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Sample records for adrenergic signaling interact

  1. Thyroid hormone and adrenergic signaling interact to control pineal expression of the dopamine receptor D4 gene (Drd4)

    DEFF Research Database (Denmark)

    Kim, Jong-So; Bailey, Michael J; Weller, Joan L;

    2009-01-01

    Dopamine plays diverse and important roles in vertebrate biology, impacting behavior and physiology through actions mediated by specific G-protein-coupled receptors, one of which is the dopamine receptor D4 (Drd4). Here we present studies on the >100-fold daily rhythm in rat pineal Drd4 expressio...... and whether thyroid hormone controls expression of other genes in the pineal gland........ Our studies indicate that Drd4 is the dominant dopamine receptor gene expressed in the pineal gland. The gene is expressed in pinealocytes at levels which are approximately 100-fold greater than in other tissues, except the retina, in which transcript levels are similar. Pineal Drd4 expression...... is circadian in nature and under photoneural control. Whereas most rhythmically expressed genes in the pineal are controlled by adrenergic/cAMP signaling, Drd4 expression also requires thyroid hormone. This advance raises the questions of whether Drd4 expression is regulated by this mechanism in other systems...

  2. Adrenergic signaling and oxidative stress: a role for sirtuins?

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    Graziamaria eCorbi

    2013-11-01

    Full Text Available The adrenergic system plays a central role in stress signaling and stress is often associated with increased production of ROS. However, ROS overproduction generates oxidative stress, that occurs in response to several stressors. β-adrenergic signaling is markedly attenuated in conditions such as heart failure, with downregulation and desensitization of the receptors and their uncoupling from adenylyl cyclase. Transgenic activation of β2-adrenoceptor leads to elevation of NADPH oxidase activity, with greater ROS production and p38MAPK phosphorylation. Inhibition of NADPH oxidase or ROS significantly reduced the p38MAPK signaling cascade. Chronic β2-adrenoceptor activation is associated with greater cardiac dilatation and dysfunction, augmented pro-inflammatory and profibrotic signaling, while antioxidant treatment protected hearts against these abnormalities, indicating ROS production to be central to the detrimental signaling of β2-adrenoceptors. It has been demonstrated that sirtuins are involved in modulating the cellular stress response directly by deacetylation of some factors. Sirt1 increases cellular stress resistance, by an increased insulin sensitivity, a decreased circulating free fatty acids and insulin-like growth factor (IGF-1, an increased activity of AMPK, increased activity of PGC-1a, and increased mitochondrial number. Sirt1 acts by involving signaling molecules such P-I-3-kinase-Akt, MAPK and p38-MAPK-β. βAR stimulation antagonizes the protective effect of the AKT pathway through inhibiting induction of Hif-1α and Sirt1 genes, key elements in cell survival. More studies are needed to better clarify the involvement of sirtuins in the β-adrenergic response and, overall, to better define the mechanisms by which tools such as exercise training are able to counteract the oxidative stress, by both activation of sirtuins and inhibition of GRK2 in many cardiovascular conditions and can be used to prevent or treat diseases such

  3. Optodynamic simulation of β-adrenergic receptor signalling

    Science.gov (United States)

    Siuda, Edward R.; McCall, Jordan G.; Al-Hasani, Ream; Shin, Gunchul; Il Park, Sung; Schmidt, Martin J.; Anderson, Sonya L.; Planer, William J.; Rogers, John A.; Bruchas, Michael R.

    2015-01-01

    Optogenetics has provided a revolutionary approach to dissecting biological phenomena. However, the generation and use of optically active GPCRs in these contexts is limited and it is unclear how well an opsin-chimera GPCR might mimic endogenous receptor activity. Here we show that a chimeric rhodopsin/β2 adrenergic receptor (opto-β2AR) is similar in dynamics to endogenous β2AR in terms of: cAMP generation, MAP kinase activation and receptor internalization. In addition, we develop and characterize a novel toolset of optically active, functionally selective GPCRs that can bias intracellular signalling cascades towards either G-protein or arrestin-mediated cAMP and MAP kinase pathways. Finally, we show how photoactivation of opto-β2AR in vivo modulates neuronal activity and induces anxiety-like behavioural states in both fiber-tethered and wireless, freely moving animals when expressed in brain regions known to contain β2ARs. These new GPCR approaches enhance the utility of optogenetics and allow for discrete spatiotemporal control of GPCR signalling in vitro and in vivo. PMID:26412387

  4. A compartmentalized mathematical model of the β1-adrenergic signaling system in mouse ventricular myocytes.

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    Vladimir E Bondarenko

    Full Text Available The β1-adrenergic signaling system plays an important role in the functioning of cardiac cells. Experimental data shows that the activation of this system produces inotropy, lusitropy, and chronotropy in the heart, such as increased magnitude and relaxation rates of [Ca(2+]i transients and contraction force, and increased heart rhythm. However, excessive stimulation of β1-adrenergic receptors leads to heart dysfunction and heart failure. In this paper, a comprehensive, experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is developed, which includes major subcellular functional compartments (caveolae, extracaveolae, and cytosol. The model describes biochemical reactions that occur during stimulation of β1-adrenoceptors, changes in ionic currents, and modifications of Ca(2+ handling system. Simulations describe the dynamics of major signaling molecules, such as cyclic AMP and protein kinase A, in different subcellular compartments; the effects of inhibition of phosphodiesterases on cAMP production; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca(2+ handling proteins; modifications of action potential shape and duration; magnitudes and relaxation rates of [Ca(2+]i transients; changes in intracellular and transmembrane Ca(2+ fluxes; and [Na(+]i fluxes and dynamics. The model elucidates complex interactions of ionic currents upon activation of β1-adrenoceptors at different stimulation frequencies, which ultimately lead to a relatively modest increase in action potential duration and significant increase in [Ca(2+]i transients. In particular, the model includes two subpopulations of the L-type Ca(2+ channels, in caveolae and extracaveolae compartments, and their effects on the action potential and [Ca(2+]i transients are investigated. The presented model can be used by researchers for the interpretation of experimental data and for the developments of

  5. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment.

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    Kim-Fuchs, Corina; Le, Caroline P; Pimentel, Matthew A; Shackleford, David; Ferrari, Davide; Angst, Eliane; Hollande, Frédéric; Sloan, Erica K

    2014-08-01

    Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of β-adrenergic signaling induced similar effects to chronic stress, and pharmacological β-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural β-adrenergic signaling regulates pancreatic cancer progression and suggest β-blockade as a novel strategy to complement existing therapies for pancreatic cancer.

  6. Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with β-adrenergic activity

    Science.gov (United States)

    Careaga, Mariella B. L.; Tiba, Paula A.; Ota, Simone M.; Suchecki, Deborah

    2015-01-01

    Cognitive processes, such as learning and memory, are essential for our adaptation to environmental changes and consequently for survival. Numerous studies indicate that hormones secreted during stressful situations, such as glucocorticoids (GCs), adrenaline and noradrenaline, regulate memory functions, modulating aversive memory consolidation and retrieval, in an interactive and complementary way. Thus, the facilitatory effects of GCs on memory consolidation as well as their suppressive effects on retrieval are substantially explained by this interaction. On the other hand, low levels of GCs are also associated with negative effects on memory consolidation and retrieval and the mechanisms involved are not well understood. The present study sought to investigate the consequences of blocking the rise of GCs on fear memory retrieval in multiple tests, assessing the participation of β-adrenergic signaling on this effect. Metyrapone (GCs synthesis inhibitor; 75 mg/kg), administered 90 min before the first test of contextual or tone fear conditioning (TFC), negatively affected animals’ performances, but this effect did not persist on a subsequent test, when the conditioned response was again expressed. This result suggested that the treatment impaired fear memory retrieval during the first evaluation. The administration immediately after the first test did not affect the animals’ performances in contextual fear conditioning (CFC), suggesting that the drug did not interfere with processes triggered by memory reactivation. Moreover, metyrapone effects were independent of β-adrenergic signaling, since concurrent administration with propranolol (2 mg/kg), a β-adrenergic antagonist, did not modify the effects induced by metyrapone alone. These results demonstrate that pre-test metyrapone administration led to negative effects on fear memory retrieval and this action was independent of a β-adrenergic signaling. PMID:25784866

  7. Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with β-adrenergic activity

    Directory of Open Access Journals (Sweden)

    Mariella B.L. Careaga

    2015-03-01

    Full Text Available Cognitive processes, such as learning and memory, are essential for our adaptation to environmental changes and consequently for survival. Numerous studies indicate that hormones secreted during stressful situations, such as glucocorticoids (GCs, adrenaline and noradrenaline, regulate memory functions, modulating aversive memory consolidation and retrieval, in an interactive and complementary way. Thus, the facilitatory effects of GCs on memory consolidation as well as their suppressive effects on retrieval are substantially explained by this interaction. On the other hand, low levels of GCs are also associated with negative effects on memory consolidation and retrieval and the mechanisms involved are not well understood. The present study sought to investigate the consequences of blocking the rise of GCs on fear memory retrieval in multiple tests, assessing the participation of β-adrenergic signaling on this effect. Metyrapone (GCs synthesis inhibitor, administered 90 min before the first test of contextual or auditory fear conditioning, negatively affected animals’ performances, but this effect did not persist on a subsequent test, when the conditioned response was again expressed. This result suggested that the treatment impaired fear memory retrieval during the first evaluation. The administration immediately after the first test did not affect the animals’ performances in contextual fear conditioning, suggesting that the drug did not interfere with processes triggered by memory reactivation. Moreover, metyrapone effects were independent of β-adrenergic signaling, since concurrent administration with propranolol, a β-adrenergic antagonist, did not modify the effects induced by metyrapone alone. These results demonstrate that pre-test metyrapone administration led to negative effects on fear memory retrieval and this action was independent of a β-adrenergic signaling.

  8. Beta(3)-adrenergic signaling acutely down regulates adipose triglyceride lipase in brown adipocytes.

    Science.gov (United States)

    Deiuliis, Jeffrey A; Liu, Li-Fen; Belury, Martha A; Rim, Jong S; Shin, Sangsu; Lee, Kichoon

    2010-06-01

    Mice exposed to cold rely upon brown adipose tissue (BAT)-mediated nonshivering thermogenesis to generate body heat using dietary glucose and lipids from the liver and white adipose tissue. In this report, we investigate how cold exposure affects the PI3 K/Akt signaling cascade and the expression of genes involved in lipid metabolism and trafficking in BAT. Cold exposure at an early time point led to the activation of the PI3 K/Akt, insulin-like signaling cascade followed by a transient decrease in adipose triglyceride lipase (ATGL) gene and protein expression in BAT. To further investigate how cold exposure-induced signaling altered ATGL expression, cultured primary brown adipocytes were treated with the beta(3)-adrenergic receptor (beta(3)AR) agonist CL 316,243 (CL) resulting in activation of PI3 K/Akt, ERK 1/2, and p38 signaling pathways and significantly decreased ATGL protein levels. ATGL protein levels decreased significantly 30 min post CL treatment suggesting protein degradation. Inhibition of PKA signaling by H89 rescued ATGL levels. The effects of PKA signaling on ATGL were shown to be independent of relevant pathways downstream of PKA such as PI3 K/Akt, ERK 1/2, and p38. However, CL treatment in 3T3-L1 adipocytes did not decrease ATGL protein and mRNA expression, suggesting a distinct response in WAT to beta3-adrenergic agonism. Transitory effects, possibly attributed to acute Akt activation during the early recruitment phase, were noted as well as stable changes in gene expression which may be attributed to beta3-adrenergic signaling in BAT.

  9. AHNAK deficiency promotes browning and lipolysis in mice via increased responsiveness to β-adrenergic signalling.

    Science.gov (United States)

    Shin, Jae Hoon; Lee, Seo Hyun; Kim, Yo Na; Kim, Il Yong; Kim, Youn Ju; Kyeong, Dong Soo; Lim, Hee Jung; Cho, Soo Young; Choi, Junhee; Wi, Young Jin; Choi, Jae-Hoon; Yoon, Yeo Sung; Bae, Yun Soo; Seong, Je Kyung

    2016-01-01

    In adipose tissue, agonists of the β3-adrenergic receptor (ADRB3) regulate lipolysis, lipid oxidation, and thermogenesis. The deficiency in the thermogenesis induced by neuroblast differentiation-associated protein AHNAK in white adipose tissue (WAT) of mice fed a high-fat diet suggests that AHNAK may stimulate energy expenditure via development of beige fat. Here, we report that AHNAK deficiency promoted browning and thermogenic gene expression in WAT but not in brown adipose tissue of mice stimulated with the ADRB3 agonist CL-316243. Consistent with the increased thermogenesis, Ahnak(-/-) mice exhibited an increase in energy expenditure, accompanied by elevated mitochondrial biogenesis in WAT depots in response to CL-316243. Additionally, AHNAK-deficient WAT contained more eosinophils and higher levels of type 2 cytokines (IL-4/IL-13) to promote browning of WAT in response to CL-316243. This was associated with enhanced sympathetic tone in the WAT via upregulation of adrb3 and tyrosine hydroxylase (TH) in response to β-adrenergic activation. CL-316243 activated PKA signalling and enhanced lipolysis, as evidenced by increased phosphorylation of hormone-sensitive lipase and release of free glycerol in Ahnak(-/-) mice compared to wild-type mice. Overall, these findings suggest an important role of AHNAK in the regulation of thermogenesis and lipolysis in WAT via β-adrenergic signalling. PMID:26987950

  10. Beta-adrenergic stimulation of skeletal muscle HSL can be overridden by AMPK signaling.

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    Watt, Matthew J; Steinberg, Gregory R; Chan, Stanley; Garnham, Andrew; Kemp, Bruce E; Febbraio, Mark A

    2004-09-01

    Hormone-sensitive lipase (HSL), an important regulatory enzyme for triacylglycerol hydrolysis within skeletal muscle, is controlled by beta-adrenergic signaling as well as intrinsic factors related to contraction and energy turnover. In the current study, we tested the capacity of 5'AMP-activated protein kinase (AMPK) to suppress beta-adrenergic stimulation of HSL activity. Eight male subjects completed 60 min of cycle exercise at 70% VO2 peak on two occasions: either with normal (CON) or low (LG) pre-exercise muscle glycogen content, which is known to enhance exercise-induced AMPK activity. Muscle samples were obtained before and immediately after exercise. Pre-exercise glycogen averaged 375 +/- 35 and 163 +/- 27 mmol x kg(-1) dm for CON and LG, respectively. AMPK alpha-2 was not different between trials at rest and was increased (3.7-fold, PHSL activity did not differ between trials at rest and increased (0 min: 1.67 +/- 0.13; 60 min: 2.60 +/- 0.26 mmol x min(-1) x kg(-1) dm) in CON. The exercise-induced increase in HSL activity was attenuated by AMPK alpha-2 activation in LG. The attenuated HSL activity during LG occurred despite higher plasma epinephrine levels (60 min: CON, 1.96 +/- 0.29 vs LG, 4.25 +/- 0.60 nM, PHSL activity in LG, IMTG was decreased by exercise (0 min: 27.1 +/- 2.0; 60 min: 22.5 +/- 2.0 mmol x kg(-1) dm, PHSL activity, we performed experiments in muscle cell culture. The epineprine-induced increase in HSL activity was totally attenuated (PHSL activity that can override beta-adrenergic stimulation. However, the increased IMTG degradation in LG suggests factors other than HSL activity are important for IMTG degradation.

  11. Environmental Novelty Activates β2-Adrenergic Signaling to Prevent the Impairment of Hippocampal LTP by Aβ Oligomers

    OpenAIRE

    Li, Shaomin; Jin, Ming; Zhang, Dainan; Yang, Ting; Koeglsperger, Thomas; Fu, Hongjun; Selkoe, Dennis J.

    2013-01-01

    A central question about human brain aging is whether cognitive enrichment slows the development of Alzheimer changes. Here we show that prolonged exposure to an enriched environment (EE) facilitated signaling in the hippocampus of wild-type mice that promoted long-term potentiation. A key feature of the EE effect was activation of β2-adrenergic receptors and downstream cAMP/PKA signaling. This EE pathway prevented LTP inhibition by soluble oligomers of amyloid β-protein (Aβ) isolated from AD...

  12. Norepinephrine-Induced Adrenergic Activation Strikingly Increased the Atrial Fibrillation Duration through β1- and α1-Adrenergic Receptor-Mediated Signaling in Mice.

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    Kenji Suita

    Full Text Available Atrial fibrillation (AF is the most common arrhythmias among old people. It causes serious long-term health problems affecting the quality of life. It has been suggested that the autonomic nervous system is involved in the onset and maintenance of AF in human. However, investigation of its pathogenesis and potential treatment has been hampered by the lack of suitable AF models in experimental animals.Our aim was to establish a long-lasting AF model in mice. We also investigated the role of adrenergic receptor (AR subtypes, which may be involved in the onset and duration of AF.Trans-esophageal atrial burst pacing in mice could induce AF, as previously shown, but with only a short duration (29.0 ± 8.1 sec. We found that adrenergic activation by intraperitoneal norepinephrine (NE injection strikingly increased the AF duration. It increased the duration to more than 10 minutes, i.e., by more than 20-fold (656.2 ± 104.8 sec; P<0.001. In this model, a prior injection of a specific β1-AR blocker metoprolol and an α1-AR blocker prazosin both significantly attenuated NE-induced elongation of AF. To further explore the mechanisms underlying these receptors' effects on AF, we assessed the SR Ca(2+ leak, a major trigger of AF, and consequent spontaneous SR Ca(2+ release (SCR in atrial myocytes. Consistent with the results of our in-vivo experiments, both metoprolol and prazosin significantly inhibited the NE-induced SR Ca(2+ leak and SCR. These findings suggest that both β1-AR and α1-AR may play important roles in the development of AF.We have established a long-lasting AF model in mice induced by adrenergic activation, which will be valuable in future AF study using experimental animals, such as transgenic mice. We also revealed the important role of β1- and α1-AR-mediated signaling in the development of AF through in-vivo and in-vitro experiments.

  13. β-Adrenergic receptor subtype signaling in heart:From bench to bedside

    Institute of Scientific and Technical Information of China (English)

    Anthony Yiu Ho WOO; Rui-ping XIAO

    2012-01-01

    β-Adrenergic receptor (βAR) stimulation by the sympathetic nervous system or circulating catecholamines is broadly involved in peripheral blood circulation,metabolic regulation,muscle contraction,and central neural activities.In the heart,acute βAR stimulation serves as the most powerful means to regulate cardiac output in response to a fight-or-flight situation,whereas chronic βAR stimulation plays an important role in physiological and pathological cardiac remodeling.There are three βAR subtypes,β1AR,β2AR and β3AR,in cardiac myocytes.Over the past two decades,we systematically investi-gated the molecular and cellular mechanisms underlying the different even opposite functional roles of β1AR and β2AR subtypes in regulating cardiac structure and function,with keen interest in the development of novel therapies based on our discoveries.We have made three major discoveries,including (1) dual coupling of β2AR to Gs and Gi proteins in cardiomyocytes,(2) cardioprotection by β2AR signaling in improving cardiac function and myocyte viability,and (3) PKA-independent,CaMKII-mediated β1AR apoptotic and maladaptive remodeling signaling in the heart.Based on these discoveries and salutary effects of β1AR blockade on patients with heart failure,we envision that activation of β2AR in combination with clinically used β1AR blockade should provide a safer and more effective therapy for the treatment of heart failure.

  14. Stress and glucocorticoids impair memory retrieval via β2-adrenergic, Gi/o-coupled suppression of cAMP signaling.

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    Schutsky, Keith; Ouyang, Ming; Castelino, Christina B; Zhang, Lei; Thomas, Steven A

    2011-10-01

    Acute stress impairs the retrieval of hippocampus-dependent memory, and this effect is mimicked by exogenous administration of stress-responsive glucocorticoid hormones. It has been proposed that glucocorticoids affect memory by promoting the release and/or blocking the reuptake of norepinephrine (NE), a stress-responsive neurotransmitter. It has also been proposed that this enhanced NE signaling impairs memory retrieval by stimulating β(1)-adrenergic receptors and elevating levels of cAMP. In contrast, other evidence indicates that NE, β(1), and cAMP signaling is transiently required for the retrieval of hippocampus-dependent memory. To resolve this discrepancy, wild-type rats and mice with and without gene-targeted mutations were stressed or treated with glucocorticoids and/or adrenergic receptor drugs before testing memory for inhibitory avoidance or fear conditioning. Here we report that glucocorticoids do not require NE to impair retrieval. However, stress- and glucocorticoid-induced impairments of retrieval depend on the activation of β(2) (but not β(1))-adrenergic receptors. Offering an explanation for the opposing functions of these two receptors, the impairing effects of stress, glucocorticoids and β(2) agonists on retrieval are blocked by pertussis toxin, which inactivates signaling by G(i/o)-coupled receptors. In hippocampal slices, β(2) signaling decreases cAMP levels and greatly reduces the increase in cAMP mediated by β(1) signaling. Finally, augmenting cAMP signaling in the hippocampus prevents the impairment of retrieval by systemic β(2) agonists or glucocorticoids. These results demonstrate that the β(2) receptor can be a critical effector of acute stress, and that β(1) and β(2) receptors can have quite distinct roles in CNS signaling and cognition.

  15. The roles of beta-adrenergic receptors in tumorigenesis and the possible use of beta-adrenergic blockers for cancer treatment: possible genetic and cell-signaling mechanisms

    International Nuclear Information System (INIS)

    Cancer is the leading cause of death in the USA, and the incidence of cancer increases dramatically with age. Beta-adrenergic blockers appear to have a beneficial clinical effect in cancer patients. In this paper, we review the evidence of an association between β-adrenergic blockade and cancer. Genetic studies have provided the opportunity to determine which proteins link β-adrenergic blockade to cancer pathology. In particular, this link involves the major histocompatibility complex class II molecules, the renin–angiotensin system, transcription factor nuclear factor-kappa-light-chain-enhancer of activated B cells, poly(ADP-ribose) polymerase-1, vascular endothelial growth factor, and the reduced form of nicotinamide adenine dinucleotide phosphate oxidase. Beta-adrenergic blockers also exert anticancer effects through non-genomic factors, including matrix metalloproteinase, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase-2, oxidative stress, and nitric oxide synthase. In conclusion, β-adrenergic blockade may play a beneficial role in cancer treatment. Additional investigations that examine β-adrenergic blockers as cancer therapeutics are required to further elucidate this role

  16. Tailoring therapy for heart failure: the pharmacogenomics of adrenergic receptor signaling

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    Femminella GD

    2014-09-01

    Full Text Available Grazia Daniela Femminella,1 Vincenzo Barrese,2,3 Nicola Ferrara,1,4 Giuseppe Rengo4 1Department of Translational Medical Sciences, Federico II University, Naples, Italy; 2Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy; 3Division of Biomedical Sciences, St George’s University of London, London, UK; 4”Salvatore Maugeri” Foundation – IRCCS – Scientific Institute of Telese Terme, Telese Terme, Benevento, Italy Abstract: Heart failure is one of the leading causes of mortality in Western countries, and β-blockers are a cornerstone of its treatment. However, the response to these drugs is variable among individuals, which might be explained, at least in part, by genetic differences. Pharmacogenomics is the study of genetic contributions to drug response variability in order to provide evidence for a tailored therapy in an individual patient. Several studies have investigated the pharmacogenomics of the adrenergic receptor system and its role in the context of the use of β-blockers in treating heart failure. In this review, we will focus on the most significant polymorphisms described in the literature involving adrenergic receptors and adrenergic receptor-related proteins, as well as genetic variations influencing β-blocker metabolism. Keywords: adrenergic system, polymorphisms, β-blockers, functional recovery

  17. Cardiovascular effects of the novel histamine H2 receptor agonist amthamine: interaction with the adrenergic system.

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    Coruzzi, G; Gambarelli, E; Bertaccini, G; Timmerman, H

    1996-03-01

    The cardiovascular effects of the new histamine H2 receptor agonist amthamine were studied in the anaesthetized rat, with particular reference to a possible interaction with the adrenergic system. Amthamine (0.03-3 mumol/kg i.v.) caused vasodepressor responses which were antagonized by famotidine (3 mumol/kg i.v.). At higher doses (30-100 mumol/kg i.v.), amthamine induced a modest increase in the mean arterial pressure, which was significantly enhanced by the blockade of H2 receptors and significantly reduced by the alpha 2 adrenoceptor antagonist yohimbine (1 mumol/kg i.v.). The vasopressor response to amthamine was not modified in rats pre-treated with reserpine or 6-hydroxydopamine, and was only minimally modified in adrenalectomized animals, thus suggesting a predominant interaction with postjunctional alpha 2 adrenoceptors in the vascular muscle. The H2 receptor agonist dimaprit (0.3-100 mumol/kg i.v.) caused a reduction in arterial pressure, which was antagonized by famotidine, no pressor response being unmasked. Dimaprit (0.1-30 mumol/kg i.v.) did not modify heart rate but caused a modest bradycardia at 100 mumol/kg i.v. Amthamine (1-100 mumol/kg i.v.) induced a dose-dependent tachycardia, which was only partially (approximately 20%) reduced by famotidine and was totally blocked by propranolol (0.3 mg/kg i.v.). This effect was significantly reduced in rats pre-treated with reserpine or 6-hydroxydopamine and was further reduced by cocaine, thus suggesting a tyramine-like action of amthamine. In conclusion, these data demonstrate that the H2 receptor agonist amthamine can also interact with the adrenergic system when used at doses higher than those necessary to activate H2 receptors. Whereas the increase in blood pressure induced by amthamine seems to be mainly mediated by a direct activation of postjunctional alpha 2 adrenoceptors, the increase in heart rate is predominantly due to neuronal release of catecholamines. These effects should be considered when

  18. AHNAK deficiency promotes browning and lipolysis in mice via increased responsiveness to β-adrenergic signalling

    OpenAIRE

    Jae Hoon Shin; Seo Hyun Lee; Yo Na Kim; Il Yong Kim; Youn Ju Kim; Dong Soo Kyeong; Hee Jung Lim; Soo Young Cho; Junhee Choi; Young Jin Wi; Jae-Hoon Choi; Yeo Sung Yoon; Yun Soo Bae; Je Kyung Seong

    2016-01-01

    In adipose tissue, agonists of the β3-adrenergic receptor (ADRB3) regulate lipolysis, lipid oxidation, and thermogenesis. The deficiency in the thermogenesis induced by neuroblast differentiation-associated protein AHNAK in white adipose tissue (WAT) of mice fed a high-fat diet suggests that AHNAK may stimulate energy expenditure via development of beige fat. Here, we report that AHNAK deficiency promoted browning and thermogenic gene expression in WAT but not in brown adipose tissue of mice ...

  19. Yeast two-hybrid screening for proteins that interact with α1-adrenergic receptors

    Institute of Scientific and Technical Information of China (English)

    TanZHANG; QiXU; Feng-rongCHEN; Qi-deHAN; You-yiZHANG

    2004-01-01

    AIM: To find novel proteins that may bind to α1A-adrenergic receptor (α1A-AR) and investigate their interactions with the other two α1-AR subtypes (α1B-AR and α1D-AR) with an expectation to provide new leads for the function study of the receptors. METHODS: Yeast two-hybrid assay was performed to screen a human brain cDNA library using the C terminus of α1A-AR (α1A-AR-CT) as bait. X-Gal assay and o-nitrophenyl-beta-D-galactopyranoside (ONPG) assay were subsequently conducted to further qualitatively or quantitatively confirm the interactions between receptors and the three identified proteins. RESULTS: (1) Selection medium screening identified segments of bone morphogenetic protein-1 (BMP-1), active Bcr-related protein (Abr), and filamin-C as binding partners of α1A-AR-CT in yeast cells respectively. Besides, protein segments of BMP-1 and Abr could only specifically interact with α1A-AR-CT while filamin-C segment interacted with all three α1-AR subtypes. (2) In X-Gal assay, the cotransformants of α1A-AR-CT and BMP-1 segments turned strong blue at about 30 min while other positive transformants only developed weak blue at about 5-6 h. (3) In ONPG assay, interaction (shown in β-galactosidase activity) between α1A-AR-CT and BMP-1 segments was about 30 times stronger than that of control (P<0.01), while other positive interactions were only about 2-5 times as strong as those of controls (P<0.05). CONCLUSION: In yeast cells BMP-1, Abr and/or filamin-C could interact with three α1-AR subtypes, among which, interaction between BMP-1 and α1A-AR was the strongest while other interactions between proteins and receptors were relatively weak.

  20. Yeast two-hybrid screening for proteins that interact with α1-adrenergic receptors

    Institute of Scientific and Technical Information of China (English)

    Tan ZHANG; Qi XU; Feng-rong CHEN; Qi-de HAN; You-yi ZHANG

    2004-01-01

    AIM: To find novel proteins that may bind to α1A-adrenergic receptor (α1A-AR) and investigate their interactions with the other two α1-AR subtypes (α1B-AR and α1D-AR) with an expectation to provide new leads for the function study of the receptors. METHODS: Yeast two-hybrid assay was performed to screen a human brain cDNA library using the C terminus of α1A-AR (α1A-AR-CT) as bait. X-Gal assay and o-nitrophenyl-beta-D-galactopyranoside(ONPG) assay were subsequently conducted to further qualitatively or quantitatively confirm the interactions between receptors and the three identified proteins. RESULTS: (1) Selection medium screening identified segments of bone morphogenetic protein-1 (BMP-1), active Bcr-related protein (Abr), and filamin-C as binding partners ofα1A-AR-CT in yeast cells respectively. Besides, protein segments of BMP-1 and Abr could only specifically interact with α1A-AR-CT while filamin-C segment interacted with all three α1-AR subtypes. (2) In X-Gal assay, the cotransformants of α1A-AR-CT and BMP-1 segments turned strong blue at about 30 min while other positive transformants only developed weak blue at about 5-6 h. (3) In ONPG assay, interaction (shown in β-galactosidase activity) between α1A-AR-CT and BMP-1 segments was about 30 times stronger than that of control (P<0.01),while other positive interactions were only about 2-5 times as strong as those of controls (P<0.05). CONCLUSION:In yeast cells BMP-1, Abr and/or filamin-C could interact with three α1-AR subtypes, among which, interaction between BMP-1 and α1A-AR was the strongest while other interactions between proteins and receptors were relatively weak.

  1. The biological clock is regulated by adrenergic signaling in brown fat but is dispensable for cold-induced thermogenesis.

    Directory of Open Access Journals (Sweden)

    Siming Li

    Full Text Available The biological clock plays an important role in integrating nutrient and energy metabolism with other cellular processes. Previous studies have demonstrated that core clock genes are rhythmically expressed in peripheral tissues, including the liver, skeletal muscle, pancreatic islets, and white and brown adipose tissues. These peripheral clocks are entrained by physiological cues, thereby aligning the circadian pacemaker to tissue functions. The mechanisms that regulate brown adipose tissue clock in response to physiological signals remain poorly understood. Here we found that the expression of core clock genes is highly responsive to cold exposure in brown fat, but not in white fat. This cold-inducible regulation of the clock network is mediated by adrenergic receptor activation and the transcriptional coactivator PGC-1α. Brown adipocytes in mice lacking a functional clock contain large lipid droplets accompanied by dysregulation of genes involved in lipid metabolism and adaptive thermogenesis. Paradoxically, the "clockless" mice were competent in maintaining core body temperature during cold exposure. These studies elucidated the presence of adrenergic receptor/clock crosstalk that appears to be required for normal thermogenic gene expression in brown fat.

  2. Receptor subtype involved in α1-adrenergic receptor-mediated Ca2+ sig-naling in cardiomyocytes

    Institute of Scientific and Technical Information of China (English)

    Da-li LUO; Jian GAO; Lin-lin FAN; Yu TANG; You-yi ZHANG; Qi-de HAN

    2007-01-01

    Aim: The enhancement of intracellular Ca2+ signaling in response to α1-adrener-gic receptor (α1-AR) stimulation is an essential signal transduction event in the regulation of cardiac functions, such as cardiac growth, cardiac contraction, and cardiac adaptation to various situations. The present study was intended to determine the role(s) of the α1-AR subtype(s) in mediating this response. Methods: We evaluated the effects of subtype-specific agonists and antagonists of the α1- AR on the intracellular Ca2+ signaling of neonatal rat ventricular myocytes using a confocal microscope. Results: After being cultured for 48 h, the myocytes exhibited spontaneous local Ca2+ release, sparks, and global Ca2+ transients. The activation of the α1-AR with phenylephrine, a selective agonist of the α1-AR, dose-dependently increased the frequency of Ca2+ transients with an EC50 value of 2.3 μmol/L. Blocking the α1A-AR subtype with 5-methyhirapidil (5-Mu) inhi-bited the stimulatory effect of phenylephrine with an IC50 value of 6.7 nmol/L. In contrast, blockade of the α1B-AR and α1D-AR subtypes with chloroethylclonidine and BMY 7378, respectively, did not affect the phenylephrine effect. Similarly, the local Ca2+ spark numbers were also increased by the activation of theα1-AR, and this effect could be abolished selectively by 5-Mu. More importantly, A61603, a novel selective α1A-AR agonist, mimicked the effects of phenylephrine, but with more potency (EC50 value =6.9 nmol/L) in the potentiation of Ca2+ transients, and blockade of the α1A-AR by 5-Mu caused abolishment of its effects. Conclusion: These results indicate that α1-adrenergic stimulation of intracellular Ca2+ activity is mediated selectively by the α1A-AR.

  3. Detection of visual signals by rats: effects of chlordiazepoxide and cholinergic and adrenergic drugs on sustained attention.

    Science.gov (United States)

    Bushnell, P J; Oshiro, W M; Padnos, B K

    1997-12-01

    Central cholinergic and adrenergic pathways support the attentional processes necessary for detecting and reporting temporally unpredictable stimuli. To assess the functional effects of pharmacological manipulations of these pathways, male Long-Evans rats performed a two-choice, discrete-trial signal-detection task in which food was provided for pressing one lever after presentation of a signal (a 300-ms light flash), and for pressing a second lever at the end of a trial lacking a signal. Seven signal intensities were presented during each 1-h session in a pseudo-random order across three 100-trial blocks. After acquisition of a stable performance baseline, the acute effects of chlordiazepoxide (0, 3, 5, 8 mg/kg i.p.), pilocarpine (0, 1.0, 1.8, 3.0 mg/kg s.c.), scopolamine 0, 0.030, 0.056, 0.100 mg/kg s.c.), nicotine (0, 0.08, 0.25, 0.75 mg/kg s.c.), mecamylamine (0, 1.8, 3.0, 5.6 mg/kg i.p.), clonidine (0, 0.003, 0.010, 0.030 mg/kg s.c.), and idazoxan (0, 1, 3, 10 mg/kg s.c.) were assessed. Five measures of performance were analyzed: response failures; the proportion of "hits" [P(hit): the proportion of correct responses on signal trials]; the proportion of "false alarms" [P(fa): the proportion of incorrect responses on non-signal trials]; and response times (RT) for hits and for correct rejections. All drugs which slowed responding affected RT for hits and correct rejections equivalently, suggesting little or no influence of motor slowing on choice accuracy. Chlordiazepoxide reduced P(hit) at low signal intensities only, without affecting P(fa) or RT, consistent with sensory impairment (reduced visual sensitivity). All other drugs except nicotine reduced P(hit) at high signal intensities preferentially, suggesting a non-visual source of the impairment. Scopolamine, mecamylamine and clonidine affected both P(hit) and P(fa); pilocarpine and idazoxan reduced P(hit) without affecting P(fa). Nicotine at 0.75 mg/kg decreased P(hit) in the first block of trials; at 0

  4. Psychological stress promotes neutrophil infiltration in colon tissue through adrenergic signaling in DSS-induced colitis model.

    Science.gov (United States)

    Deng, Que; Chen, Hongyu; Liu, Yanjun; Xiao, Fengjun; Guo, Liang; Liu, Dan; Cheng, Xiang; Zhao, Min; Wang, Xiaomeng; Xie, Shuai; Qi, Siyong; Yin, Zhaoyang; Gao, Jiangping; Chen, Xintian; Wang, Jiangong; Guo, Ning; Ma, Yuanfang; Shi, Ming

    2016-10-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition. Psychological stress has been postulated to affect the clinical symptoms and recurrence of IBD. The exact molecular mechanisms are not fully understood. In the present study, we demonstrate that psychological stress promotes neutrophil infiltration into colon tissues in dextran sulfate sodium (DSS)-induced colitis model. The psychological stress resulted in abnormal expression of the proinflammatory cytokines (IL-1β, IL-6, IL-17A, and IL-22) and neutrophil chemokines (CXCL1 and CXCL2) and overactivation of the STAT3 inflammatory signaling pathway. Under chronic unpredictable stress, the adrenergic nervous system was markedly activated, as the expression of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, in bone marrow and colonic epithelium was enhanced, especially in the myenteric ganglia. The β-AR agonist isoproterenol mimicked the effects of psychological stress on neutrophilia, neutrophil infiltration, and colonic damage in DSS-induced colitis. The β1-AR/β2-AR inhibitor propranolol reduced the numbers of the neutrophils in the circulation, suppressed neutrophil infiltration into colonic tissues, and attenuated the colonic tissue damage promoted by chronic stress. Propranolol also abolished stress-induced upregulation of proinflammatory cytokines and neutrophil chemokines. Our data reveal a close linkage between the β1-AR/β2-AR activation and neutrophil trafficking and also suggest the critical roles of adrenergic nervous system in exacerbation of inflammation and damage of colonic tissues in experimental colitis. The current study provides a new insight into the mechanisms underlying the association of psychological stress with excessive inflammatory response and pathophysiological consequences in IBD. The findings also suggest a potential application of neuroprotective agents to prevent relapsing immune activation in the treatment of IBD.

  5. Activation of α2A-adrenergic signal transduction in chondrocytes promotes degenerative remodelling of temporomandibular joint

    Science.gov (United States)

    Jiao, Kai; Zeng, Guang; Niu, Li-Na; Yang, Hong-xu; Ren, Gao-tong; Xu, Xin-yue; Li, Fei-fei; Tay, Franklin R.; Wang, Mei-qing

    2016-01-01

    This study tested whether activation of adrenoreceptors in chondrocytes has roles in degenerative remodelling of temporomandibular joint (TMJ) and to determine associated mechanisms. Unilateral anterior crossbite (UAC) was established to induce TMJ degeneration in rats. Saline vehicle, α2- and β-adrenoreceptor antagonists or agonists were injected locally into the TMJ area of UAC rats. Cartilage degeneration, subchondral bone microarchitecture and the expression of adrenoreceptors, aggrecans, matrix metalloproteinases (MMPs) and RANKL by chondrocytes were evaluated. Chondrocytes were stimulated by norepinephrine to investigate signal transduction of adrenoreceptors. Increased α2A-adrenoreceptor expression was observed in condylar cartilage of UAC rats, together with cartilage degeneration and subchondral bone loss. Norepinephrine depresses aggrecans expression but stimulates MMP-3, MMP-13 and RANKL production by chondrocytes through ERK1/2 and PKA pathway; these effects were abolished by an α2A-adrenoreceptor antagonist. Furthermore, inhibition of α2A-adrenoreceptor attenuated degenerative remodelling in the condylar cartilage and subchondral bone, as revealed by increased cartilage thickness, proteoglycans and aggrecan expression, and decreased MMP-3, MMP-13 and RANKL expressions in cartilage, increased BMD, BV/TV, and decreased Tb.Sp in subchondral bone. Conversely, activation of α2A-adrenoreceptor intensified aforementioned degenerative changes in UAC rats. It is concluded that activation of α2A-adrenergic signal in chondrocytes promotes TMJ degenerative remodelling by chondrocyte-mediated pro-catabolic activities. PMID:27452863

  6. α1B-Adrenergic receptor signaling controls circadian expression of Tnfrsf11b by regulating clock genes in osteoblasts

    Directory of Open Access Journals (Sweden)

    Takao Hirai

    2015-11-01

    Full Text Available Circadian clocks are endogenous and biological oscillations that occur with a period of <24 h. In mammals, the central circadian pacemaker is localized in the suprachiasmatic nucleus (SCN and is linked to peripheral tissues through neural and hormonal signals. In the present study, we investigated the physiological function of the molecular clock on bone remodeling. The results of loss-of-function and gain-of-function experiments both indicated that the rhythmic expression of Tnfrsf11b, which encodes osteoprotegerin (OPG, was regulated by Bmal1 in MC3T3-E1 cells. We also showed that REV-ERBα negatively regulated Tnfrsf11b as well as Bmal1 in MC3T3-E1 cells. We systematically investigated the relationship between the sympathetic nervous system and the circadian clock in osteoblasts. The administration of phenylephrine, a nonspecific α1-adrenergic receptor (AR agonist, stimulated the expression of Tnfrsf11b, whereas the genetic ablation of α1B-AR signaling led to the alteration of Tnfrsf11b expression concomitant with Bmal1 and Per2 in bone. Thus, this study demonstrated that the circadian regulation of Tnfrsf11b was regulated by the clock genes encoding REV-ERBα (Nr1d1 and Bmal1 (Bmal1, also known as Arntl, which are components of the core loop of the circadian clock in osteoblasts.

  7. α1A-adrenergic receptor induces activation of extracellular signal-regulated kinase 1/2 through endocytic pathway.

    Directory of Open Access Journals (Sweden)

    Fei Liu

    Full Text Available G protein-coupled receptors (GPCRs activate mitogen-activated protein kinases through a number of distinct pathways in cells. Increasing evidence has suggested that endosomal signaling has an important role in receptor signal transduction. Here we investigated the involvement of endocytosis in α(1A-adrenergic receptor (α(1A-AR-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2. Agonist-mediated endocytic traffic of α(1A-AR was assessed by real-time imaging of living, stably transfected human embryonic kidney 293A cells (HEK-293A. α(1A-AR was internalized dynamically in cells with agonist stimulation, and actin filaments regulated the initial trafficking of α(1A-AR. α(1A-AR-induced activation of ERK1/2 but not p38 MAPK was sensitive to disruption of endocytosis, as demonstrated by 4°C chilling, dynamin mutation and treatment with cytochalasin D (actin depolymerizing agent. Activation of protein kinase C (PKC and C-Raf by α(1A-AR was not affected by 4°C chilling or cytochalasin D treatment. U73122 (a phospholipase C [PLC] inhibitor and Ro 31-8220 (a PKC inhibitor inhibited α(1B-AR- but not α(1A-AR-induced ERK1/2 activation. These data suggest that the endocytic pathway is involved in α(1A-AR-induced ERK1/2 activation, which is independent of G(q/PLC/PKC signaling.

  8. The Regulatory Role of Rolipram on Inflammatory Mediators and Cholinergic/Adrenergic Stimulation-Induced Signals in Isolated Primary Mouse Submandibular Gland Cells

    Directory of Open Access Journals (Sweden)

    Dong Un Lee

    2016-01-01

    Full Text Available Exposure to bacterial lipopolysaccharides (LPS induces inflammatory signals in salivary glands. We investigated the regulatory role of phosphodiesterase 4 (PDE4 inhibitor rolipram on inflammatory mediators and cholinergic/adrenergic stimulation-induced intracellular Ca2+ signaling in salivary acinar and ductal cells. Submandibular gland (SMG expressed PDE4A through 4D mRNA and PDE4 was localized in the luminal membrane of SMG. LPS induced Ca2+ signaling and ROS production in SMG. Treatment with rolipram blocked LPS-induced Ca2+ increase and ROS production. The application of histamine evoked Ca2+ signals and ROS production, which were attenuated by rolipram in SMG cells. Moreover, LPS-induced NLRP3 inflammasome and cleaved caspase-1 were inhibited by rolipram. The inhibitory role of rolipram in ROS-induced Ca2+ signaling was mainly observed in acinar cells and not in ductal cells. Rolipram also protected SMG acinar but not ductal cells from LPS-induced cell membrane damage. In the case of cholinergic/adrenergic stimulation, carbachol/isoproterenol-induced Ca2+ signals were upregulated by the treatment of rolipram in SMG. In the case of cAMP-dependent ductal bicarbonate secretion by rolipram, no effect was observed on the modulation of ductal chloride/bicarbonate exchange activity. Rolipram could suppress the inflammatory signals and could be a potential therapeutic strategy against LPS-induced inflammation to protect the salivary gland cells.

  9. The Regulatory Role of Rolipram on Inflammatory Mediators and Cholinergic/Adrenergic Stimulation-Induced Signals in Isolated Primary Mouse Submandibular Gland Cells

    Science.gov (United States)

    Lee, Dong Un; Shin, Dong Min; Hong, Jeong Hee

    2016-01-01

    Exposure to bacterial lipopolysaccharides (LPS) induces inflammatory signals in salivary glands. We investigated the regulatory role of phosphodiesterase 4 (PDE4) inhibitor rolipram on inflammatory mediators and cholinergic/adrenergic stimulation-induced intracellular Ca2+ signaling in salivary acinar and ductal cells. Submandibular gland (SMG) expressed PDE4A through 4D mRNA and PDE4 was localized in the luminal membrane of SMG. LPS induced Ca2+ signaling and ROS production in SMG. Treatment with rolipram blocked LPS-induced Ca2+ increase and ROS production. The application of histamine evoked Ca2+ signals and ROS production, which were attenuated by rolipram in SMG cells. Moreover, LPS-induced NLRP3 inflammasome and cleaved caspase-1 were inhibited by rolipram. The inhibitory role of rolipram in ROS-induced Ca2+ signaling was mainly observed in acinar cells and not in ductal cells. Rolipram also protected SMG acinar but not ductal cells from LPS-induced cell membrane damage. In the case of cholinergic/adrenergic stimulation, carbachol/isoproterenol-induced Ca2+ signals were upregulated by the treatment of rolipram in SMG. In the case of cAMP-dependent ductal bicarbonate secretion by rolipram, no effect was observed on the modulation of ductal chloride/bicarbonate exchange activity. Rolipram could suppress the inflammatory signals and could be a potential therapeutic strategy against LPS-induced inflammation to protect the salivary gland cells. PMID:27143817

  10. Indices of brain beta-adrenergic receptor signal transduction in the learned helplessness animal model of depression.

    Science.gov (United States)

    Gurguis, G N; Kramer, G; Petty, F

    1996-01-01

    Both stress response and antidepressant drug action may be mediated by beta-adrenergic receptors (beta AR). Since learned helplessness is a stress-induced animal model of depression, beta AR are relevant to investigate in this model. To date, studies have measured changes in total receptor density (RT), but have not examined more detailed aspects of signal transduction mechanisms such as coupling of the receptor to GS protein. We have investigated brain beta AR coupling in the frontal cortex, hippocampus and hypothalamus of rats exposed to inescapable shock and then tested for learned helplessness, and in both tested and naive controls using [125I]-iodocyanopindolol (ICYP) as the ligand. Both antagonist-saturation and agonist-displacement experiments were conducted, and the specificity for the beta AR was optimized by excluding ICYP binding to 5HT1B receptors. The percentage receptor density in the high-conformational state (%RH) and the ratio of agonist (isoproterenol) dissociation constant from the receptor in the low-/high-conformational states (KL/KH) were used as indices of coupling to GS protein. No significant differences were found between rats developing learned helplessness and non-helpless rats after inescapable stress in any parameter measured in any brain region. In the frontal cortex, exposure to inescapable shock induced beta AR uncoupling from GS protein as suggested by a low KL/KH ratio both in helpless and non-helpless rats but not in either control group. In the hypothalamus, there were trends for higher RL, RT and KL/KH ratio in helpless rats and stressed controls compared to naive controls. These findings suggest that beta AR binding parameters in frontal cortex, hippocampus or hypothalamus did not differentiate between helpless and non-helpless rats. Changes in beta AR coupling observed in these brain regions may reflect effects of stress, which appeared to be region-specific, rather than stress-induced behavioral depression.

  11. Enhanced cardiac function in Gravin mutant mice involves alterations in the β-adrenergic receptor signaling cascade.

    Directory of Open Access Journals (Sweden)

    Ashley N Guillory

    Full Text Available Gravin, an A-kinase anchoring protein, targets protein kinase A (PKA, protein kinase C (PKC, calcineurin and other signaling molecules to the beta2-adrenergic receptor (β2-AR. Gravin mediates desensitization/resensitization of the receptor by facilitating its phosphorylation by PKA and PKC. The role of gravin in β-AR mediated regulation of cardiac function is unclear. The purpose of this study was to determine the effect of acute β-AR stimulation on cardiac contractility in mice lacking functional gravin. Using echocardiographic analysis, we observed that contractility parameters such as left ventricular fractional shortening and ejection fraction were increased in gravin mutant (gravin-t/t animals lacking functional protein compared to wild-type (WT animals both at baseline and following acute isoproterenol (ISO administration. In isolated gravin-t/t cardiomyocytes, we observed increased cell shortening fraction and decreased intracellular Ca(2+ in response to 1 µmol/L ISO stimulation. These physiological responses occurred in the presence of decreased β2-AR phosphorylation in gravin-t/t hearts, where PKA-dependent β2-AR phosphorylation has been shown to lead to receptor desensitization. cAMP production, PKA activity and phosphorylation of phospholamban and troponin I was comparable in WT and gravin-t/t hearts both with and without ISO stimulation. However, cardiac myosin binding protein C (cMyBPC phosphorylation site at position 273 was significantly increased in gravin-t/t versus WT hearts, in the absence of ISO. Additionally, the cardioprotective heat shock protein 20 (Hsp20 was significantly more phosphorylated in gravin-t/t versus WT hearts, in response to ISO. Our results suggest that disruption of gravin's scaffold mediated signaling is able to increase baseline cardiac function as well as to augment contractility in response to acute β-AR stimulation by decreasing β2-AR phosphorylation and thus attenuating receptor

  12. Intracellular β2-adrenergic receptor signaling specificity in mouse skeletal muscle in response to single-dose β2-agonist clenbuterol treatment and acute exercise

    OpenAIRE

    Sato, Shogo; Shirato, Ken; Mitsuhashi, Ryosuke; Inoue, Daisuke; Kizaki, Takako; Ohno, Hideki; Tachiyashiki, Kaoru; Imaizumi, Kazuhiko

    2013-01-01

    The aim of this study was to clarify the intracellular β2-adrenergic receptor signaling specificity in mouse slow-twitch soleus and fast-twitch tibialis anterior (TA) muscles, resulting from single-dose β2-agonist clenbuterol treatment and acute exercise. At 1, 4, and 24 h after single-dose treatment with clenbuterol or after acute running exercise, the soleus and TA muscles were isolated and subjected to analysis. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) increased a...

  13. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)-mediated Calcium Signaling and Arrhythmias in the Heart Evoked by β-Adrenergic Stimulation*♦

    Science.gov (United States)

    Nebel, Merle; Schwoerer, Alexander P.; Warszta, Dominik; Siebrands, Cornelia C.; Limbrock, Ann-Christin; Swarbrick, Joanna M.; Fliegert, Ralf; Weber, Karin; Bruhn, Sören; Hohenegger, Martin; Geisler, Anne; Herich, Lena; Schlegel, Susan; Carrier, Lucie; Eschenhagen, Thomas; Potter, Barry V. L.; Ehmke, Heimo; Guse, Andreas H.

    2013-01-01

    Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+-releasing second messenger known to date. Here, we report a new role for NAADP in arrhythmogenic Ca2+ release in cardiac myocytes evoked by β-adrenergic stimulation. Infusion of NAADP into intact cardiac myocytes induced global Ca2+ signals sensitive to inhibitors of both acidic Ca2+ stores and ryanodine receptors and to NAADP antagonist BZ194. Furthermore, in electrically paced cardiac myocytes BZ194 blocked spontaneous diastolic Ca2+ transients caused by high concentrations of the β-adrenergic agonist isoproterenol. Ca2+ transients were recorded both as increases of the free cytosolic Ca2+ concentration and as decreases of the sarcoplasmic luminal Ca2+ concentration. Importantly, NAADP antagonist BZ194 largely ameliorated isoproterenol-induced arrhythmias in awake mice. We provide strong evidence that NAADP-mediated modulation of couplon activity plays a role for triggering spontaneous diastolic Ca2+ transients in isolated cardiac myocytes and arrhythmias in the intact animal. Thus, NAADP signaling appears an attractive novel target for antiarrhythmic therapy. PMID:23564460

  14. Glycyrrhetic acid synergistically enhances β₂-adrenergic receptor-Gs signaling by changing the location of Gαs in lipid rafts.

    Directory of Open Access Journals (Sweden)

    Qian Shi

    Full Text Available Glycyrrhetic acid (GA exerts synergistic anti-asthmatic effects via a β₂-adrenergic receptor (β₂AR-mediated pathway. Cholesterol is an important component of the structure and function of lipid rafts, which play critical roles in the β₂AR-Gs-adenylate cyclase (AC-mediated signaling pathway. Owing to the structural similarities between GA and cholesterol, we investigated the possibility that GA enhances β₂AR signaling by altering cholesterol distribution. Azide-terminal GA (ATGA was synthesized and applied to human embryonic kidney 293 (HEK293 cells expressing fusion β₂AR, and the electron spin resonance (ESR technique was utilized. GA was determined to be localized predominantly on membrane and decreased their cholesterol contents. Thus, the fluidity of the hydrophobic region increased but not the polar surface of the cell membrane. The conformations of membrane proteins were also changed. GA further changed the localization of Gαs from lipid rafts to non-raft regions, resulting the binding of β₂AR and Gαs, as well as in reduced β₂AR internalization. Co-localization of β₂AR, Gαs, and AC increased isoproterenol-induced cAMP production and cholesterol reloading attenuated this effect. A speculation wherein GA enhances beta-adrenergic activity by increasing the functional linkage between the subcomponents of the membrane β₂AR-protein kinase A (PKA signaling pathway was proposed. The enhanced efficacy of β₂AR agonists by this novel mechanism could prevent tachyphylaxis.

  15. Gravin orchestrates protein kinase A and β2-adrenergic receptor signaling critical for synaptic plasticity and memory

    NARCIS (Netherlands)

    Havekes, Robbert; Canton, David A; Park, Alan J; Huang, Ted; Nie, Ting; Day, Jonathan P; Guercio, Leonardo A; Grimes, Quinn; Luczak, Vincent; Gelman, Irwin H; Baillie, George S; Scott, John D; Abel, Ted

    2012-01-01

    A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of protein kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plast

  16. Night/day changes in pineal expression of >600 genes: central role of adrenergic/cAMP signaling

    DEFF Research Database (Denmark)

    Bailey, Michael J; Coon, Steven L; Carter, John David;

    2009-01-01

    The pineal gland plays an essential role in vertebrate chronobiology by converting time into a hormonal signal, melatonin, which is always elevated at night. Here we have analyzed the rodent pineal transcriptome using Affymetrix GeneChip(R) technology to obtain a more complete description of pineal...

  17. Signal Use by Octopuses in Agonistic Interactions.

    Science.gov (United States)

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  18. From signal to signification in interactive environments

    DEFF Research Database (Denmark)

    Fritsch, Jonas

    2012-01-01

    replace the other. Rather, we should investigate what the fusion between paradigms allows us to say about digital and interactive technologies. This article attempts to do this through a thinking-together of signal and signification as well as affect and emotion based on the work of French philosopher......There is no doubt that the shift to real-time interactive and electronic media can benefit from a renewed focus on the signal and a signaletic paradigm in addition to the sign. However, in this article I argue that we must be careful not to simply fall into the idea of one paradigm to simply...... of technology Gilbert Simondon. Through an analysis of the minimal media installation Touched Echo, I argue that it is necessary to account for the dynamics of a larger experiential continuum to uncover the affective-emotive relations that occur through the transindividual workings of the signal...

  19. The effect of hydroalcoholic extract of Juglans regia L. leaf on blood pressure and its interaction with adrenergic system of male rats

    Directory of Open Access Journals (Sweden)

    Hajar Ebrahimiyan

    2016-03-01

    Full Text Available Background: Hypertension is one of the most common diseases in recent century with several complications. The purpose of this study was to evaluate the effect of hydroalcoholic extract of Juglans regia L. leaves (Walnut tree on blood pressure and its interaction with the adrenergic system in male rats. Methods: In this experimental study that established in the physiology lab, School of scinse in Shiraz University from September to October 2013, in order to determine some of hydroalcoholic extract of Juglans regia L. leaves effect on blood pressure, the present study was performed by following procedure: 10 adult male wistar rats weighing between 180-250g were used. They were divided into two groups (Each group contained 5 rats randomly: Juglans regia L. leaf extract group and Juglans regia L. leaf extract and adrenaline group. Then each rat was anesthetized by IP injection of 1.2 g/kg urethane. After tracheostomy the femoral vine and artery were cannulated for drug injection and blood pressure recording respectively. Arterial cannula for recording arterial blood pressure connected to a pressure transducer (PowerLab, ADInstruments, Sydney, Australia. Blood pressure parameters were recorded before and after IV administration of hydroalcoholic extract of Juglans regia L. leaf, solvent, adrenalin and extract with adrenaline. Results: The result showed a significant decrease of mean arterial pressure, systolic and diastolic pressure in response to extract with compare to control and sham group (P<0.05. Also a significant decrease of blood pressure showed in presence of walnut leaf extract and adrenaline with compare to sham group (P<0.05. Conclusion: It can be concluded that hydroalcoholic extract of Juglans regia L. leaf suggested as a hypotensive agent. It seems that this effect is probably due to inhibitory effect on adrenergic system.

  20. Interactive Teaching of Adaptive Signal Processing

    OpenAIRE

    Stewart, R W; Harteneck, M; WEISS S.

    2000-01-01

    Over the last 30 years adaptive digital signal processing has progressed from being a strictly graduate level advanced class in signal processing theory to a topic that is part of the core curriculum for many undergraduate signal processing classes. The key reason is the continued advance of communications technology, with its need for echo control and equalisation, and the widespread use of adaptive filters in audio, biomedical, and control applications. In this paper we will review the basi...

  1. Adrenergic gene polymorphisms and cardiovascular risk in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation

    OpenAIRE

    Sharaf Barry L; McNamara Dennis M; Bittner Vera; Cooper-DeHoff Rhonda M; Johnson B Delia; Li Haihong; Zineh Issam; Pacanowski Michael A; Merz C Noel; Pepine Carl J; Johnson Julie A

    2008-01-01

    Abstract Background Adrenergic gene polymorphisms are associated with cardiovascular and metabolic phenotypes. We investigated the influence of adrenergic gene polymorphisms on cardiovascular risk in women with suspected myocardial ischemia. Methods We genotyped 628 women referred for coronary angiography for eight polymorphisms in the α1A-, β1-, β2- and β3-adrenergic receptors (ADRA1A, ADRB1, ADRB2, ADRB3, respectively), and their signaling proteins, G-protein β 3 subunit (GNB3) and G-protei...

  2. Adrenergic receptors are a fallible index of adrenergic denervation hypersensitivity

    DEFF Research Database (Denmark)

    Dejgaard, Anders; Liggett, S B; Christensen, N J;

    1991-01-01

    accumulation, in samples from patients with insulin-dependent diabetes mellitus (IDDM) with diabetic autonomic neuropathy (n = 8), were no different from those in samples from patients with IDDM without neuropathy (n = 8), or from non-diabetic subjects (n = 8). In addition, platelet alpha 2-adrenergic receptor......In view of evidence that neither interindividual nor induced intra-individual variations of adrenergic receptor status are related to metabolic or haemodynamic sensitivity to adrenaline in vivo, we took an alternative approach to assessment of the relevance of adrenergic receptor measurement...... by measuring these in a group of subjects with well-documented adrenergic denervation hypersensitivity, patients with diabetic autonomic neuropathy. Mononuclear leukocyte beta 2-adrenergic receptor densities (and binding affinities), measured with 125I-labelled pindolol, and isoproterenol-stimulated cyclic AMP...

  3. Subthreshold α2-Adrenergic Activation Counteracts Glucagon-Like Peptide-1 Potentiation of Glucose-Stimulated Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Minglin Pan

    2011-01-01

    Full Text Available The pancreatic β cell harbors α2-adrenergic and glucagon-like peptide-1 (GLP-1 receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX- sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α2-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.

  4. Language adapts to signal disruption in interaction

    OpenAIRE

    Macuch Silva, V.; Roberts, S

    2016-01-01

    Linguistic traits are often seen as reflecting cognitive biases and constraints (e.g. Christiansen & Chater, 2008). However, language must also adapt to properties of the channel through which communication between individuals occurs. Perhaps the most basic aspect of any communication channel is noise. Communicative signals can be blocked, degraded or distorted by other sources in the environment. This poses a fundamental problem for communication. On average, channel disruption accompanies p...

  5. β-Adrenergic receptor antagonists inhibit vasculogenesis of embryonic stem cells by downregulation of nitric oxide generation and interference with VEGF signalling.

    Science.gov (United States)

    Sharifpanah, Fatemeh; Saliu, Fatjon; Bekhite, Mohamed M; Wartenberg, Maria; Sauer, Heinrich

    2014-11-01

    The β-adrenoceptor antagonist Propranolol has been successfully used to treat infantile hemangioma. However, its mechanism of action is so far unknown. The hypothesis of this research was that β-adrenoceptor antagonists may interfere with endothelial cell differentiation of stem cells. Specifically, the effects of the non-specific β-adrenergic receptor (β-adrenoceptor) antagonist Propranolol, the β1-adrenoceptor-specific antagonist Atenolol and the β2-adrenoceptor-specific antagonist ICI118,551 on vasculogenesis of mouse embryonic stem (ES) cells were investigated. All three β-blockers dose-dependently downregulated formation of capillary structures in ES cell-derived embryoid bodies and decreased the expression of the vascular cell markers CD31 and VE-cadherin. Furthermore, β-blockers downregulated the expression of fibroblast growth factor-2 (FGF-2), hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor 165 (VEGF165), VEGF receptor 2 (VEGF-R2) and phospho VEGF-R2, as well as neuropilin 1 (NRP1) and plexin-B1 which are essential modulators of embryonic angiogenesis with additional roles in vessel remodelling and arteriogenesis. Under conditions of β-adrenoceptor inhibition, the endogenous generation of nitric oxide (NO) as well as the phosphorylation of endothelial nitric oxide synthase (eNOS) was decreased in embryoid bodies, whereas an increase in NO generation was observed with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP). Consequently, vasculogenesis of ES cells was restored upon treatment of differentiating ES cells with β-adrenoceptor antagonists in the presence of NO donor. In summary, our data suggest that β-blockers impair vasculogenesis of ES cells by interfering with NO generation which could be the explanation for their anti-angiogenic effects in infantile hemangioma.

  6. Interactive Task Estimation From Unlabelled Teaching Signals

    OpenAIRE

    Jonathan Grizou; I\\xf1aki Iturrate; Luis Montesano; Manuel Lopes; Pierre-Yves Oudeyer

    2013-01-01

    International audience At home, workplaces or schools, an increasing amount of intelligent robotic systems are starting to be able to help us in our daily life (windows or vacuum cleaners, self-driving cars) [1] and in flexible manufacturing systems [2]. A key feature in these new domains is the close interaction between people and robots. In particular, such robotic systems need to be teachable by non-technical users, i.e. programmable for new tasks in novel environments through intuitive...

  7. Warning signals for poor performance improve human-robot interaction

    NARCIS (Netherlands)

    Brule, R. van den; Bijlstra, G.; Dotsch, R.; Haselager, W.F.G.; Wigboldus, D.H.J.

    2016-01-01

    The present research was aimed at investigating whether human-robot interaction (HRI) can be improved by a robot's nonverbal warning signals. Ideally, when a robot signals that it cannot guarantee good performance, people could take preventive actions to ensure the successful completion of the robot

  8. An Interactive Graphics Program for Investigating Digital Signal Processing.

    Science.gov (United States)

    Miller, Billy K.; And Others

    1983-01-01

    Describes development of an interactive computer graphics program for use in teaching digital signal processing. The program allows students to interactively configure digital systems on a monitor display and observe their system's performance by means of digital plots on the system's outputs. A sample program run is included. (JN)

  9. Interactions between radiofrequency signals and living organisms

    International Nuclear Information System (INIS)

    This dossier is composed of 13 articles dealing with the interactions between radio-frequencies and living organisms. It is an overview of various scientific approaches to the field and is of interest for all citizens as the use of mobile phones is widely spread. In the first article it is shown how a model has been built to assess the distribution of the whole body exposure of the population. The second article reviews the state of the art in personal exposure measurements at radio-frequencies. The third article shows that the knowledge of the mechanism of action by which exposure increases the risk of health hazards is necessary. The fourth article shows that individual neuro-psychic factors take a prominent but maybe not unique, part in electromagnetic hypersensitivity. The fifth article shows that no evidence was found to link health disturbances of electromagnetic hypersensitive individuals with radiofrequency exposure. The sixth article shows that the wireless phone is not an athermal hazard to the brain. The seventh article shows that the in utero and post-natal exposure to Wi-Fi does not damage the brains of young rats. The eighth article concludes that recent studies provide no convincing proof of deleterious effects of radiofrequency exposure on the integrity of the blood-brain barrier for specific absorption rates up to 6 W/kg. The ninth article shows that no co-genotoxic effect of radiofrequency was found at levels of exposure that did not induce heating. The tenth article confirms that industry-sponsored studies were least likely to report results suggesting effects. The last article shows that general practitioners are increasingly questioned by their patients about the issue of electromagnetic waves. (A.C.)

  10. AT(1) receptor Gαq protein-independent signalling transcriptionally activates only a few genes directly, but robustly potentiates gene regulation from the β2-adrenergic receptor

    DEFF Research Database (Denmark)

    Christensen, Gitte Lund; Knudsen, Steen; Schneider, Mikael;

    2011-01-01

    of Gαq protein-dependent and -independent regulation of AT(1)R mediated gene expression. We found angiotensin II to regulate 212 genes, whereas Gαq-independent signalling obtained with the biased agonist, SII angiotensin II only regulated few genes. Interestingly, SII angiotensin II, like Ang II vastly...

  11. Root signals that mediate mutualistic interactions in the rhizosphere.

    Science.gov (United States)

    Rasmann, Sergio; Turlings, Ted Cj

    2016-08-01

    A recent boom in research on belowground ecology is rapidly revealing a multitude of fascinating interactions, in particular in the rhizosphere. Many of these interactions are mediated by photo-assimilates that are excreted by plant roots. Root exudates are not mere waste products, but serve numerous functions to control abiotic and biotic processes. These functions range from changing the chemical and physical properties of the soil, inhibiting the growth of competing plants, combatting herbivores, and regulating the microbial community. Particularly intriguing are root-released compounds that have evolved to serve mutualistic interactions with soil-dwelling organisms. These mutually beneficial plant-mediated signals are not only of fundamental ecological interest, but also exceedingly important from an agronomical perspective. Here, we attempt to provide an overview of the plant-produced compounds that have so far been implicated in mutualistic interactions. We propose that these mutualistic signals may have evolved from chemical defenses and we point out that they can be (mis)used by specialized pathogens and herbivores. We speculate that many more signals and interactions remain to be uncovered and that a good understanding of the mechanisms and ecological implications can be the basis for exploitation and manipulation of the signals for crop improvement and protection. PMID:27393937

  12. Recent progress in α1-adrenergic receptor research

    Institute of Scientific and Technical Information of China (English)

    Zhong-jian CHEN; Kenneth P MINNEMAN

    2005-01-01

    α1-Adrenergic receptors (AR) play an important role in the regulation of physiological responses mediated by norepinephrine and epinephrine, particularly in the cardiovascular system. The three cloned α1-AR subtypes (α1A, α1B, and α1D)are G protein-coupled receptors that signal through the Gq/11 signaling pathway,each showing distinct pharmacological properties and tissue distributions.However, due to the lack of highly subtype-selective drugs, the functional rolesof individual subtypes are still not clear. Development of new subtype-specific drugs will greatly facilitate the identification of the functions of each subtype.Conopeptide ρ-TIA has been found to be a new α1B-AR selective antagonist withdifferent modes of inhibition at α1-AR subtypes. In addition, recent studies using genetically engineered mice have shed some light on α1-AR functions in vivo,especially in the cardiovascular system and brain. Several proteins have been shown to interact directly with particular α1-AR, and may be important in regulating receptor function. Receptor heterodimerization has been shown to be important for cell surface expression, signaling and internalization. These new observations are likely to help elucidate the functional roles of individual α1-AR subtypes.

  13. Interaction between telencephalic signals and respiratory dynamics in songbirds

    OpenAIRE

    Méndez, Jorge M.; Mindlin, Gabriel B.; Goller, Franz

    2012-01-01

    The mechanisms by which telencephalic areas affect motor activities are largely unknown. They could either take over motor control from downstream motor circuits or interact with the intrinsic dynamics of these circuits. Both models have been proposed for telencephalic control of respiration during learned vocal behavior in birds. The interactive model postulates that simple signals from the telencephalic song control areas are sufficient to drive the nonlinear respiratory network into produc...

  14. DNA-Metallodrugs Interactions Signaled by Electrochemical Biosensors: An Overview

    Directory of Open Access Journals (Sweden)

    Mauro Ravera

    2007-01-01

    Full Text Available The interaction of drugs with DNA is an important aspect in pharmacology. In recent years, many important technological advances have been made to develop new techniques to monitor biorecognition and biointeraction on solid devices. The interaction between DNA and drugs can cause chemical and conformational modifications and, thus, variation of the electrochemical properties of nucleobases. The propensity of a given compound to interact with DNA is measured as a function of the decrease of guanine oxidation signal on a DNA electrochemical biosensor. Covalent binding at N7 of guanine, electrostatic interactions, and intercalation are the events that this kind of biosensor can detect. In this context, the interaction between a panel of antitumoral Pt-, Ru-, and Ti-based metallodrugs with DNA immobilized on screen-printed electrodes has been studied. The DNA biosensors are used for semiquantitative evaluation of the analogous interaction occurring in the biological environment.

  15. Social signal processing for studying parent-infant interaction

    Directory of Open Access Journals (Sweden)

    Marie eAvril

    2014-12-01

    Full Text Available Studying early interactions is a core issue of infant development and psychopathology. Automatic social signal processing theoretically offers the possibility to extract and analyse communication by taking an integrative perspective, considering the multimodal nature and dynamics of behaviours (including synchrony. This paper proposes an explorative method to acquire and extract relevant social signals from a naturalistic early parent-infant interaction. An experimental setup is proposed based on both clinical and technical requirements. We extracted various cues from body postures and speech productions of partners using the IMI2S (Interaction, Multimodal Integration, and Social Signal Framework. Preliminary clinical and computational results are reported for two dyads (one pathological in a situation of severe emotional neglect and one normal control as an illustration of our cross-disciplinary protocol. The results from both clinical and computational analyses highlight similar differences: the pathological dyad shows dyssynchronic interaction led by the infant whereas the control dyad shows synchronic interaction and a smooth interactive dialog. The results suggest that the current method might be promising for future studies.

  16. Social signal processing for studying parent–infant interaction

    Science.gov (United States)

    Avril, Marie; Leclère, Chloë; Viaux, Sylvie; Michelet, Stéphane; Achard, Catherine; Missonnier, Sylvain; Keren, Miri; Cohen, David; Chetouani, Mohamed

    2014-01-01

    Studying early interactions is a core issue of infant development and psychopathology. Automatic social signal processing theoretically offers the possibility to extract and analyze communication by taking an integrative perspective, considering the multimodal nature and dynamics of behaviors (including synchrony). This paper proposes an explorative method to acquire and extract relevant social signals from a naturalistic early parent–infant interaction. An experimental setup is proposed based on both clinical and technical requirements. We extracted various cues from body postures and speech productions of partners using the IMI2S (Interaction, Multimodal Integration, and Social Signal) Framework. Preliminary clinical and computational results are reported for two dyads (one pathological in a situation of severe emotional neglect and one normal control) as an illustration of our cross-disciplinary protocol. The results from both clinical and computational analyzes highlight similar differences: the pathological dyad shows dyssynchronic interaction led by the infant whereas the control dyad shows synchronic interaction and a smooth interactive dialog. The results suggest that the current method might be promising for future studies. PMID:25540633

  17. Social signal processing for studying parent-infant interaction.

    Science.gov (United States)

    Avril, Marie; Leclère, Chloë; Viaux, Sylvie; Michelet, Stéphane; Achard, Catherine; Missonnier, Sylvain; Keren, Miri; Cohen, David; Chetouani, Mohamed

    2014-01-01

    Studying early interactions is a core issue of infant development and psychopathology. Automatic social signal processing theoretically offers the possibility to extract and analyze communication by taking an integrative perspective, considering the multimodal nature and dynamics of behaviors (including synchrony). This paper proposes an explorative method to acquire and extract relevant social signals from a naturalistic early parent-infant interaction. An experimental setup is proposed based on both clinical and technical requirements. We extracted various cues from body postures and speech productions of partners using the IMI2S (Interaction, Multimodal Integration, and Social Signal) Framework. Preliminary clinical and computational results are reported for two dyads (one pathological in a situation of severe emotional neglect and one normal control) as an illustration of our cross-disciplinary protocol. The results from both clinical and computational analyzes highlight similar differences: the pathological dyad shows dyssynchronic interaction led by the infant whereas the control dyad shows synchronic interaction and a smooth interactive dialog. The results suggest that the current method might be promising for future studies.

  18. Orally applied doxazosin disturbed testosterone homeostasis and changed the transcriptional profile of steroidogenic machinery, cAMP/cGMP signalling and adrenergic receptors in Leydig cells of adult rats.

    Science.gov (United States)

    Stojkov, N J; Janjic, M M; Kostic, T S; Andric, S A

    2013-03-01

    Doxazosin (Doxa) is an α1-selective adrenergic receptor (ADR) antagonist widely used, alone or in combination, to treat high blood pressure, benign prostatic hyperplasia symptoms, and recently has been suggested as a potential drug for prostate cancer prevention/treatment. This study was designed to evaluate the effect of in vivo Doxa po-application, in clinically relevant dose, on: (i) steroidogenic machinery homeostasis; (ii) cAMP/cGMP signalling; (iii) transcription profile of ADR in Leydig cells of adult rats. The results showed that po-application of Doxa for once (1×Doxa), or for two (2×Doxa) or 10 (10×Doxa) consecutive days significantly disturbed steroidogenic machinery homeostasis in Leydig cells. Doxa po-application significantly decreased circulating luteinizing hormone and androgens levels. The level of androgens in testicular interstitial fluid and that extracted from testes obtained from 1×Doxa/2×Doxa rats decreased, although it remained unchanged in 10×Doxa rats. Similarly, the ex vivo basal androgen production followed in testes isolated from 1×Doxa/2×Doxa rats decreased, while remained unchanged in 10×Doxa rats. Differently, ex vivo testosterone production and steroidogenic capacity of Leydig cells isolated from 1×Doxa/2×Doxa rats was stimulated, while 10×Doxa had opposite effect. In the same cells, cAMP content/release showed similar stimulatory effect, but back to control level in Leydig cells of 10×Doxa. 1×Doxa/2×Doxa decreased transcripts for cAMP specific phosphodiesterases Pde7b/Pde8b, whereas 10×Doxa increased Pde4d. All types of treatment reduced the expression of genes encoding protein kinase A (PRKA) regulatory subunit (Prkar2b), whereas only 10×Doxa stimulated catalytic subunit (Prkaca). Doxa application more affected cGMP signalling: stimulated transcription of constitutive nitric oxide synthases (Nos1, Nos3) in time-dependent manner, whereas reduced inducible Nos2. 10×Doxa increased guanylyl cyclase 1 transcript and

  19. Identification of four nuclear transport signal-binding proteins that interact with diverse transport signals.

    Science.gov (United States)

    Yamasaki, L; Kanda, P; Lanford, R E

    1989-07-01

    The transport of proteins into the nucleus requires not only the presence of a nuclear transport signal on the targeted protein but also the signal recognition proteins and the nuclear pore translocation apparatus. Complicating the search for the signal recognition proteins is the fact that the nuclear transport signals identified share little obvious homology. In this study, synthetic peptides homologous to the nuclear transport signals from the simian virus 40 large T antigen, Xenopus oocyte nucleoplasmin, adenovirus E1A, and Saccharomyces cerevisiae MAT alpha 2 proteins were coupled to a UV-photoactivable cross-linker and iodinated for use in an in vitro cross-linking reaction with cellular lysates. Four proteins, p140, p100, p70, and p55, which specifically interacted with the nuclear transport signal peptides were identified. Unique patterns of reactivity were observed with closely related pairs of nuclear transport signal peptides. Competition experiments with labeled and unlabeled peptides demonstrated that heterologous signals were able to bind the same protein and suggested that diverse signals use a common transport pathway. The subcellular distribution of the four nuclear transport signal-binding proteins suggested that nuclear transport involves both cytoplasmic and nuclear receptors. The four proteins were not bound by wheat germ agglutinin and were not associated tightly with the nuclear pore complex.

  20. Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling

    Science.gov (United States)

    Samoshkin, Alexander; Convertino, Marino; Viet, Chi T.; Wieskopf, Jeffrey S.; Kambur, Oleg; Marcovitz, Jaclyn; Patel, Pinkal; Stone, Laura S.; Kalso, Eija; Mogil, Jeffrey S.; Schmidt, Brian L.; Maixner, William; Dokholyan, Nikolay V.; Diatchenko, Luda

    2015-01-01

    The primary molecular target for clinically used opioids is the μ-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with β2-adrenergic receptors (β2-ARs) through an interaction with the fifth and sixth helices of β2-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective β2-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and β2-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with β2-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by β2-AR antagonists, providing a new avenue for opioid therapy. PMID:26657998

  1. β-Adrenergic cAMP signals are predominantly regulated by phosphodiesterase type 4 in cultured adult rat aortic smooth muscle cells.

    Directory of Open Access Journals (Sweden)

    Kui Zhai

    Full Text Available BACKGROUND: We investigated the role of cyclic nucleotide phosphodiesterases (PDEs in the spatiotemporal control of intracellular cAMP concentrations in rat aortic smooth muscle cells (RASMCs. METHODOLOGY/PRINCIPAL FINDINGS: The rank order of PDE families contributing to global cAMP-PDE activity was PDE4> PDE3  =  PDE1. PDE7 mRNA expression but not activity was confirmed. The Fluorescence Resonance Energy Transfer (FRET-based cAMP sensor, Epac1-camps, was used to monitor the time course of cytosolic cAMP changes. A pulse application of the β-adrenoceptor (β-AR agonist isoproterenol (Iso induced a transient FRET signal. Both β(1- and β(2-AR antagonists decreased the signal amplitude without affecting its kinetics. The non-selective PDE inhibitor (IBMX dramatically increased the amplitude and delayed the recovery phase of Iso response, in agreement with a role of PDEs in degrading cAMP produced by Iso. Whereas PDE1, PDE3 and PDE7 blockades [with MIMX, cilostamide (Cil and BRL 50481 (BRL, respectively] had no or minor effect on Iso response, PDE4 inhibition [with Ro-20-1724 (Ro] strongly increased its amplitude and delayed its recovery. When Ro was applied concomitantly with MIMX or Cil (but not with BRL, the Iso response was drastically further prolonged. PDE4 inhibition similarly prolonged both β(1- and β(2-AR-mediated responses. When a membrane-targeted FRET sensor was used, PDE3 and PDE4 acted in a synergistic manner to hydrolyze the submembrane cAMP produced either at baseline or after β-AR stimulation. CONCLUSION/SIGNIFICANCE: Our study underlines the importance of cAMP-PDEs in the dynamic control of intracellular cAMP signals in RASMCs, and demonstrates the prominent role of PDE4 in limiting β-AR responses. PDE4 inhibition unmasks an effect of PDE1 and PDE3 on cytosolic cAMP hydrolyzis, and acts synergistically with PDE3 inhibition at the submembrane compartment. This suggests that mixed PDE4/PDE1 or PDE4/PDE3 inhibitors would be

  2. CLE peptide signaling and nitrogen interactions in plant root development.

    Science.gov (United States)

    Araya, Takao; von Wirén, Nicolaus; Takahashi, Hideki

    2016-08-01

    The CLAVATA signaling pathway is essential for the regulation of meristem activities in plants. This signaling pathway consists of small signaling peptides of the CLE family interacting with CLAVATA1 and leucine-rich repeat receptor-like kinases (LRR-RLKs). The peptide-receptor relationships determine the specificities of CLE-dependent signals controlling stem cell fate and differentiation that are critical for the establishment and maintenance of shoot and root apical meristems. Plants root systems are highly organized into three-dimensional structures for successful anchoring and uptake of water and mineral nutrients from the soil environment. Recent studies have provided evidence that CLE peptides and CLAVATA signaling pathways play pivotal roles in the regulation of lateral root development and systemic autoregulation of nodulation (AON) integrated with nitrogen (N) signaling mechanisms. Integrations of CLE and N signaling pathways through shoot-root vascular connections suggest that N demand modulates morphological control mechanisms and optimize N uptake as well as symbiotic N fixation in roots. PMID:26994997

  3. Interactive proofs with competing teams of no-signaling provers

    CERN Document Server

    Gutoski, Gus

    2010-01-01

    This paper studies a generalization of multi-prover interactive proofs in which a verifier interacts with two competing teams of provers: one team attempts to convince the verifier to accept while the other attempts to convince the verifier to reject. Each team consists of two provers who jointly implement a no-signaling strategy. No-signaling strategies are a curious class of joint strategy that cannot in general be implemented without communication between the provers, yet cannot be used as a black box to establish communication between them. Attention is restricted in this paper to two-turn interactions in which the verifier asks questions of each of the four provers and decides whether to accept or reject based on their responses. We prove that the complexity class of decision problems that admit two-turn interactive proofs with competing teams of no-signaling provers is a subset of PSPACE. This upper bound matches existing PSPACE lower bounds on the following two disparate and weaker classes of interacti...

  4. Applications of muon signal to electromagnetic signal showers universality for mass composition and hadronic interactions studies

    CERN Document Server

    D'Urso, D; Aramo, C; Cilmo, M; Guarino, F; Valore, L; Yushkov, A

    2011-01-01

    We present the first results of the application of the recently found universality of behavior of muon signal to electromagnetic (EM) signal ratio with respect to the vertical depth of showers maximum for mass composition and hadronic interaction studies. Making use of the fact that for zenith angles above 45 degrees the dependence of the ratio on the vertical depth of shower maximum is very similar for QGSJET II and EPOS 1.99 we show that this provides the possibility to estimate muon shower content in almost interaction model independent way. To evaluate the excess of signal in the data in respect to Monte-Carlo predictions we propose to use mass independence of the electromagnetic signal. Using the simulations with EPOS 1.99 as a fake data we show that one can determine the absolute scaling factor between these fake data and the interaction model under test (QGSJET II in our case). Applying this scaling factor to the total and muon signals of QGSJET II one can make accurate conclusions on the primary mass ...

  5. Phosphoinositide metabolism and adrenergic receptors in astrocytes

    International Nuclear Information System (INIS)

    Agonist-induced phosphoinositide (PI) breakdown functions as a signal generating system. Diacylglycerol, one breakdown product of phosphotidylinositol-4,5-diphosphate hydrolysis, can stimulate protein kinase C, whereas inositol triphosphate, the other product, has been proposed to be a second messenger for Ca++ mobilization. Using purified astrocyte cultures from neonatal rat brain, the effects of adrenergic agonists and antagonists at 10-5 M were measured on PI breakdown. Astrocytes grown in culture were prelabeled with (3H)inositol, and basal (3H) inositol phosphate (IP1) accumulation was measured in the presence of Li+. Epinephrine > norepinephrine (NE) were the most active stimulants of IP1 production. The α1 adrenoreceptor blockers, phentolamine and phenoxybenzamine, added alone had no effect on IP1 production was reduced below basal levels. Propranolol partially blocked the effects of NE. Clonidine and isoproterenol, separately added, reduced IP1 below basal levels and when added together diminished IP1 accumulation even further. The role of adrenergic stimulation in the production of c-AMP

  6. Signals, processes, and systems an interactive multimedia introduction to signal processing

    CERN Document Server

    Karrenberg, Ulrich

    2013-01-01

    This is a very new concept for learning Signal Processing, not only from the physically-based scientific fundamentals, but also from the didactic perspective, based on modern results of brain research. The textbook together with the DVD form a learning system that provides investigative studies and enables the reader to interactively visualize even complex processes. The unique didactic concept is built on visualizing signals and processes on the one hand, and on graphical programming of signal processing systems on the other. The concept has been designed especially for microelectronics, computer technology and communication. The book allows to develop, modify, and optimize useful applications using DasyLab - a professional and globally supported software for metrology and control engineering. With the 3rd edition, the software is also suitable for 64 bit systems running on Windows 7. Real signals can be acquired, processed and played on the sound card of your computer. The book provides more than 200 pre-pr...

  7. Calcium signaling during reproduction and biotrophic fungal interactions in plants.

    Science.gov (United States)

    Chen, Junyi; Gutjahr, Caroline; Bleckmann, Andrea; Dresselhaus, Thomas

    2015-04-01

    Many recent studies have indicated that cellular communications during plant reproduction, fungal invasion, and defense involve identical or similar molecular players and mechanisms. Indeed, pollen tube invasion and sperm release shares many common features with infection of plant tissue by fungi and oomycetes, as a tip-growing intruder needs to communicate with the receptive cells to gain access into a cell and tissue. Depending on the compatibility between cells, interactions may result in defense, invasion, growth support, or cell death. Plant cells stimulated by both pollen tubes and fungal hyphae secrete, for example, small cysteine-rich proteins and receptor-like kinases are activated leading to intracellular signaling events such as the production of reactive oxygen species (ROS) and the generation of calcium (Ca(2+)) transients. The ubiquitous and versatile second messenger Ca(2+) thereafter plays a central and crucial role in modulating numerous downstream signaling processes. In stimulated cells, it elicits both fast and slow cellular responses depending on the shape, frequency, amplitude, and duration of the Ca(2+) transients. The various Ca(2+) signatures are transduced into cellular information via a battery of Ca(2+)-binding proteins. In this review, we focus on Ca(2+) signaling and discuss its occurrence during plant reproduction and interactions of plant cells with biotrophic filamentous microbes. The participation of Ca(2+) in ROS signaling pathways is also discussed.

  8. Adrenergic regulation of innate immunity: a review

    Directory of Open Access Journals (Sweden)

    Angela eScanzano

    2015-08-01

    Full Text Available The sympathetic nervous system has a major role in the brain-immune cross-talk, but few information exist on the sympathoadrenergic regulation of innate immune system.The aim of this review is to summarize available knowledge regarding the sympathetic modulation of the innate immune response, providing a rational background for the possible repurposing of adrenergic drugs as immunomodulating agents.The cells of immune system express adrenoceptors (AR, which represent the target for noradrenaline and adrenaline. In human neutrophils, adrenaline and noradrenaline inhibit migration, CD11b/CD18 expression, and oxidative metabolism, possibly through β-AR, although the role of α1- and α2-AR requires further investigation. Natural Killer express β-AR, which are usually inhibitory. Monocytes express β-AR and their activation is usually antiinflammatory. On murine Dentritic cells (DC, β-AR mediate sympathetic influence on DC-T cells interactions. In human DC β2-AR may affect Th1/2 differentiation of CD4+ T cells. In microglia and in astrocytes, β2-AR dysregulation may contribute to neuroinflammation in autoimmune and neurodegenerative disease.In conclusion, extensive evidence supports a critical role for adrenergic mechanisms in the regulation of innate immunity, in peripheral tissues as well as in the CNS. Sympathoadrenergic pathways in the innate immune system may represent novel antiinflammatory and immunomodulating targets with significant therapeutic potential.

  9. Interaction between telencephalic signals and respiratory dynamics in songbirds.

    Science.gov (United States)

    Méndez, Jorge M; Mindlin, Gabriel B; Goller, Franz

    2012-06-01

    The mechanisms by which telencephalic areas affect motor activities are largely unknown. They could either take over motor control from downstream motor circuits or interact with the intrinsic dynamics of these circuits. Both models have been proposed for telencephalic control of respiration during learned vocal behavior in birds. The interactive model postulates that simple signals from the telencephalic song control areas are sufficient to drive the nonlinear respiratory network into producing complex temporal sequences. We tested this basic assumption by electrically stimulating telencephalic song control areas and analyzing the resulting respiratory patterns in zebra finches and in canaries. We found strong evidence for interaction between the rhythm of stimulation and the intrinsic respiratory rhythm, including naturally emerging subharmonic behavior and integration of lateralized telencephalic input. The evidence for clear interaction in our experimental paradigm suggests that telencephalic vocal control also uses a similar mechanism. Furthermore, species differences in the response of the respiratory system to stimulation show parallels to differences in the respiratory patterns of song, suggesting that the interactive production of respiratory rhythms is manifested in species-specific specialization of the involved circuitry. PMID:22402649

  10. Boosted dark matter signals uplifted with self-interaction

    International Nuclear Information System (INIS)

    We explore detection prospects of a non-standard dark sector in the context of boosted dark matter. We focus on a scenario with two dark matter particles of a large mass difference, where the heavier candidate is secluded and interacts with the standard model particles only at loops, escaping existing direct and indirect detection bounds. Yet its pair annihilation in the galactic center or in the Sun may produce boosted stable particles, which could be detected as visible Cherenkov light in large volume neutrino detectors. In such models with multiple candidates, self-interaction of dark matter particles is naturally utilized in the assisted freeze-out mechanism and is corroborated by various cosmological studies such as N-body simulations of structure formation, observations of dwarf galaxies, and the small scale problem. We show that self-interaction of the secluded (heavier) dark matter greatly enhances the capture rate in the Sun and results in promising signals at current and future experiments. We perform a detailed analysis of the boosted dark matter events for Super-Kamiokande, Hyper-Kamiokande and PINGU, including notable effects such as evaporation due to self-interaction and energy loss in the Sun

  11. Interaction of LRRK2 with kinase and GTPase signaling cascades

    Directory of Open Access Journals (Sweden)

    Joon Y Boon

    2014-07-01

    Full Text Available LRRK2 is a protein that interacts with a plethora of signaling molecules, but the complexity of LRRK2 function presents a challenge for understanding the role of LRRK2 in the pathophysiology of Parkinson’s disease. Studies of LRRK2 using over-expression in transgenic mice have been disappointing, however studies using invertebrate systems have yielded a much clearer picture, with clear effects of LRRK2 expression, knockdown or deletion in C. elegans and Drosophila on modulation of survival of dopaminergic neurons. Recent studies have begun to focus attention on particular signaling cascades that are a target of LRRK2 function. LRRK2 interacts with members of the MAPK pathway and might regulate the pathway action by acting as a scaffold that directs the location of MAPK pathway activity, without strongly affecting the amount of MAPK pathway activity. Binding to GTPases, GAPs and GEFs are another strong theme in LRRK2 biology, with LRRK2 binding to Rac1, cdc42, rab5, rab7L1, endoA, RGS2, ArfGAP1 and ArhGEF7. All of these molecules appear to feed into a function output for LRRK2 that modulates cytoskeletal outgrowth and vesicular dynamics, including autophagy. These functions likely impact modulation of α-synuclein aggregation and associated toxicity eliciting the disease processes that we term Parkinson’s disease.

  12. Heparan sulfate proteoglycans: structure, protein interactions and cell signaling

    Directory of Open Access Journals (Sweden)

    Juliana L. Dreyfuss

    2009-09-01

    Full Text Available Heparan sulfate proteoglycans are ubiquitously found at the cell surface and extracellular matrix in all the animal species. This review will focus on the structural characteristics of the heparan sulfate proteoglycans related to protein interactions leading to cell signaling. The heparan sulfate chains due to their vast structural diversity are able to bind and interact with a wide variety of proteins, such as growth factors, chemokines, morphogens, extracellular matrix components, enzymes, among others. There is a specificity directing the interactions of heparan sulfates and target proteins, regarding both the fine structure of the polysaccharide chain as well precise protein motifs. Heparan sulfates play a role in cellular signaling either as receptor or co-receptor for different ligands, and the activation of downstream pathways is related to phosphorylation of different cytosolic proteins either directly or involving cytoskeleton interactions leading to gene regulation. The role of the heparan sulfate proteoglycans in cellular signaling and endocytic uptake pathways is also discussed.Proteoglicanos de heparam sulfato são encontrados tanto superfície celular quanto na matriz extracelular em todas as espécies animais. Esta revisão tem enfoque nas características estruturais dos proteoglicanos de heparam sulfato e nas interações destes proteoglicanos com proteínas que levam à sinalização celular. As cadeias de heparam sulfato, devido a sua variedade estrutural, são capazes de se ligar e interagir com ampla gama de proteínas, como fatores de crescimento, quimiocinas, morfógenos, componentes da matriz extracelular, enzimas, entreoutros. Existe uma especificidade estrutural que direciona as interações dos heparam sulfatos e proteínas alvo. Esta especificidade está relacionada com a estrutura da cadeia do polissacarídeo e os motivos conservados da cadeia polipeptídica das proteínas envolvidas nesta interação. Os heparam

  13. Boosted Dark Matter Signals Uplifted with Self-Interaction

    CERN Document Server

    Kong, Kyoungchul; Park, Jong-Chul

    2015-01-01

    We explore detection prospects of a non-standard dark sector in the context of boosted dark matter. We focus on a scenario with two dark matter particles of a large mass difference, where the heavier candidate is secluded and interacts with the standard model particles only at loops, escaping existing direct and indirect detection bounds. Yet its pair annihilation in the galactic center or in the Sun may produce boosted stable particles, which could be detected as visible Cherenkov light in large volume neutrino detectors. In such models with multiple candidates, self-interaction of dark matter particles is naturally utilized in the {\\it assisted freeze-out} mechanism and is corroborated by various cosmological studies such as N-body simulations of structure formation, observations of dwarf galaxies, and the small scale problem. We show that self-interaction of the secluded (heavier) dark matter greatly enhances the capture rate in the Sun and results in promising signals at current and future experiments. We...

  14. Interactions between visceral afferent signaling and stimulus processing

    Directory of Open Access Journals (Sweden)

    Hugo D Critchley

    2015-08-01

    Full Text Available Visceral afferent signals to the brain influence thoughts, feelings and behaviour. Here we highlight the findings of a set of empirical investigations in humans concerning body-mind interaction that focus on how feedback from states of autonomic arousal shapes cognition and emotion. There is a longstanding debate regarding the contribution of the body, to mental processes. Recent theoretical models broadly acknowledge the role of (autonomically-mediated physiological arousal to emotional, social and motivational behaviours, yet the underlying mechanisms are only partially characterized. Neuroimaging is overcoming this shortfall; first, by demonstrating correlations between autonomic change and discrete patterns of evoked, and task-independent, neural activity; second, by mapping the central consequences of clinical perturbations in autonomic response and; third, by probing how dynamic fluctuations in peripheral autonomic state are integrated with perceptual, cognitive and emotional processes. Building on the notion that an important source of the brain’s representation of physiological arousal is derived from afferent information from arterial baroreceptors, we have exploited the phasic nature of these signals to show their differential contribution to the processing of emotionally-salient stimuli. This recent work highlights the facilitation at neural and behavioral levels of fear and threat processing that contrasts with the more established observations of the inhibition of central pain processing during baroreceptors activation. The implications of this body-brain-mind axis are discussed.

  15. Developmental and diurnal dynamics of Pax4 expression in the mammalian pineal gland: nocturnal down-regulation is mediated by adrenergic-cyclic adenosine 3',5'-monophosphate signaling

    DEFF Research Database (Denmark)

    Rath, Martin F; Bailey, Michael J; Kim, Jong-So;

    2009-01-01

    Pax4 is a homeobox gene that is known to be involved in embryonic development of the endocrine pancreas. In this tissue, Pax4 counters the effects of the related protein, Pax6. Pax6 is essential for development of the pineal gland. In this study we report that Pax4 is strongly expressed in the pi...... findings suggest that the nocturnal decrease in pineal Pax4 mRNA is controlled by the sympathetic neural pathway that controls pineal function acting via an adrenergic-cAMP mechanism. The daily changes in Pax4 expression may influence gene expression in the pineal gland....

  16. Audiovisual integration of emotional signals from others’ social interactions.

    Directory of Open Access Journals (Sweden)

    Lukasz ePiwek

    2015-05-01

    Full Text Available Audiovisual perception of emotions has been typically examined using displays of a solitary character (e.g. the face-voice and/or body-sound of one actor. However, in real life humans often face more complex multisensory social situations, involving more than one person. Here we ask if the audiovisual facilitation in emotion recognition previously found in simpler social situations extends to more complex and ecological situations. Stimuli consisting of the biological motion and voice of two interacting agents were used in two experiments. In Experiment 1, participants were presented with visual, auditory, auditory filtered/noisy, and audiovisual congruent and incongruent clips. We asked participants to judge whether the two agents were interacting happily or angrily. In Experiment 2, another group of participants repeated the same task, as in Experiment 1, while trying to ignore either the visual or the auditory information. The findings from both experiments indicate that when the reliability of the auditory cue was decreased participants weighted more the visual cue in their emotional judgments. This in turn translated in increased emotion recognition accuracy for the multisensory condition. Our findings thus point to a common mechanism of multisensory integration of emotional signals irrespective of social stimulus complexity.

  17. Effect of Increased Cyclic AMP Concentration on Muscle Protein Synthesis and Beta-Adrenergic Receptor Expression in Chicken Skeletal Muscle Cells in Culture

    Science.gov (United States)

    Young, R. B.; Vaughn, J. R.; Bridge, K. Y.; Smith, C. K.

    1998-01-01

    Analogies of epinephrine are known to cause hypertrophy of skeletal muscle when fed to animals. These compounds presumably exert their physiological action through interaction with the P-adrenergic receptor. Since the intracellular signal generated by the Beta-adrenergic receptor is cyclic AMP (cAMP), experiments were initiated in cell culture to determine if artificial elevation of cAMP by treatment with forskolin would alter muscle protein metabolism and P-adrenergic receptor expression. Chicken skeletal muscle cells after 7 days in culture were treated with 0.2-30 micrometers forskolin for a total of three days. At the end of the treatment period, both the concentration of cAMP and the quantity of myosin heavy chain (MHC) were measured. Concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. In contrast, the quantity of MHC was increased approximately 50% above control cells at 0.2 micrometers forskolin, but exhibited a gradual decline at higher levels of forskolin so that the quantity of MHC in cells treated with 30 micrometers forskolin was not significantly different from controls. Curiously, the intracellular concentration of cAMP which elicited the maximum increase in the quantity of MHC was only 40% higher than cAMP concentration in control cells.

  18. An interactive system for seismic signal detection and identification

    International Nuclear Information System (INIS)

    The methods to distinguish an underground explosion from an earthquake are mainly based on exploiting the differences in the source functions of the two processes and locating the depth of source. Various characteristics of seismic signals generated by these sources are usually represented by different parameters or identifiers. However, it is not possible for a single identifier to distinguish an explosion from an earthquake with equal effectiveness in all situations. Usually a combination of several identifiers is found to provide effective means for the identification of seismic sources. In order to use the multiple parameters in an optimum way, an interactive system (IS) for detection and identification of global events has been developed using short period data of Gauribidanur array. This report describes the salient features of the IS and demonstrates its effectiveness in identifying an event using weighted combination of the parameters together with the depth of source. It is intended to augment the system with long period data in the next phase of the development. (author). 37 refs., 14 figs., 2 tabs

  19. Adrenergic blockade in diabetic and uninephrectomized rats

    DEFF Research Database (Denmark)

    Thulesen, J; Poulsen, Steen Seier; Jørgensen, P E;

    1999-01-01

    The present study reports on the effects of adrenergic blocking agents on the renal growth and on the renal content and urinary excretion of epidermal growth factor (EGF) in streptozotocin-induced diabetic or uninephrectomized rats. Diabetic and uninephrectomized rats were allocated to groups...... was not affected by adrenergic blocking agents. These results provide evidence for fundamental differences between diabetes-related renal growth and that observed in compensation to nephrectomy and suggest a connection between adrenergic activity, renal growth, and EGF in diabetes....

  20. Adrenergic and noradrenergic regulation of poultry behavior and production.

    Science.gov (United States)

    Dennis, R L

    2016-07-01

    Norepinephrine and epinephrine (noradrenaline and adrenaline) are integral in maintaining behavioral and physiological homeostasis during both aversive and rewarding events. They regulate the response to stressful stimuli through direct activation of adrenergic receptors in the central and sympathetic nervous systems, hormonal activity and through the interaction of the brain, gut, and microbiome. The multiple functions of these catecholamines work synergistically to prepare an individual for a "fight or flight" response. However, hyper-reactivity of this system can lead to increased fearfulness and aggression, decreased health and productivity, and a reduction in overall well-being. Behaviors, such as aggression and certain fear-related behaviors, are a serious problem in the poultry industry that can lead to injury and cannibalism. For decades, catecholamines have been used as a measure of stress in animals. However, few studies have specifically targeted the adrenergic systems as means to reduce behaviors that are damaging or maladapted to their rearing environments and improve animal well-being. This article attempts to address our current understanding of specific, adrenergic-regulated behaviors that impact chicken well-being and production. PMID:27345328

  1. Interactions among oscillatory pathways in NF-kappa B signaling

    Directory of Open Access Journals (Sweden)

    White Michael RH

    2011-02-01

    Full Text Available Abstract Background Sustained stimulation with tumour necrosis factor alpha (TNF-alpha induces substantial oscillations—observed at both the single cell and population levels—in the nuclear factor kappa B (NF-kappa B system. Although the mechanism has not yet been elucidated fully, a core system has been identified consisting of a negative feedback loop involving NF-kappa B (RelA:p50 hetero-dimer and its inhibitor I-kappa B-alpha. Many authors have suggested that this core oscillator should couple to other oscillatory pathways. Results First we analyse single-cell data from experiments in which the NF-kappa B system is forced by short trains of strong pulses of TNF-alpha. Power spectra of the ratio of nuclear-to-cytoplasmic concentration of NF-kappa B suggest that the cells' responses are entrained by the pulsing frequency. Using a recent model of the NF-kappa B system due to Caroline Horton, we carried out extensive numerical simulations to analyze the response frequencies induced by trains of pulses of TNF-alpha stimulation having a wide range of frequencies and amplitudes. These studies suggest that for sufficiently weak stimulation, various nonlinear resonances should be observable. To explore further the possibility of probing alternative feedback mechanisms, we also coupled the model to sinusoidal signals with a wide range of strengths and frequencies. Our results show that, at least in simulation, frequencies other than those of the forcing and the main NF-kappa B oscillator can be excited via sub- and superharmonic resonance, producing quasiperiodic and even chaotic dynamics. Conclusions Our numerical results suggest that the entrainment phenomena observed in pulse-stimulated experiments is a consequence of the high intensity of the stimulation. Computational studies based on current models suggest that resonant interactions between periodic pulsatile forcing and the system's natural frequencies may become evident for sufficiently

  2. Predicting Pharmacodynamic Drug-Drug Interactions through Signaling Propagation Interference on Protein-Protein Interaction Networks.

    Directory of Open Access Journals (Sweden)

    Kyunghyun Park

    Full Text Available As pharmacodynamic drug-drug interactions (PD DDIs could lead to severe adverse effects in patients, it is important to identify potential PD DDIs in drug development. The signaling starting from drug targets is propagated through protein-protein interaction (PPI networks. PD DDIs could occur by close interference on the same targets or within the same pathways as well as distant interference through cross-talking pathways. However, most of the previous approaches have considered only close interference by measuring distances between drug targets or comparing target neighbors. We have applied a random walk with restart algorithm to simulate signaling propagation from drug targets in order to capture the possibility of their distant interference. Cross validation with DrugBank and Kyoto Encyclopedia of Genes and Genomes DRUG shows that the proposed method outperforms the previous methods significantly. We also provide a web service with which PD DDIs for drug pairs can be analyzed at http://biosoft.kaist.ac.kr/targetrw.

  3. The Alpha-1A Adrenergic Receptor in the Rabbit Heart

    OpenAIRE

    R Croft Thomas; Cowley, Patrick M.; Abhishek Singh; Bat-Erdene Myagmar; Swigart, Philip M.; Baker, Anthony J.; Simpson, Paul C.

    2016-01-01

    The alpha-1A-adrenergic receptor (AR) subtype is associated with cardioprotective signaling in the mouse and human heart. The rabbit is useful for cardiac disease modeling, but data on the alpha-1A in the rabbit heart are limited. Our objective was to test for expression and function of the alpha-1A in rabbit heart. By quantitative real-time reverse transcription PCR (qPCR) on mRNA from ventricular myocardium of adult male New Zealand White rabbits, the alpha-1B was 99% of total alpha-1-AR mR...

  4. Neurohumoral activation in heart failure: the role of adrenergic receptors

    Directory of Open Access Journals (Sweden)

    Patricia C. Brum

    2006-09-01

    Full Text Available Heart failure (HF is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. However, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. On a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of HF. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. In this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in HF. The myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. Finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of HF.A insuficiência cardíaca (IC é a via final comum da maioria das doenças cardiovasculares e uma das maiores causas de morbi-mortalidade. O desenvolvimento do estágio final da IC freqüentemente envolve um insulto inicial do miocárdio, reduzindo o débito cardíaco e levando ao aumento compensatório da atividade do sistema nervoso simpático (SNS. Existem evidências de que apesar da exposição aguda ser benéfica, exposições crônicas a elevadas concentra

  5. Macroecological signals of species interactions in the Danish avifauna

    DEFF Research Database (Denmark)

    Gotelli, N.J.; Graves, Christopher R.; Rahbek, C.

    2010-01-01

    The role of intraspecific and interspecific interactions in structuring biotic communities at fine spatial scales is well documented, but the signature of species interactions at coarser spatial scales is unclear. We present evidence that species interactions may be a significant factor in mediat...

  6. Targeting of beta adrenergic receptors results in therapeutic efficacy against models of hemangioendothelioma and angiosarcoma.

    Directory of Open Access Journals (Sweden)

    Jessica M Stiles

    Full Text Available Therapeutic targeting of the beta-adrenergic receptors has recently shown remarkable efficacy in the treatment of benign vascular tumors such as infantile hemangiomas. As infantile hemangiomas are reported to express high levels of beta adrenergic receptors, we examined the expression of these receptors on more aggressive vascular tumors such as hemangioendotheliomas and angiosarcomas, revealing beta 1, 2, and 3 receptors were indeed present and therefore aggressive vascular tumors may similarly show increased susceptibility to the inhibitory effects of beta blockade. Using a panel of hemangioendothelioma and angiosarcoma cell lines, we demonstrate that beta adrenergic inhibition blocks cell proliferation and induces apoptosis in a dose dependent manner. Beta blockade is selective for vascular tumor cells over normal endothelial cells and synergistically effective when combined with standard chemotherapeutic or cytotoxic agents. We demonstrate that inhibition of beta adrenergic signaling induces large scale changes in the global gene expression patterns of vascular tumors, including alterations in the expression of established cell cycle and apoptotic regulators. Using in vivo tumor models we demonstrate that beta blockade shows remarkable efficacy as a single agent in reducing the growth of angiosarcoma tumors. In summary, these experiments demonstrate the selective cytotoxicity and tumor suppressive ability of beta adrenergic inhibition on malignant vascular tumors and have laid the groundwork for a promising treatment of angiosarcomas in humans.

  7. cAMP-synthesis in a medullary thyroid carcinoma cell line: response to adrenergic agents and prostaglandines.

    Science.gov (United States)

    Mertens, P R; Goretzki, P E; Keck, E

    1999-01-01

    Calcitonin secretion by C-cells is mediated through intracellular 3'5'-cyclic adenosine monophosphate (cAMP) and calcium signaling. Calcitonin release stimulation tests may take advantage of both signaling cascades in screening for medullary thyroid carcinomas (MTC). To elucidate the regulation of the adenylyl cyclase system we have determined cAMP levels of a calcitonin-expressing MTC cell line (RG) after exposure to adrenergic agents and prostaglandines. In early passages (20-30) cAMP concentrations were significantly elevated in RG cells after exposure to beta-adrenergic agents and prostaglandines E1 and E2. In advanced passages (60-80) the beta-adrenergic response was no longer detectable and adrenergic receptors were uncoupled from the adenylyl cyclase complex; while the effect of prostaglandines E1 and E2 remained unaffected. Preincubation with dexamethasone, in a process requiring protein new synthesis, re-established the adrenergic response in later passages, indicating that RG cells dedifferentiated in culture over time. Our in vitro findings suggest that MTC cell dedifferentiation may be accompanied by adrenergic receptor-uncoupling from the adenylate cyclase system and that this process may be reversed by dexamethasone incubation.

  8. Crystal structure of the β2 adrenergic receptor-Gs protein complex

    Energy Technology Data Exchange (ETDEWEB)

    Rasmussen, Søren G.F.; DeVree, Brian T; Zou, Yaozhong; Kruse, Andrew C; Chung, Ka Young; Kobilka, Tong Sun; Thian, Foon Sun; Chae, Pil Seok; Pardon, Els; Calinski, Diane; Mathiesen, Jesper M; Shah, Syed T.A.; Lyons, Joseph A; Caffrey, Martin; Gellman, Samuel H; Steyaert, Jan; Skiniotis, Georgios; Weis, William I; Sunahara, Roger K; Kobilka, Brian K [Brussels; (Trinity); (Michigan); (Stanford-MED); (Michigan-Med); (UW)

    2011-12-07

    G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The β2 adrenergic receptor (β2AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric β2AR and nucleotide-free Gs heterotrimer. The principal interactions between the β2AR and Gs involve the amino- and carboxy-terminal α-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the β2AR include a 14Å outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an α-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR.

  9. Signalling pathway impact analysis based on the strength of interaction between genes.

    Science.gov (United States)

    Bao, Zhenshen; Li, Xianbin; Zan, Xiangzhen; Shen, Liangzhong; Ma, Runnian; Liu, Wenbin

    2016-08-01

    Signalling pathway analysis is a popular approach that is used to identify significant cancer-related pathways based on differentially expressed genes (DEGs) from biological experiments. The main advantage of signalling pathway analysis lies in the fact that it assesses both the number of DEGs and the propagation of signal perturbation in signalling pathways. However, this method simplifies the interactions between genes by categorising them only as activation (+1) and suppression (-1), which does not encompass the range of interactions in real pathways, where interaction strength between genes may vary. In this study, the authors used newly developed signalling pathway impact analysis (SPIA) methods, SPIA based on Pearson correlation coefficient (PSPIA), and mutual information (MSPIA), to measure the interaction strength between pairs of genes. In analyses of a colorectal cancer dataset, a lung cancer dataset, and a pancreatic cancer dataset, PSPIA and MSPIA identified more candidate cancer-related pathways than were identified by SPIA. Generally, MSPIA performed better than PSPIA. PMID:27444024

  10. Inter-signal interaction and uncertain information in anuran multimodal signals

    Institute of Scientific and Technical Information of China (English)

    Ryan C.TAYLOR; Barrett A.KLEIN; Michael J.RYAN

    2011-01-01

    Disentangling the influence of multiple signal components on receivers and elucidating general processes influencing complex signal evolution are deffcult tasks.In this study we test mate preferences of female squirres treefrogs Hyla squirella and female tǘngara frogs Physalaemus pustulosus for similar combinations of acoustic and visual components of their multimodal courtship signals.In a two-choice playback expenment with squirrel treefrogs,the visual stimulus of a male model significantly increased the attractivness of a relatively unattractive slow call rate.A previous study demonstrated that faster call rates are more attractive to female squirrel treefrogs,and all else being equal,models of male frogs with large body stripes are more attractive.In a similar experiment with female tǘngar afrogs,the visul istimulus of a robotic frog failed to increse the attracCtivenes of relatively unattractive call.Females also showed no preference for the distinct stripe on the robot that males commonly bear on their throat.Thus,features of conspicuous signal components such as body stripes are not universally important and signal funchon is likely to differ even among species with similar ecologies and communication systems.Finally,we discuss the putative information content of anuran signals and suggest that the categorization of redundant versus multiple messages may not be sufficient as a general explanation for the evolution of multimodal signaling.Instead of relying on untested assumptions concerning the information content of signals,we discuss the value of initially collecting comparative empirical data sets related to receiver responses.

  11. Comparison of the β-Adrenergic Receptor Antagonists Landiolol and Esmolol: Receptor Selectivity, Partial Agonism, and Pharmacochaperoning Actions.

    Science.gov (United States)

    Nasrollahi-Shirazi, Shahrooz; Sucic, Sonja; Yang, Qiong; Freissmuth, Michael; Nanoff, Christian

    2016-10-01

    Blockage of β1-adrenergic receptors is one of the most effective treatments in cardiovascular medicine. Esmolol was introduced some three decades ago as a short-acting β1-selective antagonist. Landiolol is a more recent addition. Here we compared the two compounds for their selectivity for β1-adrenergic receptors over β2-adrenergic receptors, partial agonistic activity, signaling bias, and pharmacochaperoning action by using human embryonic kidney (HEK)293 cell lines, which heterologously express each human receptor subtype. The affinity of landiolol for β1-adrenergic receptors and β2-adrenergic receptors was higher and lower than that of esmolol, respectively, resulting in an improved selectivity (216-fold versus 30-fold). The principal metabolite of landiolol (M1) was also β1-selective, but its affinity was very low. Both landiolol and esmolol caused a very modest rise in cAMP levels but a robust increase in the phosphorylation of extracellular signal regulated kinases 1 and 2, indicating that the two drugs exerted partial agonist activity with a signaling bias. If cells were incubated for ≥24 hours in the presence of ≥1 μM esmolol, the levels of β1-adrenergic-but not of β2-adrenergic-receptors increased. This effect was contingent on export of the β1-receptor from endoplasmic reticulum and was not seen in the presence of landiolol. On the basis of these observations, we conclude that landiolol offers the advantage of: 1) improved selectivity and 2) the absence of pharmacochaperoning activity, which sensitizes cells to rebound effects upon drug discontinuation. PMID:27451411

  12. Stress response, gut microbial diversity and sexual signals correlate with social interactions.

    Science.gov (United States)

    Levin, Iris I; Zonana, David M; Fosdick, Bailey K; Song, Se Jin; Knight, Rob; Safran, Rebecca J

    2016-06-01

    Theory predicts that social interactions are dynamically linked to phenotype. Yet because social interactions are difficult to quantify, little is known about the precise details on how interactivity is linked to phenotype. Here, we deployed proximity loggers on North American barn swallows (Hirundo rustica erythrogaster) to examine intercorrelations among social interactions, morphology and features of the phenotype that are sensitive to the social context: stress-induced corticosterone (CORT) and gut microbial diversity. We analysed relationships at two spatial scales of interaction: (i) body contact and (ii) social interactions occurring between 0.1 and 5 m. Network analysis revealed that relationships between social interactions, morphology, CORT and gut microbial diversity varied depending on the sexes of the individuals interacting and the spatial scale of interaction proximity. We found evidence that body contact interactions were related to diversity of socially transmitted microbes and that looser social interactions were related to signalling traits and CORT.

  13. Stress response, gut microbial diversity and sexual signals correlate with social interactions.

    Science.gov (United States)

    Levin, Iris I; Zonana, David M; Fosdick, Bailey K; Song, Se Jin; Knight, Rob; Safran, Rebecca J

    2016-06-01

    Theory predicts that social interactions are dynamically linked to phenotype. Yet because social interactions are difficult to quantify, little is known about the precise details on how interactivity is linked to phenotype. Here, we deployed proximity loggers on North American barn swallows (Hirundo rustica erythrogaster) to examine intercorrelations among social interactions, morphology and features of the phenotype that are sensitive to the social context: stress-induced corticosterone (CORT) and gut microbial diversity. We analysed relationships at two spatial scales of interaction: (i) body contact and (ii) social interactions occurring between 0.1 and 5 m. Network analysis revealed that relationships between social interactions, morphology, CORT and gut microbial diversity varied depending on the sexes of the individuals interacting and the spatial scale of interaction proximity. We found evidence that body contact interactions were related to diversity of socially transmitted microbes and that looser social interactions were related to signalling traits and CORT. PMID:27354713

  14. Nonlocal signaling in the configuration space model of quantum-classical interactions

    CERN Document Server

    Hall, Michael J W; Savage, C M

    2012-01-01

    When interactions are turned off, the theory of interacting quantum and classical ensembles due to Hall and Reginatto is shown to suffer from a nonlocal signaling effect that is effectively action at a distance. This limits the possible applicability of the theory. In its present form, it is restricted to those situations in which interactions are always on, such as classical gravity interacting with quantized matter.

  15. Prediction of oncogenic interactions and cancer-related signaling networks based on network topology.

    Directory of Open Access Journals (Sweden)

    Marcio Luis Acencio

    Full Text Available Cancer has been increasingly recognized as a systems biology disease since many investigators have demonstrated that this malignant phenotype emerges from abnormal protein-protein, regulatory and metabolic interactions induced by simultaneous structural and regulatory changes in multiple genes and pathways. Therefore, the identification of oncogenic interactions and cancer-related signaling networks is crucial for better understanding cancer. As experimental techniques for determining such interactions and signaling networks are labor-intensive and time-consuming, the development of a computational approach capable to accomplish this task would be of great value. For this purpose, we present here a novel computational approach based on network topology and machine learning capable to predict oncogenic interactions and extract relevant cancer-related signaling subnetworks from an integrated network of human genes interactions (INHGI. This approach, called graph2sig, is twofold: first, it assigns oncogenic scores to all interactions in the INHGI and then these oncogenic scores are used as edge weights to extract oncogenic signaling subnetworks from INHGI. Regarding the prediction of oncogenic interactions, we showed that graph2sig is able to recover 89% of known oncogenic interactions with a precision of 77%. Moreover, the interactions that received high oncogenic scores are enriched in genes for which mutations have been causally implicated in cancer. We also demonstrated that graph2sig is potentially useful in extracting oncogenic signaling subnetworks: more than 80% of constructed subnetworks contain more than 50% of original interactions in their corresponding oncogenic linear pathways present in the KEGG PATHWAY database. In addition, the potential oncogenic signaling subnetworks discovered by graph2sig are supported by experimental evidence. Taken together, these results suggest that graph2sig can be a useful tool for investigators involved

  16. Muscle Plasticity and β2-Adrenergic Receptors: Adaptive Responses of β2-Adrenergic Receptor Expression to Muscle Hypertrophy and Atrophy

    OpenAIRE

    Shogo Sato; Ken Shirato; Kaoru Tachiyashiki; Kazuhiko Imaizumi

    2011-01-01

    We discuss the functional roles of β2-adrenergic receptors in skeletal muscle hypertrophy and atrophy as well as the adaptive responses of β2-adrenergic receptor expression to anabolic and catabolic conditions. β2-Adrenergic receptor stimulation using anabolic drugs increases muscle mass by promoting muscle protein synthesis and/or attenuating protein degradation. These effects are prevented ...

  17. Leptonic Indirect Detection Signals from Strongly Interacting Asymmetric Dark Matter

    OpenAIRE

    Cai, Yi; Kaplan, David E.; Luty, Markus A.

    2009-01-01

    Particles with TeV mass and strong self-interactions generically have the right annihilation cross section to explain an observed excess of cosmic electrons and positrons if the end-product of the annihilation is charged leptons. We present an explicit model of strongly-coupled TeV-scale dark matter whose relic abundance related to the matter-antimatter asymmetry of the observed universe. The B - L asymmetry of the standard model is transfered to the dark sector by an operator carrying standa...

  18. NORADRENERGIC AND ADRENERGIC FUNCTIONING IN AUTISM

    NARCIS (Netherlands)

    MINDERAA, RB; ANDERSON, GM; VOLKMAR, FR; AKKERHUIS, GW; COHEN, DJ

    1994-01-01

    A neurochemical assessment of noradrenergic and adrenergic functioning was carried out with autistic patients and normal control individuals. Norepinephrine and related compounds were measured in autistic (n = 17 unmedicated, 23 medicated; age range 9-29 years old) and normal controls (n = 27; age r

  19. Human sensorimotor communication: a theory of signaling in online social interactions.

    Directory of Open Access Journals (Sweden)

    Giovanni Pezzulo

    Full Text Available Although the importance of communication is recognized in several disciplines, it is rarely studied in the context of online social interactions and joint actions. During online joint actions, language and gesture are often insufficient and humans typically use non-verbal, sensorimotor forms of communication to send coordination signals. For example, when playing volleyball, an athlete can exaggerate her movements to signal her intentions to her teammates (say, a pass to the right or to feint an adversary. Similarly, a person who is transporting a table together with a co-actor can push the table in a certain direction to signal where and when he intends to place it. Other examples of "signaling" are over-articulating in noisy environments and over-emphasizing vowels in child-directed speech. In all these examples, humans intentionally modify their action kinematics to make their goals easier to disambiguate. At the moment no formal theory exists of these forms of sensorimotor communication and signaling. We present one such theory that describes signaling as a combination of a pragmatic and a communicative action, and explains how it simplifies coordination in online social interactions. We cast signaling within a "joint action optimization" framework in which co-actors optimize the success of their interaction and joint goals rather than only their part of the joint action. The decision of whether and how much to signal requires solving a trade-off between the costs of modifying one's behavior and the benefits in terms of interaction success. Signaling is thus an intentional strategy that supports social interactions; it acts in concert with automatic mechanisms of resonance, prediction, and imitation, especially when the context makes actions and intentions ambiguous and difficult to read. Our theory suggests that communication dynamics should be studied within theories of coordination and interaction rather than only in terms of the

  20. Human sensorimotor communication: a theory of signaling in online social interactions.

    Science.gov (United States)

    Pezzulo, Giovanni; Donnarumma, Francesco; Dindo, Haris

    2013-01-01

    Although the importance of communication is recognized in several disciplines, it is rarely studied in the context of online social interactions and joint actions. During online joint actions, language and gesture are often insufficient and humans typically use non-verbal, sensorimotor forms of communication to send coordination signals. For example, when playing volleyball, an athlete can exaggerate her movements to signal her intentions to her teammates (say, a pass to the right) or to feint an adversary. Similarly, a person who is transporting a table together with a co-actor can push the table in a certain direction to signal where and when he intends to place it. Other examples of "signaling" are over-articulating in noisy environments and over-emphasizing vowels in child-directed speech. In all these examples, humans intentionally modify their action kinematics to make their goals easier to disambiguate. At the moment no formal theory exists of these forms of sensorimotor communication and signaling. We present one such theory that describes signaling as a combination of a pragmatic and a communicative action, and explains how it simplifies coordination in online social interactions. We cast signaling within a "joint action optimization" framework in which co-actors optimize the success of their interaction and joint goals rather than only their part of the joint action. The decision of whether and how much to signal requires solving a trade-off between the costs of modifying one's behavior and the benefits in terms of interaction success. Signaling is thus an intentional strategy that supports social interactions; it acts in concert with automatic mechanisms of resonance, prediction, and imitation, especially when the context makes actions and intentions ambiguous and difficult to read. Our theory suggests that communication dynamics should be studied within theories of coordination and interaction rather than only in terms of the maximization of information

  1. In brown adipocytes, adrenergically induced β{sub 1}-/β{sub 3}-(G{sub s})-, α{sub 2}-(G{sub i})- and α{sub 1}-(G{sub q})-signalling to Erk1/2 activation is not mediated via EGF receptor transactivation

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yanling; Fälting, Johanna M.; Mattsson, Charlotte L.; Holmström, Therése E.; Nedergaard, Jan, E-mail: jan@metabol.su.se

    2013-10-15

    Brown adipose tissue is unusual in that the neurotransmitter norepinephrine influences cell destiny in ways generally associated with effects of classical growth factors: regulation of cell proliferation, of apoptosis, and progression of differentiation. The norepinephrine effects are mediated through G-protein-coupled receptors; further mediation of such stimulation to e.g. Erk1/2 activation is in cell biology in general accepted to occur through transactivation of the EGF receptor (by external or internal pathways). We have examined here the significance of such transactivation in brown adipocytes. Stimulation of mature brown adipocytes with cirazoline (α{sub 1}-adrenoceptor coupled via G{sub q}), clonidine (α{sub 2} via G{sub i}) or CL316243 (β{sub 3} via G{sub s}) or via β{sub 1}-receptors significantly activated Erk1/2. Pretreatment with the EGF receptor kinase inhibitor AG1478 had, remarkably, no significant effect on Erk1/2 activation induced by any of these adrenergic agonists (although it fully abolished EGF-induced Erk1/2 activation), demonstrating absence of EGF receptor-mediated transactivation. Results with brown preadipocytes (cells in more proliferative states) were not qualitatively different. Joint stimulation of all adrenoceptors with norepinephrine did not result in synergism on Erk1/2 activation. AG1478 action on EGF-stimulated Erk1/2 phosphorylation showed a sharp concentration–response relationship (IC{sub 50} 0.3 µM); a minor apparent effect of AG1478 on norepinephrine-stimulated Erk1/2 phosphorylation showed nonspecific kinetics, implying caution in interpretation of partial effects of AG1478 as reported in other systems. Transactivation of the EGF receptor is clearly not a universal prerequisite for coupling of G-protein coupled receptors to Erk1/2 signalling cascades. - Highlights: • In brown adipocytes, norepinephrine regulates proliferation, apoptosis, differentiation. • EGF receptor transactivation is supposed to mediate GPCR

  2. Progesterone in pregnancy; receptor-ligand interaction and signaling pathways.

    Science.gov (United States)

    Szekeres-Bartho, Julia; Halasz, Melinda; Palkovics, Tamas

    2009-12-01

    Progesterone is indispensable in creating a suitable endometrial environment for implantation, and also for the maintenance of pregnancy. Successful pregnancy depends on an appropriate maternal immune response to the fetus. Along with its endocrine effects, progesterone also acts as an "immunosteroid", by contributing to the establishment of a pregnancy protective immune milieu. Progesterone plays a role in uterine homing of NK cells and upregulates HLA-G gene expression, the ligand for NK inhibitory and activating receptors. At high concentrations, progesterone is a potent inducer of Th2-type cytokines as well as of LIF and M-CSF production by T cells. A protein called progesterone-induced blocking factor (PIBF), by inducing a Th2-dominant cytokine production mediates the immunological effects of progesterone. PIBF binds to a novel type of the IL-4 receptor and signals via the Jak/STAT pathway, to induce a number of genes, that not only affect the immune response, but might also play a role in trophoblast invasiveness. PMID:19880194

  3. Bispectral pairwise interacting source analysis for identifying systems of cross-frequency interacting brain sources from electroencephalographic or magnetoencephalographic signals

    Science.gov (United States)

    Chella, Federico; Pizzella, Vittorio; Zappasodi, Filippo; Nolte, Guido; Marzetti, Laura

    2016-05-01

    Brain cognitive functions arise through the coordinated activity of several brain regions, which actually form complex dynamical systems operating at multiple frequencies. These systems often consist of interacting subsystems, whose characterization is of importance for a complete understanding of the brain interaction processes. To address this issue, we present a technique, namely the bispectral pairwise interacting source analysis (biPISA), for analyzing systems of cross-frequency interacting brain sources when multichannel electroencephalographic (EEG) or magnetoencephalographic (MEG) data are available. Specifically, the biPISA makes it possible to identify one or many subsystems of cross-frequency interacting sources by decomposing the antisymmetric components of the cross-bispectra between EEG or MEG signals, based on the assumption that interactions are pairwise. Thanks to the properties of the antisymmetric components of the cross-bispectra, biPISA is also robust to spurious interactions arising from mixing artifacts, i.e., volume conduction or field spread, which always affect EEG or MEG functional connectivity estimates. This method is an extension of the pairwise interacting source analysis (PISA), which was originally introduced for investigating interactions at the same frequency, to the study of cross-frequency interactions. The effectiveness of this approach is demonstrated in simulations for up to three interacting source pairs and for real MEG recordings of spontaneous brain activity. Simulations show that the performances of biPISA in estimating the phase difference between the interacting sources are affected by the increasing level of noise rather than by the number of the interacting subsystems. The analysis of real MEG data reveals an interaction between two pairs of sources of central mu and beta rhythms, localizing in the proximity of the left and right central sulci.

  4. iNOS signaling interacts with COX-2 pathway in colonic fibroblasts.

    Science.gov (United States)

    Zhu, Yingting; Zhu, Min; Lance, Peter

    2012-10-01

    COX-2 and iNOS are two major inflammatory mediators implicated in colorectal inflammation and cancer. Previously, the role of colorectal fibroblasts involved in regulation of COX-2 and iNOS expression was largely ignored. In addition, the combined interaction of COX-2 and iNOS signalings and their significance in the progression of colorectal inflammation and cancer within the fibroblasts have received little investigation. To address those issues, we investigated the role of colonic fibroblasts in the regulation of COX-2 and iNOS gene expression, and explored possible mechanisms of interaction between COX-2 and iNOS signalings using a colonic CCD-18Co fibroblast line and LPS, a potential stimulator of COX-2 and iNOS. Our results clearly demonstrated that LPS activated COX-2 gene expression and enhanced PGE(2) production, stimulated iNOS gene expression and promoted NO production in the fibroblasts. Interestingly, activation of COX-2 signaling by LPS was not involved in activation of iNOS signaling, while activation of iNOS signaling by LPS contributed in part to activation of COX-2 signaling. Further analysis indicated that PKC plays a major role in the activation and interaction of COX-2 and iNOS signalings induced by LPS in the fibroblasts. PMID:22683859

  5. Neural interactions in unilateral colliculus and between bilateral colliculi modulate auditory signal processing

    Science.gov (United States)

    Mei, Hui-Xian; Cheng, Liang; Chen, Qi-Cai

    2013-01-01

    In the auditory pathway, the inferior colliculus (IC) is a major center for temporal and spectral integration of auditory information. There are widespread neural interactions in unilateral (one) IC and between bilateral (two) ICs that could modulate auditory signal processing such as the amplitude and frequency selectivity of IC neurons. These neural interactions are either inhibitory or excitatory, and are mostly mediated by γ-aminobutyric acid (GABA) and glutamate, respectively. However, the majority of interactions are inhibitory while excitatory interactions are in the minority. Such unbalanced properties between excitatory and inhibitory projections have an important role in the formation of unilateral auditory dominance and sound location, and the neural interaction in one IC and between two ICs provide an adjustable and plastic modulation pattern for auditory signal processing. PMID:23626523

  6. Neural interactions in unilateral colliculus and between bilateral colliculi modulate auditory signal processing.

    Science.gov (United States)

    Mei, Hui-Xian; Cheng, Liang; Chen, Qi-Cai

    2013-01-01

    In the auditory pathway, the inferior colliculus (IC) is a major center for temporal and spectral integration of auditory information. There are widespread neural interactions in unilateral (one) IC and between bilateral (two) ICs that could modulate auditory signal processing such as the amplitude and frequency selectivity of IC neurons. These neural interactions are either inhibitory or excitatory, and are mostly mediated by γ-aminobutyric acid (GABA) and glutamate, respectively. However, the majority of interactions are inhibitory while excitatory interactions are in the minority. Such unbalanced properties between excitatory and inhibitory projections have an important role in the formation of unilateral auditory dominance and sound location, and the neural interaction in one IC and between two ICs provide an adjustable and plastic modulation pattern for auditory signal processing.

  7. Long distance root-shoot signalling in plant-insect community interactions.

    Science.gov (United States)

    Soler, Roxina; Erb, Matthias; Kaplan, Ian

    2013-03-01

    Plants mediate interactions between insects, including leaf- and root-feeders; yet the underlying mechanisms and connection with ecological theory remain unresolved. In this review, based on novel insights into long-distance (i.e., leaf-leaf, root-shoot) defence signalling, we explore the role of phytohormones in driving broad-scale patterns of aboveground-belowground interactions that can be extrapolated to general plant-insect relationships. We propose that the outcome of intra-feeding guild interactions is generally negative due to induction of similar phytohormonal pathways, whereas between-guild interactions are often positive due to negative signal crosstalk. However, not all outcomes could be explained by feeding guild; we argue that future studies should target ecologically representative plant-insect systems, distinguish subguilds, and include plant growth hormones to improve our understanding of plant-mediated interactions.

  8. Oxidative Stress in Fungi: Its Function in Signal Transduction, Interaction with Plant Hosts, and Lignocellulose Degradation

    Directory of Open Access Journals (Sweden)

    Michael Breitenbach

    2015-04-01

    Full Text Available In this review article, we want to present an overview of oxidative stress in fungal cells in relation to signal transduction, interaction of fungi with plant hosts, and lignocellulose degradation. We will discuss external oxidative stress which may occur through the interaction with other microorganisms or plant hosts as well as internally generated oxidative stress, which can for instance originate from NADPH oxidases or “leaky” mitochondria and may be modulated by the peroxiredoxin system or by protein disulfide isomerases thus contributing to redox signaling. Analyzing redox signaling in fungi with the tools of molecular genetics is presently only in its beginning. However, it is already clear that redox signaling in fungal cells often is linked to cell differentiation (like the formation of perithecia, virulence (in plant pathogens, hyphal growth and the successful passage through the stationary phase.

  9. Oxidative stress in fungi: its function in signal transduction, interaction with plant hosts, and lignocellulose degradation.

    Science.gov (United States)

    Breitenbach, Michael; Weber, Manuela; Rinnerthaler, Mark; Karl, Thomas; Breitenbach-Koller, Lore

    2015-01-01

    In this review article, we want to present an overview of oxidative stress in fungal cells in relation to signal transduction, interaction of fungi with plant hosts, and lignocellulose degradation. We will discuss external oxidative stress which may occur through the interaction with other microorganisms or plant hosts as well as internally generated oxidative stress, which can for instance originate from NADPH oxidases or "leaky" mitochondria and may be modulated by the peroxiredoxin system or by protein disulfide isomerases thus contributing to redox signaling. Analyzing redox signaling in fungi with the tools of molecular genetics is presently only in its beginning. However, it is already clear that redox signaling in fungal cells often is linked to cell differentiation (like the formation of perithecia), virulence (in plant pathogens), hyphal growth and the successful passage through the stationary phase. PMID:25854186

  10. Hypersomnolence with beta-adrenergic blockers.

    Science.gov (United States)

    Thachil, J; Zeller, J R; Kochar, M S

    1987-11-01

    An elderly, mildly demented, hypertensive male patient developed hypersomnolence on administration of propranolol for treatment of hypertension; no other cause for hypersomnolence was detected. Upon replacement of propranolol with atenolol, he felt better but continued to be quite somnolent. When atenolol was discontinued, he reported to have lack of sleep. On readministration of subtherapeutic doses of the same beta-adrenergic blocking agents, he once again experienced excessive sleepiness. By discontinuing beta-blocking agents and introducing captopril, he felt much better, became pleasant and talkative, and blood pressure was well controlled. Beta antagonists are important drugs in the management of many cardiovascular problems. Propranolol, a lipophilic beta-blocking agent, and atenolol, a hydrophilic beta-blocking agent, are two of the major agents currently used clinically in the United States. Numerous neuropsychiatric side-effects of the beta-adrenergic blocking drugs have been reported, but hypersomnolence is not readily recognized as one of them. PMID:3665616

  11. Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells.

    Science.gov (United States)

    Souilhol, Céline; Gonneau, Christèle; Lendinez, Javier G; Batsivari, Antoniana; Rybtsov, Stanislav; Wilson, Heather; Morgado-Palacin, Lucia; Hills, David; Taoudi, Samir; Antonchuk, Jennifer; Zhao, Suling; Medvinsky, Alexander

    2016-01-01

    During embryonic development, adult haematopoietic stem cells (HSCs) emerge preferentially in the ventral domain of the aorta in the aorta-gonad-mesonephros (AGM) region. Several signalling pathways such as Notch, Wnt, Shh and RA are implicated in this process, yet how these interact to regulate the emergence of HSCs has not previously been described in mammals. Using a combination of ex vivo and in vivo approaches, we report here that stage-specific reciprocal dorso-ventral inductive interactions and lateral input from the urogenital ridges are required to drive HSC development in the aorta. Our study strongly suggests that these inductive interactions in the AGM region are mediated by the interplay between spatially polarized signalling pathways. Specifically, Shh produced in the dorsal region of the AGM, stem cell factor in the ventral and lateral regions, and BMP inhibitory signals in the ventral tissue are integral parts of the regulatory system involved in the development of HSCs. PMID:26952187

  12. Modeling beta-adrenergic control of cardiac myocyte contractility in silico

    Science.gov (United States)

    Saucerman, Jeffrey J.; Brunton, Laurence L.; Michailova, Anushka P.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)

    2003-01-01

    The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.

  13. The Potential for Signal Integration and Processing in Interacting Map Kinase Cascades

    OpenAIRE

    John H Schwacke; Voit, Eberhard O.

    2007-01-01

    The cellular response to environmental stimuli requires biochemical information processing through which sensory inputs and cellular status are integrated and translated into appropriate responses by way of interacting networks of enzymes. One such network, the Mitogen Activated Protein (MAP) kinase cascade is a highly conserved signal transduction module that propagates signals from cell surface receptors to various cytosolic and nuclear targets by way of a phosphorylation cascade. We have i...

  14. The protein interaction network of a taxis signal transduction system in a Halophilic Archaeon

    Directory of Open Access Journals (Sweden)

    Schlesner Matthias

    2012-11-01

    Full Text Available Abstract Background The taxis signaling system of the extreme halophilic archaeon Halobacterium (Hbt. salinarum differs in several aspects from its model bacterial counterparts Escherichia coli and Bacillus subtilis. We studied the protein interactions in the Hbt. salinarum taxis signaling system to gain an understanding of its structure, to gain knowledge about its known components and to search for new members. Results The interaction analysis revealed that the core signaling proteins are involved in different protein complexes and our data provide evidence for dynamic interchanges between them. Fifteen of the eighteen taxis receptors (halobacterial transducers, Htrs can be assigned to four different groups depending on their interactions with the core signaling proteins. Only one of these groups, which contains six of the eight Htrs with known signals, shows the composition expected for signaling complexes (receptor, kinase CheA, adaptor CheW, response regulator CheY. From the two Hbt. salinarum CheW proteins, only CheW1 is engaged in signaling complexes with Htrs and CheA, whereas CheW2 interacts with Htrs but not with CheA. CheY connects the core signaling structure to a subnetwork consisting of the two CheF proteins (which build a link to the flagellar apparatus, CheD (the hub of the subnetwork, two CheC complexes and the receptor methylesterase CheB. Conclusions Based on our findings, we propose two hypotheses. First, Hbt. salinarum might have the capability to dynamically adjust the impact of certain Htrs or Htr clusters depending on its current needs or environmental conditions. Secondly, we propose a hypothetical feedback loop from the response regulator to Htr methylation made from the CheC proteins, CheD and CheB, which might contribute to adaptation analogous to the CheC/CheD system of B. subtilis.

  15. Glucose and Auxin Signaling Interaction in Controlling Arabidopsis thaliana Seedlings Root Growth and Development

    OpenAIRE

    Mishra, Bhuwaneshwar S.; Manjul Singh; Priyanka Aggrawal; Ashverya Laxmi

    2009-01-01

    BACKGROUND: Plant root growth and development is highly plastic and can adapt to many environmental conditions. Sugar signaling has been shown to affect root growth and development by interacting with phytohormones such as gibberellins, cytokinin and abscisic acid. Auxin signaling and transport has been earlier shown to be controlling plant root length, number of lateral roots, root hair and root growth direction. PRINCIPAL FINDINGS: Increasing concentration of glucose not only controls root ...

  16. Astrocytic β2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice

    Science.gov (United States)

    Jensen, Cathy Joanna; Demol, Frauke; Bauwens, Romy; Kooijman, Ron; Massie, Ann; Villers, Agnès; Ris, Laurence; De Keyser, Jacques

    2016-01-01

    In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the β2-adrenergic receptor on astrocytes might contribute to this energy balance, it has not yet been shown conclusively in vivo. Inducible astrocyte specific β2-adrenergic receptor knock-out mice were generated by crossing homozygous β2-adrenergic receptor floxed mice (Adrb2flox) and mice with heterozygous tamoxifen-inducible Cre recombinase-expression driven by the astrocyte specific L-glutamate/L-aspartate transporter promoter (GLAST-CreERT2). Assessments using the modified SHIRPA (SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment) test battery, swimming ability test, and accelerating rotarod test, performed at 1, 2 and 4 weeks, 6 and 12 months after tamoxifen (or vehicle) administration did not reveal any differences in physical health or motor functions between the knock-out mice and controls. However deficits were found in the cognitive ability of aged, but not young adult mice, reflected in impaired learning in the Morris Water Maze. Similarly, long-term potentiation (LTP) was impaired in hippocampal brain slices of aged knock-out mice maintained in low glucose media. Using microdialysis in cerebellar white matter we found no significant differences in extracellular lactate or glucose between the young adult knock-out mice and controls, although trends were detected. Our results suggest that β2-adrenergic receptor expression on astrocytes in mice may be important for maintaining cognitive health at advanced age, but is dispensable for motor function. PMID:27776147

  17. The Mutual Interaction effects between Array Antenna Parameters and Receiving Signals Bandwidth

    Directory of Open Access Journals (Sweden)

    Shahad D. Sateaa

    2014-03-01

    Full Text Available The presence of a single complex adaptive weight in each element channel of an adaptive array antenna is sufficient for processing of narrowband signals. The ability of an adaptive array antenna to null interference deteriorates rapidly as the interference bandwidth increases. The performance of narrowband adaptive array antenna with LMCV Beamforming algorithm is examined. The interaction effects between received signal angle of arrival and array parameters like the interelement spacing and the number of array element and the received signal bandwidth were studied. The output Signal to Interference plus Noise Ratio (SINR and Interference to Noise Ratio (INR are used as performance parameters for evaluation of these effects. It is found that the amount of degradation in the output SINR is increased significantly with the increase of array interelement spacing, number of array elements and when the angle of arrival of received signals are closet to end fire.

  18. Simultaneous stimulation of GABA and beta adrenergic receptors stabilizes isotypes of activated adenylyl cyclase heterocomplex

    Directory of Open Access Journals (Sweden)

    Robichon Alain

    2004-06-01

    Full Text Available Abstract Background We investigated how the synthesis of cAMP, stimulated by isoproterenol acting through β-adrenoreceptors and Gs, is strongly amplified by simultaneous incubation with baclofen. Baclofen is an agonist of δ-aminobutyric acid type B receptors [GABAB], known to inhibit adenylyl cyclase via Gi. Because these agents have opposite effects on cAMP levels, the unexpected increase in cAMP synthesis when they are applied simultaneously has been intensively investigated. From previous reports, it appears that cyclase type II contributes most significantly to this phenomenon. Results We found that simultaneous application of isoproterenol and baclofen specifically influences the association/dissociation of molecules involved in the induction and termination of cyclase activity. Beta/gamma from [GABA]B receptor-coupled Gi has a higher affinity for adenylyl cyclase isoform(s when these isoforms are co-associated with Gs. Our data also suggest that, when beta/gamma and Gαs are associated with adenylyl cyclase isoform(s, beta/gamma from [GABA]B receptor-coupled Gi retards the GTPase activity of Gαs from adrenergic receptor. These reciprocal regulations of subunits of the adenylyl cyclase complex might be responsible for the drastic increase of cAMP synthesis in response to the simultaneous signals. Conclusions Simultaneous signals arriving at a particular synapse converge on molecular detectors of coincidence and trigger specific biochemical events. We hypothesize that this phenomenon comes from the complex molecular architectures involved, including scaffolding proteins that make reciprocal interactions between associated molecules possible. The biochemistry of simultaneous signaling is addressed as a key to synaptic function.

  19. Observing social signals in scaffolding interactions: how to detect when a helping intention risks falling short.

    Science.gov (United States)

    Leone, Giovanna

    2012-10-01

    In face-to-face interactions, some social signals are aimed at regulating scaffolding processes, by which more knowledgeable people try to help less knowledgeable ones, to enable them to learn new concepts or skills (Vygotsky 1978). Observing face-to-face scaffolding interactions might not only allow us to grasp a large variety of these highly interesting social signals but may also be useful for the sake of scaffolding processes themselves. It often happens, in fact, that the empowering intentions implicit in these processes end up falling short, if the social signals regulating this specific kind of face-to-face interaction are misunderstood. Interestingly, many of these misunderstood aspects are related to the recipient's role. Indeed, attention is usually focused on the behavior of those imparting the knowledge, while skills already mastered by the learners, as well as their feedback, tend not to be taken as much into account. For the purpose of exploring the often very subtly nuanced social signals regulating on-going scaffolding processes in real-life interactions, an example of a methodological tool is presented: one already used to observe the interactions of dyads of Italian primary school teachers and their pupils, and mothers and their children. The article leads to two main conclusions: that the results of instances of scaffolding may be predicted as to their success or otherwise simply by telescoping crucial social signals during the scaffolding's initial phases, and that when helpers disregard these signals the effects of their actions may be detrimental or even humiliating for the receivers, notwithstanding the helper's intentions. PMID:22009169

  20. Axo-Glia Interaction Preceding CNS Myelination Is Regulated by Bidirectional Eph-Ephrin Signaling

    Directory of Open Access Journals (Sweden)

    Cecilie Linneberg

    2015-09-01

    Full Text Available In the central nervous system, myelination of axons is required to ensure fast saltatory conduction and for survival of neurons. However, not all axons are myelinated, and the molecular mechanisms involved in guiding the oligodendrocyte processes toward the axons to be myelinated are not well understood. Only a few negative or positive guidance clues that are involved in regulating axo-glia interaction prior to myelination have been identified. One example is laminin, known to be required for early axo-glia interaction, which functions through α6β1 integrin. Here, we identify the Eph-ephrin family of guidance receptors as novel regulators of the initial axo-glia interaction, preceding myelination. We demonstrate that so-called forward and reverse signaling, mediated by members of both Eph and ephrin subfamilies, has distinct and opposing effects on processes extension and myelin sheet formation. EphA forward signaling inhibits oligodendrocyte process extension and myelin sheet formation, and blocking of bidirectional signaling through this receptor enhances myelination. Similarly, EphB forward signaling also reduces myelin membrane formation, but in contrast to EphA forward signaling, this occurs in an integrin-dependent manner, which can be reversed by overexpression of a constitutive active β1-integrin. Furthermore, ephrin-B reverse signaling induced by EphA4 or EphB1 enhances myelin sheet formation. Combined, this suggests that the Eph-ephrin receptors are important mediators of bidirectional signaling between axons and oligodendrocytes. It further implies that balancing Eph-ephrin forward and reverse signaling is important in the selection process of axons to be myelinated.

  1. Paradigms and Paradox in the Ethylene Signaling Pathway and Interaction Network

    Institute of Scientific and Technical Information of China (English)

    Qiong Zhao; Hong-Wei Guo

    2011-01-01

    Phytohormone ethylene plays pivotal roles in plant response to developmental and environmental signals.During the past few years, the emerging evidence has led us to a new understanding of the signaling mechanisms and regulatory networks of the ethylene action. In this review, we focus on the major advances made in the past three years,particularly the findings leading to new paradigms and the observations under debate. With the recent demonstration of the regulation of the protein stability of numerous key signaling components including EIN3, ELL1, EIN2, ETR2, EBF1/EBF2,and ETP1/ETP2, we highlight proteasome-dependent protein degradation as an essential regulatory mechanism that is widely adopted in the ethylene signaling pathway. We also discuss the implication of the negative feedback mechanism in the ethylene signaling pathway in light of ethylene-induced ETR2 and EBF2 gene expression. Meanwhile, we summarize the controversy on the involvement of MKK9-MPK3/6 cascade in the ethylene signaling versus biosynthesis pathway, and discuss the possible role of this MAPK module in the ethylene action. Finally, we describe the complex interactions be-tween ethylene and other signaling pathways including auxin, light, and plant innate immunity, and propose that EIN3/ElL1 act as a convergence point in the ethylene-initiated signaling network.

  2. Muscle Plasticity and β2-Adrenergic Receptors: Adaptive Responses of β2-Adrenergic Receptor Expression to Muscle Hypertrophy and Atrophy

    Directory of Open Access Journals (Sweden)

    Shogo Sato

    2011-01-01

    Full Text Available We discuss the functional roles of β2-adrenergic receptors in skeletal muscle hypertrophy and atrophy as well as the adaptive responses of β2-adrenergic receptor expression to anabolic and catabolic conditions. β2-Adrenergic receptor stimulation using anabolic drugs increases muscle mass by promoting muscle protein synthesis and/or attenuating protein degradation. These effects are prevented by the downregulation of the receptor. Endurance training improves oxidative performance partly by increasing β2-adrenergic receptor density in exercise-recruited slow-twitch muscles. However, excessive stimulation of β2-adrenergic receptors negates their beneficial effects. Although the preventive effects of β2-adrenergic receptor stimulation on atrophy induced by muscle disuse and catabolic hormones or drugs are observed, these catabolic conditions decrease β2-adrenergic receptor expression in slow-twitch muscles. These findings present evidence against the use of β2-adrenergic agonists in therapy for muscle wasting and weakness. Thus, β2-adrenergic receptors in the skeletal muscles play an important physiological role in the regulation of protein and energy balance.

  3. Bilateral collicular interaction: modulation of auditory signal processing in frequency domain.

    Science.gov (United States)

    Cheng, L; Mei, H-X; Tang, J; Fu, Z-Y; Jen, P H-S; Chen, Q-C

    2013-04-01

    In the ascending auditory pathway, the inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from a variety of lower auditory nuclei, intrinsic projections within the IC, contralateral IC through the commissure of the IC and the auditory cortex. All these connections make the IC a major center for subcortical temporal and spectral integration of auditory information. In this study, we examine bilateral collicular interaction in the modulation of frequency-domain signal processing of mice using electrophysiological recording and focal electrical stimulation. Focal electrical stimulation of neurons in one IC produces widespread inhibition and focused facilitation of responses of neurons in the other IC. This bilateral collicular interaction decreases the response magnitude and lengthens the response latency of inhibited IC neurons but produces an opposite effect on the response of facilitated IC neurons. In the frequency domain, the focal electrical stimulation of one IC sharpens or expands the frequency tuning curves (FTCs) of neurons in the other IC to improve frequency sensitivity and the frequency response range. The focal electrical stimulation also produces a shift in the best frequency (BF) of modulated IC (ICMdu) neurons toward that of electrically stimulated IC (ICES) neurons. The degree of bilateral collicular interaction is dependent upon the difference in the BF between the ICES neurons and ICMdu neurons. These data suggest that bilateral collicular interaction is a part of dynamic acoustic signal processing that adjusts and improves signal processing as well as reorganizes collicular representation of signal parameters according to the acoustic experience.

  4. Long distance root-shoot signalling in plant-insect community interactions

    NARCIS (Netherlands)

    Soler, R.; Erb, M.; Kaplan, I.

    2013-01-01

    Plants mediate interactions between insects, including leaf- and root-feeders; yet the underlying mechanisms and connection with ecological theory remain unresolved. In this review, based on novel insights into long-distance (i.e., leaf-leaf, root-shoot) defence signalling, we explore the role of ph

  5. Expression of inwardly rectifying potassium channels (GIRKs and beta-adrenergic regulation of breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Cakir Yavuz

    2004-12-01

    Full Text Available Abstract Background Previous research has indicated that at various organ sites there is a subset of adenocarcinomas that is regulated by beta-adrenergic and arachidonic acid-mediated signal transduction pathways. We wished to determine if this regulation exists in breast adenocarcinomas. Expression of mRNA that encodes a G-protein coupled inwardly rectifying potassium channel (GIRK1 has been shown in tissue samples from approximately 40% of primary human breast cancers. Previously, GIRK channels have been associated with beta-adrenergic signaling. Methods Breast cancer cell lines were screened for GIRK channels by RT-PCR. Cell cultures of breast cancer cells were treated with beta-adrenergic agonists and antagonists, and changes in gene expression were determined by both relative competitive and real time PCR. Potassium flux was determined by flow cytometry and cell signaling was determined by western blotting. Results Breast cancer cell lines MCF-7, MDA-MB-361 MDA-MB 453, and ZR-75-1 expressed mRNA for the GIRK1 channel, while MDA-MB-468 and MDA-MB-435S did not. GIRK4 was expressed in all six breast cancer cell lines, and GIRK2 was expressed in all but ZR-75-1 and MDA-MB-435. Exposure of MDA-MB-453 cells for 6 days to the beta-blocker propranolol (1 μM increased the GIRK1 mRNA levels and decreased beta2-adrenergic mRNA levels, while treatment for 30 minutes daily for 7 days had no effect. Exposure to a beta-adrenergic agonist and antagonist for 24 hours had no effect on gene expression. The beta adrenergic agonist, formoterol hemifumarate, led to increases in K+ flux into MDA-MB-453 cells, and this increase was inhibited by the GIRK channel inhibitor clozapine. The tobacco carcinogen 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK, a high affinity agonist for beta-adrenergic receptors stimulated activation of Erk 1/2 in MDA-MB-453 cells. Conclusions Our data suggests β-adrenergic receptors and GIRK channels may play a role in breast cancer.

  6. Adrenergic Modulation of Pancreatic Glucagon Secretion in Man

    Science.gov (United States)

    Gerich, John E.; Langlois, Maurice; Noacco, Claudio; Schneider, Victor; Forsham, Peter H.

    1974-01-01

    In order to characterize the influence of the adrenergic system on pancreatic glucagon secretion in man, changes in basal glucagon secretion during infusions of pure alpha and beta adrenergic agonists and their specific antagonists were studied. During infusion of isoproterenol (3 μg/min), a beta adrenergic agonist, plasma glucagon rose from a mean (±SE) basal level of 104±10 to 171±15 pg/ml, P < 0.0002. Concomitant infusion of propranolol (80 μg/min), a beta adrenergic antagonist, prevented the effects of isoproterenol, although propranolol itself had no effect on basal glucagon secretion. During infusion of methoxamine (0.5 mg/min), an alpha adrenergic agonist, plasma glucagon declined from a mean basal level of 122±15 to 75±17 pg/ml, P < 0.001. Infusion of phentolamine (0.5 mg/min), an alpha adrenergic antagonist, caused a rise in plasma glucagon from a mean basal level of 118±16 to 175±21 pg/ml, P < 0.0001. Concomitant infusion of methoxamine with phentolamine caused a reversal of the effects of phentolamine. The present studies thus confirm that catecholamines affect glucagon secretion in man and demonstrate that the pancreatic alpha cell possesses both alpha and beta adrenergic receptors. Beta adrenergic stimulation augments basal glucagon secretion, while alpha adrenergic stimulation diminishes basal glucagon secretion. Furthermore, since infusion of phentolamine, an alpha adrenergic antagonist, resulted in an elevation of basal plasma glucagon levels, there appears to be an inhibitory alpha adrenergic tone governing basal glucagon secretion. The above findings suggest that catecholamines may influence glucose homeostasis in man through their effects on both pancreatic alpha and beta cell function. Images PMID:4825234

  7. Inhibition of Protein-Protein Interactions and Signaling by Small Molecules

    Science.gov (United States)

    Freire, Ernesto

    2010-03-01

    Protein-protein interactions are at the core of cell signaling pathways as well as many bacterial and viral infection processes. As such, they define critical targets for drug development against diseases such as cancer, arthritis, obesity, AIDS and many others. Until now, the clinical inhibition of protein-protein interactions and signaling has been accomplished with the use of antibodies or soluble versions of receptor molecules. Small molecule replacements of these therapeutic agents have been extremely difficult to develop; either the necessary potency has been hard to achieve or the expected biological effect has not been obtained. In this presentation, we show that a rigorous thermodynamic approach that combines differential scanning calorimetry (DSC) and isothermal titration calorimetry (ITC) provides a unique platform for the identification and optimization of small molecular weight inhibitors of protein-protein interactions. Recent advances in the development of cell entry inhibitors of HIV-1 using this approach will be discussed.

  8. Forget-me-not:Complex floral displays,inter-signal interactions,and pollinator cognition

    Institute of Scientific and Technical Information of China (English)

    Anne S.LEONARD; Anna DORNHAUS; Daniel R.PAPAJ

    2011-01-01

    Flowers are multisensory displays used by plants to influence the behavior of pollinators.Although we know a great deal about how individual signal components are preduced by plants and detected or learned by pollinators,very few experiments directly address the function of floral signal complexity,I.e.how the multicompenent nature of these signals benefits plant or pollinator.Yet,experimental psychology suggests that increasing complexity can enhance subjects'ability to deteCt,learn and remember stimuli,and the plant,sreproductive success depends upon ensuring that pollinators learn their signals and so transport pollen to other similar(conspecific)flowers.Here we explore functional hypotheses for why plants invest in complex floral displays focusing on hypotheses in which floral signals interact to promote pollinator learning and memory'Specifically,we discuss how an attention-altering or context-providing function of one signal may promote acquisition or recall of a second signal.Although we focus on communication between plants and poilinators,these process-based hypotheses should apply to any situation where a sender benefits from enhancing a receiver's acquisition or recall of informtion.

  9. Lipid rafts and Alzheimer’s disease: protein-lipid interactions and perturbation of signalling

    Directory of Open Access Journals (Sweden)

    David A. Hicks

    2012-06-01

    Full Text Available Lipid rafts are membrane domains, more ordered than the bulk membrane and enriched in cholesterol and sphingolipids. They represent a platform for protein-lipid and protein-protein interactions and for cellular signalling events. In addition to their normal functions, including membrane trafficking, ligand binding (including viruses, axonal development and maintenance of synaptic integrity, rafts have also been implicated in the pathogenesis of several neurodegenerative diseases including Alzheimer’s disease (AD. Lipid rafts promote interaction of the amyloid precursor protein (APP with the secretase (BACE-1 responsible for generation of the amyloid β peptide, Aβ. Rafts also regulate cholinergic signalling as well as acetylcholinesterase and Aβ interaction. In addition, such major lipid raft components as cholesterol and GM1 ganglioside have been directly implicated in pathogenesis of the disease. Perturbation of lipid raft integrity can also affect various signalling pathways leading to cellular death and AD. In this review, we discuss modulation of APP cleavage by lipid rafts and their components, while also looking at more recent findings on the role of lipid rafts in signalling events.

  10. Amphetamine administration into the ventral striatum facilitates behavioral interaction with unconditioned visual signals in rats.

    Directory of Open Access Journals (Sweden)

    Rick Shin

    Full Text Available BACKGROUND: Administration of psychomotor stimulants like amphetamine facilitates behavior in the presence of incentive distal stimuli, which have acquired the motivational properties of primary rewards through associative learning. This facilitation appears to be mediated by the mesolimbic dopamine system, which may also be involved in facilitating behavior in the presence of distal stimuli that have not been previously paired with primary rewards. However, it is unclear whether psychomotor stimulants facilitate behavioral interaction with unconditioned distal stimuli. PRINCIPAL FINDINGS: We found that noncontingent administration of amphetamine into subregions of the rat ventral striatum, particularly in the vicinity of the medial olfactory tubercle, facilitates lever pressing followed by visual signals that had not been paired with primary rewards. Noncontingent administration of amphetamine failed to facilitate lever pressing when it was followed by either tones or delayed presentation or absence of visual signals, suggesting that visual signals are key for enhanced behavioral interaction. Systemic administration of amphetamine markedly increased locomotor activity, but did not necessarily increase lever pressing rewarded by visual signals, suggesting that lever pressing is not a byproduct of heightened locomotor activity. Lever pressing facilitated by amphetamine was reduced by co-administration of the dopamine receptor antagonists SCH 23390 (D1 selective or sulpiride (D2 selective. CONCLUSIONS: Our results suggest that amphetamine administration into the ventral striatum, particularly in the vicinity of the medial olfactory tubercle, activates dopaminergic mechanisms that strongly enhance behavioral interaction with unconditioned visual stimuli.

  11. P-Finder: Reconstruction of Signaling Networks from Protein-Protein Interactions and GO Annotations.

    Science.gov (United States)

    Young-Rae Cho; Yanan Xin; Speegle, Greg

    2015-01-01

    Because most complex genetic diseases are caused by defects of cell signaling, illuminating a signaling cascade is essential for understanding their mechanisms. We present three novel computational algorithms to reconstruct signaling networks between a starting protein and an ending protein using genome-wide protein-protein interaction (PPI) networks and gene ontology (GO) annotation data. A signaling network is represented as a directed acyclic graph in a merged form of multiple linear pathways. An advanced semantic similarity metric is applied for weighting PPIs as the preprocessing of all three methods. The first algorithm repeatedly extends the list of nodes based on path frequency towards an ending protein. The second algorithm repeatedly appends edges based on the occurrence of network motifs which indicate the link patterns more frequently appearing in a PPI network than in a random graph. The last algorithm uses the information propagation technique which iteratively updates edge orientations based on the path strength and merges the selected directed edges. Our experimental results demonstrate that the proposed algorithms achieve higher accuracy than previous methods when they are tested on well-studied pathways of S. cerevisiae. Furthermore, we introduce an interactive web application tool, called P-Finder, to visualize reconstructed signaling networks.

  12. Holophytochrome-interacting proteins in Physcomitrella: putative actors in phytochrome cytoplasmic signaling

    Directory of Open Access Journals (Sweden)

    Anna Lena eErmert

    2016-05-01

    Full Text Available Phytochromes are the principle photoreceptors in light-regulated plant development, primarily acting via translocation of the light-activated photoreceptor into the nucleus and subsequent gene regulation. However, several independent lines of evidence indicate unambiguously that an additional cytoplasmic signaling mechanism must exist. Directional responses in filament tip cells of the moss Physcomitrella patens are steered by phy4 which has been shown to interact physically with the blue light receptor phototropin at the plasma membrane. This complex might perceive and transduce vectorial information leading to cytoskeleton reorganization and finally a directional growth response. We developed yeast two-hybrid procedures using photochemically-functional, full-length phy4 as bait in Physcomitrella cDNA library screens and growth assays under different light conditions, revealing Pfr-dependent interactions possibly associated with phytochrome cytoplasmic signaling. Candidate proteins were then expressed in planta with fluorescent protein tags to determine their intracellular localization in darkness and red light. Of 14 candidates, 12 were confirmed to interact with phy4 in planta using bimolecular fluorescence complementation. We discuss the roles these putative holophytochrome-interacting proteins (HIP's might have in signaling.

  13. Signal-noise interaction in nonlinear optical fibers: a hydrodynamic approach

    CERN Document Server

    Barletti, Luigi

    2015-01-01

    We present a new perturbative approach to the study of signal-noise interactions in amplified optical fibers. The approach is based on the hydrodynamic formulation of the nonlinear Schr\\"odinger equation that governs the propagation of light in the fiber. Our method is discussed in general and is developed in more details for some special cases, namely the small-dispersion regime, the continuous-wave (CW) signal and the solitonic pulse. The accuracy of the approach is numerically tested in the CW case.

  14. Physiological and Clinical Implications of Adrenergic Pathways at High Altitude.

    Science.gov (United States)

    Richalet, Jean-Paul

    2016-01-01

    The adrenergic system is part of a full array of mechanisms allowing the human body to adapt to the hypoxic environment. Triggered by the stimulation of peripheral chemoreceptors, the adrenergic centers in the medulla are activated in acute hypoxia and augment the adrenergic drive to the organs, especially to the heart, leading to tachycardia. With prolonged exposure to altitude hypoxia, the adrenergic drive persists, as witnessed by elevated blood concentrations of catecholamines and nerve activity in adrenergic fibers. In response to this persistent stimulation, the pathways leading to the activation of adenylate cyclase are modified. A downregulation of β-adrenergic and adenosinergic receptors is observed, while muscarinic receptors are upregulated. The expression and activity of Gi and Gs proteins are modified, leading to a decreased response of adenylate cyclase activity to adrenergic stimulation. The clinical consequences of these cellular and molecular changes are of importance, especially for exercise performance and protection of heart function. The decrease in maximal exercise heart rate in prolonged hypoxia is fully accounted for the observed changes in adrenergic and muscarinic pathways. The decreased heart rate response to isoproterenol infusion is another marker of the desensitization of adrenergic pathways. These changes can be considered as mechanisms protecting the heart from a too high oxygen consumption in conditions where the oxygen availability is severely reduced. Similarly, intermittent exposure to hypoxia has been shown to protect the heart from an ischemic insult with similar mechanisms involving G proteins and downregulation of β receptors. Other pathways with G proteins are concerned in adaptation to hypoxia, such as lactate release by the muscles and renal handling of calcium. Altogether, the activation of the adrenergic system is useful for the acute physiological response to hypoxia. With prolonged exposure to hypoxia, the autonomous

  15. A proteomics strategy to elucidate functional protein-protein interactions applied to EGF signaling

    DEFF Research Database (Denmark)

    Blagoev, B.; Kratchmarova, I.; Ong, S.E.;

    2003-01-01

    Mass spectrometry-based proteomics can reveal protein-protein interactions on a large scale, but it has been difficult to separate background binding from functionally important interactions and still preserve weak binders. To investigate the epidermal growth factor receptor (EGFR) pathway, we...... and Src homologous and collagen (Shc) protein. We identified 228 proteins, of which 28 were selectively enriched upon stimulation. EGFR and Shc, which interact directly with the bait, had large differential ratios. Many signaling molecules specifically formed complexes with the activated EGFR-Shc, as did...... plectin, epiplakin, cytokeratin networks, histone H3, the glycosylphosphatidylinositol (GPI)-anchored molecule CD59, and two novel proteins. SILAC combined with modification-based affinity purification is a useful approach to detect specific and functional protein-protein interactions....

  16. Akt1 mediates neuronal differentiation in zebrafish via a reciprocal interaction with notch signaling.

    Directory of Open Access Journals (Sweden)

    Yi-Chuan Cheng

    Full Text Available Akt1 is well known for its role in regulating cell proliferation, differentiation, and apoptosis and is implicated in tumors and several neurological disorders. However, the role of Akt1 in neural development has not been well defined. We have isolated zebrafish akt1 and shown that this gene is primarily transcribed in the developing nervous system, and its spatiotemporal expression pattern suggests a role in neural differentiation. Injection of akt1 morpholinos resulted in loss of neuronal precursors with a concomitant increase in post-mitotic neurons, indicating that knockdown of Akt1 is sufficient to cause premature differentiation of neurons. A similar phenotype was observed in embryos deficient for Notch signaling. Both the ligand (deltaA and the downstream target of Notch (her8a were downregulated in akt1 morphants, indicating that Akt1 is required for Delta-Notch signaling. Furthermore, akt1 expression was downregulated in Delta-Notch signaling-deficient embryos and could be induced by constitutive activation of Notch signaling. In addition, knockdown of Akt1 was able to nullify the inhibition of neuronal differentiation caused by constitutive activation of Notch signaling. Taken together, these results provide in vivo evidence that Akt1 interacts with Notch signaling reciprocally and provide an explanation of why Akt1 is essential for the inhibition of neuronal differentiation.

  17. Association between Selective Beta-adrenergic Drugs and Blood Pressure Elevation: Data Mining of the Japanese Adverse Drug Event Report (JADER) Database.

    Science.gov (United States)

    Ohyama, Katsuhiro; Inoue, Michiko

    2016-01-01

    Selective beta-adrenergic drugs are used clinically to treat various diseases. Because of imperfect receptor selectivity, beta-adrenergic drugs cause some adverse drug events by stimulating other adrenergic receptors. To examine the association between selective beta-adrenergic drugs and blood pressure elevation, we reviewed the Japanese Adverse Drug Event Reports (JADERs) submitted to the Japan Pharmaceuticals and Medical Devices Agency. We used the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms extracted from Standardized MedDRA queries for hypertension to identify events related to blood pressure elevation. Spontaneous adverse event reports from April 2004 through May 2015 in JADERs, a data mining algorithm, and the reporting odds ratio (ROR) were used for quantitative signal detection, and assessed by the case/non-case method. Safety signals are considered significant if the ROR estimates and lower bound of the 95% confidence interval (CI) exceed 1. A total of 2021 reports were included in this study. Among the nine drugs examined, significant signals were found, based on the 95%CI for salbutamol (ROR: 9.94, 95%CI: 3.09-31.93) and mirabegron (ROR: 7.52, 95%CI: 4.89-11.55). The results of this study indicate that some selective beta-adrenergic drugs are associated with blood pressure elevation. Considering the frequency of their indications, attention should be paid to their use in elderly patients to avoid adverse events. PMID:27374969

  18. Glucose and auxin signaling interaction in controlling Arabidopsis thaliana seedlings root growth and development.

    Directory of Open Access Journals (Sweden)

    Bhuwaneshwar S Mishra

    Full Text Available BACKGROUND: Plant root growth and development is highly plastic and can adapt to many environmental conditions. Sugar signaling has been shown to affect root growth and development by interacting with phytohormones such as gibberellins, cytokinin and abscisic acid. Auxin signaling and transport has been earlier shown to be controlling plant root length, number of lateral roots, root hair and root growth direction. PRINCIPAL FINDINGS: Increasing concentration of glucose not only controls root length, root hair and number of lateral roots but can also modulate root growth direction. Since root growth and development is also controlled by auxin, whole genome transcript profiling was done to find out the extent of interaction between glucose and auxin response pathways. Glucose alone could transcriptionally regulate 376 (62% genes out of 604 genes affected by IAA. Presence of glucose could also modulate the extent of regulation 2 fold or more of almost 63% genes induced or repressed by IAA. Interestingly, glucose could affect induction or repression of IAA affected genes (35% even if glucose alone had no significant effect on the transcription of these genes itself. Glucose could affect auxin biosynthetic YUCCA genes family members, auxin transporter PIN proteins, receptor TIR1 and members of a number of gene families including AUX/IAA, GH3 and SAUR involved in auxin signaling. Arabidopsis auxin receptor tir1 and response mutants, axr2, axr3 and slr1 not only display a defect in glucose induced change in root length, root hair elongation and lateral root production but also accentuate glucose induced increase in root growth randomization from vertical suggesting glucose effects on plant root growth and development are mediated by auxin signaling components. CONCLUSION: Our findings implicate an important role of the glucose interacting with auxin signaling and transport machinery to control seedling root growth and development in changing nutrient

  19. Image informatics for studying signal transduction in cells interacting with 3D matrices

    Science.gov (United States)

    Tzeranis, Dimitrios S.; Guo, Jin; Chen, Chengpin; Yannas, Ioannis V.; Wei, Xunbin; So, Peter T. C.

    2014-03-01

    Cells sense and respond to chemical stimuli on their environment via signal transduction pathways, complex networks of proteins whose interactions transmit chemical information. This work describes an implementation of image informatics, imaging-based methodologies for studying signal transduction networks. The methodology developed focuses on studying signal transduction networks in cells that interact with 3D matrices. It utilizes shRNA-based knock down of network components, 3D high-content imaging of cells inside the matrix by spectral multi-photon microscopy, and single-cell quantification using features that describe both cell morphology and cell-matrix adhesion pattern. The methodology is applied in a pilot study of TGFβ signaling via the SMAD pathway in fibroblasts cultured inside porous collagen-GAG scaffolds, biomaterials similar to the ones used clinically to induce skin regeneration. Preliminary results suggest that knocking down all rSMAD components affects fibroblast response to TGFβ1 and TGFβ3 isoforms in different ways, and suggest a potential role for SMAD1 and SMAD5 in regulating TGFβ isoform response. These preliminary results need to be verified with proteomic results that can provide solid evidence about the particular role of individual components of the SMAD pathway.

  20. Interactions between radiofrequency signals and living organisms; Interactions entre signaux radiofrequences et vivants

    Energy Technology Data Exchange (ETDEWEB)

    Boudin, F.; Hours, M.; Lacronique, J.F.; Conil, E.; Hadjem, A.; El Habachi, A.; Wiart, K.; Mann, S.; Kundi, M.; Marc-Vergnes, J.P.; Roosli, M.; Mohler, E.; Frei, P.; Davis, Ch.C.; Balzano, Q.; Ait-Aissa, S.; Billaudel, B.; Poulletier De Gannes, F.; Hurtier, A.; Haro, E.; Taxile, M.; Veyret, B.; Lagroye, I.; Ait-Aissa, S.; Poulletier De Gannes, F.; Athane, A.; Veyret, B.; Lagroye, I.; Yardin, C.; Perrin, A.; Freire, M.; Bachelet, Ch.; Collin, A.; Pla, S.; Debouzy, J.C.; Leveque, Ph.; Van Nierop, L.E.; Huss, A.; Roosli, M.; Egger, M.; Calvez, M.; Salomon, D.

    2010-11-15

    This dossier is composed of 13 articles dealing with the interactions between radio-frequencies and living organisms. It is an overview of various scientific approaches to the field and is of interest for all citizens as the use of mobile phones is widely spread. In the first article it is shown how a model has been built to assess the distribution of the whole body exposure of the population. The second article reviews the state of the art in personal exposure measurements at radio-frequencies. The third article shows that the knowledge of the mechanism of action by which exposure increases the risk of health hazards is necessary. The fourth article shows that individual neuro-psychic factors take a prominent but maybe not unique, part in electromagnetic hypersensitivity. The fifth article shows that no evidence was found to link health disturbances of electromagnetic hypersensitive individuals with radiofrequency exposure. The sixth article shows that the wireless phone is not an athermal hazard to the brain. The seventh article shows that the in utero and post-natal exposure to Wi-Fi does not damage the brains of young rats. The eighth article concludes that recent studies provide no convincing proof of deleterious effects of radiofrequency exposure on the integrity of the blood-brain barrier for specific absorption rates up to 6 W/kg. The ninth article shows that no co-genotoxic effect of radiofrequency was found at levels of exposure that did not induce heating. The tenth article confirms that industry-sponsored studies were least likely to report results suggesting effects. The last article shows that general practitioners are increasingly questioned by their patients about the issue of electromagnetic waves. (A.C.) Available from doi:

  1. Extracellular matrix proteins interact with cell-signaling pathways in modifying risk of achilles tendinopathy.

    Science.gov (United States)

    Saunders, Colleen J; van der Merwe, Lize; Cook, Jill; Handley, Christopher J; Collins, Malcolm; September, Alison V

    2015-06-01

    The aim of this study was to investigate interactions between variants within genes encoding components of the collagen fibril and components of cell-signaling pathways within the extracellular matrix, and determine the relative contribution of these variants to Achilles tendinopathy risk in a polygenic model. A total of 339 asymptomatic control participants and 179 participants clinically diagnosed with Achilles tendinopathy were genotyped for variants within six genes encoding components of the collagen fibril and three genes encoding components of cell-signaling pathways. Logistic regression, stepwise selection, and receiver operating characteristic curve (ROC) analysis was used to select and evaluate genetic interactions and determine the relative contribution of these variants to overall genetic risk. The strongest, best fit polygenic risk model included the variables sex, three COL27A1 variants (rs4143245; rs1249744; rs946053), COL5A1 rs12722, CASP8 rs1045485, and CASP8 rs2824129 with an area under the ROC curve of 0.737 and the maximum sum of sensitivity and specificity indicators equal to 134%. Significant interactions between genes encoding components of the collagen fibril and genes encoding components of the cell-signaling pathways modify risk of Achilles tendinopathy.

  2. Signaling through urokinase and urokinase receptor in lung cancer cells requires interactions with beta1 integrins.

    Science.gov (United States)

    Tang, Chi-Hui; Hill, Marla L; Brumwell, Alexis N; Chapman, Harold A; Wei, Ying

    2008-11-15

    The urokinase receptor (uPAR) is upregulated upon tumor cell invasion and correlates with poor lung cancer survival. Although a cis-interaction with integrins has been ascribed to uPAR, whether this interaction alone is critical to urokinase (uPA)- and uPAR-dependent signaling and tumor promotion is unclear. Here we report the functional consequences of point mutations of uPAR (H249A-D262A) that eliminate beta1 integrin interactions but maintain uPA binding, vitronectin attachment and association with alphaV integrins, caveolin and epidermal growth factor receptor. Disruption of uPAR interactions with beta1 integrins recapitulated previously reported findings with beta1-integrin-derived peptides that attenuated matrix-dependent ERK activation, MMP expression and in vitro migration by human lung adenocarcinoma cell lines. The uPAR mutant cells acquired enhanced capacity to adhere to vitronectin via uPAR-alphaVbeta5-integrin, rather than through the uPAR-alpha3beta1-integrin complex and they were unable to initiate uPA signaling to activate ERK, Akt or Stat1. In an orthotopic lung cancer model, uPAR mutant cells exhibited reduced tumor size compared with cells expressing wild-type uPAR. Taken together, the results indicate that uPAR-beta1-integrin interactions are essential to signals induced by integrin matrix ligands or uPA that support lung cancer cell invasion in vitro and progression in vivo. PMID:18940913

  3. Cholinergic and adrenergic influence on the teleost heart in vivo.

    Science.gov (United States)

    Axelsson, M; Ehrenström, F; Nilsson, S

    1987-01-01

    The tonical cholinergic and adrenergic influence on the heart rate was investigated in vivo in seven species of marine teleosts (pollack, Pollachius pollachius; cuckoo wrasse, Labrus mixtus; ballan wrasse, Labrus berggylta; five-bearded rockling, Ciliata mustela; tadpole fish, Raniceps raninus; eel-pout, Zoarces viviparus and short-spined sea scorpion, Myoxocephalus scor pius) during rest and, in two of the species (P. pollachius and L. mixtus), also during moderate swimming exercise in a Blazka-type swim tunnel. Ventral aortic blood pressure and heart rate were recorded via a catheter implanted in an afferent branchial artery, and the influence of the cholinergic and adrenergic tonus on the heart rate was assessed by injection of atropine and sotalol respectively. During rest the adrenergic tonus was higher than the cholinergic tonus in all species except L. berggylta, where the reverse was true. In P. pollachius and L. mixtus, exercise appeared to produce a lowering of the cholinergic tonus on the heart and, possibly, a slight increase of the adrenergic tonus. The nature of the adrenergic tonus (humoral or neural) is not clear, but the low plasma concentrations of catecholamines both during rest and exercise could be interpreted in favour of a mainly neural adrenergic tonus on the teleost heart. These experiments are compatible with the view that both a cholinergic inhibitory tonus and an adrenergic excitatory tonus are general features in the control of the teleost heart in vivo, both at rest and during moderate swimming exercise.

  4. Interactions between Trypanosoma cruzi Secreted Proteins and Host Cell Signaling Pathways

    Science.gov (United States)

    Watanabe Costa, Renata; da Silveira, Jose F.; Bahia, Diana

    2016-01-01

    Chagas disease is one of the prevalent neglected tropical diseases, affecting at least 6–7 million individuals in Latin America. It is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to vertebrate hosts by blood-sucking insects. After infection, the parasite invades and multiplies in the myocardium, leading to acute myocarditis that kills around 5% of untreated individuals. T. cruzi secretes proteins that manipulate multiple host cell signaling pathways to promote host cell invasion. The primary secreted lysosomal peptidase in T. cruzi is cruzipain, which has been shown to modulate the host immune response. Cruzipain hinders macrophage activation during the early stages of infection by interrupting the NF-kB P65 mediated signaling pathway. This allows the parasite to survive and replicate, and may contribute to the spread of infection in acute Chagas disease. Another secreted protein P21, which is expressed in all of the developmental stages of T. cruzi, has been shown to modulate host phagocytosis signaling pathways. The parasite also secretes soluble factors that exert effects on host extracellular matrix, such as proteolytic degradation of collagens. Finally, secreted phospholipase A from T. cruzi contributes to lipid modifications on host cells and concomitantly activates the PKC signaling pathway. Here, we present a brief review of the interaction between secreted proteins from T. cruzi and the host cells, emphasizing the manipulation of host signaling pathways during invasion. PMID:27065960

  5. SPC toolbox: An interactive MATLAB (tm) package for signal modeling, analysis, and communications

    Science.gov (United States)

    Brown, Dennis W.; Fargues, Monique P.

    1993-10-01

    This report presents the Signal Processing and Communications (SPC) software package. SPC is an interactive package designed to provide the user with a series of data manipulation tools which use MATLAB version 4 graphical interface controls. SPC includes various filtering techniques, AutoRegressive (AR) and linear Moving Average AutoRegressive (ARMA) modeling methods, speech processing, and communication functions. SPC can be used in the classroom to illustrate and to reinforce basic concepts in signal processing and communications. It allows the user to concentrate on the principles presented in class instead of the details related to software usage. It can also be used as a basic analysis and modeling tool for research in signal processing. SPC was designed for Electrical Engineering applications. As a result, it is well suited to reinforce basic concepts presented in the following courses offered at the Naval Postgraduate School: EC 4410: Speech Processing, EC 4420: Modern Spectral Estimation, EC 3420: Statistical Digital Signal Processing, EC 3400: Digital Signal Processing, and EC 2500: Communication Theory. We hope that users will find this package useful, and we welcome any comments and suggestions regarding this software at browndw ece.nps.navy.mil (until 6/94), or fargues ece.nps.navy.mil.

  6. Palmitoylation controls DLK localization, interactions and activity to ensure effective axonal injury signaling

    Science.gov (United States)

    Holland, Sabrina M.; Collura, Kaitlin M.; Ketschek, Andrea; Noma, Kentaro; Ferguson, Toby A.; Jin, Yishi; Gallo, Gianluca; Thomas, Gareth M.

    2016-01-01

    Dual leucine-zipper kinase (DLK) is critical for axon-to-soma retrograde signaling following nerve injury. However, it is unknown how DLK, a predicted soluble kinase, conveys long-distance signals and why homologous kinases cannot compensate for loss of DLK. Here, we report that DLK, but not homologous kinases, is palmitoylated at a conserved site adjacent to its kinase domain. Using short-hairpin RNA knockdown/rescue, we find that palmitoylation is critical for DLK-dependent retrograde signaling in sensory axons. This functional importance is because of three novel cellular and molecular roles of palmitoylation, which targets DLK to trafficking vesicles, is required to assemble DLK signaling complexes and, unexpectedly, is essential for DLK’s kinase activity. By simultaneously controlling DLK localization, interactions, and activity, palmitoylation ensures that only vesicle-bound DLK is active in neurons. These findings explain how DLK specifically mediates nerve injury responses and reveal a novel cellular mechanism that ensures the specificity of neuronal kinase signaling. PMID:26719418

  7. Improved Protein Arrays for Quantitative Systems Analysis of the Dynamics of Signaling Pathway Interactions

    Energy Technology Data Exchange (ETDEWEB)

    YANG, CHIN-RANG [NHLBI, NIH

    2013-12-11

    Astronauts and workers in nuclear plants who repeatedly exposed to low doses of ionizing radiation (IR, <10 cGy) are likely to incur specific changes in signal transduction and gene expression in various tissues of their body. Remarkable advances in high throughput genomics and proteomics technologies enable researchers to broaden their focus from examining single gene/protein kinetics to better understanding global gene/protein expression profiling and biological pathway analyses, namely Systems Biology. An ultimate goal of systems biology is to develop dynamic mathematical models of interacting biological systems capable of simulating living systems in a computer. This Glue Grant is to complement Dr. Boothman’s existing DOE grant (No. DE-FG02-06ER64186) entitled “The IGF1/IGF-1R-MAPK-Secretory Clusterin (sCLU) Pathway: Mediator of a Low Dose IR-Inducible Bystander Effect” to develop sensitive and quantitative proteomic technology that suitable for low dose radiobiology researches. An improved version of quantitative protein array platform utilizing linear Quantum dot signaling for systematically measuring protein levels and phosphorylation states for systems biology modeling is presented. The signals are amplified by a confocal laser Quantum dot scanner resulting in ~1000-fold more sensitivity than traditional Western blots and show the good linearity that is impossible for the signals of HRP-amplification. Therefore this improved protein array technology is suitable to detect weak responses of low dose radiation. Software is developed to facilitate the quantitative readout of signaling network activities. Kinetics of EGFRvIII mutant signaling was analyzed to quantify cross-talks between EGFR and other signaling pathways.

  8. Adrenergic gene polymorphisms and cardiovascular risk in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation

    Directory of Open Access Journals (Sweden)

    Sharaf Barry L

    2008-03-01

    Full Text Available Abstract Background Adrenergic gene polymorphisms are associated with cardiovascular and metabolic phenotypes. We investigated the influence of adrenergic gene polymorphisms on cardiovascular risk in women with suspected myocardial ischemia. Methods We genotyped 628 women referred for coronary angiography for eight polymorphisms in the α1A-, β1-, β2- and β3-adrenergic receptors (ADRA1A, ADRB1, ADRB2, ADRB3, respectively, and their signaling proteins, G-protein β 3 subunit (GNB3 and G-protein α subunit (GNAS. We compared the incidence of death, myocardial infarction, stroke, or heart failure between genotype groups in all women and women without obstructive coronary stenoses. Results After a median of 5.8 years of follow-up, 115 women had an event. Patients with the ADRB1 Gly389 polymorphism were at higher risk for the composite outcome due to higher rates of myocardial infarction (adjusted hazard ratio [HR] 3.63, 95% confidence interval [95%CI] 1.17–11.28; Gly/Gly vs. Arg/Arg HR 4.14, 95%CI 0.88–19.6. The risk associated with ADRB1 Gly389 was limited to those without obstructive CAD (n = 400, Pinteraction = 0.03, albeit marginally significant in this subset (HR 1.71, 95%CI 0.91–3.19. Additionally, women without obstructive CAD carrying the ADRB3 Arg64 variant were at higher risk for the composite endpoint (HR 2.10, 95%CI 1.05–4.24 due to subtle increases in risk for all of the individual endpoints. No genetic associations were present in women with obstructive CAD. Conclusion In this exploratory analysis, common coding polymorphisms in the β1- and β3-adrenergic receptors increased cardiovascular risk in women referred for diagnostic angiography, and could improve risk assessment, particularly for women without evidence of obstructive CAD. Trial Registration ClinicalTrials.gov NCT00000554.

  9. Bilateral Collicular Interaction: Modulation of Auditory Signal Processing in Amplitude Domain

    Science.gov (United States)

    Fu, Zi-Ying; Wang, Xin; Jen, Philip H.-S.; Chen, Qi-Cai

    2012-01-01

    In the ascending auditory pathway, the inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from many lower auditory nuclei, intrinsic projections within the IC, contralateral IC through the commissure of the IC and from the auditory cortex. All these connections make the IC a major center for subcortical temporal and spectral integration of auditory information. In this study, we examine bilateral collicular interaction in modulating amplitude-domain signal processing using electrophysiological recording, acoustic and focal electrical stimulation. Focal electrical stimulation of one (ipsilateral) IC produces widespread inhibition (61.6%) and focused facilitation (9.1%) of responses of neurons in the other (contralateral) IC, while 29.3% of the neurons were not affected. Bilateral collicular interaction produces a decrease in the response magnitude and an increase in the response latency of inhibited IC neurons but produces opposite effects on the response of facilitated IC neurons. These two groups of neurons are not separately located and are tonotopically organized within the IC. The modulation effect is most effective at low sound level and is dependent upon the interval between the acoustic and electric stimuli. The focal electrical stimulation of the ipsilateral IC compresses or expands the rate-level functions of contralateral IC neurons. The focal electrical stimulation also produces a shift in the minimum threshold and dynamic range of contralateral IC neurons for as long as 150 minutes. The degree of bilateral collicular interaction is dependent upon the difference in the best frequency between the electrically stimulated IC neurons and modulated IC neurons. These data suggest that bilateral collicular interaction mainly changes the ratio between excitation and inhibition during signal processing so as to sharpen the amplitude sensitivity of IC neurons. Bilateral interaction may be also involved in acoustic

  10. Evolution of NMDA receptor cytoplasmic interaction domains: implications for organisation of synaptic signalling complexes

    Directory of Open Access Journals (Sweden)

    Emes Richard D

    2008-01-01

    Full Text Available Abstract Background Glutamate gated postsynaptic receptors in the central nervous system (CNS are essential for environmentally stimulated behaviours including learning and memory in both invertebrates and vertebrates. Though their genetics, biochemistry, physiology, and role in behaviour have been intensely studied in vitro and in vivo, their molecular evolution and structural aspects remain poorly understood. To understand how these receptors have evolved different physiological requirements we have investigated the molecular evolution of glutamate gated receptors and ion channels, in particular the N-methyl-D-aspartate (NMDA receptor, which is essential for higher cognitive function. Studies of rodent NMDA receptors show that the C-terminal intracellular domain forms a signalling complex with enzymes and scaffold proteins, which is important for neuronal and behavioural plasticity Results The vertebrate NMDA receptor was found to have subunits with C-terminal domains up to 500 amino acids longer than invertebrates. This extension was specific to the NR2 subunit and occurred before the duplication and subsequent divergence of NR2 in the vertebrate lineage. The shorter invertebrate C-terminus lacked vertebrate protein interaction motifs involved with forming a signaling complex although the terminal PDZ interaction domain was conserved. The vertebrate NR2 C-terminal domain was predicted to be intrinsically disordered but with a conserved secondary structure. Conclusion We highlight an evolutionary adaptation specific to vertebrate NMDA receptor NR2 subunits. Using in silico methods we find that evolution has shaped the NMDA receptor C-terminus into an unstructured but modular intracellular domain that parallels the expansion in complexity of an NMDA receptor signalling complex in the vertebrate lineage. We propose the NR2 C-terminus has evolved to be a natively unstructured yet flexible hub organising postsynaptic signalling. The evolution of

  11. Evolution of a Novel Antiviral Immune-Signaling Interaction by Partial-Gene Duplication.

    Directory of Open Access Journals (Sweden)

    Bryan Korithoski

    Full Text Available The RIG-like receptors (RLRs are related proteins that identify viral RNA in the cytoplasm and activate cellular immune responses, primarily through direct protein-protein interactions with the signal transducer, IPS1. Although it has been well established that the RLRs, RIG-I and MDA5, activate IPS1 through binding between the twin caspase activation and recruitment domains (CARDs on the RLR and a homologous CARD on IPS1, it is less clear which specific RLR CARD(s are required for this interaction, and almost nothing is known about how the RLR-IPS1 interaction evolved. In contrast to what has been observed in the presence of immune-modulating K63-linked polyubiquitin, here we show that-in the absence of ubiquitin-it is the first CARD domain of human RIG-I and MDA5 (CARD1 that binds directly to IPS1 CARD, and not the second (CARD2. Although the RLRs originated in the earliest animals, both the IPS1 gene and the twin-CARD domain architecture of RIG-I and MDA5 arose much later in the deuterostome lineage, probably through a series of tandem partial-gene duplication events facilitated by tight clustering of RLRs and IPS1 in the ancestral deuterostome genome. Functional differentiation of RIG-I CARD1 and CARD2 appears to have occurred early during this proliferation of RLR and related CARDs, potentially driven by adaptive coevolution between RIG-I CARD domains and IPS1 CARD. However, functional differentiation of MDA5 CARD1 and CARD2 occurred later. These results fit a general model in which duplications of protein-protein interaction domains into novel gene contexts could facilitate the expansion of signaling networks and suggest a potentially important role for functionally-linked gene clusters in generating novel immune-signaling pathways.

  12. Adrenergic receptors in human fetal liver membranes

    Energy Technology Data Exchange (ETDEWEB)

    Falkay, G.; Kovacs, L. (Albert Szent-Gyoergyi Medical Univ. Szeged, Semmelweis (Hungary))

    1990-01-01

    The adrenergic receptor binding capacities in human fetal and adult livers were measured to investigate the mechanism of the reduced alpha-1 adrenoreceptor response of the liver associated with a reciprocal increase in beta-adrenoreceptor activity in a number of conditions. Alpha-1 and beta-adrenoreceptor density were determined using {sup 3}H-prazosin and {sup 3}H-dihydroalprenolol, respectively, as radioligand. Heterogeneous populations of beta-adrenoreceptors were found in fetal liver contrast to adult. Decreased alpha-1 and increased beta-receptor density were found which may relate to a decreased level in cellular differentiation. These findings may be important for the investigation of perinatal hypoglycemia of newborns after treatment of premature labor with beta-mimetics. This is the first demonstration of differences in the ratio of alpha-1 and beta-adrenoceptors in human fetal liver.

  13. Creating and analyzing pathway and protein interaction compendia for modelling signal transduction networks

    Directory of Open Access Journals (Sweden)

    Kirouac Daniel C

    2012-05-01

    Full Text Available Abstract Background Understanding the information-processing capabilities of signal transduction networks, how those networks are disrupted in disease, and rationally designing therapies to manipulate diseased states require systematic and accurate reconstruction of network topology. Data on networks central to human physiology, such as the inflammatory signalling networks analyzed here, are found in a multiplicity of on-line resources of pathway and interactome databases (Cancer CellMap, GeneGo, KEGG, NCI-Pathway Interactome Database (NCI-PID, PANTHER, Reactome, I2D, and STRING. We sought to determine whether these databases contain overlapping information and whether they can be used to construct high reliability prior knowledge networks for subsequent modeling of experimental data. Results We have assembled an ensemble network from multiple on-line sources representing a significant portion of all machine-readable and reconcilable human knowledge on proteins and protein interactions involved in inflammation. This ensemble network has many features expected of complex signalling networks assembled from high-throughput data: a power law distribution of both node degree and edge annotations, and topological features of a “bow tie” architecture in which diverse pathways converge on a highly conserved set of enzymatic cascades focused around PI3K/AKT, MAPK/ERK, JAK/STAT, NFκB, and apoptotic signaling. Individual pathways exhibit “fuzzy” modularity that is statistically significant but still involving a majority of “cross-talk” interactions. However, we find that the most widely used pathway databases are highly inconsistent with respect to the actual constituents and interactions in this network. Using a set of growth factor signalling networks as examples (epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, and wingless, we find a multiplicity of network topologies in which receptors couple to downstream

  14. β-Adrenergic agonist and antagonist regulation of autophagy in HepG2 cells, primary mouse hepatocytes, and mouse liver.

    Directory of Open Access Journals (Sweden)

    Benjamin L Farah

    Full Text Available Autophagy recently has been shown to be involved in normal hepatic function and in pathological conditions such as non-alcoholic fatty liver disease. Adrenergic signalling also is an important regulator of hepatic metabolism and function. However, currently little is known about the potential role of adrenergic signaling on hepatic autophagy, and whether the β-adrenergic receptor itself may be a key regulator of autophagy. To address these issues, we investigated the actions of the β2-adrenergic receptor agonist, clenbuterol on hepatic autophagy. Surprisingly, we found that clenbuterol stimulated autophagy and autophagic flux in hepatoma cells, primary hepatocytes and in vivo. Similar effects also were observed with epinephrine treatment. Interestingly, propranolol caused a late block in autophagy in the absence and presence of clenbuterol, both in cell culture and in vivo. Thus, our results demonstrate that the β2-adrenergic receptor is a key regulator of hepatic autophagy, and that the β-blocker propranolol can independently induce a late block in autophagy.

  15. Hydrogen sulfide interacts with calcium signaling to enhance the chromium tolerance in Setaria italica.

    Science.gov (United States)

    Fang, Huihui; Jing, Tao; Liu, Zhiqiang; Zhang, Liping; Jin, Zhuping; Pei, Yanxi

    2014-12-01

    The oscillation of intracellular calcium (Ca(2+)) concentration is a primary event in numerous biological processes in plants, including stress response. Hydrogen sulfide (H2S), an emerging gasotransmitter, was found to have positive effects in plants responding to chromium (Cr(6+)) stress through interacting with Ca(2+) signaling. While Ca(2+) resemblances H2S in mediating biotic and abiotic stresses, crosstalk between the two pathways remains unclear. In this study, Ca(2+) signaling interacted with H2S to produce a complex physiological response, which enhanced the Cr(6+) tolerance in foxtail millet (Setaria italica). Results indicate that Cr(6+) stress activated endogenous H2S synthesis as well as Ca(2+) signaling. Moreover, toxic symptoms caused by Cr(6+) stress were strongly moderated by 50μM H2S and 20mM Ca(2+). Conversely, treatments with H2S synthesis inhibitor and Ca(2+) chelators prior to Cr(6+)-exposure aggravated these toxic symptoms. Interestingly, Ca(2+) upregulated expression of two important factors in metal metabolism, MT3A and PCS, which participated in the biosynthesis of heavy metal chelators, in a H2S-dependent manner to cope with Cr(6+) stress. These findings also suggest that the H2S dependent pathway is a component of the Ca(2+) activating antioxidant system and H2S partially contributes Ca(2+)-activating antioxidant system.

  16. Functional interaction of TCF4 with ATF5 to regulate the Wnt signaling pathway

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Wnt signaling directs cell-fate choices during embryonic development and tissue tumorigenesis. T cell factor 4 (TCF4) plays a pivotal role in the Wnt signaling pathway. We demonstrate that a specific protein-protein interaction occurs between TCF4 and ATF5 (activating transcription factor 5) -- a new member of cAMP response element binding protein (CREB) with the yeast two-hybrid system. The N-terminal and DNA binding domain of TCF4 (TCF4ND, 1-495 aa) and the C-terminal spanning bZIP domain of ATF5 (162-282 aa) were found to be responsible for the interaction, and the C-terminal of ATF5 (ATF5/C) showed a much stronger interaction with TCF4ND than the full-length of ATF5 by detecting the ?-gal activity. Furthermore, overexpression of ATF5/C enhanced transcriptional activation by TCF4 proteins in luciferase assay by transient transfection. Taken together, these data suggest that ATF5 may function as a co-activator to potentiate the ability of TCF4 to activate transcription.

  17. The branching gene RAMOSUS1 mediates interactions among two novel signals and auxin in pea.

    Science.gov (United States)

    Foo, Eloise; Bullier, Erika; Goussot, Magali; Foucher, Fabrice; Rameau, Catherine; Beveridge, Christine Anne

    2005-02-01

    In Pisum sativum, the RAMOSUS genes RMS1, RMS2, and RMS5 regulate shoot branching via physiologically defined mobile signals. RMS1 is most likely a carotenoid cleavage enzyme and acts with RMS5 to control levels of an as yet unidentified mobile branching inhibitor required for auxin inhibition of branching. Our work provides molecular, genetic, and physiological evidence that RMS1 plays a central role in a shoot-to-root-to-shoot feedback system that regulates shoot branching in pea. Indole-3-acetic acid (IAA) positively regulates RMS1 transcript level, a potentially important mechanism for regulation of shoot branching by IAA. In addition, RMS1 transcript levels are dramatically elevated in rms3, rms4, and rms5 plants, which do not contain elevated IAA levels. This degree of upregulation of RMS1 expression cannot be achieved in wild-type plants by exogenous IAA application. Grafting studies indicate that an IAA-independent mobile feedback signal contributes to the elevated RMS1 transcript levels in rms4 plants. Therefore, the long-distance signaling network controlling branching in pea involves IAA, the RMS1 inhibitor, and an IAA-independent feedback signal. Consistent with physiological studies that predict an interaction between RMS2 and RMS1, rms2 mutations appear to disrupt this IAA-independent regulation of RMS1 expression. PMID:15659639

  18. The arginine of the DRY motif in transmembrane segment III functions as a balancing micro-switch in the activation of the β2-adrenergic receptor

    DEFF Research Database (Denmark)

    Hansen, Louise Valentin; Groenen, Marleen; Nygaard, Rie;

    2012-01-01

    Recent high resolution x-ray structures of the β2-adrenergic receptor confirmed a close salt-bridge interaction between the suspected micro-switch residue ArgIII:26 (Arg3.50) and the neighboring AspIII:25 (Asp3.49). However, neither the expected "ionic lock" interactions between ArgIII:26 and Glu...

  19. Interaction of the Arabidopsis UV-B-Specific Signaling Component UVR8 with Chromatin

    Institute of Scientific and Technical Information of China (English)

    Catherine Cloix; Gareth I.Jenkins

    2008-01-01

    Arabidopsis UV RESISTANCE LOCUS8 (UVR8) is a UV-B-specific signaling component that regulates expression of a range of genes concerned with UV protection. Here, we investigate the interaction of UVR8 with chromatin. Using antibodies specific to UVR8 in chromatin immunoprecipitation (CHIP) assays with wild-type plants, we show that native UVR8 binds to chromatin in vivo. Similar experiments using an anti-GFP antibody with plants expressing a GFP-UVR8 fusion show that UVR8 associates with a relatively small region of chromatin containing the HY5 gene. UVR8 interacts with chromatin containing the promoter regions of other genes, but not with all the genes it regulates. UV-B is not required for the interaction of UVR8 with chromatin because association with several gene loci is observed in the absence of UV-B. Pulldown assays demonstrate that UVR8 associates with histones in vivo and competition experiments indicate that the interaction is preferentially with histone H2B. ChIP experiments using antibodies that recognize specific histone modifications indicate that the UV-B-stimulated transcription of some genes may be correlated with histone modification. In particular, the ELIP1 promoter showed a significant enrichment of diacetyl histone H3 (K9/K14) following UV-B exposure.These findings increase understanding of the interaction of the key UV-B-specific regulator UVR8 with chromatin.

  20. Signalling through the type 1 insulin-like growth factor receptor (IGF1R interacts with canonical Wnt signalling to promote neural proliferation in developing brain

    Directory of Open Access Journals (Sweden)

    Qichen Hu

    2012-07-01

    Full Text Available Signalling through the IGF1R [type 1 IGF (insulin-like growth factor receptor] and canonical Wnt signalling are two signalling pathways that play critical roles in regulating neural cell generation and growth. To determine whether the signalling through the IGF1R can interact with the canonical Wnt signalling pathway in neural cells in vivo, we studied mutant mice with altered IGF signalling. We found that in mice with blunted IGF1R expression specifically in nestin-expressing neural cells (IGF1RNestin−KO mice the abundance of neural β-catenin was significantly reduced. Blunting IGF1R expression also markedly decreased: (i the activity of a LacZ (β-galactosidase reporter transgene that responds to Wnt nuclear signalling (LacZTCF reporter transgene and (ii the number of proliferating neural precursors. In contrast, overexpressing IGF-I (insulin-like growth factor I in brain markedly increased the activity of the LacZTCF reporter transgene. Consistently, IGF-I treatment also markedly increased the activity of the LacZTCF reporter transgene in embryonic neuron cultures that are derived from LacZTCF Tg (transgenic mice. Importantly, increasing the abundance of β-catenin in IGF1RNestin−KO embryonic brains by suppressing the activity of GSK3β (glycogen synthase kinase-3β significantly alleviated the phenotypic changes induced by IGF1R deficiency. These phenotypic changes includes: (i retarded brain growth, (ii reduced precursor proliferation and (iii decreased neuronal number. Our current data, consistent with our previous study of cultured oligodendrocytes, strongly support the concept that IGF signalling interacts with canonical Wnt signalling in the developing brain to promote neural proliferation. The interaction of IGF and canonical Wnt signalling plays an important role in normal brain development by promoting neural precursor proliferation.

  1. Probing the CP violation signal at DUNE in the presence of non-standard neutrino interactions

    Science.gov (United States)

    Masud, Mehedi; Chatterjee, Animesh; Mehta, Poonam

    2016-09-01

    We discuss the impact of non-standard neutrino matter interactions (NSIs) in propagation on the determination of the CP phase in the context of long baseline accelerator experiments such as the Deep Underground Neutrino Experiment (DUNE). DUNE will mainly address the issue of CP violation in the leptonic sector. Here we study the role of NSI and its impact on observing the CP violation signal at DUNE. We consider two scenarios of oscillation with three active neutrinos in the absence and presence of NSI. We elucidate the importance of ruling out subdominant new physics effects introduced by NSI in inferring the CP violation signal at DUNE by considering NSI terms collectively as well as by exploiting the non-trivial interplay of moduli and phases of the NSI terms. We demonstrate the existence of NSI-SI degeneracies which need to be eliminated in reliable manner in order to make conclusive statements about the CP phase.

  2. Neuron-glia interactions through the Heartless FGF receptor signaling pathway mediate morphogenesis of Drosophila astrocytes.

    Science.gov (United States)

    Stork, Tobias; Sheehan, Amy; Tasdemir-Yilmaz, Ozge E; Freeman, Marc R

    2014-07-16

    Astrocytes are critically important for neuronal circuit assembly and function. Mammalian protoplasmic astrocytes develop a dense ramified meshwork of cellular processes to form intimate contacts with neuronal cell bodies, neurites, and synapses. This close neuron-glia morphological relationship is essential for astrocyte function, but it remains unclear how astrocytes establish their intricate morphology, organize spatial domains, and associate with neurons and synapses in vivo. Here we characterize a Drosophila glial subtype that shows striking morphological and functional similarities to mammalian astrocytes. We demonstrate that the Fibroblast growth factor (FGF) receptor Heartless autonomously controls astrocyte membrane growth, and the FGFs Pyramus and Thisbe direct astrocyte processes to ramify specifically in CNS synaptic regions. We further show that the shape and size of individual astrocytes are dynamically sculpted through inhibitory or competitive astrocyte-astrocyte interactions and Heartless FGF signaling. Our data identify FGF signaling through Heartless as a key regulator of astrocyte morphological elaboration in vivo.

  3. Peptides interfering with protein-protein interactions in the ethylene signaling pathway delay tomato fruit ripening.

    Science.gov (United States)

    Bisson, Melanie M A; Kessenbrock, Mareike; Müller, Lena; Hofmann, Alexander; Schmitz, Florian; Cristescu, Simona M; Groth, Georg

    2016-01-01

    The plant hormone ethylene is involved in the regulation of several processes with high importance for agricultural applications, e.g. ripening, aging and senescence. Previous work in our group has identified a small peptide (NOP-1) derived from the nuclear localization signal of the Arabidopsis ethylene regulator ETHYLENE INSENSITIVE-2 (EIN2) C-terminal part as efficient inhibitor of ethylene responses. Here, we show that NOP-1 is also able to efficiently disrupt EIN2-ETR1 complex formation in tomato, indicating that the NOP-1 inhibition mode is conserved across plant species. Surface application of NOP-1 on green tomato fruits delays ripening similar to known inhibitors of ethylene perception (MCP) and ethylene biosynthesis (AVG). Fruits treated with NOP-1 showed similar ethylene production as untreated controls underlining that NOP-1 blocks ethylene signaling by targeting an essential interaction in this pathway, while having no effect on ethylene biosynthesis. PMID:27477591

  4. HER/ErbB Receptor Interactions and Signaling Patterns in Human Mammary Epithelial Cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yi; Opresko, Lee K.; Shankaran, Harish; Chrisler, William B.; Wiley, H. S.; Resat, Haluk

    2009-10-31

    Knowledge about signaling pathways is typically compiled based on data gathered using different cell lines. This approach implicitly assumes that cell line dependence is not important, which can be misleading because different cell lines do not always respond to a particular stimulus in the same way. The lack of coherent data collected from closely related cellular systems can be detrimental to the efforts to understand the regulation of biological processes. In this study, we report the development of a library of human mammary epithelial (HME) cell lines which express endogenous levels of the cell surface receptor EGFR/HER1, and different levels of HER2 and HER3. Using our clone library, we have quantified the interactions among the HER1-3 receptors and systematically investigated the existing hypotheses about their interaction patterns. Contrary to earlier suggestions, we find that lateral interactions with HER2 do not lead to strong transactivation between EGFR and HER3. Our study identified HER2 as the dominant dimerization partner for both EGFR and HER3, and revealed that EGFR and HER3 activations are only weakly linked in HME cells. We have also quantified the time-dependent activation patterns of the downstream effectors Erk and Akt. We found that HER3 signaling makes the strongest contribution to Akt activation and that, stimulation of either EGFR or HER3 pathways activate Erk at significant levels. Our study shows that cell libraries formed from closely related clones can be a powerful resource for pursuing the quantitative investigations that are necessary for developing a systems level understanding of cell signaling.

  5. Broccoli consumption interacts with GSTM1 to perturb oncogenic signalling pathways in the prostate.

    Directory of Open Access Journals (Sweden)

    Maria Traka

    Full Text Available BACKGROUND: Epidemiological studies suggest that people who consume more than one portion of cruciferous vegetables per week are at lower risk of both the incidence of prostate cancer and of developing aggressive prostate cancer but there is little understanding of the underlying mechanisms. In this study, we quantify and interpret changes in global gene expression patterns in the human prostate gland before, during and after a 12 month broccoli-rich diet. METHODS AND FINDINGS: Volunteers were randomly assigned to either a broccoli-rich or a pea-rich diet. After six months there were no differences in gene expression between glutathione S-transferase mu 1 (GSTM1 positive and null individuals on the pea-rich diet but significant differences between GSTM1 genotypes on the broccoli-rich diet, associated with transforming growth factor beta 1 (TGFbeta1 and epidermal growth factor (EGF signalling pathways. Comparison of biopsies obtained pre and post intervention revealed more changes in gene expression occurred in individuals on a broccoli-rich diet than in those on a pea-rich diet. While there were changes in androgen signalling, regardless of diet, men on the broccoli diet had additional changes to mRNA processing, and TGFbeta1, EGF and insulin signalling. We also provide evidence that sulforaphane (the isothiocyanate derived from 4-methylsuphinylbutyl glucosinolate that accumulates in broccoli chemically interacts with TGFbeta1, EGF and insulin peptides to form thioureas, and enhances TGFbeta1/Smad-mediated transcription. CONCLUSIONS: These findings suggest that consuming broccoli interacts with GSTM1 genotype to result in complex changes to signalling pathways associated with inflammation and carcinogenesis in the prostate. We propose that these changes may be mediated through the chemical interaction of isothiocyanates with signalling peptides in the plasma. This study provides, for the first time, experimental evidence obtained in humans to

  6. Dissecting the specificity of protein-protein interaction in bacterial two-component signaling: orphans and crosstalks.

    Directory of Open Access Journals (Sweden)

    Andrea Procaccini

    Full Text Available Predictive understanding of the myriads of signal transduction pathways in a cell is an outstanding challenge of systems biology. Such pathways are primarily mediated by specific but transient protein-protein interactions, which are difficult to study experimentally. In this study, we dissect the specificity of protein-protein interactions governing two-component signaling (TCS systems ubiquitously used in bacteria. Exploiting the large number of sequenced bacterial genomes and an operon structure which packages many pairs of interacting TCS proteins together, we developed a computational approach to extract a molecular interaction code capturing the preferences of a small but critical number of directly interacting residue pairs. This code is found to reflect physical interaction mechanisms, with the strongest signal coming from charged amino acids. It is used to predict the specificity of TCS interaction: Our results compare favorably to most available experimental results, including the prediction of 7 (out of 8 known interaction partners of orphan signaling proteins in Caulobacter crescentus. Surveying among the available bacterial genomes, our results suggest 15∼25% of the TCS proteins could participate in out-of-operon "crosstalks". Additionally, we predict clusters of crosstalking candidates, expanding from the anecdotally known examples in model organisms. The tools and results presented here can be used to guide experimental studies towards a system-level understanding of two-component signaling.

  7. Raf-1 Physically Interacts with Rb and Regulates Its Function: a Link between Mitogenic Signaling and Cell Cycle Regulation

    OpenAIRE

    Wang, Sheng; Ghosh, Richik N.; Chellappan, Srikumar P

    1998-01-01

    Cells initiate proliferation in response to growth factor stimulation, but the biochemical mechanisms linking signals received at the cell surface receptors to the cell cycle regulatory molecules are not yet clear. In this study, we show that the signaling molecule Raf-1 can physically interact with Rb and p130 proteins in vitro and in vivo and that this interaction can be detected in mammalian cells without overexpressing any component. The binding of Raf-1 to Rb occurs subsequent to mitogen...

  8. The Arabidopsis LYST INTERACTING PROTEIN 5 Acts in Regulating Abscisic Acid Signaling and Drought Response.

    Science.gov (United States)

    Xia, Zongliang; Huo, Yongjin; Wei, Yangyang; Chen, Qiansi; Xu, Ziwei; Zhang, Wei

    2016-01-01

    Multivesicular bodies (MVBs) are unique endosomes containing vesicles in the lumens and play essential roles in many eukaryotic cellular processes. The Arabidopsis LYST INTERACTING PROTEIN 5 (LIP5), a positive regulator of MVB biogenesis, has critical roles in biotic and abiotic stress responses. However, whether the abscisic acid (ABA) signaling is involved in LIP5-mediated stress response is largely unknown. Here, we report that LIP5 functions in regulating ABA signaling and drought response in Arabidopsis. Analyses of a LIP5 promoter-β-glucuronidase (GUS) construct revealed substantial GUS activity in whole seedlings. The expression of LIP5 was induced by ABA and drought, and overexpression of LIP5 led to ABA hypersensitivity, enhanced stomatal closure, reduced water loss, and, therefore, increased drought tolerance. On the contrary, LIP5 knockdown mutants showed ABA-insensitive phenotypes and reduced drought tolerance; suggesting that LIP5 acts in regulating ABA response. Further analysis using a fluorescent dye revealed that ABA and water stress induced cell endocytosis or vesicle trafficking in a largely LIP5-dependent manner. Furthermore, expression of several drought- or ABA-inducible marker genes was significantly down-regulated in the lip5 mutant seedlings. Collectively, our data suggest that LIP5 positively regulates drought tolerance through ABA-mediated cell signaling. PMID:27313589

  9. Structural basis of SUFU–GLI interaction in human Hedgehog signalling regulation

    Energy Technology Data Exchange (ETDEWEB)

    Cherry, Amy L.; Finta, Csaba; Karlström, Mikael; Jin, Qianren; Schwend, Thomas [Karolinska Institutet, Novum, Hälsovägen 7, SE-141 83 Huddinge (Sweden); Astorga-Wells, Juan [Karolinska Institutet, Scheeles väg 2, SE-171 77 Stockholm (Sweden); Biomotif AB, Enhagsvägen 7, SE-182 12 Danderyd (Sweden); Zubarev, Roman A. [Karolinska Institutet, Scheeles väg 2, SE-171 77 Stockholm (Sweden); Del Campo, Mark; Criswell, Angela R. [Rigaku Americas Corporation, 9009 New Trails Drive, The Woodlands, TX 77381 (United States); Sanctis, Daniele de [European Synchrotron Radiation Facility, 6 Rue Jules Horowitz, 38043 Grenoble (France); Jovine, Luca, E-mail: luca.jovine@ki.se; Toftgård, Rune, E-mail: luca.jovine@ki.se [Karolinska Institutet, Novum, Hälsovägen 7, SE-141 83 Huddinge (Sweden)

    2013-12-01

    Crystal and small-angle X-ray scattering structures of full-length human SUFU alone and in complex with the conserved SYGHL motif from GLI transcription factors show major conformational changes associated with binding and reveal an intrinsically disordered region crucial for pathway activation. Hedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU–GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU–GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics.

  10. Cutting Edge: A Cullin-5-TRAF6 Interaction Promotes TRAF6 Polyubiquitination and Lipopolysaccharide Signaling.

    Science.gov (United States)

    Zhu, Ziyan; Wang, Lili; Hao, Rui; Zhao, Bo; Sun, Lei; Ye, Richard D

    2016-07-01

    TNFR-associated factor (TRAF)6 integrates signals from multiple cell surface receptors for the activation of NF-κB. However, the mechanism underlying LPS-induced TRAF6 signaling remains unclear. We report that cullin-5 (Cul-5), a cullin family scaffold protein, binds to TRAF6 and promotes TRAF6 polyubiquitination at Lys(63) in response to LPS stimulation. A direct interaction between the C-terminal domain of Cul-5 and the TRAF-C domain of TRAF6 facilitates polyubiquitination of TRAF6. Hemizygous Cul-5 knockout is associated with improved survival of mice following LPS challenge and significant delays in the phosphorylation of p65/RelA, ERK, JNK, and p38 MAPKs in LPS-stimulated macrophages, along with a marked decrease in NF-κB activation. These findings identify Cul-5 as a signaling component that connects an LPS-activated TLR4-MyD88 complex to TRAF6 for efficient activation of NF-κB. PMID:27233966

  11. The potential of metabolomic analysis techniques for the characterisation of α1-adrenergic receptors in cultured N1E-115 mouse neuroblastoma cells.

    Science.gov (United States)

    Wenner, Maria I; Maker, Garth L; Dawson, Linda F; Drummond, Peter D; Mullaney, Ian

    2016-08-01

    Several studies of neuropathic pain have linked abnormal adrenergic signalling to the development and maintenance of pain, although the mechanisms underlying this are not yet fully understood. Metabolomic analysis is a technique that can be used to give a snapshot of biochemical status, and can aid in the identification of the mechanisms behind pathological changes identified in cells, tissues and biological fluids. This study aimed to use gas chromatography-mass spectrometry-based metabolomic profiling in combination with reverse transcriptase-polymerase chain reaction and immunocytochemistry to identify functional α1-adrenergic receptors on cultured N1E-115 mouse neuroblastoma cells. The study was able to confirm the presence of mRNA for the α1D subtype, as well as protein expression of the α1-adrenergic receptor. Furthermore, metabolomic data revealed changes to the metabolite profile of cells when exposed to adrenergic pharmacological intervention. Agonist treatment with phenylephrine hydrochloride (10 µM) resulted in altered levels of several metabolites including myo-inositol, glucose, fructose, alanine, leucine, phenylalanine, valine, and n-acetylglutamic acid. Many of the changes observed in N1E-115 cells by agonist treatment were modulated by additional antagonist treatment (prazosin hydrochloride, 100 µM). A number of these changes reflected what is known about the biochemistry of α1-adrenergic receptor activation. This preliminary study therefore demonstrates the potential of metabolomic profiling to confirm the presence of functional receptors on cultured cells. PMID:26408527

  12. A membrane protein / signaling protein interaction network for Arabidopsis version AMPv2

    Directory of Open Access Journals (Sweden)

    Sylvie Lalonde

    2010-09-01

    Full Text Available Interactions between membrane proteins and the soluble fraction are essential for signal transduction and for regulating nutrient transport. To gain insights into the membrane-based interactome, 3,852 open reading frames (ORFs out of a target list of 8,383 representing membrane and signaling proteins from Arabidopsis thaliana were cloned into a Gateway compatible vector. The mating-based split-ubiquitin system was used to screen for potential protein-protein interactions (pPPIs among 490 Arabidopsis ORFs. A binary robotic screen between 142 receptor-like kinases, 72 transporters, 57 soluble protein kinases and phosphatases, 40 glycosyltransferases, 95 proteins of various functions and 89 proteins with unknown function detected 387 out of 90,370 possible PPIs. A secondary screen confirmed 343 (of 387 pPPIs between 179 proteins, yielding a scale-free network (r2=0.863. Eighty of 142 transmembrane receptor-like kinases (RLK tested positive, identifying three homomers, 63 heteromers and 80 pPPIs with other proteins. Thirty-one out of 142 RLK interactors (including RLKs had previously been found to be phosphorylated; thus interactors may be substrates for respective RLKs. None of the pPPIs described here had been reported in the major interactome databases, including potential interactors of G protein-coupled receptors, phospholipase C, and AMT ammonium transporters. Two RLKs found as putative interactors of AMT1;1 were independently confirmed using a split luciferase assay in Arabidopsis protoplasts. These RLKs may be involved in ammonium-dependent phosphorylation of the C-terminus and regulation of ammonium uptake activity. The robotic screening method established here will enable a systematic analysis of membrane protein interactions in fungi, plants and metazoa.

  13. Potential relevance of alpha(1-adrenergic receptor autoantibodies in refractory hypertension.

    Directory of Open Access Journals (Sweden)

    Katrin Wenzel

    Full Text Available BACKGROUND: Agonistic autoantibodies directed at the alpha(1-adrenergic receptor (alpha(1-AAB have been described in patients with hypertension. We implied earlier that alpha(1-AAB might have a mechanistic role and could represent a therapeutic target. METHODOLOGY/PRINCIPAL FINDINGS: To pursue the issue, we performed clinical and basic studies. We observed that 41 of 81 patients with refractory hypertension had alpha(1-AAB; after immunoadsorption blood pressure was significantly reduced in these patients. Rabbits were immunized to generate alpha(1-adrenergic receptor antibodies (alpha(1-AB. Patient alpha(1-AAB and rabbit alpha(1-AB were purified using affinity chromatography and characterized both by epitope mapping and surface plasmon resonance measurements. Neonatal rat cardiomyocytes, rat vascular smooth muscle cells (VSMC, and Chinese hamster ovary cells transfected with the human alpha(1A-adrenergic receptor were incubated with patient alpha(1-AAB and rabbit alpha(1-AB and the activation of signal transduction pathways was investigated by Western blot, confocal laser scanning microscopy, and gene expression. We found that phospholipase A2 group IIA (PLA2-IIA and L-type calcium channel (Cacna1c genes were upregulated in cardiomyocytes and VSMC after stimulation with both purified antibodies. We showed that patient alpha(1-AAB and rabbit alpha(1-AB result in protein kinase C alpha activation and transient extracellular-related kinase (EKR1/2 phosphorylation. Finally, we showed that the antibodies exert acute effects on intracellular Ca(2+ in cardiomyocytes and induce mesentery artery segment contraction. CONCLUSIONS/SIGNIFICANCE: Patient alpha(1-AAB and rabbit alpha(1-AB can induce signaling pathways important for hypertension and cardiac remodeling. Our data provide evidence for a potential clinical relevance for alpha(1-AAB in hypertensive patients, and the notion of immunity as a possible cause of hypertension.

  14. Randomly organized lipids and marginally stable proteins: a coupling of weak interactions to optimize membrane signaling.

    Science.gov (United States)

    Rice, Anne M; Mahling, Ryan; Fealey, Michael E; Rannikko, Anika; Dunleavy, Katie; Hendrickson, Troy; Lohese, K Jean; Kruggel, Spencer; Heiling, Hillary; Harren, Daniel; Sutton, R Bryan; Pastor, John; Hinderliter, Anne

    2014-09-01

    Eukaryotic lipids in a bilayer are dominated by weak cooperative interactions. These interactions impart highly dynamic and pliable properties to the membrane. C2 domain-containing proteins in the membrane also interact weakly and cooperatively giving rise to a high degree of conformational plasticity. We propose that this feature of weak energetics and plasticity shared by lipids and C2 domain-containing proteins enhance a cell's ability to transduce information across the membrane. We explored this hypothesis using information theory to assess the information storage capacity of model and mast cell membranes, as well as differential scanning calorimetry, carboxyfluorescein release assays, and tryptophan fluorescence to assess protein and membrane stability. The distribution of lipids in mast cell membranes encoded 5.6-5.8bits of information. More information resided in the acyl chains than the head groups and in the inner leaflet of the plasma membrane than the outer leaflet. When the lipid composition and information content of model membranes were varied, the associated C2 domains underwent large changes in stability and denaturation profile. The C2 domain-containing proteins are therefore acutely sensitive to the composition and information content of their associated lipids. Together, these findings suggest that the maximum flow of signaling information through the membrane and into the cell is optimized by the cooperation of near-random distributions of membrane lipids and proteins. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.

  15. Interactive Computing and Graphics in Undergraduate Digital Signal Processing. Microcomputing Working Paper Series F 84-9.

    Science.gov (United States)

    Onaral, Banu; And Others

    This report describes the development of a Drexel University electrical and computer engineering course on digital filter design that used interactive computing and graphics, and was one of three courses in a senior-level sequence on digital signal processing (DSP). Interactive and digital analysis/design routines and the interconnection of these…

  16. Conversion of agonist site to metal-ion chelator site in the β2-adrenergic receptor

    OpenAIRE

    Elling, Christian E.; Thirstrup, Kenneth; Holst, Birgitte; Thue W. Schwartz

    1999-01-01

    Previously metal-ion sites have been used as structural and functional probes in seven transmembrane receptors (7TM), but as yet all the engineered sites have been inactivating. Based on presumed agonist interaction points in transmembrane III (TM-III) and -VII of the β2-adrenergic receptor, in this paper we construct an activating metal-ion site between the amine-binding Asp-113 in TM-III—or a His residue introduced at this position—and a Cys residue substituted for Asn-312 in TM-VII. No inc...

  17. Maize and Arabidopsis ARGOS Proteins Interact with Ethylene Receptor Signaling Complex, Supporting a Regulatory Role for ARGOS in Ethylene Signal Transduction[OPEN

    Science.gov (United States)

    Shi, Jinrui; Wang, Hongyu; Habben, Jeffrey E.

    2016-01-01

    The phytohormone ethylene regulates plant growth and development as well as plant response to environmental cues. ARGOS genes reduce plant sensitivity to ethylene when overexpressed in transgenic Arabidopsis (Arabidopsis thaliana) and maize (Zea mays). A previous genetic study suggested that the endoplasmic reticulum and Golgi-localized maize ARGOS1 targets the ethylene signal transduction components at or upstream of CONSTITUTIVE TRIPLE RESPONSE1, but the mechanism of ARGOS modulating ethylene signaling is unknown. Here, we demonstrate in Arabidopsis that ZmARGOS1, as well as the Arabidopsis ARGOS homolog ORGAN SIZE RELATED1, physically interacts with Arabidopsis REVERSION-TO-ETHYLENE SENSITIVITY1 (RTE1), an ethylene receptor interacting protein that regulates the activity of ETHYLENE RESPONSE1. The protein-protein interaction was also detected with the yeast split-ubiquitin two-hybrid system. Using the same yeast assay, we found that maize RTE1 homolog REVERSION-TO-ETHYLENE SENSITIVITY1 LIKE4 (ZmRTL4) and ZmRTL2 also interact with maize and Arabidopsis ARGOS proteins. Like AtRTE1 in Arabidopsis, ZmRTL4 and ZmRTL2 reduce ethylene responses when overexpressed in maize, indicating a similar mechanism for ARGOS regulating ethylene signaling in maize. A polypeptide fragment derived from ZmARGOS8, consisting of a Pro-rich motif flanked by two transmembrane helices that are conserved among members of the ARGOS family, can interact with AtRTE1 and maize RTL proteins in Arabidopsis. The conserved domain is necessary and sufficient to reduce ethylene sensitivity in Arabidopsis and maize. Overall, these results suggest a physical association between ARGOS and the ethylene receptor signaling complex via AtRTE1 and maize RTL proteins, supporting a role for ARGOS in regulating ethylene perception and the early steps of signal transduction in Arabidopsis and maize. PMID:27268962

  18. Dark matter with pseudoscalar-mediated interactions explains the DAMA signal and the galactic center excess.

    Science.gov (United States)

    Arina, Chiara; Del Nobile, Eugenio; Panci, Paolo

    2015-01-01

    We study a Dirac dark matter particle interacting with ordinary matter via the exchange of a light pseudoscalar, and analyze its impact on both direct and indirect detection experiments. We show that this candidate can accommodate the long-standing DAMA modulated signal and yet be compatible with all exclusion limits at 99(S)% C.L. This result holds for natural choices of the pseudoscalar-quark couplings (e.g., flavor universal), which give rise to a significant enhancement of the dark matter-proton coupling with respect to the coupling to neutrons. We also find that this candidate can accommodate the observed 1-3 GeV gamma-ray excess at the Galactic center and at the same time have the correct relic density today. The model could be tested with measurements of rare meson decays, flavor changing processes, and searches for axionlike particles with mass in the MeV range.

  19. Information theory in systems biology. Part II: protein-protein interaction and signaling networks.

    Science.gov (United States)

    Mousavian, Zaynab; Díaz, José; Masoudi-Nejad, Ali

    2016-03-01

    By the development of information theory in 1948 by Claude Shannon to address the problems in the field of data storage and data communication over (noisy) communication channel, it has been successfully applied in many other research areas such as bioinformatics and systems biology. In this manuscript, we attempt to review some of the existing literatures in systems biology, which are using the information theory measures in their calculations. As we have reviewed most of the existing information-theoretic methods in gene regulatory and metabolic networks in the first part of the review, so in the second part of our study, the application of information theory in other types of biological networks including protein-protein interaction and signaling networks will be surveyed.

  20. The Molecular Interaction of CAR and JAML Recruits the Central Cell Signal Transducer PI3K

    Energy Technology Data Exchange (ETDEWEB)

    Verdino, Petra; Witherden, Deborah A.; Havran, Wendy L.; Wilson, Ian A. (Scripps)

    2010-11-15

    Coxsackie and adenovirus receptor (CAR) is the primary cellular receptor for group B coxsackieviruses and most adenovirus serotypes and plays a crucial role in adenoviral gene therapy. Recent discovery of the interaction between junctional adhesion molecule-like protein (JAML) and CAR uncovered important functional roles in immunity, inflammation, and tissue homeostasis. Crystal structures of JAML ectodomain (2.2 angstroms) and its complex with CAR (2.8 angstroms) reveal an unusual immunoglobulin-domain assembly for JAML and a charged interface that confers high specificity. Biochemical and mutagenesis studies illustrate how CAR-mediated clustering of JAML recruits phosphoinositide 3-kinase (P13K) to a JAML intracellular sequence motif as delineated for the {alpha}{beta} T cell costimulatory receptor CD28. Thus, CAR and JAML are cell signaling receptors of the immune system with implications for asthma, cancer, and chronic nonhealing wounds.

  1. Nutritional and signal interactions in a tumor-host social relationship

    Institute of Scientific and Technical Information of China (English)

    LOU Mei-qing; HUANG Qiang; ZHAO Yao-dong

    2011-01-01

    @@ To the Editor: We read with great enthusiasm an interesting and exciting viewpoint by Lin,1 who believed that the core relationship between a tumor and its host microenvironment is the nutritional and signal interactions between cancer stem cells and endothelial cells.Our group is long-termly engaged in the study of glioma and glioma stem cell, and we also put much concern upon the research of tumor invasion. One of the most marked bionomics of malignant gliomas is invasion, which leads to the spreading of tumor masses along nerve fibers and blood vessels, and even distant dissemination.However, a benign tumor grows only by expansive growth.Therefore, it is of a quite benefit to illuminate or even partly illuminate the "tumor-host social (THS) relationship".

  2. Adrenergic Metabolic and Hemodynamic Effects of Octopamine in the Liver

    Directory of Open Access Journals (Sweden)

    Adelar Bracht

    2013-11-01

    Full Text Available The fruit extracts of Citrus aurantium (bitter orange are traditionally used as weight-loss products and as appetite suppressants. A component of these extracts is octopamine, which is an adrenergic agent. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of octopamine on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways and hemodynamics. Octopamine increased glycogenolysis, glycolysis, oxygen uptake, gluconeogenesis and the portal perfusion pressure. Octopamine also accelerated the oxidation of exogenous fatty acids (octanoate and oleate, as revealed by the increase in 14CO2 production derived from 14C labeled precursors. The changes in glycogenolysis, oxygen uptake and perfusion pressure were almost completely abolished by α1-adrenergic antagonists. The same changes were partly sensitive to the β-adrenergic antagonist propranolol. It can be concluded that octopamine accelerates both catabolic and anabolic processes in the liver via adrenergic stimulation. Acceleration of oxygen uptake under substrate-free perfusion conditions also means acceleration of the oxidation of endogenous fatty acids, which are derived from lipolysis. All these effects are compatible with an overall stimulating effect of octopamine on metabolism, which is compatible with its reported weight-loss effects in experimental animals.

  3. Adrenergic Receptors and Metabolism: Role in development of cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Michele eCiccarelli

    2013-10-01

    Full Text Available Activation of the adrenergic system has a profound effects on metabolism. Increased circulating catecholamine and activation of the different adrenergic receptors deployed in the various organs produce important metabolic responses which include: 1 increased lipolysis and elevated levels of fatty acids in plasma, 2 increased gluconeogenesis by the liver to provide substrate for the brain and 3 moderate inhibition of insulin release by the pancreas to conserve glucose and to shift fuel metabolism of muscle in the direction of fatty acid oxidation. These physiological responses, typical of the stress conditions, are demonstrated to be detrimental for the functioning of different organs like the cardiac muscle when they become chronic. Indeed, a common feature of many pathological conditions involving over-activation of the adrenergic system is the development of metabolic alterations which can include insulin resistance, altered glucose and lipid metabolism and mitochondrial dysfunction. These patterns are involved with a variably extent among the different pathologies , however they are in general strictly correlated to the level of activation of the adrenergic system. Here we will review the effects of the different adrenergic receptors subtypes on the metabolic variation observed in important disease like Heart Failure.

  4. Distal Hydrogen-bonding Interactions in Ligand Sensing and Signaling by Mycobacterium tuberculosis DosS.

    Science.gov (United States)

    Basudhar, Debashree; Madrona, Yarrow; Yukl, Erik T; Sivaramakrishnan, Santhosh; Nishida, Clinton R; Moënne-Loccoz, Pierre; Ortiz de Montellano, Paul R

    2016-07-29

    Mycobacterium tuberculosis DosS is critical for the induction of M. tuberculosis dormancy genes in response to nitric oxide (NO), carbon monoxide (CO), or hypoxia. These environmental stimuli, which are sensed by the DosS heme group, result in autophosphorylation of a DosS His residue, followed by phosphotransfer to an Asp residue of the response regulator DosR. To clarify the mechanism of gaseous ligand recognition and signaling, we investigated the hydrogen-bonding interactions of the iron-bound CO and NO ligands by site-directed mutagenesis of Glu-87 and His-89. Autophosphorylation assays and molecular dynamics simulations suggest that Glu-87 has an important role in ligand recognition, whereas His-89 is essential for signal transduction to the kinase domain, a process for which Arg-204 is important. Mutation of Glu-87 to Ala or Gly rendered the protein constitutively active as a kinase, but with lower autophosphorylation activity than the wild-type in the Fe(II) and the Fe(II)-CO states, whereas the E87D mutant had little kinase activity except for the Fe(II)-NO complex. The H89R mutant exhibited attenuated autophosphorylation activity, although the H89A and R204A mutants were inactive as kinases, emphasizing the importance of these residues in communication to the kinase core. Resonance Raman spectroscopy of the wild-type and H89A mutant indicates the mutation does not alter the heme coordination number, spin state, or porphyrin deformation state, but it suggests that interdomain interactions are disrupted by the mutation. Overall, these results confirm the importance of the distal hydrogen-bonding network in ligand recognition and communication to the kinase domain and reveal the sensitivity of the system to subtle differences in the binding of gaseous ligands. PMID:27235395

  5. Translational arrest by a prokaryotic signal recognition particle is mediated by RNA interactions.

    Science.gov (United States)

    Beckert, Bertrand; Kedrov, Alexej; Sohmen, Daniel; Kempf, Georg; Wild, Klemens; Sinning, Irmgard; Stahlberg, Henning; Wilson, Daniel N; Beckmann, Roland

    2015-10-01

    The signal recognition particle (SRP) recognizes signal sequences of nascent polypeptides and targets ribosome-nascent chain complexes to membrane translocation sites. In eukaryotes, translating ribosomes are slowed down by the Alu domain of SRP to allow efficient targeting. In prokaryotes, however, little is known about the structure and function of Alu domain-containing SRPs. Here, we report a complete molecular model of SRP from the Gram-positive bacterium Bacillus subtilis, based on cryo-EM. The SRP comprises two subunits, 6S RNA and SRP54 or Ffh, and it facilitates elongation slowdown similarly to its eukaryotic counterpart. However, protein contacts with the small ribosomal subunit observed for the mammalian Alu domain are substituted in bacteria by RNA-RNA interactions of 6S RNA with the α-sarcin-ricin loop and helices H43 and H44 of 23S rRNA. Our findings provide a structural basis for cotranslational targeting and RNA-driven elongation arrest in prokaryotes. PMID:26344568

  6. Metabolite transport and associated sugar signalling systems underpinning source/sink interactions.

    Science.gov (United States)

    Griffiths, Cara A; Paul, Matthew J; Foyer, Christine H

    2016-10-01

    Metabolite transport between organelles, cells and source and sink tissues not only enables pathway co-ordination but it also facilitates whole plant communication, particularly in the transmission of information concerning resource availability. Carbon assimilation is co-ordinated with nitrogen assimilation to ensure that the building blocks of biomass production, amino acids and carbon skeletons, are available at the required amounts and stoichiometry, with associated transport processes making certain that these essential resources are transported from their sites of synthesis to those of utilisation. Of the many possible posttranslational mechanisms that might participate in efficient co-ordination of metabolism and transport only reversible thiol-disulphide exchange mechanisms have been described in detail. Sucrose and trehalose metabolism are intertwined in the signalling hub that ensures appropriate resource allocation to drive growth and development under optimal and stress conditions, with trehalose-6-phosphate acting as an important signal for sucrose availability. The formidable suite of plant metabolite transporters provides enormous flexibility and adaptability in inter-pathway coordination and source-sink interactions. Focussing on the carbon metabolism network, we highlight the functions of different transporter families, and the important of thioredoxins in the metabolic dialogue between source and sink tissues. In addition, we address how these systems can be tailored for crop improvement. PMID:27487250

  7. Functional interactions and signaling properties of mammalian DNA mismatch repair proteins.

    Science.gov (United States)

    Bellacosa, A

    2001-11-01

    The mismatch repair (MMR) system promotes genomic fidelity by repairing base-base mismatches, insertion-deletion loops and heterologies generated during DNA replication and recombination. This function is critically dependent on the assembling of multimeric complexes involved in mismatch recognition and signal transduction to downstream repair events. In addition, MMR proteins coordinate a complex network of physical and functional interactions that mediate other DNA transactions, such as transcription-coupled repair, base excision repair and recombination. MMR proteins are also involved in activation of cell cycle checkpoint and induction of apoptosis when DNA damage overwhelms a critical threshold. For this reason, they play a role in cell death by alkylating agents and other chemotherapeutic drugs, including cisplatin. Inactivation of MMR genes in hereditary and sporadic cancer is associated with a mutator phenotype and inhibition of apoptosis. In the future, a deeper understanding of the molecular mechanisms and functional interactions of MMR proteins will lead to the development of more effective cancer prevention and treatment strategies. PMID:11687886

  8. Signal interactions and interference in insect choruses: singing and listening in the social environment.

    Science.gov (United States)

    Greenfield, Michael D

    2015-01-01

    Acoustic insects usually sing amidst conspecifics, thereby creating a social environment-the chorus-in which individuals communicate, find mates, and avoid predation. A temporal structure may arise in a chorus because of competitive and cooperative factors that favor certain signal interactions between neighbors. This temporal structure can generate significant acoustic interference among singers that pose problems for communication, mate finding, and predator detection. Acoustic insects can reduce interference by means of selective attention to only their nearest neighbors and by alternating calls with neighbors. Alternatively, they may synchronize, allowing them to preserve call rhythm and also to listen for predators during the silent intervals between calls. Moreover, males singing in choruses may benefit from reduced per capita predation risk as well as enhanced vigilance. They may also enjoy greater per capita attractiveness to females, particularly in the case of synchronous choruses. In many cases, however, the overall temporal structure of the chorus is only an emergent property of simple, pairwise interactions between neighbors. Nonetheless, the chorus that emerges can impose significant selection pressure on the singing of those individual males. Thus, feedback loops may occur and potentially influence traits at both individual and group levels in a chorus. PMID:25236356

  9. Chemical signals might mediate interactions between females and juveniles of Latrodectus geometricus (Araneae: Theridiidae).

    Science.gov (United States)

    Guimarães, Ingrid de Carvalho; Cardoso, Claudia Andrea Lima; Lima, Sandro Marcio; Andrade, Luis Humberto da Cunha; Antonialli Junior, William Fernnando

    2016-05-01

    Studies related to communication on spiders show that, as in other invertebrates, the interactions between conspecifics are also made through chemical signals. Therefore, in order to assess whether the composition of cuticular compounds might be involved in interactions that occur during the days after the emergence of juveniles in Latrodectus geometricus, we conducted behavioral and cuticular chemical profiles analysis of females and juveniles of different ages. The results show that females, regardless of their reproductive state, tolerate juveniles of other females with up to 40 days post-emergence and attack juveniles of 80 days post-emergence. Cuticlar chemical analysis shows that while the profile of juveniles is similar to adult's profile, they can remain in the web without being confused with threat or prey. Also, cuticular chemical profiles vary between different populations probably due to genetic and environmental differences or similarities between them. Finally, females in incubation period are able to detect the presence of eggs within any egg sac, but cannot distinguish egg sacs produced by conspecifics from the ones they had produced.

  10. Signal and noise transfer properties of photoelectric interactions in diagnostic x-ray imaging detectors.

    Science.gov (United States)

    Hajdok, G; Yao, J; Battista, J J; Cunningham, I A

    2006-10-01

    Image quality in diagnostic x-ray imaging is ultimately limited by the statistical properties governing how, and where, x-ray energy is deposited in a detector. This in turn depends on the physics of the underlying x-ray interactions. In the diagnostic energy range (10-100 keV), most of the energy deposited in a detector is through photoelectric interactions. We present a theoretical model of the photoelectric effect that specifically addresses the statistical nature of energy absorption by photoelectrons, K and L characteristic x rays, and Auger electrons. A cascaded-systems approach is used that employs a complex structure of parallel cascades to describe signal and noise transfer through the photoelectric effect in terms of the modulation transfer function, Wiener noise power spectrum, and detective quantum efficiency (DQE). The model was evaluated by comparing results with Monte Carlo calculations for x-ray converters based on amorphous selenium (a-Se) and lead (Pb), representing both low and high-Z materials. When electron transport considerations can be neglected, excellent agreement (within 3%) is obtained for each metric over the entire diagnostic energy range in both a-Se and Pb detectors up to 30 cycles/mm, the highest frequency tested. The cascaded model overstates the DQE when the electron range cannot be ignored. This occurs at approximately two cycles/mm in a-Se at an incident photon energy of 80 keV, whereas in Pb, excellent agreement is obtained for the DQE over the entire diagnostic energy range. However, within the context of mammography (20 keV) and micro-computed tomography (40 keV), the effects of electron transport on the DQE are negligible compared to fluorescence reabsorption, which can lead to decreases of up to 30% and 20% in a-Se and Pb, respectively, at 20 keV; and 10% and 5%, respectively, at 40 keV. It is shown that when Swank noise is identified in a Fourier model, the Swank factor must be frequency dependent. This factor decreases

  11. Elements toward novel therapeutic targeting of the adrenergic system.

    Science.gov (United States)

    Ghanemi, Abdelaziz; Hu, Xintian

    2015-02-01

    Adrenergic receptors belong to the family of the G protein coupled receptors that represent important targets in the modern pharmacotherapies. Studies on different physiological and pathophysiological properties of the adrenergic system have led to novel evidences and theories that suggest novel possible targeting of such system in a variety of pathologies and disorders, even beyond the classical known therapeutic possibilities. Herein, those advances have been illustrated with selected concepts and different examples. Furthermore, we illustrated the applications and the therapeutic implications that such findings and advances might have in the contexts of experimental pharmacology, therapeutics and clinic. We hope that the content of this work will guide researches devoted to the adrenergic aspects that combine neurosciences with pharmacology. PMID:25481798

  12. Signal processing by T-type calcium channel interactions in the cerebellum

    Directory of Open Access Journals (Sweden)

    Jordan D.T. Engbers

    2013-11-01

    Full Text Available T-type calcium channels of the Cav3 family are unique among voltage-gated calcium channels due to their low activation voltage, rapid inactivation, and small single channel conductance. These special properties allow Cav3 calcium channels to regulate neuronal processing in the subthreshold voltage range. Here, we review two different subthreshold ion channel interactions involving Cav3 channels and explore the ability of these interactions to expand the functional roles of Cav3 channels. In cerebellar Purkinje cells, Cav3 and intermediate conductance calcium-activated potassium (IKCa channels form a novel complex which creates a low voltage-activated, transient outward current capable of suppressing temporal summation of excitatory postsynaptic potentials (EPSPs. In large diameter neurons of the deep cerebellar nuclei, Cav3-mediated calcium current (IT and hyperpolarization-activated cation current (IH are activated during trains of IPSPs. These currents have distinct, and yet synergistic, roles in the subthreshold domain with IT generating a rebound burst and IH controlling first spike latency and rebound spike precision. However, by shortening the membrane time constant the membrane returns towards resting value at a faster rate, allowing IH to increase the efficacy of IT, and increase the range of burst frequencies that can be generated. The net effect of Cav3 channels thus depends on the channels with which they are paired. When expressed in a complex with a KCa channel, Cav3 channels reduce excitability when processing excitatory inputs. If functionally coupled with an HCN channel, the depolarizing effect of Cav3 channels is accentuated, allowing for efficient inversion of inhibitory inputs to generate a rebound burst output. Therefore, signal processing relies not only on the activity of individual subtypes of channels but also on complex interactions between ion channels whether based on a physical complex or by indirect effects on

  13. Signal processing by T-type calcium channel interactions in the cerebellum.

    Science.gov (United States)

    Engbers, Jordan D T; Anderson, Dustin; Zamponi, Gerald W; Turner, Ray W

    2013-11-27

    T-type calcium channels of the Cav3 family are unique among voltage-gated calcium channels due to their low activation voltage, rapid inactivation, and small single channel conductance. These special properties allow Cav3 calcium channels to regulate neuronal processing in the subthreshold voltage range. Here, we review two different subthreshold ion channel interactions involving Cav3 channels and explore the ability of these interactions to expand the functional roles of Cav3 channels. In cerebellar Purkinje cells, Cav3 and intermediate conductance calcium-activated potassium (IKCa) channels form a novel complex which creates a low voltage-activated, transient outward current capable of suppressing temporal summation of excitatory postsynaptic potentials (EPSPs). In large diameter neurons of the deep cerebellar nuclei, Cav3-mediated calcium current (I T) and hyperpolarization-activated cation current (I H) are activated during trains of inhibitory postsynaptic potentials. These currents have distinct, and yet synergistic, roles in the subthreshold domain with I T generating a rebound burst and I H controlling first spike latency and rebound spike precision. However, by shortening the membrane time constant the membrane returns towards resting value at a faster rate, allowing I H to increase the efficacy of I T and increase the range of burst frequencies that can be generated. The net effect of Cav3 channels thus depends on the channels with which they are paired. When expressed in a complex with a KCa channel, Cav3 channels reduce excitability when processing excitatory inputs. If functionally coupled with an HCN channel, the depolarizing effect of Cav3 channels is accentuated, allowing for efficient inversion of inhibitory inputs to generate a rebound burst output. Therefore, signal processing relies not only on the activity of individual subtypes of channels but also on complex interactions between ion channels whether based on a physical complex or by indirect

  14. Signal processing by T-type calcium channel interactions in the cerebellum

    Science.gov (United States)

    Engbers, Jordan D. T.; Anderson, Dustin; Zamponi, Gerald W.; Turner, Ray W.

    2013-01-01

    T-type calcium channels of the Cav3 family are unique among voltage-gated calcium channels due to their low activation voltage, rapid inactivation, and small single channel conductance. These special properties allow Cav3 calcium channels to regulate neuronal processing in the subthreshold voltage range. Here, we review two different subthreshold ion channel interactions involving Cav3 channels and explore the ability of these interactions to expand the functional roles of Cav3 channels. In cerebellar Purkinje cells, Cav3 and intermediate conductance calcium-activated potassium (IKCa) channels form a novel complex which creates a low voltage-activated, transient outward current capable of suppressing temporal summation of excitatory postsynaptic potentials (EPSPs). In large diameter neurons of the deep cerebellar nuclei, Cav3-mediated calcium current (IT) and hyperpolarization-activated cation current (IH) are activated during trains of inhibitory postsynaptic potentials. These currents have distinct, and yet synergistic, roles in the subthreshold domain with IT generating a rebound burst and IH controlling first spike latency and rebound spike precision. However, by shortening the membrane time constant the membrane returns towards resting value at a faster rate, allowing IH to increase the efficacy of IT and increase the range of burst frequencies that can be generated. The net effect of Cav3 channels thus depends on the channels with which they are paired. When expressed in a complex with a KCa channel, Cav3 channels reduce excitability when processing excitatory inputs. If functionally coupled with an HCN channel, the depolarizing effect of Cav3 channels is accentuated, allowing for efficient inversion of inhibitory inputs to generate a rebound burst output. Therefore, signal processing relies not only on the activity of individual subtypes of channels but also on complex interactions between ion channels whether based on a physical complex or by indirect

  15. Signalling-dependent interactions between the kinase-coupling protein CheW and chemoreceptors in living cells.

    Science.gov (United States)

    Pedetta, Andrea; Parkinson, John S; Studdert, Claudia A

    2014-09-01

    Chemical signals sensed on the periplasmic side of bacterial cells by transmembrane chemoreceptors are transmitted to the flagellar motors via the histidine kinase CheA, which controls the phosphorylation level of the effector protein CheY. Chemoreceptor arrays comprise remarkably stable supramolecular structures in which thousands of chemoreceptors are networked through interactions between their cytoplasmic tips, CheA, and the small coupling protein CheW. To explore the conformational changes that occur within this protein assembly during signalling, we used in vivo cross-linking methods to detect close interactions between the coupling protein CheW and the serine receptor Tsr in intact Escherichia coli cells. We identified two signal-sensitive contacts between CheW and the cytoplasmic tip of Tsr. Our results suggest that ligand binding triggers changes in the receptor that alter its signalling contacts with CheW (and/or CheA).

  16. Changes of lymphocyte beta-adrenergic receptors after surgical stress.

    Science.gov (United States)

    Eandi, M; Buraglio, M; Arduino, C; Viano, I; Sansalvadore, G; Arbinolo, M A

    1984-01-01

    In this study the authors' purpose was to observe the effects of surgical stress on the number of lymphocyte beta-adrenergic receptors in hypertensive and normotensive subjects. It was noticed that after surgery a significant reduction occurred in the number of binding sites of lymphocytes of both hypertensive and normotensive subjects. The time course of recovery to the pre-operative values of binding sites varied between the two groups, being slower in normotensive than in hypertensive patients. This might suggest a different pattern of regulation of the beta-adrenergic receptor between hypertensive and normotensive subjects.

  17. Alpha-adrenergic receptors in rat skeletal muscle

    DEFF Research Database (Denmark)

    Rattigan, S; Appleby, G J; Edwards, S J;

    1986-01-01

    Sarcolemma-enriched preparations from muscles rich in slow oxidative red fibres contained specific binding sites for the alpha 1 antagonist, prazosin (e.g. soleus Kd 0.13 nM, Bmax 29 fmol/mg protein). Binding sites for prazosin were almost absent from white muscle. Displacement of prazosin bindin...... adrenergic receptors are present on the sarcolemma of slow oxidative red fibres of rat skeletal muscle. The presence provides the mechanistic basis for apparent alpha-adrenergic effects to increase glucose and oxygen uptake in perfused rat hindquarter....

  18. Different designs of kinase-phosphatase interactions and phosphatase sequestration shapes the robustness and signal flow in the MAPK cascade

    Directory of Open Access Journals (Sweden)

    Sarma Uddipan

    2012-07-01

    Full Text Available Abstract Background The three layer mitogen activated protein kinase (MAPK signaling cascade exhibits different designs of interactions between its kinases and phosphatases. While the sequential interactions between the three kinases of the cascade are tightly preserved, the phosphatases of the cascade, such as MKP3 and PP2A, exhibit relatively diverse interactions with their substrate kinases. Additionally, the kinases of the MAPK cascade can also sequester their phosphatases. Thus, each topologically distinct interaction design of kinases and phosphatases could exhibit unique signal processing characteristics, and the presence of phosphatase sequestration may lead to further fine tuning of the propagated signal. Results We have built four architecturally distinct types of models of the MAPK cascade, each model with identical kinase-kinase interactions but unique kinases-phosphatases interactions. Our simulations unravelled that MAPK cascade’s robustness to external perturbations is a function of nature of interaction between its kinases and phosphatases. The cascade’s output robustness was enhanced when phosphatases were sequestrated by their target kinases. We uncovered a novel implicit/hidden negative feedback loop from the phosphatase MKP3 to its upstream kinase Raf-1, in a cascade resembling the B cell MAPK cascade. Notably, strength of the feedback loop was reciprocal to the strength of phosphatases’ sequestration and stronger sequestration abolished the feedback loop completely. An experimental method to verify the presence of the feedback loop is also proposed. We further showed, when the models were activated by transient signal, memory (total time taken by the cascade output to reach its unstimulated level after removal of signal of a cascade was determined by the specific designs of interaction among its kinases and phosphatases. Conclusions Differences in interaction designs among the kinases and phosphatases can

  19. Wnt/β-Catenin and Retinoic Acid Receptor Signaling Pathways Interact to Regulate Chondrocyte Function and Matrix Turnover*

    OpenAIRE

    Yasuhara, Rika; Yuasa, Takahito; Williams, Julie A.; Byers, Stephen W.; Shah, Salim; Pacifici, Maurizio; Iwamoto, Masahiro; Enomoto-Iwamoto, Motomi

    2009-01-01

    Activation of the Wnt/β-catenin and retinoid signaling pathways is known to tilt cartilage matrix homeostasis toward catabolism. Here, we investigated possible interactions between these pathways. We found that all-trans-retinoic acid (RA) treatment of mouse epiphyseal chondrocytes in culture did increase Wnt/β-catenin signaling in the absence or presence of exogenous Wnt3a, as revealed by lymphoid enhancer factor/T-cell factor/β-catenin reporter activity and β-catenin nuclear accumulation. T...

  20. Interactions between polymorphisms in the aryl hydrocarbon receptor signalling pathway and exposure to persistent organochlorine pollutants affect human semen quality

    DEFF Research Database (Denmark)

    Brokken, L J S; Lundberg, P J; Spanò, M;

    2014-01-01

    Persistent organic pollutants (POPs) may affect male reproductive function. Many dioxin-like POPs exert their effects by activation of the aryl hydrocarbon receptor (AHR) signalling pathway. We analysed whether gene-environment interactions between polymorphisms in AHR (R554K) and AHR repressor...... and the expression of the pro-apoptotic marker protein Fas. The data indicate that susceptibility to adverse effects of POP exposure on male reproductive function is dependent on polymorphisms in genes involved in AHR signalling....

  1. Regulatory Networks and Complex Interactions between the Insulin and Angiotensin II Signalling Systems: Models and Implications for Hypertension and Diabetes

    OpenAIRE

    Çizmeci, Deniz; Arkun, Yaman

    2013-01-01

    Regulatory Networks and Complex Interactions between the Insulin and Angiotensin II Signalling Systems: Models and Implications for Hypertension and Diabetes Deniz Cizmeci, Yaman Arkun* Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey Abstract The cross-talk between insulin and angiotensin II signalling pathways plays a significant role in the co-occurrence of diabetes and hypertension. We developed a mathematical model of the system of ...

  2. [Microbial endocrinology: impact of interactions between microbes and neuroendocrine hormones on infection--a review].

    Science.gov (United States)

    Xu, Fuzhou; Wu, Cun; Lin, Jun

    2013-09-01

    Microbial endocrinology is a crossdisciplinary field representing the intersection of microbiology with mammalian endocrinology and neurophysiology. In this review, effects of catecholamine on bacteria were used as an example to demonstrate the interactions between microbes and neuroendocrine hormones. Catecholamine modulates bacterial infectivity by stimulation of bacteria growth and augmentation of host tissue attachment and invasion. Moreover, the bacterial adrenergic receptors recognized by catecholamine and its relationship with quorum sensing signals were also addressed. This review will be helpful for understanding the interactions between microorganism and host as well as health breeding and food safety in animal industries.

  3. DMPD: Signal transduction pathways mediated by the interaction of CpG DNA withToll-like receptor 9. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14751759 Signal transduction pathways mediated by the interaction of CpG DNA withTo...;16(1):17-22. (.png) (.svg) (.html) (.csml) Show Signal transduction pathways mediated by the interaction of... CpG DNA withToll-like receptor 9. PubmedID 14751759 Title Signal transduction pathways media

  4. Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the β2 adrenergic receptor.

    Science.gov (United States)

    Patriarchi, Tommaso; Qian, Hai; Di Biase, Valentina; Malik, Zulfiquar A; Chowdhury, Dhrubajyoti; Price, Jennifer L; Hammes, Erik A; Buonarati, Olivia R; Westenbroek, Ruth E; Catterall, William A; Hofmann, Franz; Xiang, Yang K; Murphy, Geoffrey G; Chen, Chao-Ye; Navedo, Manuel F; Hell, Johannes W

    2016-06-15

    Agonist-triggered downregulation of β-adrenergic receptors (ARs) constitutes vital negative feedback to prevent cellular overexcitation. Here, we report a novel downregulation of β2AR signaling highly specific for Cav1.2. We find that β2-AR binding to Cav1.2 residues 1923-1942 is required for β-adrenergic regulation of Cav1.2. Despite the prominence of PKA-mediated phosphorylation of Cav1.2 S1928 within the newly identified β2AR binding site, its physiological function has so far escaped identification. We show that phosphorylation of S1928 displaces the β2AR from Cav1.2 upon β-adrenergic stimulation rendering Cav1.2 refractory for several minutes from further β-adrenergic stimulation. This effect is lost in S1928A knock-in mice. Although AMPARs are clustered at postsynaptic sites like Cav1.2, β2AR association with and regulation of AMPARs do not show such dissociation. Accordingly, displacement of the β2AR from Cav1.2 is a uniquely specific desensitization mechanism of Cav1.2 regulation by highly localized β2AR/cAMP/PKA/S1928 signaling. The physiological implications of this mechanism are underscored by our finding that LTP induced by prolonged theta tetanus (PTT-LTP) depends on Cav1.2 and its regulation by channel-associated β2AR.

  5. Anti-Inflammatory Prostanoids: Focus on the Interactions between Electrophile Signaling and Resolution of Inflammation

    Directory of Open Access Journals (Sweden)

    Beatriz Díez-Dacal

    2010-01-01

    Full Text Available Prostanoids are products of cyclooxygenase biosynthetic pathways and constitute a family of lipidic mediators of widely diverse structures and biological actions. Besides their known proinflammatory role, numerous works have revealed the anti-inflammatory effects of various prostanoids and established their role in the resolution of inflammation. Among these, prostaglandins with cyclopentenone structure (cyPG are electrophilic lipids that may act through various mechanisms, including the activation of nuclear and membrane receptors and, importantly, direct addition to protein cysteine residues and modification of protein function. Due to their ability to influence cysteine modification–mediated signaling, cyPG may play a critical role in the interplay between redox and inflammatory signaling pathways. Moreover, cellular redox status modulates cyPG addition to proteins; thus, a reciprocal regulation exists between these two factors. After initial controversy, it is becoming clear that endogenous cyPG are generated at concentrations sufficient to promote inflammatory resolution. As for other prostanoids, cyPG effects are highly dependent on context factors and they may exert pro- or anti-inflammatory actions in a cell type–dependent manner, or even biphasic or dual actions in a given cell type or tissue. In light of the growing number of cyPG protein targets identified, cyPG resemble other pleiotropic mediators acting through protein modification. However, their complex structure results in an inter- and intramolecular selectivity of the residues being modified, thus opening the way for structure-activity and drug discovery studies. Detailed characterization of cyPG interactions with cellular proteins will help us to understand their mechanism of action fully and establish their therapeutic potential in inflammation.

  6. Plasma membrane lipid–protein interactions affect signaling processes in sterol-biosynthesis mutants in Arabidopsis thaliana

    OpenAIRE

    Zauber, Henrik; Burgos, Asdrubal; Garapati, Prashanth; Schulze, Waltraud X.

    2014-01-01

    The plasma membrane is an important organelle providing structure, signaling and transport as major biological functions. Being composed of lipids and proteins with different physicochemical properties, the biological functions of membranes depend on specific protein-protein and protein-lipid interactions. Interactions of proteins with their specific sterol and lipid environment were shown to be important factors for protein recruitment into sub-compartmental structures of the plasma membrane...

  7. Cytotoxic effects of TBBPA and its interactions with signalling pathways in mammalian cells

    Energy Technology Data Exchange (ETDEWEB)

    Strack, S.; Sander, M.; Detzel, T.; Krug, H.F. [Forschungszentrum Kalsruhe (Germany). Inst. fuer Toxikologie und Genetik; Kuch, B. [Stuttgart Univ. (Germany). Inst. fuer Siedlungswasserbau und Wasserguetewirtschaft

    2004-09-15

    Toxic effects of TBBPA published so far have been recently reviewed by Birnbaum and Staskal The LC{sub 50} indicating the acute toxicity in vivo due to a single oral dose in mice and rats were higher than 4 to 5 g/kg, however, systematically long-term in vivo studies are missing. Weak estrogenic effects have been described by Meerts et al., demonstrating for TBBPA less pronounced activity than for other brominated bisphenols. The same group described competitive interactions in vitro with human transthyretin (TTR). In binding affinity assays they could demonstrate that TBBPA binds to TTR ten times more effectively than T{sub 4}. However, the available toxicological data are still extremely limited. For a comprehensive risk assessment valid data are insufficient. The aim of this study was to evaluate possible cytotoxic effects, and to gain insights into the underlying molecular mechanisms respectively the corresponding cellular signalling processes. This approach would allow to identify sensitive end-points of cellular toxicological responses. For these molecular toxicological investigations established cell lines should be used, in order to have a suitable model for appropriate toxicological studies.

  8. Involvement of adrenergic and serotonergic receptors in antidepressant-like effect of urocortin 3 in a modified forced swimming test in mice.

    Science.gov (United States)

    Tanaka, Masaru; Telegdy, Gyula

    2008-11-25

    Most of the evidence suggests that peptides in the corticotropin-releasing factor (CRF) family act on CRF receptors and are involved in depressive disorders. Urocortin 3 (Ucn 3) is specific for CRF type 2 (CRF(2)) receptors and mediates anxiolytic-like action. Little is known about the roles of Ucn 3 and CRH(2) receptors on depressive disorders. The previous study revealed that Ucn 3 elicits the antidepressant-like action by shortening the immobility time and increasing both the climbing time and the swimming time. The involvement of the adrenergic and serotonergic receptors in the antidepressant-like effect of Ucn 3 (0.5μg/2μl, i.c.v.) was studied in a modified forced swimming test (FST) in mice. Mice were pretreated with a non-selective α-adrenergic receptor antagonist, phenoxybenzamine, an α(1)/α(2β)-adrenergic receptor antagonist, prazosin, an α(2)-adrenergic receptor antagonist, yohimbine, a mixed 5-HT(1)/5-HT(2) serotonergic receptor antagonist, methysergide, a non-selective 5-HT(2) serotonergic receptor antagonist, cyproheptadine or a β-adrenergic receptor antagonist, propranolol. Phenoxybenzamine prevented the effects of Ucn 3 on the immobility time. Prazosin prevented the effects of Ucn 3 on the climbing time. Yohimbine prevented the effects of Ucn 3 on the immobility, climbing and swimming times. Methysergide prevented the effects of Ucn 3 on the immobility and climbing time. Cyproheptadine prevented the effects of Ucn 3 on the swimming time. Propranolol did not change the effects of Ucn 3. The results demonstrated that the antidepressant-like effect of Ucn 3 is mediated, at least in part, by an interaction of the α-adrenergic and serotonergic receptors in a modified mouse FST.

  9. The essential role for aromatic cluster in the β3 adrenergic receptor

    Institute of Scientific and Technical Information of China (English)

    Hai-yan CAI; Zhi-jian XU; Jie TANG; Ying SUN; Kai-xian CHEN; He-yao WANG; Wei-liang ZHU

    2012-01-01

    Aim:To explore the function of the conserved aromatic cluster F2135.47,F3086.51,and F3096.52 in human β3 adrenergic receptor (hβ3AR).Methods:Point mutation technology was used to produce plasmid mutations of hβ3AR.HEK-293 cells were transiently co-transfected with the hβ3AR (wild-type or mutant) plasmids and luciferase reporter vector pCRE-luc.The expression levels of hβ3AR in the cells were determined by Western blot analysis.The constitutive signalling and the signalling induced by the β3AR selective agonist,BRL (BRL37344),were then evaluated.To further explore the interaction mechanism between BRL and β3AR,a three-dimensional complex model of β3AR and BRL was constructed by homology modelling and molecular docking.Results:For F3086.51,Ala and Leu substitution significantly decreased the constitutive activities of β3AR to approximately 10% of that for the wild-type receptor.However,both the potency and maximal efficacy were unchanged by Ala substitution.In the F3086.51L construct,the EC50 value manifested as a "right shift" of approximately two orders of magnitude with an increased Emax.Impressively,the molecular pharmacological phenotype was similar to the wild-type receptor for the introduction of Tyr at position 3086.51,though the EC50 value increased by approximately five-fold for the mutant.For F3096.52,the constitutive signalling for both F3096.52A and F3096.52L constructs were strongly impaired.In the F3096.52A construct,BRL-stimulated signalling showed a normal Emax but reduced potency.Leu substitution of F3096.52 reduced both the Emax and potency.When F3096.52 was mutated to Tyr,the constitutive activity was decreased approximately three-fold,and BRL-stimulated signalling was significantly impaired.Furthermore,the double mutant (F3086.51A_F3096 52A) caused the total loss of β3AR function.The predicted binding mode between β3AR and BRL revealed that both F3086.51 and F3096.52 were in the BRL binding pocket of β3AR,while F2135.47 and W3056

  10. ß2-adrenergic receptor polymorphisms, asthma and COPD

    DEFF Research Database (Denmark)

    Thomsen, M; Nordestgaard, B G; Sethi, A A;

    2012-01-01

    The ß(2)-adrenergic receptor (ADRB2) is an important regulator of airway smooth muscle tone. We tested the hypothesis that three functional polymorphisms in the ADRB2 gene (Thr164Ile, Gly16Arg and Gln27Glu) are associated with reduced lung function, asthma or chronic obstructive pulmonary disease...

  11. Adrenergic receptor subtypes in the cerebral circulation of newborn piglets

    Energy Technology Data Exchange (ETDEWEB)

    Wagerle, L.C.; Delivoria-Papadopoulos, M.

    1987-06-01

    The purpose of this study was to identify the ..cap alpha..-adrenergic receptor subtype mediating cerebral vasoconstriction during sympathetic nerve stimulation in the newborn piglet. The effect of ..cap alpha../sub 1/- and ..cap alpha../sub 2/-antagonists prazosin and yohimbine on the cerebrovascular response to unilateral electrical stimulation (15 Hz, 15 V) of the superior cervical sympathetic trunk was studied in 25 newborn piglets. Regional cerebral blood flow was measured with tracer microspheres. Sympathetic stimulation decreased blood flow to the ipsilateral cerebrum hippocampus, choroid plexus, and masseter muscle. ..cap alpha../sub 1/-Adrenergic receptor blockade with prazosin inhibited the sympathetic vasoconstriction in the cerebrum, hippocampus, and masseter muscle and abolished it in the choroid plexus. ..cap alpha../sub s/-Adrenergic receptor blockade with yohimbine had no effect. Following the higher dose of yohimbine, however, blood flow to all brain regions was increased by approximately two-fold, possibly due to enhanced cerebral metabolism. These data demonstrate that vascular ..cap alpha../sub 1/-adrenergic receptors mediate vasoconstriction to neuroadrenergic stimulation in cerebral resistance vessels in the newborn piglet.

  12. ADRENERGIC RESPONSE IN CHILDREN WITH ASTHMA ON EXOGENOUS STIMULI

    NARCIS (Netherlands)

    VANAALDEREN, WMC; POSTMA, DS; KOETER, GH; DEMONCHY, JGR; KNOL, K

    1992-01-01

    In asthmatic childen it was investigated whether the degree of impairment of the adrenergic response on exogenous stimuli is related to the magnitude of the 24-hour amplitude in airflow obstructions. Urinary-adrenaline and noradrenaline excretion after house dust mite (HDM) inhalation and after exer

  13. Wnt isoform-specific interactions with coreceptor specify inhibition or potentiation of signaling by LRP6 antibodies.

    Science.gov (United States)

    Gong, Yan; Bourhis, Eric; Chiu, Cecilia; Stawicki, Scott; DeAlmeida, Venita I; Liu, Bob Y; Phamluong, Khanhky; Cao, Tim C; Carano, Richard A D; Ernst, James A; Solloway, Mark; Rubinfeld, Bonnee; Hannoush, Rami N; Wu, Yan; Polakis, Paul; Costa, Mike

    2010-01-01

    β-Catenin-dependent Wnt signaling is initiated as Wnt binds to both the receptor FZD and coreceptor LRP5/6, which then assembles a multimeric complex at the cytoplasmic membrane face to recruit and inactivate the kinase GSK3. The large number and sequence diversity of Wnt isoforms suggest the possibility of domain-specific ligand-coreceptor interactions, and distinct binding sites on LRP6 for Wnt3a and Wnt9b have recently been identified in vitro. Whether mechanistically different interactions between Wnts and coreceptors might mediate signaling remains to be determined. It is also not clear whether coreceptor homodimerization induced extracellularly can activate Wnt signaling, as is the case for receptor tyrosine kinases. We generated monoclonal antibodies against LRP6 with the unexpected ability to inhibit signaling by some Wnt isoforms and potentiate signaling by other isoforms. In cell culture, two antibodies characterized further show reciprocal activities on most Wnts, with one antibody antagonizing and the other potentiating. We demonstrate that these antibodies bind to different regions of LRP6 protein, and inhibition of signaling results from blocking Wnt binding. Antibody-mediated dimerization of LRP6 can potentiate signaling only when a Wnt isoform is also able to bind the complex, presumably recruiting FZD. Endogenous autocrine Wnt signaling in different tumor cell lines can be either antagonized or enhanced by the LRP6 antibodies, indicating expression of different Wnt isoforms. As anticipated from the roles of Wnt signaling in cancer and bone development, antibody activities can also be observed in mice for inhibition of tumor growth and in organ culture for enhancement of bone mineral density. Collectively, our results indicate that separate binding sites for different subsets of Wnt isoforms determine the inhibition or potentiation of signaling conferred by LRP6 antibodies. This complexity of coreceptor-ligand interactions may allow for

  14. Inhibitor of CDK interacting with cyclin A1 (INCA1) regulates proliferation and is repressed by oncogenic signaling

    DEFF Research Database (Denmark)

    Baumer, Nicole; Tickenbrock, Lara; Tschanter, Petra;

    2011-01-01

    in the INCA1 protein. INCA1 inhibited CDK2 activity and cell proliferation. The inihibitory effects depended on the cyclin-interacting domain. Mitogenic and oncogenic signals suppressed INCA1 expression, while it was induced by cell cycle arrest. We established a deletional mouse model that showed increased...

  15. RGS proteins destroy spare receptors: Effects of GPCR-interacting proteins and signal deamplification on measurements of GPCR agonist potency.

    Science.gov (United States)

    Chidiac, Peter

    2016-01-01

    Many GPCRs are able to activate multiple distinct signaling pathways, and these may include biochemical cascades activated via either heterotrimeric G proteins or by β-arrestins. The relative potencies and/or efficacies among a series of agonists that act on a common receptor can vary depending upon which signaling pathway is being activated. This phenomenon is known as biased signaling or functional selectivity, and is presumed to reflect underlying differences in ligand binding affinities for alternate conformational states of the receptor. The first part of this review discusses how various cellular GPCR interacting proteins (GIPs) can influence receptor conformation and thereby affect ligand-receptor interactions and contribute to signaling bias. Upon activation, receptors trigger biochemical cascades that lead to altered cellular function, and measuring points along the cascade (e.g., second messenger production) conveys information about receptor activity. As a signal continues along its way, the observed concentration dependence of a GPCR ligand may change due to amplification and saturation of biochemical steps. The second part of this review considers additional cellular factors that affect signal processing, focusing mainly on structural elements and deamplification mechanisms, and discusses the relevance of these to measurements of potency and functional selectivity. PMID:26297537

  16. Signal transduction in Plasmodium-Red Blood Cells interactions and in cytoadherence

    Directory of Open Access Journals (Sweden)

    Laura N. Cruz

    2012-06-01

    Full Text Available Malaria is responsible for more than 1.5 million deaths each year, especially among children (Snow et al. 2005. Despite of the severity of malaria situation and great effort to the development of new drug targets (Yuan et al. 2011 there is still a relative low investment toward antimalarial drugs. Briefly there are targets classes of antimalarial drugs currently being tested including: kinases, proteases, ion channel of GPCR, nuclear receptor, among others (Gamo et al. 2010. Here we review malaria signal transduction pathways in Red Blood Cells (RBC as well as infected RBCs and endothelial cells interactions, namely cytoadherence. The last process is thought to play an important role in the pathogenesis of severe malaria. The molecules displayed on the surface of both infected erythrocytes (IE and vascular endothelial cells (EC exert themselves as important mediators in cytoadherence, in that they not only induce structural and metabolic changes on both sides, but also trigger multiple signal transduction processes, leading to alteration of gene expression, with the balance between positive and negative regulation determining endothelial pathology during a malaria infection.A Malária é responsavel por mais de 1.5 milhões de mortes anualmente, especialmente entre crianças (Snow et al. 2005. Apesar da gravidade da situação e grande esforço para o desenvolvimento de novas drogas (Yuan et al. 2011, os investimentos em drogas antimaláricas ainda é relativamente baixo. Brevemente, os alvos antimaláricos atualmente testados incluem: quinases, proteases, canais iônicos para GPCR, receptores nucleares entre outros (Gamo et al. 2010. No presente trabalho nós revisamos as vias de transdução de sinal em eritrócitos assim como eritrócitos infectados e interações com células endoteliais, denominada citoaderência. Este processo é conhecido por sua importante função na patogenicidade da malária severa. As moléculas expressas na superf

  17. Special Issue: Redox Active Natural Products and Their Interaction with Cellular Signalling Pathways

    Directory of Open Access Journals (Sweden)

    Claus Jacob

    2014-11-01

    Full Text Available During the last decade, research into natural products has experienced a certain renaissance. The urgent need for more and more effective antibiotics in medicine, the demand for ecologically friendly plant protectants in agriculture, “natural” cosmetics and the issue of a sustainable and healthy nutrition in an ageing society have fuelled research into Nature’s treasure chest of “green gold”. Here, redox active secondary metabolites from plants, fungi, bacteria and other (micro-organisms often have been at the forefront of the most interesting developments. These agents provide powerful means to interfere with many, probably most cellular signaling pathways in humans, animals and lower organisms, and therefore can be used to protect, i.e., in form of antioxidants, and to frighten off or even kill, i.e., in form of repellants, antibiotics, fungicides and selective, often catalytic “sensor/effector” anticancer agents. Interestingly, whilst natural product research dates back many decades, in some cases even centuries, and compounds such as allicin and various flavonoids have been investigated thoroughly in the past, it has only recently become possible to investigate their precise interactions and mode(s of action inside living cells. Here, fluorescent staining and labelling on the one side, and appropriate detection, either qualitatively under the microscope or quantitatively in flow cytometers and plate readers, on the other, enable researchers to obtain the various pieces of information necessary to construct a fairly complete puzzle of how such compounds act and interact in living cells. Complemented by the more traditional activity assays and Western Blots, and increasingly joined by techniques such as proteomics, chemogenetic screening and mRNA profiling, these cell based bioanalytical techniques form a powerful platform for “intracellular diagnostics”. In the case of redox active compounds, especially of Reactive Sulfur

  18. Comment on "Dark Matter with Pseudoscalar-Mediated Interactions Explains the DAMA Signal and the Galactic Center Excess"

    CERN Document Server

    Yang, Kwei-Chou

    2016-01-01

    Arina et al. have proposed the Dirac fermionic dark matter with pseudoscalar-mediated interactions to explain the Galactic Center excess, correct relic density and DAMA signal. They have assumed that contact interactions remain roughly valid in calculating scattering rates at the direct detection even when the mediator mass is the same order as the typical momentum transfer. We show that such a replacement is not suitable. Adopting the full form of interactions, we show that the gamma-ray excess allowed parameters are completely outside of the DAMA iodine 3$\\sigma$ region, even for heavy-flavor-universal couplings, for which $m_{DM} \\sim 40$ GeV in the gamma-ray excess fit. As for Higgs-like couplings, the two regions overlap for $m_a\\lesssim$ 15 MeV, where long-range interactions, instead of contact interactions, occur at the DAMA.

  19. Discourse-level structuring of information in narrative:Signalling structural, interactional and cognitive shifts

    Directory of Open Access Journals (Sweden)

    Tuija Virtanen

    2011-07-01

    Full Text Available Discourse-level structuring of information is explored in narrative in the light of three parameters subsumed under this umbrella notion: (i the structural concepts of “theme-rheme”, connected to “position”; (ii the interaction-oriented pair of concepts “topic-comment”, grounded in the notion of “aboutness”; and (iii the cognitively motivated gradient from “given” to “new” information, related to interlocutors’ assumptions of their memory constraints as well as those of others. In each pair/gradient of concepts one member/pole – “theme”, “comment”, and “new” – is argued to constitute the Figure, against the (necessary Ground of the other. The linguistic signalling of the structural, interactional and cognitive shifts in information structuring is examined in two different kinds of narratives in written French. The analysis of a short legend, in its entirety, and a narrative paragraph from a news story both point to high context-sensitivity in the signalling of the three parameters of discourse-level structuring of information, with that of the discourse level “newness” differing most markedly from the others.Cet article étudie la structure informationnelle dans des textes narratifs en observant trois distinctions linguistiques que recouvre cette structure : (i au niveau textuel, le couple « thème-rhème » défini par une distinction positionnelle ; (ii au niveau interactionnel, l’opposition « topique-commentaire » reposant sur la notion d’« à propos » ; et (iii la distinction cognitive entre information donnée et information nouvelle, mettant en jeu les présomptions des interlocuteurs sur les contraintes mémorielles de l’autre. Dans chacune de ces oppositions binaires ou graduelles, l’un des concepts joue le rôle de Figure (le « thème », le « commentaire » et l’information nouvelle par rapport à un Fond, joué par l’autre concept (le « rhème », le

  20. The Alpha-1A Adrenergic Receptor in the Rabbit Heart.

    Directory of Open Access Journals (Sweden)

    R Croft Thomas

    Full Text Available The alpha-1A-adrenergic receptor (AR subtype is associated with cardioprotective signaling in the mouse and human heart. The rabbit is useful for cardiac disease modeling, but data on the alpha-1A in the rabbit heart are limited. Our objective was to test for expression and function of the alpha-1A in rabbit heart. By quantitative real-time reverse transcription PCR (qPCR on mRNA from ventricular myocardium of adult male New Zealand White rabbits, the alpha-1B was 99% of total alpha-1-AR mRNA, with <1% alpha-1A and alpha-1D, whereas alpha-1A mRNA was over 50% of total in brain and liver. Saturation radioligand binding identified ~4 fmol total alpha-1-ARs per mg myocardial protein, with 17% alpha-1A by competition with the selective antagonist 5-methylurapidil. The alpha-1D was not detected by competition with BMY-7378, indicating that 83% of alpha-1-ARs were alpha-1B. In isolated left ventricle and right ventricle, the selective alpha-1A agonist A61603 stimulated a negative inotropic effect, versus a positive inotropic effect with the nonselective alpha-1-agonist phenylephrine and the beta-agonist isoproterenol. Blood pressure assay in conscious rabbits using an indwelling aortic telemeter showed that A61603 by bolus intravenous dosing increased mean arterial pressure by 20 mm Hg at 0.14 μg/kg, 10-fold lower than norepinephrine, and chronic A61603 infusion by iPRECIO programmable micro Infusion pump did not increase BP at 22 μg/kg/d. A myocardial slice model useful in human myocardium and an anthracycline cardiotoxicity model useful in mouse were both problematic in rabbit. We conclude that alpha-1A mRNA is very low in rabbit heart, but the receptor is present by binding and mediates a negative inotropic response. Expression and function of the alpha-1A in rabbit heart differ from mouse and human, but the vasopressor response is similar to mouse.

  1. Beta-Adrenergic Receptor Expression in Muscle Cells

    Science.gov (United States)

    Young, Ronald B.; Bridge, K.; Vaughn, J. R.

    1999-01-01

    beta-adrenergic receptor (bAR) agonists presumably exert their physiological action on skeletal muscle cells through the bAR. Since the signal generated by the bAR is cyclic AMP (cAMP), experiments were initiated in primary chicken muscle cell cultures to determine if artificial elevation of intracellular cAMP by treatment with forskolin would alter the population of bAR expressed on the surface of muscle cells. Chicken skeletal muscle cells after 7 days in culture were employed for the experiments because muscle cells have attained a steady state with respect to muscle protein metabolism at this stage. Cells were treated with 0-10 uM forskolin for a total of three days. At the end of the 1, 2, and 3 day treatment intervals, the concentration of cAMP and the bAR population were measured. Receptor population was measured in intact muscle cell cultures as the difference between total binding of [H-3]CGP-12177 and non-specific binding of [H-3]CGP-12177 in the presence of 1 uM propranolol. Intracellular cAMP concentration was measured by radioimmunoassay. The concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. Increasing concentrations of forskolin also led to an increase in (beta)AR population, with a maximum increase of approximately 50% at 10 uM. This increase in (beta)AR population was apparent after only 1 day of treatment, and the pattern of increase was maintained for all 3 days of the treatment period. Thus, increasing the intracellular concentration of cAMP leads to up-regulation of (beta)AR population. Clenbuterol and isoproterenol gave similar effects on bAR population. The effect of forskolin on the quantity and apparent synthesis rate of the heavy chain of myosin (mhc) were also investigated. A maximum increase of 50% in the quantity of mhc was observed at 0.2 UM forskolin, but higher concentrations of forskolin reduced the quantity of mhc back to control levels.

  2. Juxtacrine interaction of macrophages and bone marrow stromal cells induce interleukin-6 signals and promote cell migration

    Institute of Scientific and Technical Information of China (English)

    Jia Chang; Amy J Koh; Hernan Roca; Laurie K McCauley

    2015-01-01

    The bone marrow contains a heterogeneous milieu of cells, including macrophages, which are key cellular mediators for resolving infection and inflammation. Macrophages are most well known for their ability to phagocytose foreign bodies or apoptotic cells to maintain homeostasis;however, little is known about their function in the bone microenvironment. In the current study, we investigated the in vitro interaction of murine macrophages and bone marrow stromal cells (BMSCs), with focus on the juxtacrine induction of IL-6 signaling and the resultant effect on BMSC migration and growth. The juxtacrine interaction of primary mouse macrophages and BMSCs activated IL-6 signaling in the co-cultures, which subsequently enhanced BMSC migration and increased BMSC numbers. BMSCs and macrophages harvested from IL-6 knockout mice revealed that IL-6 signaling was essential for enhancement of BMSC migration and increased BMSC numbers via juxtacrine interactions. BMSCs were the main contributor of IL-6 signaling, and hence activation of the IL-6/gp130/STAT3 pathway. Meanwhile, macrophage derived IL-6 remained important for the overall production of IL-6 protein in the co-cultures. Taken together, these findings show the function of macrophages as co-inducers of migration and growth of BMSCs, which could directly influence bone formation and turnover.

  3. TCR signal strength alters T-DC activation and interaction times and directs the outcome of differentiation.

    Directory of Open Access Journals (Sweden)

    Nicholas eVan Panhuys

    2016-01-01

    Full Text Available The ability of CD4+ T cells to differentiate into effector subsets underpins their ability to shape the immune response and mediate host protection. During T cell receptor induced activation of CD4+ T cells both the quality and quantity of specific activatory peptide/MHC ligands have been shown to control the polarization of naïve CD4+ T cells in addition to co-stimulatory and cytokine based signals. Recently, advances in two photon microscopy and tetramer based cell tracking methods have allowed investigators to greatly extend the study of the role of TCR signaling in effector differentiation under in vivo conditions. In this review we consider data from recent in vivo studies analyzing the role of TCR signal strength in controlling the outcome of CD4+ T cell differentiation and discuss the role of the TCR in controlling the critical nature of CD4+ T cell interactions with dendritic cells during activation. We further propose a model whereby TCR signal strength controls the temporal aspects of T:DC interactions and the implications for this in mediating the downstream signaling events which influence the transcriptional and epigenetic regulation of effector differentiation.

  4. Toward understanding social cues and signals in human-robot interaction: effects of robot gaze and proxemic behavior.

    Science.gov (United States)

    Fiore, Stephen M; Wiltshire, Travis J; Lobato, Emilio J C; Jentsch, Florian G; Huang, Wesley H; Axelrod, Benjamin

    2013-01-01

    As robots are increasingly deployed in settings requiring social interaction, research is needed to examine the social signals perceived by humans when robots display certain social cues. In this paper, we report a study designed to examine how humans interpret social cues exhibited by robots. We first provide a brief overview of perspectives from social cognition in humans and how these processes are applicable to human-robot interaction (HRI). We then discuss the need to examine the relationship between social cues and signals as a function of the degree to which a robot is perceived as a socially present agent. We describe an experiment in which social cues were manipulated on an iRobot Ava(TM) mobile robotics platform in a hallway navigation scenario. Cues associated with the robot's proxemic behavior were found to significantly affect participant perceptions of the robot's social presence and emotional state while cues associated with the robot's gaze behavior were not found to be significant. Further, regardless of the proxemic behavior, participants attributed more social presence and emotional states to the robot over repeated interactions than when they first interacted with it. Generally, these results indicate the importance for HRI research to consider how social cues expressed by a robot can differentially affect perceptions of the robot's mental states and intentions. The discussion focuses on implications for the design of robotic systems and future directions for research on the relationship between social cues and signals.

  5. Towards understanding social cues and signals in human-robot interaction: Effects of robot gaze and proxemic behavior

    Directory of Open Access Journals (Sweden)

    Stephen M. Fiore

    2013-11-01

    Full Text Available As robots are increasingly deployed in settings requiring social interaction, research is needed to examine the social signals perceived by humans when robots display certain social cues. In this paper, we report a study designed to examine how humans interpret social cues exhibited by robots. We first provide a brief overview of perspectives from social cognition in humans and how these processes are applicable to human-robot interaction (HRI. We then discuss the need to examine the relationship between social cues and signals as a function of the degree to which a robot is perceived as a socially present agent. We describe an experiment in which social cues were manipulated on an iRobot Ava™ Mobile Robotics Platform in a hallway navigation scenario. Cues associated with the robot’s proxemic behavior were found to significantly affect participant perceptions of the robot’s social presence and emotional state while cues associated with the robot’s gaze behavior were not found to be significant. Further, regardless of the proxemic behavior, participants attributed more social presence and emotional states to the robot over repeated interactions than when they first interacted with it. Generally, these results indicate the importance for HRI research to consider how social cues expressed by a robot can differentially affect perceptions of the robot’s mental states and intentions. The discussion focuses on implications for the design of robotic systems and future directions for research on the relationship between social cues and signals.

  6. Communication: The origin of many-particle signals in nonlinear optical spectroscopy of non-interacting particles

    Science.gov (United States)

    Mukamel, Shaul

    2016-07-01

    Nonlinear spectroscopy signals detected by fluorescence from dilute samples of N non-interacting molecules are usually adequately described by simply multiplying the single molecule response by N. We show that signals that scale with higher powers of N are generated by the joint detection of several particles. This can be accomplished by phase sensitive detection such as phase cycling, photo-acoustic modulation, or by Hanbury-Brown Twiss photon coincidence. Such measurements can dissect the ensemble according to the number of excited particles.

  7. Rapid and robust signaling in the CsrA cascade via RNA–protein interactions and feedback regulation

    OpenAIRE

    Adamson, David Nellinger; Lim, Han N.

    2013-01-01

    Bacterial survival requires the rapid propagation of signals through gene networks during stress, but how this is achieved is not well understood. This study systematically characterizes the signaling dynamics of a cascade of RNA–protein interactions in the CsrA system, which regulates stress responses and biofilm formation in Escherichia coli. Noncoding RNAs are at the center of the CsrA system; target mRNAs are bound by CsrA proteins that inhibit their translation, CsrA proteins are sequest...

  8. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor

    DEFF Research Database (Denmark)

    Cherezov, Vadim; Rosenbaum, Daniel M; Hanson, Michael A;

    2007-01-01

    Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors constitute the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human beta2-adrenergic receptor-T4 lysozyme fusion protein bound...... to the partial inverse agonist carazolol at 2.4 angstrom resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair...

  9. Cannabinoid receptor-interacting protein 1a modulates CB1 receptor signaling and regulation.

    Science.gov (United States)

    Smith, Tricia H; Blume, Lawrence C; Straiker, Alex; Cox, Jordan O; David, Bethany G; McVoy, Julie R Secor; Sayers, Katherine W; Poklis, Justin L; Abdullah, Rehab A; Egertová, Michaela; Chen, Ching-Kang; Mackie, Ken; Elphick, Maurice R; Howlett, Allyn C; Selley, Dana E

    2015-04-01

    Cannabinoid CB1 receptors (CB1Rs) mediate the presynaptic effects of endocannabinoids in the central nervous system (CNS) and most behavioral effects of exogenous cannabinoids. Cannabinoid receptor-interacting protein 1a (CRIP1a) binds to the CB1R C-terminus and can attenuate constitutive CB1R-mediated inhibition of Ca(2+) channel activity. We now demonstrate cellular colocalization of CRIP1a at neuronal elements in the CNS and show that CRIP1a inhibits both constitutive and agonist-stimulated CB1R-mediated guanine nucleotide-binding regulatory protein (G-protein) activity. Stable overexpression of CRIP1a in human embryonic kidney (HEK)-293 cells stably expressing CB1Rs (CB1-HEK), or in N18TG2 cells endogenously expressing CB1Rs, decreased CB1R-mediated G-protein activation (measured by agonist-stimulated [(35)S]GTPγS (guanylyl-5'-[O-thio]-triphosphate) binding) in both cell lines and attenuated inverse agonism by rimonabant in CB1-HEK cells. Conversely, small-interfering RNA-mediated knockdown of CRIP1a in N18TG2 cells enhanced CB1R-mediated G-protein activation. These effects were not attributable to differences in CB1R expression or endocannabinoid tone because CB1R levels did not differ between cell lines varying in CRIP1a expression, and endocannabinoid levels were undetectable (CB1-HEK) or unchanged (N18TG2) by CRIP1a overexpression. In CB1-HEK cells, 4-hour pretreatment with cannabinoid agonists downregulated CB1Rs and desensitized agonist-stimulated [(35)S]GTPγS binding. CRIP1a overexpression attenuated CB1R downregulation without altering CB1R desensitization. Finally, in cultured autaptic hippocampal neurons, CRIP1a overexpression attenuated both depolarization-induced suppression of excitation and inhibition of excitatory synaptic activity induced by exogenous application of cannabinoid but not by adenosine A1 agonists. These results confirm that CRIP1a inhibits constitutive CB1R activity and demonstrate that CRIP1a can also inhibit agonist

  10. Crystallographic analysis of NHERF1–PLCβ3 interaction provides structural basis for CXCR2 signaling in pancreatic cancer

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Yuanyuan; Wang, Shuo; Holcomb, Joshua; Trescott, Laura; Guan, Xiaoqing; Hou, Yuning [Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI (United States); Brunzelle, Joseph [Advanced Photon Source, Argonne National Lab, Argonne, IL (United States); Sirinupong, Nualpun [Nutraceuticals and Functional Food Research and Development Center, Prince of Songkla University, Hat-Yai, Songkhla (Thailand); Li, Chunying, E-mail: cl@med.wayne.edu [Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI (United States); Yang, Zhe, E-mail: zyang@med.wayne.edu [Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI (United States)

    2014-04-04

    Highlights: • CXCR2–NHERF1–PLCβ3 complex regulates CXCR2 signaling in pancreatic cancer. • The crystal structure of the NHERF1 PDZ1 domain in complex with PLCβ3. • The structure reveals specificity determinants of PDZ1–PLCβ3 interaction. • Endogenous PLCβ3 in pancreatic cancer cells interacts with both PDZ1 and PDZ2. • Structural basis of the PDZ1–PLCβ3 interaction is valuable in selective drug design. - Abstract: The formation of CXCR2–NHERF1–PLCβ3 macromolecular complex in pancreatic cancer cells regulates CXCR2 signaling activity and plays an important role in tumor proliferation and invasion. We previously have shown that disruption of the NHERF1-mediated CXCR2–PLCβ3 interaction abolishes the CXCR2 signaling cascade and inhibits pancreatic tumor growth in vitro and in vivo. Here we report the crystal structure of the NHERF1 PDZ1 domain in complex with the C-terminal PLCβ3 sequence. The structure reveals that the PDZ1–PLCβ3 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four PLCβ3 residues contributing to specific interactions. We also show that PLCβ3 can bind both NHERF1 PDZ1 and PDZ2 in pancreatic cancer cells, consistent with the observation that the peptide binding pockets of these PDZ domains are highly structurally conserved. This study provides an understanding of the structural basis for the PDZ-mediated NHERF1–PLCβ3 interaction that could prove valuable in selective drug design against CXCR2-related cancers.

  11. Crystallographic analysis of NHERF1–PLCβ3 interaction provides structural basis for CXCR2 signaling in pancreatic cancer

    International Nuclear Information System (INIS)

    Highlights: • CXCR2–NHERF1–PLCβ3 complex regulates CXCR2 signaling in pancreatic cancer. • The crystal structure of the NHERF1 PDZ1 domain in complex with PLCβ3. • The structure reveals specificity determinants of PDZ1–PLCβ3 interaction. • Endogenous PLCβ3 in pancreatic cancer cells interacts with both PDZ1 and PDZ2. • Structural basis of the PDZ1–PLCβ3 interaction is valuable in selective drug design. - Abstract: The formation of CXCR2–NHERF1–PLCβ3 macromolecular complex in pancreatic cancer cells regulates CXCR2 signaling activity and plays an important role in tumor proliferation and invasion. We previously have shown that disruption of the NHERF1-mediated CXCR2–PLCβ3 interaction abolishes the CXCR2 signaling cascade and inhibits pancreatic tumor growth in vitro and in vivo. Here we report the crystal structure of the NHERF1 PDZ1 domain in complex with the C-terminal PLCβ3 sequence. The structure reveals that the PDZ1–PLCβ3 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four PLCβ3 residues contributing to specific interactions. We also show that PLCβ3 can bind both NHERF1 PDZ1 and PDZ2 in pancreatic cancer cells, consistent with the observation that the peptide binding pockets of these PDZ domains are highly structurally conserved. This study provides an understanding of the structural basis for the PDZ-mediated NHERF1–PLCβ3 interaction that could prove valuable in selective drug design against CXCR2-related cancers

  12. In vitro modeling of endothelial interaction with macrophages and pericytes demonstrates Notch signaling function in the vascular microenvironment.

    Science.gov (United States)

    Tattersall, Ian W; Du, Jing; Cong, Zhuangzhuang; Cho, Bennet S; Klein, Alyssa M; Dieck, Chelsea L; Chaudhri, Reyhaan A; Cuervo, Henar; Herts, James H; Kitajewski, Jan

    2016-04-01

    Angiogenesis is regulated by complex interactions between endothelial cells and support cells of the vascular microenvironment, such as tissue myeloid cells and vascular mural cells. Multicellular interactions during angiogenesis are difficult to study in animals and challenging in a reductive setting. We incorporated stromal cells into an established bead-based capillary sprouting assay to develop assays that faithfully reproduce major steps of vessel sprouting and maturation. We observed that macrophages enhance angiogenesis, increasing the number and length of endothelial sprouts, a property we have dubbed "angiotrophism." We found that polarizing macrophages toward a pro-inflammatory profile further increased their angiotrophic stimulation of vessel sprouting, and this increase was dependent on macrophage Notch signaling. To study endothelial/pericyte interactions, we added vascular pericytes directly to the bead-bound endothelial monolayer. These pericytes formed close associations with the endothelial sprouts, causing increased sprout number and vessel caliber. We found that Jagged1 expression and Notch signaling are essential for the growth of both endothelial cells and pericytes and may function in their interaction. We observed that combining endothelial cells with both macrophages and pericytes in the same sprouting assay has multiplicative effects on sprouting. These results significantly improve bead-capillary sprouting assays and provide an enhanced method for modeling interactions between the endothelium and the vascular microenvironment. Achieving this in a reductive in vitro setting represents a significant step toward a better understanding of the cellular elements that contribute to the formation of mature vasculature.

  13. Beta-Adrenergic gene therapy for cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Koch Walter J

    2000-10-01

    Full Text Available Abstract Gene therapy using in vivo recombinant adenovirus-mediated gene transfer is an effective technique that offers great potential to improve existing drug treatments for the complex cardiovascular diseases of heart failure and vascular smooth muscle intimal hyperplasia. Cardiac-specific adenovirus-mediated transfer of the carboxyl-terminus of the β-adrenergic receptor kinase (βARKct, acting as a Gβγ-β-adrenergic receptor kinase (βARK1 inhibitor, improves basal and agonist-induced cardiac performance in both normal and failing rabbit hearts. In addition, βARKct adenovirus infection of vascular smooth muscle is capable of significantly diminishing neointimal proliferation after angioplasty. Therefore, further investigation is warranted to determine whether inhibition of βARK1 activity and sequestration of Gβγ via an adenovirus that encodes the βARKct transgene might be a useful clinical tool for the treatment of cardiovascular pathologies.

  14. Two distinct sites in sonic Hedgehog combine for heparan sulfate interactions and cell signaling functions

    DEFF Research Database (Denmark)

    Chang, Shu-Chun; Mulloy, Barbara; Magee, Anthony I;

    2011-01-01

    Hedgehog (Hh) proteins are morphogens that mediate many developmental processes. Hh signaling is significant for many aspects of embryonic development, whereas dysregulation of this pathway is associated with several types of cancer. Hh proteins require heparan sulfate proteoglycans (HSPGs) for...... their normal distribution and signaling activity. Here, we have used molecular modeling to examine the heparin-binding domain of sonic hedgehog (Shh). In biochemical and cell biological assays, the importance of specific residues of the putative heparin-binding domain for signaling was assessed. It was...

  15. Interactive algorithms for rapid enumeration of hybridization signals in individual whole-cell nuclei inside intact-tissue specimens

    Science.gov (United States)

    Lockett, Stephen J.; Thompson, Curtis T.; Mullikin, James C.; Sudar, Damir; Khavari, R.; Hyun, William; Pinkel, Daniel; Gray, Joe W.

    1995-03-01

    Fluorescence in situ hybridization (FISH) is useful for analyzing specific nucleic acid sequences in individual cells. Its application to tissue sections has been limited however because of the difficulties of performing the hybridization and analysis in sections that are thick enough to contain intact nuclei. Recent improvements in FISH permit hybridization with chromosome-specific, centromeric probes throughout 20 micrometers formalin fixed, paraffin- embedded sections, which do contain many intact nuclei. This paper describes software to facilitate analysis of these 3D hybridizations. We have developed two algorithms for analyzing 3D, confocal images of thick sections. One displays 2D, maximum-intensity, projection images through the original 3D image at different angles. When projections are viewed sequentially, the 3D image appears semi-transparent and rotates. The second algorithm allows interactive enumeration of FISH signals. Each signal is marked by the analyst. Then, for each pair of marked signals, a 2D slice image along the line connecting both marked signals and parallel to the z (depth) axis is displayed. From this slice, the analyst decides if the signals are in the same or different nuclei, or if the signals should be rejected because they are in a nucleus truncated by the upper or lower surface of the section. After consideration of all pairs of signals, the algorithm produces a map of the tissue section showing the numbers of signals in each of the intact nucleus. The algorithms enable analysis of small, premalignant and early malignant lesions and infiltrative lesions that cannot be analyzed by other molecular techniques and permit the direct correlation of FISH information with histology/cytology.

  16. ADRENERGIC RESPONSES TO STRESS: TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL CHANGES

    OpenAIRE

    Wong, Dona L.; Tai, T. C.; Wong-Faull, David C.; Claycomb, Robert; Kvetnansky, Richard

    2008-01-01

    Stress effects on adrenergic responses in rats were examined in adrenal medulla, the primary source of circulating epinephrine (Epi). Irrespective of duration, immobilization (IMMO) increased adrenal corticosterone to the same extent. In contrast, epinephrine changed little, suggesting that Epi synthesis replenishes adrenal pools and sustains circulating levels for the heightened alertness and physiological changes required of the "flight or fight" response. IMMO also induced the epinephrine-...

  17. Developing Novel Interface and Signal Amplification Strategies for Study of Biological Interactions by Surface Plasmon Resonance(SPR) and SPRimaing

    OpenAIRE

    Liu, Ying

    2012-01-01

    Surface plasmon resonance (SPR) has been widely used as a powerful analytical technique for the study of a broad range of biomolecular interactions. With the capability of real-time detection, SPR allows convenient and nondestructive measurement of analyte concentration and binding kinetics. To improve the performance of SPR biosensing, we have developed a series of novel methods that lead to ultrasensitive detection via signal amplification by coupling inline atom transfer radical polymeriza...

  18. A High Performance Approach to Minimizing Interactions between Inbound and Outbound Signals in Helmet Project

    Data.gov (United States)

    National Aeronautics and Space Administration — We propose a high performance approach to enhancing communications between astronauts. In the new generation of NASA audio systems for astronauts, inbound signals...

  19. Structural insights of homotypic interaction domains in the ligand-receptor signal transduction of tumor necrosis factor (TNF)

    Science.gov (United States)

    Park, Young-Hoon; Jeong, Mi Suk; Jang, Se Bok

    2016-01-01

    Several members of tumor necrosis factor receptor (TNFR) superfamily that these members activate caspase-8 from death-inducing signaling complex (DISC) in TNF ligand-receptor signal transduction have been identified. In the extrinsic pathway, apoptotic signal transduction is induced in death domain (DD) superfamily; it consists of a hexahelical bundle that contains 80 amino acids. The DD superfamily includes about 100 members that belong to four subfamilies: death domain (DD), caspase recruitment domain (CARD), pyrin domain (PYD), and death effector domain (DED). This superfamily contains key building blocks: with these blocks, multimeric complexes are formed through homotypic interactions. Furthermore, each DD-binding event occurs exclusively. The DD superfamily regulates the balance between death and survival of cells. In this study, the structures, functions, and unique features of DD superfamily members are compared with their complexes. By elucidating structural insights of DD superfamily members, we investigate the interaction mechanisms of DD domains; these domains are involved in TNF ligand-receptor signaling. These DD superfamily members play a pivotal role in the development of more specific treatments of cancer. [BMB Reports 2016; 49(3): 159-166] PMID:26615973

  20. Families on the spot: sexual signals influence parent–offspring interactions

    OpenAIRE

    Morales, Judith; Alonso-Álvarez, Carlos; Pérez, Cristóbal; Torres, Roxana; Serafino, Ester; Velando, Alberto

    2009-01-01

    In 1950, Tinbergen described the elicitation of offspring begging by the red spot on the bill of parent gulls, and this became a model system for behavioural studies. Current knowledge on colour traits suggests they can act as sexual signals revealing individual quality. However, sexual signals have never been studied simultaneously in relationship to parent–offspring and sexual conflicts. We manipulated the red-spot size in one member of yellow-legged gull pairs and observed their partners' ...

  1. An approach to emotion recognition in single-channel EEG signals: a mother child interaction

    Science.gov (United States)

    Gómez, A.; Quintero, L.; López, N.; Castro, J.

    2016-04-01

    In this work, we perform a first approach to emotion recognition from EEG single channel signals extracted in four (4) mother-child dyads experiment in developmental psychology. Single channel EEG signals are analyzed and processed using several window sizes by performing a statistical analysis over features in the time and frequency domains. Finally, a neural network obtained an average accuracy rate of 99% of classification in two emotional states such as happiness and sadness.

  2. Effects of Leptin and Melanocortin Signaling Interactions on Pubertal Development and Reproduction

    OpenAIRE

    Israel, Davelene D.; Sheffer-Babila, Sharone; de Luca, Carl; Jo, Young-Hwan; Liu, Shun Mei; Xia, Qiu; Spergel, Daniel J.; Dun, Siok L.; Dun, Nae J.; Chua, Streamson C.

    2012-01-01

    Leptin and melanocortin signaling control ingestive behavior, energy balance, and substrate utilization, but only leptin signaling defects cause hypothalamic hypogonadism and infertility. Although GnRH neurons do not express leptin receptors, leptin influences GnRH neuron activity via regulation of immediate downstream mediators including the neuropeptides neuropeptide Y and the melanocortin agonist and antagonist, α-MSH, agouti-related peptide, respectively. Here we show that modulation of m...

  3. Reconstruction of Protein-Protein Interaction Network of Insulin Signaling in Homo Sapiens

    OpenAIRE

    Saliha Durmuş Tekir; Pelin Ümit; Aysun Eren Toku; Kutlu Ö. Ülgen

    2010-01-01

    Diabetes is one of the most prevalent diseases in the world. Type 1 diabetes is characterized by the failure of synthesizing and secreting of insulin because of destroyed pancreatic β-cells. Type 2 diabetes, on the other hand, is described by the decreased synthesis and secretion of insulin because of the defect in pancreatic β-cells as well as by the failure of responding to insulin because of malfunctioning of insulin signaling. In order to understand the signaling mechanisms of responding ...

  4. Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption.

    Science.gov (United States)

    Agné, Alisa M; Baldin, Jan-Peter; Benjamin, Audra R; Orogo-Wenn, Maria C; Wichmann, Lukas; Olson, Kenneth R; Walters, Dafydd V; Althaus, Mike

    2015-04-01

    In pulmonary epithelia, β-adrenergic agonists regulate the membrane abundance of the epithelial sodium channel (ENaC) and, thereby, control the rate of transepithelial electrolyte absorption. This is a crucial regulatory mechanism for lung liquid clearance at birth and thereafter. This study investigated the influence of the gaseous signaling molecule hydrogen sulfide (H2S) on β-adrenergic agonist-regulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 μM) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the β-adrenergic agonist terbutaline. There was no additional effect of Na2S over that of the ENaC inhibitor amiloride. In electrophysiological Ussing chamber experiments with native lung epithelia (Xenopus laevis), Na2S inhibited the stimulation of amiloride-sensitive current by terbutaline. β-adrenergic agonists generally increase ENaC abundance by cAMP formation and activation of PKA. Activation of this pathway by forskolin and 3-isobutyl-1-methylxanthine increased amiloride-sensitive currents in H441 pulmonary epithelial cells. This effect was inhibited by Na2S in a dose-dependent manner (5-50 μM). Na2S had no effect on cellular ATP concentration, cAMP formation, and activation of PKA. By contrast, Na2S prevented the cAMP-induced increase in ENaC activity in the apical membrane of H441 cells. H441 cells expressed the H2S-generating enzymes cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, and they produced H2S amounts within the employed concentration range. These data demonstrate that H2S prevents the stimulation of ENaC by cAMP/PKA and, thereby, inhibits the proabsorptive effect of β-adrenergic agonists on lung liquid clearance. PMID:25632025

  5. Systematic analysis of video data from different human-robot interaction studies: a categorization of social signals during error situations.

    Science.gov (United States)

    Giuliani, Manuel; Mirnig, Nicole; Stollnberger, Gerald; Stadler, Susanne; Buchner, Roland; Tscheligi, Manfred

    2015-01-01

    Human-robot interactions are often affected by error situations that are caused by either the robot or the human. Therefore, robots would profit from the ability to recognize when error situations occur. We investigated the verbal and non-verbal social signals that humans show when error situations occur in human-robot interaction experiments. For that, we analyzed 201 videos of five human-robot interaction user studies with varying tasks from four independent projects. The analysis shows that there are two types of error situations: social norm violations and technical failures. Social norm violations are situations in which the robot does not adhere to the underlying social script of the interaction. Technical failures are caused by technical shortcomings of the robot. The results of the video analysis show that the study participants use many head movements and very few gestures, but they often smile, when in an error situation with the robot. Another result is that the participants sometimes stop moving at the beginning of error situations. We also found that the participants talked more in the case of social norm violations and less during technical failures. Finally, the participants use fewer non-verbal social signals (for example smiling, nodding, and head shaking), when they are interacting with the robot alone and no experimenter or other human is present. The results suggest that participants do not see the robot as a social interaction partner with comparable communication skills. Our findings have implications for builders and evaluators of human-robot interaction systems. The builders need to consider including modules for recognition and classification of head movements to the robot input channels. The evaluators need to make sure that the presence of an experimenter does not skew the results of their user studies.

  6. Physical and genetic interaction between ammonium transporters and the signaling protein Rho1 in the plant pathogen Ustilago maydis.

    Science.gov (United States)

    Paul, Jinny A; Barati, Michelle T; Cooper, Michael; Perlin, Michael H

    2014-10-01

    Dimorphic transitions between yeast-like and filamentous forms occur in many fungi and are often associated with pathogenesis. One of the cues for such a dimorphic switch is the availability of nutrients. Under conditions of nitrogen limitation, fungal cells (such as those of Saccharomyces cerevisiae and Ustilago maydis) switch from budding to pseudohyphal or filamentous growth. Ammonium transporters (AMTs) are responsible for uptake and, in some cases, for sensing the availability of ammonium, a preferred nitrogen source. Homodimer and/or heterodimer formation may be required for regulating the activity of the AMTs. To investigate the potential interactions of Ump1 and Ump2, the AMTs of the maize pathogen U. maydis, we first used the split-ubiquitin system, followed by a modified split-YFP (yellow fluorescent protein) system, to validate the interactions in vivo. This analysis showed the formation of homo- and hetero-oligomers by Ump1 and Ump2. We also demonstrated the interaction of the high-affinity ammonium transporter, Ump2, with the Rho1 GTPase, a central protein in signaling, with roles in controlling polarized growth. This is the first demonstration in eukaryotes of the physical interaction in vivo of an ammonium transporter with the signaling protein Rho1. Moreover, the Ump proteins interact with Rho1 during the growth of cells in low ammonium concentrations, a condition required for the expression of the Umps. Based on these results and the genetic evidence for the interaction of Ump2 with both Rho1 and Rac1, another small GTPase, we propose a model for the role of these interactions in controlling filamentation, a fundamental aspect of development and pathogenesis in U. maydis.

  7. Combinatorial signals by inflammatory cytokines and chemokines mediate leukocyte interactions with extracellular matrix.

    Science.gov (United States)

    Vaday, G G; Franitza, S; Schor, H; Hecht, I; Brill, A; Cahalon, L; Hershkoviz, R; Lider, O

    2001-06-01

    On their extravasation from the vascular system into inflamed tissues, leukocytes must maneuver through a complex insoluble network of molecules termed the extracellular matrix (ECM). Leukocytes navigate toward their target sites by adhering to ECM glycoproteins and secreting degradative enzymes, while constantly orienting themselves in response to specific signals in their surroundings. Cytokines and chemokines are key biological mediators that provide such signals for cell navigation. Although the individual effects of various cytokines have been well characterized, it is becoming increasingly evident that the mixture of cytokines encountered in the ECM provides important combinatorial signals that influence cell behavior. Herein, we present an overview of previous and ongoing studies that have examined how leukocytes integrate signals from different combinations of cytokines that they encounter either simultaneously or sequentially within the ECM, to dynamically alter their navigational activities. For example, we describe our findings that tumor necrosis factor (TNF)-alpha acts as an adhesion-strengthening and stop signal for T cells migrating toward stromal cell-derived factor-1alpha, while transforming growth factor-beta down-regulates TNF-alpha-induced matrix metalloproteinase-9 secretion by monocytes. These findings indicate the importance of how one cytokine, such as TNF-alpha, can transmit diverse signals to different subsets of leukocytes, depending on its combination with other cytokines, its concentration, and its time and sequence of exposure. The combinatorial effects of multiple cytokines thus affect leukocytes in a step-by-step manner, whereby cells react to cytokine signals in their immediate vicinity by altering their adhesiveness, directional movement, and remodeling of the ECM. PMID:11404372

  8. Plasma membrane lipid-protein interactions affect signaling processes in sterol-biosynthesis mutants of Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Henrik eZauber

    2014-03-01

    Full Text Available The plasma membrane is an important organelle providing structure, signaling and transport as major biological functions. Being composed of lipids and proteins with different physicochemical properties, the biological functions of membranes depend on specific protein-protein and protein-lipid interactions. Interactions of proteins with their specific sterol and lipid environment were shown to be important factors for protein recruitment into sub-compartmental structures of the plasma membrane. System-wide implications of altered endogenous sterol levels for membrane functions in living cells were not studied in higher plant cells. In particular, little is known how alterations in membrane sterol composition affect protein and lipid organization and interaction within membranes. Here, we conducted a comparative analysis of the plasma membrane protein and lipid composition in Arabidopsis sterol-biosynthesis mutants smt1 and ugt80A2;B1. smt1 shows general alterations in sterol composition while ugt80A2;B1 is significantly impaired in sterol glycosylation. By systematically analyzing different cellular fractions and combining proteomic with lipidomic data we were able to reveal contrasting alterations in lipid-protein interactions in both mutants, with resulting differential changes in plasma membrane signaling status.

  9. Functional Interaction between HEXIM and Hedgehog Signaling during Drosophila Wing Development.

    Science.gov (United States)

    Nguyen, Duy; Fayol, Olivier; Buisine, Nicolas; Lecorre, Pierrette; Uguen, Patricia

    2016-01-01

    Studying the dynamic of gene regulatory networks is essential in order to understand the specific signals and factors that govern cell proliferation and differentiation during development. This also has direct implication in human health and cancer biology. The general transcriptional elongation regulator P-TEFb regulates the transcriptional status of many developmental genes. Its biological activity is controlled by an inhibitory complex composed of HEXIM and the 7SK snRNA. Here, we examine the function of HEXIM during Drosophila development. Our key finding is that HEXIM affects the Hedgehog signaling pathway. HEXIM knockdown flies display strong phenotypes and organ failures. In the wing imaginal disc, HEXIM knockdown initially induces ectopic expression of Hedgehog (Hh) and its transcriptional effector Cubitus interuptus (Ci). In turn, deregulated Hedgehog signaling provokes apoptosis, which is continuously compensated by apoptosis-induced cell proliferation. Thus, the HEXIM knockdown mutant phenotype does not result from the apoptotic ablation of imaginal disc; but rather from the failure of dividing cells to commit to a proper developmental program due to Hedgehog signaling defects. Furthermore, we show that ci is a genetic suppressor of hexim. Thus, HEXIM ensures the integrity of Hedgehog signaling in wing imaginal disc, by a yet unknown mechanism. To our knowledge, this is the first time that the physiological function of HEXIM has been addressed in such details in vivo. PMID:27176767

  10. Functional Interaction between HEXIM and Hedgehog Signaling during Drosophila Wing Development

    Science.gov (United States)

    Nguyen, Duy; Fayol, Olivier; Buisine, Nicolas; Lecorre, Pierrette; Uguen, Patricia

    2016-01-01

    Studying the dynamic of gene regulatory networks is essential in order to understand the specific signals and factors that govern cell proliferation and differentiation during development. This also has direct implication in human health and cancer biology. The general transcriptional elongation regulator P-TEFb regulates the transcriptional status of many developmental genes. Its biological activity is controlled by an inhibitory complex composed of HEXIM and the 7SK snRNA. Here, we examine the function of HEXIM during Drosophila development. Our key finding is that HEXIM affects the Hedgehog signaling pathway. HEXIM knockdown flies display strong phenotypes and organ failures. In the wing imaginal disc, HEXIM knockdown initially induces ectopic expression of Hedgehog (Hh) and its transcriptional effector Cubitus interuptus (Ci). In turn, deregulated Hedgehog signaling provokes apoptosis, which is continuously compensated by apoptosis-induced cell proliferation. Thus, the HEXIM knockdown mutant phenotype does not result from the apoptotic ablation of imaginal disc; but rather from the failure of dividing cells to commit to a proper developmental program due to Hedgehog signaling defects. Furthermore, we show that ci is a genetic suppressor of hexim. Thus, HEXIM ensures the integrity of Hedgehog signaling in wing imaginal disc, by a yet unknown mechanism. To our knowledge, this is the first time that the physiological function of HEXIM has been addressed in such details in vivo. PMID:27176767

  11. Functional Interaction between HEXIM and Hedgehog Signaling during Drosophila Wing Development.

    Directory of Open Access Journals (Sweden)

    Duy Nguyen

    Full Text Available Studying the dynamic of gene regulatory networks is essential in order to understand the specific signals and factors that govern cell proliferation and differentiation during development. This also has direct implication in human health and cancer biology. The general transcriptional elongation regulator P-TEFb regulates the transcriptional status of many developmental genes. Its biological activity is controlled by an inhibitory complex composed of HEXIM and the 7SK snRNA. Here, we examine the function of HEXIM during Drosophila development. Our key finding is that HEXIM affects the Hedgehog signaling pathway. HEXIM knockdown flies display strong phenotypes and organ failures. In the wing imaginal disc, HEXIM knockdown initially induces ectopic expression of Hedgehog (Hh and its transcriptional effector Cubitus interuptus (Ci. In turn, deregulated Hedgehog signaling provokes apoptosis, which is continuously compensated by apoptosis-induced cell proliferation. Thus, the HEXIM knockdown mutant phenotype does not result from the apoptotic ablation of imaginal disc; but rather from the failure of dividing cells to commit to a proper developmental program due to Hedgehog signaling defects. Furthermore, we show that ci is a genetic suppressor of hexim. Thus, HEXIM ensures the integrity of Hedgehog signaling in wing imaginal disc, by a yet unknown mechanism. To our knowledge, this is the first time that the physiological function of HEXIM has been addressed in such details in vivo.

  12. BRCA1 interacts with Smad3 and regulates Smad3-mediated TGF-beta signaling during oxidative stress responses.

    Directory of Open Access Journals (Sweden)

    Huchun Li

    Full Text Available BACKGROUND: BRCA1 is a key regulatory protein participating in cell cycle checkpoint and DNA damage repair networks. BRCA1 plays important roles in protecting numerous cellular processes in response to cell damaging signals. Transforming growth factor-beta (TGF-beta is a potent regulator of growth, apoptosis and invasiveness of tumor cells. TFG-beta activates Smad signaling via its two cell surface receptors, the TbetaRII and ALK5/TbetaRI, leading to Smad-mediated transcriptional regulation. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report an important role of BRCA1 in modulating TGF-beta signaling during oxidative stress responses. Wild-type (WT BRCA1, but not mutated BRCA1 failed to activate TGF-beta mediated transactivation of the TGF-beta responsive reporter, p3TP-Lux. Further, WT-BRCA1, but not mutated BRCA1 increased the expression of Smad3 protein in a dose-dependent manner, while silencing of WT-BRCA1 by siRNA decreased Smad3 and Smad4 interaction induced by TGF-beta in MCF-7 breast cancer cells. BRCA1 interacted with Smad3 upon TGF-beta1 stimulation in MCF-7 cells and this interaction was mediated via the domain of 298-436aa of BRCA1 and Smad3 domain of 207-426aa. In addition, H(2O(2 increased the colocalization and the interaction of Smad3 with WT-BRCA1. Interestingly, TGF-beta1 induced Smad3 and Smad4 interaction was increased in the presence of H(2O(2 in cells expressing WT-BRCA1, while the TGF-beta1 induced interaction between Smad3 and Smad4 was decreased upon H(2O(2 treatment in a dose-dependent manner in HCC1937 breast cancer cells, deficient for endogenous BRCA1. This interaction between Smad3 and Smad4 was increased in reconstituted HCC1937 cells expressing WT-BRCA1 (HCC1937/BRCA1. Further, loss of BRCA1 resulted in H(2O(2 induced nuclear export of phosphor-Smad3 protein to the cytoplasm, resulting decreased of Smad3 and Smad4 interaction induced by TGF-beta and in significant decrease in Smad3 and Smad4 transcriptional

  13. The role of docking interactions in mediating signaling input, output, and discrimination in the yeast MAPK network.

    Science.gov (United States)

    Reményi, Attila; Good, Matthew C; Bhattacharyya, Roby P; Lim, Wendell A

    2005-12-22

    Cells use a network of mitogen-activated protein kinases (MAPKs) to coordinate responses to diverse extracellular signals. Here, we examine the role of docking interactions in determining connectivity of the yeast MAPKs Fus3 and Kss1. These closely related kinases are activated by the common upstream MAPK kinase Ste7 yet generate distinct output responses, mating and filamentous growth, respectively. We find that docking interactions are necessary for communication with the kinases and that they can encode subtle differences in pathway-specific input and output. The cell cycle arrest mediator Far1, a mating-specific substrate, has a docking motif that selectively binds Fus3. In contrast, the shared partner Ste7 has a promiscuous motif that binds both Fus3 and Kss1. Structural analysis reveals that Fus3 interacts with specific and promiscuous peptides in conformationally distinct modes. Induced fit recognition may allow docking peptides to achieve discrimination by exploiting subtle differences in kinase flexibility. PMID:16364919

  14. An additive interaction between the NFκB and estrogen receptor signalling pathways in human endometrial epithelial cells

    Science.gov (United States)

    King, A.E.; Collins, F.; Klonisch, T.; Sallenave, J.-M.; Critchley, H.O.D.; Saunders, P.T.K.

    2010-01-01

    BACKGROUND Human embryo implantation is regulated by estradiol (E2), progesterone and locally produced mediators including interleukin-1β (IL-1β). Interactions between the estrogen receptor (ER) and NF kappa B (NFκB) signalling pathways have been reported in other systems but have not been detailed in human endometrium. METHODS AND RESULTS Real-time PCR showed that mRNA for the p65 and p105 NFκB subunits is maximally expressed in endometrium from the putative implantation window. Both subunits are localized in the endometrial epithelium throughout the menstrual cycle. Reporter assays for estrogen response element (ERE) activity were used to examine functional interactions between ER and NFκB in telomerase immortalized endometrial epithelial cells (TERT-EEC). E2 and IL-1β treatment of TERT-EECs enhances ERE activity by a NFκB and ER dependent mechanism; this effect could be mediated by ERα or ERβ. E2 and IL-1β also positively interact to increase endogenous gene expression of prostaglandin E synthase and c-myc. This is a gene-dependent action as there is no additive effect on cyclin D1 or progesterone receptor expression. CONCLUSION In summary, we have established that NFκB signalling proteins are expressed in normal endometrium and report that IL-1β can enhance the actions of E2 in a cell line derived from healthy endometrium. This mechanism may allow IL-1β, possibly from the developing embryo, to modulate the function of the endometrial epithelium to promote successful implantation, for example by regulating prostaglandin production. Aberrations in the interaction between the ER and NFκB signalling pathways may have a negative impact on implantation contributing to pathologies such as early pregnancy loss and infertility. PMID:19955102

  15. Chemical signals and their interactions change transpiration processes in tomato wild-type and flacca mutant

    DEFF Research Database (Denmark)

    Prokic, Ljiljana; Wollenweber, Bernd; Stikic, Radmila

    2011-01-01

    the effects of chemicalsignals on the mechanism of transpiration of isolated leaves of L. esculentum Mill. cv. Ailsa Craig (WT) and mutant flacca. In bioassays, exogenic activity of different ABA concentrations and pH were tested in both genotype of tomato in order to stimulate chemical signals occurring...

  16. Evidence for Interaction between the Stop Signal and the Stroop Task Conflict

    Science.gov (United States)

    Kalanthroff, Eyal; Goldfarb, Liat; Henik, Avishai

    2013-01-01

    Performance of the Stroop task reflects two conflicts--informational (between the incongruent word and ink color) and task (between relevant color naming and irrelevant word reading). The task conflict is usually not visible, and is only seen when task control is damaged. Using the stop-signal paradigm, a few studies demonstrated longer…

  17. Calcium signaling during the plant-plant interaction of parasitic Cuscuta reflexa with its hosts

    NARCIS (Netherlands)

    Albert, M.; Kaiser, B.; Krol, van der A.R.; Kaldenhoff, R.

    2010-01-01

    The plant parasite Cuscuta reflexa induces various responses in compatible and incompatible host plants. The visual reactions of both types of host plants including obvious morphological changes require the recognition of Cuscuta ssp. A consequently initiated signaling cascade is triggered which lea

  18. A Brassinosteroid-Signaling Kinase Interacts withMultiple Receptor-Like Kinases in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    2014-01-01

    Dear Editor, Higher plants have evolved hundreds of genes encodingreceptor-like kinases (RLKs), which function as cell surfacereceptors perceiving developmental and environmental sig-nals (Shiu et al., 2004). Many RLKs have been shown to playspecific roles in hormone responses, developmental regula-tion, defense against pathogen infection, and adaptationto abiotic stresses (Chae et al., 2009; Antolin-Llovera et al.,2012). The mechanisms that ensure specific signal transduc-tion from each RLK to target cellular responses remain poorlyunderstood. Recent studies revealed that many RLKs trans-duce signals by phosphorylating receptor-like cytoplasmickinases (RLCKs), which lack the transmembrane domainsbut are anchored at the plasma membrane through lipidmodification (Tang et al., 2008; Zhang et al., 2010; Shi et al.,2013). There are over 400 RLKs and only about 150 RLCKs inArabidopsis (Shiu et al., 2004). One outstanding question iswhether each RLCK mediates signaling downstream of a spe-cific RLK, participates in multiple RLK pathways, or mediatescrosstalk between RLK pathways.

  19. Study of Torsional Interactions in Multi-terminal DC Systems through Small Signal Stability Analysis

    OpenAIRE

    Padiyar, KR; Geetha, MK

    1991-01-01

    Turbo-generators can be subjected to negatively damped subsynchronous frequency oscillations caused by the interactions between the generator and the external network. This phenomena is termed as subsynchronous resonance (SSR) and it is well known that series compensated AC lines are the major contributors. In recent years, it has been established that HVDC systems with converter controllers can also cause unfavourable torsional interactions. Report the development of the mathematical model b...

  20. Estimation of kinetic parameters related to biochemical interactions between hydrogen peroxide and signal transduction proteins

    Science.gov (United States)

    Brito, Paula; Antunes, Fernando

    2014-10-01

    The lack of kinetic data concerning the biological effects of reactive oxygen species is slowing down the development of the field of redox signaling. Herein, we deduced and applied equations to estimate kinetic parameters from typical redox signaling experiments. H2O2-sensing mediated by the oxidation of a protein target and the switch-off of this sensor, by being converted back to its reduced form, are the two processes for which kinetic parameters are determined. The experimental data required to apply the equations deduced is the fraction of the H2O2 sensor protein in the reduced or in the oxidized state measured in intact cells or living tissues after exposure to either endogenous or added H2O2. Either non-linear fittings that do not need transformation of the experimental data or linearized plots in which deviations from the equations are easily observed can be used. The equations were shown to be valid by fitting to them virtual time courses simulated with a kinetic model. The good agreement between the kinetic parameters estimated in these fittings and those used to simulate the virtual time courses supported the accuracy of the kinetic equations deduced. Finally, equations were successfully tested with real data taken from published experiments that describe redox signaling mediated by the oxidation of two protein tyrosine phosphatases, PTP1B and SHP-2, which are two of the few H2O2-sensing proteins with known kinetic parameters. Whereas for PTP1B estimated kinetic parameters fitted in general the present knowledge, for SHP-2 results obtained suggest that reactivity towards H2O2 as well as the rate of SHP-2 regeneration back to its reduced form are higher than previously thought. In conclusion, valuable quantitative kinetic data can be estimated from typical redox signaling experiments, thus improving our understanding about the complex processes that underline the interplay between oxidative stress and redox signaling responses.

  1. Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion.

    Directory of Open Access Journals (Sweden)

    Haifeng Wang

    Full Text Available Viral infection leads to induction of pattern-recognition receptor signaling, which leads to interferon regulatory factor (IRF activation and ultimately interferon (IFN production. To establish infection, many viruses have strategies to evade the innate immunity. For the hepatitis B virus (HBV, which causes chronic infection in the liver, the evasion strategy remains uncertain. We now show that HBV polymerase (Pol blocks IRF signaling, indicating that HBV Pol is the viral molecule that effectively counteracts host innate immune response. In particular, HBV Pol inhibits TANK-binding kinase 1 (TBK1/IkappaB kinase-epsilon (IKKepsilon, the effector kinases of IRF signaling. Intriguingly, HBV Pol inhibits TBK1/IKKepsilon activity by disrupting the interaction between IKKepsilon and DDX3 DEAD box RNA helicase, which was recently shown to augment TBK1/IKKepsilon activity. This unexpected role of HBV Pol may explain how HBV evades innate immune response in the early phase of the infection. A therapeutic implication of this work is that a strategy to interfere with the HBV Pol-DDX3 interaction might lead to the resolution of life-long persistent infection.

  2. SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1 and Is Required for Hedgehog Signaling.

    Directory of Open Access Journals (Sweden)

    Rannar Airik

    Full Text Available Recessive mutations in the SDCCAG8 gene cause a nephronophthisis-related ciliopathy with Bardet-Biedl syndrome-like features in humans. Our previous characterization of the orthologous Sdccag8gt/gt mouse model recapitulated the retinal-renal disease phenotypes and identified impaired DNA damage response signaling as an underlying disease mechanism in the kidney. However, several other phenotypic and mechanistic features of Sdccag8gt/gt mice remained unexplored. Here we show that Sdccag8gt/gt mice exhibit developmental and structural abnormalities of the skeleton and limbs, suggesting impaired Hedgehog (Hh signaling. Indeed, cell culture studies demonstrate the requirement of SDCCAG8 for ciliogenesis and Hh signaling. Using an affinity proteomics approach, we demonstrate that SDCCAG8 interacts with proteins of the centriolar satellites (OFD1, AZI1, of the endosomal sorting complex (RABEP2, ERC1, and with non-muscle myosin motor proteins (MYH9, MYH10, MYH14 at the centrosome. Furthermore, we show that RABEP2 localization at the centrosome is regulated by SDCCAG8. siRNA mediated RABEP2 knockdown in hTERT-RPE1 cells leads to defective ciliogenesis, indicating a critical role for RABEP2 in this process. Together, this study identifies several centrosome-associated proteins as novel SDCCAG8 interaction partners, and provides new insights into the function of SDCCAG8 at this structure.

  3. A protein–protein interaction network linking the energy-sensor kinase SnRK1 to multiple signaling pathways in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Madlen Nietzsche

    2016-04-01

    Full Text Available In plants, the sucrose non-fermenting (SNF1-related protein kinase 1 (SnRK1 represents a central integrator of low energy signaling and acclimation towards many environmental stress responses. Although SnRK1 acts as a convergent point for many different environmental and metabolic signals to control growth and development, it is currently unknown how these many different signals could be translated into a cell-type or stimulus specific response since many components of SnRK1-regulated signaling pathways remain unidentified. Recently, we have demonstrated that proteins containing a domain of unknown function (DUF 581 interact with the catalytic α subunits of SnRK1 (AKIN10/11 from Arabidopsis thaliana and could potentially act as mediators conferring tissue- and stimulus-type specific differences in SnRK1 regulation. To further extend the SnRK1 signaling network in plants, we systematically screened for novel DUF581 interaction partners using the yeast two-hybrid system. A deep and exhaustive screening identified 17 interacting partners for 10 of the DUF581 proteins tested. Many of these novel interaction partners are implicated in cellular processes previously associated with SnRK1 signaling. Furthermore, we mined publicly available interaction data to identify additional DUF581 interacting proteins. A protein–protein interaction network resulting from our studies suggests connections between SnRK1 signaling and other central signaling pathways involved in growth regulation and environmental responses. These include TOR and MAP-kinase signaling as well as hormonal pathways. The resulting protein–protein interaction network promises to be effective in generating hypotheses to study the precise mechanisms SnRK1 signaling on a functional level.

  4. Cardiac Effects of Attenuating Gsα - Dependent Signaling.

    Directory of Open Access Journals (Sweden)

    Marcus R Streit

    Full Text Available Inhibition of β-adrenergic signalling plays a key role in treatment of heart failure. Gsα is essential for β-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing β-adrenergic signalling in the heart at the level of Gsα is a promising option.We analyzed the influence of Gsα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice overexpressing a dominant negative Gsα-mutant under control of the α-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic β-adrenergic stimulation. At rest, Gsα-DN-mice showed bradycardia (602 ± 13 vs. 660 ± 17 bpm, p<0.05 and decreased dp/dtmax (5037 ± 546- vs. 6835 ± 505 mmHg/s, p = 0.02. No significant differences were found regarding ejection fraction, heart weight and cardiomyocyte size. β-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gsα-DN-mice. Acute adrenergic stimulation resulted in decreased β-adrenergic responsiveness in Gsα-DN-mice. Under chronic adrenergic stimulation, wildtype mice developed myocardial hypertrophy associated with increase of LV/BW-ratio by 23% (4.4 ± 0.2 vs. 3.5 ± 0.1 mg/g, p<0.01 and cardiac myocyte size by 24% (14927 ± 442 px vs. 12013 ± 583 px, p<0.001. In contrast, both parameters were unchanged in Gsα-DN-mice after chronic isoproterenol stimulation.Overexpression of a dominant negative mutant of Gsα leads to decreased β-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gsα-DN-mice provide novel insights into β-adrenergic signal transduction and its modulation in myocardial overload and failure.

  5. Suramin blocks interaction between human FGF1 and FGFR2 D2 domain and reduces downstream signaling activity.

    Science.gov (United States)

    Wu, Zong-Sian; Liu, Che Fu; Fu, Brian; Chou, Ruey-Hwang; Yu, Chin

    2016-09-01

    The extracellular portion of the human fibroblast growth factor receptor2 D2 domain (FGFR2 D2) interacts with human fibroblast growth factor 1 (hFGF1) to activate a downstream signaling cascade that ultimately affects mitosis and differentiation. Suramin is an antiparasiticdrug and a potent inhibitor of FGF-induced angiogenesis. Suramin has been shown to bind to hFGF1, and might block the interaction between hFGF1 and FGFR2 D2. Here, we titrated hFGF1 with FGFR2 D2 and suramin to elucidate their interactions using the detection of NMR. The docking results of both hFGF1-FGFR2 D2 domain and hFGF1-suramin complex were superimposed. The results indicate that suramin blocks the interaction between hFGF1 and FGFR2 D2. We used the PyMOL software to show the hydrophobic interaction of hFGF1-suramin. In addition, we used a Water-soluble Tetrazolium salts assay (WST1) to assess hFGF1 bioactivity. The results will be useful for the development of new antimitogenic activity drugs. PMID:27387234

  6. Molecular Mechanisms Underlying β-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells

    Directory of Open Access Journals (Sweden)

    Dianne Lorton

    2015-03-01

    Full Text Available Cross-talk between the sympathetic nervous system (SNS and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE in lymphoid organs and tissues. NE stimulation of β2-adrenergic receptors (ARs in immune cells activates the cAMP-protein kinase A (PKA intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune–SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β2-AR-induced cAMP is immunosuppressive. However, many studies report actions of β2-AR stimulation in immune cells that are inconsistent with typical cAMP–PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β2-AR activation, such as a signaling switch from cAMP–PKA to mitogen-activated protein kinase (MAPK pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β2-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for “signal switching” in immune cells.

  7. Colored nectar as an honest signal in plant-animal interactions

    OpenAIRE

    Zhang, Feng-Ping; Larson-Rabin, Zachary; Li, De-Zhu; Wang, Hong

    2012-01-01

    Many flowering plants obtain the services of pollinators by using their floral traits as signals to advertise the rewards they offer to visitors—such as nectar, pollen and other food resources. Some plants use colorful pigments to draw pollinators’ attention to their nectar, instead of relying on the appeal of nectar taste. Although this rare floral trait of colored nectar was first recorded by the Greek poet Homer in the Odyssey, it has only recently received the attention of modern science....

  8. Redox signaling in inflammation: interactions of endogenous electrophiles and mitochondria in cardiovascular disease

    OpenAIRE

    Koenitzer, Jeffrey R.; Freeman, Bruce A.

    2010-01-01

    Reactive species derived from oxygen and nitric oxide are produced during inflammation and promote oxidation and nitration of biomolecules, including unsaturated fatty acids. Among the products of these reactions are α,β-unsaturated carbonyl and nitro derivatives of fatty acids, electrophilic species whose reactivity with nucleophilic amino acids provides a means of posttranslational protein modification and signaling. These electrophilic fatty acids activate cytosolic and nuclear stress–resp...

  9. SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival

    DEFF Research Database (Denmark)

    Jamshidi, Maral; Fagerholm, Rainer; Khan, Sofia;

    2015-01-01

    , in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models......In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here...... of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare...

  10. Does a Common Pathway Transduce Symbiotic Signals in Plant-Microbe Interactions?

    Science.gov (United States)

    Genre, Andrea; Russo, Giulia

    2016-01-01

    Recent years have witnessed major advances in our knowledge of plant mutualistic symbioses such as the rhizobium-legume symbiosis (RLS) and arbuscular mycorrhizas (AM). Some of these findings caused the revision of longstanding hypotheses, but one of the most solid theories is that a conserved set of plant proteins rules the transduction of symbiotic signals from beneficial glomeromycetes and rhizobia in a so-called common symbiotic pathway (CSP). Nevertheless, the picture still misses several elements, and a few crucial points remain unclear. How does one common pathway discriminate between - at least - two symbionts? Can we exclude that microbes other than AM fungi and rhizobia also use this pathway to communicate with their host plants? We here discuss the possibility that our current view is biased by a long-lasting focus on legumes, whose ability to develop both AM and RLS is an exception among plants and a recent innovation in their evolution; investigations in non-legumes are starting to place legume symbiotic signaling in a broader perspective. Furthermore, recent studies suggest that CSP proteins act in a wider scenario of symbiotic and non-symbiotic signaling. Overall, evidence is accumulating in favor of distinct activities for CSP proteins in AM and RLS, depending on the molecular and cellular context where they act. PMID:26909085

  11. Ghost-in-the-Machine reveals human social signals for human-robot interaction.

    Science.gov (United States)

    Loth, Sebastian; Jettka, Katharina; Giuliani, Manuel; de Ruiter, Jan P

    2015-01-01

    We used a new method called "Ghost-in-the-Machine" (GiM) to investigate social interactions with a robotic bartender taking orders for drinks and serving them. Using the GiM paradigm allowed us to identify how human participants recognize the intentions of customers on the basis of the output of the robotic recognizers. Specifically, we measured which recognizer modalities (e.g., speech, the distance to the bar) were relevant at different stages of the interaction. This provided insights into human social behavior necessary for the development of socially competent robots. When initiating the drink-order interaction, the most important recognizers were those based on computer vision. When drink orders were being placed, however, the most important information source was the speech recognition. Interestingly, the participants used only a subset of the available information, focussing only on a few relevant recognizers while ignoring others. This reduced the risk of acting on erroneous sensor data and enabled them to complete service interactions more swiftly than a robot using all available sensor data. We also investigated socially appropriate response strategies. In their responses, the participants preferred to use the same modality as the customer's requests, e.g., they tended to respond verbally to verbal requests. Also, they added redundancy to their responses, for instance by using echo questions. We argue that incorporating the social strategies discovered with the GiM paradigm in multimodal grammars of human-robot interactions improves the robustness and the ease-of-use of these interactions, and therefore provides a smoother user experience.

  12. Ghost-in-the-Machine reveals human social signals for human–robot interaction

    Science.gov (United States)

    Loth, Sebastian; Jettka, Katharina; Giuliani, Manuel; de Ruiter, Jan P.

    2015-01-01

    We used a new method called “Ghost-in-the-Machine” (GiM) to investigate social interactions with a robotic bartender taking orders for drinks and serving them. Using the GiM paradigm allowed us to identify how human participants recognize the intentions of customers on the basis of the output of the robotic recognizers. Specifically, we measured which recognizer modalities (e.g., speech, the distance to the bar) were relevant at different stages of the interaction. This provided insights into human social behavior necessary for the development of socially competent robots. When initiating the drink-order interaction, the most important recognizers were those based on computer vision. When drink orders were being placed, however, the most important information source was the speech recognition. Interestingly, the participants used only a subset of the available information, focussing only on a few relevant recognizers while ignoring others. This reduced the risk of acting on erroneous sensor data and enabled them to complete service interactions more swiftly than a robot using all available sensor data. We also investigated socially appropriate response strategies. In their responses, the participants preferred to use the same modality as the customer’s requests, e.g., they tended to respond verbally to verbal requests. Also, they added redundancy to their responses, for instance by using echo questions. We argue that incorporating the social strategies discovered with the GiM paradigm in multimodal grammars of human–robot interactions improves the robustness and the ease-of-use of these interactions, and therefore provides a smoother user experience. PMID:26582998

  13. Ghost-in-the-Machine Reveals Human Social Signals for Human-Robot Interaction

    Directory of Open Access Journals (Sweden)

    Sebastian eLoth

    2015-11-01

    Full Text Available We used a new method called Ghost-in-the-Machine (GiM to investigate social interactions with a robotic bartender taking orders for drinks and serving them. Using the GiM paradigm allowed us to identify how human participants recognise the intentions of customers on the basis of the output of the robotic recognisers. Specifically, we measured which recogniser modalities (e.g., speech, the distance to the bar were relevant at different stages of the interaction. This provided insights into human social behaviour necessary for the development of socially competent robots. When initiating the drink-order interaction, the most important recognisers were those based on computer vision. When drink orders were being placed, however, the most important information source was the speech recognition. Interestingly, the participants used only a subset of the available information, focussing only on a few relevant recognisers while ignoring others. This reduced the risk of acting on erroneous sensor data and enabled them to complete service interactions more swiftly than a robot using all available sensor data. We also investigated socially appropriate response strategies. In their responses, the participants preferred to use the same modality as the customer’s requests, e.g., they tended to respond verbally to verbal requests. Also, they added redundancy to their responses, for instance by using echo questions. We argue that incorporating the social strategies discovered with the GiM paradigm in multimodal grammars of human-robot interactions improves the robustness and the ease-of-use of these interactions, and therefore provides a smoother user experience.

  14. H2S AND NO SIGNALING INTERACTIONS IN THALE CRESS (ARABIDOPSIS THALIANA L. AND PEPPER (CAPSICUM ANNUUM L. LEAVES

    Directory of Open Access Journals (Sweden)

    Miroslav Lisjak

    2012-06-01

    Full Text Available This research comprehends a set of experiments with several thale cress (Arabidopsis thaliana L. and pepper (Capsicum annuum L. genotypes in controlled conditions using growth chambers, with the aim of determining the physiological role of hydrogen sulfide (H2S in plants, as well as its potential effect as a signaling compound, particularly in potential interaction with nitric oxide (NO signaling pathways. Special emphasis was focused on stomatal mechanisms and signaling in their opening and closing. Moreover, the effect of treatment of pepper plants with H2S was investigated in salt stress conditions. It was established that the applied H2S donors, NaHS and GYY4137, inhibit stomata closing in both plant species through the reduction of NO accumulation in stomata, which was proven to occur in SNP or ABA treatment. The effects of NO and H2S were opposite those in pepper plants response to salt stress as well, with increased antioxidative activity in leaf obtained after H2S treatments, and with NaHS in particular. In addition, GYY4137 could be considered as a convenient H2S donor for research into H2S functions in plants. The results point out the interactions of H2S and NO in plant cell signaling in both normal and salt stress conditions. Further research of this type should uncover H2S functions in plant metabolism more precisely, especially considering the potential practical value of this knowledge for plant stress resistance improvement and their productivity enhancement.

  15. An additive interaction between the NFκB and estrogen receptor signalling pathways in human endometrial epithelial cells

    OpenAIRE

    King, A E; Collins, F; Klonisch, T; Sallenave, J-M; Critchley, H.O.D.; Saunders, P T K

    2009-01-01

    Human embryo implantation is regulated by estradiol (E2), progesterone and locally produced mediators including interleukin-1 beta (IL-1 beta). Interactions between the estrogen receptor (ER) and NF kappa B (NF kappa B) signalling pathways have been reported in other systems but have not been detailed in human endometrium.Real-time PCR showed that mRNA for the p65 and p105 NF kappa B subunits is maximally expressed in endometrium from the putative implantation window. Both subunits are locali...

  16. Adrenergic effects on exocrine secretion of rat submandibular epidermal growth factor

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba

    1984-01-01

    The present study was undertaken to investigate the effect of alpha- and beta-adrenergic agonists on secretion of epidermal growth factor (EGF) from the rat submandibular glands and to test the possibility of intestinal absorption of EGF. Alpha-adrenergic agonists increased the concentration of s...

  17. Adrenergic deficiency leads to impaired electrical conduction and increased arrhythmic potential in the embryonic mouse heart.

    Science.gov (United States)

    Baker, Candice; Taylor, David G; Osuala, Kingsley; Natarajan, Anupama; Molnar, Peter J; Hickman, James; Alam, Sabikha; Moscato, Brittany; Weinshenker, David; Ebert, Steven N

    2012-07-01

    To determine if adrenergic hormones play a critical role in the functional development of the cardiac pacemaking and conduction system, we employed a mouse model where adrenergic hormone production was blocked due to targeted disruption of the dopamine β-hydroxylase (Dbh) gene. Immunofluorescent histochemical evaluation of the major gap junction protein, connexin 43, revealed that its expression was substantially decreased in adrenergic-deficient (Dbh-/-) relative to adrenergic-competent (Dbh+/+ and Dbh+/-) mouse hearts at embryonic day 10.5 (E10.5), whereas pacemaker and structural protein staining appeared similar. To evaluate cardiac electrical conduction in these hearts, we cultured them on microelectrode arrays (8×8, 200 μm apart). Our results show a significant slowing of atrioventricular conduction in adrenergic-deficient hearts compared to controls (31.4±6.4 vs. 15.4±1.7 ms, respectively, pheart rate and rhythm, mouse hearts from adrenergic-competent and deficient embryos were cultured ex vivo at E10.5, and heart rates were measured before and after challenge with the β-adrenergic receptor agonist, isoproterenol (0.5 μM). On average, all hearts showed increased heart rate responses following isoproterenol challenge, but a significant (phearts. These results show that adrenergic hormones may influence heart development by stimulating connexin 43 expression, facilitating atrioventricular conduction, and helping to maintain cardiac rhythm during a critical phase of embryonic development.

  18. Molecular aspects of adrenergic modulation of cardiac L-type Ca2+ channels.

    NARCIS (Netherlands)

    Heyden, M.A. van der; Wijnhoven, T.J.M.; Opthof, T.

    2005-01-01

    L-type Ca(2+) channels are predominantly regulated by beta-adrenergic stimulation, enhancing L-type Ca(2+) current by increasing the mean channel open time and/or the opening probability of functional Ca(2+) channels. Stimulation of beta-adrenergic receptors (ARs) results in an increased cyclic aden

  19. Regulation of coronary vascular tone via redox modulation in the alpha1-adrenergic-angiotensin-endothelin axis of the myocardium.

    Science.gov (United States)

    Yamaguchi, Osamu; Kaneshiro, Takashi; Saitoh, Shu-ichi; Ishibashi, Toshiyuki; Maruyama, Yukio; Takeishi, Yasuchika

    2009-01-01

    We hypothesized that alpha(1)-adrenoceptor stimulation of cardiac myocytes results in the production of an endothelin (ET)-releasing factor that stimulates the coronary vasculature to release ET and, by manipulating the redox state of cardiac and vascular cells, may influence the extent of alpha(1)-adrenergic-ET-1 vasoconstriction. Dihydroethidium (DHE) and dichlorodihydrofluorescein (DCF) intensities were increased by phenylephrine stimulation in isolated rat cardiac myocytes, which were enhanced by the mitochondrial electron transport chain complex I inhibitor rotenone (DHE: 20.4 +/- 1.2-fold and DCF: 25.2 +/- 0.9-fold, n = 8, P < 0.01, respectively) but not by the NADPH oxidase inhibitor apocynin. Olmesartan, an angiotensin II type 1 receptor antagonist, and enalaprilate did not change DHE and DCF intensities by phenylephrine. Next, we measured the vasoconstriction of isolated, pressurized rat coronary arterioles (diameter: 74 +/- 8 microm) in response to supernatant collected from isolated cardiac myocytes. The addition of supernatant from phenylephrine-stimulated myocytes to a 2-ml vessel bath (n = 8 each) caused volume-dependent vasoconstriction (500 microl: -14.8 +/- 2.2%). Olmesartan and TA0201, an ET type A receptor antagonist, converted vasoconstriction into vasodilation (8.5 +/- 1.2% and 10.5 +/- 0.5%, P < 0.01, respectively) in response to supernatant from phenylephrine-stimulated myocytes, which was eliminated with catalase. Vasoconstriction was weakened using supernatant from phenylephrine with rotenone-treated myocytes. Treatment of arterioles with apocynin to myocyte supernatant converted vasoconstriction into vasodilation (7.8 +/- 0.8%, P < 0.01). These results suggest that alpha(1)-adrenergic stimulation in cardiac myocytes produces angiotensin I and H(2)O(2) and that angiotensin releases ET-1 through NADPH oxidase in coronary arterioles. Thus, coronary vasoconstriction via the alpha-adrenergic-angiotensin-ET axis appears to require redox

  20. Association of interacting genes in the toll-like receptor signaling pathway and the antibody response to pertussis vaccination.

    Directory of Open Access Journals (Sweden)

    Tjeerd G Kimman

    Full Text Available BACKGROUND: Activation of the Toll-like receptor (TLR signaling pathway through TLR4 may be important in the induction of protective immunity against Bordetella pertussis with TLR4-mediated activation of dendritic and B cells, induction of cytokine expression, and reversal of tolerance as crucial steps. We examined whether single nucleotide polymorphisms (SNPs in genes of the TLR4 pathway and their interaction are associated with the response to whole-cell vaccine (WCV pertussis vaccination in 490 one-year-old children. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed associations of 75 haplotype-tagging SNPs in genes in the TLR4 signaling pathway with pertussis toxin (PT-IgG titers. We found significant associations between the PT-IgG titer and SNPs in CD14, TLR4, TOLLIP, TIRAP, IRAK3, IRAK4, TICAM1, and TNFRSF4 in one or more of the analyses. The strongest evidence for association was found for two SNPs (rs5744034 and rs5743894 in TOLLIP that were almost completely in linkage disequilibrium, provided statistically significant associations in all tests with the lowest p-values, and displayed a dominant mode of inheritance. However, none of these single gene associations would withstand correction for multiple testing. In addition, Multifactor Dimensionality Reduction Analysis, an approach that does not need correction for multiple testing, showed significant and strong two and three locus interactions between SNPs in TOLLIP (rs4963060, TLR4 (rs6478317 and IRAK1 (rs1059703. CONCLUSIONS/SIGNIFICANCE: We have identified significant interactions between genes in the TLR pathway in the induction of vaccine-induced immunity. These interactions underline that these genes are functionally related and together form a true biological relationship in a protein-protein interaction network. Practically all our findings may be explained by genetic variation in directly or indirectly interacting proteins at the extra- and intracytoplasmic sites of the cell

  1. A Saccharomyces cerevisiae Assay System to Investigate Ligand/AdipoR1 Interactions That Lead to Cellular Signaling

    KAUST Repository

    Aouida, Mustapha

    2013-06-07

    Adiponectin is a mammalian hormone that exerts anti-diabetic, anti-cancer and cardioprotective effects through interaction with its major ubiquitously expressed plasma membrane localized receptors, AdipoR1 and AdipoR2. Here, we report a Saccharomyces cerevisiae based method for investigating agonist-AdipoR interactions that is amenable for high-throughput scale-up and can be used to study both AdipoRs separately. Agonist-AdipoR1 interactions are detected using a split firefly luciferase assay based on reconstitution of firefly luciferase (Luc) activity due to juxtaposition of its N- and C-terminal fragments, NLuc and CLuc, by ligand induced interaction of the chimeric proteins CLuc-AdipoR1 and APPL1-NLuc (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif 1-NLuc) in a S. cerevisiae strain lacking the yeast homolog of AdipoRs (Izh2p). The assay monitors the earliest known step in the adiponectin-AdipoR anti-diabetic signaling cascade. We demonstrate that reconstituted Luc activity can be detected in colonies or cells using a CCD camera and quantified in cell suspensions using a microplate reader. AdipoR1-APPL1 interaction occurs in absence of ligand but can be stimulated specifically by agonists such as adiponectin and the tobacco protein osmotin that was shown to have AdipoR-dependent adiponectin-like biological activity in mammalian cells. To further validate this assay, we have modeled the three dimensional structures of receptor-ligand complexes of membrane-embedded AdipoR1 with cyclic peptides derived from osmotin or osmotin-like plant proteins. We demonstrate that the calculated AdipoR1-peptide binding energies correlate with the peptides\\' ability to behave as AdipoR1 agonists in the split luciferase assay. Further, we demonstrate agonist-AdipoR dependent activation of protein kinase A (PKA) signaling and AMP activated protein kinase (AMPK) phosphorylation in S. cerevisiae, which are homologous to

  2. A Saccharomyces cerevisiae assay system to investigate ligand/AdipoR1 interactions that lead to cellular signaling.

    Directory of Open Access Journals (Sweden)

    Mustapha Aouida

    Full Text Available Adiponectin is a mammalian hormone that exerts anti-diabetic, anti-cancer and cardioprotective effects through interaction with its major ubiquitously expressed plasma membrane localized receptors, AdipoR1 and AdipoR2. Here, we report a Saccharomyces cerevisiae based method for investigating agonist-AdipoR interactions that is amenable for high-throughput scale-up and can be used to study both AdipoRs separately. Agonist-AdipoR1 interactions are detected using a split firefly luciferase assay based on reconstitution of firefly luciferase (Luc activity due to juxtaposition of its N- and C-terminal fragments, NLuc and CLuc, by ligand induced interaction of the chimeric proteins CLuc-AdipoR1 and APPL1-NLuc (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif 1-NLuc in a S. cerevisiae strain lacking the yeast homolog of AdipoRs (Izh2p. The assay monitors the earliest known step in the adiponectin-AdipoR anti-diabetic signaling cascade. We demonstrate that reconstituted Luc activity can be detected in colonies or cells using a CCD camera and quantified in cell suspensions using a microplate reader. AdipoR1-APPL1 interaction occurs in absence of ligand but can be stimulated specifically by agonists such as adiponectin and the tobacco protein osmotin that was shown to have AdipoR-dependent adiponectin-like biological activity in mammalian cells. To further validate this assay, we have modeled the three dimensional structures of receptor-ligand complexes of membrane-embedded AdipoR1 with cyclic peptides derived from osmotin or osmotin-like plant proteins. We demonstrate that the calculated AdipoR1-peptide binding energies correlate with the peptides' ability to behave as AdipoR1 agonists in the split luciferase assay. Further, we demonstrate agonist-AdipoR dependent activation of protein kinase A (PKA signaling and AMP activated protein kinase (AMPK phosphorylation in S. cerevisiae, which are

  3. Adrenergic Drugs Blockers or Enhancers for Cognitive Decline ? What to Choose for Alzheimer's Disease Patients?

    Science.gov (United States)

    Femminella, Grazia D; Leosco, Dario; Ferrara, Nicola; Rengo, Giuseppe

    2016-01-01

    The adrenergic system has an important role in normal central nervous system function as well as in brain disease. The locus coeruleus, the main source of norepinephrine in brain, is involved in the regulation of learning and memory, reinforcement of sleep-wake cycle and synaptic plasticity. In Alzheimer's disease, locus coeruleus degeneration is observed early in the course of the disease, years before the onset of clinical cognitive signs, with neurofibrillary detected at the stage of mild cognitive impairment, preceding amyloid deposition. Thus, in the last years, a great interest has grown in evaluating the possibility of central adrenergic system modulation as a therapeutic tool in Alzheimer's disease. However, evidences do not show univocal results, with some studies suggesting that adrenergic stimulation might be beneficial in Alzheimer's Disease and some others favoring adrenergic blockade. In this review, we summarize data from both hypothesis and describe the pathophysiological role of the adrenergic system in neurodegeneration. PMID:27189470

  4. Cross talk between H2O2 and interacting signal molecules under plant stress response

    Directory of Open Access Journals (Sweden)

    Ina eSaxena

    2016-04-01

    Full Text Available It is well established that oxidative stress is an important cause of cellular damage. During stress condition plants have evolved regulatory mechanism to adapt to various environmental stresses. One of the consequences of stress is an increase in the cellular concentration of ROS, which is subsequently converted to H2O2. H2O2 is continuously produced as the by-product of oxidative plant aerobic metabolism. Organelles with a high oxidizing metabolic activity or with an intense rate of electron flow, such as chloroplasts, mitochondria, or peroxisomes are major sources of H2O2 production. H2O2 acts as a versatile molecule because of its dual role in cells. Under normal conditions, H2O2 acts as a key regulator of many biological processes because H2O2 has been identified as an important second messenger in signal transduction networks. In this review we discuss potential roles of H2O2 and other signaling molecule during various stress responses.

  5. Mapping dynamic protein interactions in MAP kinase signaling using live-cell fluorescence fluctuation spectroscopy and imaging.

    Science.gov (United States)

    Slaughter, Brian D; Schwartz, Joel W; Li, Rong

    2007-12-18

    Fluorescence correlation spectroscopy (FCS), fluorescence cross-correlation spectroscopy (FCCS), and photon counting histograms (PCH) are fluctuation methods that emerged recently as potentially useful tools for obtaining parameters of molecular dynamics, interactions, and oligomerization in vivo. Here, we report the successful implementation of FCS, FCCS, and PCH in live yeast cells using fluorescent protein-tagged proteins expressed from their native chromosomal loci, examining cytosolic dynamics and interactions among components of the mitogen activated protein kinase (MAPK) cascade, a widely occurring signaling motif, in response to mating pheromone. FCS analysis detailed the diffusion characteristics and mobile concentrations of MAPK proteins. FCCS analysis using EGFP and mCherry-tagged protein pairs observed the interactions of Ste7 (MAPK kinase) with the MAPKs, Fus3 or Kss1, and of the scaffold protein, Ste5, with Ste7 and Ste11 (MAPK kinase kinase) in the cytosol, providing in vivo constants of their binding equilibrium. The interaction of Ste5 with Fus3 in the cytosol was below the limit of detection, suggesting a weak interaction, if it exists, with K(d) >400-500 nM. Using PCH, we show that cytosolic Ste5 were mostly monomers. Artificial dimerization of Ste5, as confirmed by PCH, using a dimerizing tag, stimulated the interaction between Ste5 and Fus3. Native Ste5 was found to bind Fus3 preferentially at the cortex in pheromone-treated cells, as detected by fluorescence resonance energy transfer (FRET). These results provide a quantitative spatial map of MAPK complexes in vivo and directly support the model that membrane association and regulation of the Ste5 scaffold are critical steps in MAPK activation. PMID:18077328

  6. Modulation of fluorescence signals from biomolecules along nanowires due to interaction of light with oriented nanostructures

    DEFF Research Database (Denmark)

    Frederiksen, Rune Schøneberg; Alarcon-Llado, Esther; Madsen, Morten H.;

    2015-01-01

    High aspect ratio nanostructures have gained increasing interest as highly sensitive platforms for biosensing. Here, well-defined biofunctionalized vertical indium arsenide nanowires are used to map the interaction of light with nanowires depending on their orientation and the excitation waveleng....... We show how nanowires act as antennas modifying the light distribution and the emitted fluorescence. This work highlights an important optical phenomenon in quantitative fluorescence studies and constitutes an important step for future studies using such nanostructures....

  7. On the role of exchange of power and information signals in control and stability of the human-robot interaction

    Science.gov (United States)

    Kazerooni, H.

    1991-01-01

    A human's ability to perform physical tasks is limited, not only by his intelligence, but by his physical strength. If, in an appropriate environment, a machine's mechanical power is closely integrated with a human arm's mechanical power under the control of the human intellect, the resulting system will be superior to a loosely integrated combination of a human and a fully automated robot. Therefore, we must develop a fundamental solution to the problem of 'extending' human mechanical power. The work presented here defines 'extenders' as a class of robot manipulators worn by humans to increase human mechanical strength, while the wearer's intellect remains the central control system for manipulating the extender. The human, in physical contact with the extender, exchanges power and information signals with the extender. The aim is to determine the fundamental building blocks of an intelligent controller, a controller which allows interaction between humans and a broad class of computer-controlled machines via simultaneous exchange of both power and information signals. The prevalent trend in automation has been to physically separate the human from the machine so the human must always send information signals via an intermediary device (e.g., joystick, pushbutton, light switch). Extenders, however are perfect examples of self-powered machines that are built and controlled for the optimal exchange of power and information signals with humans. The human wearing the extender is in physical contact with the machine, so power transfer is unavoidable and information signals from the human help to control the machine. Commands are transferred to the extender via the contact forces and the EMG signals between the wearer and the extender. The extender augments human motor ability without accepting any explicit commands: it accepts the EMG signals and the contact force between the person's arm and the extender, and the extender 'translates' them into a desired position. In

  8. Phospholipase D and phosphatidic acid in plant defence response: from protein-protein and lipid-protein interactions to hormone signalling.

    Science.gov (United States)

    Zhao, Jian

    2015-04-01

    Phospholipase Ds (PLDs) and PLD-derived phosphatidic acids (PAs) play vital roles in plant hormonal and environmental responses and various cellular dynamics. Recent studies have further expanded the functions of PLDs and PAs into plant-microbe interaction. The molecular diversities and redundant functions make PLD-PA an important signalling complex regulating lipid metabolism, cytoskeleton dynamics, vesicle trafficking, and hormonal signalling in plant defence through protein-protein and protein-lipid interactions or hormone signalling. Different PLD-PA signalling complexes and their targets have emerged as fast-growing research topics for understanding their numerous but not yet established roles in modifying pathogen perception, signal transduction, and downstream defence responses. Meanwhile, advanced lipidomics tools have allowed researchers to reveal further the mechanisms of PLD-PA signalling complexes in regulating lipid metabolism and signalling, and their impacts on jasmonic acid/oxylipins, salicylic acid, and other hormone signalling pathways that essentially mediate plant defence responses. This review attempts to summarize the progress made in spatial and temporal PLD/PA signalling as well as PLD/PA-mediated modification of plant defence. It presents an in-depth discussion on the functions and potential mechanisms of PLD-PA complexes in regulating actin filament/microtubule cytoskeleton, vesicle trafficking, and hormonal signalling, and in influencing lipid metabolism-derived metabolites as critical signalling components in plant defence responses. The discussion puts PLD-PA in a broader context in order to guide future research.

  9. Genetic interaction of two abscisic acid signaling regulators, HY5 and FIERY1, in mediating lateral root formation

    KAUST Repository

    Chen, Hao

    2011-01-01

    Root architecture is continuously shaped in a manner that helps plants to better adapt to the environment. Gene regulation at the transcriptional or post-transcriptional levels largely controls this environmental response. Recently, RNA silencing has emerged as an important player in gene regulation and is involved in many aspects of plant development, including lateral root formation. In a recent study, we found that FIERY1, a bifunctional abiotic stress and abscisic acid (ABA) signaling regulator and an endogenous RNA silencing suppressor, mediates auxin response during lateral root formation in Arabidopsis. We proposed that FRY1 regulates lateral root development through its activity on adenosine 3,5-bisphosphate (PAP), a strong inhibitor of exoribonucleases (XRNs). Interestingly, some of the phenotypes of fry1, such as enhanced response to light in repressing hypocotyl elongation and hypersensitivity to ABA in lateral root growth, are opposite to those of another light- and ABA-signaling mutant, hy5. Here we analyzed the hy5 fry1 double mutant for root and hypocotyl growth. We found that the hy5 mutation can suppress the enhanced light sensitivity in fry1 hypocotyl elongation and restore the lateral root formation. The genetic interaction between HY5 and FRY1 indicates that HY5 and FRY1 may act in overlapping pathways that mediate light signaling and lateral root development. © 2011 Landes Bioscience.

  10. CD44: molecular interactions, signalling and functions in the nervous system.

    Directory of Open Access Journals (Sweden)

    Grzegorz Marek Wilczynski

    2015-05-01

    Full Text Available CD44 is the major surface hyaluronan receptor implicated in intercellular and cell-matrix adhesion, cell migration and signalling. It is a transmembrane, highly glycosylated protein with several isoforms resulting from alternative gene splicing. The CD44 molecule consists of several domains serving different functions: the N-terminal extracellular domain, the stem region, the transmembrane domain and the C-terminal tail. In the nervous system, CD44 expression occurs in both glial and neuronal cells. The role of CD44 in the physiology and pathology of the nervous system is not entirely understood, however, there exists evidence suggesting it might be involved in the axon guidance, cytoplasmic Ca2+ clearance, dendritic arborization, synaptic transmission, epileptogenesis, oligodendrocyte and astrocyte differentiation, post-traumatic brain repair and brain tumour development.

  11. Interacting inflammatory and growth factor signals underlie the obesity-cancer link.

    Science.gov (United States)

    Lashinger, Laura M; Ford, Nikki A; Hursting, Stephen D

    2014-02-01

    The prevalence of obesity, an established risk factor for many chronic diseases (including diabetes, cardiovascular disease, stroke, and several types of cancer), has risen steadily for the past several decades in the United States and many parts of the world. Today, ∼70% of U.S. adults and 30% of children are at an unhealthy weight. The evidence on key biologic mechanisms underlying the obesity-cancer link, with an emphasis on local and systemic inflammatory processes and their crosstalk with energy-sensing growth factor signaling pathways, will be discussed. Understanding the influence and underlying mechanisms of obesity on chronic inflammation and cancer will identify promising mechanistic targets and strategies for disrupting the obesity-cancer link and provide important lessons regarding the associations between obesity, inflammation, and other chronic diseases.

  12. Divergent Label-free Cell Phenotypic Pharmacology of Ligands at the Overexpressed β2-Adrenergic Receptors

    Science.gov (United States)

    Ferrie, Ann M.; Sun, Haiyan; Zaytseva, Natalya; Fang, Ye

    2014-01-01

    We present subclone sensitive cell phenotypic pharmacology of ligands at the β2-adrenergic receptor (β2-AR) stably expressed in HEK-293 cells. The parental cell line was transfected with green fluorescent protein (GFP)-tagged β2-AR. Four stable subclones were established and used to profile a library of sixty-nine AR ligands. Dynamic mass redistribution (DMR) profiling resulted in a pharmacological activity map suggesting that HEK293 endogenously expresses functional Gi-coupled α2-AR and Gs-coupled β2-AR, and the label-free cell phenotypic activity of AR ligands are subclone dependent. Pathway deconvolution revealed that the DMR of epinephrine is originated mostly from the remodeling of actin microfilaments and adhesion complexes, to less extent from the microtubule networks and receptor trafficking, and certain agonists displayed different efficacy towards the cAMP-Epac pathway. We demonstrate that receptor signaling and ligand pharmacology is sensitive to the receptor expression level, and the organization of the receptor and its signaling circuitry.

  13. Direct interaction between the Arabidopsis disease resistance signaling proteins, EDS1 and PAD4.

    Science.gov (United States)

    Feys, B J; Moisan, L J; Newman, M A; Parker, J E

    2001-10-01

    The Arabidopsis EDS1 and PAD4 genes encode lipase-like proteins that function in resistance (R) gene-mediated and basal plant disease resistance. Phenotypic analysis of eds1 and pad4 null mutants shows that EDS1 and PAD4 are required for resistance conditioned by the same spectrum of R genes but fulfil distinct roles within the defence pathway. EDS1 is essential for elaboration of the plant hypersensitive response, whereas EDS1 and PAD4 are both required for accumulation of the plant defence-potentiating molecule, salicylic acid. EDS1 is necessary for pathogen-induced PAD4 mRNA accumulation, whereas mutations in PAD4 or depletion of salicylic acid only partially compromise EDS1 expression. Yeast two-hybrid analysis reveals that EDS1 can dimerize and interact with PAD4. However, EDS1 dimerization is mediated by different domains to those involved in EDS1-PAD4 association. Co-immunoprecipitation experiments show that EDS1 and PAD4 proteins interact in healthy and pathogen-challenged plant cells. We propose two functions for EDS1. The first is required early in plant defence, independently of PAD4. The second recruits PAD4 in the amplification of defences, possibly by direct EDS1-PAD4 association.

  14. The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice.

    Science.gov (United States)

    Bermudez-Silva, Francisco J; Romero-Zerbo, Silvana Y; Haissaguerre, Magalie; Ruz-Maldonado, Inmaculada; Lhamyani, Said; El Bekay, Rajaa; Tabarin, Antoine; Marsicano, Giovanni; Cota, Daniela

    2016-01-01

    The endocannabinoid system (ECS) is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the β-cell mass. The downstream signalling pathways mediating these effects are poorly understood. Mammalian target of rapamycin complex 1 (mTORC1) signalling is a key intracellular pathway involved in energy homeostasis and is known to importantly affect the physiology of pancreatic islets. We investigated the possible relationship between cannabinoid type 1 (CB1) receptor signalling and the mTORC1 pathway in the endocrine pancreas of mice by using pharmacological analysis as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, the kinase p70S6K1. In vitro static secretion experiments on islets, western blotting, and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS) at 0.1 µM while increasing phosphorylation of p70S6K1 and ribosomal protein S6 (rpS6) within the islets. Specific pharmacological blockade of mTORC1 by 3 nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3 mg/kg body weight rimonabant decreased insulin levels and induced glucose intolerance in lean mice without altering peripheral insulin sensitivity; this effect was prevented by peripheral administration of low doses of rapamycin (0.1 mg/kg body weight), which increased insulin sensitivity. These findings suggest a functional interaction between the ECS and the mTORC1 pathway within the endocrine pancreas and at the whole-organism level, which could have implications for the development of new therapeutic approaches for pancreatic β-cell diseases.

  15. Traf2 interacts with Smad4 and regulates BMP signaling pathway in MC3T3-E1 osteoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Koichi, E-mail: shimada-ki@dent.nihon-u.ac.jp [Department of Periodontology, Nihon University School of Dentistry, Tokyo (Japan); Division of Advanced Dental Treatment, Dental Research Center, Nihon University School of Dentistry, Tokyo (Japan); Ikeda, Kyoko [Department of Periodontology, Nihon University School of Dentistry, Tokyo (Japan); Ito, Koichi [Department of Periodontology, Nihon University School of Dentistry, Tokyo (Japan); Division of Advanced Dental Treatment, Dental Research Center, Nihon University School of Dentistry, Tokyo (Japan)

    2009-12-18

    Bone morphogenetic proteins (BMPs) play important roles in osteoblast differentiation and maturation. In mammals, the BMP-induced receptor-regulated Smads form complexes with Smad4. These complexes translocate and accumulate in the nucleus, where they regulate the transcription of various target genes. However, the function of Smad4 remains unclear. We performed a yeast two-hybrid screen using Smad4 as bait and a cDNA library derived from bone marrow, to indentify the proteins interacting with Smad4. cDNA clones for Tumor necrosis factor (TNF) receptor-associated factor 2 (Traf2) were identified, and the interaction between the endogenous proteins was confirmed in the mouse osteoblast cell line MC3T3-E1. To investigate the function of Traf2, we silenced it with siRNA. The level of BMP-2 protein in the medium, the expression levels of the Bmp2 gene and BMP-induced transcription factor genes, including Runx2, Dlx5, Msx2, and Sp7, and the phosphorylated-Smad1 protein level were increased in cells transfected with Traf2 siRNA. The nuclear accumulation of Smad1 increased with TNF-{alpha} stimulation for 30 min at Traf2 silencing. These results suggest that the TNF-{alpha}-stimulated nuclear accumulation of Smad1 may be dependent on Traf2. Thus, the interaction between Traf2 and Smad4 may play a role in the cross-talk between TNF-{alpha} and BMP signaling pathways.

  16. Relevancies of multiple-interaction events and signal-to-noise ratio for Anger-logic based PET detector designs

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Hao, E-mail: penghao@mcmaster.ca [Department of Medical Physics, McMaster University, Canada L8S 4K1 (Canada); Department of Electrical and Computer Engineering, McMaster University, Canada L8S 4K1 (Canada)

    2015-10-21

    A fundamental challenge for PET block detector designs is to deploy finer crystal elements while limiting the number of readout channels. The standard Anger-logic scheme including light sharing (an 8 by 8 crystal array coupled to a 2×2 photodetector array with an optical diffuser, multiplexing ratio: 16:1) has been widely used to address such a challenge. Our work proposes a generalized model to study the impacts of two critical parameters on spatial resolution performance of a PET block detector: multiple interaction events and signal-to-noise ratio (SNR). The study consists of the following three parts: (1) studying light output profile and multiple interactions of 511 keV photons within crystal arrays of different crystal widths (from 4 mm down to 1 mm, constant height: 20 mm); (2) applying the Anger-logic positioning algorithm to investigate positioning/decoding uncertainties (i.e., “block effect”) in terms of peak-to-valley ratio (PVR), with light sharing, multiple interactions and photodetector SNR taken into account; and (3) studying the dependency of spatial resolution on SNR in the context of modulation transfer function (MTF). The proposed model can be used to guide the development and evaluation of a standard Anger-logic based PET block detector including: (1) selecting/optimizing the configuration of crystal elements for a given photodetector SNR; and (2) predicting to what extent additional electronic multiplexing may be implemented to further reduce the number of readout channels.

  17. Pentamidine blocks the interaction between mutant S100A5 and RAGE V domain and inhibits the RAGE signaling pathway.

    Science.gov (United States)

    Cho, Ching Chang; Chou, Ruey Hwang; Yu, Chin

    2016-08-19

    The human S100 protein family contains small, dimeric and acidic proteins that contain two EF-hand motifs and bind calcium. When S100A5 binds calcium, its conformation changes and promotes interaction with the target protein. The extracellular domain of RAGE (Receptor of Advanced Glycation End products) contain three domains: C1, C2 and V. The RAGE V domain is the target protein of S100A5 that promotes cell survival, growth and differentiation by activating several signaling pathways. Pentamidine is an apoptotic and antiparasitic drug that is used to treat or prevent pneumonia. Here, we found that pentamidine interacts with S100A5 using HSQC titration. We elucidated the interactions of S100A5 with RAGE V domain and pentamidine using fluorescence and NMR spectroscopy. We generated two binary models-the S100A5-RAGE V domain and S100A5-Pentamidine complex-and then observed that the pentamidine and RAGE V domain share a similar binding region in mS100A5. We also used the WST-1 assay to investigate the bioactivity of S100A5, RAGE V domain and pentamidine. These results indicated that pentamidine blocks the binding between S100A5 and RAGE V domain. This finding is useful for the development of new anti-proliferation drugs. PMID:27297108

  18. Arsenite-activated JNK signaling enhances CPEB4-Vinexin interaction to facilitate stress granule assembly and cell survival.

    Directory of Open Access Journals (Sweden)

    Yu-Wei Chang

    Full Text Available Stress granules (SGs are compartmentalized messenger ribonucleoprotein particles (mRNPs where translationally repressed mRNAs are stored when cells encounter environmental stress. Cytoplasmic polyadenylation element-binding protein (CPEB4 is a sequence-specific RNA-binding protein and translational regulator. In keeping with the results obtained from the study of other RNA-binding proteins, we found CPEB4 localized in SGs in various arsenite-treated cells. In this study, we identified that Vinexin, a CPEB4-interacting protein, is a novel component of SGs. Vinexin is a SH3-domain-containing adaptor protein and affects cell migration through its association with Vinculin to localize at focal adhesions (FAs. Unexpectedly, Vinexin is translocated from FAs to SGs under arsenite-induced stress. The recruitment of Vinexin to SGs depends on its interaction with CPEB4 and influences SG formation and cell survival. Arsenite-activated c-Jun N-terminal kinase (JNK signaling enhances the association between CPEB4 and Vinexin, which consequently facilitates SG localization of Vinexin. Taken together, this study uncovers a novel interaction between a translational regulator and an adaptor protein to influence SG assembly and cell survival.

  19. Relevancies of multiple-interaction events and signal-to-noise ratio for Anger-logic based PET detector designs

    Science.gov (United States)

    Peng, Hao

    2015-10-01

    A fundamental challenge for PET block detector designs is to deploy finer crystal elements while limiting the number of readout channels. The standard Anger-logic scheme including light sharing (an 8 by 8 crystal array coupled to a 2×2 photodetector array with an optical diffuser, multiplexing ratio: 16:1) has been widely used to address such a challenge. Our work proposes a generalized model to study the impacts of two critical parameters on spatial resolution performance of a PET block detector: multiple interaction events and signal-to-noise ratio (SNR). The study consists of the following three parts: (1) studying light output profile and multiple interactions of 511 keV photons within crystal arrays of different crystal widths (from 4 mm down to 1 mm, constant height: 20 mm); (2) applying the Anger-logic positioning algorithm to investigate positioning/decoding uncertainties (i.e., "block effect") in terms of peak-to-valley ratio (PVR), with light sharing, multiple interactions and photodetector SNR taken into account; and (3) studying the dependency of spatial resolution on SNR in the context of modulation transfer function (MTF). The proposed model can be used to guide the development and evaluation of a standard Anger-logic based PET block detector including: (1) selecting/optimizing the configuration of crystal elements for a given photodetector SNR; and (2) predicting to what extent additional electronic multiplexing may be implemented to further reduce the number of readout channels.

  20. In situ monitoring the pulse CO2 laser interaction with 316-L stainless steel using acoustical signals and plasma analysis

    International Nuclear Information System (INIS)

    In most laser material processing, material removal by different mechanisms is involved. Here, application of acoustic signals with thermoelastic (below threshold) and breakdown origin (above threshold) together with plasma plume analysis as a simple monitoring system of interaction process is suggested. In this research the interaction of pulse CO2 laser with 200 ns duration and maximum energy of 1.3 J operating at 1 Hz with austenitic stainless steel (316-L) is reported. The results showed that the non-linear point of the curve can serve as a useful indicator of melting fluence threshold (in this case ∼830 J cm-2) with corresponding temperature calculated using plasma plume analysis. Higher acoustic amplitudes and larger plasma plume volume indicates more intense interaction. Also, analysis showed that a phase explosion process with material removal (ejecta) in the form of non-adiabatic (i.e., dt >> α-1) is at play after laser pulse is ended. Also, SEM photographs show different surface quality medication at different laser intensities, which indicates the importance of recoil momentum pressure and possibly electrons and ions densities in heat transfer. Finally, electrochemical test indicate an improved corrosion resistance for laser treated samples compared to untreated ones.

  1. In situ monitoring the pulse CO 2 laser interaction with 316-L stainless steel using acoustical signals and plasma analysis

    Science.gov (United States)

    Khosroshahi, M. E.; pour, F. Anoosheh; Hadavi, M.; Mahmoodi, M.

    2010-10-01

    In most laser material processing, material removal by different mechanisms is involved. Here, application of acoustic signals with thermoelastic (below threshold) and breakdown origin (above threshold) together with plasma plume analysis as a simple monitoring system of interaction process is suggested. In this research the interaction of pulse CO 2 laser with 200 ns duration and maximum energy of 1.3 J operating at 1 Hz with austenitic stainless steel (316-L) is reported. The results showed that the non-linear point of the curve can serve as a useful indicator of melting fluence threshold (in this case ≈830 J cm -2) with corresponding temperature calculated using plasma plume analysis. Higher acoustic amplitudes and larger plasma plume volume indicates more intense interaction. Also, analysis showed that a phase explosion process with material removal (ejecta) in the form of non-adiabatic (i.e., dt ≫ α-1) is at play after laser pulse is ended. Also, SEM photographs show different surface quality medication at different laser intensities, which indicates the importance of recoil momentum pressure and possibly electrons and ions densities in heat transfer. Finally, electrochemical test indicate an improved corrosion resistance for laser treated samples compared to untreated ones.

  2. Traf2 interacts with Smad4 and regulates BMP signaling pathway in MC3T3-E1 osteoblasts

    International Nuclear Information System (INIS)

    Bone morphogenetic proteins (BMPs) play important roles in osteoblast differentiation and maturation. In mammals, the BMP-induced receptor-regulated Smads form complexes with Smad4. These complexes translocate and accumulate in the nucleus, where they regulate the transcription of various target genes. However, the function of Smad4 remains unclear. We performed a yeast two-hybrid screen using Smad4 as bait and a cDNA library derived from bone marrow, to indentify the proteins interacting with Smad4. cDNA clones for Tumor necrosis factor (TNF) receptor-associated factor 2 (Traf2) were identified, and the interaction between the endogenous proteins was confirmed in the mouse osteoblast cell line MC3T3-E1. To investigate the function of Traf2, we silenced it with siRNA. The level of BMP-2 protein in the medium, the expression levels of the Bmp2 gene and BMP-induced transcription factor genes, including Runx2, Dlx5, Msx2, and Sp7, and the phosphorylated-Smad1 protein level were increased in cells transfected with Traf2 siRNA. The nuclear accumulation of Smad1 increased with TNF-α stimulation for 30 min at Traf2 silencing. These results suggest that the TNF-α-stimulated nuclear accumulation of Smad1 may be dependent on Traf2. Thus, the interaction between Traf2 and Smad4 may play a role in the cross-talk between TNF-α and BMP signaling pathways.

  3. Convergence of CONSTITUTIVE PHOTOMORPHOGENESIS 1 and PHYTOCHROME INTERACTING FACTOR signalling during shade avoidance.

    Science.gov (United States)

    Pacín, Manuel; Semmoloni, Mariana; Legris, Martina; Finlayson, Scott A; Casal, Jorge J

    2016-08-01

    Shade-avoidance responses require CONSTITUTIVE PHOTOMORPHOGENESIS 1 (COP1) but the mechanisms of action of COP1 under shade have not been elucidated. Using simulated shade and control conditions, we analysed: the transcriptome and the auxin levels of cop1 and phytochrome interacting factor 1 (pif1) pif3 pif4 pif5 (pifq) mutants; the dynamics of ELONGATED HYPOCOTYL 5 (HY5) and LONG HYPOCOTYL IN FAR-RED (HFR1) proteins; and the epistatic relationships between cop1 and pif3, pif4, pif5, hy5 and hfr1 mutations in Arabidopsis thaliana. Despite severely impaired shade-avoidance responses, only a few genes that responded to shade in the wild-type failed to do so in cop1. Shade enhanced the convergence between cop1 and pifq transcriptomes, mainly on shade-avoidance marker genes. Shade failed to increase auxin levels in cop1. Residual shade avoidance in cop1 was not further reduced by the pif3, pif4 or pif5 mutations, suggesting convergent pathways. HFR1 stability decreased under shade in a COP1-dependent manner but shade increased HY5 stability. The cop1 mutant retains responses to shade and is more specifically impaired in shade avoidance. COP1 promotes the degradation of HFR1 under shade, thus increasing the ability of PIFs to control gene expression, increase auxin levels and promote stem growth.

  4. Direct interaction of natural and synthetic catechins with signal transducer activator of transcription 1 affects both its phosphorylation and activity

    KAUST Repository

    Menegazzi, Marta

    2013-12-10

    Our previous studies showed that (-)-epigallocatechin-3-gallate (EGCG) inhibits signal transducer activator of transcription 1 (STAT1) activation. Since EGCG may be a promising lead compound for new anti-STAT1 drug design, 15 synthetic catechins, characterized by the (-)-gallocatechin-3-gallate stereochemistry, were studied in the human mammary MDA-MB-231 cell line to identify the minimal structural features that preserve the anti-STAT1 activity. We demonstrate that the presence of three hydroxyl groups of B ring and one hydroxyl group in D ring is essential to preserve their inhibitory action. Moreover, a possible molecular target of these compounds in the STAT1 pathway was investigated. Our results demonstrate a direct interaction between STAT1 protein and catechins displaying anti-STAT1 activity. In particular, surface plasmon resonance (SPR) analysis and molecular modeling indicate the presence of two putative binding sites (a and b) with different affinity. Based on docking data, site-directed mutagenesis was performed, and interaction of the most active catechins with STAT1 was studied with SPR to test whether Gln518 on site a and His568 on site b could be important for the catechin-STAT1 interaction. Data indicate that site b has higher affinity for catechins than site a as the highest affinity constant disappears in the H568ASTAT1 mutant. Furthermore, Janus kinase 2 (JAK2) kinase assay data suggest that the contemporary presence in vitro of STAT1 and catechins inhibits JAK2-elicited STAT1 phosphorylation. The very tight catechin-STAT1 interaction prevents STAT1 phosphorylation and represents a novel, specific and efficient molecular mechanism for the inhibition of STAT1 activation. © Copyright 2014 Federation of European Biochemical Societies. All rights reserved.

  5. Alpha and beta adrenergic effects on metabolism in contracting, perfused muscle

    DEFF Research Database (Denmark)

    Richter, Erik; Ruderman, N B; Galbo, H

    1982-01-01

    The role of alpha- and beta-adrenergic receptor stimulation for the effect of epinephrine on muscle glycogenolysis, glucose- and oxygen uptake and muscle performance was studied in the perfused rat hindquarter at rest and during electrical stimulation (60 contractions/min). Adrenergic stimulation...... was obtained by epinephrine in a physiological concentration (2.4 X 10(-8) M) and alpha- and beta-adrenergic blockade by 10(-5) M phentolamine and propranolol, respectively. Epinephrine enhanced net glycogenolysis during contractions most markedly in slow-twitch red fibers. In these fibers the effect...

  6. Adrenergic effects on secretion of epidermal growth factor from Brunner's glands

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier

    1985-01-01

    The influence of the sympathetic nervous system and adrenergic agonists on flow rate and secretion of epidermal growth factor (EGF) from Brunner's glands has been investigated in the rat. Chemical sympathectomy by administration of 6-hydroxydopamine increased volume secretion and output of EGF from...... also increased the amount of EGF in Brunner's gland tissue and this was unchanged after simultaneous infusion of VIP and noradrenaline as well as VIP and isoproterenol, a beta-adrenergic agonist. Isoproterenol had no effect on basal and VIP stimulated secretion of EGF from Brunner's glands...... secretion, output of EGF and mucus content in Brunner's glands probably by activation of alpha-adrenergic pathways....

  7. Are glutathione S transferases involved in DNA damage signalling? Interactions with DNA damage and repair revealed from molecular epidemiology studies

    Energy Technology Data Exchange (ETDEWEB)

    Dusinska, Maria, E-mail: Maria.DUSINSKA@nilu.no [CEE-Health Effects Group, NILU - Norwegian Institute for Air Research, Kjeller (Norway); Staruchova, Marta; Horska, Alexandra [Department of Experimental and Applied Genetics, Slovak Medical University, Bratislava (Slovakia); Smolkova, Bozena [Laboratory of Cancer Genetics, Cancer Research Institute of the Slovak Academy of Sciences, Bratislava (Slovakia); Collins, Andrew [Department of Nutrition, Faculty of Medicine, University of Oslo (Norway); Bonassi, Stefano [Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, Rome (Italy); Volkovova, Katarina [Department of Experimental and Applied Genetics, Slovak Medical University, Bratislava (Slovakia)

    2012-08-01

    Glutathione S-transferases (GSTs) are members of a multigene family of isoenzymes that are important in the control of oxidative stress and in phase II metabolism. Acting non-enzymically, GSTs can modulate signalling pathways of cell proliferation, cell differentiation and apoptosis. Using a molecular epidemiology approach, we have investigated a potential involvement of GSTs in DNA damage processing, specifically the modulation of DNA repair in a group of 388 healthy adult volunteers; 239 with at least 5 years of occupational exposure to asbestos, stone wool or glass fibre, and 149 reference subjects. We measured DNA damage in lymphocytes using the comet assay (alkaline single cell gel electrophoresis): strand breaks (SBs) and alkali-labile sites, oxidised pyrimidines with endonuclease III, and oxidised purines with formamidopyrimidine DNA glycosylase. We also measured GST activity in erythrocytes, and the capacity for base excision repair (BER) in a lymphocyte extract. Polymorphisms in genes encoding three GST isoenzymes were determined, namely deletion of GSTM1 and GSTT1 and single nucleotide polymorphism Ile105Val in GSTP1. Consumption of vegetables and wine correlated negatively with DNA damage and modulated BER. GST activity correlated with oxidised bases and with BER capacity, and differed depending on polymorphisms in GSTP1, GSTT1 and GSTM1. A significantly lower BER rate was associated with the homozygous GSTT1 deletion in all asbestos site subjects and in the corresponding reference group. Multifactorial analysis revealed effects of sex and exposure in GSTP1 Ile/Val heterozygotes but not in Ile/Ile homozygotes. These variants affected also SBs levels, mainly by interactions of GSTP1 genotype with exposure, with sex, and with smoking habit; and by an interaction between sex and smoking. Our results show that GST polymorphisms and GST activity can apparently influence DNA stability and repair of oxidised bases, suggesting a potential new role for these

  8. Interaction between Cl- channels and CRAC-related Ca2+ signaling during T lymphocyte activation and proliferation

    Institute of Scientific and Technical Information of China (English)

    Guan-lei WANG; Yan QIAN; Qin-ying QIU; Xiu-jian LAN; Hua HE; Yong-yuan GUAN

    2006-01-01

    Aim:To test the hypothesis that Cl- channel blockers affect T cell proliferation through Ca2+-release-activated Ca2+ (CRAC) signaling and examine the effects of the combination of a CRAC channel blocker and a Cl- channel blocker on concanavalin A (ConA;5 mg/mL) -induced Ca2+ signaling,gene expression and cellular proliferation in human peripheral T lymphocytes.Methods:[3H]Thymidine incorporation,Fura-2 fluorescent probe,RNase protection assay,and reverse transcription.polymerase chain reaction were used.Results:The Cl- channel blocker 4,4'-diisothiocvanostilbene-2,2'-disulfonic acid (DIDS) inhibited ConA-induced Ca2+influx.interleukin-2 mRNA expression and T lymphocyte proliferation in a concentration.dependent manner,and also enhanced the inhibitory effects of 1-{beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl}-1H-imidazole (SK&F96365) on the above key events during T cell activation.A combination ofDIDS (1μmol/L) and SK&F96365 (1μmol/L) significantly diminished ConA-induced ClC-3 mRNA expression by 64%,whereas DIDS (1μmol/L) or SK&F96365 (1μmol/L) alone decreased ConA-induced ClC-3 mRNA expression by only 16% and 9%.respectively.Conclusion:These results suggest that there is an interaction between CRAC-mediated Ca2+ signaling and DIDS-sensitive C1-channels during ConA-induced T cell activation and proliferation.Moreover,the DIDS-sensitive Cl-channels may be related to the ClC-3 Cl- channels.

  9. Interaction between cAMP and intracellular Ca(2+)-signaling pathways during odor-perception and adaptation in Drosophila.

    Science.gov (United States)

    Murmu, Meena Sriti; Martin, Jean-René

    2016-09-01

    Binding of an odorant to olfactory receptors triggers cascades of second messenger systems in olfactory receptor neurons (ORNs). Biochemical studies indicate that the transduction mechanism at ORNs is mediated by cyclic adenosine monophosphate (cAMP) and/or inositol,1,4,5-triphosphate (InsP3)-signaling pathways in an odorant-dependent manner. However, the interaction between these two second messenger systems during olfactory perception or adaptation processes is much less understood. Here, we used interfering-RNAi to disrupt the level of cAMP alone or in combination with the InsP3-signaling pathway cellular targets, InsP3 receptor (InsP3R) or ryanodine receptor (RyR) in ORNs, and quantify at ORN axon terminals in the antennal lobe, the odor-induced Ca(2+)-response. In-vivo functional bioluminescence Ca(2+)-imaging indicates that a single 5s application of an odor increased Ca(2+)-transients at ORN axon terminals. However, compared to wild-type controls, the magnitude and duration of ORN Ca(2+)-response was significantly diminished in cAMP-defective flies. In a behavioral assay, perception of odorants was defective in flies with a disrupted cAMP level suggesting that the ability of flies to correctly detect an odor depends on cAMP. Simultaneous disruption of cAMP level and InsP3R or RyR further diminished the magnitude and duration of ORN response to odorants and affected the flies' ability to detect an odor. In conclusion, this study provides functional evidence that cAMP and InsP3-signaling pathways act in synergy to mediate odor processing within the ORN axon terminals, which is encoded in the magnitude and duration of ORN response. PMID:27212269

  10. OVATE Family Protein 8 Positively Mediates Brassinosteroid Signaling through Interacting with the GSK3-like Kinase in Rice.

    Directory of Open Access Journals (Sweden)

    Chao Yang

    2016-06-01

    Full Text Available OVATE gene was first identified as a key regulator of fruit shape in tomato. OVATE family proteins (OFPs are characterized as plant-specific transcription factors and conserved in Arabidopsis, tomato, and rice. Roles of OFPs involved in plant development and growth are largely unknown. Brassinosteroids (BRs are a class of steroid hormones involved in diverse biological functions. OsGKS2 plays a critical role in BR signaling by phosphorylating downstream components such as OsBZR1 and DLT. Here we report in rice that OsOFP8 plays a positive role in BR signaling pathway. BL treatment induced the expression of OsOFP8 and led to enhanced accumulation of OsOFP8 protein. The gain-of-function mutant Osofp8 and OsOFP8 overexpression lines showed enhanced lamina joint inclination, whereas OsOFP8 RNAi transgenic lines showed more upright leaf phenotype, which suggest that OsOFP8 is involved in BR responses. Further analyses indicated that OsGSK2 interacts with and phosphorylates OsOFP8. BRZ treatment resulted in the cytoplasmic distribution of OsOFP8, and bikinin treatment reduced the cytoplasmic accumulation of OsOFP8. Phosphorylation of OsOFP8 by OsGSK2 is needed for its nuclear export. The phospphorylated OsOFP8 shuttles to the cytoplasm and is targeted for proteasomal degradation. These results indicate that OsOFP8 is a substrate of OsGSK2 and the function of OsOFP8 in plant growth and development is at least partly through the BR signaling pathway.

  11. The influenza virus protein PB1-F2 interacts with IKKβ and modulates NF-κB signalling.

    Directory of Open Access Journals (Sweden)

    Ana Luísa Reis

    Full Text Available PB1-F2, a protein encoded by a second open reading frame of the influenza virus RNA segment 2, has emerged as a modulator of lung inflammatory responses but the molecular mechanisms underlying this are only poorly understood. Here we show that PB1-F2 inhibits the activation of NF-κB dependent signalling pathways in luciferase reporter assays. PB1-F2 proteins from four different viruses interact with IKKβ in yeast two-hybrid assays and by co-immunoprecipitation. PB1-F2 expression did not inhibit IKKβ kinase activity or NF-κB translocation into the nucleus, but NF-κB binding to DNA was severely impaired in PB1-F2 transfected cells as assessed by Electrophoretic Mobility Shift Assay. Neither the N-terminal 57 amino acid truncated forms nor the C-terminus of PB1-F2 were able to inhibit NF-κB dependent signalling, indicating that the full length protein is necessary for the inhibition.

  12. Targeting the interaction of Aurora kinases and SIRT1 mediated by Wnt signaling pathway in colorectal cancer: A critical review.

    Science.gov (United States)

    Subramaniyan, Boopathi; Jagadeesan, Kaviya; Ramakrishnan, Sabitha; Mathan, Ganeshan

    2016-08-01

    The Aurora kinases belong to the family of serine/threonine kinase, a central regulator of mitosis and their expression increased during G2/M phase. It is classified into Aurora A, B and C, each has distinct roles in cellular processes, which includes regulation of spindle assembly, function of centrosomes, cytoskeleton and cytokinesis. During cancer growth, their rapid increase makes most attractive marker for cancer treatment at present. However Aurora A kinase is known to be a marker for cancer therapy, the most important serine/threonine kinase of Aurora B kinase involvement in cancer is still inadequate. Subsequently, the recent findings revealed that the class III histone deacetylase of SIRT1 is a key regulator to activate Aurora kinases from S phase damaged DNA through Wnt signaling pathway. Even if both Aurora A kinase and SIRT1 serve as a marker for cancer therapy, the present review reveals it is interaction in Wnt signaling pathway that solely for colorectal cancer. PMID:27470380

  13. Development of a system based on 3D vision, interactive virtual environments, ergonometric signals and a humanoid for stroke rehabilitation.

    Science.gov (United States)

    Ibarra Zannatha, Juan Manuel; Tamayo, Alejandro Justo Malo; Sánchez, Angel David Gómez; Delgado, Jorge Enrique Lavín; Cheu, Luis Eduardo Rodríguez; Arévalo, Wilson Alexander Sierra

    2013-11-01

    This paper presents a stroke rehabilitation (SR) system for the upper limbs, developed as an interactive virtual environment (IVE) based on a commercial 3D vision system (a Microsoft Kinect), a humanoid robot (an Aldebaran's Nao), and devices producing ergonometric signals. In one environment, the rehabilitation routines, developed by specialists, are presented to the patient simultaneously by the humanoid and an avatar inside the IVE. The patient follows the rehabilitation task, while his avatar copies his gestures that are captured by the Kinect 3D vision system. The information of the patient movements, together with the signals obtained from the ergonometric measurement devices, is used also to supervise and to evaluate the rehabilitation progress. The IVE can also present an RGB image of the patient. In another environment, that uses the same base elements, four game routines--Touch the balls 1 and 2, Simon says, and Follow the point--are used for rehabilitation. These environments are designed to create a positive influence in the rehabilitation process, reduce costs, and engage the patient. PMID:23827333

  14. Development of a system based on 3D vision, interactive virtual environments, ergonometric signals and a humanoid for stroke rehabilitation.

    Science.gov (United States)

    Ibarra Zannatha, Juan Manuel; Tamayo, Alejandro Justo Malo; Sánchez, Angel David Gómez; Delgado, Jorge Enrique Lavín; Cheu, Luis Eduardo Rodríguez; Arévalo, Wilson Alexander Sierra

    2013-11-01

    This paper presents a stroke rehabilitation (SR) system for the upper limbs, developed as an interactive virtual environment (IVE) based on a commercial 3D vision system (a Microsoft Kinect), a humanoid robot (an Aldebaran's Nao), and devices producing ergonometric signals. In one environment, the rehabilitation routines, developed by specialists, are presented to the patient simultaneously by the humanoid and an avatar inside the IVE. The patient follows the rehabilitation task, while his avatar copies his gestures that are captured by the Kinect 3D vision system. The information of the patient movements, together with the signals obtained from the ergonometric measurement devices, is used also to supervise and to evaluate the rehabilitation progress. The IVE can also present an RGB image of the patient. In another environment, that uses the same base elements, four game routines--Touch the balls 1 and 2, Simon says, and Follow the point--are used for rehabilitation. These environments are designed to create a positive influence in the rehabilitation process, reduce costs, and engage the patient.

  15. RT-PCR and Northern blot analysis in search for a putative Paramecium beta-adrenergic receptor.

    Science.gov (United States)

    Płatek, A; Wiejak, J; Wyroba, E

    1999-01-01

    RT-PCR and Northern blot analysis were performed in order to search for a putative beta-adrenergic receptor (beta-AR) in Paramecium using several beta2-adrenergic-specific molecular probes. Under strictly defined RT-PCR conditions DNA species of expected molecular size about 360 bp were generated with the primers corresponding to the universal mammalian beta2-AR sequence tagged sites (located within the 4th and the 6th transmembrane regions of the receptor). This RT-PCR product hybridized in Southern blot analysis with the oligonucleotide probe designed to the highly conservative beta2-AR region involved in G-proteins interaction and located within the amplified region. Northern hybridization was performed on Paramecium total RNA and mRNA with human beta2-AR cDNA and two oligonucleotide probes: the first included Phe 290 involved in agonist binding (Strader et al., 1995) and the second was the backward RT-PCR primer. All these probes revealed the presence of about 2 kb mRNA which is consistent with the size of beta2-AR transcripts found in higher eukaryotes.

  16. Dopaminergic and beta-adrenergic effects on gastric antral motility

    DEFF Research Database (Denmark)

    Bech, K; Hovendal, C P; Gottrup, F;

    1984-01-01

    bethanechol or pentagastrin inducing motor activity patterns as in the phase III of the MMC and the digestive state respectively. The stimulated antral motility was dose-dependently inhibited by dopamine. The effect was significantly blocked by specifically acting dopaminergic blockers, while alpha- and beta......-adrenergic blockers were without any significant effects. Dose-response experiments with bethanechol and dopamine showed inhibition of a non-competitive type. Isoprenaline was used alone and in conjunction with selective blockade of beta 1- and beta 2-receptors during infusion of bethanechol which induces a pattern...... similar to phase III in the migrating myoelectric complex. The stimulated antral motility was dose-dependently inhibited by isoprenaline. The effect could be significantly blocked by propranolol (beta 1 + beta 2-adrenoceptor blocker) and by using in conjunction the beta 1-adrenoceptor blocker practolol...

  17. EEG differences between the opioid and adrenergic psyhoneuroendocrine rat types

    DEFF Research Database (Denmark)

    Cristea, A; Moldovan, M; Munteanu, A M;

    2000-01-01

    Our work is based on the hypothesis of the existence of an opioid psychoneuroendocrine type named "O" type (Cristea, 1993), opposed to the well known adrenergic "A" type described by Roseman and Friedman in 1980. In the present study we tested the differences between the background EEG activity...... adult (140 g) male Wistar population using the distribution of the tail retraction time (TRT) during a tail-flick test. The epidural EEG activity, was quantified within the 1-30 Hz band by six numerical parameters: root mean square (RMS), mean spectral frequency (MSF), spectral edge frequency at 95...... theta RSP asymmetry both during consciousness and ether anesthesia while no such theta gradient could be shown for the "O" type. The differences between the "A" and "O" types are enhanced under light Ether anesthesia to which the "A" type is more resistant. The EEG complementarity between the "A" and "O...

  18. The human thoracic duct is functionally innervated by adrenergic nerves

    DEFF Research Database (Denmark)

    Telinius, Niklas; Baandrup, Ulrik; Rumessen, Jüri;

    2014-01-01

    Lymphatic vessels from animals have been shown to be innervated. While morphological studies have confirmed human lymphatic vessels are innervated, functional studies supporting this are lacking. The present study demonstrates a functional innervation of the human thoracic duct (TD) that is predo......Lymphatic vessels from animals have been shown to be innervated. While morphological studies have confirmed human lymphatic vessels are innervated, functional studies supporting this are lacking. The present study demonstrates a functional innervation of the human thoracic duct (TD......) that is predominantly adrenergic. TDs harvested from 51 patients undergoing esophageal and cardia cancer surgery were either fixed for structural investigations or maintained in vitro for the functional assessment of innervation by isometric force measurements and electrical field stimulation (EFS). Electron microscopy...

  19. Adrenergic receptors and gastric secretion in dogs. Is a "tonic balance" relationship between vagal and beta 2-adrenergic activity a possibility?

    DEFF Research Database (Denmark)

    Gottrup, F; Hovendal, C; Bech, K;

    1984-01-01

    The relative influence of adrenergic receptors on gastric acid secretion in the dog stomach with different vagal activity or "tone" is almost unknown. beta-adrenoceptors seem to be most important for the direct effect of adrenergic stimulation on acid secretion. In this study the effects of vagot...... that a counterbalance between beta 2-adrenergic and cholinergic vagal tone exists. A "tonic balance theory" is suggested and is probably involved in the resulting acid secretion after vagotomy.......The relative influence of adrenergic receptors on gastric acid secretion in the dog stomach with different vagal activity or "tone" is almost unknown. beta-adrenoceptors seem to be most important for the direct effect of adrenergic stimulation on acid secretion. In this study the effects...... of vagotomy and beta 2-adrenoceptor activity were studied in conscious gastric fistula dogs. Pentagastrin stimulated acid output was increased slightly in non-vagotomized dogs and to its prevagotomy level in vagotomized dogs after propranolol infusion. Practolol showed no such effect. Histamine stimulated...

  20. EFFECTS OF EXERCISE TRAINING ON CARDIOVASCULAR ADRENERGIC SYSTEM

    Directory of Open Access Journals (Sweden)

    Dario eLeosco

    2013-11-01

    Full Text Available In heart failure (HF, exercise has been shown to modulate cardiac sympathetic hyperactivation which is one of the earliest features of neurohormonal derangement in this syndrome and correlates with adverse outcome. An important molecular alteration related to chronic sympathetic overstimulation in HF is represented by cardiac β-adrenergic receptor (β-AR dysfunction . It has been demonstrated that exercise reverses β-AR dysfunction by restoring cardiac receptor membrane density and G-protein-dependent adenylyl cyclase activation. In particular, several evidence indicate that exercise reduces levels of cardiac G-protein coupled receptor kinase-2 (GRK2 which is known to be involved in both β1-AR and β2-AR dysregulation in HF. Similar alterations of β-AR system have been described also in the senescent heart. It has also been demonstrated that exercise training restores adrenal GRK2/α-2AR/cathecolamine (CA production axis. At vascular level, exercise shows a therapeutic effect on age-related impairment of vascular reactivity to adrenergic stimulation and restores β-AR-dependent vasodilatation by increasing vascular β-AR responsiveness and reducing endothelial GRK2 activity. Sympathetic nervous system overdrive is thought to account for >50 % of all cases of hypertension and a lack of balance between parasympathetic and sympathetic modulation has been observed in hypertensive subjects. Non-pharmacological, lifestyle interventions have been associated with reductions in SNS overactivity and blood pressure in hypertension. Several evidence have highlighted the blood pressure lowering effects of aerobic endurance exercise in patients with hypertension and the significant reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining the favourable effects of exercise on blood pressure control.

  1. Proapoptotic RYBP interacts with FANK1 and induces tumor cell apoptosis through the AP-1 signaling pathway.

    Science.gov (United States)

    Ma, Wen; Zhang, Xuan; Li, Meng; Ma, Xiaoli; Huang, Bingren; Chen, Hong; Chen, Deng

    2016-08-01

    Ring1 and YY1 Binding Protein (RYBP) induces tumor-specific cell apoptosis, but the underlying molecular mechanism has not been fully understood. Here we conducted a yeast two hybrid screen and identified FANK1 (Fibronectin type III and ankyrin repeat domains 1) as a novel RYBP-interacting protein. This interaction was confirmed by coimmunoprecipitation, GST pulldown and immunofluorescence assays. We mapped that the FNIII domain at the N-terminal of FANK1 binds to the Serine/Threonine-rich region at the C-terminal of RYBP. Further studies showed that overexpression of RYBP stabilized, whereas knockdown of RYBP by its specific shRNAs reduced, the expression of FANK1. Mechanistic studies revealed that RYBP inhibited the proteasome degradation of polyubiquitinated FANK1, thus prolonging the half-life of FANK1 protein. Functional studies indicated that RYBP activates FANK1-mediated activator protein 1 (AP-1) signaling pathway which contributes to tumor cell apoptosis. Taken together, our current study uncovered a new mechanism which RYBP utilizes to exert its pro-apoptotic activity in human tumor cells. PMID:27060496

  2. A Cyclic di-GMP-binding Adaptor Protein Interacts with Histidine Kinase to Regulate Two-component Signaling.

    Science.gov (United States)

    Xu, Linghui; Venkataramani, Prabhadevi; Ding, Yichen; Liu, Yang; Deng, Yinyue; Yong, Grace Lisi; Xin, Lingyi; Ye, Ruijuan; Zhang, Lianhui; Yang, Liang; Liang, Zhao-Xun

    2016-07-29

    The bacterial messenger cyclic di-GMP (c-di-GMP) binds to a diverse range of effectors to exert its biological effect. Despite the fact that free-standing PilZ proteins are by far the most prevalent c-di-GMP effectors known to date, their physiological function and mechanism of action remain largely unknown. Here we report that the free-standing PilZ protein PA2799 from the opportunistic pathogen Pseudomonas aeruginosa interacts directly with the hybrid histidine kinase SagS. We show that PA2799 (named as HapZ: histidine kinase associated PilZ) binds directly to the phosphoreceiver (REC) domain of SagS, and that the SagS-HapZ interaction is further enhanced at elevated c-di-GMP concentration. We demonstrate that binding of HapZ to SagS inhibits the phosphotransfer between SagS and the downstream protein HptB in a c-di-GMP-dependent manner. In accordance with the role of SagS as a motile-sessile switch and biofilm growth factor, we show that HapZ impacts surface attachment and biofilm formation most likely by regulating the expression of a large number of genes. The observations suggest a previously unknown mechanism whereby c-di-GMP mediates two-component signaling through a PilZ adaptor protein.

  3. Radial position of single-site gamma-ray interactions from a parametric pulse shape analysis of germanium detector signals

    CERN Document Server

    Orrell, J L; Cooper, M W; Kephart, J D; Seifert, C E; Orrell, John L.; Aalseth, Craig E.; Cooper, Matthew W.; Kephart, Jeremy D.; Seifert, Carolyn E.

    2007-01-01

    Pulse shape analysis of germanium gamma-ray spectrometer signals can yield information on the radial position of individual gamma-ray interactions within the germanium crystal. A parametric pulse shape analysis based on calculation of moments of the reconstructed current pulses from a closed-ended coaxial germanium detector is used to preferentially select single-site gamma-ray interactions. The double escape peak events from the 2614.5 keV gamma-ray of 208-Tl are used as a training set to optimize the single-site event selection region in the pulse shape parameter space. A collimated source of 320.1 keV gamma-rays from 51-Cr is used to scan different radial positions of the same semi-coaxial germanium detector. The previously trained single-site selection region is used to preferentially identify the single-site photoelectric absorption events from the 320.1 keV full-energy peak. From the identified events, a comparison of the pulse shape parameter space distributions between different scan positions allows ...

  4. A Cyclic di-GMP-binding Adaptor Protein Interacts with Histidine Kinase to Regulate Two-component Signaling.

    Science.gov (United States)

    Xu, Linghui; Venkataramani, Prabhadevi; Ding, Yichen; Liu, Yang; Deng, Yinyue; Yong, Grace Lisi; Xin, Lingyi; Ye, Ruijuan; Zhang, Lianhui; Yang, Liang; Liang, Zhao-Xun

    2016-07-29

    The bacterial messenger cyclic di-GMP (c-di-GMP) binds to a diverse range of effectors to exert its biological effect. Despite the fact that free-standing PilZ proteins are by far the most prevalent c-di-GMP effectors known to date, their physiological function and mechanism of action remain largely unknown. Here we report that the free-standing PilZ protein PA2799 from the opportunistic pathogen Pseudomonas aeruginosa interacts directly with the hybrid histidine kinase SagS. We show that PA2799 (named as HapZ: histidine kinase associated PilZ) binds directly to the phosphoreceiver (REC) domain of SagS, and that the SagS-HapZ interaction is further enhanced at elevated c-di-GMP concentration. We demonstrate that binding of HapZ to SagS inhibits the phosphotransfer between SagS and the downstream protein HptB in a c-di-GMP-dependent manner. In accordance with the role of SagS as a motile-sessile switch and biofilm growth factor, we show that HapZ impacts surface attachment and biofilm formation most likely by regulating the expression of a large number of genes. The observations suggest a previously unknown mechanism whereby c-di-GMP mediates two-component signaling through a PilZ adaptor protein. PMID:27231351

  5. Adipogenic role of alternatively activated macrophages in β-adrenergic remodeling of white adipose tissue.

    Science.gov (United States)

    Lee, Yun-Hee; Kim, Sang-Nam; Kwon, Hyun-Jung; Maddipati, Krishna Rao; Granneman, James G

    2016-01-01

    De novo brown adipogenesis involves the proliferation and differentiation of progenitors, yet the mechanisms that guide these events in vivo are poorly understood. We previously demonstrated that treatment with a β3-adrenergic receptor (ADRB3) agonist triggers brown/beige adipogenesis in gonadal white adipose tissue following adipocyte death and clearance by tissue macrophages. The close physical relationship between adipocyte progenitors and tissue macrophages suggested that the macrophages that clear dying adipocytes might generate proadipogenic factors. Flow cytometric analysis of macrophages from mice treated with CL 316,243 identified a subpopulation that contained elevated lipid and expressed CD44. Lipidomic analysis of fluorescence-activated cell sorting-isolated macrophages demonstrated that CD44+ macrophages contained four- to five-fold higher levels of the endogenous peroxisome-proliferator activated receptor gamma (PPARγ) ligands 9-hydroxyoctadecadienoic acid (HODE), and 13-HODE compared with CD44- macrophages. Gene expression profiling and immunohistochemistry demonstrated that ADRB3 agonist treatment upregulated expression of ALOX15, the lipoxygenase responsible for generating 9-HODE and 13-HODE. Using an in vitro model of adipocyte efferocytosis, we found that IL-4-primed tissue macrophages accumulated lipid from dying fat cells and upregulated expression of Alox15. Furthermore, treatment of differentiating adipocytes with 9-HODE and 13-HODE potentiated brown/beige adipogenesis. Collectively, these data indicate that noninflammatory removal of adipocyte remnants and coordinated generation of PPARγ ligands by M2 macrophages provides localized adipogenic signals to support de novo brown/beige adipogenesis.

  6. Adipogenic role of alternatively activated macrophages in β-adrenergic remodeling of white adipose tissue.

    Science.gov (United States)

    Lee, Yun-Hee; Kim, Sang-Nam; Kwon, Hyun-Jung; Maddipati, Krishna Rao; Granneman, James G

    2016-01-01

    De novo brown adipogenesis involves the proliferation and differentiation of progenitors, yet the mechanisms that guide these events in vivo are poorly understood. We previously demonstrated that treatment with a β3-adrenergic receptor (ADRB3) agonist triggers brown/beige adipogenesis in gonadal white adipose tissue following adipocyte death and clearance by tissue macrophages. The close physical relationship between adipocyte progenitors and tissue macrophages suggested that the macrophages that clear dying adipocytes might generate proadipogenic factors. Flow cytometric analysis of macrophages from mice treated with CL 316,243 identified a subpopulation that contained elevated lipid and expressed CD44. Lipidomic analysis of fluorescence-activated cell sorting-isolated macrophages demonstrated that CD44+ macrophages contained four- to five-fold higher levels of the endogenous peroxisome-proliferator activated receptor gamma (PPARγ) ligands 9-hydroxyoctadecadienoic acid (HODE), and 13-HODE compared with CD44- macrophages. Gene expression profiling and immunohistochemistry demonstrated that ADRB3 agonist treatment upregulated expression of ALOX15, the lipoxygenase responsible for generating 9-HODE and 13-HODE. Using an in vitro model of adipocyte efferocytosis, we found that IL-4-primed tissue macrophages accumulated lipid from dying fat cells and upregulated expression of Alox15. Furthermore, treatment of differentiating adipocytes with 9-HODE and 13-HODE potentiated brown/beige adipogenesis. Collectively, these data indicate that noninflammatory removal of adipocyte remnants and coordinated generation of PPARγ ligands by M2 macrophages provides localized adipogenic signals to support de novo brown/beige adipogenesis. PMID:26538237

  7. Adrenergic effects on secretion of amylase from the rat salivary glands

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba

    1988-01-01

    The present study was undertaken to investigate the effect of adrenergic agents on secretion of amylase from the salivary glands in vivo. Saliva was collected from the distal oesophagus in conscious rats. Adrenaline increased the concentration of amylase in saliva and serum significantly....... The result of infusion of alpha- and beta-adrenergic antagonists as well as noradrenaline and isoproterenol showed that secretion of salivary amylase is predominantly mediated by stimulation of beta-adrenergic receptors, especially of the beta 1-subtype. Investigation of the isoenzyme pattern in saliva......, pancreatic juice and serum demonstrated that the major component in serum is salivary amylase. This study has shown that beta-adrenergic agents stimulate secretion of amylase from the salivary glands in rats. Though the secretion is mainly exocrine small amounts of amylase is found in serum, which seems...

  8. β2-adrenergic receptor Thr164Ile polymorphism, obesity, and diabetes

    DEFF Research Database (Denmark)

    Thomsen, Mette; Dahl, Morten; Tybjærg-Hansen, Anne;

    2012-01-01

    The β(2)-adrenergic receptor (ADRB2) influences regulation of energy balance by stimulating catecholamine-induced lipolysis in adipose tissue. The rare functional ADRB2rs1800888(Thr164Ile) polymorphism could therefore influence risk of obesity and subsequently diabetes.......The β(2)-adrenergic receptor (ADRB2) influences regulation of energy balance by stimulating catecholamine-induced lipolysis in adipose tissue. The rare functional ADRB2rs1800888(Thr164Ile) polymorphism could therefore influence risk of obesity and subsequently diabetes....

  9. On the adrenergic system of ganoid fish: the beluga, Huso huso (chondrostei).

    Science.gov (United States)

    Balashov, N V; Fänge, R; Govyrin, V A; Leont'eva, G R; Nilsson, S; Prozorovskaya, M P

    1981-04-01

    The adrenergic system of the beluga, Huso huso, was studied by glyoxylic acid fluorescence histochemistry, analyses of catecholamine content in various organs and studies of the effects of acetylcholine and adrenaline on isolated strip preparations from blood vessels, spleen, atrium and ventricle. Chromaffin cells were found mainly in the walls of the posterior cardinal veins, and to some extent also in the wall of the celiaco-mesenteric artery. The plasma concentration of adrenaline was high enough to affect the contraction force of the isolated atrial and ventricular strips, thus adding an adrenergic component to a possible cholinergic inhibitory vagal control of the heart. Fluorescence histochemistry revealed no direct adrenergic innervation of the heart, but blood vessels in the heart and elsewhere received a rich supply of adrenergic nerve terminals. Adrenaline contracted the celiaco-mesenteric artery and the spleen, and produced positive inotropic effects on the paced atrial and ventricular strip preparations. Acetylcholine contracted the ventral aorta and the celiaco-mesenteric artery, and reduced the contraction force of paced ventricular and, especially, atrial preparations. It is concluded that the beluga has a well developed adrenergic system consisting of both chromaffin cells and adrenergic neurons with varicose nerve terminals of the type found in the higher vertebrates. PMID:7304205

  10. Immunoanalogue of vertebrate beta-adrenergic receptor in the unicellular eukaryote Paramecium.

    Science.gov (United States)

    Wiejak, Jolanta; Surmacz, Liliana; Wyroba, Elzbieta

    2002-01-01

    Cell fractionation, SDS-PAGE, quantitative Western blot, confocal immunolocalization and immunogold labelling were performed to find an interpretation of the physiological response of the unicellular eukaryote Paramecium to beta-adrenergic ligands. The 69 kDa polypeptide separated by SDS-PAGE in S2 and P2 Paramecium subcellular fractions cross-reacted with antibody directed against human beta2-adrenergic receptor. This was detected by Western blotting followed by chemiluminescent detection. Quantitative image analysis showed that beta-selective adrenergic agonist (-)-isoproterenol--previously shown to enhance phagocytic activity--evoked redistribution of the adrenergic receptor analogue from membraneous (P2) to cytosolic (S2) fraction. The relative increase in immunoreactive band intensity in S2 reached 80% and was paralleled by a 59% decrease in P2 fraction. Confocal immunofluorescence revealed beta2-adrenergic receptor sites on the cell surface and at the ridge of the cytopharynx--where nascent phagosomes are formed. This localization was confirmed by immunoelectron microscopy. These results indicate that the 69 kDa Paramecium polypeptide immunorelated to vertebrate beta2-adrenergic receptor appeared in this evolutionary ancient cell as a nutrient receptor.

  11. Analysis of adrenergic regulation of melatonin synthesis in Siberian hamster pineal emphasizes the role of HIOMT.

    Science.gov (United States)

    Ceinos, R M; Chansard, M; Revel, F; Calgari, C; Míguez, J M; Simonneaux, V

    2004-01-01

    Seasonal variations of environmental factors are translated into annual fluctuations in synthesis and release of melatonin, which in turn acts as a neuroendocrine messenger for the synchronization of annual functions. So far, most studies performed to understand the regulation of melatonin synthesis have used the non seasonal laboratory rat. It was demonstrated that nocturnal melatonin synthesis depends on alpha- and beta-adrenergic activation of the enzyme arylalkylamine N-acetyltransferase (AA-NAT). In this study, we investigated the mechanisms of melatonin synthesis in the Siberian hamster, a seasonal species with marked photoperiodic variation in melatonin peak duration and amplitude. A beta-adrenergic receptor agonist alone markedly stimulated AA-NAT activity and melatonin synthesis and release. An alpha-adrenergic receptor agonist, while having no effect per se, potentiated the beta-adrenergic stimulation of AA-NAT activity both in vitro and in vivo. Strikingly, the potentiation of AA-NAT activity did not result in a potentiation of melatonin synthesis, suggesting that the rate of melatonin production is limited downstream in the metabolic pathway, most probably at the level of hydroxyindole-O-methyltransferase (HIOMT). HIOMT presented a constitutively high activity that was not acutely (within hours) stimulated by beta-adrenergic agonist, but was rather up-regulated by chronic application of the agonist. This long-term beta-adrenergic regulation may explain the reported large photoperiodic variation of HIOMT activity that drives the photoperiodic variation in melatonin peak.

  12. Effect of β3-adrenergic agonists on alveolar fluid clearance in hypoxic rat lungs

    Institute of Scientific and Technical Information of China (English)

    LI Nai-jing; LI Wei; HE Ping; GU Xiu; LI Sheng-qi

    2010-01-01

    Background Recent research suggests that β_2-adrenergic agonists increase alveolar fluid clearance (AFC) under physiologic and pathologic conditions. It is unknown whether β_3-adrenergic agonists also increase AFC under pathologic conditions. The aim of this study was to investigate the effect of β_3 -adrenergic agonists on AFC following hypoxic lung injury and the mechanisms involved.Methods Hypoxic rats were exposed to 10% oxygen. BRL-37344 (β_3-adrenergic agonist) or CGP-12177 (selective β_3-adrenergic agonist) alone or combined with β receptor antagonists, sodium channel blockers, or Na~+/K~+-ATPase blockers were perfused into the alveolar space of rats exposed to 10% oxygen for 48 hours. Total lung water content (TLW) and AFC were measured.Results AFC did not change for the first 24 hours but then decreased after 48-hour exposure to 10% oxygen. The perfusion of BRL-37344 or CGP-12177 significantly increased AFC in normal and hypoxic rats. The AFC-stimulating effect of CGP-12177 was lowered with amiloride (a Na~+ channel blocker) and ouabain (a Na~+/K~+-ATPase inhibitor) by 37% and 49%, respectively. Colchicine significantly inhibited the effect of CGP-12177.Conclusions These findings suggest that (β3-adrenergic agonists can increase AFC during hypoxic lung injury in rats and accelerate the amelioration of pulmonary edema.

  13. Calcium homeostasis and cone signaling are regulated by interactions between calcium stores and plasma membrane ion channels.

    Directory of Open Access Journals (Sweden)

    Tamas Szikra

    Full Text Available Calcium is a messenger ion that controls all aspects of cone photoreceptor function, including synaptic release. The dynamic range of the cone output extends beyond the activation threshold for voltage-operated calcium entry, suggesting another calcium influx mechanism operates in cones hyperpolarized by light. We have used optical imaging and whole-cell voltage clamp to measure the contribution of store-operated Ca(2+ entry (SOCE to Ca(2+ homeostasis and its role in regulation of neurotransmission at cone synapses. Mn(2+ quenching of Fura-2 revealed sustained divalent cation entry in hyperpolarized cones. Ca(2+ influx into cone inner segments was potentiated by hyperpolarization, facilitated by depletion of intracellular Ca(2+ stores, unaffected by pharmacological manipulation of voltage-operated or cyclic nucleotide-gated Ca(2+ channels and suppressed by lanthanides, 2-APB, MRS 1845 and SKF 96365. However, cation influx through store-operated channels crossed the threshold for activation of voltage-operated Ca(2+ entry in a subset of cones, indicating that the operating range of inner segment signals is set by interactions between store- and voltage-operated Ca(2+ channels. Exposure to MRS 1845 resulted in approximately 40% reduction of light-evoked postsynaptic currents in photopic horizontal cells without affecting the light responses or voltage-operated Ca(2+ currents in simultaneously recorded cones. The spatial pattern of store-operated calcium entry in cones matched immunolocalization of the store-operated sensor STIM1. These findings show that store-operated channels regulate spatial and temporal properties of Ca(2+ homeostasis in vertebrate cones and demonstrate their role in generation of sustained excitatory signals across the first retinal synapse.

  14. Predicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Stefano Vanni

    Full Text Available Understanding the binding mode of agonists to adrenergic receptors is crucial to enabling improved rational design of new therapeutic agents. However, so far the high conformational flexibility of G protein-coupled receptors has been an obstacle to obtaining structural information on agonist binding at atomic resolution. In this study, we report microsecond classical molecular dynamics simulations of β(1 and β(2 adrenergic receptors bound to the full agonist isoprenaline and in their unliganded form. These simulations show a novel agonist binding mode that differs from the one found for antagonists in the crystal structures and from the docking poses reported by in silico docking studies performed on rigid receptors. Internal water molecules contribute to the stabilization of novel interactions between ligand and receptor, both at the interface of helices V and VI with the catechol group of isoprenaline as well as at the interface of helices III and VII with the ethanolamine moiety of the ligand. Despite the fact that the characteristic N-C-C-OH motif is identical in the co-crystallized ligands and in the full agonist isoprenaline, the interaction network between this group and the anchor site formed by Asp(3.32 and Asn(7.39 is substantially different between agonists and inverse agonists/antagonists due to two water molecules that enter the cavity and contribute to the stabilization of a novel network of interactions. These new binding poses, together with observed conformational changes in the extracellular loops, suggest possible determinants of receptor specificity.

  15. Molecular characterization of banana NAC transcription factors and their interactions with ethylene signalling component EIL during fruit ripening.

    Science.gov (United States)

    Shan, Wei; Kuang, Jian-fei; Chen, Lei; Xie, Hui; Peng, Huan-huan; Xiao, Yun-yi; Li, Xue-ping; Chen, Wei-xin; He, Quan-guang; Chen, Jian-ye; Lu, Wang-jin

    2012-09-01

    The plant-specific NAC (NAM, ATAF1/2, and CUC2) transcription factors (TFs) play important roles in plant growth, development, and stress responses. However, the precise role of NAC TFs in relation to fruit ripening is poorly understood. In this study, six NAC genes, designated MaNAC1-MaNAC6, were isolated and characterized from banana fruit. Subcellular localization showed that MaNAC1-MaNAC5 proteins localized preferentially to the nucleus, while MaNAC6 was distributed throughout the entire cell. A transactivation assay in yeast demonstrated that MaNAC4 and MaNAC6, as well as their C-terminal regions, possessed trans-activation activity. Gene expression profiles in fruit with four different ripening characteristics, including natural, ethylene-induced, 1-methylcyclopropene (1-MCP)-delayed, and a combination of 1-MCP with ethylene treatment, revealed that the MaNAC genes were differentially expressed in peel and pulp during post-harvest ripening. MaNAC1 and MaNAC2 were apparently upregulated by ethylene in peel and pulp, consistent with the increase in ethylene production. In contrast, MaNAC3 in peel and pulp and MaNAC5 in peel were constitutively expressed, and transcripts of MaNAC4 in peel and pulp and MaNAC6 in peel decreased, while MaNAC5 or MaNAC6 in pulp increased slightly during fruit ripening. Furthermore, the MaNAC2 promoter was activated after ethylene application, further enhancing the involvement of MaNAC2 in fruit ripening. More importantly, yeast two-hybrid and bimolecular fluorescence complementation analyses confirmed that MaNAC1/2 physically interacted with a downstream component of ethylene signalling, ethylene insensitive 3 (EIN3)-like protein, termed MaEIL5, which was downregulated during ripening. Taken together, these results suggest that MaNACs such as MaNAC1/MaNAC2, may be involved in banana fruit ripening via interaction with ethylene signalling components.

  16. ABA Signaling in Guard Cells Entails a Dynamic Protein-Protein Interaction Relay from the PYL-RCAR Family Receptors to Ion Channels

    Institute of Scientific and Technical Information of China (English)

    Sung Chul Lee; Chae Woo Lim; Wenzhi Lan; Kai He; Sheng Luan

    2013-01-01

    Plant hormone abscisic acid (ABA) serves as an integrator of environmental stresses such as drought to trigger stomatal closure by regulating specific ion channels in guard cells.We previously reported that SLACl,an outward anion channel required for stomatal closure,was regulated via reversible protein phosphorylation events involving ABA signaling components,including protein phosphatase 2C members and a SnRK2-type kinase (OST1).In this study,we reconstituted the ABA signaling pathway as a protein-protein interaction relay from the PYL/RCAR-type receptors,to the PP2C-SnRK2 phosphatase-kinase pairs,to the ion channel SLACl.The ABA receptors interacted with and inhibited PP2C phosphatase activity against the SnRK2-type kinase,releasing active SnRK2 kinase to phosphorylate,and activate the SLACl channel,leading to reduced guard cell turgor and stomatal closure.Both yeast two-hybrid and bimolecular fluorescence complementation assays were used to verify the interactions among the components in the pathway.These biochemical assays demonstrated activity modifications of phosphatases and kinases by their interaction partners.The SLACl channel activity was used as an endpoint readout for the strength of the signaling pathway,depending on the presence of different combinations of signaling components.Further study using transgenic plants overexpressing one of the ABA receptors demonstrated that changing the relative level of interacting partners would change ABA sensitivity.

  17. β2 Adrenergic Receptor Fluorescent Protein Fusions Traffic to the Plasma Membrane and Retain Functionality

    Science.gov (United States)

    Bubnell, Jaclyn; Pfister, Patrick; Sapar, Maria L.; Rogers, Matthew E.; Feinstein, Paul

    2013-01-01

    Green fluorescent protein (GFP) has proven useful for the study of protein interactions and dynamics for the last twenty years. A variety of new fluorescent proteins have been developed that expand the use of available excitation spectra. We have undertaken an analysis of seven of the most useful fluorescent proteins (XFPs), Cerulean (and mCerulean3), Teal, GFP, Venus, mCherry and TagRFP657, as fusions to the archetypal G-protein coupled receptor, the β2 adrenergic receptor (β2AR). We have characterized these β2AR::XFP fusions in respect to membrane trafficking and G-protein activation. We noticed that in the mouse neural cell line, OP 6, that membrane bound β2AR::XFP fusions robustly localized in the filopodia identical to gap::XFP fusions. All β2AR::XFP fusions show responses indistinguishable from each other and the non-fused form after isoprenaline exposure. Our results provide a platform by which G-protein coupled receptors can be dissected for their functionality. PMID:24086401

  18. The adrenergic retulation of the cardiovascular system in the South American rattlesnake, Crotalus durissus

    DEFF Research Database (Denmark)

    Galli, G.L.J.; Jensen, Nini Skovgaard; Abe, A.S.;

    2007-01-01

    The present study investigates adrenergic regulation of the systemic and pulmonary circulations of the anaesthetised South American rattlesnake, Crotalus durissus. Haemodynamic measurements were made following bolus injections of adrenaline and adrenergic antagonists administered through a systemic...... arterial catheter. Adrenaline caused a marked systemic vasoconstriction that was abolished by phentolamine, indicating this response was mediated through α-adrenergic receptors. Injection of phentolamine gave rise to a pronounced vasodilatation (systemic conductance (Gsys) more than doubled), while...... injection of propranolol caused a systemic vasoconstriction, pointing to a potent α-adrenergic, and a weaker β-adrenergic tone in the systemic vasculature of Crotalus. Overall, the pulmonary vasculature was far less responsive to adrenergic stimulation than the systemic circulation. Adrenaline caused...

  19. SGT1 interacts with the Prf resistance protein and is required for Prf accumulation and Prf-mediated defense signaling.

    Science.gov (United States)

    Kud, Joanna; Zhao, Zhulu; Du, Xinran; Liu, Yule; Zhao, Yun; Xiao, Fangming

    2013-02-15

    The highly conserved eukaryotic co-chaperone SGT1 (suppressor of the G2 allele of skp1) is an important signaling component of plant defense responses and positively regulates disease resistance conferred by many resistance (R) proteins. In this study, we investigated the contribution of SGT1 in the Prf-mediated defense responses in both Nicotiana benthamiana and tomato (Solanum lycopersicum). SGT1 was demonstrated to interact with Prf in plant cells by co-immunoprecipitation. The requirement of SGT1 in the accumulation of Prf or autoactive Prf(D1416V) was determined by the degradation of these proteins in N. benthamiana, in which SGT1 was repressed by virus-induced gene silencing (VIGS). Pseudomonas pathogen assay on the SGT1-silenced tomato plants implicates SGT1 is required for the Prf-mediated full resistance to Pseudomonas syringae pv. tomato (Pst). These results suggest that, in both N. benthamiana and tomato, SGT1 contributes to the Prf-mediated defense responses by stabilizing Prf protein via its co-chaperone activity.

  20. Gene-environment interactions in male reproductive health: special reference to the aryl hydrocarbon receptor signaling pathway

    Directory of Open Access Journals (Sweden)

    Leon J S Brokken

    2014-02-01

    Full Text Available Over the last few decades, there have been numerous reports of adverse effects on the reproductive health of wildlife and laboratory animals caused by exposure to endocrine disrupting chemicals (EDCs. The increasing trends in human male reproductive disorders and the mounting evidence for causative environmental factors have therefore sparked growing interest in the health threat posed to humans by EDCs, which are substances in our food, environment and consumer items that interfere with hormone action, biosynthesis or metabolism, resulting in disrupted tissue homeostasis or reproductive function. The mechanisms of EDCs involve a wide array of actions and pathways. Examples include the estrogenic, androgenic, thyroid and retinoid pathways, in which the EDCs may act directly as agonists or antagonists, or indirectly via other nuclear receptors. Dioxins and dioxin-like EDCs exert their biological and toxicological actions through activation of the aryl hydrocarbon-receptor, which besides inducing transcription of detoxifying enzymes also regulates transcriptional activity of other nuclear receptors. There is increasing evidence that genetic predispositions may modify the susceptibility to adverse effects of toxic chemicals. In this review, potential consequences of hereditary predisposition and EDCs are discussed, with a special focus on the currently available publications on interactions between dioxin and androgen signaling.

  1. Interaction of signal transduction between angiotensin AT1 and AT2 receptor subtypes in rat senescent heart

    Institute of Scientific and Technical Information of China (English)

    SHI Shu-tian; LI Yan-fang

    2007-01-01

    Background Angiotensin Ⅱ (Ang Ⅱ) acting at angiotensin AT1 receptor (AT1R) has well documented effects on cardiovascular structure such as the promotion of cardiovascular hypertrophy and fibrosis, which are believed to be opposed by angiotensin AT2 receptor (AT2R) stimulation. The expressions of AT1R and AT2R are up-regulated in senescent hearts. The purpose of this study was to investigate the interaction of signal transduction between AT1R and AT2R, and to detect whether there is any difference in the interaction in rat hearts of different age.Methods In 3.5-, 12-, 18- and 24-month-old rats, the heart cell membrane activities of protein kinase C (PKC) andtyrosine kinase were measured when AT1R and AT2R were both activated by Ang Ⅱ or just the AT1R was activated by Ang Ⅱ and PD123319. The activities of cytosolic phospholipase A2 (cPLA2) and the levels of cGMP were investigated when AT1R and AT2R were both activated by Ang Ⅱ or just the AT2R was activated by Ang Ⅱ and Iosartan.Results When AT1R and AT2R were both activated compared to when the AT1R was activated, the activities of PKC were not different in hearts from 3.5- and 12-month-old rats, but decreased significantly in 18- and 24-month-old rats; the activities of tyrosine kinase were not different in 3.5-month-old rats but decreased significantly in 12-, 18- and 24-month-old rats. The activities of cPLA2 were all decreased significantly in rats of different age when AT1R and AT2R were both activated compared to when the AT2R was activated. Treatment with Ang Ⅱ alone compared to Ang Ⅱ and losartan decreased the levels of cGMP (fmol/mg) in rats of different age (102.7±12.7 versus 86.0±8.0 in 3.5-month-old rats, P<0.05; 81.0±9.4 versus 70.0±6.3 in 12-month-old rats, P<0.05; 69.8±5.6 versus 54.2±5.3 in 18-month-old rats,P<0.01; 57.7±8.0 versus 39.0±3.0 in 24-month-old rats, P<0.01).Conclusions The activation of AT1R inhibited the signal transduction of AT2R during the aging

  2. Stress-induced enhancement of mouse amygdalar synaptic plasticity depends on glucocorticoid and ß-adrenergic activity.

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    Ratna Angela Sarabdjitsingh

    Full Text Available BACKGROUND: Glucocorticoid hormones, in interaction with noradrenaline, enable the consolidation of emotionally arousing and stressful experiences in rodents and humans. Such interaction is thought to occur at least partly in the basolateral nucleus of the amygdala (BLA which is crucially involved in emotional memory formation. Extensive evidence points to long-term synaptic potentiation (LTP as a mechanism contributing to memory formation. Here we determined in adolescent C57/Bl6 mice the effects of stress on LTP in the LA-BLA pathway and the specific roles of corticosteroid and β-adrenergic receptor activation in this process. PRINCIPAL FINDINGS: Exposure to 20 min of restraint stress (compared to control treatment prior to slice preparation enhanced subsequent LTP induction in vitro, without affecting baseline fEPSP responses. The role of glucocorticoid receptors, mineralocorticoid receptors and β2-adrenoceptors in the effects of stress was studied by treating mice with the antagonists mifepristone, spironolactone or propranolol respectively (or the corresponding vehicles prior to stress or control treatment. In undisturbed controls, mifepristone and propranolol administration in vivo did not influence LTP induced in vitro. By contrast, spironolactone caused a gradually attenuating form of LTP, both in unstressed and stressed mice. Mifepristone treatment prior to stress strongly reduced the ability to induce LTP in vitro. Propranolol normalized the stress-induced enhancement of LTP to control levels during the first 10 min after high frequency stimulation, after which synaptic responses further declined. CONCLUSIONS: Acute stress changes BLA electrical properties such that subsequent LTP induction is facilitated. Both β-adrenergic and glucocorticoid receptors are involved in the development of these changes. Mineralocorticoid receptors are important for the maintenance of LTP in the BLA, irrespective of stress-induced changes in the

  3. Postnatal development of adrenergic responsiveness in the rabbit heart.

    Science.gov (United States)

    Feng, Z P; Dryden, W F; Gordon, T

    1989-08-01

    It is uncertain how changes in the beta-adrenoceptor population influence the contractility of developing heart. To resolve this we have examined postnatal developmental changes in the adrenergic responsiveness of the rabbit heart. The inotropic effect of isoproterenol on isolated left ventricular papillary muscles from rabbits aged 3, 21, and 90 days was compared with the relative number of beta-adrenoceptors at each age measured using [3H]dihydroalprenolol ([3H]DHA) as the specific ligand. The maximum tension developed in response to isoproterenol increases from 37 +/- 7 to 175 +/- 33% above control twitch tension between 3 and 21 days of age; this is followed by a decrease to 68 +/- 12% in the young adult. During this period of development, there is a decline in EC50 towards increased sensitivity. These differences are partially accounted for by an increase in the numbers of specific [3H]DHA binding sites from 17.3 +/- 2.3 to 56.6 +/- 9.9 fmol/mg wet tissue weight from 3 to 21 days, and a subsequent decrease to 32 +/- 4.5 fmol/mg tissue in the young adult. The proportionally larger increase in contractility compared with the number of beta-adrenoceptor binding sites during the first 3 weeks of life is discussed in terms of the developmental changes in the efficacy of coupling between receptor occupancy and contraction.

  4. Retromer in Osteoblasts Interacts With Protein Phosphatase 1 Regulator Subunit 14C, Terminates Parathyroid Hormone's Signaling, and Promotes Its Catabolic Response.

    Science.gov (United States)

    Xiong, Lei; Xia, Wen-Fang; Tang, Fu-Lei; Pan, Jin-Xiu; Mei, Lin; Xiong, Wen-Cheng

    2016-07-01

    Parathyroid hormone (PTH) plays critical, but distinct, roles in bone remodeling, including bone formation (anabolic response) and resorption (catabolic response). Although its signaling and function have been extensively investigated, it just began to be understood how distinct functions are induced by PTH activating a common receptor, the PTH type 1 receptor (PTH1R), and how PTH1R signaling is terminated. Here, we provide evidence for vacuolar protein sorting 35 (VPS35), a major component of retromer, in regulating PTH1R trafficking, turning off PTH signaling, and promoting its catabolic function. VPS35 is expressed in osteoblast (OB)-lineage cells. VPS35-deficiency in OBs impaired PTH(1-34)-promoted PTH1R translocation to the trans-Golgi network, enhanced PTH(1-34)-driven signaling, and reduced PTH(1-34)'s catabolic response in culture and in mice. Further mechanical studies revealed that VPS35 interacts with not only PTH1R, but also protein phosphatase 1 regulatory subunit 14C (PPP1R14C), an inhibitory subunit of PP1 phosphatase. PPP1R14C also interacts with PTH1R, which is necessary for the increased endosomal PTH1R signaling and decreased PTH(1-34)'s catabolic response in VPS35-deficient OB-lineage cells. Taken together, these results suggest that VPS35 deregulates PTH1R-signaling likely by its interaction with PTH1R and PPP1R14C. This event is critical for the control of PTH(1-34)-signaling dynamics, which may underlie PTH-induced catabolic response and adequate bone remodeling. PMID:27333042

  5. Looking for a needle in a haystack: Cellular proteins that may interact with the tyrosine-based sorting signal of the TGEV S protein.

    Science.gov (United States)

    Trincone, Anna; Schwegmann-Weßels, Christel

    2015-04-16

    The spike protein S of transmissible gastroenteritis virus, an Alphacoronavirus, contains a tyrosine-based sorting signal that is responsible for ERGIC retention and may be important for a correct viral assembly process. To find out whether the S protein interacts with cellular proteins via this sorting signal, a pulldown assay with GST fusion proteins was performed. Filamin A has been identified as a putative interaction candidate. Immunofluorescence assays confirmed a co-localization between the TGEV S protein and filamin A. Further experiments have to be performed to prove a significant impact of filamin A on TGEV infection. Different approaches of several researchers for the identification of cellular interaction candidates relevant for coronavirus replication are summarized. These results may help in the future to identify the role of cellular proteins during coronavirus assembly at the ER-Golgi intermediate compartment. PMID:25481285

  6. Neuromodulatory signaling in hippocampus-dependent memory retrieval.

    Science.gov (United States)

    Thomas, Steven A

    2015-04-01

    Considerable advances have been made toward understanding the molecular signaling events that underlie memory acquisition and consolidation. In contrast, less is known about memory retrieval, despite its necessity for utilizing learned information. This review focuses on neuromodulatory and intracellular signaling events that underlie memory retrieval mediated by the hippocampus, for which the most information is currently available. Among neuromodulators, adrenergic signaling is required for the retrieval of various types of hippocampus-dependent memory. Although they contribute to acquisition and/or consolidation, cholinergic and dopaminergic signaling are generally not required for retrieval. Interestingly, while not required for retrieval, serotonergic and opioid signaling may actually constrain memory retrieval. Roles for histamine and non-opioid neuropeptides are currently unclear but possible. A critical effector of adrenergic signaling in retrieval is reduction of the slow afterhyperpolarization mediated by β1 receptors, cyclic AMP, protein kinase A, Epac, and possibly ERK. In contrast, stress and glucocorticoids impair retrieval by decreasing cyclic AMP, mediated in part by the activation of β2 -adrenergic receptors. Clinically, alterations in neuromodulatory signaling and in memory retrieval occur in Alzheimer's disease, Down syndrome, depression, and post-traumatic stress disorder, and recent evidence has begun to link changes in neuromodulatory signaling with effects on memory retrieval.

  7. Therapeutic synergy and complementarity for ischemia/reperfusion injury: β1-adrenergic blockade and phosphodiesterase-3 inhibition.

    Science.gov (United States)

    Huang, Ming-He; Poh, Kian-Keong; Tan, Huay-Cheem; Welt, Frederick G P; Lui, Charles Y

    2016-07-01

    The β1-blocker when administered before reperfusion activates myocyte prosurvival signaling via β2-adrenergic receptor (β2-AR) and protein kinase A (PKA)-dependent mechanism during ischemia/reperfusion (I/R). The heart is endowed with powerful self-protective ability executed by endogenous β2-adrenopeptide receptor activation. I/R triggers cardiac epinephrine and neuropeptide calcitonin gene-related peptide (CGRP) release. Cardiac β1- and β2-AR stimulation mediates pro- and anti-apoptotic cell signaling, respectively. Removal of myocardial β1-AR-derived proapoptotic force with β1-AR blockade unmasks the dominance of β2-AR mediated prosurvival cell signaling through the well-defined PKA-Akt dependent mechanism. This review focuses on recent clinical and experimental findings including intrinsic cardiac β2-adrenopeptide neuroparacrine signaling mechanisms involved in I/R injury protection. While β2-adrenopeptide-mediated cardioprotection is important, age-related β2-adrenopeptide receptor decoupling can result in their ineffectiveness in response to the receptor-specific therapies. Accordingly, direct activation of receptor-coupled upstream PKA-dependent signaling may serve as a therapeutic alternative to achieve cardioprotection bypassing adrenopeptidergic receptor decoupling accompanied with aging. Phosphodiesterase-3 (PDE3) inhibitor reduces infarct-size via cAMP-dependent PKA signaling. Non-β1-AR-mediated PKA activation activates multiple prosurvival signaling pathways eventually leading to Akt activation. Combination therapy with β1-blocker esmolol and PDE3 inhibitor milrinone additively reduced infarct-size in preclinical studies. Concurrent β1-AR blockade and PDE3 inhibition provides complementary synergy with promising therapeutic potential in patients with acute myocardial infarction and beyond. PMID:27085132

  8. Structural determinants of heparin-transforming growth factor-β1 interactions and their effects on signaling.

    Science.gov (United States)

    Lee, Jonathan; Wee, Sheena; Gunaratne, Jayantha; Chua, R J E; Smith, Raymond A A; Ling, Ling; Fernig, David G; Swaminathan, Kunchithapadam; Nurcombe, Victor; Cool, Simon M

    2015-12-01

    Transforming growth factor-β1 (TGF-β1, Uniprot: P01137) is a heparin-binding protein that has been implicated in a number of physiological processes, including the initiation of chondrogenesis by human mesenchymal stem cells (hMSCs). Here, we identify the molecular features in the protein and in heparin required for binding and their effects on the potentiation of TGF-β1's activity on hMSCs. Using a proteomics "Protect and Label" approach, lysines K291, K304, K309, K315, K338, K373, K375 and K388 were identified as being directly involved in binding heparin (Data are available via ProteomeXchange with identifier PXD002772). Competition assays in an optical biosensor demonstrated that TGF-β1 does require N- and 6-O-sulfate groups for binding but that 2-O-sulfate groups are unlikely to underpin the interaction. Heparin-derived oligosaccharides as short as degree of polymerization (dp) 4 have a weak ability to compete for TGF-β1 binding to heparin, which increases with the length of the oligosaccharide to reach a maximum between dp18 and dp24. In cell-based assays, heparin, 2-O-, 6-O- and N-desulfated re-N-acetylated heparin and oligosaccharides 14-24 saccharides (dp14-24) in length all increased the phosphorylation of mothers against decapentaplegic homolog 2 (SMAD2) after 6 h of stimulation with TGF-β1. The results provide the structural basis for a model of heparin/heparan sulfate binding to TGF-β1 and demonstrate that the features in the polysaccharide required for binding are not identical to those required for sustaining the signaling by TGF-β1 in hMSCs.

  9. Ganglioside GM2 mediates migration of tumor cells by interacting with integrin and modulating the downstream signaling pathway.

    Science.gov (United States)

    Kundu, Manjari; Mahata, Barun; Banerjee, Avisek; Chakraborty, Sohini; Debnath, Shibjyoti; Ray, Sougata Sinha; Ghosh, Zhumur; Biswas, Kaushik

    2016-07-01

    The definitive role of ganglioside GM2 in mediating tumor-induced growth and progression is still unknown. Here we report a novel role of ganglioside GM2 in mediating tumor cell migration and uncovered its mechanism. Data shows differential expression levels of GM2-synthase as well as GM2 in different human cancer cells. siRNA mediated knockdown of GM2-synthase in CCF52, A549 and SK-RC-26B cells resulted in significant inhibition of tumor cell migration as well as invasion in vitro without affecting cellular proliferation. Over-expression of GM2-synthase in low-GM2 expressing SK-RC-45 cells resulted in a consequent increase in migration thus confirming the potential role GM2 and its downstream partners play in tumor cell migration and motility. Further, treatment of SK-RC-45 cells with exogenous GM2 resulted in a dramatic increase in migratory and invasive capacity with no change in proliferative capacity, thereby confirming the role of GM2 in tumorigenesis specifically by mediating tumor migration and invasion. Gene expression profiling of GM2-synthase silenced cells revealed altered expression of several genes involved in cell migration primarily those controlling the integrin mediated signaling. GM2-synthase knockdown resulted in decreased phosphorylation of FAK, Src as well as Erk, while over-expression and/or exogenous GM2 treatment caused increased FAK and Erk phosphorylation respectively. Again, GM2 mediated invasion and Erk phosphorylation is blocked in integrin knockdown SK-RC-45 cells, thus confirming that GM2 mediated migration and phosphorylation of Erk is integrin dependent. Finally, confocal microscopy suggested co-localization while co-immunoprecipitation and surface plasmon resonance (SPR) confirmed direct interaction of membrane bound ganglioside, GM2 with the integrin receptor.

  10. Heart rate control with adrenergic blockade: Clinical outcomes in cardiovascular medicine

    Directory of Open Access Journals (Sweden)

    David Feldman

    2010-05-01

    Full Text Available David Feldman1, Terry S Elton2, Doron M Menachemi3, Randy K Wexler41Heart Failure/Transplant and VAD Programs, Minneapolis Heart Institute, Minneapolis, Minnesota, USA; 2Division of Pharmacology, College of Pharmacology, The Ohio State University, Columbus, Ohio, USA; 3Heart Failure Services, Edith Wolfson Medical Center, The Heart Institute, Sakler School of Medicine, Tel-Aviv University, Holon, Israel; 4Department of Clinical Family Medicine, The Ohio State University, Columbus, Ohio, USAAbstract: The sympathetic nervous system is involved in regulating various cardiovascular parameters including heart rate (HR and HR variability. Aberrant sympathetic nervous system expression may result in elevated HR or decreased HR variability, and both are independent risk factors for development of cardiovascular disease, including heart failure, myocardial infarction, and hypertension. Epidemiologic studies have established that impaired HR control is linked to increased cardiovascular morbidity and mortality. One successful way of decreasing HR and cardiovascular mortality has been by utilizing β-blockers, because their ability to alter cell signaling at the receptor level has been shown to mitigate the pathogenic effects of sympathetic nervous system hyperactivation. Numerous clinical studies have demonstrated that β-blocker-mediated HR control improvements are associated with decreased mortality in postinfarct and heart failure patients. Although improved HR control benefits have yet to be established in hypertension, both traditional and vasodilating β-blockers exert positive HR control effects in this patient population. However, differences exist between traditional and vasodilating β-blockers; the latter reduce peripheral vascular resistance and exert neutral or positive effects on important metabolic parameters. Clinical evidence suggests that attainment of HR control is an important treatment objective for patients with cardiovascular

  11. Endogenous N-terminal Domain Cleavage Modulates α1D-Adrenergic Receptor Pharmacodynamics.

    Science.gov (United States)

    Kountz, Timothy S; Lee, Kyung-Soon; Aggarwal-Howarth, Stacey; Curran, Elizabeth; Park, Ji-Min; Harris, Dorathy-Ann; Stewart, Aaron; Hendrickson, Joseph; Camp, Nathan D; Wolf-Yadlin, Alejandro; Wang, Edith H; Scott, John D; Hague, Chris

    2016-08-26

    The α1D-adrenergic receptor (ADRA1D) is a key regulator of cardiovascular, prostate, and central nervous system functions. This clinically relevant G protein-coupled receptor has proven difficult to study, as it must form an obligate modular homodimer containing the PDZ proteins scribble and syntrophin or become retained in the endoplasmic reticulum as non-functional protein. We previously determined that targeted removal of the N-terminal (NT) 79 amino acids facilitates ADRA1D plasma membrane expression and agonist-stimulated functional responses. However, whether such an event occurs in physiological contexts was unknown. Herein, we report the ADRA1D is subjected to innate NT processing in cultured human cells. SNAP near-infrared imaging and tandem-affinity purification revealed the ADRA1D is expressed as both full-length and NT truncated forms in multiple human cell lines. Serial truncation mapping identified the cleavage site as Leu(90)/Val(91) in the 95-amino acid ADRA1D NT domain, suggesting human cells express a Δ1-91 ADRA1D species. Tandem-affinity purification MS/MS and co-immunoprecipitation analysis indicate NT processing of ADRA1D is not required to form scribble-syntrophin macromolecular complexes. Yet, label-free dynamic mass redistribution signaling assays demonstrate that Δ1-91 ADRA1D agonist responses were greater than WT ADRA1D. Mutagenesis of the cleavage site nullified the processing event, resulting in ADRA1D agonist responses less than the WT receptor. Thus, we propose that processing of the ADRA1D NT domain is a physiological mechanism employed by cells to generate a functional ADRA1D isoform with optimal pharmacodynamic properties. PMID:27382054

  12. Sexual dimorphism in adrenergic regulation of hepatic glycogenolysis

    Energy Technology Data Exchange (ETDEWEB)

    Studer, R.K.

    1987-04-01

    The total phosphorylase a plus b of hepatocytes isolated from females and incubated in the absence or presence of estradiol and progesterone at concentrations found in vivo does not vary during the estrous cycle. However, there is a slight but significant influence of the estrous cycle on basal and epinephrine-stimulated phosphorylase a activity, with a nadir being seen on diestrus. The relative contributions of the ..cap alpha..- and ..beta..-mediated pathways to phosphorylase a activation do not vary with the estrous cycle but are constant at 75 and 56%, respectively, of the response to 5 x 10/sup -8/ M epinephrine. When the epinephrine-stimulated glucose release from glycogen stores in cells from females and males is compared, the release from the female is greater than that from the male, while the ..cap alpha..-receptor-mediated stimulation in the female is comparable with that in the male. The epinephrine-stimulated increase in cytostolic free calcium (Ca/sub i/) is greater in the male than the female at 10/sup -6/ M but greater in the female than the male at 5 x 10/sup -9/ M. The changes in Ca/sub i/ are equivalent at intermediate epinephrine concentrations. When considered with the prior analysis of /sup 45/Ca efflux after adrenergic stimulation, this suggests there may be a sexual dimorphism in hepatocyte calcium transport systems. The glucose release for a given increase in Ca/sub i/ is greater in the female than the male probably due to the concomitant action of the ..beta..-mediated increase in cAMP and the ..cap alpha..-mediated increase in Ca/sub i/. This supports the conclusion that the ..beta..-mediated component does make a significant contribution to the catecholamine regulation of glycogenolysis in hepatocytes from adult female rats.

  13. Cerebral aterial spasm. I. Adrenergic mechanism in experimental cerebral vasospasm.

    Directory of Open Access Journals (Sweden)

    Morooka,Hiroshi

    1978-04-01

    Full Text Available This study demonstrates that an adrenergic mechanism plays an important role in producing the delayed cerebral vasospasm which follows subarachnoid hemorrhage. Results were as follows: 1. Experimental subarachnoid hemorrhage (SAH was produced by injection of fresh arterial blood into the cisterna magna in cats. The cerebral vasospasm was shown angiographically to be biphasic in nature: immediate constriction lasting 1 h and marked prolonged spasm occurring between the 3rd and 5th day after SAH. The amount of noradrenaline (NA and dopamine-beta-hydroxylase (DBH activity decreased over a period of 24 h both within the wall of the basilar artery and in the locus ceruleus and then gradually increased, reaching a maximum on the 3rd day after SAH. 2. Topical application of spasmogenic substances (NA and blood produced a marked constriction of the hypersensitive basilar artery on the 3rd day after SAH. 3. 6-Hydroxydopamine (6-OHDA injection into the cisterna magna produced prolonged vasocilatation. The dilated vessel responded with mild transient constriction after the topical application of NA or fresh blood. DBH activity and NA concentration in the vessels, locus ceruleus and medial hypothalamus decreased markedly on the 3rd day after the cisternal injection of 6-OHDA. 4. Various spasmogenic substances (i.e. serotonin, NA, prostaglandins and methemoglobin were measured in a mixture of equal volume of CSF and blood in cats. ONly the serotonin in the mixed fluid produced vasoconstriction. Spasmogenic substances decreased markedly in the mixed fluid incubated for 3 days at 37 degrees C, and none of these substances apart from methemoglobin was present in a concentration sufficient to produce constriction of vessels. 5. These results suggest that early spasm is induced by serotonin around the arteries of the cranial base, and delayed spasm might be caused by hyperreaction of cerebral vessels to spasmogenic substances such as methemoglobin, during the

  14. Beta-adrenergic agonists as additive in beef cattle

    Directory of Open Access Journals (Sweden)

    Marcelo Vedovatto

    2014-10-01

    Full Text Available The agonists receptor beta-adrenergic (β-AA are present in virtually all types of mammalian cells and are stimulated by catecholamines (epinephrine and norepinephrine produced by the organism itself. The β-AA agonists are synthetic substances with similar structure to these amines. When provided in the diet they alter the body composition of animals, affecting the distribution of nutrients toward to protein deposition, and decreasing lipogenesis. Although the mechanisms of action are not fully understood, these may cause morphological and physiological changes such as increased blood flow decrease in plasma insulin, decreased lipogenesis, and muscle hypertrophy mainly in type II fibers. We also observed changes in motility and secretions grastointestinal tract, beyond the direct influence on the rumen bacteria, altering the digestibility of the diet. The β-AA agonists released in some countries for use in beef cattle are ractopamine hydrochloride and zilpaterol hydrochloride. According to literature data, the inclusion of these additives in the diet of feedlot cattle has been associated with an increase infeed efficiency with the increase in daily weight gain and with equal or lower feed intake. Carcass characteristics improvement was verified in carcass weight, and increased loin eye area, but with the possibility to decrease the subcutaneous fat thickness and marbling. Reviews in sensory panel of meat from animals consuming β-AA agonists showed decreased tenderness and juiciness. Thus β-AA improve performance and carcass characteristics, but more studies are needed to confirm whether they have negative influence on the organoleptic characteristics of the meat.

  15. Molecular Modeling Study of Chiral Separation and Recognition Mechanism of β-Adrenergic Antagonists by Capillary Electrophoresis

    Directory of Open Access Journals (Sweden)

    Yifeng Chai

    2012-01-01

    Full Text Available Chiral separations of five β-adrenergic antagonists (propranolol, esmolol, atenolol, metoprolol, and bisoprolol were studied by capillary electrophoresis using six cyclodextrins (CDs as the chiral selectors. Carboxymethylated-β-cyclodextrin (CM-β-CD exhibited a higher enantioselectivity power compared to the other tested CDs. The influences of the concentration of CM-β-CD, buffer pH, buffer concentration, temperature, and applied voltage were investigated. The good chiral separation of five β-adrenergic antagonists was achieved using 50 mM Tris buffer at pH 4.0 containing 8 mM CM-β-CD with an applied voltage of 24 kV at 20 °C. In order to understand possible chiral recognition mechanisms of these racemates with CM-β-CD, host-guest binding procedures of CM-β-CD and these racemates were studied using the molecular docking software Autodock. The binding free energy was calculated using the Autodock semi-empirical binding free energy function. The results showed that the phenyl or naphthyl ring inserted in the hydrophobic cavity of CM-β-CD and the side chain was found to point out of the cyclodextrin rim. Hydrogen bonding between CM-β-CD and these racemates played an important role in the process of enantionseparation and a model of the hydrogen bonding interaction positions was constructed. The difference in hydrogen bonding formed with the –OH next to the chiral center of the analytes may help to increase chiral discrimination and gave rise to a bigger separation factor. In addition, the longer side chain in the hydrophobic phenyl ring of the enantiomer was not beneficial for enantioseparation and the chiral selectivity factor was found to correspond to the difference in binding free energy.

  16. Maintained cerebral metabolic ratio during exercise in patients with beta-adrenergic blockade

    DEFF Research Database (Denmark)

    Gam, Christiane M B; Rasmussen, Peter; Secher, Niels H;

    2009-01-01

    BACKGROUND: Decreased cerebral metabolic ratio (CMR) [molar uptake of O(2) versus molar uptake of (glucose + (1/2) lactate)] during exercise is attenuated by intravenous administration of the non-selective beta-adrenergic receptor antagonist propranolol. We evaluated to what extent cirrhotic pati......-selective beta-adrenergic receptor antagonist attenuates cerebral non-oxidative metabolism Udgivelsesdato: 2009/11......BACKGROUND: Decreased cerebral metabolic ratio (CMR) [molar uptake of O(2) versus molar uptake of (glucose + (1/2) lactate)] during exercise is attenuated by intravenous administration of the non-selective beta-adrenergic receptor antagonist propranolol. We evaluated to what extent cirrhotic...... patients in oral treatment with propranolol are able to mobilize brain non-oxidative carbohydrate metabolism. METHODS: Incremental cycle ergometry to exhaustion (86 +/- 4.2 W; mean +/- SD) was performed in eight cirrhotic patients instrumented with a catheter in the brachial artery and one retrograde...

  17. Osmotic versus adrenergic control of ion transport by ionocytes of Fundulus heteroclitus in the cold

    DEFF Research Database (Denmark)

    Tait, Janet C; Mercer, Evan W; Gerber, Lucie;

    2017-01-01

    to full strength seawater (SW) at 21°C and 5°C for four weeks, gill samples and blood were taken and opercular epithelia mounted in Ussing style chambers. Short-circuit current Isc at 21°C and 5°C (measured at acclimation temperature), was significantly inhibited by the α2-adrenergic agonist clonidine......In eurythermic vertebrates, acclimation to the cold may produce changes in physiological control systems. We hypothesize that relatively direct osmosensitive control will operate better than adrenergic receptor mediated control of ion transport in cold vs. warm conditions. Fish were acclimated...... acclimated fish had significantly shorter mitochondria. These data are consistent with a shift in these eurythermic animals from complex adrenergic control to relatively simple biomechanical osmotic control of ion secretion in the cold....

  18. Investigation of cyclooxygenase and signaling pathways involved in human platelet aggregation mediated by synergistic interaction of various agonists

    Directory of Open Access Journals (Sweden)

    Khan N

    2015-07-01

    Full Text Available Nadia Khan,1,2 Ahsana Dar Farooq,1 Bassem Sadek21Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; 2Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab EmiratesAbstract: In the present study, the mechanism(s of synergistic interaction of various platelet mediators such as arachidonic acid (AA when combined with 5-hydroxytryptamine (5-HT or adenosine diphosphate (ADP on human platelet aggregation were examined. The results demonstrated that 5-HT had no or negligible effect on aggregation but it did potentiate the aggregation response of AA. Similarly, the combination of subeffective concentrations of ADP and AA exhibited noticeable rise in platelet aggregation. Moreover, the observed synergistic effect of AA with 5-HT on platelets was inhibited by different cyclooxygenase (COX inhibitors, namely ibuprofen and celecoxib, with half maximal inhibitory effect (IC50 values of 18.0±1.8 and 15.6±3.4 µmol/L, respectively. Interestingly, the synergistic effect observed for AA with 5-HT was, also, blocked by the 5-HT receptor blockers cyproheptadine (IC50=22.0±7 µmol/L, ketanserin (IC50=152±23 µmol/L, phospholipase C (PLC inhibitor (U73122; IC50=6.1±0.8 µmol/L, and mitogen activated protein kinase (MAPK inhibitor (PD98059; IC50=3.8±0.5 µmol/L. Likewise, the synergism of AA and ADP was, also, attenuated by COX inhibitors (ibuprofen; IC50=20±4 µmol/L and celecoxib; IC50=24±7 µmol/L, PLC inhibitor (U73122; IC50=3.7±0.3 µmol/L, and MAPK inhibitor (PD98059; IC50=2.8±1.1 µmol/L. Our observed data demonstrate that the combination of subthreshold concentrations of agonists amplifies platelet aggregation and that these synergistic effects largely depend on activation of COX/thromboxane A2, receptor-operated Ca2+ channels, Gq/PLC, and MAPK signaling

  19. In silico study of interaction between rice proteins enhanced disease susceptibility 1 and phytoalexin deficient 4, the regulators of salicylic acid signalling pathway.

    Science.gov (United States)

    Singh, Indra; Shah, Kavita

    2012-07-01

    Enhanced disease susceptibility 1 (EDS1), a plant-specific protein has homology with the eukaryotic lipase in their N-terminal halves and a unique domain at its C-termini. EDS1 is known to be an important regulator of biotic stress and an essential component of basal immunity. EDS1 interacts with its positive co-regulator phytoalexin deficient 4 (PAD4), resulting in mobilization of the salicylic acid defence pathway. Limited information regarding this interaction in rice is available. To study this interaction, a model of EDS1 and PAD4 proteins from rice was generated and validated with Accelrys DS software version 3.1 using bioinformatics interface. The in silico docking between the two proteins showed a significant protein-protein interaction between rice EDS1 and PAD4, suggesting that they form a dimeric protein complex, which, similar to that in Arabidopsis, is perhaps also important for triggering the salicylic acid signalling pathway in plants.

  20. In silico study of interaction between rice proteins enhanced disease susceptibility 1 and phytoalexin deficient 4, the regulators of salicylic acid signalling pathway

    Indian Academy of Sciences (India)

    Indra Singh; Kavita Shah

    2012-07-01

    Enhanced disease susceptibility 1 (EDS1), a plant-specific protein has homology with the eukaryotic lipase in their N-terminal halves and a unique domain at its C-termini. EDS1 is known to be an important regulator of biotic stress and an essential component of basal immunity. EDS1 interacts with its positive co-regulator phytoalexin deficient 4 (PAD4), resulting in mobilization of the salicylic acid defence pathway. Limited information regarding this interaction in rice is available. To study this interaction, a model of EDS1 and PAD4 proteins from rice was generated and validated with Accelrys DS software version 3.1 using bioinformatics interface. The in silico docking between the two proteins showed a significant protein–protein interaction between rice EDS1 and PAD4, suggesting that they form a dimeric protein complex, which, similar to that in Arabidopsis, is perhaps also important for triggering the salicylic acid signalling pathway in plants.

  1. Biochemical and pharmacological studies of the hepatic alpha sub 1 -adrenergic receptor

    Energy Technology Data Exchange (ETDEWEB)

    Tchakarov, L.E.

    1988-01-01

    The structure and the regulation of the hepatic {alpha}{sub 1}-adrenergic receptors have been studied in the rat. The in vitro incubation of isolated liver cells in a serum-free buffer for 4 hr leads to the conversion of the adrenergic activation of glycogen phosphorylase from an {alpha}{sub 1}- to a {beta}-adrenoceptor-mediated event. This change is associated with no change in the glycogenolytic response to vasopressin and a reduction of the glycogenolytic response to glucagon. The time-dependent shift in the adrenergic control of glycogenolysis does not influence the density or the affinity of ({sup 3}H)prazosin-labeled {alpha}{sub 1}-receptors and ({sup 3}H)CGP-12177-labeled {beta}-receptors. The change in the adrenergic control of glycogenolysis is reversed by a 30-min incubation with 50 nM lipomodulin, whereas in freshly isolated cells lipomodulin doesn't affect the predominant {alpha}-receptor response. Conversely, exposure of freshly isolated cells to a monoclonal antibody to lipomodulin in the presence of 10 {mu}M phenylephrine, or to 2 {mu}g/ml mellitin, results in a shift in the adrenergic control of glycogenolysis from {alpha}{sub 1}- to {beta}-type within 30 min. The mechanism of activation of the Ca{sup 2+}-linked receptors for vasopressin and adrenaline was studied in isolated liver cells. A novel irreversible antagonist for the {alpha}{sub 1}-adrenergic receptors, I-phenyoxybenzamine (I-POB) has been synthesized and pharmacologically characterized.

  2. Distinctive left-sided distribution of adrenergic-derived cells in the adult mouse heart.

    Directory of Open Access Journals (Sweden)

    Kingsley Osuala

    Full Text Available Adrenaline and noradrenaline are produced within the heart from neuronal and non-neuronal sources. These adrenergic hormones have profound effects on cardiovascular development and function, yet relatively little information is available about the specific tissue distribution of adrenergic cells within the adult heart. The purpose of the present study was to define the anatomical localization of cells derived from an adrenergic lineage within the adult heart. To accomplish this, we performed genetic fate-mapping experiments where mice with the cre-recombinase (Cre gene inserted into the phenylethanolamine-n-methyltransferase (Pnmt locus were cross-mated with homozygous Rosa26 reporter (R26R mice. Because Pnmt serves as a marker gene for adrenergic cells, offspring from these matings express the β-galactosidase (βGAL reporter gene in cells of an adrenergic lineage. βGAL expression was found throughout the adult mouse heart, but was predominantly (89% located in the left atrium (LA and ventricle (LV (p<0.001 compared to RA and RV, where many of these cells appeared to have cardiomyocyte-like morphological and structural characteristics. The staining pattern in the LA was diffuse, but the LV free wall displayed intermittent non-random staining that extended from the apex to the base of the heart, including heavy staining of the anterior papillary muscle along its perimeter. Three-dimensional computer-aided reconstruction of XGAL+ staining revealed distribution throughout the LA and LV, with specific finger-like projections apparent near the mid and apical regions of the LV free wall. These data indicate that adrenergic-derived cells display distinctive left-sided distribution patterns in the adult mouse heart.

  3. Signal interaction between nitric oxide and hydrogen peroxide in heat shock-induced hypericin production of Hypericum perforatum suspension cells

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Heat shock(HS, 40℃, 10 min) induces hypericin production, nitric oxide(NO) generation, and hydrogen peroxide(H2O2) accumulation of Hypericum perforatum suspension cells.Catalase(CAT) and NO spe-cific scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide(cPTIO) suppress not only the HS-induced H2O2 generation and NO burst, but also the HS-triggered hypericin produc-tion.Hypericin contents of the cells treated with both NO and H2O2 are significantly higher than those of the cells treated with NO alone, although H2O2 per se has no effects on hypericin production of the cells, which suggests the synergistic action between H2O2 and NO on hypericin production.NO treatment enhances H2O2 levels of H.perforatum cells, while external application of H2O2 induces NO generation of cells.Thus, the results reveal a mutually amplifying action between H2O2 and NO in H.perforatum cells.CAT treatment inhibits both HS-induced H2O2 accumulation and NO generation, while cPTIO can also suppress H2O2 levels of the heat shocked cells.The results imply that H2O2 and NO may enhance each other’s levels by their mutually amplifying action in the heat shocked cells.Membrane NAD(P)H oxidase inhibitor diphenylene iodonium(DPI) and nitric oxide synthase(NOS) inhibitor S,S′-1,3-phenylene-bis(1,2-ethanediyl)-bis-isothiourea(PBITU) not only inhibit the mutually amplifying action between H2O2 and NO but also abolish the synergistic effects of H2O2 and NO on hypericin production, showing that the synergism of H2O2 and NO on secondary metabolite biosynthesis might be dependent on their mutual amplification.Taken together, data of the present work demonstrate that both H2O2 and NO are essential for HS-induced hypericin production of H.perforatum suspension cells.Furthermore, the results reveal a special interaction between the two signal molecules in mediating HS-triggered secondary metabolite biosynthesis of the cells.

  4. Signal interaction between nitric oxide and hydrogen peroxide in heat shock-induced hypericin production of Hypericum perforatum suspension cells

    Institute of Scientific and Technical Information of China (English)

    XU MaoJun; DONG JuFang; ZHANG XinBo

    2008-01-01

    Heat shock (HS, 40℃, 10 min) induces hypericin production, nitric oxide (NO) generation, and hydrogen peroxide (H2O2) accumulation of Hypericum perforatum suspension cells. Catalase (CAT) and NO spe-cific scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) suppress not only the HS-induced H2O2 generation and NO burst, but also the HS-triggered hypericin produc-tion. Hypericin contents of the cells treated with both NO and H2O2 are significantly higher than those of the cells treated with NO alone, although H2O2 per se has no effects on hypericin production of the cells, which suggests the synergistic action between H2O2 and NO on hypericin production. NO treatmentenhances H2O2 levels of H. perforatum cells, while external application of H2O2 induces NO generation of cells. Thus, the results reveal a mutually amplifying action between H2O2 and NO in H. perforatum cells. CAT treatment inhibits both HS-induced H2O2 accumulation and NO generation, while cPTIO can also suppress H2O2 levels of the heat shocked cells. The results imply that H2O2 and NO may enhance each other's levels by their mutually amplifying action in the heat shocked cells. Membrane NAD(P)H oxidase inhibitor diphenylene iodonium (DPI) and nitric oxide synthase (NOS) inhibitor S,S'-1,3-phenylene-bis(1,2-ethanediyl)-bis-isothiourea (PBITU) not only inhibit the mutually amplifying action between H2O2 and NO but also abolish the synergistic effects of H2O2 and NO on hypericin production, showing that the synergism of H2O2 and NO on secondary metsbolite biosynthesis might be dependent on their mutual amplification. Taken together, data of the present work demonstrate that both H2O2 and NO are essential for HS-induced hypericin production of H. perforatum suspension cells. Furthermore, the results reveal a special interaction between the two signal molecules in mediating HS-triggered secondary metabolite biosynthesis of the cells.

  5. Interactive signal transfer between host and pathogen during successful infection of barley leaves by Blumeria graminis and Bipolaris sorokiniana.

    Science.gov (United States)

    Felle, Hubert H; Herrmann, Almut; Schäfer, Patrick; Hückelhoven, Ralph; Kogel, Karl-Heinz

    2008-01-01

    Using ion-selective microprobes, interactive signalling between barley and Blumeria graminis or Bipolaris sorokiniana has been investigated. The question was raised whether a biotrophically growing fungus manipulates the electrical driving forces (membrane potential, transmembrane pH), required for H+ cotransport of energy-rich compounds. Electrodes were positioned in the substomatal cavity of open stomata or on the leaf surface, and pH was measured continuously up to several days during fungal development. We demonstrate that surface and apoplastic fluids are electrically coupled and respond in a similar manner to stimuli. Apoplastic pH, monitored from the moment of inoculation with conidia, reveals several phases: 2-4h after inoculation of the barley leaf with either fungus, the host displays rapid transient responses after its first contact with the fungal cell wall; apoplastic pH and pCa increases, cytoplasmic pH and pCa decreases. About 1 day after inoculation, the apoplastic pH increases by up to 2 pH units, which is thought to reflect a resistance response against the intruder. Whereas barley leaf cells possess a membrane potential of -152+/-5 mV, hyphae of B. graminis yield -251+/-8 mV, indicative of a substantial driving force advantage for the fungus. Although the resting membrane potential of barley remains constant during the first days after inoculation, leaves infected with B. sorokiniana get confronted with an energy problem, indicated by a retarded repolarization following a "light-off" stimulus. Five days after inoculation, apoplastic pH has increased to 5.97+/-0.47 (n=11) and does no longer respond to "light-off" when measured within lesions. In contrast, it stays at near normal values outside the lesions and responds to "light-off". It is concluded that biotrophically growing fungi do not manipulate the cotransport driving forces since (i) any change in apoplastic pH would be experienced by both partners; (ii) the resting membrane potential is

  6. Bridging the gap between modules in isolation and as part of networks: A systems framework for elucidating interaction and regulation of signalling modules

    Science.gov (United States)

    Menon, Govind; Krishnan, J.

    2016-07-01

    While signalling and biochemical modules have been the focus of numerous studies, they are typically studied in isolation, with no examination of the effects of the ambient network. In this paper we formulate and develop a systems framework, rooted in dynamical systems, to understand such effects, by studying the interaction of signalling modules. The modules we consider are (i) basic covalent modification, (ii) monostable switches, (iii) bistable switches, (iv) adaptive modules, and (v) oscillatory modules. We systematically examine the interaction of these modules by analyzing (a) sequential interaction without shared components, (b) sequential interaction with shared components, and (c) oblique interactions. Our studies reveal that the behaviour of a module in isolation may be substantially different from that in a network, and explicitly demonstrate how the behaviour of a given module, the characteristics of the ambient network, and the possibility of shared components can result in new effects. Our global approach illuminates different aspects of the structure and functioning of modules, revealing the importance of dynamical characteristics as well as biochemical features; this provides a methodological platform for investigating the complexity of natural modules shaped by evolution, elucidating the effects of ambient networks on a module in multiple cellular contexts, and highlighting the capabilities and constraints for engineering robust synthetic modules. Overall, such a systems framework provides a platform for bridging the gap between non-linear information processing modules, in isolation and as parts of networks, and a basis for understanding new aspects of natural and engineered cellular networks.

  7. Bridging the gap between modules in isolation and as part of networks: A systems framework for elucidating interaction and regulation of signalling modules.

    Science.gov (United States)

    Menon, Govind; Krishnan, J

    2016-07-21

    While signalling and biochemical modules have been the focus of numerous studies, they are typically studied in isolation, with no examination of the effects of the ambient network. In this paper we formulate and develop a systems framework, rooted in dynamical systems, to understand such effects, by studying the interaction of signalling modules. The modules we consider are (i) basic covalent modification, (ii) monostable switches, (iii) bistable switches, (iv) adaptive modules, and (v) oscillatory modules. We systematically examine the interaction of these modules by analyzing (a) sequential interaction without shared components, (b) sequential interaction with shared components, and (c) oblique interactions. Our studies reveal that the behaviour of a module in isolation may be substantially different from that in a network, and explicitly demonstrate how the behaviour of a given module, the characteristics of the ambient network, and the possibility of shared components can result in new effects. Our global approach illuminates different aspects of the structure and functioning of modules, revealing the importance of dynamical characteristics as well as biochemical features; this provides a methodological platform for investigating the complexity of natural modules shaped by evolution, elucidating the effects of ambient networks on a module in multiple cellular contexts, and highlighting the capabilities and constraints for engineering robust synthetic modules. Overall, such a systems framework provides a platform for bridging the gap between non-linear information processing modules, in isolation and as parts of networks, and a basis for understanding new aspects of natural and engineered cellular networks.

  8. Beta-adrenergic stimulation of phagocytosis in the unicellular eukaryote Paramecium aurelia.

    Science.gov (United States)

    Wyroba, E

    1989-08-01

    Bete-adrenergic agonists isoproterenol and norepinephrine enhanced phagocytosis in Paramecium. Stimulation was stereospecific, dose-dependent and inhibited by the beta-agonists propranolol and alprenolol. Phorbol ester and forskolin potentiated the stimulatory effect of catecholamines on Paramecium phagocytosis. The dansyl analogue of propranolol (DAPN) was used for fluorescent visualization of the beta-adrenergic receptor sites in Paramecium which have been found to be localized at the cell membrane and within the membrane of the nascent digestive vacuoles. The appearance of the characteristic fluorescent pattern has been blocked by 1-propranolol.

  9. Altered β-adrenergic response in mice lacking myotonic dystrophy protein kinase (DMPK)

    Science.gov (United States)

    Llagostera, Esther; López, María Jesús Álvarez; Scimia, Cecilia; Catalucci, Daniele; Párrizas, Marcelina; Ruiz-Lozano, Pilar; Kaliman, Perla

    2011-01-01

    The protein kinase product of the gene mutated in myotonic dystrophy 1 (DMPK) is reported to play a role in cardiac pathophysiology. To gain insight into the molecular mechanisms modulated by DMPK, we characterize the impact of DMPK ablation in the context of cardiac β-adrenergic function. Our data demonstrate that DMPK knock-out mice present altered β-agonist-induced responses and suggest that this is due, at least in part, to a reduced density of β1-adrenergic receptors in cardiac plasma membranes. PMID:22190319

  10. Altered β-adrenergic response in mice lacking myotonic dystrophy protein kinase (DMPK)

    OpenAIRE

    Llagostera, Esther; López, María Jesús Álvarez; Scimia, Cecilia; Catalucci, Daniele; Párrizas, Marcelina; Ruiz-Lozano, Pilar; Kaliman, Perla

    2012-01-01

    The protein kinase product of the gene mutated in myotonic dystrophy 1 (DMPK) is reported to play a role in cardiac pathophysiology. To gain insight into the molecular mechanisms modulated by DMPK, we characterize the impact of DMPK ablation in the context of cardiac β-adrenergic function. Our data demonstrate that DMPK knock-out mice present altered β-agonist-induced responses and suggest that this is due, at least in part, to a reduced density of β1-adrenergic receptors in cardiac plasma me...

  11. Altered β-adrenergic response in mice lacking myotonic dystrophy protein kinase.

    Science.gov (United States)

    Llagostera, Esther; Álvarez López, María Jesús; Scimia, Cecilia; Catalucci, Daniele; Párrizas, Marcelina; Ruiz-Lozano, Pilar; Kaliman, Perla

    2012-01-01

    The protein kinase product of the gene mutated in myotonic dystrophy 1 (DMPK) is reported to play a role in cardiac pathophysiology. To gain insight into the molecular mechanisms modulated by DMPK, we characterize the impact of DMPK ablation in the context of cardiac β-adrenergic function. Our data demonstrate that DMPK knockout mice present altered β-agonist-induced responses and suggest that this is due, at least in part, to a reduced density of β(1)-adrenergic receptors in cardiac plasma membranes. PMID:22190319

  12. Adrenergic regulation of cellular plasticity in brown, beige/brite and white adipose tissues.

    Science.gov (United States)

    Ramseyer, Vanesa D; Granneman, James G

    2016-01-01

    The discovery of brown adipose tissue in adult humans along with the recognition of adipocyte heterogeneity and plasticity of white fat depots has renewed the interest in targeting adipose tissue for therapeutic benefit. Adrenergic activation is a well-established means of recruiting catabolic adipocyte phenotypes in brown and white adipose tissues. In this article, we review mechanisms of brown adipocyte recruitment by the sympathetic nervous system and by direct β-adrenergic receptor activation. We highlight the distinct modes of brown adipocyte recruitment in brown, beige/brite, and white adipose tissues, UCP1-independent thermogenesis, and potential non-thermogenic, metabolically beneficial effects of brown adipocytes.

  13. Inhaled adrenergics and anticholinergics in obstructive lung disease: do they enhance mucociliary clearance?

    Science.gov (United States)

    Restrepo, Ruben D

    2007-09-01

    Pulmonary mucociliary clearance is an essential defense mechanism against bacteria and particulate matter. Mucociliary dysfunction is an important feature of obstructive lung diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, and bronchiectasis. This dysfunction in airway clearance is associated with accelerated loss of lung function in patients with obstructive lung disease. The involvement of the cholinergic and adrenergic neural pathways in the pathophysiology of mucus hypersecretion suggests the potential therapeutic role of bronchodilators as mucoactive agents. Although anticholinergics and adrenergic agonist bronchodilators have been routinely used, alone or in combination, to enhance mucociliary clearance in patients with obstructive lung disease, the existing evidence does not consistently show clinical effectiveness.

  14. INTERACT

    DEFF Research Database (Denmark)

    Jochum, Elizabeth; Borggreen, Gunhild; Murphey, TD

    This paper considers the impact of visual art and performance on robotics and human-computer interaction and outlines a research project that combines puppetry and live performance with robotics. Kinesics—communication through movement—is the foundation of many theatre and performance traditions...... interaction between a human operator and an artificial actor or agent. We can apply insights from puppetry to develop culturally-aware robots. Here we describe the development of a robotic marionette theatre wherein robotic controllers assume the role of human puppeteers. The system has been built, tested......, and demonstrated in public settings. We then describe INTERACT, a proposed research project that stages the robotic marionettes in a live performance. The interdisciplinary project brings humanities research to bear on scientific and technological inquiry, and culminates in the development a live performance which...

  15. Interactions

    DEFF Research Database (Denmark)

    The main theme of this anthology is the unique interaction between mathematics, physics and philosophy during the beginning of the 20th century. Seminal theories of modern physics and new fundamental mathematical structures were discovered or formed in this period. Significant physicists such as ......The main theme of this anthology is the unique interaction between mathematics, physics and philosophy during the beginning of the 20th century. Seminal theories of modern physics and new fundamental mathematical structures were discovered or formed in this period. Significant physicists...... also key figures in the philosophical discussions of nature and science - from philosophical tendencies like logical empiricism via critical rationalism to various neo-Kantian trends....

  16. Landscape mapping of functional proteins in insulin signal transduction and insulin resistance: a network-based protein-protein interaction analysis.

    Directory of Open Access Journals (Sweden)

    Chiranjib Chakraborty

    Full Text Available The type 2 diabetes has increased rapidly in recent years throughout the world. The insulin signal transduction mechanism gets disrupted sometimes and it's known as insulin-resistance. It is one of the primary causes associated with type-2 diabetes. The signaling mechanisms involved several proteins that include 7 major functional proteins such as INS, INSR, IRS1, IRS2, PIK3CA, Akt2, and GLUT4. Using these 7 principal proteins, multiple sequences alignment has been created. The scores between sequences also have been developed. We have constructed a phylogenetic tree and modified it with node and distance. Besides, we have generated sequence logos and ultimately developed the protein-protein interaction network. The small insulin signal transduction protein arrangement shows complex network between the functional proteins.

  17. Mechanisms of Disease: detrimental adrenergic signaling in acute decompensated heart failure

    OpenAIRE

    Feldman, David S.; Elton, Terry S; Sun, Benjamin; Martin, Mickey M.; Ziolo, Mark T

    2008-01-01

    Acute decompensated heart failure (ADHF) is responsible for more than 1 million hospital admissions each year in the US. Clinicians and scientists have developed therapeutic strategies that reduce mortality in patients with chronic heart failure (HF). Despite the widely appreciated magnitude of the ADHF problem, there is still a critical gap in our understanding of the cellular mechanisms involved and effective treatment strategies for hospitalized patients. Irrespective of the etiology, pati...

  18. In Vivo Phosphoproteomics Analysis Reveals the Cardiac Targets of β-Adrenergic Receptor Signaling

    DEFF Research Database (Denmark)

    Lundby, Alicia; Andersen, Martin N; Steffensen, Annette B;

    2013-01-01

    used quantitative in vivo phosphoproteomics to identify 670 site-specific phosphorylation changes in murine hearts in response to acute treatment with specific βAR agonists. The residues adjacent to the regulated phosphorylation sites exhibited a sequence-specific preference (R-X-X-pS/T), and...

  19. Signal transduction in cultered cardiomyocytes : alpha1-adrenergic and endothelin receptor mediated responses

    NARCIS (Netherlands)

    H.W. de Jonge (Jet)

    1996-01-01

    textabstractAlready in ancient times the Greek were aware of the heart in the human body and they gave it the name kardia, which is still in use in words as cardiac, myocardial, tachycardia and bradycardia. In those times the importance of the heart was appraised by Aristotle (384-322 B.C.), who tho

  20. Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle – pivotal roles in Ca2+ and reactive oxygen species signaling

    OpenAIRE

    Eisner, Verónica; Csordás, György; Hajnóczky, György

    2013-01-01

    Mitochondria are strategically and dynamically positioned in the cell to spatially coordinate ATP production with energy needs and to allow the local exchange of material with other organelles. Interactions of mitochondria with the sarco-endoplasmic reticulum (SR/ER) have been receiving much attention owing to emerging evidence on the role these sites have in cell signaling, dynamics and biosynthetic pathways. One of the most important physiological and pathophysiological paradigms for SR/ER–...

  1. Confirmation of a soft photon signal in excess of Q.E.D. expectations in $\\pi^- p$ interactions at 280 GeV/c

    CERN Document Server

    Belogianni, A; Brodbeck, T J; Evans, D; French, Bernard R; Jacholkowski, A; Kinson, J B; Kirk, A; Lenti, V; Loconsole, R A; Manzari, V; Minashvili, I A; Perepelitsa, V F; Rusakovitch, N A; Sonderegger, P; Spyropoulou-Stassinaki, M; Tchlatchidze, G A; Vasileiadis, G; Vichou, I; Villalobos Baillie, O

    1997-01-01

    Photons produced in \\pip interactions at 280 GeV/$c$ were detected by reconstructing the $e^+e^-$ pairs produced via the materialisation of the photons in a 1 mm thick lead sheet placed in front of the MWPC's of the OMEGA spectrometer at CERN. A soft photon signal $ 7.8\\pm 1.6$ times the Q.E.D. inner bremsstrahlung prediction was observed confirming the results of a previous experiment.

  2. Protein Interaction Screening for the Ankyrin Repeats and Suppressor of Cytokine Signaling (SOCS) Box (ASB) Family Identify Asb11 as a Novel Endoplasmic Reticulum Resident Ubiquitin Ligase

    DEFF Research Database (Denmark)

    Andresen, Christina Aaen; Smedegaard, Stine; Sylvestersen, Kathrine Beck;

    2014-01-01

    The Ankyrin and SOCS (Suppressor of Cytokine Signaling) box (ASB) family of proteins function as the substrate recognition subunit in a subset of Elongin-Cullin-SOCS (ECS) E3 ubiquitin ligases. Despite counting with 18 members in humans, the identity of the physiological targets of the Asb protei...... in vivo. In summary, we provide a comprehensive protein-protein interaction data resource that can aid the biological and functional characterization of ASB ubiquitin ligases....

  3. A Stochastic Model of the Germinal Center Integrating Local Antigen Competition, Individualistic T-B Interactions, and B Cell Receptor Signaling.

    Science.gov (United States)

    Wang, Peng; Shih, Chang-Ming; Qi, Hai; Lan, Yue-Heng

    2016-08-15

    The germinal center (GC) reaction underlies productive humoral immunity by orchestrating competition-based affinity maturation to produce plasma cells and memory B cells. T cells are limiting in this process. How B cells integrate signals from T cells and BCRs to make fate decisions while subjected to a cyclic selection process is not clear. In this article, we present a spatiotemporally resolved stochastic model that describes cell behaviors as rate-limited stochastic reactions. We hypothesize a signal integrator protein integrates follicular helper T (Tfh)- and Ag-derived signals to drive different B cell fates in a probabilistic manner and a dedicated module of Tfh interaction promoting factors control the efficiency of contact-dependent Tfh help delivery to B cells. Without assuming deterministic affinity-based decisions or temporal event sequence, this model recapitulates GC characteristics, highlights the importance of efficient T cell help delivery during individual contacts with B cells and intercellular positive feedback for affinity maturation, reveals the possibility that antagonism between BCR signaling and T cell help accelerates affinity maturation, and suggests that the dichotomy between affinity and magnitude of GC reaction can be avoided by tuning the efficiency of contact-dependent help delivery during reiterative T-B interactions. PMID:27421481

  4. Suppressor of Cytokine Signaling (SOCS 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1.

    Directory of Open Access Journals (Sweden)

    Edmond M Linossi

    Full Text Available Suppressor of Cytokine Signaling (SOCS5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. We show for the first time that SOCS5 can interact directly with JAK via a unique, conserved region in its N-terminus, which we have termed the JAK interaction region (JIR. Co-expression of SOCS5 was able to specifically reduce JAK1 and JAK2 (but not JAK3 or TYK2 autophosphorylation and this function required both the conserved JIR and additional sequences within the long SOCS5 N-terminal region. We further demonstrate that SOCS5 can directly inhibit JAK1 kinase activity, although its mechanism of action appears distinct from that of SOCS1 and SOCS3. In addition, we identify phosphoTyr317 in Shc-1 as a high-affinity substrate for the SOCS5-SH2 domain and suggest that SOCS5 may negatively regulate EGF and growth factor-driven Shc-1 signaling by binding to this site. These findings suggest that different domains in SOCS5 contribute to two distinct mechanisms for regulation of cytokine and growth factor signaling.

  5. β-Arrestin 1’s Interaction with TC45 Attenuates Stat signaling by dephosphorylating Stat to inhibit antimicrobial peptide expression

    Science.gov (United States)

    Sun, Jie-Jie; Yang, Hui-Ting; Niu, Guo-Juan; Feng, Xiao-Wu; Lan, Jiang-Feng; Zhao, Xiao-Fan; Wang, Jin-Xing

    2016-01-01

    Impaired phosphatase activity leads to the persistent activation of signal transducers and activators of transcription (Stat). In mammals, Stat family members are often phosphorylated or dephosphorylated by the same enzymes. To date, only one Stat similar to mammalian Stat5a/b has been found in crustaceans and there have been few studies in Stat signal regulation in crustaceans. Here, we report that β-arrestin1 interacts with TC45 (45-kDa form of T cell protein tyrosine phosphatase) in the nucleus to attenuate Stat signaling by promoting dephosphorylation of Stat. Initially, we showed that Stat translocates into the nucleus to induce antimicrobial peptide (AMP) expression after bacterial infection. βArr1 enters the nucleus of hemocytes and recruits TC45 to form the βarr1-TC45-Stat complex, which dephosphorylates Stat efficiently. The interaction of TC45 with Stat decreased and Stat phosphorylation increased in βarr1-silenced shrimp (Marsupenaeus japonicus) after challenge with Vibrio anguillarum. βArr1 directly interacts with Stat in nucleus and accelerates Stat dephosphorylation by recruiting TC45 after V. anguillarum challenge. Further study showed that βarr1 and TC45 also affect AMP expression, which is regulated by Stat. Therefore, βarr1 and TC45 are involved in the anti-V. anguillarum immune response by regulating Stat activity negatively to decrease AMP expression in shrimp. PMID:27782165

  6. The effect of high-fructose intake on the vasopressor response to angiotensin II and adrenergic agonists in Sprague-Dawley rats.

    Science.gov (United States)

    Abdulla, Mohammed Hadi; Sattar, Munavvar Abdul; Abdullah, Nor Azizan; Johns, Edward James

    2013-07-01

    Effect of losartan was assessed on systemic haemodynamic responses to angiotensin II (Ang II) and adrenergic agonists in the model of high-fructose-fed rat. Twenty-four Sprague-Dawley (SD) rats were fed for 8 weeks either 20% fructose solution (FFR) or tap water (C) ad libitum. FFR or C group received losartan (10mg/kg/day p.o.) for 1 week at the end of feeding period (FFR-L and L) respectively, then the vasopressor responses to Ang II, noradrenaline (NA), phenylephrine (PE) and methoxamine (ME) were determined. The responses (%) to NA, PE, ME and Ang II in FFR were lower (P<0.05) than C (FFR vs. C; 22±2 vs. 32±2, 30±3 vs. 40±3, 9±1 vs. 13±1, 10±1 vs. 17±1) respectively. L group had blunted (P<0.05) responses to NA, PE, ME and Ang II compared to C (L vs. C; 26±2 vs. 32±2, 30±3 vs. 40±3, 7±0.7 vs. 13±1, 5±0.4 vs. 17±1) respectively. FFR-L group had aggravated (P<0.05) response to NA and ME, but blunted response to Ang II compared to FFR (FFR-L vs. FFR; 39±3 vs. 22±2, 11±1 vs. 9±1, 3±0.4 vs. 10±1) respectively. Fructose intake for 8 weeks results in smaller vasopressor response to adrenergic agonists and Ang II. Data also demonstrated an important role played by Ang II in the control of systemic haemodynamics in FFR and point to its interaction with adrenergic neurotransmission. PMID:23811449

  7. Nitric oxide-dependent activation of CaMKII increases diastolic sarcoplasmic reticulum calcium release in cardiac myocytes in response to adrenergic stimulation.

    Directory of Open Access Journals (Sweden)

    Jerry Curran

    Full Text Available Spontaneous calcium waves in cardiac myocytes are caused by diastolic sarcoplasmic reticulum release (SR Ca(2+ leak through ryanodine receptors. Beta-adrenergic (β-AR tone is known to increase this leak through the activation of Ca-calmodulin-dependent protein kinase (CaMKII and the subsequent phosphorylation of the ryanodine receptor. When β-AR drive is chronic, as observed in heart failure, this CaMKII-dependent effect is exaggerated and becomes potentially arrhythmogenic. Recent evidence has indicated that CaMKII activation can be regulated by cellular oxidizing agents, such as reactive oxygen species. Here, we investigate how the cellular second messenger, nitric oxide, mediates CaMKII activity downstream of the adrenergic signaling cascade and promotes the generation of arrhythmogenic spontaneous Ca(2+ waves in intact cardiomyocytes. Both SCaWs and SR Ca(2+ leak were measured in intact rabbit and mouse ventricular myocytes loaded with the Ca-dependent fluorescent dye, fluo-4. CaMKII activity in vitro and immunoblotting for phosphorylated residues on CaMKII, nitric oxide synthase, and Akt were measured to confirm activity of these enzymes as part of the adrenergic cascade. We demonstrate that stimulation of the β-AR pathway by isoproterenol increased the CaMKII-dependent SR Ca(2+ leak. This increased leak was prevented by inhibition of nitric oxide synthase 1 but not nitric oxide synthase 3. In ventricular myocytes isolated from wild-type mice, isoproterenol stimulation also increased the CaMKII-dependent leak. Critically, in myocytes isolated from nitric oxide synthase 1 knock-out mice this effect is ablated. We show that isoproterenol stimulation leads to an increase in nitric oxide production, and nitric oxide alone is sufficient to activate CaMKII and increase SR Ca(2+ leak. Mechanistically, our data links Akt to nitric oxide synthase 1 activation downstream of β-AR stimulation. Collectively, this evidence supports the hypothesis

  8. Wnt signaling interacts with bmp and edn1 to regulate dorsal-ventral patterning and growth of the craniofacial skeleton.

    Directory of Open Access Journals (Sweden)

    Courtney Alexander

    2014-07-01

    Full Text Available Craniofacial development requires signals from epithelia to pattern skeletogenic neural crest (NC cells, such as the subdivision of each pharyngeal arch into distinct dorsal (D and ventral (V elements. Wnt signaling has been implicated in many aspects of NC and craniofacial development, but its roles in D-V arch patterning remain unclear. To address this we blocked Wnt signaling in zebrafish embryos in a temporally-controlled manner, using transgenics to overexpress a dominant negative Tcf3, (dntcf3, (Tg(hsp70I:tcf3-GFP, or the canonical Wnt inhibitor dickkopf1 (dkk1, (Tg(hsp70i:dkk1-GFP after NC migration. In dntcf3 transgenics, NC cells in the ventral arches of heat-shocked embryos show reduced proliferation, expression of ventral patterning genes (hand2, dlx3b, dlx5a, msxe, and ventral cartilage differentiation (e.g. lower jaws. These D-V patterning defects resemble the phenotypes of zebrafish embryos lacking Bmp or Edn1 signaling, and overexpression of dntcf3 dramatically reduces expression of a subset of Bmp receptors in the arches. Addition of ectopic BMP (or EDN1 protein partially rescues ventral development and expression of dlx3b, dlx5a, and msxe in Wnt signaling-deficient embryos, but surprisingly does not rescue hand2 expression. Thus Wnt signaling provides ventralizing patterning cues to arch NC cells, in part through regulation of Bmp and Edn1 signaling, but independently regulates hand2. Similarly, heat-shocked dkk1+ embryos exhibit ventral arch reductions, but also have mandibular clefts at the ventral midline not seen in dntcf3+ embryos. Dkk1 is expressed in pharyngeal endoderm, and cell transplantation experiments reveal that dntcf3 must be overexpressed in pharyngeal endoderm to disrupt D-V arch patterning, suggesting that distinct endodermal roles for Wnts and Wnt antagonists pattern the developing skeleton.

  9. Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism.

    Science.gov (United States)

    Dienel, Gerald A; Cruz, Nancy F

    2016-07-01

    Aerobic glycolysis occurs during brain activation and is characterized by preferential up-regulation of glucose utilization compared with oxygen consumption even though oxygen level and delivery are adequate. Aerobic glycolysis is a widespread phenomenon that underlies energetics of diverse brain activities, such as alerting, sensory processing, cognition, memory, and pathophysiological conditions, but specific cellular functions fulfilled by aerobic glycolysis are poorly understood. Evaluation of evidence derived from different disciplines reveals that aerobic glycolysis is a complex, regulated phenomenon that is prevented by propranolol, a non-specific β-adrenoceptor antagonist. The metabolic pathways that contribute to excess utilization of glucose compared with oxygen include glycolysis, the pentose phosphate shunt pathway, the malate-aspartate shuttle, and astrocytic glycogen turnover. Increased lactate production by unidentified cells, and lactate dispersal from activated cells and lactate release from the brain, both facilitated by astrocytes, are major factors underlying aerobic glycolysis in subjects with low blood lactate levels. Astrocyte-neuron lactate shuttling with local oxidation is minor. Blockade of aerobic glycolysis by propranolol implicates adrenergic regulatory processes including adrenal release of epinephrine, signaling to brain via the vagus nerve, and increased norepinephrine release from the locus coeruleus. Norepinephrine has a powerful influence on astrocytic metabolism and glycogen turnover that can stimulate carbohydrate utilization more than oxygen consumption, whereas β-receptor blockade 're-balances' the stoichiometry of oxygen-glucose or -carbohydrate metabolism by suppressing glucose and glycogen utilization more than oxygen consumption. This conceptual framework may be helpful for design of future studies to elucidate functional roles of preferential non-oxidative glucose utilization and glycogen turnover during brain

  10. Phylogenetic divergence of CD47 interactions with human signal regulatory protein alpha reveals locus of species specificity. Implications for the binding site.

    Science.gov (United States)

    Subramanian, Shyamsundar; Boder, Eric T; Discher, Dennis E

    2007-01-19

    Cell-cell interactions between ubiquitously expressed integrin-associated protein (CD47) and its counterreceptor signal regulatory protein (SIRPalpha) on phagocytes regulate a wide range of adhesive signaling processes, including the inhibition of phagocytosis as documented in mice. We show that CD47-SIRPalpha binding interactions are different between mice and humans, and we exploit phylogenetic divergence to identify the species-specific binding locus on the immunoglobulin domain of human CD47. All of the studies are conducted in the physiological context of membrane protein display on Chinese hamster ovary (CHO) cells. Novel quantitative flow cytometry analyses with CD47-green fluorescent protein and soluble human SIRPalpha as a probe show that neither human CD47 nor SIRPalpha requires glycosylation for interaction. Human CD47-expressing CHO cells spread rapidly on SIRPalpha-coated glass surfaces, correlating well with the spreading of primary human T cells. In contrast, CHO cells expressing mouse CD47 spread minimally and show equally weak binding to soluble human SIRPalpha. Further phylogenetic analyses and multisite substitutions of the CD47 Ig domain show that human to cow mutation of a cluster of seven residues on adjacent strands near the middle of the domain decreases the association constant for human SIRPalpha to about one-third that of human CD47. Direct tests of cell-cell adhesion between human monocytes and CD47-displaying CHO cells affirm the species specificity as well as the importance of the newly identified binding locus in cell-cell interactions.

  11. Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca(2+)/cAMP intracellular signalling interaction.

    Science.gov (United States)

    Bergantin, Leandro Bueno; Caricati-Neto, Afonso

    2016-10-01

    In 2013, we discovered that the entitled "calcium paradox" phenomenon, which means a paradoxical sympathetic hyperactivity produced by l-type Ca(2+) channel blockers (CCBs), used in antihypertensive therapy, is due to interaction between the intracellular signalling pathways mediated by Ca(2+) and cAMP (Ca(2+)/cAMP interaction). In 2015, we proposed that the pharmacological manipulation of this interaction could be a new therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases. Besides the paradoxical sympathetic hyperactivity produced by CCBs, several clinical studies have been demonstrating pleiotropic effects of CCBs, including neuroprotective effects. CCBs genuinely exhibit cognitive-enhancing abilities and reduce the risk of dementia, including Alzheimer's, Parkinson´s disease and others. The molecular mechanisms involved in these pleiotropic effects remain under debate. Our recent discovery that the "calcium paradox" phenomenon is due to Ca(2+)/cAMP interaction may provide new insights for the pharmacological treatment of neurological and psychiatric disorders, including enhancement of current therapies mainly by reducing adverse effects, and improving effectiveness of modern medicines. Whether Ca(2+)/cAMP interaction is involved in CCBs pleiotropic effects also deserves special attention. Then, the pharmacological manipulation of the Ca(2+)/cAMP interaction could be a more efficient therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases. Thus, in this review we summarize the current knowledge of this field, making new directions and future perspectives.

  12. β3-Adrenergic receptor gene polymorphism and type 2 diabetes in a Caucasian population

    NARCIS (Netherlands)

    Oeveren van-Dybicz, A.M.; Vonkeman, H.E.; Bon, M.A.M.; Bergh, van den F.A.J.T.M.; Vermes, I.

    2008-01-01

    Aim: The β3-adrenergic receptor (β3-AR) is suspected to play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. A mutation in the β3-AR gene (Trp64Arg) has been associated with the capacity of weight gain and with early onset of noninsulin dependent diabetes me

  13. Molecular characterization of a rat α2B-adrenergic receptor

    International Nuclear Information System (INIS)

    α2-Adrenergic receptors comprise a heterogeneous population based on pharmacologic and molecular evidence. The authors have isolated a cDNA clone (pRNGα2) encoding a rat α2-adrenergic receptor. A rat kidney cDNA library was screened with an oligonucleotide complementary to a highly conserved region found in all biogenic amine receptors described to date. The deduced amino acid sequence displays many features of guanyl nucleotide-binding protein-coupled receptors except it does not have a consensus N-linked glycosylation site near the amino terminus. Membranes prepared from COS cells transfected with pRNGα2 DNA display high affinity an saturable binding to [3H]rauwolscine. Competition curve data analysis shows that RNGα2 protein binds to a variety of adrenergic drugs with the following rank order of potency: yohimbine ≥ chlorpromazine > prazosin ≥ clonidine > norepinephrine ≥ oxymetazoline. RNGα2 RNA accumulates in both rat kidney and neonatal rat lung. When a cysteine residue (Cys-169) that is conserved among all members of the seven-transmembrane-region superfamily is changed to phenylalanine, the RNGα2 protein fails to bind [3H]rauwolscine after expression in COS cells. They conclude that pRNGα2 likely represents a cDNA for a rat α2B-adrenergic receptor

  14. Cholesterol increases kinetic, energetic, and mechanical stability of the human β2-adrenergic receptor

    DEFF Research Database (Denmark)

    Zocher, Michael; Zhang, Cheng; Rasmussen, Søren Gøgsig Faarup;

    2012-01-01

    to quantify the mechanical strength and flexibility, conformational variability, and kinetic and energetic stability of structural segments stabilizing the human β(2)-adrenergic receptor (β(2)AR) in the absence and presence of the cholesterol analog cholesteryl hemisuccinate (CHS). CHS considerably increased...

  15. Hypoxia increases exercise heart rate despite combined inhibition of β-adrenergic and muscarinic receptors.

    Science.gov (United States)

    Siebenmann, C; Rasmussen, P; Sørensen, H; Bonne, T C; Zaar, M; Aachmann-Andersen, N J; Nordsborg, N B; Secher, N H; Lundby, C

    2015-06-15

    Hypoxia increases the heart rate response to exercise, but the mechanism(s) remains unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate, but not combined, inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exercise to exhaustion in normoxia and hypoxia (fraction of inspired O2 = 12%) after intravenous administration of 1) no drugs (Cont), 2) propranolol (Prop), 3) glycopyrrolate (Glyc), or 4) Prop + Glyc. HR increased with exercise in all drug conditions (P hypoxia than normoxia (P hypoxia and normoxia was 19.8 ± 13.8 beats/min during Cont and similar (17.2 ± 7.7 beats/min, P = 0.95) during Prop but smaller (P hypoxia (P 0.4) but larger during Prop (3.4 ± 1.6 l/min, P = 0.004). Our results demonstrate that the tachycardic effect of hypoxia during exercise partially relies on vagal withdrawal. Conversely, sympathoexcitation either does not contribute or increases heart rate through mechanisms other than β-adrenergic transmission. A potential candidate is α-adrenergic transmission, which could also explain why a tachycardic effect of hypoxia persists during combined β-adrenergic and muscarinic receptor inhibition. PMID:25888515

  16. Substrate utilization and thermogenic responses to beta-adrenergic stimulation in obese subjects with NIDDM

    NARCIS (Netherlands)

    Blaak, E E; Saris, W H; Wolffenbuttel, B H

    1999-01-01

    OBJECTIVE: This study intended to investigate disturbances in beta-adrenergically-mediated substrate utilization and thermogenesis in obese subjects with mild non insulin-dependent diabetes mellitus (NIDDM). DESIGN: Following a baseline period of 30 min, the beta-agonist isoproterenol (ISO) was admi

  17. The role of adrenergic activation on murine luteal cell viability and progesterone production.

    Science.gov (United States)

    Wang, Jing; Tang, Min; Jiang, Huaide; Wu, Bing; Cai, Wei; Hu, Chuan; Bao, Riqiang; Dong, Qiming; Xiao, Li; Li, Gang; Zhang, Chunping

    2016-09-15

    Sympathetic innervations exist in mammalian CL. The action of catecholaminergic system on luteal cells has been the focus of a variety of studies. Norepinephrine (NE) increased progesterone secretion of cattle luteal cells by activating β-adrenoceptors. In this study, murine luteal cells were treated with NE and isoprenaline (ISO). We found that NE increased the viability of murine luteal cells and ISO decreased the viability of luteal cells. Both NE and ISO promoted the progesterone production. Nonselective β-adrenergic antagonist, propranolol reversed the effect of ISO on cell viability but did not reverse the effect of NE on cell viability. Propranolol blocked the influence of NE and ISO on progesterone production. These results reveal that the increase of luteal cell viability induced by NE is not dependent on β-adrenergic activation. α-Adrenergic activation possibly contributes to it. Both NE and ISO increased progesterone production through activating β-adrenergic receptor. Further study showed that CyclinD2 is involved in the increase of luteal cell induced by NE. 3β-Hydroxysteroid dehydrogenase, LHR, steroidogenic acute regulatory protein (StAR), and PGF2α contribute to the progesterone production induced by NE and ISO. PMID:27173955

  18. Pet measurements of postsynaptic muscarinic and beta adrenergic receptors in the heart

    International Nuclear Information System (INIS)

    There is ample evidence from both experimental and clinical studies that changes in β-adrenergic and muscarinic receptor density can be associated with such cardiac diseases as congestive heart failure, myocardial ischemia and infarction, cardiomyopathy, diabetes, or thyroid-induced muscle disease. Changes in B-adrenergic density also have been shown in the denervated transplanted heart. These alterations of cardiac receptors have been demonstrated in vitro on homogenates from samples collected mainly during surgery or post mortem. Recent developments of Positron Emission Tomography (PET) techniques and of radioligands suitable for cardiac receptor binding studies in vivo have made possible both the imaging and the measurement of receptor density. From these studies, important information is now available concerning physiologic and pathologic conditions, as well as alterations induced by treatment. For the investigation of myocardial B-adrenergic receptors we have used [11C] CGP 12177, a potent hydrophilic antagonist of the 3-adrenergic receptor. The quantification of myocardial muscarinic receptors in vivo has been obtained with [11C] MQNB, a nonmetabolized hydrophilic antagonist of the muscarinic receptor. Receptor density and affinity have been measured by a kinetic, nonequilibrium approach in an experimental protocol that provides sufficient data to determine values for all parameters from a single experiment

  19. Hypoxia increases exercise heart rate despite combined inhibition of β-adrenergic and muscarinic receptors

    DEFF Research Database (Denmark)

    Siebenmann, Christoph; Rasmussen, Peter; Sørensen, Henrik;

    2015-01-01

    Hypoxia increases the heart rate (HR) response to exercise but the mechanism(s) remain unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate but not combined inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exerci...

  20. Beta-adrenergically stimulated fat oxidation is diminished in middle-aged compared to young subjects.

    NARCIS (Netherlands)

    Blaak, E.E.; van Baak, M.A.; Saris, W.H.M.

    1999-01-01

    The effect of aging on beta-adrenergically mediated substrate utilization was investigated in nine young (25.2 +/- 1.7 yr old) and eight older males (52.9 +/- 2.1 yr old), matched for body weight and body composition. In a first experiment, the nonselective beta-agonist isoprenaline (ISO) was infuse

  1. Strong signal of dynamical long-range correlating among target fragments in relativistic and ultra-relativistic nuclear interactions

    CERN Document Server

    Ghosh, D; Bhattacharya, S; Ghosh, J; Das, R

    2003-01-01

    This paper reports an investigation on the two-particle long-range angular correlation among the target fragments produced in sup 2 sup 8 Si-AgBr interactions at 14.5 AGeV, sup 1 sup 6 O-AgBr interactions at 60 AGeV and sup 3 sup 2 S-AgBr interactions at 200 AGeV. The experimental data have been compared with Monte Carlo simulated events to extract dynamical correlation. The data exhibit two-particle long-range correlation in emission angle space at all energies. (author)

  2. Some Interactions of Speech Rate, Signal Distortion, and Certain Linguistic Factors in Listening Comprehension. Professional Paper No. 39-68.

    Science.gov (United States)

    Sticht, Thomas G.

    This experiment was designed to determine the relative effects of speech rate and signal distortion due to the time-compression process on listening comprehension. In addition, linguistic factors--including sequencing of random words into story form, and inflection and phraseology--were qualitatively considered for their effects on listening…

  3. Drosophila Lipin interacts with insulin and TOR signaling pathways in the control of growth and lipid metabolism.

    Science.gov (United States)

    Schmitt, Sandra; Ugrankar, Rupali; Greene, Stephanie E; Prajapati, Meenakshi; Lehmann, Michael

    2015-12-01

    Lipin proteins have key functions in lipid metabolism, acting as both phosphatidate phosphatases (PAPs) and nuclear regulators of gene expression. We show that the insulin and TORC1 pathways independently control functions of Drosophila Lipin (dLipin). Reduced signaling through the insulin receptor strongly enhanced defects caused by dLipin deficiency in fat body development, whereas reduced signaling through TORC1 led to translocation of dLipin into the nucleus. Reduced expression of dLipin resulted in decreased signaling through the insulin-receptor-controlled PI3K-Akt pathway and increased hemolymph sugar levels. Consistent with this, downregulation of dLipin in fat body cell clones caused a strong growth defect. The PAP but not the nuclear activity of dLipin was required for normal insulin pathway activity. Reduction of other enzymes of the glycerol-3 phosphate pathway affected insulin pathway activity in a similar manner, suggesting an effect that is mediated by one or more metabolites associated with the pathway. Taken together, our data show that dLipin is subject to intricate control by the insulin and TORC1 pathways, and that the cellular status of dLipin impacts how fat body cells respond to signals relayed through the PI3K-Akt pathway.

  4. Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin

    OpenAIRE

    Xie, Yang; Zamponi, Raffaella; Charlat, Olga; Ramones, Melissa; Swalley, Susanne; Jiang, Xiaomo; Rivera, Daniel; Tschantz, William; Lu, Bo; Quinn, Lisa; Dimitri, Chris; Parker, Jefferson; Jeffery, Doug; Wilcox, Sheri K; Watrobka, Mike

    2013-01-01

    This study shows that both ZNRF3- and LGR4-binding motifs of R-spondin are required for its Wnt-promoting activity. These results support a dual receptor model of R-spondin signalling, where LGR4 serves as the engagement receptor while ZNRF3 functions as the effector receptor.

  5. Peptides derived from specific interaction sites of the fibroblast growth factor 2 - FGF receptor complexes induce receptor activation and signaling

    DEFF Research Database (Denmark)

    Manfè, Valentina; Kochoyan, Artur; Bock, Elisabeth;

    2010-01-01

    , promoting survival of cerebellar granule neurons induced to undergo apoptosis. Our results suggest that canofins mirror the effect of specific interaction sites in FGF2 for FGFR. Thus, canofins are valuable pharmacological tools to study the functional roles of specific molecular interactions of FGF2...... by canofins, indicating that canofins are partial FGFR agonists. Furthermore, canofins were demonstrated to induce neuronal differentiation determined by neurite outgrowth from cerebellar granule neurons, and this effect was dependent on FGFR activation. Additionally, canofins acted as neuroprotectants...

  6. Cellular Prion Protein and Caveolin-1 Interaction in a Neuronal Cell Line Precedes Fyn/Erk 1/2 Signal Transduction

    Directory of Open Access Journals (Sweden)

    Mattia Toni

    2006-01-01

    Full Text Available It has been reported that cellular prion protein (PrPc is enriched in caveolae or caveolae-like domains with caveolin-1 (Cav-1 participating to signal transduction events by Fyn kinase recruitment. By using the Glutathione-S-transferase (GST-fusion proteins assay, we observed that PrPc strongly interacts in vitro with Cav-1. Thus, we ascertained the PrPc caveolar localization in a hypothalamic neuronal cell line (GN11, by confocal microscopy analysis, flotation on density gradient, and coimmunoprecipitation experiments. Following the anti-PrPc antibody-mediated stimulation of live GN11 cells, we observed that PrPc clustered on plasma membrane domains rich in Cav-1 in which Fyn kinase converged to be activated. After these events, a signaling cascade through p42/44 MAP kinase (Erk 1/2 was triggered, suggesting that following translocations from rafts to caveolae or caveolae-like domains PrPc could interact with Cav-1 and induce signal transduction events.

  7. The Wnt and Delta-Notch signalling pathways interact to direct pair-rule gene expression via caudal during segment addition in the spider Parasteatoda tepidariorum.

    Science.gov (United States)

    Schönauer, Anna; Paese, Christian L B; Hilbrant, Maarten; Leite, Daniel J; Schwager, Evelyn E; Feitosa, Natália Martins; Eibner, Cornelius; Damen, Wim G M; McGregor, Alistair P

    2016-07-01

    In short-germ arthropods, posterior segments are added sequentially from a segment addition zone (SAZ) during embryogenesis. Studies in spiders such as Parasteatoda tepidariorum have provided insights into the gene regulatory network (GRN) underlying segment addition, and revealed that Wnt8 is required for dynamic Delta (Dl) expression associated with the formation of new segments. However, it remains unclear how these pathways interact during SAZ formation and segment addition. Here, we show that Delta-Notch signalling is required for Wnt8 expression in posterior SAZ cells, but represses the expression of this Wnt gene in anterior SAZ cells. We also found that these two signalling pathways are required for the expression of the spider orthologues of even-skipped (eve) and runt-1 (run-1), at least in part via caudal (cad). Moreover, it appears that dynamic expression of eve in this spider does not require a feedback loop with run-1, as is found in the pair-rule circuit of the beetle Tribolium Taken together, our results suggest that the development of posterior segments in Parasteatoda is directed by dynamic interactions between Wnt8 and Delta-Notch signalling that are read out by cad, which is necessary but probably not sufficient to regulate the expression of eve and run-1 Our study therefore provides new insights towards better understanding the evolution and developmental regulation of segmentation in other arthropods, including insects.

  8. The EGF repeat-specific O-GlcNAc-transferase Eogt interacts with notch signaling and pyrimidine metabolism pathways in Drosophila.

    Directory of Open Access Journals (Sweden)

    Reto Müller

    Full Text Available The O-GlcNAc transferase Eogt modifies EGF repeats in proteins that transit the secretory pathway, including Dumpy and Notch. In this paper, we show that the Notch ligands Delta and Serrate are also substrates of Eogt, that mutation of a putative UDP-GlcNAc binding DXD motif greatly reduces enzyme activity, and that Eogt and the cytoplasmic O-GlcNAc transferase Ogt have distinct substrates in Drosophila larvae. Loss of Eogt is larval lethal and disrupts Dumpy functions, but does not obviously perturb Notch signaling. To identify novel genetic interactions with eogt, we investigated dominant modification of wing blister formation caused by knock-down of eogt. Unexpectedly, heterozygosity for several members of the canonical Notch signaling pathway suppressed wing blister formation. And importantly, extensive genetic interactions with mutants in pyrimidine metabolism were identified. Removal of pyrimidine synthesis alleles suppressed wing blister formation, while removal of uracil catabolism alleles was synthetic lethal with eogt knock-down. Therefore, Eogt may regulate protein functions by O-GlcNAc modification of their EGF repeats, and cellular metabolism by affecting pyrimidine synthesis and catabolism. We propose that eogt knock-down in the wing leads to metabolic and signaling perturbations that increase cytosolic uracil levels, thereby causing wing blister formation.

  9. The Wnt and Delta-Notch signalling pathways interact to direct pair-rule gene expression via caudal during segment addition in the spider Parasteatoda tepidariorum.

    Science.gov (United States)

    Schönauer, Anna; Paese, Christian L B; Hilbrant, Maarten; Leite, Daniel J; Schwager, Evelyn E; Feitosa, Natália Martins; Eibner, Cornelius; Damen, Wim G M; McGregor, Alistair P

    2016-07-01

    In short-germ arthropods, posterior segments are added sequentially from a segment addition zone (SAZ) during embryogenesis. Studies in spiders such as Parasteatoda tepidariorum have provided insights into the gene regulatory network (GRN) underlying segment addition, and revealed that Wnt8 is required for dynamic Delta (Dl) expression associated with the formation of new segments. However, it remains unclear how these pathways interact during SAZ formation and segment addition. Here, we show that Delta-Notch signalling is required for Wnt8 expression in posterior SAZ cells, but represses the expression of this Wnt gene in anterior SAZ cells. We also found that these two signalling pathways are required for the expression of the spider orthologues of even-skipped (eve) and runt-1 (run-1), at least in part via caudal (cad). Moreover, it appears that dynamic expression of eve in this spider does not require a feedback loop with run-1, as is found in the pair-rule circuit of the beetle Tribolium Taken together, our results suggest that the development of posterior segments in Parasteatoda is directed by dynamic interactions between Wnt8 and Delta-Notch signalling that are read out by cad, which is necessary but probably not sufficient to regulate the expression of eve and run-1 Our study therefore provides new insights towards better understanding the evolution and developmental regulation of segmentation in other arthropods, including insects. PMID:27287802

  10. TRAF6 mediates IL-1β/LPS-induced suppression of TGF-β signaling through its interaction with the type III TGF-β receptor.

    Directory of Open Access Journals (Sweden)

    Seunghwan Lim

    Full Text Available Transforming growth factor-β1 (TGF-β1 is an important anti-inflammatory cytokine that modulates and resolves inflammatory responses. Recent studies have demonstrated that inflammation enhances neoplastic risk and potentiates tumor progression. In the evolution of cancer, pro-inflammatory cytokines such as IL-1β must overcome the anti-inflammatory effects of TGF-β to boost pro-inflammatory responses in epithelial cells. Here we show that IL-1β or Lipopolysaccharide (LPS suppresses TGF-β-induced anti-inflammatory signaling in a NF-κB-independent manner. TRAF6, a key molecule in IL-1β signaling, mediates this suppressive effect through interaction with the type III TGF-β receptor (TβRIII, which is TGF-β-dependent and requires type I TGF-β receptor (TβRI kinase activity. TβRI phosphorylates TβRIII at residue S829, which promotes the TRAF6/TβRIII interaction and consequent sequestration of TβRIII from the TβRII/TβRI complex. Our data indicate that IL-1β enhances the pro-inflammatory response by suppressing TGF-β signaling through TRAF6-mediated sequestration of TβRIII, which may be an important contributor to the early stages of tumor progression.

  11. Inhibition of Wnt/β-catenin signaling by a soluble collagen-derived frizzled domain interacting with Wnt3a and the receptors frizzled 1 and 8.

    Directory of Open Access Journals (Sweden)

    Ismaïl Hendaoui

    Full Text Available The Wnt/β-catenin pathway controls cell proliferation, death and differentiation. Several families of extracellular proteins can antagonize Wnt/β-catenin signaling, including the decoy receptors known as secreted frizzled related proteins (SFRPs, which have a cysteine-rich domain (CRD structurally similar to the extracellular Wnt-binding domain of the frizzled receptors. SFRPs inhibit Wnt signaling by sequestering Wnts through the CRD or by forming inactive complexes with the frizzled receptors. Other endogenous molecules carrying frizzled CRDs inhibit Wnt signaling, such as V3Nter, which is proteolytically derived from the cell surface component collagen XVIII and contains a biologically active frizzled domain (FZC18 inhibiting in vivo cell proliferation and tumor growth in mice. We recently showed that FZC18 expressing cells deliver short-range signals to neighboring cells, decreasing their proliferation in vitro and in vivo through the Wnt/β-catenin signaling pathway. Here, using low concentrations of soluble FZC18 and Wnt3a, we show that they physically interact in a cell-free system. In addition, soluble FZC18 binds the frizzled 1 and 8 receptors' CRDs, reducing cell sensitivity to Wnt3a. Conversely, inhibition of Wnt/β-catenin signaling was partially rescued by the expression of full-length frizzled 1 and 8 receptors, but enhanced by the expression of a chimeric cell-membrane-tethered frizzled 8 CRD. Moreover, soluble, partially purified recombinant FZC18_CRD inhibited Wnt3a-induced β-catenin activation. Taken together, the data indicate that collagen XVIII-derived frizzled CRD shifts Wnt sensitivity of normal cells to a lower pitch and controls their growth.

  12. Signal peptidase complex subunit 1 participates in the assembly of hepatitis C virus through an interaction with E2 and NS2.

    Directory of Open Access Journals (Sweden)

    Ryosuke Suzuki

    Full Text Available Hepatitis C virus (HCV nonstructural protein 2 (NS2 is a hydrophobic, transmembrane protein that is required not only for NS2-NS3 cleavage, but also for infectious virus production. To identify cellular factors that interact with NS2 and are important for HCV propagation, we screened a human liver cDNA library by split-ubiquitin membrane yeast two-hybrid assay using full-length NS2 as a bait, and identified signal peptidase complex subunit 1 (SPCS1, which is a component of the microsomal signal peptidase complex. Silencing of endogenous SPCS1 resulted in markedly reduced production of infectious HCV, whereas neither processing of structural proteins, cell entry, RNA replication, nor release of virus from the cells was impaired. Propagation of Japanese encephalitis virus was not affected by knockdown of SPCS1, suggesting that SPCS1 does not widely modulate the viral lifecycles of the Flaviviridae family. SPCS1 was found to interact with both NS2 and E2. A complex of NS2, E2, and SPCS1 was formed in cells as demonstrated by co-immunoprecipitation assays. Knockdown of SPCS1 impaired interaction of NS2 with E2. Our findings suggest that SPCS1 plays a key role in the formation of the membrane-associated NS2-E2 complex via its interaction with NS2 and E2, which leads to a coordinating interaction between the structural and non-structural proteins and facilitates the early step of assembly of infectious particles.

  13. Phosphorylation of APP-CTF-AICD domains and interaction with adaptor proteins: signal transduction and/or transcriptional role--relevance for Alzheimer pathology.

    Science.gov (United States)

    Schettini, Gennaro; Govoni, Stefano; Racchi, Marco; Rodriguez, Guido

    2010-12-01

    In recent decades, the study of the amyloid precursor protein (APP) and of its proteolytic products carboxy terminal fragment (CTF), APP intracellular C-terminal domain (AICD) and amyloid beta has been mostly focussed on the role of APP as a producer of the toxic amyloid beta peptide. Here, we reconsider the role of APP suggesting, in a provocative way, the protein as a central player in a putative signalling pathway. We highlight the presence in the cytosolic tail of APP of the YENPTY motif which is typical of tyrosine kinase receptors, the phosphorylation of the tyrosine, serine and threonine residues, the kinases involved and the interaction with intracellular adaptor proteins. In particular, we examine the interaction with Shc and Grb2 regulators, which through the activation of Ras proteins elicit downstream signalling events such as the MAPK pathway. The review also addresses the interaction of APP, CTFs and AICD with other adaptor proteins and in particular with Fe65 for nuclear transcriptional activity and the importance of phosphorylation for sorting the secretases involved in the amyloidogenic or non-amyloidogenic pathways. We provide a novel perspective on Alzheimer's disease pathogenesis, focussing on the perturbation of the physiological activities of APP-CTFs and AICD as an alternative perspective from that which normally focuses on the accumulation of neurotoxic proteolytic fragments. PMID:21039524

  14. DNA replication checkpoint signaling depends on a Rad53-Dbf4 N-terminal interaction in Saccharomyces cerevisiae.

    Science.gov (United States)

    Chen, Ying-Chou; Kenworthy, Jessica; Gabrielse, Carrie; Hänni, Christine; Zegerman, Philip; Weinreich, Michael

    2013-06-01

    Dbf4-dependent kinase (DDK) and cyclin-dependent kinase (CDK) are essential to initiate DNA replication at individual origins. During replication stress, the S-phase checkpoint inhibits the DDK- and CDK-dependent activation of late replication origins. Rad53 kinase is a central effector of the replication checkpoint and both binds to and phosphorylates Dbf4 to prevent late-origin firing. The molecular basis for the Rad53-Dbf4 physical interaction is not clear but occurs through the Dbf4 N terminus. Here we found that both Rad53 FHA1 and FHA2 domains, which specifically recognize phospho-threonine (pT), interacted with Dbf4 through an N-terminal sequence and an adjacent BRCT domain. Purified Rad53 FHA1 domain (but not FHA2) bound to a pT Dbf4 peptide in vitro, suggesting a possible phospho-threonine-dependent interaction between FHA1 and Dbf4. The Dbf4-Rad53 interaction is governed by multiple contacts that are separable from the Cdc5- and Msa1-binding sites in the Dbf4 N terminus. Importantly, abrogation of the Rad53-Dbf4 physical interaction blocked Dbf4 phosphorylation and allowed late-origin firing during replication checkpoint activation. This indicated that Rad53 must stably bind to Dbf4 to regulate its activity.

  15. Iron Metabolism Regulates p53 Signaling through Direct Heme-p53 Interaction and Modulation of p53 Localization, Stability, and Function

    Directory of Open Access Journals (Sweden)

    Jia Shen

    2014-04-01

    Full Text Available Iron excess is closely associated with tumorigenesis in multiple types of human cancers, with underlying mechanisms yet unclear. Recently, iron deprivation has emerged as a major strategy for chemotherapy, but it exerts tumor suppression only on select human malignancies. Here, we report that the tumor suppressor protein p53 is downregulated during iron excess. Strikingly, the iron polyporphyrin heme binds to p53 protein, interferes with p53-DNA interactions, and triggers both nuclear export and cytosolic degradation of p53. Moreover, in a tumorigenicity assay, iron deprivation suppressed wild-type p53-dependent tumor growth, suggesting that upregulation of wild-type p53 signaling underlies the selective efficacy of iron deprivation. Our findings thus identify a direct link between iron/heme homeostasis and the regulation of p53 signaling, which not only provides mechanistic insights into iron-excess-associated tumorigenesis but may also help predict and improve outcomes in iron-deprivation-based chemotherapy.

  16. Stress-Immune-Growth Interactions: Cortisol Modulates Suppressors of Cytokine Signaling and JAK/STAT Pathway in Rainbow Trout Liver.

    Directory of Open Access Journals (Sweden)

    Anju M Philip

    Full Text Available Chronic stress is a major factor in the poor growth and immune performance of salmonids in aquaculture. However, the molecular mechanisms linking stress effects to growth and immune dysfunction is poorly understood. The suppressors of cytokine signaling (SOCS, a family of genes involved in the inhibition of JAK/STAT pathway, negatively regulates growth hormone and cytokine signaling, but their role in fish is unclear. Here we tested the hypothesis that cortisol modulation of SOCS gene expression is a key molecular mechanism leading to growth and immune suppression in response to stress in fish. Exposure of rainbow trout (Oncorhynchus mykiss liver slices to cortisol, mimicking stress level, upregulated SOCS-1 and SOCS-2 mRNA abundance and this response was abolished by the glucocorticoid receptor antagonist mifepristone. Bioinformatics analysis confirmed the presence of putative glucocorticoid response elements in rainbow trout SOCS-1 and SOCS-2 promoters. Prior cortisol treatment suppressed acute growth hormone (GH-stimulated IGF-1 mRNA abundance in trout liver and this involved a reduction in STAT5 phosphorylation and lower total JAK2 protein expression. Prior cortisol treatment also suppressed lipopolysaccharide (LPS-induced IL-6 but not IL-8 transcript levels; the former but not the latter cytokine expression is via JAK/STAT phosphorylation. LPS treatment reduced GH signaling, but this was associated with the downregulation of GH receptors and not due to the upregulation of SOCS transcript levels by this endotoxin. Collectively, our results suggest that upregulation of SOCS-1 and SOCS-2 transcript levels by cortisol, and the associated reduction in JAK/STAT signaling pathway, may be a novel mechanism leading to growth reduction and immune suppression during stress in trout.

  17. Fluvial-aeolian interactions in sediment routing and sedimentary signal buffering: an example from the Indus Basin and Thar Desert

    Science.gov (United States)

    East, Amy E.; Clift, Peter D.; Carter, Andrew; Alizai, Anwar; VanLaningham, Sam

    2015-01-01

    Sediment production and its subsequent preservation in the marine stratigraphic record offshore of large rivers are linked by complex sediment-transfer systems. To interpret the stratigraphic record it is critical to understand how environmental signals transfer from sedimentary source regions to depositional sinks, and in particular to understand the role of buffering in obscuring climatic or tectonic signals. In dryland regions, signal buffering can include sediment cycling through linked fluvial and eolian systems. We investigate sediment-routing connectivity between the Indus River and the Thar Desert, where fluvial and eolian systems exchanged sediment over large spatial scales (hundreds of kilometers). Summer monsoon winds recycle sediment from the lower Indus River and delta northeastward, i.e., downwind and upstream, into the desert. Far-field eolian recycling of Indus sediment is important enough to control sediment provenance at the downwind end of the desert substantially, although the proportion of Indus sediment of various ages varies regionally within the desert; dune sands in the northwestern Thar Desert resemble the Late Holocene–Recent Indus delta, requiring short transport and reworking times. On smaller spatial scales (1–10 m) along fluvial channels in the northern Thar Desert, there is also stratigraphic evidence of fluvial and eolian sediment reworking from local rivers. In terms of sediment volume, we estimate that the Thar Desert could be a more substantial sedimentary store than all other known buffer regions in the Indus basin combined. Thus, since the mid-Holocene, when the desert expanded as the summer monsoon rainfall decreased, fluvial-eolian recycling has been an important but little recognized process buffering sediment flux to the ocean. Similar fluvial-eolian connectivity likely also affects sediment routing and signal transfer in other dryland regions globally.

  18. Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development

    Science.gov (United States)

    Bar, Carmit; Tsai, Pai-Chi; Valdes, Victor J.; Cohen, Idan; Santoriello, Francis J.; Zhao, Dejian; Hsu, Ya-Chieh; Ezhkova, Elena

    2016-01-01

    An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures. PMID:27414999

  19. Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development.

    Directory of Open Access Journals (Sweden)

    Carolina N Perdigoto

    2016-07-01

    Full Text Available An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2 in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures.

  20. Strategic Sexual Signals: Women's Display versus Avoidance of the Color Red Depends on the Attractiveness of an Anticipated Interaction Partner.

    Directory of Open Access Journals (Sweden)

    Daniela Niesta Kayser

    Full Text Available The color red has special meaning in mating-relevant contexts. Wearing red can enhance perceptions of women's attractiveness and desirability as a potential romantic partner. Building on recent findings, the present study examined whether women's (N = 74 choice to display the color red is influenced by the attractiveness of an expected opposite-sex interaction partner. Results indicated that female participants who expected to interact with an attractive man displayed red (on clothing, accessories, and/or makeup more often than a baseline consisting of women in a natural environment with no induced expectation. In contrast, when women expected to interact with an unattractive man, they eschewed red, displaying it less often than in the baseline condition. Findings are discussed with respect to evolutionary and cultural perspectives on mate evaluation and selection.

  1. Strategic Sexual Signals: Women's Display versus Avoidance of the Color Red Depends on the Attractiveness of an Anticipated Interaction Partner.

    Science.gov (United States)

    Niesta Kayser, Daniela; Agthe, Maria; Maner, Jon K

    2016-01-01

    The color red has special meaning in mating-relevant contexts. Wearing red can enhance perceptions of women's attractiveness and desirability as a potential romantic partner. Building on recent findings, the present study examined whether women's (N = 74) choice to display the color red is influenced by the attractiveness of an expected opposite-sex interaction partner. Results indicated that female participants who expected to interact with an attractive man displayed red (on clothing, accessories, and/or makeup) more often than a baseline consisting of women in a natural environment with no induced expectation. In contrast, when women expected to interact with an unattractive man, they eschewed red, displaying it less often than in the baseline condition. Findings are discussed with respect to evolutionary and cultural perspectives on mate evaluation and selection. PMID:26960135

  2. Stimulation of Wnt/β-Catenin Signaling to Improve Bone Development by Naringin via Interacting with AMPK and Akt

    Directory of Open Access Journals (Sweden)

    Dawei Wang

    2015-07-01

    Full Text Available Background/Aims: Naringin is a naturally existing compound in citrus fruits and has been elucidated to promote bone development and maintenance. Methods: The biological roles of naringin were investigated in vitro using osteoblast-like UMR-106 cells, and in vivo through performing ovariectomy to mimic osteoporosis in female mice. Since Wnt/β-catenin signaling is involved in osteoblastogenesis, the effect of naringin on Wnt/β-catenin signaling was studied. Results: Naringin promoted the mRNA and protein expressions of β-catenin, and improved Ser552 phosphorylation on β-catenin in UMR-106 cells, which leads to the activation of lymphoid enhancer factor (LEF/ T-cell factor (TCF transcription factors. The recruitments of protein kinase B (Akt inhibitor (Akti-1/2 and AMP-activated protein kinase (AMPK inhibitor (Dorsomorphin reduced the influence of naringin on β-catenin phosphorylation, suggesting naringin activates β-catenin via regulating Akt and AMPK. In ovariectomized (OVX mice naringin treatment improved the bone strength while AMPK and Akt inhibitors partly reversed the effect, which further proved the involvements of Akt and AMPK in the action of naringin in vivo. Conclusion: Our study points to a novel finding on the mechanism of naringin in facilitating bone formation via Akt and AMPK signaling.

  3. Selective hyaluronan-CD44 signaling promotes miRNA-21 expression and interacts with vitamin D function during cutaneous squamous cell carcinomas progression following UV irradiation

    Directory of Open Access Journals (Sweden)

    Lilly YW Bourguignon

    2015-05-01

    Full Text Available Hyaluronan (HA, the major extracellular matrix component, is often anchored to CD44 isoforms, a family of structurally/functionally important cell surface receptors. Our recent results indicate that UV irradiation (UVR-induced cutaneous squamous cell carcinomas (SCC overexpress a variety of CD44 variant isoforms (CD44v, with different CD44v isoforms appear to confer malignant SCC properties. UVR also stimulates HA degradation in epidermal keratinocytes. Both large HA polymers and their UVR-induced catabolic products (small HA selectively activate CD44 isoform-mediated cellular signaling in normal keratinocytes and SCC cells, with all of the downstream processes being mediated by RhoGTPases (e.g., RhoA and Rac1. Importantly, we found that the hormonally active form of vitamin D (1,25(OH2D3 not only prevents the UVR-induced small HA activation of abnormal keratinocyte behavior and SCC progression, but also enhances large HA stimulation of normal keratinocyte activities and epidermal function(s. Furthermore, we found that HA and its UVR-induced catabolic products (e.g., large and small HA selectively activate CD44-mediated Rac and RhoA signaling. Specifically, large HA-CD44 interaction promotes Rac/PKNγ-dependent normal keratinocyte differentiation, DNA repair and keratinocyte survival. Conversely, small HA-CD44v isoform interaction stimulates RhoA/ROK-dependent NFκB signaling and microRNA-21 (miR-21 production, leading to inflammation, proliferation (following acute UVR response and SCC progression (following chronic UVR exposure. Active vitamin D inhibits small HA-CD44v-mediated RhoA/ROK signaling and SCC progression; and it also enhances large HA-CD44-mediated differentiation, DNA repair and normal epidermal function. Selective applications of large HA and vitamin D will be used to improve the UVR-induced HA (small vs. large HA-CD44 isoform interaction with RhoGTPase signaling and skin inflammation as a potential therapeutic treatment for skin

  4. Arabidopsis STO/BBX24 negatively regulates UV-B signaling by interacting with COP1 and repressing HY5 transcriptional activity

    Institute of Scientific and Technical Information of China (English)

    Lei Jiang; Yan Wang; Qian-Feng Li; Lars Olof Bj(o)rn; Jun-Xian He; Shao-Shan Li

    2012-01-01

    UV-B (280-315 nm) is an integral part of solar radiation and can act either as a stress inducer or as a developmental signal.In recent years,increasing attention has been paid to the Iow-fluence UV-B-induced photomorphogenic response and several key players in this response have been identified,which include UVR8 (a UV-B-specific photoreceptor),COPI (a WD40-repeat-containing RING finger protein),HY5 (a basic zipper transcription factor),and RUP1/2 (two UVR8-interacting proteins).Here we report that Arabidopsis SALT TOLERANCE (STO/BBX24),a known regulator for light signaling in plants,defines a new signaling component in UV-B-mediated photomorphogenesis.The bbx24 mutant is hypersensitive to UV-B radiation and becomes extremely dwarfed under UV-B treatment.By contrast,BBX24 overexpression transgenic lines respond much more weakly to UV-B than the bbx24 and wild-type plants.BBX24 expression is UV-B-inducible and its accumulation under UV-B requires COP1.Co-immunoprecipitation experiments indicate that BBX24 interacts with COP1 in planta upon UV-B illumination.Moreover,BBX24 interacts with HY5 and acts antagonistically with HY5 in UV-B-induced inhibition of hypocotyl elongation.Furthermore,BBX24 attenuates UV-B-induced HY5 accumulation and suppresses its transcription-activation activity.Taken together,our results reveal a previously uncharacterized function of the light-regulated BBX24 in UV-B responses and demonstrate that BBX24 functions as a negative regulator of photomorphogenic UV-B responses by interacting with both COP1 and HY5.The UV-B-inducible expression pattern and its suppression of HY5 activity suggest that BBX24 could be a new component of the feedback regulatory module of UV-B signaling in plants.

  5. Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells

    OpenAIRE

    Cai, Liquan; Wang, Dan; Fisher, Alfred L.; Zhou WANG

    2014-01-01

    The tumor suppressor EAF2 is regulated by androgen signaling and associated with prostate cancer. While EAF2 and its partner ELL have been shown to be members of protein complexes involved in RNA polymerase II transcriptional elongation, the biologic roles for EAF2 especially with regards to the development of cancer remains poorly understood. We have previously identified the eaf-1 gene in C. elegans as the ortholog of EAF2, and shown that eaf-1 interacts with the ELL ortholog ell-1 to contr...

  6. Cross-Modal Interactions during Perception of Audiovisual Speech and Nonspeech Signals: An fMRI Study

    Science.gov (United States)

    Hertrich, Ingo; Dietrich, Susanne; Ackermann, Hermann

    2011-01-01

    During speech communication, visual information may interact with the auditory system at various processing stages. Most noteworthy, recent magnetoencephalography (MEG) data provided first evidence for early and preattentive phonetic/phonological encoding of the visual data stream--prior to its fusion with auditory phonological features [Hertrich,…

  7. Palmitoylation regulates intracellular trafficking of β2 adrenergic receptor/arrestin/phosphodiesterase 4D complexes in cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Ruijie Liu

    Full Text Available β(2 adrenergic receptor (β(2AR is a prototypical G-protein coupled receptor that stimulates the classic cAMP-protein kinase A (PKA signaling pathway. Recent studies indicate that the cAMP-PKA activities are spatiotemporally regulated in part due to dynamic association of β(2AR with phosphodiesterase 4D (PDE4D, a group of cAMP degradation enzymes. Here, we demonstrate that in cardiomyocytes, palmitoylation of β(2AR, the covalent acylation of cysteine residue 341, plays a critical role in shaping subcellular cAMP-PKA activities in cardiomyocytes via regulating β(2AR association with arrestin/PDE4D. Replacing cysteine 341 on β(2AR with alanine (C341A leads to an impaired binding to β arrestin 2. Surprisingly, the C341A mutant is able to internalize via an arrestin-independent pathway at saturated concentration of agonist stimulation; the internalization becomes caveolae-dependent and requires dynamin GTPase. However, the impaired binding to β arrestin 2 also leads to an impaired recruitment of PDE4D to the C341A mutant. Thus, the mutant C341A β(2AR is transported alone from the plasma membrane to the endosome without recruiting PDE4D. This alteration leads to an enhanced cytoplasmic cAMP signal for PKA activation under β(2AR stimulation. Functionally, Mutation of the C341 residue or inhibition of palmitoylation modification of β(2AR enhances the receptor-induced PKA activities in the cytoplasm and increases in myocyte contraction rate. Our data reveal a novel function of palmitoylation in shaping subcellular cAMP-PKA signaling in cardiomyocytes via modulating the recruitment of β arrestin 2-PDE4D complexes to the agonist-stimulated β(2AR.

  8. The phenomenon of acquired resistance to metformin in breast cancer cells: The interaction of growth pathways and estrogen receptor signaling.

    Science.gov (United States)

    Scherbakov, Alexander M; Sorokin, Danila V; Tatarskiy, Victor V; Prokhorov, Nikolay S; Semina, Svetlana E; Berstein, Lev M; Krasil'nikov, Mikhail A

    2016-04-01

    Metformin, a biguanide antidiabetic drug, is used to decrease hyperglycemia in patients with type 2 diabetes. Recently, the epidemiological studies revealed the potential of metformin as an anti-tumor drug for several types of cancer, including breast cancer. Anti-tumor metformin action was found to be mediated, at least in part, via activation of adenosine monophosphate-activated protein kinase (AMPK)-intracellular energy sensor, which inhibits the mammalian target of rapamycin (mTOR) and some other signaling pathways. Nevertheless, some patients can be non-sensitive or resistant to metformin action. Here we analyzed the mechanism of the formation of metformin-resistant phenotype in breast cancer cells and its role in estrogen receptor (ER) regulation. The experiments were performed on the ER-positive MCF-7 breast cancer cells and metformin-resistant MCF-7 subline (MCF-7/M) developed due to long-term metformin treatment. The transcriptional activity of NF-κB and ER was measured by the luciferase reporter gene analysis. The protein expression was determined by immunoblotting (Snail1, (phospho)AMPK, (phospho)IκBα, (phospho)mTOR, cyclin D1, (phospho)Akt and ERα) and immunohistochemical analysis (E-cadherin). We have found that: 1) metformin treatment of MCF-7 cells is accompanied with the stimulation of AMPK and inhibition of growth-related proteins including IκBα, NF-κB, cyclin D1 and ERα; 2) long-term metformin treatment lead to the appearance and progression of cross-resistance to metformin and tamoxifen; the resistant cells are characterized with the unaffected AMPK activity, but the irreversible ER suppression and constitutive activation of Akt/Snail1 signaling; 3) Akt/Snail1 signaling is involved into progression of metformin resistance. The results presented may be considered as the first evidence of the progression of cross-resistance to metformin and tamoxifen in breast cancer cells. Importantly, the acquired resistance to both drugs is based on the

  9. Identification of a novel nuclear localization signal and speckle-targeting sequence of tuftelin-interacting protein 11, a splicing factor involved in spliceosome disassembly

    Energy Technology Data Exchange (ETDEWEB)

    Tannukit, Sissada [Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA Rm103, Los Angeles, CA 90033-1004 (United States); Crabb, Tara L.; Hertel, Klemens J. [Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA 92697-4025 (United States); Wen, Xin [Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA Rm103, Los Angeles, CA 90033-1004 (United States); Jans, David A. [Department of Biochemistry and Molecular Biology, Nuclear Signalling Laboratory, Monash University, Clayton, Victoria 3800 (Australia); Paine, Michael L., E-mail: paine@usc.edu [Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA Rm103, Los Angeles, CA 90033-1004 (United States)

    2009-12-18

    Tuftelin-interacting protein 11 (TFIP11) is a protein component of the spliceosome complex that promotes the release of the lariat-intron during late-stage splicing through a direct recruitment and interaction with DHX15/PRP43. Expression of TFIP11 is essential for cell and organismal survival. TFIP11 contains a G-patch domain, a signature motif of RNA-processing proteins that is responsible for TFIP11-DHX15 interactions. No other functional domains within TFIP11 have been described. TFIP11 is localized to distinct speckled regions within the cell nucleus, although excluded from the nucleolus. In this study sequential C-terminal deletions and mutational analyses have identified two novel protein elements in mouse TFIP11. The first domain covers amino acids 701-706 (VKDKFN) and is an atypical nuclear localization signal (NLS). The second domain is contained within amino acids 711-735 and defines TFIP11's distinct speckled nuclear localization. The identification of a novel TFIP11 nuclear speckle-targeting sequence (TFIP11-STS) suggests that this domain directly interacts with additional spliceosomal components. These data help define the mechanism of nuclear/nuclear speckle localization of the splicing factor TFIP11, with implications for it's function.

  10. PCNA-interacting peptides reduce Akt phosphorylation and TLR-mediated cytokine secretion suggesting a role of PCNA in cellular signaling.

    Science.gov (United States)

    Olaisen, Camilla; Müller, Rebekka; Nedal, Aina; Otterlei, Marit

    2015-07-01

    Proliferating cell nuclear antigen (PCNA), commonly known as a nuclear protein essential for regulation of DNA replication, DNA repair, and epigenetics, has recently been associated with multiple cytosolic functions. Many proteins containing one of the two known PCNA-interacting motifs, the AlkB homologue 2 PCNA interacting motif (APIM) and the PCNA-interacting peptide (PIP)-box, are considered to be mainly cytosolic. APIM is found in more than 20 kinases and/or associated proteins including several direct or indirect members of the mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways. Mass spectrometry analysis of PCNA-pull downs verified that many cytosolic proteins involved in the MAPK and PI3K/Akt pathways are in complex with PCNA. Furthermore, treatment of cells with a PCNA-interacting APIM-containing peptide (APIM-peptide) reduced Akt phosphorylation in human peripheral blood monocytes and a human keratinocyte cell line (HaCaT). Additionally, the APIM-peptide strongly reduced the cytokine secretion from monocytes stimulated with toll like receptor (TLR) ligands and potentiated the effects of MAPK and PI3K/Akt inhibitors. Interestingly, the protein level of the APIM-containing PKR/RIG-1 activator protein (PACT) was initially strongly reduced in HaCaT cells stimulated with APIM-peptide in combination with the TLR ligand polyinosinic-polycytidylic acid (polyIC). Our results suggest that PCNA has a platform role in cytosol affecting cellular signaling.

  11. Alpha-amylase activity in blood increases after pharmacological, but not psychological, activation of the adrenergic system

    OpenAIRE

    Nater, Urs M.; Roberto La Marca; Katja Erni; Ulrike Ehlert

    2015-01-01

    BACKGROUND & AIM: Alpha-amylase in both blood and saliva has been used as a diagnostic parameter. While studies examining alpha-amylase activity in saliva have shown that it is sensitive to physiological and psychological challenge of the adrenergic system, no challenge studies have attempted to elucidate the role of the adrenergic system in alpha-amylase activity in blood. We set out to examine the impact of psychological and pharmacological challenge on alpha-amylase in blood in two separat...

  12. Possible association of β2- and β3-adrenergic receptor gene polymorphisms with susceptibility to breast cancer

    OpenAIRE

    Xin-en HUANG; Hamajima, Nobuyuki; Saito, Toshiko; Matsuo, Keitaro; Mizutani, Mitsuhiro; Iwata, Hiroji; Iwase, Takuji; Miura, Shigeto; Mizuno, Tsutomu; Tokudome, Shinkan; Tajima, Kazuo

    2001-01-01

    Background The involvement of β2-adrenergic receptor (ADRB2) and β3-adrenergic receptor (ADRB3) in both adipocyte lipolysis and thermogenic activity suggests that polymorphisms in the encoding genes might be linked with interindividual variation in obesity, an important risk factor for postmenopausal breast cancer. In order to examine the hypothesis that genetic variations in ADRB2 and ADRB3 represent interindividual susceptibility factors for obesity and breast cancer, we conducted a hospita...

  13. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors.

    Science.gov (United States)

    Willingham, Stephen B; Volkmer, Jens-Peter; Gentles, Andrew J; Sahoo, Debashis; Dalerba, Piero; Mitra, Siddhartha S; Wang, Jian; Contreras-Trujillo, Humberto; Martin, Robin; Cohen, Justin D; Lovelace, Patricia; Scheeren, Ferenc A; Chao, Mark P; Weiskopf, Kipp; Tang, Chad; Volkmer, Anne Kathrin; Naik, Tejaswitha J; Storm, Theresa A; Mosley, Adriane R; Edris, Badreddin; Schmid, Seraina M; Sun, Chris K; Chua, Mei-Sze; Murillo, Oihana; Rajendran, Pradeep; Cha, Adriel C; Chin, Robert K; Kim, Dongkyoon; Adorno, Maddalena; Raveh, Tal; Tseng, Diane; Jaiswal, Siddhartha; Enger, Per Øyvind; Steinberg, Gary K; Li, Gordon; So, Samuel K; Majeti, Ravindra; Harsh, Griffith R; van de Rijn, Matt; Teng, Nelson N H; Sunwoo, John B; Alizadeh, Ash A; Clarke, Michael F; Weissman, Irving L

    2012-04-24

    CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.

  14. The Interaction of Adrenomedullin and Macrophages Induces Ovarian Cancer Cell Migration via Activation of RhoA Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Xiaoyan Pang

    2013-01-01

    Full Text Available Tumor-associated macrophages (TAMs are correlated with poor prognosis in many human cancers; however, the mechanism by which TAMs facilitate ovarian cancer cell migration and invasion remains unknown. This study was aimed to examine the function of adrenomedullin (ADM in macrophage polarization and their further effects on the migration of ovarian cancer cells. Exogenous ADM antagonist and small interfering RNA (siRNA specific for ADM expression were treated to macrophages and EOC cell line HO8910, respectively. Then macrophages were cocultured with HO8910 cells without direct contact. Flow cytometry, Western blot and real-time PCR were used to detect macrophage phenotype and cytokine production. The migration ability and cytoskeleton rearrangement of ovarian cancer cells were determined by Transwell migration assay and phalloidin staining. Western blot was performed to evaluate the activity status of signaling molecules in the process of ovarian cancer cell migration. The results showed that ADM induced macrophage phenotype and cytokine production similar to TAMs. Macrophages polarized by ADM promoted the migration and cytoskeleton rearrangement of HO8910 cells. The expression of RhoA and its downstream effector, cofilin, were upregulated in macrophage-induced migration of HO8910 cells. In conclusion, ADM could polarize macrophages similar to TAMs, and then polarized macrophages promote the migration of ovarian cancer cells via activation of RhoA signaling pathway in vitro.

  15. Phosphoproteomic analysis of induced resistance reveals activation of signal transduction processes by beneficial and pathogenic interaction in grapevine.

    Science.gov (United States)

    Perazzolli, Michele; Palmieri, Maria Cristina; Matafora, Vittoria; Bachi, Angela; Pertot, Ilaria

    2016-05-20

    Protein phosphorylation regulates several key processes of the plant immune system. Protein kinases and phosphatases are pivotal regulators of defense mechanisms elicited by resistance inducers. However, the phosphorylation cascades that trigger the induced resistance mechanisms in plants have not yet been deeply investigated. The beneficial fungus Trichoderma harzianum T39 (T39) induces resistance against grapevine downy mildew (Plasmopara viticola), but its efficacy could be further improved by a better understanding of the cellular regulations involved. We investigated quantitative changes in the grapevine phosphoproteome during T39-induced resistance to get an overview of regulatory mechanisms of downy mildew resistance. Immunodetection experiments revealed activation of the 45 and 49kDa kinases by T39 treatment both before and after pathogen inoculation, and the phosphoproteomic analysis identified 103 phosphopeptides that were significantly affected by the phosphorylation cascades during T39-induced resistance. Peptides affected by T39 treatment showed comparable phosphorylation levels after P. viticola inoculation, indicating activation of the microbial recognition machinery before pathogen infection. Phosphorylation profiles of proteins related to photosynthetic processes and protein ubiquitination indicated a partial overlap of cellular responses in T39-treated and control plants. However, phosphorylation changes of proteins involved in response to stimuli, signal transduction, hormone signaling, gene expression regulation, and RNA metabolism were exclusively elicited by P. viticola inoculation in T39-treated plants. These results highlighted the relevance of phosphorylation changes during T39-induced resistance and identified key regulator candidates of the grapevine defense against downy mildew. PMID:27010348

  16. Dynamic NF-κB and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation.

    Science.gov (United States)

    Ankers, John M; Awais, Raheela; Jones, Nicholas A; Boyd, James; Ryan, Sheila; Adamson, Antony D; Harper, Claire V; Bridge, Lloyd; Spiller, David G; Jackson, Dean A; Paszek, Pawel; Sée, Violaine; White, Michael Rh

    2016-01-01

    Dynamic cellular systems reprogram gene expression to ensure appropriate cellular fate responses to specific extracellular cues. Here we demonstrate that the dynamics of Nuclear Factor kappa B (NF-κB) signalling and the cell cycle are prioritised differently depending on the timing of an inflammatory signal. Using iterative experimental and computational analyses, we show physical and functional interactions between NF-κB and the E2 Factor 1 (E2F-1) and E2 Factor 4 (E2F-4) cell cycle regulators. These interactions modulate the NF-κB response. In S-phase, the NF-κB response was delayed or repressed, while cell cycle progression was unimpeded. By contrast, activation of NF-κB at the G1/S boundary resulted in a longer cell cycle and more synchronous initial NF-κB responses between cells. These data identify new mechanisms by which the cellular response to stress is differentially controlled at different stages of the cell cycle. PMID:27185527

  17. Bispectrum Analysis of Non-linear wave-wave Interaction between VLF Transmitter signal and ELF emission on the Basis of DEMETER satellite observations

    Science.gov (United States)

    Sondhiya, Deepak Kumar; Gwal, Ashok Kumar; Kasde, Satish Kumar

    2016-07-01

    Symmetric sidebands are observed in the ionosphere by the DEMETER (Detection of Electromagnetic Radiation Transmitted through Earthquake Region) satellite, when it passes above the Indian VLF transmitter, named VTX (18.2 kHz), located near Kanyakumari, India. The spectral boarding phenomena may be divided into two types: (1) spectrally broadened components occurring without any association with ELF/VLF emissions under disturbed ionospheric condition, (2) Spectrally broadened components with predominant side band structure in association with ELF emission. Generally spectral analysis at second order (Power spectrum) is used to analyze the frequency component of signal, but it losses the phase information among the different Fourier components. To retain this information the bispectrum (third order) and/or the bicoherence (normalized bispectrum) are used. Results suggest a non-linear mode coupling between the transmitter signal and ELF emission which produces sidebands that are quasi-electrostatic in nature. However, faint spectral broadened components in both types 1 and 2 may be connected with Doppler shift of quasi-electrostatic, whistler mode waves with a broad spectrum near resonance cone, due to scattering of the transmitter signals from ionospheric irregularities in the F-region. Keywords: spectral boarding, wave-wave Interaction, whistler mode waves and Doppler shift

  18. Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice.

    Science.gov (United States)

    Chan, Elizabeth S; Chen, Christopher; Cole, Gregory M; Wong, Boon-Seng

    2015-09-08

    It is unclear how human apolipoprotein E4 (ApoE4) increases the risk for Alzheimer's disease (AD). Although Aβ levels can lead to insulin signaling impairment, these experiments were done in the absence of human ApoE. To examine ApoE role, we crossed the human ApoE-targeted replacement mice with mutant human amyloid precursor protein (APP) mice. In 26 week old mice with lower Aβ levels, the expression and phosphorylation of insulin signaling proteins remained comparable among APP, ApoE3xAPP and ApoE4xAPP mouse brains. When the mice aged to 78 weeks, these proteins were markedly reduced in APP and ApoE4xAPP mouse brains. While Aβ can bind to insulin receptor, how ApoE isoforms modulate this interaction remains unknown. Here, we showed that ApoE3 had greater association with insulin receptor as compared to ApoE4, regardless of Aβ42 concentration. In contrast, ApoE4 bound more Aβ42 with increasing peptide levels. Using primary hippocampal neurons, we showed that ApoE3 and ApoE4 neurons are equally sensitive to physiological levels of insulin. However, in the presence of Aβ42, insulin failed to elicit a downstream response only in ApoE4 hippocampal neurons. Taken together, our data show that ApoE genotypes can modulate this Aβ-mediated insulin signaling impairment.

  19. Fibroblast growth factor receptor 3 interacts with and activates TGFβ-activated kinase 1 tyrosine phosphorylation and NFκB signaling in multiple myeloma and bladder cancer.

    Directory of Open Access Journals (Sweden)

    Lisa Salazar

    Full Text Available Cancer is a major public health problem worldwide. In the United States alone, 1 in 4 deaths is due to cancer and for 2013 a total of 1,660,290 new cancer cases and 580,350 cancer-related deaths are projected. Comprehensive profiling of multiple cancer genomes has revealed a highly complex genetic landscape in which a large number of altered genes, varying from tumor to tumor, impact core biological pathways and processes. This has implications for therapeutic targeting of signaling networks in the development of treatments for specific cancers. The NFκB transcription factor is constitutively active in a number of hematologic and solid tumors, and many signaling pathways implicated in cancer are likely connected to NFκB activation. A critical mediator of NFκB activity is TGFβ-activated kinase 1 (TAK1. Here, we identify TAK1 as a novel interacting protein and target of fibroblast growth factor receptor 3 (FGFR3 tyrosine kinase activity. We further demonstrate that activating mutations in FGFR3 associated with both multiple myeloma and bladder cancer can modulate expression of genes that regulate NFκB signaling, and promote both NFκB transcriptional activity and cell adhesion in a manner dependent on TAK1 expression in both cancer cell types. Our findings suggest TAK1 as a potential therapeutic target for FGFR3-associated cancers, and other malignancies in which TAK1 contributes to constitutive NFκB activation.

  20. Role of plant growth regulators as chemical signals in plant-microbe interactions: a double edged sword.

    Science.gov (United States)

    Spence, Carla; Bais, Harsh

    2015-10-01

    Growth regulators act not only as chemicals that modulate plant growth but they also act as signal molecules under various biotic and abiotic stresses. Of all growth regulators, abscisic acid (ABA) is long known for its role in modulating plants response against both biotic and abiotic stress. Although the genetic information for ABA biosynthesis in plants is well documented, the knowledge about ABA biosynthesis in other organisms is still in its infancy. It is known that various microbes including bacteria produce and secrete ABA, but the overall functional significance of why ABA is synthesized by microbes is not known. Here we discuss the functional involvement of ABA biosynthesis by a pathogenic fungus. Furthermore, we propose that ABA biosynthesis in plant pathogenic fungi could be targeted for novel fungicidal discovery.

  1. Transport of receptors, receptor signaling complexes and ion channels via neuropeptide-secretory vesicles

    Institute of Scientific and Technical Information of China (English)

    Bo Zhao; Hai-Bo Wang; Ying-Jin Lu; Jian-Wen Hu; Lan Bao; Xu Zhang

    2011-01-01

    Stimulus-induced exocytosis of large dense-core vesicles(LDCVs)leads to discharge of neuropeptides and fusion of LDCV membranes with the plasma membrane. However, the contribution of LDCVs to the properties of the neuronal membrane remains largely unclear. The present study found that LDCVs were associated with multiple receptors, channels and signaling molecules, suggesting that neuronal sensitivity is modulated by an LDCV-mediated mechanism. Liquid chromatography-mass spectrometry combined with immunoblotting of subcellular fractions identified 298 proteins in LDCV membranes purified from the dorsal spinal cord, including Gprotein-coupled receptors, Gproteins and other signaling molecules, ion channels and trafficking-related proteins. Morphological assays showed that δ-opioid receptor 1(DORI), β2 adrenergic receptor(AR), Gα12,voltage-gated calcium channel a2δ1subunit and P2X purinoceptor 2 were localized in substance P(SP)-positive LDCVs in small-diameter dorsal root ganglion neurons, whereas β1 AR, Wnt receptor frizzled 8 and dishevelled 1 were present in SP-negative LDCVs.Furthermore, DOR1/α12/Gβ1γ5/phospholipase C β2 complexes were associated with LDCVs. Blockade of the DOR1/Gαi2 interaction largely abolished the LDCV localization of Gαi2 and impaired stimulation-induced surface expression of Gαi2. Thus, LDCVs serve as carriers of receptors, ion channels and preassembled receptor signaling complexes, enabling a rapid, activity-dependent modulation of neuronal sensitivity.

  2. β2 Adrenergic receptor on T lymphocytes and its clinical implications

    Institute of Scientific and Technical Information of China (English)

    Xuelai Fan; Yuedan Wang

    2009-01-01

    Sustained complex cross-talk between the immune system and the nervous system plays a vital role in retaining homeostasis in a healthy individual.One of the central regulatory mechanisms involved is the existence and functions of β2-adrenergic receptors (β2AR) on T lymphocytes.This article reviews research progress made recently,including the expression of adrenergic receptors on Tlymphocytes,the structure and intracellular pathways of β2AR,the activation of I32AR by either endogenous or exogenous agonists,and the effect of β2AR stimulation on T cells which alters T cell proliferation,differentiation,cytokine production and T-helper-mediated antibody production.Furthermore,we discuss the roles of β2AR played in the pathogenesis and treatment of autoimmune diseases.

  3. Significance of adrenergic receptors for the development of nevus flammeus and nevus anemicus

    Energy Technology Data Exchange (ETDEWEB)

    Raff, M. (Vienna Univ. (Austria). 2. Hautklinik)

    1981-01-01

    Examination of patients with nevus flammeus or nevus anemicus showed disturbed sensibility in the area of the nevus in the majority of cases. Histologically and with special technique of histochemistry and fluorescence microscopy there was no evidence for neurogenic lesions. However, signs of vegetative disfunction were present: hyperhidrosis and absent reactivity of vasculature in the nevus area to vasoconstrictive and vasodilatatory stimuli. Based on these findings a disturbed regulation of vascular intramural adrenergic receptors seemed possible and really could be demonstrated by means of autoradiography. In both types of nevi only one of the adrenergic receptors could be marked with specific antagonists. Therefore, the persistent vascular dilatation and constriction can be accounted for by the absence of one of these receptors. This abnormal distribution of receptors could be due to a developmental defect influenced by the ''nerve growth factor''.

  4. Expression of hippocampal adrenergic receptor mRNA in a rat model of depression

    Institute of Scientific and Technical Information of China (English)

    Jianbin Zhang; Lingling Wang; Xinjun Wang; Jingfeng Jiang; Xiaoren Xiang; Tianjun Wang

    2011-01-01

    Adrenergic receptor dysfunction is suggested as a potential cause of hippocampal vulnerability to stress-related pathology. We examined mRNA expression of adrenergic receptor (AR) subtypes α1-AR, α2-AR, and β1-AR in hippocampal subregions (CA1, CA3, dentate gyrus) using in situ hybridization in a depression model induced by chronic unpredictable mild stress and social isolation. α1-AR mRNA expression was significantly increased in the CA3 and dentate gyrus, β1-AR mRNA was significantly increased in the CA1, and α2-AR mRNA remained unchanged in all regions of depression rats compared with controls. Thus, different AR subtypes exhibit a differing pattern of mRNA expression in various hippocampal subregions following depression.

  5. Exercise training modulates functional sympatholysis and alpha-adrenergic vasoconstrictor responsiveness in hypertensive and normotensive individuals

    DEFF Research Database (Denmark)

    Mortensen, Stefan Peter; Nyberg, Michael Permin; Gliemann Hybholt, Lasse;

    2014-01-01

    Essential hypertension is linked to an increased sympathetic vasoconstrictor activity and reduced tissue perfusion. We investigated the role of exercise training on functional sympatholysis and postjunctional α-adrenergic responsiveness in individuals with essential hypertension. Leg haemodynamics...... exercise training improves functional sympatholysis and reduces postjunctional α-adrenergic responsiveness in both normo- and hypertensive individuals. The ability for functional sympatholysis and the vasodilator and sympatholytic effect of intravascular ATP appears not to be altered in essential...... were measured before and after 8 weeks of aerobic training (3-4 times/week) in 8 hypertensive (47 ± 2 years) and 8 normotensive untrained individuals (46 ± 1 years) during arterial tyramine infusion, arterial ATP infusion and/or one-legged knee extensions. Before training, exercise hypaeremia and leg...

  6. Altered hepatic vasopressin and alpha 1-adrenergic receptors after chronic endotoxin infusion

    Energy Technology Data Exchange (ETDEWEB)

    Roth, B.L.; Spitzer, J.A.

    1987-05-01

    Sepsis and septic shock are complicated by a number of hemodynamic and metabolic aberrations. These include catecholamine refractoriness and altered glucose metabolism. Recently, a nonshock rat model of continuous endotoxin infusion via an implanted osmotic pump was developed that reproduces some of the metabolic and cardiovascular findings of human sepsis. By using this model, we have found a decreased number of hepatic plasma membrane alpha 1-adrenergic and (Arg8)vasopressin receptors in rats continuously infused with endotoxin. There was a significant decrease in (/sup 3/H)prazosin (35 +/- 7%) and (/sup 3/H) (Arg8)vasopressin (43 +/- 8%) receptors after 30 h of continuous endotoxin infusion with no change in affinity. The ability of norepinephrine to form the high-affinity complex with alpha 1-adrenergic receptors was not altered after chronic endotoxin infusion. The results are consistent with the concept that alterations in receptor number might underlie certain of the metabolic consequences of chronic sepsis.

  7. Turning-Off Signaling by Siglecs, Selectins, and Galectins: Chemical Inhibition of Glycan-Dependent Interactions in Cancer

    Science.gov (United States)

    Cagnoni, Alejandro J.; Pérez Sáez, Juan M.; Rabinovich, Gabriel A.; Mariño, Karina V.

    2016-01-01

    Aberrant glycosylation, a common feature associated with malignancy, has been implicated in important events during cancer progression. Our understanding of the role of glycans in cancer has grown exponentially in the last few years, concurrent with important advances in glycomics and glycoproteomic technologies, paving the way for the validation of a number of glycan structures as potential glycobiomarkers. However, the molecular bases underlying cancer-associated glycan modifications are still far from understood. Glycans exhibit a natural heterogeneity, crucial for their diverse functional roles as specific carriers of biologically relevant information. This information is decoded by families of proteins named lectins, including sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), C-type lectin receptors (CLRs), and galectins. Siglecs are primarily expressed on the surface of immune cells and differentially control innate and adaptive immune responses. Among CLRs, selectins are a family of cell adhesion molecules that mediate interactions between cancer cells and platelets, leukocytes, and endothelial cells, thus facilitating tumor cell invasion and metastasis. Galectins, a family of soluble proteins that bind β-galactoside-containing glycans, have been implicated in diverse events associated with cancer biology such as apoptosis, homotypic cell aggregation, angiogenesis, cell migration, and tumor-immune escape. Consequently, individual members of these lectin families have become promising targets for the design of novel anticancer therapies. During the past decade, a number of inhibitors of lectin–glycan interactions have been developed including small-molecule inhibitors, multivalent saccharide ligands, and more recently peptides and peptidomimetics have offered alternatives for tackling tumor progression. In this article, we review the current status of the discovery and development of chemical lectin inhibitors and discuss novel strategies to

  8. A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure

    Science.gov (United States)

    Zhang, Xiaojian; Shen, Chengwu; Zhai, Shujun; Liu, Yukun; Yue, Wen-Wei; Han, Li

    2016-01-01

    Adrenergic β-blockers are drugs that bind to, but do not activate β-adrenergic receptors. Instead they block the actions of β-adrenergic agonists and are used for the treatment of various diseases such as cardiac arrhythmias, angina pectoris, myocardial infarction, hypertension, headache, migraines, stress, anxiety, prostate cancer, and heart failure. Several meta-analysis studies have shown that β-blockers improve the heart function and reduce the risks of cardiovascular events, rate of mortality, and sudden death through chronic heart failure (CHF) of patients. The present study identified results from recent meta-analyses of β-adrenergic blockers and their usefulness in CHF. Databases including Medline/Embase/Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were searched for the periods May, 1985 to March, 2011 and June, 2013 to August, 2015, and a number of studies identified. Results of those studies showed that use of β-blockers was associated with decreased sudden cardiac death in patients with heart failure. However, contradictory results have also been reported. The present meta-analysis aimed to determine the efficacy of β-blockers on mortality and morbidity in patients with heart failure. The results showed that mortality was significantly reduced by β-blocker treatment prior to the surgery of heart failure patients. The results from the meta-analysis studies showed that β-blocker treatment in heart failure patients correlated with a significant decrease in long-term mortality, even in patients that meet one or more exclusion criteria of the MERIT-HF study. In summary, the findings of the current meta-analysis revealed beneficial effects different β-blockers have on patients with heart failure or related heart disease. PMID:27703506

  9. β2-Adrenergic Receptor-Dependent Sexual Dimorphism For Murine Leukocyte Migration

    OpenAIRE

    de Coupade, Catherine; Brown, Adrienne S.; Dazin, Paul F; Levine, Jon D.; Green, Paul G.

    2007-01-01

    In wild-type FVB mice, leukocyte recruitment to lipopolysaccharide was sexually dimorphic, with a greater number of leukocytes recruited in females. In male β2-adrenergic receptor knock out mice (bred on a congenic FVB background) the number leukocytes recruited was increased ~4-fold, while in females there was no change, eliminating sexual dimorphism in leukocyte migration. While there were significantly fewer recruited CD62L+ and CD11a+ leukocytes in wild-type males, only in male β2-adrener...

  10. The rush to adrenaline: drugs in sport acting on the β-adrenergic system

    OpenAIRE

    Davis, E.; Loiacono, R.; Summers, R. J.

    2008-01-01

    Athletes attempt to improve performance with drugs that act on the β-adrenergic system directly or indirectly. Of three β-adrenoceptor (AR) subtypes, the β2-AR is the main target in sport; they have bronchodilator and anabolic actions and enhance anti-inflammatory actions of corticosteroids. Although demonstrable in animal experiments and humans, there is little evidence that these properties can significantly improve performance in trained athletes. Their actions may also be compromised by r...

  11. Evaluation of spirometry values in relation to beta-2-adrenergic receptor gene polymorphism

    OpenAIRE

    Poziomkowska-Gesicka, I; Dzieciolowska-Baran, E; Gawlikowska-Sroka, A; Slowik-Zylka, D; Sroczynski, T

    2010-01-01

    Introduction The vagus nerve plays a special role in the control of respiratory system activity which represents the parasympathetic part of the autonomic nervous system. A small bronchial innervation by the sympathetic system also is observed, and there is a significant expression of adrenergic receptors, in particular β2 receptors, in the airways. The development of genetics and molecular biology allows for a detailed study which can clarify the essential elements in the pathogenesis of man...

  12. α1A-adrenergic receptor mediated pressor response to phenylephrine in anesthetized rat

    Institute of Scientific and Technical Information of China (English)

    XU Qi; ZHU Weizhong; L(U) Zhizhen; ZHANG Youyi; HAN Qide

    2004-01-01

    To determine which subtype of α1A-adrenergic receptors plays a role in the regulation of blood pressure, with α1A-adrenergic receptor-mediated vasoconstriction in perfused hindlimb as a control, we compared the inhibitory effects of various α1A-adrenergic receptor selective antagonists on the vasopressure responses to phenylephrine between the mean arterial pressure and hindlimb perfusion pressure in anesthetized rats. In Normotensive Wistar rats, the results showed that the inhibitory effects (dose ratios of ED50, Dr) of α1A-adrenoceptor selective antagonist (prazosin, Dr 13.5 ± 3.6 vs.15.1 ± 4.3, n = 11), α1A-adrenoceptor selective antagonist (5- methyl-urapidil, Dr 2.4 ± 0.9 vs. 3.7 ± 2.3, n = 12; RS-17053, Dr 3.2 ± 1.6 vs. 4.4 ± 3.3, n =12) and α1D- adrenoceptor selective antagonist (BMY7378, Dr 1.9 ± 0.9 vs. 2.2 ± 0.8, n = 8) on phenylephrine- induced increases of perfusion pressure in the autoperfused femoral beds were the same as that in the mean arterial blood pressure in normotensive Wistar rats. The inhibitory effects of antagonists (RS-17053, Dr 3.4 ± 0.6 vs. 4.3 ± 0.9, n = 5; BMY7378, Dr 1.7±0.5 vs. 1.7 ± 0.5, n = 8) in spontaneous hypertensive rats were similar with the Wistar rats. These results suggest that the mean arterial pressure induced by phenylephrine was mainly mediated by α1A-adrenergic receptor in both the anesthetized Wistar rats and spontaneous hypertensive rats.

  13. The role of basolateral amygdala adrenergic receptors in hippocampus dependent spatial memory in rat

    OpenAIRE

    Vafaei A.L.; Rashidy-Pour A

    2008-01-01

    Background and the purpose of the study: There are extensive evidences indicating that the noradrenergic system of the basolateral nucleus of the amygdala (BLA) is involved in memory processes. The present study investigated the role of the BLA adrenergic receptors (ARs) in hippocampus dependent spatial memory in place avoidance task in male rat. Material and Methods: Long Evans rats (n=150) were trained to avoid footshock in a 60° segment while foraging for scattered food on a circul...

  14. Beta-2-Adrenergic Receptor Methylation Influences Asthma Phenotype in The School Inner City Asthma Study

    OpenAIRE

    Gaffin, Jonathan M.; Phipatanakul, Wanda

    2014-01-01

    Asthma is the most common chronic illness of childhood and inner city residents suffer a disproportionately high rate of asthma diagnosis and asthma morbidity. The School Inner City Asthma Study investigates the school classroom based environmental exposures that may lead to asthma morbidity in inner city school children with asthma. Within this cohort, we investigated the role of methylation at the promoter region of the beta-2-adrenergic receptor in relation to asthma morbidity. We found th...

  15. Phorbol esters promote alpha 1-adrenergic receptor phosphorylation and receptor uncoupling from inositol phospholipid metabolism.

    OpenAIRE

    Leeb-Lundberg, L M; Cotecchia, S; Lomasney, J W; DeBernardis, J F; Lefkowitz, R J; Caron, M G

    1985-01-01

    DDT1 MF-2 cells, which are derived from hamster vas deferens smooth muscle, contain alpha 1-adrenergic receptors (54,800 +/- 2700 sites per cell) that are coupled to stimulation of inositol phospholipid metabolism. Incubation of these cells with tumor-promoting phorbol esters, which stimulate calcium- and phospholipid-dependent protein kinase, leads to a marked attenuation of the ability of alpha 1-receptor agonists such as norepinephrine to stimulate the turnover of inositol phospholipids. T...

  16. α2A-Adrenergic Receptors Heterosynaptically Regulate Glutamatergic Transmission in the BNST

    OpenAIRE

    Shields, Angela D.; Wang, Qin; Winder, Danny G.

    2009-01-01

    Stress is a major driving force in reinstatement of drug-seeking behavior. The bed nucleus of the stria terminalis (BNST) has been identified as a key brain region in this behavior, and receives a dense input of the stress-neurotransmitter norepinephrine through the ventral noradrenergic bundle. Activation of α2-adrenergic receptors (α2-ARs) in the BNST blocks stress-induced reinstatement of drug-seeking, indicating a potentially important role for these receptors. Currently, it is unclear ho...

  17. Effect of beta2-adrenergic agonists on eosinophil adhesion, superoxide anion generation, and degranulation

    OpenAIRE

    Toru Noguchi; Kazuyuki Nakagome; Takehito Kobayashi; Yutaka Ueda; Tomoyuki Soma; Hidetomo Nakamoto; Makoto Nagata

    2015-01-01

    Background: Eosinophils play important roles in the development of asthma exacerbation. Viral infection is a major cause of asthma exacerbation, and the expression of IFN-γ-inducible protein of 10 kDa (IP-10) and cysteinyl leukotrienes (cysLTs) is up-regulated in virus-induced asthma. As β2-adrenergic agonists, such as formoterol or salbutamol, are used to treat asthma exacerbation, we examined whether formoterol or salbutamol could modify eosinophil functions such as adhesiveness, particular...

  18. Cardiac pressure overload hypertrophy is differentially regulated by β-adrenergic receptor subtypes

    OpenAIRE

    Zhao, Mingming; Fajardo, Giovanni; Urashima, Takashi; Spin, Joshua M; Poorfarahani, Sara; Rajagopalan, Viswanathan; Huynh, Diem; Connolly, Andrew; Quertermous, Thomas; Bernstein, Daniel

    2011-01-01

    In isolated myocytes, hypertrophy induced by norepinephrine is mediated via α1-adrenergic receptors (ARs) and not β-ARs. However, mice with deletions of both major cardiac α1-ARs still develop hypertrophy in response to pressure overload. Our purpose was to better define the role of β-AR subtypes in regulating cardiac hypertrophy in vivo, important given the widespread clinical use of β-AR antagonists and the likelihood that patients treated with these agents could develop conditions of furth...

  19. a-Adrenergic vasoconstrictor responsiveness is preserved in the heated human leg

    DEFF Research Database (Denmark)

    Keller, David M; Sander, Mikael; Stallknecht, Bente Merete;

    2010-01-01

    This study tested the hypothesis that passive leg heating attenuates a-adrenergic vasoconstriction within that limb. Femoral blood flow (FBF, femoral artery ultrasound Doppler) and femoral vascular conductance (FVC, FBF/mean arterial blood pressure), as well as calf muscle blood flow (Calf...... leg). Passive leg heating (~46¿C water temperature) increased FVC from 4.5 ± 0.5 to 11.9 ± 1.3 ml min¿1 mmHg¿1 (P

  20. ADRB3 adrenergic receptor is a key regulator of human myometrial apoptosis and inflammation during chorioamnionitis.

    OpenAIRE

    Lirussi, Fréderic; Rakotoniaina, Zo; Madani, Siham; Goirand, Françoise; Breuiller-Fouché, Michelle; Leroy, Marie-Josèphe; Sagot, Paul; Morrison, John; Dumas, Monique; Bardou, Marc

    2008-01-01

    The pathophysiology underlying preterm labor triggered by inflammatory conditions such as chorioamnionitis remains largely unclear. It has already been suggested that beta-3 adrenergic (ADRB3) agonists might be of interest in the pharmacological management of preterm labor. Although there is evidence implicating ADRB receptors in the control of inflammation, there are minimal data relating specifically to ADRB3. To explore the cellular consequences of chorioamnionitis and detect apoptosis, we...

  1. Stimulation of the ADRB3 adrenergic receptor induces relaxation of human placental arteries: influence of preeclampsia.

    OpenAIRE

    Rouget, Céline; Barthez, O.; Goirand, Françoise; Leroy, Marie-Josephe; Breuiller-Fouché, Michelle; Rakotoniaina, Zo; Guérard, P.; Morcillo, Esteban; Advenier, C; Sagot, Paul; Cabrol, Dominique; Dumas, Monique; Bardou, Marc

    2006-01-01

    Preeclampsia, which complicates 3-8% of pregnancies, is one of the leading causes of neonatal morbidity and mortality. Its pathophysiology remains unclear. The aim of the present study was to investigate the presence and the role of beta2- and beta2-adrenergic receptors (ADRB2 and ADRB3, respectively) in human placental arteries and to assess the influence of preeclampsia on ADRB responsiveness. SR 59119A, salbutamol, and isoproterenol (ADRB3, ADRB2, and nonselective ADRB agonists, respective...

  2. Agonist-promoted desensitization and phosphorylation of α1-adrenergic receptors coupled to stimulation of phosphatidylinositol metabolism

    International Nuclear Information System (INIS)

    In the DDT1 MF-2 hamster vas deferens smooth muscle cell line the α1-adrenergic receptor (α1-AR) agonist norepinephrine (NE) promotes rapid attenuation of α1-AR-mediated phosphatidylinositol (PI) metabolism which is paralleled by rapid phosphorylation of the α1-AR. Cells were labeled by incubation with 32P/sub i/. Coincubation with NE (100 μM) significantly increases the rate of 32P-labeling of both PI and phosphatidic acid. Pretreatment of cells with 100 μM NE (in the presence of 1 μM propranolol to prevent β-AR interactions) results in a drastic attenuation of the NE response on PI metabolism. α1-AR from labeled cells can be solubilized and purified by affinity chromatography on Affigel-A55414 and wheat germ agglutinin agarose chromatography. SDS-PAGE of purified α1-AR shows a NE-promoted increase in phosphorylation of the M/sub r/ 80K ligand binding peptide. Stoichiometry of phosphorylation increases from ∼ 1 mol phosphate/mol α1-AR in the basal condition to ∼ 2.5 after NE treatment. Both desensitization and phosphorylation are rapid being maximal within 10-20 min of agonist exposure. These results together with previous findings that phorbol esters promote rapid α1-AR uncoupling and phosphorylation suggest that receptor phosphorylation is an important mechanism of regulation of α1-AR receptor responsiveness

  3. Haplotype structure of the beta2-adrenergic receptor gene in 814 Danish Caucasian subjects and association with body mass index

    DEFF Research Database (Denmark)

    Jensen, Mette Kamp; Nielsen, Morten; Koefoed, Pernille;

    2009-01-01

    .50-16.38). In conclusion, the haplotype analysis clearly revealed the prevalence of four major ADRB2 haplotypes in Caucasians. The results suggest that unique interactions in specific haplotype pairs rather than individual SNPs may affect BMI and that this effect of ADRB2 haplotypes is blunted by age-related factors.......Several single nucleotide polymorphisms (SNPs) have been identified in the beta(2)-adrenergic receptor gene (ADRB2). By the use of five SNPs (G46A, C79G, C491T, C523A, G1053C) for identification of ADRB2 haplotypes in 814 Danish Caucasians, we investigated whether ADRB2 haplotypes are associated...... with body mass index (BMI). The SNPs showed organization into 13 distinct haplotypes and 41 haplotype pairs. The study identified four common haplotypes: ACCCC (10.1 +/- 0.3 %), ACCCG (27.9 +/- 0.3 %), GCCAC (10.8 +/- 0.1 %) and GGCCG (41.0 +/- 0.2 %) (frequencies (SD), seen in 91 % of the population...

  4. FERONIA interacts with ABI2-type phosphatases to facilitate signaling cross-talk between abscisic acid and RALF peptide in Arabidopsis.

    Science.gov (United States)

    Chen, Jia; Yu, Feng; Liu, Ying; Du, Changqing; Li, Xiushan; Zhu, Sirui; Wang, Xianchun; Lan, Wenzhi; Rodriguez, Pedro L; Liu, Xuanming; Li, Dongping; Chen, Liangbi; Luan, Sheng

    2016-09-13

    Receptor-like kinase FERONIA (FER) plays a crucial role in plant response to small molecule hormones [e.g., auxin and abscisic acid (ABA)] and peptide signals [e.g., rapid alkalinization factor (RALF)]. It remains unknown how FER integrates these different signaling events in the control of cell growth and stress responses. Under stress conditions, increased levels of ABA will inhibit cell elongation in the roots. In our previous work, we have shown that FER, through activation of the guanine nucleotide exchange factor 1 (GEF1)/4/10-Rho of Plant 11 (ROP11) pathway, enhances the activity of the phosphatase ABA Insensitive 2 (ABI2), a negative regulator of ABA signaling, thereby inhibiting ABA response. In this study, we found that both RALF and ABA activated FER by increasing the phosphorylation level of FER. The FER loss-of-function mutant displayed strong hypersensitivity to both ABA and abiotic stresses such as salt and cold conditions, indicating that FER plays a key role in ABA and stress responses. We further showed that ABI2 directly interacted with and dephosphorylated FER, leading to inhibition of FER activity. Several other ABI2-like phosphatases also function in this pathway, and ABA-dependent FER activation required PYRABACTIN RESISTANCE (PYR)/PYR1-LIKE (PYL)/REGULATORY COMPONENTS OF ABA RECEPTORS (RCAR)-A-type protein phosphatase type 2C (PP2CA) modules. Furthermore, suppression of RALF1 gene expression, similar to disruption of the FER gene, rendered plants hypersensitive to ABA. These results formulated a mechanism for ABA activation of FER and for cross-talk between ABA and peptide hormone RALF in the control of plant growth and responses to stress signals. PMID:27566404

  5. Food restriction modulates β-adrenergic-sensitive adenylate cyclase in rat liver during aging

    International Nuclear Information System (INIS)

    Adenylate cyclase activities were studied in rat liver during postmaturational aging of male Fischer 344 rats fed ad libitum or restricted to 60% of the ad libitum intake. Catecholamine-stimulated adenylate cyclase activity increased by 200-300% between 6 and 24-27 mo of age in ad libitum-fed rats, whereas in food-restricted rats catecholamine response increased by only 58-84% between 6 and 30 mo. In ad libitum-fed rats, glucagon-stimulated enzyme activity also increased by 40% between 6 and 12 mo and in restricted rats a similar age-related increase was delayed until 18 mo. β-Adrenergic receptor density increased by 50% between 6 and 24 mo in livers from ad libitum-fed but not food-restricted rats and showed a highly significant correlation with maximal isoproterenol-stimulated adenylate cyclase activity over the postmaturational life span. Age-related increases in unstimulated (basal) adenylate cyclase activity and nonreceptor-mediated enzyme activation were retarded by food restriction. The results demonstrate that food restriction diminishes a marked age-related increase in β-adrenergic-sensitive adenylate cyclase activity of rat liver. Alterations of adrenergic-responsive adenylate cyclase with age and the modulatory effects of food restriction appear to be mediated by changes in both receptor and nonreceptor components of adenylate cyclase

  6. GENETIC VARIATION IN THE ALPHA1B - ADRENERGIC RECEPTOR AND VASCULAR RESPONSE

    Science.gov (United States)

    Adefurin, Abiodun; Ghimire, Laxmi V.; Kohli, Utkarsh; Muszkat, Mordechai; Sofowora, Gbenga G.; Li, Chun; Levinson, Rebecca T.; Paranjape, Sachin Y.; Stein, C. Michael; Kurnik, Daniel

    2016-01-01

    α1B- adrenergic receptors contribute to vasoconstriction in humans. We tested the hypothesis that variation in the ADRA1B gene contributes to interindividual variability and ethnic differences in adrenergic vasoconstriction. We measured dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 41 African-Americans and genotyped 34 ADRA1B variants. We validated findings in another model of catecholamine-induced vasoconstriction, the increase in mean arterial pressure (ΔMAP) during a cold pressor test (CPT). One ADRA1B variant, rs10070745, present in 14 African-American heterozygotes but not in Caucasians, was associated with a lower phenylephrine ED50 (geometric mean [95% CI], 144 [69–299] ng/ml) compared to 27 African-American non-carriers (208 [130–334] ng/ml; P=0.015) and contributed to the ethnic differences in ED50. The same variant was also associated with a greater ΔMAP during CPT (P=0.008). In conclusion, ADRA1B rs10070745 was significantly associated with vasoconstrictor responses after adrenergic stimulation and contributed to the ethnic difference in phenylephrine sensitivity. PMID:27089938

  7. Adrenergic mechanism responsible for pathological alteration in gastric mucosal blood flow in rats with ulcer bleeding

    Science.gov (United States)

    Semyachkina-Glushkovskaya, O. V.; Pavlov, A. N.; Semyachkin-Glushkovskiy, I. A.; Gekalyuk, A. S.; Ulanova, M. V.; Lychagov, V. V.; Tuchin, V. V.

    2014-09-01

    The adrenergic system plays an important role in regulation of central and peripheral circulation in normal state and during hemorrhage. Because the impaired gastric mucosal blood flow (GMBF) is the major cause of gastroduodenal lesions, including ulcer bleeding (UB), we studied the adrenergic mechanism responsible for regulation of GMBF in rats with a model of stress-induced UB (SUB) using the laser Doppler flowmetry (LDF). First, we examined the effect of adrenaline on GMBF in rats under normal state and during UB. In all healthy animals the submucosal adrenaline injection caused a decrease in local GMBF. During UB the submucosal injection of adrenaline was accompanied by less pronounced GMBF suppression in 30,3% rats with SUB vs. healthy ones. In 69,7% rats with SUB we observed the increase in local GMBF after submucosal injection of adrenaline. Second, we studied the sensitivity of gastric β2-adrenoreceptors and the activity of two factors which are involved in β2-adrenomediated vasorelaxation-KATP -channels and NO. The effects of submucosal injection of isoproterenol, ICI118551 and glybenclamide on GMBF as well as NO levels in gastric tissue were significantly elevated in rats with SUB vs. healthy rats. Thus, our results indicate that high activation of gastric β2-adrenoreceptors associated with the increased vascular KATP -channels activity and elevated NO production is the important adrenergic mechanism implicated in the pathogenesis of UB.

  8. Effect of alpha 1-adrenergic blockade on myocardial blood flow during exercise after myocardial infarction.

    Science.gov (United States)

    Herzog, C A; Dai, X Z; Bache, R J

    1991-08-01

    The effect of alpha 1-adrenergic blockade with prazosin on myocardial blood flow at rest and during two levels of treadmill exercise was assessed in 16 chronically instrumented dogs 9-14 days after myocardial infarction had been produced by occlusion of the left circumflex coronary artery. During resting conditions prazosin did not alter mean myocardial blood flow or the subendocardial-to-subepicardial flow ratio in either normally perfused or collateral-dependent myocardium. However, during exercise at comparable external work loads and comparable rate-pressure products, prazosin significantly increased blood flow to normally perfused (27% increase at the second level of exercise, P less than 0.001) and collateral-dependent myocardium (35% increase at the second level of exercise, P less than 0.001) compared with control. In addition, prazosin caused a small but significant decrease in the subendocardial-to-subepicardial flow ratio in both normal (1.27 +/- 0.04 to 1.19 +/- 0.04; P less than 0.01) and collateral-dependent myocardium (0.57 +/- 0.11 to 0.52 +/- 0.11; P less than 0.01) compared with control, reflecting a disproportionally greater increase in subepicardial flow in response to alpha 1-adrenergic blockade. These data demonstrate that alpha 1-adrenergic vasoconstriction inhibits coronary vasodilation during exercise, even in areas of collateral-dependent myocardium relatively early after coronary artery occlusion. PMID:1678929

  9. Effects of central imidazolinergic and alpha2-adrenergic activation on water intake

    Directory of Open Access Journals (Sweden)

    Sugawara A.M.

    2001-01-01

    Full Text Available Non-adrenergic ligands that bind to imidazoline receptors (I-R, a selective ligand that binds to alpha2-adrenoceptors (alpha2-AR and mixed ligands that bind to both receptors were tested for their action on water intake behavior of 24-h water-deprived rats. All drugs were injected into the third cerebral ventricle. Except for agmatine (80 nmol, mixed ligands binding to I-R/alpha2-AR such as guanabenz (40 nmol and UK 14304 (20 nmol inhibited water intake by 65% and up to 95%, respectively. The selective non-imidazoline alpha2-AR agonist, alpha-methylnoradrenaline, produced inhibition of water intake similar to that obtained with guanabenz, but at higher doses (80 nmol. The non-adrenergic I-R ligands histamine (160 nmol, mixed histaminergic and imidazoline ligand and imidazole-4-acetic acid (80 nmol, imidazoline ligand did not alter water intake. The results show that selective, non-imidazoline alpha2-AR activation suppresses water intake, and suggest that the action on imidazoline sites by non-adrenergic ligands is not sufficient to inhibit water intake.

  10. Concanavalin a increases beta-adrenergic and glucocorticoid receptors in porcine splenocytes

    International Nuclear Information System (INIS)

    We identified specific glucocorticoid and beta-adrenergic receptors on porcine splenocytes. There are 2000 to 4000 glucocorticoid receptors per cell with a K /SUB D/ of 2 to 4 nM and 1000 beta-adrenergic receptors with a K /SUB D/ of 0.3 to 0.6 nM. When splenocytes were incubated with concanavalin A (Con A), there was an approximate 2-fold increase in both gluococorticoid and beta-adrenergic receptors with no change in binding affinity. Incubation of splenocytes with cortisol as low as 40 nM (13 ng/ml) inhibited proliferation in response to Con A. This inhibitory effect of cortisol was not due to cytotoxic effects of glucocorticoids. At maximal physiologic concentrations (400 nM; 135 ng/ml), cortisol caused reductions in Con A activation of thymocytes and peripheral blood mononuclear cells. When eight wk old pigs were restrained, there was an increase in plasma cortisol, atrophy of thymus and reduction in skin test responses to phytohemagglutinin. On the basis of the data, we suggest that physiologic concentrations of stress asociated hormones affect functional activities of porcine lymphoid cells. Since activated splenocytes display increased numbers of receptors for these hormones, perhaps glucocorticoids or catecholamines normally function in vivo to suppress clonal expansion of antigen activated and autoreactive T lymphocytes

  11. α1- and α2-adrenergic receptors in the retrotrapezoid nucleus differentially regulate breathing in anesthetized adult rats.

    Science.gov (United States)

    Oliveira, Luiz M; Moreira, Thiago S; Kuo, Fu-Shan; Mulkey, Daniel K; Takakura, Ana C

    2016-09-01

    Norepinephrine (NE) is a potent modulator of breathing that can increase/decrease respiratory activity by α1-/α2-adrenergic receptor (AR) activation, respectively. The retrotrapezoid nucleus (RTN) is known to contribute to central chemoreception, inspiration, and active expiration. Here we investigate the sources of catecholaminergic inputs to the RTN and identify respiratory effects produced by activation of ARs in this region. By injecting the retrograde tracer Fluoro-Gold into the RTN, we identified back-labeled catecholaminergic neurons in the A7 region. In urethane-anesthetized, vagotomized, and artificially ventilated male Wistar rats unilateral injection of NE or moxonidine (α2-AR agonist) blunted diaphragm muscle activity (DiaEMG) frequency and amplitude, without changing abdominal muscle activity. Those inhibitory effects were reduced by preapplication of yohimbine (α2-AR antagonist) into the RTN. Conversely, unilateral RTN injection of phenylephrine (α1-AR agonist) increased DiaEMG amplitude and frequency and facilitated active expiration. This response was blocked by prior RTN injection of prazosin (α1-AR antagonist). Interestingly, RTN injection of propranolol (β-AR antagonist) had no effect on respiratory inhibition elicited by applications of NE into the RTN; however, the combined blockade of α2- and β-ARs (coapplication of propranolol and yohimbine) revealed an α1-AR-dependent excitatory response to NE that resulted in increase in DiaEMG frequency and facilitation of active expiration. However, blockade of α1-, α2-, or β-ARs in the RTN had minimal effect on baseline respiratory activity, on central or peripheral chemoreflexes. These results suggest that NE signaling can modulate RTN chemoreceptor function; however, endogenous NE signaling does not contribute to baseline breathing or the ventilatory response to central or peripheral chemoreceptor activity in urethane-anesthetized rats. PMID:27306670

  12. Role of inositol 1,4,5-trisphosphate receptors in α1-adrenergic receptor-induced cardiomyocyte hypertrophy

    Institute of Scientific and Technical Information of China (English)

    Da-li LUO; Jian GAO; Xiao-mei LAN; Gang WANG; Sheng WEI; Rui-ping XIAO; Qi-de HAN

    2006-01-01

    Aim: Intracellular Ca2+ plays pivotal roles in diverse cellular functions, including gene transcription that underlies cardiac remodeling during stress responses. However, the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) in the mediation of cardiac intracellular Ca2+ and hypertrophic growth remains elusive. Prior work with neonatal rat ventricular myocytes suggests that activation of IP3Rs may be linked to α1 adrenergic receptor (α1AR) increased stereotyped Ca2+ spark occurrence and global Ca2+ oscillations. Thus, we hypothesized that Ca2+ release through IP3Rs was necessary for α1AR-stimulated cardiac hypertrophy. Methods: We used myoinositol 1,4,5-trisphosphate hexakis (butyryloxymethyl) ester (IP3BM), a membrane-permeant ester of IP3, to activate IP3Rs directly, and Fluo 4/AM to measure intracellular Ca2+ signaling. Results: IP3BM (10μmol·L-1) mimicked the effects of phenylephrine, a selective agonist of α1AR, in increments in local Ca2+ spark release (especially in the perinuclear area) and global Ca2+ transient frequencies. More importantly, IP3R inhibitors, 2-aminoethoxydiphenyl borate and Xestospongin C, abolished the IP3BM-induced Ca2+ responses, and significantly suppressed α1AR-induced cardiomyocyte hypertrophy assayed by cell size, [3H] leucine incorporation and atrial natriuretic factor gene expression, during sustained (48 h) phenylephrine stimulation. Conclusion: These results, therefore, provide cellular mechanisms that link IP3R signaling to α1AR-stimulated gene expression and cardiomyocyte hypertrophy.

  13. Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Liquan; Wang, Dan [Department of Urology, The University of Pittsburgh, 5200 Centre Avenue, Pittsburgh, PA 15216 (United States); Fisher, Alfred L., E-mail: fishera2@uthscsa.edu [Division of Geriatrics, Gerontology, and Palliative Medicine, Department of Medicine, UTHSCSA, San Antonio, TX 78229 (United States); Center for Healthy Aging, UTHSCSA, San Antonio, TX 78229 (United States); GRECC, STVAHCS, San Antonio, TX 78229 (United States); Wang, Zhou, E-mail: wangz2@upmc.edu [Department of Urology, The University of Pittsburgh, 5200 Centre Avenue, Pittsburgh, PA 15216 (United States); GRECC, STVAHCS, San Antonio, TX 78229 (United States)

    2014-05-02

    Highlights: • RNAi screen identified genetic enhancers for the C. elegans homolog of EAF2. • EAF2 and RBBP4 proteins physically bind to each other and alter transcription. • Overexpression of EAF2 and RBBP4 induces the cell death in prostate cancer cells. - Abstract: The tumor suppressor EAF2 is regulated by androgen signaling and associated with prostate cancer. While EAF2 and its partner ELL have been shown to be members of protein complexes involved in RNA polymerase II transcriptional elongation, the biologic roles for EAF2 especially with regards to the development of cancer remains poorly understood. We have previously identified the eaf-1 gene in Caenorhabditiselegans as the ortholog of EAF2, and shown that eaf-1 interacts with the ELL ortholog ell-1 to control development and fertility in worms. To identify genetic pathways that interact with eaf-1, we screened RNAi libraries consisting of transcription factors, phosphatases, and chromatin-modifying factors to identify genes which enhance the effects of eaf-1(tm3976) on fertility. From this screen, we identified lin-53, hmg-1.2, pha-4, ruvb-2 and set-6 as hits. LIN-53 is the C. elegans ortholog of human retinoblastoma binding protein 4/7 (RBBP 4/7), which binds to the retinoblastoma protein and inhibits the Ras signaling pathway. We find that lin-53 showed a synthetic interaction with eaf-1(tm3976) where knockdown of lin-53 in an eaf-1(tm3976) mutant resulted in sterile worms. This phenotype may be due to cell death as the treated worms contain degenerated embryos with increased expression of the ced-1:GFP cell death marker. Further we find that the interaction between eaf-1 and lin-53/RBBP4/7 also exists in vertebrates, which is reflected by the formation of a protein complex between EAF2 and RBBP4/7. Finally, overexpression of either human EAF2 or RBBP4 in LNCaP cells induced the cell death while knockdown of EAF2 in LNCaP enhanced cell proliferation, indicating an important role of EAF2 in

  14. Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells.

    Science.gov (United States)

    Cai, Liquan; Wang, Dan; Fisher, Alfred L; Wang, Zhou

    2014-05-01

    The tumor suppressor EAF2 is regulated by androgen signaling and associated with prostate cancer. While EAF2 and its partner ELL have been shown to be members of protein complexes involved in RNA polymerase II transcriptional elongation, the biologic roles for EAF2 especially with regards to the development of cancer remains poorly understood. We have previously identified the eaf-1 gene in Caenorhabditiselegans as the ortholog of EAF2, and shown that eaf-1 interacts with the ELL ortholog ell-1 to control development and fertility in worms. To identify genetic pathways that interact with eaf-1, we screened RNAi libraries consisting of transcription factors, phosphatases, and chromatin-modifying factors to identify genes which enhance the effects of eaf-1(tm3976) on fertility. From this screen, we identified lin-53, hmg-1.2, pha-4, ruvb-2 and set-6 as hits. LIN-53 is the C. elegans ortholog of human retinoblastoma binding protein 4/7 (RBBP 4/7), which binds to the retinoblastoma protein and inhibits the Ras signaling pathway. We find that lin-53 showed a synthetic interaction with eaf-1(tm3976) where knockdown of lin-53 in an eaf-1(tm3976) mutant resulted in sterile worms. This phenotype may be due to cell death as the treated worms contain degenerated embryos with increased expression of the ced-1:GFP cell death marker. Further we find that the interaction between eaf-1 and lin-53/RBBP4/7 also exists in vertebrates, which is reflected by the formation of a protein complex between EAF2 and RBBP4/7. Finally, overexpression of either human EAF2 or RBBP4 in LNCaP cells induced the cell death while knockdown of EAF2 in LNCaP enhanced cell proliferation, indicating an important role of EAF2 in controlling the growth and survival of prostate cancer cells. Together these findings identify a novel physical and functional interaction between EAF2 and the Rb pathway.

  15. Stabilization of cancer-specific gene carrier via hydrophobic interaction for a clear-cut response to cancer signaling.

    Science.gov (United States)

    Kim, Chan Woo; Toita, Riki; Kang, Jeong-Hun; Li, Kai; Lee, Eun Kyung; Zhao, Guo Xi; Funamoto, Daiki; Nobori, Takanobu; Nakamura, Yuta; Mori, Takeshi; Niidome, Takuro; Katayama, Yoshiki

    2013-09-28

    Here, we developed a new gene carrier, comprising a linear polyethylenimine (LPEI) grafted with a hydrophobically modified cationic peptide containing a long alkyl chain, for use in cancer-specific gene delivery. The cationic peptide is a substrate of protein kinase Cα (PKCα), which is known to be activated specifically in cancer cells. The hydrophobically modified LPEI-peptide conjugate (LPEI-C10-peptide) could form a polyplex with DNA through electrostatic and hydrophobic interactions between the anionic DNA strands and the cationic peptide substrate. The hydrophobic modification of the peptide did not affect the reactivity of the peptide toward PKCα, while the polyplex showed improved intracellular uptake. Because of the efficient endosomal escape and enhanced stability, the polyplex significantly improved the transgene regulation responding to intracellular PKCα activity.

  16. Functions of the conserved thrombospondin carboxy-terminal cassette in cell-extracellular matrix interactions and signaling.

    Science.gov (United States)

    Adams, Josephine C

    2004-06-01

    Thrombospondins (TSPs) are extracellular, multidomain, calcium-binding glycoproteins that function at cell surfaces, in extracellular matrix (ECM) and as bridging molecules in cell-cell interactions. TSPs are multifunctional and modulate cell behavior during development, wound-healing, immune response, tumor growth and in the homeostasis of adult tissues. TSPs are assembled as oligomers that are composed of homologous polypeptides. In all the TSP polypeptides, the most highly-conserved region is the carboxyl-region, which contains a characteristic set of domains comprising EGF domains, TSP type 3 repeats and a globular carboxy-terminal domain. This large region is termed here the thrombospondin carboxy-terminal cassette (TSP-CTC). The strong conservation of the TSP-CTC suggests that it may mediate ancestral functions that are shared by all TSPs. This review summarizes the current knowledge of the TSP-CTC and areas of future interest. PMID:15094125

  17. In situ monitoring the pulse CO{sub 2} laser interaction with 316-L stainless steel using acoustical signals and plasma analysis

    Energy Technology Data Exchange (ETDEWEB)

    Khosroshahi, M.E., E-mail: khosro@aut.ac.ir [Amirkabir University of Technology, Faculty of Biomedical Eng., Biomaterial Group, Laser and Nanobiophotonics Lab., Tehran (Iran, Islamic Republic of); Anoosheh pour, F. [Amirkabir University of Technology, Faculty of Biomedical Eng., Biomaterial Group, Laser and Nanobiophotonics Lab., Tehran (Iran, Islamic Republic of); Hadavi, M. [Amirkabir University of Technology, Faculty of Mining and Metallurgical Eng., Tehran (Iran, Islamic Republic of); Mahmoodi, M. [Amirkabir University of Technology, Faculty of Biomedical Eng., Biomaterial Group, Laser and Nanobiophotonics Lab., Tehran (Iran, Islamic Republic of)

    2010-10-01

    In most laser material processing, material removal by different mechanisms is involved. Here, application of acoustic signals with thermoelastic (below threshold) and breakdown origin (above threshold) together with plasma plume analysis as a simple monitoring system of interaction process is suggested. In this research the interaction of pulse CO{sub 2} laser with 200 ns duration and maximum energy of 1.3 J operating at 1 Hz with austenitic stainless steel (316-L) is reported. The results showed that the non-linear point of the curve can serve as a useful indicator of melting fluence threshold (in this case {approx}830 J cm{sup -2}) with corresponding temperature calculated using plasma plume analysis. Higher acoustic amplitudes and larger plasma plume volume indicates more intense interaction. Also, analysis showed that a phase explosion process with material removal (ejecta) in the form of non-adiabatic (i.e., d{sub t} >> {alpha}{sup -1}) is at play after laser pulse is ended. Also, SEM photographs show different surface quality medication at different laser intensities, which indicates the importance of recoil momentum pressure and possibly electrons and ions densities in heat transfer. Finally, electrochemical test indicate an improved corrosion resistance for laser treated samples compared to untreated ones.

  18. β-adrenergic receptor activation in immortalized human urothelial cells stimulates inflammatory responses by PKA-independent mechanisms

    Directory of Open Access Journals (Sweden)

    Porter James E

    2005-08-01

    Full Text Available Abstract Background Interstitial cystitis (IC is a debilitating disease characterized by chronic inflammation of the urinary bladder, yet specific cellular mechanisms of inflammation in IC are largely unknown. Multiple lines of evidence suggest that β-adrenergic receptor (AR signaling is increased in the inflamed urothelium, however the precise effects of these urothelial cell signals have not been studied. In order to better elucidate the AR signaling mechanisms of inflammation associated with IC, we have examined the effects of β-AR stimulation in an immortalized human urothelial cell line (UROtsa. For these studies, UROtsa cells were treated with effective concentrations of the selective β-AR agonist isoproterenol, in the absence or presence of selective inhibitors of protein kinase A (PKA. Cell lysates were analyzed by radioimmunoassay for generation of cAMP or by Western blotting for induction of protein products associated with inflammatory responses. Results Radioligand binding demonstrated the presence of β-ARs on human urothelial UROtsa cell membranes. Stimulating UROtsa cells with isoproterenol led to concentration-dependent increases of cAMP production that could be inhibited by pretreatment with a blocking concentration of the selective β-AR antagonist propranolol. In addition, isoproterenol activation of these same cells led to significant increases in the amount of phosphorylated extracellular signal-regulated kinase (pERK, inducible nitric oxide synthase (iNOS and the induced form of cyclooxygenase (COX-2 when compared to control. Moreover, preincubation of UROtsa cells with the selective PKA inhibitors H-89 or Rp-cAMPs did not diminish this isoproterenol mediated phosphorylation of ERK or production of iNOS and COX-2. Conclusion Functional β-ARs expressed on human urothelial UROtsa cell membranes increase the generation of cAMP and production of protein products associated with inflammation when activated by the selective

  19. OsbHLH148, a basic helix-loop-helix protein, interacts with OsJAZ proteins in a jasmonate signaling pathway leading to drought tolerance in rice.

    Science.gov (United States)

    Seo, Ju-Seok; Joo, Joungsu; Kim, Min-Jeong; Kim, Yeon-Ki; Nahm, Baek Hie; Song, Sang Ik; Cheong, Jong-Joo; Lee, Jong Seob; Kim, Ju-Kon; Choi, Yang Do

    2011-03-01

    Jasmonates play important roles in development, stress responses and defense in plants. Here, we report the results of a study using a functional genomics approach that identified a rice basic helix-loop-helix domain gene, OsbHLH148, that conferred drought tolerance as a component of the jasmonate signaling module in rice. OsbHLH148 transcript levels were rapidly increased by treatment with methyl jasmonate (MeJA) or abscisic acid, and abiotic stresses including dehydration, high salinity, low temperature and wounding. Transgenic over-expression of OsbHLH148 in rice confers plant tolerance to drought stress. Expression profiling followed by DNA microarray and RNA gel-blot analyses of transgenic versus wild-type rice identified genes that are up-regulated by OsbHLH148 over-expression. These include OsDREB and OsJAZ genes that are involved in stress responses and the jasmonate signaling pathway, respectively. OsJAZ1, a rice ZIM domain protein, interacted with OsbHLH148 in yeast two-hybrid and pull-down assays, but it interacted with the putative OsCOI1 only in the presence of coronatine. Furthermore, the OsJAZ1 protein was degraded by rice and Arabidopsis extracts in the presence of coronatine, and its degradation was inhibited by MG132, a 26S proteasome inhibitor, suggesting 26S proteasome-mediated degradation of OsJAZ1 via the SCF(OsCOI1) complex. The transcription level of OsJAZ1 increased upon exposure of rice to MeJA. These results show that OsJAZ1 could act as a transcriptional regulator of the OsbHLH148-related jasmonate signaling pathway leading to drought tolerance. Thus, our study suggests that OsbHLH148 acts on an initial response of jasmonate-regulated gene expression toward drought tolerance, constituting the OsbHLH148-OsJAZ-OsCOI1 signaling module in rice.

  20. Systems Biology Model of Interactions Between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFbeta and ATM Signaling

    Energy Technology Data Exchange (ETDEWEB)

    O' Neill, Peter [University of Oxford; Anderson, Jennifer [University of Oxford

    2014-10-02

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to cross- talk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  1. Saturated high-fat diet-induced obesity increases adenylate cyclase of myocardial β-adrenergic system and does not compromise cardiac function.

    Science.gov (United States)

    Vileigas, Danielle F; de Deus, Adriana F; da Silva, Danielle C T; de Tomasi, Loreta C; de Campos, Dijon H S; Adorni, Caroline S; de Oliveira, Scarlet M; Sant'Ana, Paula G; Okoshi, Katashi; Padovani, Carlos R; Cicogna, Antonio C

    2016-09-01

    Obesity is a worldwide pandemic associated with high incidence of cardiovascular disease. The mechanisms by which the obesity leads cardiac dysfunction are not fully elucidated and few studies have evaluated the relationship between obesity and proteins involved in myocardial β-adrenergic (βA) system. The purpose of this study was to evaluate the cardiac function and βA pathway components in myocardium of obese rats. Male Wistar rats were distributed into two groups: control (n = 17; standard diet) and obese (n = 17; saturated high-fat diet) fed for 33 weeks. Nutritional profile and comorbidities were assessed. Cardiac structure and function was evaluated by macroscopic postmortem, echocardiographic and isolated papillary muscle analyzes. Myocardial protein expression of β1- and β2-adrenergic receptors, Gαs protein, adenylate cyclase (AC) and protein kinase A (PKA) was performed by Western blot. Cardiac cyclic adenosine monophosphate (cAMP) levels and PKA activity were assessed by ELISA Obese rats showed increased adiposity index (P < 0.001) and several comorbidities as hypertension, glucose intolerance, insulin resistance, and dyslipidemia compared with control rats. Echocardiographic assessment revealed increased left atrium diameter (C: 4.98 ± 0.38 vs. Ob: 5.47 ± 0.53, P = 0.024) and posterior wall shortening velocity (C: 37.1 ± 3.6 vs. Ob: 41.8 ± 3.8, P = 0.007) in obese group. Papillary muscle evaluation indicated that baseline data and myocardial responsiveness to isoproterenol stimulation were similar between the groups. Protein expression of myocardial AC was higher in obese group than in the control (C: 1.00 ± 0.21 vs. Ob: 1.25 ± 0.10, P = 0.025), whereas the other components were unchanged. These results suggest that saturated high-fat diet-induced obesity was not effective in triggering cardiac dysfunction and impair the beta-adrenergic signaling. PMID:27582064

  2. Nitric Oxide Synthase 1 Modulates Basal and β-Adrenergic-Stimulated Contractility by Rapid and Reversible Redox-Dependent S-Nitrosylation of the Heart.

    Science.gov (United States)

    Vielma, Alejandra Z; León, Luisa; Fernández, Ignacio C; González, Daniel R; Boric, Mauricio P

    2016-01-01

    S-nitrosylation of several Ca2+ regulating proteins in response to β-adrenergic stimulation was recently described in the heart; however the specific nitric oxide synthase (NOS) isoform and signaling pathways responsible for this modification have not been elucidated. NOS-1 activity increases inotropism, therefore, we tested whether β-adrenergic stimulation induces NOS-1-dependent S-nitrosylation of total proteins, the ryanodine receptor (RyR2), SERCA2 and the L-Type Ca2+ channel (LTCC). In the isolated rat heart, isoproterenol (10 nM, 3-min) increased S-nitrosylation of total cardiac proteins (+46±14%) and RyR2 (+146±77%), without affecting S-nitrosylation of SERCA2 and LTCC. Selective NOS-1 blockade with S-methyl-L-thiocitrulline (SMTC) and Nω-propyl-l-arginine decreased basal contractility and relaxation (-25-30%) and basal S-nitrosylation of total proteins (-25-60%), RyR2, SERCA2 and LTCC (-60-75%). NOS-1 inhibition reduced (-25-40%) the inotropic response and protein S-nitrosylation induced by isoproterenol, particularly that of RyR2 (-85±7%). Tempol, a superoxide scavenger, mimicked the effects of NOS-1 inhibition on inotropism and protein S-nitrosylation; whereas selective NOS-3 inhibitor L-N5-(1-Iminoethyl)ornithine had no effect. Inhibition of NOS-1 did not affect phospholamban phosphorylation, but reduced its oligomerization. Attenuation of contractility was abolished by PKA blockade and unaffected by guanylate cyclase inhibition. Additionally, in isolated mouse cardiomyocytes, NOS-1 inhibition or removal reduced the Ca2+-transient amplitude and sarcomere shortening induced by isoproterenol or by direct PKA activation. We conclude that 1) normal cardiac performance requires basal NOS-1 activity and S-nitrosylation of the calcium-cycling machinery; 2) β-adrenergic stimulation induces rapid and reversible NOS-1 dependent, PKA and ROS-dependent, S-nitrosylation of RyR2 and other proteins, accounting for about one third of its inotropic effect.

  3. Loss of bone marrow adrenergic beta 1 and 2 receptors modifies transcriptional networks, reduces circulating inflammatory factors, and regulates blood pressure.

    Science.gov (United States)

    Ahmari, Niousha; Schmidt, Jordan T; Krane, Gregory A; Malphurs, Wendi; Cunningham, Bruce E; Owen, Jennifer L; Martyniuk, Christopher J; Zubcevic, Jasenka

    2016-07-01

    Hypertension (HTN) is a prevalent condition with complex etiology and pathophysiology. Evidence exists of significant communication between the nervous system and the immune system (IS), and there appears to be a direct role for inflammatory bone marrow (BM) cells in the pathophysiology of hypertension. However, the molecular and neural mechanisms underlying this interaction have not been characterized. Here, we transplanted whole BM cells from the beta 1 and 2 adrenergic receptor (AdrB1(tm1Bkk)AdrB2(tm1Bkk)/J) knockout (KO) mice into near lethally irradiated C57BL/6J mice to generate a BM AdrB1.B2 KO chimera. This allowed us to evaluate the role of the BM beta 1 and beta 2 adrenergic receptors in mediating BM IS homeostasis and regulating blood pressure (BP) in an otherwise intact physiological setting. Fluorescence-activated cell sorting demonstrated that a decrease in systolic and mean BP in the AdrB1.B2 KO chimera is associated with a decrease in circulating inflammatory T cells, macrophage/monocytes, and neutrophils. Transcriptomics in the BM identified 7,419 differentially expressed transcripts between the C57 and AdrB1.B2 KO chimera. Pathway analysis revealed differentially expressed transcripts related to several cell processes in the BM of C57 compared with AdrB1.B2 KO chimera, including processes related to immunity (e.g., T-cell activation, T-cell recruitment, cytokine production, leukocyte migration and function), the cardiovascular system (e.g., blood vessel development, peripheral nerve blood flow), and the brain (e.g., central nervous system development, neurite development) among others. This study generates new insight into the molecular events that underlie the interaction between the sympathetic drive and IS in modulation of BP. PMID:27235450

  4. Control of heart rate during thermoregulation in the heliothermic lizard Pogona barbata: importance of cholinergic and adrenergic mechanisms.

    Science.gov (United States)

    Seebacher, F; Franklin, C E

    2001-12-01

    During thermoregulation in the bearded dragon Pogona barbata, heart rate when heating is significantly faster than when cooling at any given body temperature (heart rate hysteresis), resulting in faster rates of heating than cooling. However, the mechanisms that control heart rate during heating and cooling are unknown. The aim of this study was to test the hypothesis that changes in cholinergic and adrenergic tone on the heart are responsible for the heart rate hysteresis during heating and cooling in P. barbata. Heating and cooling trials were conducted before and after the administration of atropine, a muscarinic antagonist, and sotalol, a beta-adrenergic antagonist. Cholinergic and beta-adrenergic blockade did not abolish the heart rate hysteresis, as the heart rate during heating was significantly faster than during cooling in all cases. Adrenergic tone was extremely high (92.3 %) at the commencement of heating, and decreased to 30.7 % at the end of the cooling period. Moreover, in four lizards there was an instantaneous drop in heart rate (up to 15 beats min(-1)) as the heat source was switched off, and this drop in heart rate coincided with either a drop in beta-adrenergic tone or an increase in cholinergic tone. Rates of heating were significantly faster during the cholinergic blockade, and least with a combined cholinergic and beta-adrenergic blockade. The results showed that cholinergic and beta-adrenergic systems are not the only control mechanisms acting on the heart during heating and cooling, but they do have a significant effect on heart rate and on rates of heating and cooling. PMID:11815660

  5. Ischemia- and agonist-induced changes in. alpha. - and. beta. -adrenergic receptor traffic in guinea pig hearts

    Energy Technology Data Exchange (ETDEWEB)

    Maisel, A.S.; Motulsky, H.J.; Ziegler, M.G.; Insel, P.A. (Univ. of California, La Jolla (USA))

    1987-11-01

    The authors have used radioligand binding techniques and subcellular fraction to assess whether changes in expression of myocardial {alpha}{sub 1}- and {beta}-adrenergic receptors are mediated by a redistribution of receptors between various membrane fractions. Three fractions were prepared from the left ventricles of guinea pigs that underwent either 1 h of ischemia or injection of epinephrine a crude membrane, a purified sarcolemma, and a light vesicle fraction. In control animals {alpha}{sub 1}-adrenergic receptors (({sup 3}H)prazosin binding) in light vesicles was only 25% of the total {alpha}{sub 1}-receptor density found in sarcolemmal and light vesicle fractions as compared with 50% for {beta}-adrenergic receptors (({sup 125}I)iodocyanopindolol binding sites). Although ischemia was associated with a 53% decrease in the number of light vesicle {beta}-adrenergic receptors and a 42% increase in the number of sarcolemma {beta}-receptors there was no change in the number of light vesicle {alpha}{sub 1}-receptors, even though the number of sarcolemmal {alpha}{sub 1}-receptors increased 34%. Epinephrine treatment promoted internalization of {beta}-adrenergic receptors. These results indicate that {alpha}{sub 1} and {beta}{sub 1}-adrenergic receptors may undergo a different cellular itinerary in guinea pig myocardium. Agonist and ischemia-induced changes in surface {beta}-receptors, but not {alpha}{sub 1}-receptors, appear to result from entry and exit of receptors from an intracellular pool that can be isolated in a light vesicle fraction. Changes in expression of {alpha}{sub 1}-adrenergic receptors may represent changes in the properties of receptors found in the sarcolemma or in a membrane fraction other than the light vesicle fraction that they have isolated.

  6. Cannabinoid receptor 2 expression modulates Gβ(1)γ(2) protein interaction with the activator of G protein signalling 2/dynein light chain protein Tctex-1.

    Science.gov (United States)

    Nagler, Marina; Palkowitsch, Lysann; Rading, Sebastian; Moepps, Barbara; Karsak, Meliha

    2016-01-01

    The activator of G protein signalling AGS2 (Tctex-1) forms protein complexes with Gβγ, and controls cell proliferation by regulating cell cycle progression. A direct interaction of Tctex-1 with various G protein-coupled receptors has been reported. Since the carboxyl terminal portion of CB2 carries a putative Tctex-1 binding motif, we investigated the potential interplay of CB2 and Tctex-1 in the absence and presence of Gβγ. The supposed interaction of cannabinoid receptor CB2 with Tctex-1 and the influence of CB2 on the formation of Tctex-1-Gβγ-complexes were studied by co- and/or immunoprecipitation experiments in transiently transfected HEK293 cells. The analysis on Tctex-1 protein was performed in the absence and presence of the ligands JWH 133, 2-AG, and AM 630, the protein biosynthesis inhibitor cycloheximide or the protein degradation blockers MG132, NH4Cl/leupeptin or bafilomycin. Our results show that CB2 neither directly nor indirectly via Gβγ interacts with Tctex-1, but competes with Tctex-1 in binding to Gβγ. The Tctex-1-Gβγ protein interaction was disrupted by CB2 receptor expression resulting in a release of Tctex-1 from the complex, and its degradation by the proteasome and partly by lysosomes. The decrease in Tctex-1 protein levels is induced by CB2 expression "dose-dependently" and is independent of stimulation by agonist or blocking by an inverse agonist treatment. The results suggest that CB2 receptor expression independent of its activation by agonists is sufficient to competitively disrupt Gβγ-Tctex-1 complexes, and to initiate Tctex-1 degradation. These findings implicate that CB2 receptor expression modifies the stability of intracellular protein complexes by a non-canonical pathway.

  7. Drought and root herbivory interact to alter the response of above-ground parasitoids to aphid infested plants and associated plant volatile signals.

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    Muhammad Tariq

    Full Text Available Multitrophic interactions are likely to be altered by climate change but there is little empirical evidence relating the responses of herbivores and parasitoids to abiotic factors. Here we investigated the effects of drought on an above/below-ground system comprising a generalist and a specialist aphid species (foliar herbivores, their parasitoids, and a dipteran species (root herbivore.We tested the hypotheses that: (1 high levels of drought stress and below-ground herbivory interact to reduce the performance of parasitoids developing in aphids; (2 drought stress and root herbivory change the profile of volatile organic chemicals (VOCs emitted by the host plant; (3 parasitoids avoid ovipositing in aphids feeding on plants under drought stress and root herbivory. We examined the effect of drought, with and without root herbivory, on the olfactory response of parasitoids (preference, plant volatile emissions, parasitism success (performance, and the effect of drought on root herbivory. Under drought, percentage parasitism of aphids was reduced by about 40-55% compared with well watered plants. There was a significant interaction between drought and root herbivory on the efficacy of the two parasitoid species, drought stress partially reversing the negative effect of root herbivory on percent parasitism. In the absence of drought, root herbivory significantly reduced the performance (e.g. fecundity of both parasitoid species developing in foliar herbivores. Plant emissions of VOCs were reduced by drought and root herbivores, and in olfactometer experiments parasitoids preferred the odour from well-watered plants compared with other treatments. The present work demonstrates that drought stress can change the outcome of interactions between herbivores feeding above- and below-ground and their parasitoids, mediated by changes in the chemical signals from plants to parasitoids. This provides a new insight into how the structure of terrestrial

  8. Drought and root herbivory interact to alter the response of above-ground parasitoids to aphid infested plants and associated plant volatile signals.

    Science.gov (United States)

    Tariq, Muhammad; Wright, Denis J; Bruce, Toby J A; Staley, Joanna T

    2013-01-01

    Multitrophic interactions are likely to be altered by climate change but there is little empirical evidence relating the responses of herbivores and parasitoids to abiotic factors. Here we investigated the effects of drought on an above/below-ground system comprising a generalist and a specialist aphid species (foliar herbivores), their parasitoids, and a dipteran species (root herbivore).We tested the hypotheses that: (1) high levels of drought stress and below-ground herbivory interact to reduce the performance of parasitoids developing in aphids; (2) drought stress and root herbivory change the profile of volatile organic chemicals (VOCs) emitted by the host plant; (3) parasitoids avoid ovipositing in aphids feeding on plants under drought stress and root herbivory. We examined the effect of drought, with and without root herbivory, on the olfactory response of parasitoids (preference), plant volatile emissions, parasitism success (performance), and the effect of drought on root herbivory. Under drought, percentage parasitism of aphids was reduced by about 40-55% compared with well watered plants. There was a significant interaction between drought and root herbivory on the efficacy of the two parasitoid species, drought stress