hvMFs (94 kPa). At submaximal Ca2+-activation, where intact cardiomyocytes normally operate, contractile parameters of d-hESC-CMs and hvMFs exhibited differences. Ca2+ sensitivity of force was higher for d-hESC-CMs (pCa50 = 6.04) than for hvMFs (pCa50 = 5.80). At half-maximum activation, the rate constant for force redevelopment was significantly faster for d-hESC-CMs (0.51 s−1) than for hvMFs (0.28 s−1). During myofibril relaxation, kinetics of the slow force decay phase were significantly faster for d-hESC-CMs (0.26 s−1) than for hvMFs (0.21 s−1), while kinetics of the fast force decay were similar and ~20x faster. Protein analysis revealed that hESC-CMs had essentially no cardiac troponin-I, and partially non-ventricular isoforms of some other sarcomeric proteins, explaining the functional discrepancies. The sarcomeric protein isoform pattern of hESC-CMs had features of human cardiomyocytes at an early developmental stage. The study indicates that morphological and ultrastructural maturation of βMyHC isoform-expressing hESC-CMs is not necessarily accompanied by ventricular-like expression of all sarcomeric proteins. Our data suggest that hPSC-CMs could provide useful tools for investigating inherited cardiac diseases affecting contractile function during early developmental stages. PMID:29403388

Pressure overload differentially affects respiratory capacity in interfibrillar and subsarcolemmal mitochondria.

PubMed

Schwarzer, Michael; Schrepper, Andrea; Amorim, Paulo A; Osterholt, Moritz; Doenst, Torsten

2013-02-15

Years ago a debate arose as to whether two functionally different mitochondrial subpopulations, subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), exist in heart muscle. Nowadays potential differences are often ignored. Presumably, SSM are providing ATP for basic cell function, whereas IFM provide energy for the contractile apparatus. We speculated that two distinguishable subpopulations exist that are differentially affected by pressure overload. Male Sprague-Dawley rats were subjected to transverse aortic constriction for 20 wk or sham operation. Contractile function was assessed by echocardiography. Heart tissue was analyzed by electron microscopy. Mitochondria were isolated by differential centrifugation, and respiratory capacity was analyzed using a Clark electrode. Pressure overload induced left ventricular hypertrophy with increased posterior wall diameter and impaired contractile function. Mitochondrial state 3 respiration in control was 50% higher in IFM than in SSM. Pressure overload significantly impaired respiratory rates in both IFM and SSM, but in SSM to a lower extent. As a result, there were no differences between SSM and IFM after 20 wk of pressure overload. Pressure overload reduced total citrate synthase activity, suggesting reduced total mitochondrial content. Electron microscopy revealed normal morphology of mitochondria but reduced total mitochondrial volume density. In conclusion, IFM show greater respiratory capacity in the healthy rat heart and a greater depression of respiratory capacity by pressure overload than SSM. The differences in respiratory capacity of cardiac IFM and SSM in healthy hearts are eliminated with pressure overload-induced heart failure. The strong effect of pressure overload on IFM together with the simultaneous appearance of mitochondrial and contractile dysfunction may support the notion of IFM primarily producing ATP for contractile function.

A new orthodontic force system for moment control utilizing the flexibility of common wires: Evaluation of the effect of contractile force and hook length.

PubMed

Lai, Wei-Jen; Midorikawa, Yoshiyuki; Kanno, Zuisei; Takemura, Hiroshi; Suga, Kazuhiro; Soga, Kohei; Ono, Takashi; Uo, Motohiro

2018-01-01

The application of an appropriate force system is indispensable for successful orthodontic treatments. Second-order moment control is especially important in many clinical situations, so we developed a new force system composed of a straight orthodontic wire and two crimpable hooks of different lengths to produce the second-order moment. The objective of this study was to evaluate this new force system and determine an optimum condition that could be used in clinics. We built a premolar extraction model with two teeth according to the concept of a modified orthodontic simulator. This system was activated by applying contractile force from two hooks that generated second-order moment and force. The experimental device incorporated two sensors, and forces and moments were measured along six axes. We changed the contractile force and hook length to elucidate their effects. Three types of commercial wires were tested. The second-order moment was greater on the longer hook side of the model. Vertical force balanced the difference in moments between the two teeth. Greater contractile force generated a greater second-order moment, which reached a limit of 150 g. Excessive contractile force induced more undesired reactions in the other direction. Longer hooks induced greater moment generation, reaching their limit at 10 mm in length. The system acted similar to an off-center V-bend and can be applied in clinical practice as an unconventional loop design. We suggest that this force system has the potential for second-order moment control in clinical applications. Copyright © 2017. Published by Elsevier B.V.

Spontaneous myometrial contractility in cows suffering from endometritis-Influence of localisation, smooth muscle layer and cycle phase. An in vitro study.

PubMed

Hirsbrunner, Gaby; Kaufmann, Ch; Keller, Ch; Hüsler, J; Steiner, A

2010-04-01

Contractility of the healthy bovine myometrium depends on the reproductive state. Furthermore, contractility is influenced by localisation and the direction of smooth muscle strips. However, little is known about the contractile behaviour of the uterus when affected by endometritis. In our study, myometrial specimens from the larger horn (near the corpus and near the tip) in cows suffering from endometritis in estrus (n=8) or diestrus (n=8) were collected after slaughter. Two strips were prepared from each region corresponding to the circular and the longitudinal muscle layers, respectively. The spontaneous contractility of these strips was recorded in an organ bath. To analyse the results, the 2.5h recordings were divided into five periods of 30 min each. The variables area under curve (AUC) and maximal (A(max)) and minimal amplitude (A(min)) were calculated separately for each period, and the results were analysed using a non-parametric model regarding the influence of cycle phase (estrus vs. diestrus), region (corpus vs. tip) and muscle layer (circular vs. longitudinal). The values of both AUC and A(max) increased significantly over time. Muscle layer had a significant effect on AUC (corpus, tip) and A(max) (tip): the values of circular layers were increased compared to longitudinal layers. Dividing the data into subgroups allowed us to analyse them additionally according to muscle layer: In longitudinal layers, A(max) was increased at the corpus as compared with the tip. In this model, the factor cycle phase did not produce any significant difference in spontaneous myometrial activity. However, data of all variables showed non-significant higher values in estrus than in diestrus samples. Copyright 2009 Elsevier B.V. All rights reserved.

Tuning of shortening speed in coleoid cephalopod muscle: no evidence for tissue-specific muscle myosin heavy chain isoforms

PubMed Central

Shaffer, Justin F.; Kier, William M.

2015-01-01

The contractile protein myosin II is ubiquitous in muscle. It is widely accepted that animals express tissue-specific myosin isoforms that differ in amino acid sequence and ATPase activity in order to tune muscle contractile velocities. Recent studies, however, suggested that the squid Doryteuthis pealeii might be an exception; members of this species do not express muscle-specific myosin isoforms, but instead alter sarcomeric ultrastructure to adjust contractile velocities. We investigated whether this alternative mechanism of tuning muscle contractile velocity is found in other coleoid cephalopods. We analyzed myosin heavy chain transcript sequences and expression profiles from muscular tissues of a cuttlefish, Sepia officinalis, and an octopus, Octopus bimaculoides, in order to determine if these cephalopods express tissue-specific myosin heavy chain isoforms. We identified transcripts of four and six different myosin heavy chain isoforms in S. officinalis and O. bimaculoides muscular tissues, respectively. Transcripts of all isoforms were expressed in all muscular tissues studied, and thus S. officinalis and O. bimaculoides do not appear to express tissue-specific muscle myosin isoforms. We also examined the sarcomeric ultrastructure in the transverse muscle fibers of the arms of O. bimaculoides and the arms and tentacles of S. officinalis using transmission electron microscopy and found that the fast contracting fibers of the prey capture tentacles of S. officinalis have shorter thick filaments than those found in the slower transverse muscle fibers of the arms of both species. It thus appears that coleoid cephalopods, including the cuttlefish and octopus, may use ultrastructural modifications rather than tissue-specific myosin isoforms to adjust contractile velocities. PMID:26997860

Role of myometrial activity in sperm transport through the genital tract and in fertilization in sows.

PubMed

Langendijk, P; Bouwman, E G; Kidson, A; Kirkwood, R N; Soede, N M; Kemp, B

2002-05-01

The effects of stimulation and suppression of uterine contractility at about the time of insemination on sperm distribution and fertilization in multiparous sows are described. For assessment of fertilization, sows were inseminated about 28 h before (synchronized) ovulation and killed at day 5 after ovulation (n = 53). For assessment of sperm distribution, sows were inseminated about 20 h before expected ovulation and were killed 12 h later (n = 26). At 10 min before insemination, sows received an intrauterine infusion of one of three solutions: (i) saline (control); (ii) 0.60 mg clenbuterol hydrochloride to suppress contractility; or (iii) 1 mg cloprostenol to stimulate contractility. Both clenbuterol and cloprostenol reduced median fertilization rate (P < 0.05) and median number of accessory sperm cells (P < 0.05). Distribution of sperm cells was also affected by treatments. Clenbuterol increased, and cloprostenol decreased, the number of sperm cells (P < 0.05) in the proximal 20 cm of the uterine horn and in the uterotubal junction. In addition, clenbuterol tended to increase and cloprostenol tended to decrease the number of sperm cells in the isthmus, although these effects were not significant. However, relative to the number of sperm cells in the uterus, clenbuterol treatment reduced the number of sperm cells in the uterotubal junction and oviduct, in contrast to cloprostenol. Cloprostenol increased the reflux of semen during insemination. It is hypothesized that suppression of uterine contractility increases transuterine transport time, reducing the ability of sperm cells to enter the uterotubal junction and the oviduct. Stimulation of uterine contractility above a certain level probably increases reflux and impedes transuterine transport of sufficient numbers of sperm cells.

The retardation of myometrial infiltration, reduction of uterine contractility, and alleviation of generalized hyperalgesia in mice with induced adenomyosis by levo-tetrahydropalmatine (l-THP) and andrographolide.

PubMed

Mao, Xiaoyan; Wang, Yuedong; Carter, Andrew V; Zhen, Xuechu; Guo, Sun-Wei

2011-10-01

Adenomyosis is a tough disease to manage nonsurgically. Levo-tetrahydropalmatine (l-THP), a known analgesic, and andrographolide, a nuclear factor kappa B (NF-κB) inhibitor, are both active ingredients extracted from Chinese medicinal herbs. We sought to determine whether treatment of l-THP, andrographolide, and valproic acid (VPA) would suppress the myometrial infiltration, improve pain behavior, and reduce uterine contractility in a mice model of adenomyosis. Adenomyosis was induced in 55 female ICR mice neonatally dosed with tamoxifen, while another 8 (group C) were dosed with solvent only. Starting from 4 weeks after birth, hotplate test was administrated to all mice every 4 weeks. At the 16th week, all mice with induced adenomyosis were randomly divided into 6 groups, each receiving different treatment for 3 weeks: low- or high-dose l-THP, andrographolide, low-dose l-THP and andrographolide jointly, VPA, and untreated. Group C received no treatment. After treatment, the hotplate test was administered and all mice were killed. The depth of myometrial infiltration of ectopic endometrium and uterine contractility were measured and compared across groups. We found that induction of adenomyosis resulted in progressive generalized hyperalgesia, along with elevated amplitude and irregularity of uterine contractions. Treatment with either l-THP, andrographolide, VPA, or l-THP and andrographolide jointly suppressed myometrial infiltration, improved generalized hyperalgesia, and reduced the amplitude and irregularity of uterine contractions. These results suggest that increased uterine contractility, in the form of increased contractile amplitude and irregularity, may contribute to dysmenorrhea in women with adenomyosis. More importantly, l-THP, andrographolide, and VPA all seem to be promising compounds for treating adenomyosis.

Impaired M3 and enhanced M2 muscarinic receptor contractile function in a streptozotocin model of mouse diabetic urinary bladder

PubMed Central

Pak, K. J.; Ostrom, R. S.; Matsui, M.

2010-01-01

We investigated the contractile roles of M2 and M3 muscarinic receptors in urinary bladder from streptozotocin-treated mice. Wild-type and M2 muscarinic receptor knockout (M2 KO) mice were given a single injection of vehicle or streptozotocin (125 mg kg−1) 2–24 weeks prior to bladder assays. The effect of forskolin on contractions elicited to the muscarinic agonist, oxotremorine-M, was measured in isolated urinary bladder (intact or denuded of urothelium). Denuded urinary bladder from vehicle-treated wild-type and M2 KO mice exhibited similar contractile responses to oxotremorine-M, when contraction was normalized relative to that elicited by KCl (50 mM). Eight to 9 weeks after streptozotocin treatment, the EC50 value of oxotremorine-M increased 3.1-fold in urinary bladder from the M2 KO mouse (N = 5) compared to wild type (N = 6; P < 0.001). Analogous changes were observed in intact bladder. In denuded urinary bladder from vehicle-treated mice, forskolin (5 µM) caused a much greater inhibition of contraction in M2 KO bladder compared to wild type. Following streptozotocin treatment, this forskolin effect increased 1.6-fold (P = 0.032). At the 20- to 24-week time point, the forskolin effect increased 1.7-fold for denuded as well as intact bladders (P = 0.036, 0.01, respectively). Although streptozotocin treatment inhibits M3 receptor-mediated contraction in denuded urinary bladder, muscarinic contractile function is maintained in wild-type bladder by enhanced M2 contractile function. M2 receptor activation opposes forskolin-induced relaxation of the urinary bladder, and this M2 function is enhanced following streptozotocin treatment. PMID:20349044

Impaired M3 and enhanced M2 muscarinic receptor contractile function in a streptozotocin model of mouse diabetic urinary bladder.

PubMed

Pak, K J; Ostrom, R S; Matsui, M; Ehlert, F J

2010-05-01

We investigated the contractile roles of M2 and M3 muscarinic receptors in urinary bladder from streptozotocin-treated mice. Wild-type and M2 muscarinic receptor knockout (M2 KO) mice were given a single injection of vehicle or streptozotocin (125 mg kg(-1)) 2-24 weeks prior to bladder assays. The effect of forskolin on contractions elicited to the muscarinic agonist, oxotremorine-M, was measured in isolated urinary bladder (intact or denuded of urothelium). Denuded urinary bladder from vehicle-treated wild-type and M2 KO mice exhibited similar contractile responses to oxotremorine-M, when contraction was normalized relative to that elicited by KCl (50 mM). Eight to 9 weeks after streptozotocin treatment, the EC(50) value of oxotremorine-M increased 3.1-fold in urinary bladder from the M2 KO mouse (N = 5) compared to wild type (N = 6; P < 0.001). Analogous changes were observed in intact bladder. In denuded urinary bladder from vehicle-treated mice, forskolin (5 microM) caused a much greater inhibition of contraction in M2 KO bladder compared to wild type. Following streptozotocin treatment, this forskolin effect increased 1.6-fold (P = 0.032). At the 20- to 24-week time point, the forskolin effect increased 1.7-fold for denuded as well as intact bladders (P = 0.036, 0.01, respectively). Although streptozotocin treatment inhibits M3 receptor-mediated contraction in denuded urinary bladder, muscarinic contractile function is maintained in wild-type bladder by enhanced M2 contractile function. M2 receptor activation opposes forskolin-induced relaxation of the urinary bladder, and this M(2) function is enhanced following streptozotocin treatment.

The guinea pig ileum lacks the direct, high-potency, M(2)-muscarinic, contractile mechanism characteristic of the mouse ileum.

PubMed

Griffin, Michael T; Matsui, Minoru; Ostrom, Rennolds S; Ehlert, Frederick J

2009-10-01

We explored whether the M(2) muscarinic receptor in the guinea pig ileum elicits a highly potent, direct-contractile response, like that from the M(3) muscarinic receptor knockout mouse. First, we characterized the irreversible receptor-blocking activity of 4-DAMP mustard in ileum from muscarinic receptor knockout mice to verify its M(3) selectivity. Then, we used 4-DAMP mustard to inactivate M(3) responses in the guinea pig ileum to attempt to reveal direct, M(2) receptor-mediated contractions. The muscarinic agonist, oxotremorine-M, elicited potent contractions in ileum from wild-type, M(2) receptor knockout, and M(3) receptor knockout mice characterized by negative log EC(50) (pEC (50)) values +/- SEM of 6.75 +/- 0.03, 6.26 +/- 0.05, and 6.99 +/- 0.08, respectively. The corresponding E (max) values in wild-type and M(2) receptor knockout mice were approximately the same, but that in the M(3) receptor knockout mouse was only 36% of wild type. Following 4-DAMP mustard treatment, the concentration-response curve of oxotremorine-M in wild-type ileum resembled that of the M(3) knockout mouse in terms of its pEC (50), E (max), and inhibition by selective muscarinic antagonists. Thus, 4-DAMP mustard treatment appears to inactivate M(3) responses selectively and renders the muscarinic contractile behavior of the wild-type ileum similar to that of the M(3) knockout mouse. Following 4-DAMP mustard treatment, the contractile response of the guinea pig ileum to oxotremorine-M exhibited low potency and a competitive-antagonism profile consistent with an M(3) response. The guinea pig ileum, therefore, lacks a direct, highly potent, M(2)-contractile component but may have a direct, lower potency M(2) component.

Cardiac-specific knockout of ETA receptor mitigates low ambient temperature-induced cardiac hypertrophy and contractile dysfunction

PubMed Central

Zhang, Yingmei; Li, Linlin; Hua, Yinan; Nunn, Jennifer M.; Dong, Feng; Yanagisawa, Masashi; Ren, Jun

2012-01-01

Cold exposure is associated with oxidative stress and cardiac dysfunction. The endothelin (ET) system, which plays a key role in myocardial homeostasis, may participate in cold exposure-induced cardiovascular dysfunction. This study was designed to examine the role of ET-1 in cold stress-induced cardiac geometric and contractile responses. Wild-type (WT) and ETA receptor knockout (ETAKO) mice were assigned to normal or cold exposure (4°C) environment for 2 and 5 weeks prior to evaluation of cardiac geometry, contractile, and intracellular Ca2+ properties. Levels of the temperature sensor transient receptor potential vanilloid (TRPV1), mitochondrial proteins for biogenesis and oxidative phosphorylation, including UCP2, HSP90, and PGC1α were evaluated. Cold stress triggered cardiac hypertrophy, depressed myocardial contractile capacity, including fractional shortening, peak shortening, and maximal velocity of shortening/relengthening, reduced intracellular Ca2+ release, prolonged intracellular Ca2+ decay and relengthening duration, generation of ROS and superoxide, as well as apoptosis, the effects of which were blunted by ETAKO. Western blotting revealed downregulated TRPV1 and PGC1α as well as upregulated UCP2 and activation of GSK3β, GATA4, and CREB in cold-stressed WT mouse hearts, which were obliterated by ETAKO. Levels of HSP90, an essential regulator for thermotolerance, were unchanged. The TRPV1 agonist SA13353 attenuated whereas TRPV1 antagonist capsazepine mimicked cold stress- or ET-1-induced cardiac anomalies. The GSK3β inhibitor SB216763 ablated cold stress-induced cardiac contractile (but not remodeling) changes and ET-1-induced TRPV1 downregulation. These data suggest that ETAKO protects against cold exposure-induced cardiac remodeling and dysfunction mediated through TRPV1 and mitochondrial function. PMID:22442497

Levothyroxine treatment generates an abnormal uterine contractility patterns in an in vitro animal model.

PubMed

Corriveau, Stéphanie; Blouin, Simon; Raiche, Évelyne; Nolin, Marc-Antoine; Rousseau, Éric; Pasquier, Jean-Charles

2015-12-01

Abnormal uterine contraction patterns were recently demonstrated in uterine strips from pregnant women treated with Levothyroxine (T4). These abnormalities were correlated with an increased risk of C-section delivery and associated surgical complications. To date, no study has investigated whether uterine contractility is modified by hypothyroidism or T4 treatment. Herein, we analyze the physiological role of T4 on uterine contractions. Female non-pregnant Sprague-Dawley rats ( N  = 22) were used and divided into four groups: 1) control, 2) hypothyroidism, 3) hypothyroidism treated with low T4 doses (20 μg/kg/day) and 4) with high T4 doses (100 μg/kg/day). Hypothyroidism was induced by an iodine-deficient diet. Isometric tension measurements were performed in vitro on myometrium tissues in isolated organ baths. Contractile activity parameters were quantified (amplitude, duration, frequency and area under the curve) using pharmacological tools to assess their effect. Screening of thyroid function confirmed a hypothyroid state for all rats under iodine-free diet to which T4 was subsequently administered to counterbalance hypothyroidism. Results demonstrate that hypothyroidism significantly decreased contractile duration (-17%) and increased contractile frequency (+26%), while high doses of T4 increased duration (+200%) and decreased frequency (-51%). These results thus mimic the pattern of abnormal contractions previously observed in uterine tissue from T4-treated hypothyroid pregnant women. Our data suggest that changes in myometrial reactivity are induced by T4 treatment. Thus, in conjunction with our previous observations on human myometrial strips, management of hypothyroidism should be improved to reduce the rate of C-sections in this group of patients.

Effects of sodium metabisulphite on guinea pig contractile airway smooth muscle responses in vitro.

PubMed Central

Sun, J.; Sakamoto, T.; Chung, K. F.

1995-01-01

BACKGROUND--Sodium metabisulphite (MBS) is known to induce bronchoconstriction in asthmatic patients. The effects of MBS on guinea pig airway smooth muscle and on neurally mediated contraction in vitro have been examined. METHODS--Tracheal and bronchial airway segments were placed in oxygenated buffer solution and electrical field stimulation was performed in the presence of indomethacin (10(-5) M) and propranolol (10(-6) M) for the measurement of isometric tension. Atropine (10(-6) M) was added to bronchial tissues. RESULTS--Concentrations of MBS up to 10(-3) M had no direct effect on airway smooth muscle contraction and did not alter either tracheal smooth muscle contraction induced by electrical field stimulation at all frequencies or acetylcholine-induced tracheal smooth muscle contraction. There was a similar response in the absence of epithelium, except for potentiation of the response induced by electrical field stimulation at 0.5 Hz (24 (10)% increase). However, MBS (10(-5), 10(-6) and 10(-7) M) augmented neurally-mediated non-adrenergic non-cholinergic contractile responses in the bronchi (13.3 (3.2)%, 23.8 (9.6)%, and 6.4 (1.6)%, respectively). MBS had no effect on the contractile response induced by substance P, but at higher concentrations (10(-3) M and 10(-4) M) it caused a time-dependent attenuation of responses induced by either electrical field stimulation or exogenously applied acetylcholine or substance P. CONCLUSIONS--MBS had no direct contractile responses but enhanced bronchoconstriction induced by activation of non-cholinergic neural pathways in the bronchus, probably through increased release of neuropeptides. At high concentrations MBS inhibited contractile responses initiated by receptor or neural stimulation. Images PMID:7570440

Hydrogen peroxide modulates Ca2+-activation of single permeabilized fibres from fast- and slow-twitch skeletal muscles of rats.

PubMed

Plant, D R; Lynch, G S; Williams, D A

2000-01-01

We examined the effects of redox modulation on single membrane-permeabilized fibre segments from the fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles of adult rats to determine whether the contractile apparatus was the redox target responsible for the increased contractility of muscles exposed to low concentrations of H2O2. The effects of H2O2 on maximum Ca2+-activated force were dose-dependent with 30 min exposure to 5 mM H2O2 causing a progressive decrease by 22+/-3 and 13+/-2% in soleus and EDL permeabilized muscle fibres, respectively. Lower concentrations of exogenous H2O2 (100 microM and 1 mM) had no effect on maximum Ca2+-activated force. Subsequent exposure to the reductant dithiothreitol (DTT, 10 mM, 10 min) fully reversed the H2O2-induced depression of force in EDL, but not in soleus muscle fibres. Incubation with DTT alone for 10 min did not alter Ca2+-activated force in either soleus or EDL muscle fibres. The sensitivity of the contractile filaments to Ca2+ (pCa50) was not altered by exposure to any concentration of exogenous H2O2. However, all concentrations of H2O2 diminished the Hill coefficient in permeabilized fibres from the EDL muscle, indicating that the cooperativity of Ca2+ binding to troponin is altered. H2O2 (5 mM) did not affect rigor force, which indicates that the number of crossbridges participating in contraction was not reduced. In conclusion, H2O2 may reduce the maximum Ca2+ activated force production in skinned muscle fibres by decreasing the force per crossbridge.

Neuro-muscular fatigue and recovery dynamics following anaerobic interval workload.

PubMed

Skof, B; Strojnik, V

2006-03-01

The aim of this study was to determine the influence of anaerobic running on muscle contractile characteristics and voluntary muscle activation level during MVC as well as the dynamics of their recovery during a 2-hour period. Seven well-trained runners performed 5 x 300 m at submaximal velocity with a 1-minute active recovery interval between the runs. The average run velocity was 6.69 m.s(-1), which represented 77 % of their top velocity. Contractile characteristics of the vastus lateralis and activation level of quadriceps femoris muscles were measured before and immediately after the runs and within the 120-minute time interval that followed the workload. To do this we used: single twitch, low- and high-frequency electrical stimulation, maximal voluntary knee extension test, and muscle activation level test. After the exercise the maximal twitch torque (T(TW)) decreased for 28 +/- 3.7 % (p < 0.001) and torque at stimulation with 20 Hz and 100 Hz were 19.2 +/- 4.6 % (p < 0.01) and 7.5 +/- 2.3 % (p < 0.05) lower, respectively, while MVC torque and activation level remained unchanged. Subjects with higher blood lactate accumulation level showed significant decrease in the torque at low frequency stimulation (T(F20)) (r = - 0.80; p < 0.01) and T(TW) (r = - 0.92; p < 0.01). The restoration of twitch torque took a short time despite the fact that blood lactate concentration remained high. Ten minutes after the last interval run the twitch torque exceeded the pre-workload value by 11 % (p < 0.01). Potentiation lasted until the 40th min. It was concluded that fatigue after the anaerobic interval workload was peripheral in character and caused by contractile mechanisms disturbances.

Tension cost correlates with mechanical and biochemical parameters in different myocardial contractility conditions

PubMed Central

Moreira, Cleci M.; Meira, Eduardo F.; Vestena, Luis; Stefanon, Ivanita; Vassallo, Dalton V.; Padilha, Alessandra S.

2012-01-01

OBJECTIVES: Tension cost, the ratio of myosin ATPase activity to tension, reflects the economy of tension development in the myocardium. To evaluate the mechanical advantage represented by the tension cost, we studied papillary muscle contractility and the activity of myosin ATPase in the left ventricles in normal and pathophysiological conditions. METHODS: Experimental protocols were performed using rat left ventricles from: (1) streptozotocin-induced diabetic and control Wistar rats; (2) N-nitro-L-arginine methyl ester (L-NAME) hypertensive and untreated Wistar rats; (3) deoxycorticosterone acetate (DOCA) salt-treated, nephrectomized and salt- and DOCA-treated rats; (4) spontaneous hypertensive rats (SHR) and Wistar Kyoto (WKY) rats; (5) rats with myocardial infarction and sham-operated rats. The isometric force, tetanic tension, and the activity of myosin ATPase were measured. RESULTS: The results obtained from infarcted, diabetic, and deoxycorticosterone acetate-salt-treated rats showed reductions in twitch and tetanic tension compared to the control and sham-operated groups. Twitch and tetanic tension increased in the N-nitro-L-arginine methyl ester-treated rats compared with the Wistar rats. Myosin ATPase activity was depressed in the infarcted, diabetic, and deoxycorticosterone acetate salt-treated rats compared with control and sham-operated rats and was increased in N-nitro-L-arginine methyl ester-treated rats. These parameters did not differ between SHR and WKY rats. In the studied conditions (e.g., post-myocardial infarction, deoxycorticosterone acetate salt-induced hypertension, chronic N-nitro-L-arginine methyl ester treatment, and streptozotocin-induced diabetes), a positive correlation between force or plateau tetanic tension and myosin ATPase activity was observed. CONCLUSION: Our results suggest that the myocardium adapts to force generation by increasing or reducing the tension cost to maintain myocardial contractility with a better mechanical advantage. PMID:22666794

An Asynchronous Learning Approach for the Instructional Component of a Dual-Campus Pharmacy Resident Teaching Program

PubMed Central

Baia, Patricia; Canning, Jacquelyn E.; Strang, Aimee F.

2015-01-01

Objective. To describe the shift to an asynchronous online approach for pedagogy instruction within a pharmacy resident teaching program offered by a dual-campus college. Design. The pedagogy instruction component of the teaching program (Part I) was redesigned with a focus on the content, delivery, and coordination of the learning environment. Asynchronous online learning replaced distance technology or lecture capture. Using a pedagogical content knowledge framework, residents participated in self-paced online learning using faculty recordings, readings, and discussion board activities. A learning management system was used to assess achievement of learning objectives and participation prior to progressing to the teaching experiences component of the teaching program (Part II). Assessment. Evaluation of resident pedagogical knowledge development and participation in Part I of the teaching program was achieved through the learning management system. Participant surveys and written reflections showed general satisfaction with the online learning environment. Future considerations include addition of a live orientation session and increased faculty presence in the online learning environment. Conclusion. An online approach framed by educational theory can be an effective way to provide pedagogy instruction within a teaching program. PMID:25861110

Merging the Forces of Asynchronous Tutoring and Synchronous Conferencing: A Qualitative Study of Arab ESL Academic Writers Using E-Tutoring

ERIC Educational Resources Information Center

Alqadoumi, Omar Mohamed

2012-01-01

Previous studies in the field of e-tutoring dealt either with asynchronous tutoring or synchronous conferencing as modes for providing e-tutoring services to English learners. This qualitative research study reports the experiences of Arab ESL tutees with both asynchronous tutoring and synchronous conferencing. It also reports the experiences of…

Differences in Electronic Exchanges in Synchronous and Asynchronous Computer-Mediated Communication: The Effect of Culture as a Mediating Variable

ERIC Educational Resources Information Center

Angeli, Charoula; Schwartz, Neil H.

2016-01-01

Two hundred and eighty undergraduates from universities in two countries were asked to read didactic material, and then think and write about potential solutions to an ill-defined problem. The writing was conducted within a synchronous or asynchronous computer-mediated communication (CMC) environment. Asynchronous CMC took the form of email…

Localized radio frequency communication using asynchronous transfer mode protocol

DOEpatents

Witzke, Edward L [Edgewood, NM; Robertson, Perry J [Albuquerque, NM; Pierson, Lyndon G [Albuquerque, NM

2007-08-14

A localized wireless communication system for communication between a plurality of circuit boards, and between electronic components on the circuit boards. Transceivers are located on each circuit board and electronic component. The transceivers communicate with one another over spread spectrum radio frequencies. An asynchronous transfer mode protocol controls communication flow with asynchronous transfer mode switches located on the circuit boards.

Features of the Asynchronous Correlation between the China Coal Price Index and Coal Mining Accidental Deaths.

PubMed

Huang, Yuecheng; Cheng, Wuyi; Luo, Sida; Luo, Yun; Ma, Chengchen; He, Tailin

2016-01-01

The features of the asynchronous correlation between accident indices and the factors that influence accidents can provide an effective reference for warnings of coal mining accidents. However, what are the features of this correlation? To answer this question, data from the China coal price index and the number of deaths from coal mining accidents were selected as the sample data. The fluctuation modes of the asynchronous correlation between the two data sets were defined according to the asynchronous correlation coefficients, symbolization, and sliding windows. We then built several directed and weighted network models, within which the fluctuation modes and the transformations between modes were represented by nodes and edges. Then, the features of the asynchronous correlation between these two variables could be studied from a perspective of network topology. We found that the correlation between the price index and the accidental deaths was asynchronous and fluctuating. Certain aspects, such as the key fluctuation modes, the subgroups characteristics, the transmission medium, the periodicity and transmission path length in the network, were analyzed by using complex network theory, analytical methods and spectral analysis method. These results provide a scientific reference for generating warnings for coal mining accidents based on economic indices.

Remote file inquiry (RFI) system

NASA Technical Reports Server (NTRS)

1975-01-01

System interrogates and maintains user-definable data files from remote terminals, using English-like, free-form query language easily learned by persons not proficient in computer programming. System operates in asynchronous mode, allowing any number of inquiries within limitation of available core to be active concurrently.

Cytoskeletal Role in the Contractile Dysfunction of Hypertrophied Myocardium

NASA Astrophysics Data System (ADS)

Tsutsui, Hiroyuki; Ishihara, Kazuaki; Cooper, George

1993-04-01

Cardiac hypertrophy in response to systolic pressure loading frequently results in contractile dysfunction of unknown cause. In the present study, pressure loading increased the microtubule component of the cardiac muscle cell cytoskeleton, which was responsible for the cellular contractile dysfunction observed. The linked microtubule and contractile abnormalities were persistent and thus may have significance for the deterioration of initially compensatory cardiac hypertrophy into congestive heart failure.

Damage-associated molecular pattern activated Toll-like receptor 4 signalling modulates blood pressure in L-NAME-induced hypertension.

PubMed

Sollinger, Daniel; Eißler, Ruth; Lorenz, Steffen; Strand, Susanne; Chmielewski, Stefan; Aoqui, Cristiane; Schmaderer, Christoph; Bluyssen, Hans; Zicha, Josef; Witzke, Oliver; Scherer, Elias; Lutz, Jens; Heemann, Uwe; Baumann, Marcus

2014-03-01

Recent publications have shed new light on the role of the adaptive and innate immune system in the pathogenesis of hypertension. However, there are limited data whether receptors of the innate immune system may influence blood pressure. Toll-like receptor 4 (TLR4), a pattern recognition receptor, is a key component of the innate immune system, which is activated by exogenous and endogenous ligands. Hypertension is associated with end-organ damage and thus might lead to the release of damage-associated molecular patterns (DAMPs), which are endogenous activators of TLR4 receptors. The present study aimed to elucidate whether TLR4 signalling is able to modulate vascular contractility in an experimental model of hypertension thus contributing to blood pressure regulation. NG-nitro-l-arginine methyl ester (l-NAME)-induced hypertension was blunted in TLR4(-/-) when compared with wild-type mice. Treatment with l-NAME was associated with a release of DAMPs, leading to reactive oxygen species production of smooth muscle cells in a TLR4-dependent manner. As oxidative stress leads to an impaired function of the NO-sGC-cyclic GMP (cGMP) pathway, we were able to demonstrate that TLR4(-/-) was protected from sGC inactivation. Consequently, arterial contractility was reduced in TLR4(-/-). Cell damage-associated TLR4 signalling might act as a direct mediator of vascular contractility providing a molecular link between inflammation and hypertension.

CYK-4 regulates Rac, but not Rho, during cytokinesis

PubMed Central

Zhuravlev, Yelena; Hirsch, Sophia M.; Jordan, Shawn N.; Dumont, Julien; Shirasu-Hiza, Mimi; Canman, Julie C.

2017-01-01

Cytokinesis is driven by constriction of an actomyosin contractile ring that is controlled by Rho-family small GTPases. Rho, activated by the guanine-nucleotide exchange factor ECT-2, is upstream of both myosin-II activation and diaphanous formin-mediated filamentous actin (f-actin) assembly, which drive ring constriction. The role for Rac and its regulators is more controversial, but, based on the finding that Rac inactivation can rescue cytokinesis failure when the GTPase-activating protein (GAP) CYK-4 is disrupted, Rac activity was proposed to be inhibitory to contractile ring constriction and thus specifically inactivated by CYK-4 at the division plane. An alternative model proposes that Rac inactivation generally rescues cytokinesis failure by reducing cortical tension, thus making it easier for the cell to divide when ring constriction is compromised. In this alternative model, CYK-4 was instead proposed to activate Rho by binding ECT-2. Using a combination of time-lapse in vivo single-cell analysis and Caenorhabditis elegans genetics, our evidence does not support this alternative model. First, we found that Rac disruption does not generally rescue cytokinesis failure: inhibition of Rac specifically rescues cytokinesis failure due to disruption of CYK-4 or ECT-2 but does not rescue cytokinesis failure due to disruption of two other contractile ring components, the Rho effectors diaphanous formin and myosin-II. Second, if CYK-4 regulates cytokinesis through Rho rather than Rac, then CYK-4 inhibition should decrease levels of downstream targets of Rho. Inconsistent with this, we found no change in the levels of f-actin or myosin-II at the division plane when CYK-4 GAP activity was reduced, suggesting that CYK-4 is not upstream of ECT-2/Rho activation. Instead, we found that the rescue of cytokinesis in CYK-4 mutants by Rac inactivation was Cdc42 dependent. Together our data suggest that CYK-4 GAP activity opposes Rac (and perhaps Cdc42) during cytokinesis. PMID:28298491

Contractility and Ventricular Systolic Stiffening in Hypertensive Heart Disease: Insights into the Pathogenesis of Heart Failure with Preserved Ejection Fraction

PubMed Central

Borlaug, Barry A.; Lam, Carolyn S.P.; Roger, Véronique L.; Rodeheffer, Richard J.; Redfield, Margaret M.

2009-01-01

Objectives: 1) Compare left ventricular (LV) systolic stiffness and contractility in normal subjects, hypertensives without heart failure, and patients with heart failure and preserved ejection fraction (HFpEF); and 2) Determine whether LV systolic stiffness or myocardial contractility are associated with mortality in HFpEF. Background: Arterial load is increased in hypertension and is matched by increased end-systolic LV stiffness (ventricular-arterial coupling). Increased end-systolic LV stiffness may be mediated by enhanced myocardial contractility or processes which increase passive myocardial stiffness. Methods: Healthy controls (n=617), hypertensives (No HF, n=719) and patients with HFpEF (n=244, 96% hypertensive) underwent echo-Doppler characterization of arterial (Ea) and LV end-systolic (Ees) stiffness (elastance), ventricular-arterial coupling (Ea/Ees ratio), chamber-level and myocardial contractility (stress-corrected midwall shortening). Results: Ea and Ees were similarly elevated in hypertensives with or without HFpEF compared with controls, but ventricular-arterial coupling was similar across groups. In hypertensives, elevated Ees was associated with enhanced chamber-level and myocardial contractility, while in HFpEF, chamber and myocardial contractility were depressed compared with both hypertensives and controls. Group differences persisted after adjusting for geometry. In HFpEF, impaired myocardial contractility (but not Ees) was associated with increased age-adjusted mortality. Conclusions: While arterial load is elevated and matched by increased LV systolic stiffness in hypertension with or without HFpEF, the mechanisms of systolic LV stiffening differ substantially. These data suggest that myocardial contractility increases to match arterial load in asymptomatic hypertensive heart disease, but that progression to HFpEF may be mediated by processes which simultaneously impair myocardial contractility and increase passive myocardial stiffness. PMID:19628115

Axonal flip-flops and oscillators.

PubMed

Baker, M D

2000-11-01

The strange and unpleasant sensations (paraesthesiae) or asynchronous motor-unit activation (fasciculation) that result from a period of limb ischaemia are examples of ectopic discharge in peripheral nerves. Ectopic activity also results from demyelination and is associated with serious neurological conditions, such as multiple sclerosis. A build-up of extracellular K(+) in the internode and persistent Na(+) currents are now implicated in generating the different forms of activity arising in normal and demyelinated axons.

Mechanisms underlying hypothermia-induced cardiac contractile dysfunction.

PubMed

Han, Young-Soo; Tveita, Torkjel; Prakash, Y S; Sieck, Gary C

2010-03-01

Rewarming patients after profound hypothermia may result in acute heart failure and high mortality (50-80%). However, the underlying pathophysiological mechanisms are largely unknown. We characterized cardiac contractile function in the temperature range of 15-30 degrees C by measuring the intracellular Ca(2+) concentration ([Ca(2+)](i)) and twitch force in intact left ventricular rat papillary muscles. Muscle preparations were loaded with fura-2 AM and electrically stimulated during cooling at 15 degrees C for 1.5 h before being rewarmed to the baseline temperature of 30 degrees C. After hypothermia/rewarming, peak twitch force decreased by 30-40%, but [Ca(2+)](i) was not significantly altered. In addition, we assessed the maximal Ca(2+)-activated force (F(max)) and Ca(2+) sensitivity of force in skinned papillary muscle fibers. F(max) was decreased by approximately 30%, whereas the pCa required for 50% of F(max) was reduced by approximately 0.14. In rewarmed papillary muscle, both total cardiac troponin I (cTnI) phosphorylation and PKA-mediated cTnI phosphorylation at Ser23/24 were significantly increased compared with controls. We conclude that after hypothermia/rewarming, myocardial contractility is significantly reduced, as evidenced by reduced twitch force and F(max). The reduced myocardial contractility is attributed to decreased Ca(2+) sensitivity of force rather than [Ca(2+)](i) itself, resulting from increased cTnI phosphorylation.

The pathophysiological roles of COX-1 and COX-2 in the intestinal smooth muscle contractility under the anaphylactic condition.

PubMed

Kadowaki, Hiroko; Yamamoto, Takeshi; Kageyama-Yahara, Natsuko; Kurokawa, Nobuo; Kadowaki, Makoto

2008-04-01

Various inflammatory mediators released from antigen-activated mast cells are considered to play a key role in the pathogenesis of food allergy. The aim of the present study was to determine the mechanisms underlying the antigen-induced anaphylactic responses in the rat colons. Wistar rats were sensitized by intraperitoneal injection of ovalbumin (OVA). The contractilities of isolated proximal colons of the sensitized rats were studied in the organ bath. OVA challenges of sensitized tissues induced prolonged contractile responses. The antigen-induced contractions were greatly reduced by mast cell stabilizer doxantrazole (10 microM). However, the contractions were resistant to histamine H1 receptor antagonist and prostaglandin D2 receptor antagonist. In contrast, non-selective cyclooxygenase (COX) inhibitor indomethacin (1 microM) significantly reduced the contractions by 61.0%. Furthermore, selective COX-1 inhibitor FR122047 (10 microM) as well as selective COX-2 inhibitor NS-398 (10 microM) significantly inhibited the contractions by 50.1% and 50.3%, respectively. Nevertheless, the transcript levels of COX-2 as well as COX-1 were not upregulated by OVA in the proximal colons of the sensitized rats. The present results indicate that de novo arachidonic acid metabolites synthesis by constitutive COX-1 as well as constitutive COX-2 within mast cells contribute to the altered smooth muscle contractilities in the colons under the anaphylactic condition.

Effect of aspirin on the contractility of aortic smooth muscle and the course of blood pressure development in male spontaneously hypertensive rats.

PubMed

Rahmani, M A; David, V; Huang, M; DeGray, G

1998-01-01

The effects of acetylsalicylic acid (ASA) on aortic smooth muscle contractility were studied in aortic rings of male SHR and WKY rats. The rats were administered two intraperitoneal injections of 10 mg/kg of ASA per week for ten weeks. Blood pressure of each rat was monitored twice weekly prior to the i.p. injections. Twenty four hours after the last injection the aortic smooth muscles were evaluated for generation of active tension in response to KCl, Phenylephrine (PE), Clonidine and Norepinephrine (NE). In another set of experiments calcium conductance was evaluated in the presence or absence of endothelium both in ASA treated and non treated animals. We report that aortic rings from ASA-treated SHR animals were more responsive to contractile agents than rings from non-treated SHR male rats. Also, the Ca2+ conductance in vitro was enhanced appreciably in SHR aortic rings denuded of their monolayer of endothelium in response to ASA treatment. No decrease in systolic blood pressure was observed in response to ASA treatment in SHR male rats. These results suggest that acetylsalicylic acid not only may modulate aortic smooth muscle contractility through the metabolites of arachidonic acid but may repair to a great extent the hypertension associated plasma membrane permeability defect of vascular myocytes.

PKCδ Regulates Force Signaling during VEGF/CXCL4 Induced Dissociation of Endothelial Tubes

PubMed Central

Jamison, Joshua; Wang, James H-C.; Wells, Alan

2014-01-01

Wound healing requires the vasculature to re-establish itself from the severed ends; endothelial cells within capillaries must detach from neighboring cells before they can migrate into the nascent wound bed to initiate angiogenesis. The dissociation of these endothelial capillaries is driven partially by platelets' release of growth factors and cytokines, particularly the chemokine CXCL4/platelet factor-4 (PF4) that increases cell-cell de-adherence. As this retraction is partly mediated by increased transcellular contractility, the protein kinase c-δ/myosin light chain-2 (PKCδ/MLC-2) signaling axis becomes a candidate mechanism to drive endothelial dissociation. We hypothesize that PKCδ activation induces contractility through MLC-2 to promote dissociation of endothelial cords after exposure to platelet-released CXCL4 and VEGF. To investigate this mechanism of contractility, endothelial cells were allowed to form cords following CXCL4 addition to perpetuate cord dissociation. In this study, CXCL4-induced dissociation was reduced by a VEGFR inhibitor (sunitinib malate) and/or PKCδ inhibition. During combined CXCL4+VEGF treatment, increased contractility mediated by MLC-2 that is dependent on PKCδ regulation. As cellular force is transmitted to focal adhesions, zyxin, a focal adhesion protein that is mechano-responsive, was upregulated after PKCδ inhibition. This study suggests that growth factor regulation of PKCδ may be involved in CXCL4-mediated dissociation of endothelial cords. PMID:24699667

PKCδ regulates force signaling during VEGF/CXCL4 induced dissociation of endothelial tubes.

PubMed

Jamison, Joshua; Wang, James H-C; Wells, Alan

2014-01-01

Wound healing requires the vasculature to re-establish itself from the severed ends; endothelial cells within capillaries must detach from neighboring cells before they can migrate into the nascent wound bed to initiate angiogenesis. The dissociation of these endothelial capillaries is driven partially by platelets' release of growth factors and cytokines, particularly the chemokine CXCL4/platelet factor-4 (PF4) that increases cell-cell de-adherence. As this retraction is partly mediated by increased transcellular contractility, the protein kinase c-δ/myosin light chain-2 (PKCδ/MLC-2) signaling axis becomes a candidate mechanism to drive endothelial dissociation. We hypothesize that PKCδ activation induces contractility through MLC-2 to promote dissociation of endothelial cords after exposure to platelet-released CXCL4 and VEGF. To investigate this mechanism of contractility, endothelial cells were allowed to form cords following CXCL4 addition to perpetuate cord dissociation. In this study, CXCL4-induced dissociation was reduced by a VEGFR inhibitor (sunitinib malate) and/or PKCδ inhibition. During combined CXCL4+VEGF treatment, increased contractility mediated by MLC-2 that is dependent on PKCδ regulation. As cellular force is transmitted to focal adhesions, zyxin, a focal adhesion protein that is mechano-responsive, was upregulated after PKCδ inhibition. This study suggests that growth factor regulation of PKCδ may be involved in CXCL4-mediated dissociation of endothelial cords.

LET-99 functions in the astral furrowing pathway, where it is required for myosin enrichment in the contractile ring

PubMed Central

Price, Kari L.; Rose, Lesilee S.

2017-01-01

The anaphase spindle determines the position of the cytokinesis furrow, such that the contractile ring assembles in an equatorial zone between the two spindle poles. Contractile ring formation is mediated by RhoA activation at the equator by the centralspindlin complex and midzone microtubules. Astral microtubules also inhibit RhoA accumulation at the poles. In the Caenorhabditis elegans one-cell embryo, the astral microtubule–dependent pathway requires anillin, NOP-1, and LET-99. LET-99 is well characterized for generating the asymmetric cortical localization of the Gα-dependent force-generating complex that positions the spindle during asymmetric division. However, whether the role of LET-99 in cytokinesis is specific to asymmetric division and whether it acts through Gα to promote furrowing are unclear. Here we show that LET-99 contributes to furrowing in both asymmetrically and symmetrically dividing cells, independent of its function in spindle positioning and Gα regulation. LET-99 acts in a pathway parallel to anillin and is required for myosin enrichment into the contractile ring. These and other results suggest a positive feedback model in which LET-99 localizes to the presumptive cleavage furrow in response to the spindle and myosin. Once positioned there, LET-99 enhances myosin accumulation to promote furrowing in both symmetrically and asymmetrically dividing cells. PMID:28701343

Analyzing the Social Knowledge Construction Behavioral Patterns of an Online Synchronous Collaborative Discussion Instructional Activity Using an Instant Messaging Tool: A Case Study

ERIC Educational Resources Information Center

Hou, Huei-Tse; Wu, Sheng-Yi

2011-01-01

Online discussions have been widely utilized as an educational activity, and much research has been conducted on the process and behaviors involved in asynchronous discussions. However, research on behavioral patterns in learners' synchronous discussions, including the process of social knowledge construction and project coordination is limited.…

The Effects on Health Behavior and Health Outcomes of Internet-Based Asynchronous Communication Between Health Providers and Patients With a Chronic Condition: A Systematic Review

PubMed Central

Ros, Wynand JG; Schrijvers, Guus

2014-01-01

Background In support of professional practice, asynchronous communication between the patient and the provider is implemented separately or in combination with Internet-based self-management interventions. This interaction occurs primarily through electronic messaging or discussion boards. There is little evidence as to whether it is a useful tool for chronically ill patients to support their self-management and increase the effectiveness of interventions. Objective The aim of our study was to review the use and usability of patient-provider asynchronous communication for chronically ill patients and the effects of such communication on health behavior, health outcomes, and patient satisfaction. Methods A literature search was performed using PubMed and Embase. The quality of the articles was appraised according to the National Institute for Health and Clinical Excellence (NICE) criteria. The use and usability of the asynchronous communication was analyzed by examining the frequency of use and the number of users of the interventions with asynchronous communication, as well as of separate electronic messaging. The effectiveness of asynchronous communication was analyzed by examining effects on health behavior, health outcomes, and patient satisfaction. Results Patients’ knowledge concerning their chronic condition increased and they seemed to appreciate being able to communicate asynchronously with their providers. They not only had specific questions but also wanted to communicate about feeling ill. A decrease in visits to the physician was shown in two studies (P=.07, P=.07). Increases in self-management/self-efficacy for patients with back pain, dyspnea, and heart failure were found. Positive health outcomes were shown in 12 studies, where the clinical outcomes for diabetic patients (HbA1c level) and for asthmatic patients (forced expiratory volume [FEV]) improved. Physical symptoms improved in five studies. Five studies generated a variety of positive psychosocial outcomes. Conclusions The effect of asynchronous communication is not shown unequivocally in these studies. Patients seem to be interested in using email. Patients are willing to participate and are taking the initiative to discuss health issues with their providers. Additional testing of the effects of asynchronous communication on self-management in chronically ill patients is needed. PMID:24434570

The effects on health behavior and health outcomes of Internet-based asynchronous communication between health providers and patients with a chronic condition: a systematic review.

PubMed

de Jong, Catharina Carolina; Ros, Wynand Jg; Schrijvers, Guus

2014-01-16

In support of professional practice, asynchronous communication between the patient and the provider is implemented separately or in combination with Internet-based self-management interventions. This interaction occurs primarily through electronic messaging or discussion boards. There is little evidence as to whether it is a useful tool for chronically ill patients to support their self-management and increase the effectiveness of interventions. The aim of our study was to review the use and usability of patient-provider asynchronous communication for chronically ill patients and the effects of such communication on health behavior, health outcomes, and patient satisfaction. A literature search was performed using PubMed and Embase. The quality of the articles was appraised according to the National Institute for Health and Clinical Excellence (NICE) criteria. The use and usability of the asynchronous communication was analyzed by examining the frequency of use and the number of users of the interventions with asynchronous communication, as well as of separate electronic messaging. The effectiveness of asynchronous communication was analyzed by examining effects on health behavior, health outcomes, and patient satisfaction. Patients' knowledge concerning their chronic condition increased and they seemed to appreciate being able to communicate asynchronously with their providers. They not only had specific questions but also wanted to communicate about feeling ill. A decrease in visits to the physician was shown in two studies (P=.07, P=.07). Increases in self-management/self-efficacy for patients with back pain, dyspnea, and heart failure were found. Positive health outcomes were shown in 12 studies, where the clinical outcomes for diabetic patients (HbA1c level) and for asthmatic patients (forced expiratory volume [FEV]) improved. Physical symptoms improved in five studies. Five studies generated a variety of positive psychosocial outcomes. The effect of asynchronous communication is not shown unequivocally in these studies. Patients seem to be interested in using email. Patients are willing to participate and are taking the initiative to discuss health issues with their providers. Additional testing of the effects of asynchronous communication on self-management in chronically ill patients is needed.

Remodeling the zonula adherens in response to tension and the role of afadin in this response

PubMed Central

Acharya, Bipul R.; Peyret, Grégoire; Fardin, Marc-Antoine; Mège, René-Marc; Ladoux, Benoit; Yap, Alpha S.; Fanning, Alan S.

2016-01-01

Morphogenesis requires dynamic coordination between cell–cell adhesion and the cytoskeleton to allow cells to change shape and move without losing tissue integrity. We used genetic tools and superresolution microscopy in a simple model epithelial cell line to define how the molecular architecture of cell–cell zonula adherens (ZA) is modified in response to elevated contractility, and how these cells maintain tissue integrity. We previously found that depleting zonula occludens 1 (ZO-1) family proteins in MDCK cells induces a highly organized contractile actomyosin array at the ZA. We find that ZO knockdown elevates contractility via a Shroom3/Rho-associated, coiled-coil containing protein kinase (ROCK) pathway. Our data suggest that each bicellular border is an independent contractile unit, with actin cables anchored end-on to cadherin complexes at tricellular junctions. Cells respond to elevated contractility by increasing junctional afadin. Although ZO/afadin knockdown did not prevent contractile array assembly, it dramatically altered cell shape and barrier function in response to elevated contractility. We propose that afadin acts as a robust protein scaffold that maintains ZA architecture at tricellular junctions. PMID:27114502

Asynchronous vibration problem of centrifugal compressor

NASA Technical Reports Server (NTRS)

Fujikawa, T.; Ishiguro, N.; Ito, M.

1980-01-01

An unstable asynchronous vibration problem in a high pressure centrifugal compressor and the remedial actions against it are described. Asynchronous vibration of the compressor took place when the discharge pressure (Pd) was increased, after the rotor was already at full speed. The typical spectral data of the shaft vibration indicate that as the pressure Pd increases, pre-unstable vibration appears and becomes larger, and large unstable asynchronous vibration occurs suddenly (Pd = 5.49MPa). A computer program was used which calculated the logarithmic decrement and the damped natural frequency of the rotor bearing systems. The analysis of the log-decrement is concluded to be effective in preventing unstable vibration in both the design stage and remedial actions.

Ex Vivo Assessment of Contractility, Fatigability and Alternans in Isolated Skeletal Muscles

PubMed Central

Park, Ki Ho; Brotto, Leticia; Lehoang, Oanh; Brotto, Marco; Ma, Jianjie; Zhao, Xiaoli

2012-01-01

Described here is a method to measure contractility of isolated skeletal muscles. Parameters such as muscle force, muscle power, contractile kinetics, fatigability, and recovery after fatigue can be obtained to assess specific aspects of the excitation-contraction coupling (ECC) process such as excitability, contractile machinery and Ca2+ handling ability. This method removes the nerve and blood supply and focuses on the isolated skeletal muscle itself. We routinely use this method to identify genetic components that alter the contractile property of skeletal muscle though modulating Ca2+ signaling pathways. Here, we describe a newly identified skeletal muscle phenotype, i.e., mechanic alternans, as an example of the various and rich information that can be obtained using the in vitro muscle contractility assay. Combination of this assay with single cell assays, genetic approaches and biochemistry assays can provide important insights into the mechanisms of ECC in skeletal muscle. PMID:23149471

Active cells for redundant and configurable articulated structures

NASA Astrophysics Data System (ADS)

Swensen, John P.; Nawroj, Ahsan I.; Pounds, Paul E. I.; Dollar, Aaron M.

2014-10-01

The proposed research effort explores the development of active cells—simple contractile electro-mechanical units that can be used as the material basis for larger articulable structures. Each cell, which might be considered a ‘muscle unit,’ consists of a contractile Nitinol Shape Memory Alloy (SMA) core with conductive terminals. Large numbers of these cells might be combined and externally powered to change phase, contracting to either articulate with a large strain or increase the stiffness of the ensemble, depending on the cell design. Unlike traditional work in modular robotics, the approach presented here focuses on cells that have a simplistic design and function, are inexpensive to fabricate, and are eventually scalable to sub-millimeter sizes, working toward our vision of articulated and robotic structures that can be custom-fabricated from large numbers of general cell units, similar to biological structures. In this paper, we present the design of the active cells and demonstrate their usage with three articulated structures built with them.

Properties of slow- and fast-twitch muscle fibres in a mouse model of amyotrophic lateral sclerosis.

PubMed

Atkin, Julie D; Scott, Rachel L; West, Jan M; Lopes, Elizabeth; Quah, Alvin K J; Cheema, Surindar S

2005-05-01

This investigation was undertaken to determine if there are altered histological, pathological and contractile properties in presymptomatic or endstage diseased muscle fibres from representative slow-twitch and fast-twitch muscles of SOD1 G93A mice in comparison to wildtype mice. In presymptomatic SOD1 G93A mice, there was no detectable peripheral dysfunction, providing evidence that muscle pathology is secondary to motor neuronal dysfunction. At disease endstage however, single muscle fibre contractile analysis demonstrated that fast-twitch muscle fibres and neuromuscular junctions are preferentially affected by amyotrophic lateral sclerosis-induced denervation, being unable to produce the same levels of force when activated by calcium as muscle fibres from their age-matched controls. The levels of transgenic SOD1 expression, aggregation state and activity were also examined in these muscles but there no was no preference for muscle fibre type. Hence, there is no simple correlation between SOD1 protein expression/activity, and muscle fibre type vulnerability in SOD1 G93A mice.

Buckling, stiffening, and negative dissipation in the dynamics of a biopolymer in an active medium

PubMed Central

Kikuchi, Norio; Ehrlicher, Allen; Koch, Daniel; Käs, Josef A.; Ramaswamy, Sriram; Rao, Madan

2009-01-01

We present a generic theory for the dynamics of a stiff filament under tension, in an active medium with orientational correlations, such as a microtubule in contractile actin. In sharp contrast to the case of a passive medium, we find the filament can stiffen, and possibly oscillate or buckle, depending on both the contractile or tensile nature of the activity and the filament-medium anchoring interaction. We also demonstrate a strong violation of the fluctuation–dissipation (FD) relation in the effective dynamics of the filament, including a negative FD ratio. Our approach is also of relevance to the dynamics of axons, and our model equations bear a remarkable formal similarity to those in recent work [Martin P, Hudspeth AJ, Juelicher F (2001) Proc Natl Acad Sci USA 98:14380–14385] on auditory hair cells. Detailed tests of our predictions can be made by using a single filament in actomyosin extracts or bacterial suspensions. PMID:19901332

Optimization of parameters of special asynchronous electric drives

NASA Astrophysics Data System (ADS)

Karandey, V. Yu; Popov, B. K.; Popova, O. B.; Afanasyev, V. L.

2018-03-01

The article considers the solution of the problem of parameters optimization of special asynchronous electric drives. The solution of the problem will allow one to project and create special asynchronous electric drives for various industries. The created types of electric drives will have optimum mass-dimensional and power parameters. It will allow one to realize and fulfill the set characteristics of management of technological processes with optimum level of expenses of electric energy, time of completing the process or other set parameters. The received decision allows one not only to solve a certain optimizing problem, but also to construct dependences between the optimized parameters of special asynchronous electric drives, for example, with the change of power, current in a winding of the stator or rotor, induction in a gap or steel of magnetic conductors and other parameters. On the constructed dependences, it is possible to choose necessary optimum values of parameters of special asynchronous electric drives and their components without carrying out repeated calculations.

Ascending neural pathways in the rat ileum in vitro--effect of capsaicin and involvement of nitric oxide.

PubMed

Allescher, H D; Sattler, D; Piller, C; Schusdziarra, V; Classen, M

1992-07-07

The aim of the present study was to develop and characterize an in vitro model of the rat ileum in which activation of the orally projecting neural excitatory pathway of the myenteric reflex is produced by electrical field stimulation anally to the recording site. The motility of a 10-cm segment of rat ileum was recorded using a perfused manometric assembly with side holes 2 and 4 cm orally to the stimulation site. Electrical field stimulation caused a contractile response in the oral but not in the aboral direction of the stimulation site. The contractile response, which was maximal using low stimulus frequencies (3 or 5 pulses per second (pps)) and decreased with higher frequencies (10 or 20 pps), was blocked by atropine (10(-6) M) at all frequencies tested after acute and after prolonged (greater than 30 min) treatment. The maximal contractile response at 3 pps was abolished by hexamethonium (10(-4) M), tetrodotoxin (5 x 10(-7) M) and by complete transection of the muscular wall between the stimulation and the recording site. Acute administration of capsaicin (8 x 10(-7) M) to the bath reduced the lag between the start of the electrical stimulation and the onset of the contractile response. Higher concentrations of capsaicin (10(-5) M) reduced the contractile response, but this was partly due to an unspecific effect of capsaicin. Blockade of nitric oxide (NO) synthesis by L-NG-nitro-arginine-methyl ester (L-NAME) (3 x 10(-4) M) augmented the contractile response to anal stimulation by 222.4% and reduced the lag period by 54.5%, whereas the stereoisomer D-NAME had no significant effect. The potentiating effects of L-NAME were reversed in the presence of L-arginine (3 x 10(-3) M) but not in the presence of the stereoisomer D-arginine (3 x 10(-3) M). This model can be used to study ascending neural pathways in the rat small intestine. The ascending excitatory response is abolished by atropine and hexamethonium and is modulated by capsicin-sensitive fibers. The ascending pathway is under tonic inhibition of metabolites of the L-arginine-NO pathway.

On the asynchronously continuous control of mobile robot movement by motor cortical spiking activity.

PubMed

Xu, Zhiming; So, Rosa Q; Toe, Kyaw Kyar; Ang, Kai Keng; Guan, Cuntai

2014-01-01

This paper presents an asynchronously intracortical brain-computer interface (BCI) which allows the subject to continuously drive a mobile robot. This system has a great implication for disabled patients to move around. By carefully designing a multiclass support vector machine (SVM), the subject's self-paced instantaneous movement intents are continuously decoded to control the mobile robot. In particular, we studied the stability of the neural representation of the movement directions. Experimental results on the nonhuman primate showed that the overt movement directions were stably represented in ensemble of recorded units, and our SVM classifier could successfully decode such movements continuously along the desired movement path. However, the neural representation of the stop state for the self-paced control was not stably represented and could drift.

High power-efficient asynchronous SAR ADC for IoT devices

NASA Astrophysics Data System (ADS)

Zhang, Beichen; Yao, Bingbing; Liu, Liyuan; Liu, Jian; Wu, Nanjian

2017-10-01

This paper presents a power-efficient 100-MS/s, 10-bit asynchronous successive approximation register (SAR) ADC. It includes an on-chip reference buffer and the total power dissipation is 6.8 mW. To achieve high performance with high power-efficiency in the proposed ADC, bootstrapped switch, redundancy, set-and-down switching approach, dynamic comparator and dynamic logic techniques are employed. The prototype was fabricated using 65 nm standard CMOS technology. At a 1.2-V supply and 100 MS/s, the ADC achieves an SNDR of 56.2 dB and a SFDR of 65.1 dB. The ADC core consumes only 3.1 mW, resulting in a figure of merit (FOM) of 30.27 fJ/conversionstep and occupies an active area of only 0.009 mm2.

The structural determinants responsible for c-Fos protein proteasomal degradation differ according to the conditions of expression.

PubMed

Ferrara, Patrizia; Andermarcher, Elisabetta; Bossis, Guillaume; Acquaviva, Claire; Brockly, Frédérique; Jariel-Encontre, Isabelle; Piechaczyk, Marc

2003-03-13

c-fos gene is expressed constitutively in a number of tissues as well as in certain tumor cells and is inducible, in general rapidly and transiently, in virtually all other cell types by a variety of stimuli. Its protein product, c-Fos, is a short-lived transcription factor that heterodimerizes with various protein partners within the AP-1 transcription complex via leucine zipper/leucine zipper interactions for binding to specific DNA sequences. It is mostly, if not exclusively, degraded by the proteasome. To localize the determinant(s) responsible for its instability, we have conducted a genetic analysis in which the half-lives of c-Fos mutants and chimeras made with the stable EGFP reporter protein were compared under two experimental conditions taken as example of continous and inducible expression. Those were constitutive expression in asynchronously growing Balb/C 3T3 mouse embryo fibroblasts and transient induction in the same cells undergoing the G0/G1 phase transition upon stimulation by serum. Our work shows that c-Fos is degraded faster in synchronous- than in asynchronous cells. This difference in turnover is primarily accounted for by several mechanisms. First, in asynchronous cells, a unique C-terminal destabilizer is active whereas, in serum-stimulated cells two destabilizers located at both extremities of the protein are functional. Second, heterodimerization and/or binding to DNA accelerates protein degradation only during the G0/G1 phase transition. Adding another level of complexity to turnover control, phosphorylation at serines 362 and 374, which are c-Fos phosphorylation sites largely modified during the G0/G1 phase transition, stabilizes c-Fos much more efficiently in asynchronous than in serum-stimulated cells. In both cases, the reduced degradation rate is due to inhibition of the activity of the C-terminal destabilizer. However, in serum-stimulated cells, this effect is partially masked by the activation of the N-terminal destabilizer and basic domain/leucine zipper-dependent mechanisms. Taken together, our data show that multiple degradation mechanisms, differing according to the conditions of expression, may operate on c-Fos to ensure a proper level and/or timing of expression. Moreover, they also indicate that the half-life of c-Fos during the G0/G1 phase transition is determined by a delicate balance between opposing stabilizing and destabilizing mechanisms operating at the same time.

Asynchronous Communication of TLNS3DMB Boundary Exchange

NASA Technical Reports Server (NTRS)

Hammond, Dana P.

1997-01-01

This paper describes the recognition of implicit serialization due to coarse-grain, synchronous communication and demonstrates the conversion to asynchronous communication for the exchange of boundary condition information in the Thin-Layer Navier Stokes 3-Dimensional Multi Block (TLNS3DMB) code. The implementation details of using asynchronous communication is provided including buffer allocation, message identification, and barrier control. The IBM SP2 was used for the tests presented.

[Cost-effectiveness of Synchronous vs. Asynchronous Telepsychiatry in Prison Inmates With Depression].

PubMed

Barrera-Valencia, Camilo; Benito-Devia, Alexis Vladimir; Vélez-Álvarez, Consuelo; Figueroa-Barrera, Mario; Franco-Idárraga, Sandra Milena

Telepsychiatry is defined as the use of information and communication technology (ICT) in providing remote psychiatric services. Telepsychiatry is applied using two types of communication: synchronous (real time) and asynchronous (store and forward). To determine the cost-effectiveness of a synchronous and an asynchronous telepsychiatric model in prison inmate patients with symptoms of depression. A cost-effectiveness study was performed on a population consisting of 157 patients from the Establecimiento Penitenciario y Carcelario de Mediana Seguridad de Manizales, Colombia. The sample was determined by applying Zung self-administered surveys for depression (1965) and the Hamilton Depression Rating Scale (HDRS), the latter being the tool used for the comparison. Initial Hamilton score, arrival time, duration of system downtime, and clinical effectiveness variables had normal distributions (P>.05). There were significant differences (P<.001) between care costs for the different models, showing that the mean cost of the asynchronous model is less than synchronous model, and making the asynchronous model more cost-effective. The asynchronous model is the most cost-effective model of telepsychiatry care for patients with depression admitted to a detention centre, according to the results of clinical effectiveness, cost measurement, and patient satisfaction. Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Features of the Asynchronous Correlation between the China Coal Price Index and Coal Mining Accidental Deaths

PubMed Central

Huang, Yuecheng; Cheng, Wuyi; Luo, Sida; Luo, Yun; Ma, Chengchen; He, Tailin

2016-01-01

The features of the asynchronous correlation between accident indices and the factors that influence accidents can provide an effective reference for warnings of coal mining accidents. However, what are the features of this correlation? To answer this question, data from the China coal price index and the number of deaths from coal mining accidents were selected as the sample data. The fluctuation modes of the asynchronous correlation between the two data sets were defined according to the asynchronous correlation coefficients, symbolization, and sliding windows. We then built several directed and weighted network models, within which the fluctuation modes and the transformations between modes were represented by nodes and edges. Then, the features of the asynchronous correlation between these two variables could be studied from a perspective of network topology. We found that the correlation between the price index and the accidental deaths was asynchronous and fluctuating. Certain aspects, such as the key fluctuation modes, the subgroups characteristics, the transmission medium, the periodicity and transmission path length in the network, were analyzed by using complex network theory, analytical methods and spectral analysis method. These results provide a scientific reference for generating warnings for coal mining accidents based on economic indices. PMID:27902748

Efficacy of an asynchronous electronic curriculum in emergency medicine education in the United States.

PubMed

Wray, Alisa; Bennett, Kathryn; Boysen-Osborn, Megan; Wiechmann, Warren; Toohey, Shannon

2017-01-01

The aim of this study was to measure the effect of an iPad-based asynchronous curriculum on emergency medicine resident performance on the in-training exam (ITE). We hypothesized that the implementation of an asynchronous curriculum (replacing 1 hour of weekly didactic time) would result in non-inferior ITE scores compared to the historical scores of residents who had participated in the traditional 5-hour weekly didactic curriculum. The study was a retrospective, non-inferiority study. conducted at the University of California, Irvine Emergency Medicine Residency Program. We compared ITE scores from 2012 and 2013, when there were 5 weekly hours of didactic content, with scores from 2014 and 2015, when 1 hour of conference was replaced with asynchro-nous content. Examination results were compared using a non-inferiority data analysis with a 10% margin of difference. Using a non-inferiority test with a 95% confidence interval, there was no difference between the 2 groups (before and after implementation of asynchronous learning), as the confidence interval for the change of the ITE was -3.5 to 2.3 points, whereas the 10% non-inferiority margin was 7.8 points. Replacing 1 hour of didactic conference with asynchronous learning showed no negative impact on resident ITE scores.

Operative contractility: a functional concept of the inotropic state.

PubMed

Curiel, Roberto; Perez-Gonzalez, Juan; Torres, Edwar; Landaeta, Ruben; Cerrolaza, Miguel

2005-10-01

1. Initial unsuccessful attempts to evaluate ventricular function in terms of the 'heart as a pump' led to focusing on the 'heart as a muscle' and to the concept of myocardial contractility. However, no clinically ideal index exists to assess the contractile state. The aim of the present study was to develop a mathematical model to assess cardiac contractility. 2. A tri-axial system was conceived for preload (PL), afterload (AL) and contractility, where stroke volume (SV) was represented as the volume of the tetrahedron. Based on this model, 'operative' contractility ('OperCon') was calculated from the readily measured values of PL, AL and SV. The model was tested retrospectively under a variety of different experimental and clinical conditions, in 71 studies in humans and 29 studies in dogs. A prospective echocardiographic study was performed in 143 consecutive subjects to evaluate the ability of the model to assess contractility when SV and PL were measured volumetrically (mL) or dimensionally (cm). 3. With inotropic interventions, OperCon changes were comparable to those of ejection fraction (EF), velocity of shortening (Vcf) and dP/dt-max. Only with positive inotropic interventions did elastance (Ees) show significantly larger changes. With load manipulations, OperCon showed significantly smaller changes than EF and Ees and comparable changes to Vcf and dP/dt-max. Values of OperCon were similar when AL was represented by systolic blood pressure or wall stress and when volumetric or dimensional values were used. 4. Operative contractility is a reliable, simple and versatile method to assess cardiac contractility.

Phorbol ester and spontaneous activity in SHR aorta

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moisey, D.M.; Cox, R.H.

1986-03-01

Thoracic aortas (TA) were excised from 6-week old SHR and WKY. 2mm rings were mounted isometrically at optimum preload. Spontaneous rhythmical activity developed in TA from SHR and had a frequency of 3-4/min with varying periods of quiescence between bursts of activity. The spontaneous activity often produced an increase in tension development which was associated with increased frequency of oscillations. Verapamil (10/sup -7/ M) or Ca/sup + +/-free solution added during the contractile phase resulted in an immediate loss of tension and spontaneous activity. Addition of ouabain (10/sup -4/ M) during the contractile phase of spontaneous activity, increased the frequencymore » of oscillations which appeared to fuse into a tetanus. Spontaneous rhythmical activity was infrequently observed in TA from WKY. However, addition of phorbol 12-myristate-13 acetate (TPA), frequently induced spontaneous rhythmic oscillations associated with tension development in TA from WKY. TPA contracted the SHR TA and increased the frequency of oscillations. SHR TA were more sensitive to TPA than WKY. This study demonstrates (1) spontaneous rhythmical activity, independent of agonist stimulation in TA from 6-week old SHR and (2) TPA induced spontaneous oscillatory activity. The mechanism underlying the spontaneous oscillatory activity may involve membrane coupling events and Na-pump difference between SHR and WKY.« less

Practicing Nonverbal Awareness in the Asynchronous Online Classroom

ERIC Educational Resources Information Center

Kelly, Stephanie; Claus, Christopher J.

2015-01-01

In this unit activity, students understand that social presence-one's ability to project a personality through computer-mediated communication-is critical for creating an effective online learning environment (Christen, Kelly, Fall, & Snyder, in press; Jorgensen, 2002; Kehrwald, 2010; O'Sullivan, Hunt, & Lippert, 2004). Without…

Effects of altered loading states on muscle plasticity: what have we learned from rodents?

NASA Technical Reports Server (NTRS)

Baldwin, K. M.

1996-01-01

This paper summarizes the key findings concerning the adaptive properties of rodent muscle in response to altered loading states. When the mechanical stress on the muscle is chronically increased, the muscle adapts by hypertrophying its fibers. This response is regulated by processes resulting in contractile protein expression reflecting slower phenotypes, thereby enabling the muscle to better support load-hearing activity. In contrast, reducing the load-bearing activity induces an opposite response whereby muscles used for both antigravity function and locomotion atrophy while transforming some of the slow fibers into faster contractile phenotypes. Accompanying the atrophy is both a reduced power generating and activity sustaining capability. These adaptive processes are regulated by both transcriptional and translational processes. Available evidence further suggests that the interaction of heavy resistance activity and hormonal/growth factors (insulin-like growth factor, growth hormone, glucocorticoids, etc.) are critical in the maintenance of muscle mass and function. Also resistance training, in contrast to other activities such as endurance running, provides a more economical form of stress because less mechanical activity is required to maintain muscle homeostasis in the context of chronic states of weightlessness.

Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model

PubMed Central

Patil, Avinash S.; Swamy, Geeta K.; Murtha, Amy P.; Heine, R. Phillips; Zheng, Xiaomei; Grotegut, Chad A.

2015-01-01

Objective: We seek to characterize the effect of progesterone metabolites on spontaneous and oxytocin-induced uterine contractility. Study Design: Spontaneous contractility was studied in mouse uterine horns after treatment with progesterone, 2α-hydroxyprogesterone, 6β-hydroxyprogesterone (6β-OHP), 16α-hydroxyprogesterone (16α-OHP), or 17-hydroxyprogesterone caproate (17-OHPC) at 10−9 to 10−6 mol/L. Uterine horns were exposed to progestins (10−6 mol/L), followed by increasing concentrations of oxytocin (1-100 nmol/L) to study oxytocin-induced contractility. Contraction parameters were compared for each progestin and matched vehicle control using repeated measures 2-way analysis of variance. In vitro metabolism of progesterone by recombinant cytochrome P450 3A (CYP3A) microsomes (3A5, 3A5, and 3A7) identified major metabolites. Results: Oxytocin-induced contractile frequency was decreased by 16α-OHP (P = .03) and increased by 6β-OHP (P = .05). Progesterone and 17-OHPC decreased oxytocin-induced contractile force (P = .02 and P = .04, respectively) and frequency (P = .02 and P = .03, respectively). Only progesterone decreased spontaneous contractile force (P = .02). Production of 16α-OHP and 6β-OHP metabolites were confirmed in all CYP3A isoforms tested. Conclusion: Progesterone metabolites produced by maternal or fetal CYP3A enzymes influence uterine contractility. PMID:26037300

AMP-activated Protein Kinase Phosphorylates Cardiac Troponin I at Ser-150 to Increase Myofilament Calcium Sensitivity and Blunt PKA-dependent Function*

PubMed Central

Nixon, Benjamin R.; Thawornkaiwong, Ariyoporn; Jin, Janel; Brundage, Elizabeth A.; Little, Sean C.; Davis, Jonathan P.; Solaro, R. John; Biesiadecki, Brandon J.

2012-01-01

AMP-activated protein kinase (AMPK) is an energy-sensing enzyme central to the regulation of metabolic homeostasis. In the heart AMPK is activated during cardiac stress-induced ATP depletion and functions to stimulate metabolic pathways that restore the AMP/ATP balance. Recently it was demonstrated that AMPK phosphorylates cardiac troponin I (cTnI) at Ser-150 in vitro. We sought to determine if the metabolic regulatory kinase AMPK phosphorylates cTnI at Ser-150 in vivo to alter cardiac contractile function directly at the level of the myofilament. Rabbit cardiac myofibrils separated by two-dimensional isoelectric focusing subjected to a Western blot with a cTnI phosphorylation-specific antibody demonstrates that cTnI is endogenously phosphorylated at Ser-150 in the heart. Treatment of myofibrils with the AMPK holoenzyme increased cTnI Ser-150 phosphorylation within the constraints of the muscle lattice. Compared with controls, cardiac fiber bundles exchanged with troponin containing cTnI pseudo-phosphorylated at Ser-150 demonstrate increased sensitivity of calcium-dependent force development, blunting of both PKA-dependent calcium desensitization, and PKA-dependent increases in length dependent activation. Thus, in addition to the defined role of AMPK as a cardiac metabolic energy gauge, these data demonstrate AMPK Ser-150 phosphorylation of cTnI directly links the regulation of cardiac metabolic demand to myofilament contractile energetics. Furthermore, the blunting effect of cTnI Ser-150 phosphorylation cross-talk can uncouple the effects of myofilament PKA-dependent phosphorylation from β-adrenergic signaling as a novel thin filament contractile regulatory signaling mechanism. PMID:22493448

Gastrokinetic activity of Morinda citrifolia aqueous fruit extract and its possible mechanism of action in human and rat models.

PubMed

Nima, Sawpheeyah; Kasiwong, Srirat; Ridtitid, Wibool; Thaenmanee, Niwan; Mahattanadul, Sirima

2012-07-13

This study was to investigate the gastrokinetic activity of Morinda citrifolia aqueous fruit extract (AFE) in human subjects by examining the GI absorption of ranitidine, a putative indicator of GI motility and to elucidate its possible gastrokinetic mechanism of action in rats. The single-dose, randomized, open-label and 2-period crossover study was performed on 20 Thai healthy volunteers with a washout period of 14 day between the doses. AFE or drinking water was administered orally 30 min prior to a single oral administration of ranitidine (300 mg). Blood samples were collected over a 12 h period after drug administration and the pharmacokinetic parameters of ranitidine were calculated. The gastrokinetic mechanism of action of AFE was elucidated by measurement of its contractile response on the isolated rat gastric fundus strip. The area under the plasma ranitidine concentration-time curve and the maximal plasma ranitidine concentration were significantly increased after pretreatment with AFE (p=0.001). The plasma ranitidine concentrations were significantly greater at 30-120 min after its administration. AFE produced a definite contractile response of a rat gastric fundus strip with a dose dependency. Scopoletin at the same equivalent dose present in AFE elicited a concentration-dependent contraction that amounted to 45% of the maximal response to AFE. The contractile response of both AFE and scopoletin was mediated through the 5-HT(4) receptor. AFE has a unique gastrokinetic activity in enhancement of the rate and the extent of ranitidine absorption. The underlying mechanism can be attributed, at least in part, to the ability of its active component: scopoletin to stimulate the 5-HT(4) receptor. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Longitudinal and transversal displacements between triceps surae muscles during locomotion of the rat.

PubMed

Bernabei, Michel; van Dieën, Jaap H; Maas, Huub

2017-02-15

The functional consequences of differential muscle activation and contractile behavior between mechanically coupled synergists are still poorly understood. Even though synergistic muscles exert similar mechanical effects at the joint they span, differences in the anatomy, morphology and neural drive may lead to non-uniform contractile conditions. This study aimed to investigate the patterns of activation and contractile behavior of triceps surae muscles, to understand how these contribute to the relative displacement between the one-joint soleus (SO) and two-joint lateral gastrocnemius (LG) muscle bellies and their distal tendons during locomotion in the rat. In seven rats, muscle belly lengths and muscle activation during level and upslope trotting were measured by sonomicrometry crystals and electromyographic electrodes chronically implanted in the SO and LG. Length changes of muscle-tendon units (MTUs) and tendon fascicles were estimated based on joint kinematics and muscle belly lengths. Distances between implanted crystals were further used to assess longitudinal and transversal deformations of the intermuscular volume between the SO and LG. For both slope conditions, we observed differential timing of muscle activation as well as substantial differences in contraction speeds between muscle bellies (maximal relative speed 55.9 mm s -1 ). Muscle lengths and velocities did not differ significantly between level and upslope locomotion, only EMG amplitude of the LG was affected by slope. Relative displacements between SO and LG MTUs were found in both longitudinal and transversal directions, yielding an estimated maximal length change difference of 2.0 mm between their distal tendons. Such relative displacements may have implications for the force exchanged via intermuscular and intertendinous pathways. © 2017. Published by The Company of Biologists Ltd.

[Inotropic effect of a new probiotic product on myocardial contractility. Comparison with diazoxide].

PubMed

Sobol', K V; Korotkov, S M; Nesterov, V P

2014-01-01

The inotropic effect of a new probiotic product on myocardial contractility of the frog Rana ridibunda and the effect of probiotic product on the rat cardiac mitochondria swelling were studied. In both cases, the comparison with known cardioprotector diazoxide was done. Probiotic product and diazoxide were shown to cause a dual effect on the maximum force induced by the muscle sample during spontaneous atrial contraction. Addition of agents caused a negative impact, while washing out exerted a positive inotropic effect. At the same time probiotic product has virtually no effect on the amplitude of contraction induced by electrical stimulation of the ventricle fragments. Probiotic product decreases both proton passive permeability in the inner mitochondrial membrane, and potassium active transport in mitochondria caused by activation of K(+)-uniporter of cardiomyocytes. A possible mechanism of action of probiotic product is discussed.

[Effect of different therapy options on bronchial contraction in rats with modeled obstructive pulmonary disease].

PubMed

Kuzubova, N A; Fedin, A N; Lebedeva, E S; Platonova, I S

2014-09-01

In the model of chronic obstructive pulmonary disease, produced in rats by 60-day exposure to nitrogen dioxide, the effect of different options of combination therapy (corticosteroids, anticholinergics, adrenergic agonists) on the functional state of the bronchi was studied. The contractile activity of strips of the bronchi caused by nerve or smooth muscle stimulation was evaluated. Corticosteroid monotherapy resulted in deterioration of the functional state of the bronchial wall neuromuscular apparatus due to corticosteroid resistance, evolving under the influence of long-term exposure to nitrogen dioxide. Application of M-anticholinergic tiotropium had a beneficial effect on the functional state of the bronchi smooth muscles, leading to the full restoration of the bronchial wall contractile activity and removal the morphological manifestations of inflammatory lung tissue remodeling. Most effective in terms of impact on the functional state of the bronchial wall neuromuscular apparatus was corticosteroid therapy combined with M-cholinolytik or beta2-adrenoagonist.

Continuum mechanical model for cross-linked actin networks with contractile bundles

NASA Astrophysics Data System (ADS)

Ferreira, J. P. S.; Parente, M. P. L.; Natal Jorge, R. M.

2018-01-01

In the context of a mechanical approach to cell biology, there is a close relationship between cellular function and mechanical properties. In recent years, an increasing amount of attention has been given to the coupling between biochemical and mechanical signals by means of constitutive models. In particular, on the active contractility of the actin cytoskeleton. Given the importance of the actin contraction on the physiological functions, this study propose a constitutive model to describe how the filamentous network controls its mechanics actively. Embedded in a soft isotropic ground substance, the network behaves as a viscous mechanical continuum, comprised of isotropically distributed cross-linked actin filaments and actomyosin bundles. Trough virtual rheometry experiments, the present model relates the dynamics of the myosin motors with the network stiffness, which is to a large extent governed by the time-scale of the applied deformations/forces.

Hypothermia Inhibits Endothelium-Independent Vascular Contractility via Rho-kinase Inhibition

PubMed Central

Chung, Yoon Hee; Oh, Keon Woong; Kim, Sung Tae; Park, Eon Sub; Je, Hyun Dong; Yoon, Hyuk-Jun; Sohn, Uy Dong; Jeong, Ji Hoon; La, Hyen-Oh

2018-01-01

The present study was undertaken to investigate the influence of hypothermia on endothelium-independent vascular smooth muscle contractility and to determine the mechanism underlying the relaxation. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Hypothermia significantly inhibited fluoride-, thromboxane A2-, phenylephrine-, and phorbol ester-induced vascular contractions regardless of endothelial nitric oxide synthesis, suggesting that another pathway had a direct effect on vascular smooth muscle. Hypothermia significantly inhibited the fluoride-induced increase in pMYPT1 level and phorbol ester-induced increase in pERK1/2 level, suggesting inhibition of Rho-kinase and MEK activity and subsequent phosphorylation of MYPT1 and ERK1/2. These results suggest that the relaxing effect of moderate hypothermia on agonist-induced vascular contraction regardless of endothelial function involves inhibition of Rho-kinase and MEK activities. PMID:28208012

Probenecid: novel use as a non-injurious positive inotrope acting via cardiac TRPV2 stimulation

PubMed Central

Koch, Sheryl E.; Gao, Xiaoqian; Haar, Lauren; Jiang, Min; Lasko, Valerie M.; Robbins, Nathan; Cai, Wenfeng; Brokamp, Cole; Varma, Priyanka; Tranter, Michael; Liu, Yong; Ren, Xiaoping; Lorenz, John N.; Wang, Hong-Sheng; Jones, W. Keith; Rubinstein, Jack

2012-01-01

Probenecid is a highly lipid soluble benzoic acid derivative originally used to increase serum antibiotic concentrations. It was later discovered to have uricosuric effects and was FDA approved for gout therapy. It has recently been found to be a potent agonist of Transient Receptor Potential Vanilloid 2 (TRPV2). We have shown that this receptor is in the cardiomyocyte and report a positive inotropic effect of the drug. Using echocardiography, Langendorff and isolated myocytes, we measured the change in contractility and, using TRPV2−/− mice, proved that the effect was mediated by TRPV2 channels in the cardiomyocytes. Analysis of the expression of Ca2+ handling and β-adrenergic signaling pathway proteins showed that the contractility was not increased through activation of the β-ADR. We propose that the response to probenecid is due to activation of TRPV2 channels secondary to SR release of Ca2+. PMID:22561103

Active properties of living tissues lead to size-dependent dewetting

NASA Astrophysics Data System (ADS)

Perez-Gonzalez, Carlos; Alert, Ricard; Blanch-Mercader, Carles; Gomez-Gonzalez, Manuel; Casademunt, Jaume; Trepat, Xavier

Key biological processes such as cancer and development are characterized by drastic transitions from 2D to a 3D geometry. These rearrangements have been classically studied as a wetting problem. According to this theory, wettability of a substrate by an epithelium is determined by the competition between cell-cell and cell-substrate adhesion energies. In contrast, we found that, far from a passive process, tissue dewetting is an active process driven by tissue internal forces. Experimentally, we reproduced epithelial dewetting by promoting a progressive formation of intercellular junctions in a monolayer of epithelial cells. Interestingly, the formation of intercellular junctions produces an increase in cell contractility, with the subsequent increase in traction and intercellular stress. At a certain time, tissue tension overcomes cell-substrate maximum adhesion and the monolayer spontaneously dewets the substrate. We developed an active polar fluid model, finding both theoretically and experimentally that critical contractility to promote wetting-dewetting transition depends on cell-substrate adhesion and, unexpectedly, on tissue size. As a whole, this work generalizes wetting theory to living tissues, unveiling unprecedented properties due to their unique active nature.

Glucocorticoids inhibit sulfur mustard-induced airway muscle hyperresponsiveness to substance P.

PubMed

Calvet, J H; D'Ortho, M P; Jarreau, P H; Levame, M; Harf, A; Macquin-Mavier, I

1994-11-01

To explore the mechanisms of airway hyperreactivity to aerosolized substance P observed in guinea pigs 14 days after intratracheal injection of sulfur mustard (SM), we studied the effects of epithelium removal and inhibition of neutral endopeptidase (NEP) activity on airway muscle responsiveness. Tracheal rings from SM-intoxicated guinea pigs expressed a greater contractile response to substance P than rings from nonintoxicated guinea pigs. After epithelium removal or incubation with the NEP inhibitor phosphoramidon, the contractile responses of tracheal rings to substance P did not differ in guinea pigs injected with SM or ethanol (SM solvent). Treatment of the guinea pigs with betamethasone for 7 days before measurement abolished the airway muscle hyperresponsiveness observed in untreated SM-intoxicated guinea pigs and partially restored tracheal epithelium NEP activity. In addition, the tracheal epithelium height and cell density of SM-intoxicated guinea pigs treated with betamethasone were significantly greater than in those without betamethasone. These results demonstrate that SM intoxication induces airway muscle hyperresponsiveness to substance P by reducing tracheal epithelial NEP activity and that glucocorticoids might inhibit this hyperresponsiveness by increasing this activity.

Ethanol extracts of saw palmetto contain the indirectly acting sympathomimetic: tyramine.

PubMed

Chua, Thiam; Simpson, Jamie S; Ventura, Sabatino

2011-01-01

To identify the bioactive components of saw palmetto ethanol extracts that affect contractility in the rat prostate gland. A commercially available saw palmetto ethanol extract was lyophilized then subjected to fractionation using silica gel column chromatography. Composition of fractions was assessed by proton nuclear magnetic resonance ((1)H NMR) spectroscopy and mass spectrometry (MS). Contractile activity of these fractions was evaluated pharmacologically using isolated preparations of rat prostate gland and compared to the activity of crude ethanol extract. Saw palmetto ethanol extract caused contractions of the rat prostate gland which were consistent with indirectly acting sympathomimetic activity. Fractions resulting from chromatography produced contractions of isolated rat prostates that were similar in magnitude to the contractions produced by the crude extracts. Analysis of NMR and mass spectra revealed that this bioactivity was due to tyramine in the active fraction. Tyramine is present in saw palmetto ethanol extracts and causes indirect α(1)-adrenoceptor mediated contractions via the release of noradrenaline from sympathetic neurons. This has clinical implications, as tyramine interacts with MAO inhibitors to cause hypertensive crisis. © 2010 Wiley-Liss, Inc.

A Conserved RhoGAP Limits M-phase Contractility and Coordinates with Microtubule Asters to Restrict Active RhoA to the Cell Equator During Cytokinesis

PubMed Central

Zanin, Esther; Desai, Arshad; Poser, Ina; Toyoda, Yusuke; Andree, Cordula; Moebius, Claudia; Bickle, Marc; Conradt, Barbara; Piekny, Alisa; Oegema, Karen

2014-01-01

SUMMARY During animal cell cytokinesis, the spindle directs contractile ring assembly by activating RhoA in a narrow equatorial zone. Rapid GTPase activating protein (GAP)-mediated inactivation (RhoA flux) is proposed to limit RhoA zone dimensions. Testing the significance of RhoA flux has been hampered by the fact that the GAP targeting RhoA is not known. Here, we identify M-phase GAP (MP-GAP) as the primary GAP targeting RhoA during mitosis/cytokinesis. MP-GAP inhibition caused excessive RhoA activation in M-phase leading to the uncontrolled formation of large cortical protrusions and late cytokinesis failure. RhoA zone width was broadened by attenuation of the centrosomal asters but was not affected by MP-GAP inhibition alone. Simultaneous aster attenuation and MP-GAP inhibition led to RhoA accumulation around the entire cell periphery. These results identify the major GAP restraining RhoA during cell division and delineate the relative contributions of RhoA flux and centrosomal asters in controlling RhoA zone dimensions. PMID:24012485

Oral or vaginal misoprostol administration for induction of labor: a randomized, double-blind trial.

PubMed

Adair, C D; Weeks, J W; Barrilleaux, S; Edwards, M; Burlison, K; Lewis, D F

1998-11-01

To compare the efficacy and vaginal birth intervals after intravaginal or oral misoprostol for labor induction. One hundred seventy-eight women were randomized to one of two double-blind groups: 1) oral misoprostol 200 microg and one-half tablet placebo intravaginal or 2) oral placebo tablet and one-half tablet of a 100-microg misoprostol intravaginal (dose 50 microg). Doses were repeated every 6 hours until labor was established (maximum of three doses). Ninety-three subjects were assigned to oral misoprostol and 85 to intravaginal administration. Oral administration was accompanied by significantly shorter intervals to the onset of uterine contractility (133+/-78 minutes versus 168+/-93, P < .01) but a higher incidence of abnormal uterine contractile activity (tachysystole 38.7% versus 20.0%, P < .01; hyperstimulation syndrome 44.1% versus 21.2%, P < .01). No adverse maternal or neonatal outcomes were noted, nor were there differences in cesarean delivery rates or total lengths of labor. Oral administration of 200 microg misoprostol has similar efficacy to intravaginal administration of 50 microg but is associated with more frequent abnormal uterine contractility.

Impaired gut contractility following hemorrhagic shock is accompaied by IL-6 and G-CSF production and neutrophil infiltration.

PubMed

Hierholzer, C; Kalff, J C; Chakraborty, A; Watkins, S C; Billiar, T R; Bauer, A J; Tweardy, D J

2001-02-01

Recovery from hemorrhagic shock (HS) is frequently accompanied by bowel stasis. The aim of this study was to examine whether or not HS initiates an inflammatory response that includes production of cytokines, specifically G-CSF and interleukin-6 (IL-6), and recruitment of leukocytes within the intestinal muscularis which contribute to impaired muscle contractility. Sprague-Dawley rats were subjected to HS (MAP 40 mm Hg for 156 min) followed by resuscitation, and then they were killed at 4 hr. Shock animals demonstrated accumulation of PMNs in the jejunal muscularis and decreased spontaneous and bethanechol-stimulated muscle contractility. Semiquantitative RT-PCR demonstrated elevated levels of IL-6 and G-CSF mRNA in shock animals in full-thickness jejunum and in mucosa and muscularis layers compared to sham controls. Immunostaining demonstrated increased IL-6 protein production within the muscularis externa and submucosa. In situ hybridization studies localized G-CSF mRNA production to the submucosa. Gel shift assays revealed increased NF-kappaB and Stat3 activity in full-thickness jejunum and jejunal layers of shock animals. Activation of Stat3 also was demonstrated in normal muscularis tissue exposed to IL-6 and G-CSF in vitro. IL-6 and G-CSF are produced in the muscularis and mucosa layers of the gut in HS where they may contribute to PMN recruitment and smooth muscle dysfunction.

Severe myopathy in mice lacking the MEF2/SRF-dependent gene leiomodin-3

PubMed Central

Cenik, Bercin K.; Garg, Ankit; McAnally, John R.; Shelton, John M.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.; Liu, Ning

2015-01-01

Maintenance of skeletal muscle structure and function requires a precise stoichiometry of sarcomeric proteins for proper assembly of the contractile apparatus. Absence of components of the sarcomeric thin filaments causes nemaline myopathy, a lethal congenital muscle disorder associated with aberrant myofiber structure and contractility. Previously, we reported that deficiency of the kelch-like family member 40 (KLHL40) in mice results in nemaline myopathy and destabilization of leiomodin-3 (LMOD3). LMOD3 belongs to a family of tropomodulin-related proteins that promote actin nucleation. Here, we show that deficiency of LMOD3 in mice causes nemaline myopathy. In skeletal muscle, transcription of Lmod3 was controlled by the transcription factors SRF and MEF2. Myocardin-related transcription factors (MRTFs), which function as SRF coactivators, serve as sensors of actin polymerization and are sequestered in the cytoplasm by actin monomers. Conversely, conditions that favor actin polymerization de-repress MRTFs and activate SRF-dependent genes. We demonstrated that the actin nucleator LMOD3, together with its stabilizing partner KLHL40, enhances MRTF-SRF activity. In turn, SRF cooperated with MEF2 to sustain the expression of LMOD3 and other components of the contractile apparatus, thereby establishing a regulatory circuit to maintain skeletal muscle function. These findings provide insight into the molecular basis of the sarcomere assembly and muscle dysfunction associated with nemaline myopathy. PMID:25774500

Multiple asynchronous stimulus- and task-dependent hierarchies (STDH) within the visual brain's parallel processing systems.

PubMed

Zeki, Semir

2016-10-01

Results from a variety of sources, some many years old, lead ineluctably to a re-appraisal of the twin strategies of hierarchical and parallel processing used by the brain to construct an image of the visual world. Contrary to common supposition, there are at least three 'feed-forward' anatomical hierarchies that reach the primary visual cortex (V1) and the specialized visual areas outside it, in parallel. These anatomical hierarchies do not conform to the temporal order with which visual signals reach the specialized visual areas through V1. Furthermore, neither the anatomical hierarchies nor the temporal order of activation through V1 predict the perceptual hierarchies. The latter shows that we see (and become aware of) different visual attributes at different times, with colour leading form (orientation) and directional visual motion, even though signals from fast-moving, high-contrast stimuli are among the earliest to reach the visual cortex (of area V5). Parallel processing, on the other hand, is much more ubiquitous than commonly supposed but is subject to a barely noticed but fundamental aspect of brain operations, namely that different parallel systems operate asynchronously with respect to each other and reach perceptual endpoints at different times. This re-assessment leads to the conclusion that the visual brain is constituted of multiple, parallel and asynchronously operating task- and stimulus-dependent hierarchies (STDH); which of these parallel anatomical hierarchies have temporal and perceptual precedence at any given moment is stimulus and task related, and dependent on the visual brain's ability to undertake multiple operations asynchronously. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Asynchronous RTK precise DGNSS positioning method for deriving a low-latency high-rate output

NASA Astrophysics Data System (ADS)

Liang, Zhang; Hanfeng, Lv; Dingjie, Wang; Yanqing, Hou; Jie, Wu

2015-07-01

Low-latency high-rate (1 Hz) precise real-time kinematic (RTK) can be applied in high-speed scenarios such as aircraft automatic landing, precise agriculture and intelligent vehicle. The classic synchronous RTK (SRTK) precise differential GNSS (DGNSS) positioning technology, however, is not able to obtain a low-latency high-rate output for the rover receiver because of long data link transmission time delays (DLTTD) from the reference receiver. To overcome the long DLTTD, this paper proposes an asynchronous real-time kinematic (ARTK) method using asynchronous observations from two receivers. The asynchronous observation model (AOM) is developed based on undifferenced carrier phase observation equations of the two receivers at different epochs with short baseline. The ephemeris error and atmosphere delay are the possible main error sources on positioning accuracy in this model, and they are analyzed theoretically. In a short DLTTD and during a period of quiet ionosphere activity, the main error sources decreasing positioning accuracy are satellite orbital errors: the "inverted ephemeris error" and the integration of satellite velocity error which increase linearly along with DLTTD. The cycle slip of asynchronous double-differencing carrier phase is detected by TurboEdit method and repaired by the additional ambiguity parameter method. The AOM can deal with synchronous observation model (SOM) and achieve precise positioning solution with synchronous observations as well, since the SOM is only a specific case of AOM. The proposed method not only can reduce the cost of data collection and transmission, but can also support the mobile phone network data link transfer mode for the data of the reference receiver. This method can avoid data synchronizing process besides ambiguity initialization step, which is very convenient for real-time navigation of vehicles. The static and kinematic experiment results show that this method achieves 20 Hz or even higher rate output in real time. The ARTK positioning accuracy is better and more robust than the combination of phase difference over time (PDOT) and SRTK method at a high rate. The ARTK positioning accuracy is equivalent to SRTK solution when the DLTTD is 0.5 s, and centimeter level accuracy can be achieved even when DLTTD is 15 s.

Asynchronous networks: modularization of dynamics theorem

NASA Astrophysics Data System (ADS)

Bick, Christian; Field, Michael

2017-02-01

Building on the first part of this paper, we develop the theory of functional asynchronous networks. We show that a large class of functional asynchronous networks can be (uniquely) represented as feedforward networks connecting events or dynamical modules. For these networks we can give a complete description of the network function in terms of the function of the events comprising the network: the modularization of dynamics theorem. We give examples to illustrate the main results.

Distributed Data-aggregation Consensus for Sensor Networks: Relaxation of Consensus Concept and Convergence Property

DTIC Science & Technology

2014-08-01

consensus algorithm called randomized gossip is more suitable [7, 8]. In asynchronous randomized gossip algorithms, pairs of neighboring nodes exchange...messages and perform updates in an asynchronous and unattended manner, and they also 1 The class of broadcast gossip algorithms [9, 10, 11, 12] are...dynamics [2] and asynchronous pairwise randomized gossip [7, 8], broadcast gossip algorithms do not require that nodes know the identities of their

Simulating fail-stop in asynchronous distributed systems

NASA Technical Reports Server (NTRS)

Sabel, Laura; Marzullo, Keith

1994-01-01

The fail-stop failure model appears frequently in the distributed systems literature. However, in an asynchronous distributed system, the fail-stop model cannot be implemented. In particular, it is impossible to reliably detect crash failures in an asynchronous system. In this paper, we show that it is possible to specify and implement a failure model that is indistinguishable from the fail-stop model from the point of view of any process within an asynchronous system. We give necessary conditions for a failure model to be indistinguishable from the fail-stop model, and derive lower bounds on the amount of process replication needed to implement such a failure model. We present a simple one-round protocol for implementing one such failure model, which we call simulated fail-stop.

Asynchronous Video Interviewing as a New Technology in Personnel Selection: The Applicant’s Point of View

PubMed Central

Brenner, Falko S.; Ortner, Tuulia M.; Fay, Doris

2016-01-01

The present study aimed to integrate findings from technology acceptance research with research on applicant reactions to new technology for the emerging selection procedure of asynchronous video interviewing. One hundred six volunteers experienced asynchronous video interviewing and filled out several questionnaires including one on the applicants’ personalities. In line with previous technology acceptance research, the data revealed that perceived usefulness and perceived ease of use predicted attitudes toward asynchronous video interviewing. Furthermore, openness revealed to moderate the relation between perceived usefulness and attitudes toward this particular selection technology. No significant effects emerged for computer self-efficacy, job interview self-efficacy, extraversion, neuroticism, and conscientiousness. Theoretical and practical implications are discussed. PMID:27378969

Thick Filament Length and Isoform Composition Determine Self-Organized Contractile Units in Actomyosin Bundles

PubMed Central

Thoresen, Todd; Lenz, Martin; Gardel, Margaret L.

2013-01-01

Diverse myosin II isoforms regulate contractility of actomyosin bundles in disparate physiological processes by variations in both motor mechanochemistry and the extent to which motors are clustered into thick filaments. Although the role of mechanochemistry is well appreciated, the extent to which thick filament length regulates actomyosin contractility is unknown. Here, we study the contractility of minimal actomyosin bundles formed in vitro by mixtures of F-actin and thick filaments of nonmuscle, smooth, and skeletal muscle myosin isoforms with varied length. Diverse myosin II isoforms guide the self-organization of distinct contractile units within in vitro bundles with shortening rates similar to those of in vivo myofibrils and stress fibers. The tendency to form contractile units increases with the thick filament length, resulting in a bundle shortening rate proportional to the length of constituent myosin thick filament. We develop a model that describes our data, providing a framework in which to understand how diverse myosin II isoforms regulate the contractile behaviors of disordered actomyosin bundles found in muscle and nonmuscle cells. These experiments provide insight into physiological processes that use dynamic regulation of thick filament length, such as smooth muscle contraction. PMID:23442916

Muscle-specific deletion of exons 2 and 3 of the IL15RA gene in mice: effects on contractile properties of fast and slow muscles.

PubMed

O'Connell, Grant; Guo, Ge; Stricker, Janelle; Quinn, LeBris S; Ma, Averil; Pistilli, Emidio E

2015-02-15

Interleukin-15 (IL-15) is a putative myokine hypothesized to induce an oxidative skeletal muscle phenotype. The specific IL-15 receptor alpha subunit (IL-15Rα) has also been implicated in specifying this contractile phenotype. The purposes of this study were to determine the muscle-specific effects of IL-15Rα functional deficiency on skeletal muscle isometric contractile properties, fatigue characteristics, spontaneous cage activity, and circulating IL-15 levels in male and female mice. Muscle creatine kinase (MCK)-driven IL-15Rα knockout mice (mIl15ra(fl/fl)/Cre(+)) were generated using the Cre-loxP system. We tested the hypothesis that IL-15Rα functional deficiency in skeletal muscle would increase resistance to contraction-induced fatigue, cage activity, and circulating IL-15 levels. There was a significant effect of genotype on the fatigue curves obtained in extensor digitorum longus (EDL) muscles from female mIl15ra(fl/fl)/Cre(+) mice, such that force output was greater during the repeated contraction protocol compared with mIl15ra(fl/fl)/Cre(-) control mice. Muscles from female mIl15ra(fl/fl)/Cre(+) mice also had a twofold greater amount of the mitochondrial genome-specific COXII gene compared with muscles from mIl15ra(fl/fl)/Cre(-) control mice, indicating a greater mitochondrial density in these skeletal muscles. There was a significant effect of genotype on the twitch:tetanus ratio in EDL and soleus muscles from mIl15ra(fl/fl)/Cre(+) mice, such that the ratio was lower in these muscles compared with mIl15ra(fl/fl)/Cre(-) control mice, indicating a pro-oxidative shift in muscle phenotype. However, spontaneous cage activity was not different and IL-15 protein levels were lower in male and female mIl15ra(fl/fl)/Cre(+) mice compared with control. Collectively, these data support a direct effect of muscle IL-15Rα deficiency in altering contractile properties and fatigue characteristics in skeletal muscles.

Increased O-GlcNAcylation of Endothelial Nitric Oxide Synthase Compromises the Anti-contractile Properties of Perivascular Adipose Tissue in Metabolic Syndrome.

PubMed

da Costa, Rafael M; da Silva, Josiane F; Alves, Juliano V; Dias, Thiago B; Rassi, Diane M; Garcia, Luis V; Lobato, Núbia de Souza; Tostes, Rita C

2018-01-01

Under physiological conditions, the perivascular adipose tissue (PVAT) negatively modulates vascular contractility. This property is lost in experimental and human obesity and in the metabolic syndrome, indicating that changes in PVAT function may contribute to vascular dysfunction associated with increased body weight and hyperglycemia. The O -linked β-N-acetylglucosamine ( O -GlcNAc) modification of proteins ( O -GlcNAcylation) is a unique posttranslational process that integrates glucose metabolism with intracellular protein activity. Increased flux of glucose through the hexosamine biosynthetic pathway and the consequent increase in tissue-specific O -GlcNAc modification of proteins have been linked to multiple facets of vascular dysfunction in diabetes and other pathological conditions. We hypothesized that chronic consumption of glucose, a condition that progresses to metabolic syndrome, leads to increased O -GlcNAc modification of proteins in the PVAT, decreasing its anti-contractile effects. Therefore, the current study was devised to determine whether a high-sugar diet increases O -GlcNAcylation in the PVAT and how increased O -GlcNAc interferes with PVAT vasorelaxant function. To assess molecular mechanisms by which O -GlcNAc contributes to PVAT dysfunction, thoracic aortas surrounded by PVAT were isolated from Wistar rats fed either a control or high sugar diet, for 10 and 12 weeks. Rats chronically fed a high sugar diet exhibited metabolic syndrome features, increased O -GlcNAcylated-proteins in the PVAT and loss of PVAT anti-contractile effect. PVAT from high sugar diet-fed rats for 12 weeks exhibited decreased NO formation, reduced expression of endothelial nitric oxide synthase (eNOS) and increased O -GlcNAcylation of eNOS. High sugar diet also decreased OGA activity and increased superoxide anion generation in the PVAT. Visceral adipose tissue samples from hyperglycemic patients showed increased levels of O -GlcNAc-modified proteins, increased ROS generation and decreased OGA activity. These data indicate that O -GlcNAcylation contributes to metabolic syndrome-induced PVAT dysfunction and that O -GlcNAcylation of eNOS may be targeted in the development of novel therapies for vascular dysfunction in conditions associated with hyperglycemia.

Different Roles for Contracture and Calpain in Calcium Paradox-Induced Heart Injury

PubMed Central

Zhang, Jian-Ying; Bi, Sheng-Hui; Xu, Ming; Jin, Zhen-Xiao; Yang, Yang; Jiang, Xiao-Fan; Zhou, Jing-Jun

2012-01-01

The Ca2+ paradox represents a good model to study Ca2+ overload injury in ischemic heart diseases. We and others have demonstrated that contracture and calpain are involved in the Ca2+ paradox-induced injury. This study aimed to elucidate their roles in this model. The Ca2+ paradox was elicited by perfusing isolated rat hearts with Ca2+-free KH media for 3 min or 5 min followed by 30 min of Ca2+ repletion. The LVDP was measured to reflect contractile function, and the LVEDP was measured to indicate contracture. TTC staining and the quantification of LDH release were used to define cell death. Calpain activity and troponin I release were measured after Ca2+ repletion. Ca2+ repletion of the once 3-min Ca2+ depleted hearts resulted in almost no viable tissues and the disappearance of contractile function. Compared to the effects of the calpain inhibitor MDL28170, KB-R7943, an inhibitor of the Na+/Ca2+ exchanger, reduced the LVEDP level to a greater extent, which was well correlated with improved contractile function recovery and tissue survival. The depletion of Ca2+ for 5 min had the same effects on injury as the 3-min Ca2+ depletion, except that the LVEDP in the 5-min Ca2+ depletion group was lower than the level in the 3-min Ca2+ depletion group. KB-R7943 failed to reduce the level of LVEDP, with no improvement in the LVDP recovery in the hearts subjected to the 5-min Ca2+ depletion treatment; however, KB-R7943 preserved its protective effects in surviving tissue. Both KB-R7943 and MDL28170 attenuated the Ca2+ repletion-induced increase in calpain activity in 3 min or 5 min Ca2+ depleted hearts. However, only KB-R7943 reduced the release of troponin I from the Ca2+ paradoxic heart. These results provide evidence suggesting that contracture is the main cause for contractile dysfunction, while activation of calpain mediates cell death in the Ca2+ paradox. PMID:23284963