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Recent in vivo studies have established astrocytes as a major target for locus coeruleus activation (Bekar et al., Cereb. Cortex 18, 2789–2795), renewing interest in cell culture studies on noradrenergic effects on astrocytes in primary cultures and calling for additional information about the expression of adrenoceptor subtypes on different types of brain cells. In the present communication, mRNA expression of α1-, α2- and β-adrenergic receptors and their subtypes was determined in freshly-isolated, cell marker-defined populations of astrocytes, NG2-positive cells, microglia, endothelial cells, and Thy1-positive neurons (mainly glutamatergic projection neurons) in murine cerebral cortex. Immediately after dissection of frontal, parietal and occipital cortex of 10–12-week-old transgenic mice, which combined each cell-type marker with a specific fluorescent signal, the tissue was digested, triturated and centrifuged, yielding a solution of dissociated cells of all types, which were separated by fluorescence-activated cell sorting (FACS). mRNA expression in each cell fraction was determined by microarray analysis. α1A-Receptors were unequivocally expressed in astrocytes and NG2-positive cells, but absent in other cell types, and α1B-receptors were not expressed in any cell population. Among α2-receptors only α2A-receptors were expressed, unequivocally in astrocytes and NG-positive cells, tentatively in microglia and questionably in Thy1-positive neurons and endothelial cells. β1-Receptors were unequivocally expressed in astrocytes, tentatively in microglia, and questionably in neurons and endothelial cells, whereas β2-adrenergic receptors showed tentative expression in neurons and astrocytes and unequivocal expression in other cell types. This distribution was supported by immunochemical data and its relevance established by previous studies in well-differentiated primary cultures of mouse astrocytes, showing that stimulation of α2-adrenoceptors increases glycogen formation and oxidative metabolism, the latter by a mechanism depending on intramitochondrial Ca2+, whereas α1-adrenoceptor stimulation enhances glutamate uptake, and β-adrenoceptor activation causes glycogenolysis and increased Na+,K+-ATPase activity. The Ca2+- and cAMP-mediated association between energy-consuming and energy-yielding processes is emphasized.
Procedures activating locus coeruleus in vivo have astrocytes as a major target, increasing astrocytic free cytosolic Ca2+ concentration ([Ca2+]i) in cerebral cortex. This is an α-adrenergic response, as evidenced by the ability of phentolamine, a non-specific α-adrenergic antagonist (Saeed et al., 1982) to block the response (Bekar et al., 2008). Among the two subtypes of α-adrenergic receptors α1-adrenergic receptors are mainly postjunctional, although presynaptic α1-adrenoceptors have also been reported (Herold et al., 2005). α2-Adrenergic receptors were originally supposed to be presynaptic (Langer, 1980), but it is now recognized that α2-adrenergic receptors in cerebral cortex are mainly postjunctional, reflected by adrenergic drug effects after locus administration of reserpine (depleting adrenergic nerves of noradrenaline) of or coeruleus destruction (U'Prichard et al., 1979; Reynoldson et al., 1979; Cai et al., 1993; Andrews and Lavin, 2006).
Astrocytic α1-receptors have been demonstrated in vibrodissociated astrocytes showing a phenylephrine-induced increase in [Ca2+]i, which was blocked by the α1-specific antagonist prazosin (Thorlin et al., 1998). The presence of astrocytic α2-adrenergic receptors has also been shown immunochemically in intact brain (Aoki et al., 1998; Milner et al., 1998; Glass et al., 2001), and it is reflected in primary cultures of astrocytes by α2-adrenergic receptor binding, receptor expression, and signaling, including increase in [Ca2+]i (reviewed by Hertz et al., 2004). However, neurons in situ also express postsynaptic α2-adrenergic receptors (Modirrousta et al., 2004; Schambra et al., 2005; Wang et al., 2007), as well as α1-adrenoceptors (Blume et al., 2002; Laorden et al., 2002), and cultured GABAergic cortical interneurons respond to the α2-adrenergic agonist guanfacine (Hu et al., 2008).
The increase in astrocytic [Ca2+]i observed by Bekar et al. (2008) was unaffected by the β-adrenergic antagonist propranolol, which does not indicate the absence of β-adrenergic signaling but reflects that β-adrenergic signaling generally occurs via cyclic AMP (cAMP) and protein kinase A (PKA), and thus is not linked to an increase in [Ca2+]i. It has previously been shown that β-adrenergic receptors on freshly isolated cells from cerebral cortex are more concentrated on astrocytes than on neurons (Morin et al., 1997), and that there is a huge increase of β-receptor immunoreactive profiles on astrocytes in layer 1 of the rat visual cortex between days 14 and 21 (Aoki, 1997). However, Milner et al. (2000) reported that in the rat dentate gyrus β-adrenergic receptors are primarily located on dendrites of granule cells and interneurons, although they were also found on astrocytes and a few presynaptic profiles. On the other hand Szot et al. (2007) concluded that 'even though adrenoceptors are found on astrocytes, the level of these binding sites appears to be much lower than that of neurons.' In the light of these differences of opinion more general and averaged semi-quantitative information would be desirable about expression of adrenergic receptors and their subtypes on neurons compared to astrocytes, not to mention other cell types.
Recently, dissociation procedures of freshly excised brain cortex (Lovatt et al., 2007) or forebrain (Cahoy et al., 2008) and subsequent fluorescence-activated cell sorting (FACS) of specifically labeled cell types have successfully been used to assess mRNA expression in astrocytes, neurons and oligodendrocytes. In the present study we have used the procedure of Lovatt et al. (2007), as described under 'Methods', to separate Thy1-positive neurons and astrocytes in order to determine gene expression of α1-, α2- and β-adrenergic receptors and their subtypes. Using additional fluorescent labeling, receptor expression on microglia, endothelial cells and NG-positive cells was also determined. Since the method shows mRNA expression, not protein expression, and since microarray analysis not always provides identical results in replicates from different animals, the observed gene expression is interpreted in the light of morphological, mainly immunohistochemical literature data.
An observed preferential expression of several subtypes of adrenoreceptors to astrocytes raises the question of the functional implications of adrenoceptor stimulation in astrocytes (ignoring potential astrocytic heterogeneity [Kimelberg, 2004; Maytash and Kettenmann, 2009]). Very limited information is available in vivo, but previous experiments in cultured mouse astrocytes have indicated a profound influence on astrocytic energy metabolism, including glycogen synthesis, glycogenolysis and oxidative metabolism, as well as on several energy-requiring processes, including glutamate uptake and Na+,K+-ATPase activity. This information will be reviewed, but sufficient metabolic information is not available for the other cell types. The simultaneous stimulation of energy-requiring and energy-yielding reactions is important, because it supplements the classical concept of regulation of energy metabolism by the availability of ADP (Berg et al., 2002) with a mechanism independent of previous ATP degradation (McCormack and Denton, 1990; Rutter et al., 1996; Robb-Gaspers et al., 1998; Griffiths and Rutter, 2009). In the case of oxidative metabolism the stimulation is effectuated by an increase in [Ca2+]i followed by an increase in intramitochondrial Ca2+, and in the case of glycogenolysis by cAMP/protein kinase A. Since especially the expression of the α2-adrenoceptor is critically dependent on the culturing method (Enkvist et al., 1996), a brief description of the culturing technique used and the characteristics of the cultures will be included in the 'Methods' section.
Brain tissue was from 10–12-week-old FVB/NTg(GFAP GFP)14Mes/J, Tg(Cspg4-DsRed.T1)1Akik/J, B6.129P-Cx3cr1tm1Litt/J, Tg(TIE2GFP)287Sato/J, or B6.Cg-Tg(Thy1-YFPH)2Jrs/J mice (The Jackson Laboratory, Bar Harbor, ME). These transgenic mice combine each cell-specific marker with a specific fluorescent signal, allowing fluorescence-activated sorting of specified cell fractions, although it should be emphasized that Thy1 is mainly a marker of large projection neurons rather than a general neuronal marker (Feng et al., 2000; Seki et al., 2002). The mice were anesthetized with pentobarbital (50 mg kg−1, i.p.), perfused with cold Hanks buffer (Invitrogen, Carlsbad, CA), and decapitated. The brain was immediately removed to cold Hanks buffer containing glutamate receptor antagonists, 3 µM DNQX and 100 µM APV (Tocris, Ellisville, MO). The frontal, parietal and occipital cortex was dissected free of white matter, cut into small pieces, and digested with 8 U/ml papain (Worthington, Lakewood, NJ) in Ca2+/Mg2+-free PIPES/cysteine buffer, pH 7.4, for 1 h at 37°C/5%CO2. After one wash, the tissue was further digested with 40 U/ml DNase I (Sigma, St. Louis, MO) in Mg2+-containing minimum essential medium (MEM) (Invitrogen) with 1% bovine serum albumin (BSA) (Invitrogen) for 15 min at 37°C/5% CO2. The tissue was then carefully triturated in cold MEM with 1% BSA, centrifuged over a 90% Percoll gradient (GE Healthcare, Piscataway, NJ) to collect all cells below and including the lipid layer, which then was further diluted five times (MEM with 1% BSA) and centrifuged to collect the pellet, which normally included five million viable cells per brain used. The cells were then re-suspended in cold MEM with 1% BSA and 4 µg ml−1 propidium iodide (PI) (Sigma) and immediately sorted by fluorescence-activated cell sorting (FACS).
Cells were sorted using either the BDFACSVantage Cell Sorting System (13 psi sheath pressure, Cell Quest software) or the BD FACSAria Cell Sorting System (35 psi sheath pressure, FACSDiva software; BD Biosciences, San José, CA). GFP/YFP, R-PE, and PI were all excited by a 488 nm laser, and emissions were collected by 530/30 nm, 575/26 nm, and 675/20 nm discrimination filters, respectively. The signals were manually compensated, and cells were sorted into cold MEM with 1% BSA.
After FACS, cells were immediately extracted for total RNA and DNase treatment using the RNAqueous Micro kit (Ambion, Austin, TX). RNA quantity was assessed using the NanoDrop-1000 (NanoDrop Technologies, Wilmington, DE), and RNA integrity was assessed using the 2100-Bioanalyzer (Agilent Technologies). For microarray, 20 ng of total RNA was amplified and labeled with biotin using the Ovation kit (NuGEN, San Carlos, CA) according to the manufacturer's instruction and hybridized to the Affymetrix (Santa Clara, CA) GeneChip Mouse Genome 430 2.0 Array.
Microarray data were analyzed using the Arrayassist 5.0.0 software package (Stratagene, La Jolla, CA). We normalized the data using the MAS5 algorithm, followed by log2 transformation and filtering out any probe set that had only one present call across all samples or a maximum intensity value <100 across all samples, which reduced the initial data set of 45,101 probe sets to 19,369 probe sets. To assure reproducibility among independent biological replicates in the genomic data set, we compared the correlation coefficient within groups of sorted cells (19,369 probe sets). The degree of similarity across all samples was assessed by hierarchical clustering using Euclidean average distances. All statistical comparisons between groups were performed by the nonpaired parametric Student's t test using the Benjamini-Hochberg false discovery rate (FDR) correction algorithm of 5%.
Results for each cell type was obtained in three biological replicates, i.e., in cells isolated from three different animals. If all 3 were positive for the gene in question the result is indicated in Tables 1–3 as present, present, present, if 2 of the 3 were positive by two times present and one time absent, if only one was positive by one time present and two times absent, and if all three were negative as absent, absent, absent. Three positive calls were interpreted as unequivocal presence, two positive calls as tentative presence, one positive call as questionable presence or absence, and three negative calls as absence. However, classification as absent does not necessarily exclude a minor expression, as in the case of β3-adrenergic receptors, giving three absent calls in all cell fractions but shown by Summers et al. (1995) to be weakly expressed in rodent brain.
Cultures of astrocytes were prepared as previously described (Hertz et al., 1982, 1998). The areas superficial to the lateral ventricles of the cerebral hemispheres (neopallia) were carefully dissected out of the brains of newborn Swiss mice after removal of the meninges, cut into 1 mm cubes, vortexed and passed twice through Nitex nylon meshes (80 and 10 µm pore sizes) to prepare a cell suspension in a slightly modified Dulbecco's medium (Hertz et al., 1982) with 20% horse serum. The cell suspension was introduced at low density (20 dishes per brain) directly into 35-mm Falcon Primaria tissue culture dishes for the metabolic studies or at twice this density onto very well rinsed (Chen and Hertz, 1999) glass coverslips (from Thomas Scientific Company) for studies of [Ca2+]i and incubated in the slightly modified Dulbecco's medium with 20% serum at 37°C in a 95/5% (vol/vol) mixture of atmospheric air and CO2. However, the cells grow equally well in conventional Dulbecco's medium. Due to the low seeding density oligodendrocytes do not develop, so that no subculturing is needed. The cultures were re-fed with fresh medium two times a week, and the serum concentration was decreased to 10% at the age of 7 days. The cells reached confluency after 2 weeks and were thereafter grown for another 1–2 weeks in the additional presence of 0.25 mM dibutyryl cyclic AMP (dBcAMP), an agent which induces differentiation of the cultures (Meier et al., 1991; Schubert et al., 2000) without leading to the formation of reactive astrocytes (Wandosell et al., 1993). The rationale behind this treatment is that innervation of cerebral cortex by noradrenergic fibers from locus coeruleus is just beginning at birth (Foote et al 1983), i.e., the age when the tissue for culture preparation was harvested. Therefore the cells have not received noradrenergic signals, which may be important for their functional development and can be replaced by the addition of dBcAMP. Besides a pronounced change in morphology (Fig. 1), there are major biochemical and physiological changes. In the present context it is of special importance that α2-adrenoceptor expression is deficient in cells that have not received dBcAMP (Enkvist et al., 1986). Moreover, L-channels for Ca2+, a characteristic of astrocytes in vivo (Thorlin et al., 1998) develop only after dBcAMP treatment (Hertz et al., 1989b).
Astrocytes constitute >95% of the cell population in these cultures, neurons and oligodendrocytes are absent, and the contamination with macrophages is ~3% (Hertz et al., 1982). The information the cultures have provided about uptake of glutamate and GABA, glutamate formation and degradation, energy metabolism, and K+ and Ca2+ homeostasis (Hertz et al., 1998) is consistent with subsequent observations and conclusions by other authors for astrocytic functions in the brain in vivo. The development of a key astrocytic enzyme, glutamine synthetase parallels that in the murine brain (Hertz et al., 1978) and its activity reaches under optimum conditions a value 2–3 times higher than in the brain in vivo (Juurlink et al., 1981).
Only one of the subtypes of the α1-adrenergic receptor, the α1A-adrenergic receptor was expressed in any of the cell types, and it was found only in astrocytes and NG2-positive cells (Table 1). No significant expression of α1-adrenergic receptors was reported by Cahoy et al. (2008) in their FACS-separated cellular fractions, perhaps due to their use of relatively young animals (at most 17-day-old). The expression of α1-adrenoceptors in astrocytes is consistent with the demonstration that [Ca2+]i in Bergmann glia is increased by (nor)adrenaline or the α1-adrenergic agonist phenylephrine and that the increase is inhibited by the α1-specific antagonist prazosin (Kirichuk et al., 1996), which also inhibits stimulus-induced [Ca2+]i increase in these cells (Kulik et al., 1999) and phenylephrine-induced [Ca2+]i increase in vibrodissociated astrocytes (Thorlin et al., 1998). In contrast to these observations as well as our own, Papay et al. (2006) found no expression of α1A-adrenergic receptors in astrocytes. Also in contrast to our findings, they described widespread neuronal expression of α1A-adrenergic receptors in cerebral cortex in situ. However, this expression was mainly in GABAergic interneurons, and Thy1-positive glutamatergic projection neurons were studied in the present communication.
We used adult Tg(Cspg4-DsRed.T1)1Akik/J to isolate NG2-positive cells. The majority of NG2-positive cells (>95%) in these transgenic mice are pericytes (own observation), cells apposed to CNS capillaries and containing contractile proteins (Hughes and Chan-Ling, 2004; Nishiyama et al., 2009). In cerebellar slices, superfused noradrenaline causes pericyte-mediated capillary constriction (Peppiat et al., 2006), and cultured pericytes from the mouse cerebral microvessels show isometric contractions and increase in [Ca2+]i in response to noradrenaline (Noshio et al., 2007). Although receptor subtype was not determined in these studies, expression of α1-adrenoceptor on pericytes might explain their presence in the cellular fraction identified by the presence of NG2. Of note, our observations are not relevant for other types of NG-positive brain cells (glial precursors and/or specific glial cell types (polydendrocytes; synantocytes), interacting directly with neurons, astrocytes and pericytes (Schools et al., 2003; Nishiyama et al., 2009; Bergles et al., 2009; Wigley and Butt, 2009). However, Palay et al. (2006) observed pronounced expression of α1A-adrenergic receptors on NG2-positive cells, which they regarded as oligodendrocyte precursors.
Also among α2-adrenergic receptors only one subtype, the α2A receptor was expressed, regardless of cell type. It was unequivocally expressed on astrocytes and NG2-positive cells (demonstrated in all 3 preparations), tentatively present on microglia (demonstrated in 2 out of 3 preparations), and absent or of questionable presence (demonstrated in 1 of the 3 preparations) on endothelial cells and Thy1-positive neurons (Table 2). The α2A-adrenergic receptor was also the only α2-adrenergic receptor found by Cahoy et al. (2008) to be significantly expressed in astrocytes and neurons, and they described its virtual absence on oligodendrocytes. They found astrocytic expression to be 2–3 times higher than neuronal expression. It is important that neurons both in the studies by Cahoy et al. (2008) and by ourselves show less α2A-adrenergic expression than astrocytes, since the criteria for the selection of neurons differed in the two studies (Thy1-positive cells in the present study versus cells remaining after other immunologically defined cell types had been removed in the study by Cahoy et al. (2008)). Our observations are consistent with the immunochemical demonstration of α2-adrenergic receptors on astrocytes in intact brain (Aoki et al., 1998; Glass et al., 2001). However, although little or no evidence was found for postsynaptic neuronal expression of α2-adrenoceptors, such receptors have not only been demonstrated on GABAergic interneurons (Modirrousta et al., 2004) but also been reported on glutamatergic pyramidal neurons in frontal cortex (Wang et al., 2007).
The possible α2A expression in microglia is consistent with observations by Mori et al. (2002) of upregulation by clonidine, an α2A-adrenergic agonist, of the gene encoding catecholamine-O-methyl transferase (COMT) in cultured microglial cells. The α2A receptor expression on NG2-positive cells has to our knowledge not been described earlier, but these cells are targets for noradrenaline as indicated by their expression of both α1A-adrenergic receptors and β2-adrenergic receptors. The same applies to cerebral endothelial cells, which also unequivocally express β2-adrenergic receptors (see below).
All cell types expressed β2-adrenergic receptors with relatively small differences, whereas β1-adrenergic receptors were unequivocally expressed only on astrocytes (where their expression was better established than that of β2-receptors) and microglia, of questionable presence or absence in endothelial cells and absent in Thy1-positive neurons (Table 3). These findings contrast those by Cahoy et al. (2008), who found almost equal expression of β1 receptors on astrocytes and neurons and no significant expression of β2 receptors. This discrepancy might on one hand be explained by our selection of Thy1-positive neurons (which might have reduced β1-adrenoceptor expression) and on the other hand by their use of not fully mature astrocytes (which might have reduced β2-adrenoceptor expression). The latter factor may be especially relevant for β-adrenergic receptors because of the 4–5-fold increase of β-receptor immunoreactive profiles on astrocytes in layer 1 of the rat visual cortex between days 14 and 21 (Aoki, 1997). The concept that a large fraction of β-adrenergic binding is astrocytic is consistent with binding experiments showing that β-adrenergic receptors on freshly isolated cells from cerebral cortex are more concentrated on astrocytes than on neurons (Morin et al., 1997).
On microglia β2-receptor expression was also better established than β1-receptor expression, consistent with the observation that cAMP levels were increased 10 times more strongly in cultured microglia by activation of a specific β2 receptor agonist than by activation of a specific β1 receptor (Mori et al., 2002). β-Adrenergic signaling has been demonstrated in a brain endothelial cell line (Smith and Drewes, 2006), and mRNA for β2-adrenoceptors in a pericytic cell line (Asashima et al., 2003).
β3-Adrenergic receptor expression has been demonstrated in brain but is more pronounced in hippocampus than in cerebral cortex, where its density only amounts to 3% of that in brown adipose tissue (Summers et al., 1995). Based on stimulatory effects of a β3-adrenergic agonist on glucose uptake in cultured cells from the chicken brain it appears to be confined to astrocytes (Hutchinson et al., 2009), and it has also been reported in mouse astrocytes (Catus et al., 2008).
α1A, α2A and β1 receptors have a predominantly astrocytic localization, whereas β2 receptors seem mainly to be expressed on neurons. Except for β-adrenoceptor expression NG2-positive cells are similar to astrocytes. Microglia express mainly α2A-adrenergic receptors and both β1 and β2 receptors. The only adrenoceptor which with certainty was demonstrated on endothelial cells was the β2-receptor.
In order to understand the importance of adrenoceptor effects on glucose metabolism metabolic pathways for glucose must be briefly described. Glucose is normally the predominant substrate used by the brain for energy metabolism and, in addition, it is the sole source of transmitter glutamate. Astrocytes have rates of oxidative metabolism and activities of the enzymes involved that on a per volume basis are at least equal to those in neurons (Hertz et al., 2007; Lovatt et al., 2007; Zielke et al. 2007). Moreover, in contrast to neurons, they are able to use glucose to form glutamate, which can then be transferred to glutamatergic neurons and used as transmitter glutamate or to GABAergic neurons and used as a GABA precursor. As illustrated in Fig. 2, glucose, containing six carbon atoms (C), is initially converted to 2 molecules of the 3C compound pyruvate. In both astrocytes and neurons this occurs in a multi-step glycolytic process. In astrocytes, but not in neurons, this process can be diverted by initial formation of glycogen, which is then degraded by glycogenolysis, catalyzed by glycogen phosphorylase, bypassing the initial step in glucose degradation, and thereafter followed by similar downstream processes towards pyruvate as glycolysis. Such a 'glucose-glycogen shunt' is slightly less advantageous energetically than direct degradation of glucose. Anyhow glycolysis per se contributes only little to energy formation, but it does generate pyruvate, which yields large amounts of ATP upon oxidative metabolism, and pyruvate formation from glycogen has the advantage that it can occur very rapidly. This shunt is operating during brain activation (Swanson et al., 1992; Hertz et al., 2007; Dienel et al., 2007), including learning in day-old chicken, where glycogen is used for production of glutamate, following the pathway described below (Gibbs et al., 2008).
In both neurons and astrocytes, oxidative metabolism of pyruvate in the tricarboxylic acid (TCA) cycle is initiated by an oxidative decarboxylation by pyruvate dehydrogenase and condensation with coenzyme A to form acetyl coenzyme A (Acetyl CoA). The acetyl moiety (2C) is transferred to oxaloacetate from the TCA cycle (4C) to form citrate (6C). Through an intermediate step, citrate is decarboxylated to α-ketoglutarate (5C), which is further decarboxylated to succinate (4C). Through several steps oxaloacetate is re-generated from succinate and ready to condense with another molecule of acetyl CoA for continued production of energy, but without net synthesis of any TCA cycle constituent (Fig. 2).
Pyruvate can also be carboxylated by pyruvate carboxylase to give rise to a new molecule of oxaloacetate (Fig. 2), a process which occurs in astrocytes but not in neurons, which lack pyruvate carboxylase activity (Yu et al., 1983; Shank et al., 1985; Hertz and Zielke, 2004; Hertz et al., 2007). After condensation of oxaloacetate with acetyl CoA, the resulting citrate molecule can be converted to α-ketoglutarate. α-Ketoglutarate can leave the cycle to form glutamate, which is transferred to neurons in the glutamate-glutamine cycle (which is also used for the return of astrocytically accumulated glutamate). An increase in de novo glutamate synthesis has been demonstrated in the chicken brain during the initial phase of learning (Gibbs et al., 2008). This is consistent with other evidence that increased brain activity is associated with enhanced pyruvate carboxylation (Öz et al. 2004, Serres et al. 2008). A high glutamate content in neurons is useful at times of increased glutamatergic activity, because vesicular filling with glutamate depends upon the cytosolic glutamate concentration (Wilson et al. 2005). During learning the increased brain glutamate content soon returns to normal, following glutamate exit from the TCA cycle and its oxidation predominantly in astrocytes (Yu et al. 1982, McKenna et al. 1996). These are major metabolic processes, as indicated by the conclusion that on the average about one third of all released transmitter glutamate has been recently synthesized from glucose, with the other two thirds representing recycled transmitter glutamate, to a large extent returned to neurons in the glutamate-glutamine cycle after initial accumulation in astrocytes (Hertz et al., 2007).
Stimulation of α2 receptors leads to a rapid increase of glucose incorporation into glycogen, as required for the operation of the glucose-glycogen shunt during enhanced brain activity, whereas α2 receptor inhibition leads to a decreased glycogen synthesis (Hertz et al., 2007; D. Hutchinson and M.E. Gibbs, personal communication). Noradrenaline also increases glycogenolysis in cultured astrocytes (Magistretti et al., 1983; Cummins et al., 1983), mainly by a β-adrenergic effect, although an α2-adrenergic effect also contributes to the enhanced glycogenolysis, and complete inhibition of noradrenaline-induced glycogenolysis requires administration of both β-and α2-adrenergic antagonists (Subbarao and Hertz, 1990). Brain slice experiments have identifed the β-adrenergic subtype involved in the mouse as the β1-adrenoceptor (Quach et al., 1988), but in the chicken brain it is the β2-adrenoceptor (Gibbs et al., 2008). Since glycogenolysis in brain parenchyma is virtually restricted to astrocytes these observations confirm β-adrenoceptor-mediated glycogenolysis in non-cultured brain tissue. Thus, both glycogen synthesis and glycogenolysis are activated by adrenoceptor subtypes shown to be unequivocally expressed in astrocytes, with less evidence of neuronal expression (Fig. 2).
Stimulation by noradrenaline of pyruvate dehydrogenase activity, measured as rate of production of labeled CO2 from [1-14C]pyruvate (Fig. 2), is an α2-adrenergic effect. This has been shown by the ability of noradrenaline and either clonidine (Chen and Hertz, 1999) or the highly α2-specific and potent drug dexmedetomidine (Chen et al., 2000), but not of phenylephrine or isoproterenol, a β1- and β2-adrenergic agonist, to increase 14CO2 production (Fig. 3). The concentration dependence of the stimulation by dexmedetomidine is mimicked by a similar effect of dexmedetomidine on [Ca2+]i (Fig. 4). The left, high-affinity portion of this Figure indicates an α2-adrenergic effect, which was almost completely inhibited by the α2-adrenergic antagonist yohimbine, whereas the right, low-affinity portion is mainly due to a stimulation of an imidazoline-preferring site (Chen et al., 2000). An increased [Ca2+]i is not sufficient for the metabolic response, since phenylephrine also increases [Ca2+]i in a subtype-specific manner (Fig. 5). However, removal of extracellular Ca2+ combined with the addition of 10 mM MgCl2, which prevents a concomitant increase in intramitochondrial Ca2+, abolishes the response (Table 4). A maximum [Ca2+]i response is not required for the stimulation, since full metabolic stimulation is reached at a noradrenaline concentration yielding a [Ca2+]i of only twice the resting concentration of 100 nM (Fig. 6).
α-Ketoglutarate dehydrogenation (via succinyl coenzyme A [succinyl CoA] to succinate [Fig. 2]) was examined in a similar fashion as pyruvate dehydrogenation, albeit with the difference that α-ketoglutarate does not easily enter mitochondria, so that instead production of 14CO2 from [1-14C]glutamate, an α-ketoglutarate precursor, was studied. Again, both noradrenaline and clonidine stimulated metabolism (Subbarao and Hertz, 1991). However, in addition phenylephrine had a stimulatory effect on14CO2 production, but this can probably be explained by stimulation of glutamate uptake by an α1-adrenergic effect (see below), which will increase the specific activity of the cellular pool of glutamate and thus also of its product, α-ketoglutarate.
Thus α2-adrenoceptors, shown to be unequivocally present in astrocytes, were of key importance for stimulation of both TCA cycle enzymes studied. However, there was the difference that while maximum effect on pyruvate dehydrogenation was reached at <0.2 µM noradrenaline (Fig. 6), a >10-fold higher concentration was needed for stimulation of α-ketoglutarate dehydrogenation (Subbarao and Hertz, 1991). This difference could suggest that lower concentrations of noradrenaline have little effect on α-ketoglutarate dehydrogenation, but facilitate its formation and thus might enhance glutamate formation from glucose. This may be of importance for the supply of glutamatergic neurons with transmitter glutamate during brain activation, including learning (Gibbs et al., 2008). Accordingly the α2A-adrenergic agonist guanfacine, which alleviates attention deficit hyperactivity disorder (ADHD) by acting on frontal cortex to facilitate working memory (Levy, 2008) might owe part of its therapeutic effect to an action on astrocytes. This concept is supported by the recent demonstration that pharmacological inhibition of glial cells by the toxin fluorocitrate affects working memory (Wang et al., 2009). At low doses, working memory is improved by fluorocitrate, which could be due to reduction of astrocytic uptake of released transmitter glutamate (see below). At higher doses memory is impaired, perhaps reflecting interference with astrocytic glutamate production by an inhibition of the enzyme aconitase, needed for citrate metabolism. This inhibition is more potent in astrocytes than in neurons (Zielke et al., 2009), and therefore fluorocitrate at appropriate dosage prevents α-ketoglutarate production specifically in the astrocytic TCA cycle (Fig. 2).
Glutamate is avidly taken up by astrocytes both in primary cultures (Hertz et al., 1978) and in the brain in vivo, where most of the re-uptake of released transmitter glutamate occurs in astrocytes (Danbolt, 2001). Hansson and Rönnbäck (1991) showed that phenylephrine greatly increases the Vmax for the uptake into cultured astrocytes, although with relatively low affinity. An α1-mediated uptake stimulation in cultured rat astrocytes was confirmed by Fahrig (1993), who provided the additional information that the subtype stimulated was the α1B receptor. This observation is not consistent with the present demonstration of gene expression of the α1A but not the α1B adrenoceptor in astrocytes from the mouse brain, but α1 adrenoreceptors are known to show subtype variability between species (García-Sáinz et al., 1992). Since astrocytes account for most of the re-uptake of glutamate in the brain in vivo the observation that clearance of extracellular glutamate in the brain in vivo is stimulated by the α1-adrenergic agonist phenylephrine (Alexander et al., 1997) confirms the results obtained in tissue culture.
The astrocytic Na+,K+-ATPase has sufficiently low affinity for K+ that an elevated extracellular K+ concentration stimulates its activity (Grisar et al., 1979; Hajek et al., 1996). It is now accepted that the astrocytic Na+,K+-ATPase plays a major role in clearance of activity-induced increase in extracellular K+ concentration in the brain (Somjen et al., 2008). Na+,K+-ATPase activity in astrocytes, and thus probably also K+ uptake (and Na+ extrusion), is enhanced by isoproterenol and perhaps also phenylephrine, but not by the α2-adrenergic agonist clonidine, indicating β- and possibly α1-adrenergic effects (Hajek et al., 1996). Both of these effects would be consistent with astrocytic receptor localization if the α1-adrenergic effect is exerted on α1A-adrenoceptors.
The stimulatory effects of noradrenergic receptor activation on both energy-requiring and energy-yielding processes (albeit often by activation of different subtypes of adrenoceptors) enable the energy-requiring processes to simultaneously stimulate oxidative metabolism and/or glycogenolysis (Fig. 7). Simultaneous effects on both energy use and energy production supplement the classical linkage between energy supply and demand, i.e., regulation of energy production by products of work such as ATP hydrolysis to ADP (Berg et al., 2002). In contrast to the classical mechanism they allow energy metabolism to be stimulated without preceding decreases in ATP. Stimulation of glycogenolysis matters, because brain glycogenolysis no longer is regarded as primarily an emergency function, but as an integral part of glucose breakdown via a substantial 'glucose-glycogen shunt' (Swanson et al., 1992; Dienel et al., 2007; Hertz et al., 2007). A noradrenaline-induced increase in mitochondrial Ca2+ has been observed in astrocytes (Simpson et al., 1998), but stimulation of oxidative metabolism by increased [Ca2+]i, followed by increased intramitochondrial Ca2+, has mainly been studied in muscle and liver, where a direct stimulation was demonstrated of the mitochondrial dehydrogenases pyruvate dehydrogenase, isocitrate dehydrogenase (which stimulates degradation of isocitrate, an intermediate between citrate and α-ketoglutarate in the TCA cycle) and α-ketoglutarate dehydrogenase (McCormack and Denton, 1990; Rutter et al., 1996; Gaspers and Thomas, 2008; Griffith and Rutter, 2009). Fluxes through the metabolic steps catalyzed by two of these enzymes were shown above to be stimulated by noradrenaline, whereas flux catalyzed by the isocitrate dehydrogenase has not been studied in astrocytes, because no convenient substrate entering the mitochondria exists for this reaction. In addition to the stimulation of the 3 dehydrogenases a direct stimulation of oxidative phosphorylation has also been demonstrated (Robb-Gaspers et al., 1998; Gaspers and Thomas, 2008).
Both α2A and α1-adrenergic stimulation raised [Ca2+]i, but only the former increased pyruvate dehydrogenation. These different patterns of Ca2+ signaling may result from a limited range of cytoplasmic Ca2+ diffusion from different locations towards mitochondria and temporal regulation of mitochondrial Ca2+ uptake (Thomas et al., 1996; Putney and Thomas, 2006). Both IP3- and ryanodine/caffeine-sensitive Ca2+ stores have been found in cultured astrocytes (Reyes and Parpura, 2009), and they might be differently located and differently affected by α1- and α2-adrenergic stimulation. Moreover, due to different kinetics for opening and inhibition of the mitochondrial uniporter for Ca2+, the possibilities for mitochondrial Ca2+ uptake may vary with the kinetics of the Ca2+ signal (Putney and Thomas, 2006). Additional information about the effect of locus coeruleus stimulation on intracellular distribution of increases in [Ca2+]i and its kinetics may in the future help clarifying different functions of elevated intracellular Ca2+ concentrations.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Nancy Gonzalez Opens Hong Kong Store
Luxury handbag maker Nancy Gonzalez has opened its first stand-alone store in Asia. The small store opened last month and is located at IFC shopping mall in Central Hong Kong.
"Things came together in a very organic way," said Santiago Barberi Gonzalez, president and creative director of Nancy Gonzalez. "It's very difficult to find a space in this mall and we got lucky because there was a space that could be available and it was the right space."
Gonzalez said he chose Hong Kong for the stand-alone shop because of the city's international and diverse background.
"I was more comfortable opening [a boutique] in a place that's more worldly. Maybe people traveling here on holiday are not so incredibly familiar with the brand, but the Hong Kong high-end consumer would definitely be familiar because these are people who are traveling to New York City and London and Dubai, which are places where I have a very strong presence," he said. To promote the brand, Nancy Gonzalez is relaunching their website in both English and Chinese.
"The Web site was literally done for this store because in America and other countries our presence is so well known we didn't need a Web site so huge to make the customer so aware of the brand. A store like this requires it," he explained.
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» Views
Asean-China: connecting two dreams
Publication Date : 29-07-2013
Chinese Foreign Minister Wang Yi's first major task after taking office was to meet with senior Asean officials in early April, and he immediately linked the "Chinese Dream" to the "Asean Dream".
To realise the two dreams, he said: "We need to work together, wish each other well and support each other."
What followed in the next few months was the gradual warming up of Asean-China relations after frayed tensions over the South China Sea disputes, which have dominated international news headlines. The recent decision of Asean and China to begin official negotiations over the long delayed code of conduct (COC) is a good barometer of their mutual comfort level and trust. The two sides also manifested the same determination to avoid holding their broader relations hostage to time-consuming and multi-faceted disputes.
At the April meeting, Wang described the Asean Dream as the full realisation of the Asean Community in 2015. He connected the grouping's community-building effort to China's own - the dual goals of becoming a "moderately prosperous society" by 2020 and "a strong, prosperous, democratic, culturally advanced society" by 2049 to mark the centenary of the People's Republic of China. When Asean was established in 1967, the grouping's founding fathers envisaged that the whole of Southeast Asia would come under one roof. Now that reality is within reach in less than 900 days, that is, by the end of 2015.
To fulfill the Asean and Chinese dreams, both sides will need to sustain continuous economic growth as well as maintain a stable and peaceful external environment. The Asean's economic growth, which has brought region-wide prosperity and integration, is linked to China's rapid economic rise. Their combined regional strength has served as a driving force for the overall economic development and integration of East Asia.
Asean and China are facing new challenges as their relations diversify and become more sophisticated. On their home fronts, too, there are stronger interactions between their domestic and immediately external environment. Both have their own constituencies and peculiarities, including different public and media perceptions about their relations. In the age of fast global shifts and expanding connectivity - not to mention increased national pride among East Asian countries - managing stable and rewarding cooperation without impinging on local conditions has remained at best difficult.
Asean-China relations are not immune to such dilemmas. Their leaders have to navigate more complicated bilateral and multilateral relations to avoid damages, real or imagined. Thanks to the so-called Asean+1 family, Asean and China have the most intensive cooperation with 12 ministerial meetings with nearly four dozen specialised committees at various levels, the highest among all the dialogue partners.
China is promoting a tripartite free trade arrangement with Japan and South Korea. Despite showing enthusiasm toward the US-led Trans-Pacific Partnership, China's top priority is still the Asean-led Regional Comprehensive Economic Partnership (RCEP), for which negotiations have already begun. Asean will intensify its engagement on the RCEP with the plus three countries.
Last year, their relations reached an all-time low in terms of trust because of the disagreement over how best to proceed with the COC amid growing confrontation. Earlier, China's position was quite simple: the situation is not ripe for a COC. And the lack of progress on a COC trumped other positive aspects of their multi-facet friendship.
However, with a new leadership in Beijing and a new Asean chair, Brunei, Asean and China have been able to overcome past mistrust. Brunei has forged a new consensus, painstakingly weaving the interests of Asean member states. Both sides will now start the COC drafting process. Of late, the Philippines has toughened its position threatening to derail the Asean efforts.
The four meetings in the fall - two each in Bangkok and in Beijing - at working-group and ministerial levels will zero in on establishing a working modality. The forthcoming High-Level Meeting of Asean and China Forum on August 2 and the Asean ministerial retreat on August 14 in Huahin is pivotal to review and refresh Asean-China relations. At the end of August, China will host a special ministerial meeting with Asean in commemorate the 10th anniversary of their strategic partnership to be followed by a senior official level working group on the Declaration of the Conduct of Parties in the South China Sea in September.
For both sides, the biggest task is to build on the small progress achieved in Brunei - the willingness to give-and-take and engaging in more consultative endeavours to broaden future cooperation. The Asean joint communique touched on the situation in South China Sea, which it unable to do last year. It stressed their common desire to see the COC process move forward.
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just the Round-Up - The week in drinks
By just-drinks.com editorial team | 9 July 2010
The week in drinks
The top ten stories published on just-drinks this week:
GLOBAL: Suntory eyes Eastern Europe, Middle East buys
Japanese drinks major Suntory is mulling acquisitions in Eastern Europe, the Middle East and North Africa to grow its international sales by 40% in five years, a company official has confirmed to just-drinks.
US: Constellation Brands plays down Crown Imports row
The CEO of Constellation Brands has insisted that there is no rift with Grupo Modelo over the Crown Imports beer venture.
GREECE: Drinks industry feels pinch as austerity plan bites
Drinks retailers and wholesalers are coming under pressure in Greece as duty tax increases ordered within the government's tough austerity programme start to bite.
RUSSIA: Russian Standard backs minimum vodka price
The founder and CEO of Russian Standard Vodka has welcomed the planned price controls on vodka announced by the Russian Government.
US: CEDC pulls out of Nemiroff vodka buy
Central European Distribution Corp (CEDC) has dropped plans to acquire Ukrainian vodka firm Nemiroff.
GLOBAL: Unemployment may snuff out recovery - OECD
Leading economic body the Organisation for Economic Co-operation and Development has warned that unemployment poses a serious risk to recovery in western countries.
UK: Online drinks adverts face tougher checks
The UK Government's advertising watchdog is set to enforce stricter rules for online marketing by the alcoholic drinks industry.
GLOBAL: Multinational spirits suffer as domestics thrive in 2009 - Research
Multinational spirits brands bore the brunt of a tough 2009, as local brands benefited from the economic downturn, according to recent research.
CHINA: Scotch whisky to get protected GI status
Scotch whisky distillers are toasting a commitment by China's Government to introduce protected name status for their products.
INDIA: John Distilleries confirms equity infusion
A spokesperson for John Distilleries has confirmed to just-drinks that the firm is targeting a INR750m (US$16m) private equity infusion, but that talks are ongoing and plans would soon be finalised.
Sectors: Beer & cider, Soft drinks, Spirits, Water, Wine
Companies: Suntory, Constellation, CEDC, Grupo Modelo
Comment – Wine – What's Definitely Going to Happen in 2011
As the old year decomposes slowly in its flat, forgotten by family and neighbours alike, and the newly-born one has its buttocks metaphorically slapped by the midwife of hope, Chris Losh takes his ann...
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Showcased at the 4th annual Student Experimental Film Festival in Binghamton!
'in heaven' is a short, vaguely narrative piece, shot on 16mm black & white reversal film. Primarily driven by its high contrast and static visuals, the film details the monotonous moments of a young woman's day-to-day life and the suicidal fantasies she creates.
Shot on KODAK 16mm black & white reversal film with a BOLEX H16. Edited on a STEENBECK flatbed film editing machine, and FINAL CUT Pro X. Music by Twin Sister ('6' reversed). Talent: Ashley Brown
Created for ART 435 - 16mm Filmmaking (UMBC, Spring 2013)
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4:02 am
Fri March 7, 2014
Weather Expected To Effect February Jobs Report
Originally published on Fri March 7, 2014 10:39 am
The recent bout of winter weather that many of us have felt has hit the U.S. economy. Winter storms cooled job growth in February. The only question is by how much. Economists, investors and job seekers are looking to today's employment report from the government for an answer. NPR's John Ydstie says their predictions have been dampened by the weather too.
JOHN YDSTIE, BYLINE: John Sylvia is the top economist for Wells Fargo. His forecast for job growth in February has been pounded down by the weather.
JOHN SILVIA: We're thinking 135,000, which is a little bit below the consensus.
YDSTIE: Surveys of economists show an expectation of around 150,000 new jobs, but that's well below the average monthly job growth of around 200,000 for much of last year. Silvia predicts that retail employment was affected because shoppers didn't show up, that construction job growth slowed because snow covered job sites, and that hotels, bars and restaurants needed fewer workers because they had fewer customers.
SILVIA: When you're talking about restaurants, leisure, bars, I mean now you're talking about people voluntarily going out driving someplace and certainly the weather would have a negative impact there.
YDSTIE: Losses from empty hotel rooms and restaurant tables won't be regained, but Silvia says the economy will make up some ground and grow faster in the coming months.
SILVIA: It will have a slight negative impact on our overall economic growth, but we do think the second quarter pickup will reestablish a stronger trend.
YDSTIE: And Silvia predicts this year's growth will end up being stronger than last year's. So what about the unemployment rate? It's been steadily falling over the past year and now stands at 6.6 percent. Federal Reserve policy makers have said that a 6.5 percent rate is a threshold where they will begin considering moving short term interest rates higher. John Silvia thinks that rate will be hit today.
That could roil financial markets which are very sensitive to rising interest rates.
SILVIA: 6.5 percent is significant and we think that the markets will again be a little bit defensive.
YDSTIE: The Fed has tried to reassure investors that it's likely to keep rates low long after crossing the 6.5 percent threshold. John Ydstie, NPR News, Washington. Transcript provided by NPR, Copyright NPR.


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Weber Gallagher has an immediate opening for an experienced litigation paralegal for our Philadelphia, PA office....
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Asad holds Zoya responsible for his mother's condition
Added on 2/7/2013
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... same mixed feelings as when we were about to leave. A little impatient, a little sad, a little emotional and very happy.
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The eagle had landed
It is 5:38 pm Italy time... how do I know this???... because our plane has actually landed in Italy. It's a miracle!!! The drive from our hotel is 40 minutes. Along the way I am struck by the beautiful flowering bushes, crazy fast driving and the graffiti. Once we hit about 30 minutes into the drive you start to see the tops of the famous Italian buildings and the quaint shops. The city really bustles to life with everyone vying for parking ...
Touchdown in Europe
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- Good as ever
- Excellent service at the Frankfurt Hilton
Hotel InterContinental FrankfurtInnenstadt, Frankfurt | 5 star hotelfrom $140
- Enjoyed our stay
- At least ok
- Just OK for Price
Radisson Blu Hotel, FrankfurtInnenstadt, Frankfurt | 4 star hotelfrom $92
- Obercool!
- Ausgezeichnet, sauber, modern
- Traumhaft
Leonardo Royal Hotel FrankfurtSachsenhausen-Süd, Frankfurt | 3 star hotelfrom $88
Sheraton Frankfurt Airport Hotel & Conference CenterFlughafen, Frankfurt | 5 star hotelfrom $135
- Didn't live up to reputation
- Terrific Hotel at Frankfurt Airport
- Good Hotel, Convenient to Airport
The Westin Grand FrankfurtInnenstadt, Frankfurt | 5 star hotelfrom $178
Steigenberger Frankfurter HofInnenstadt, Frankfurt | 4 star hotelfrom $235
- Very good, but has some "cheap" practices
- We Loved It for a Special Treat
- Fine Hotel
IntercityHotel FrankfurtInnenstadt, Frankfurt | 3 star hotelfrom $100
Maritim Hotel Frankfurt / MainInnenstadt, Frankfurt | 5 star hotelfrom $152
Sheraton Frankfurt Congress HotelFrankfurt Am Main West, Frankfurt | 4 star hotelfrom $115
Holiday Inn Frankfurt-Airport NorthSachsenhausen-Süd, Frankfurt | 4 star hotelfrom $74
Steigenberger Airport HotelFrankfurt Am Main Süd, Frankfurt | 5 star hotelfrom $94
- A good pick for departing flyers
- Great airport hotel
- Great relief following my Lufthansa frustration
Moevenpick Hotel Frankfurt Am Main CityInnenstadt, Frankfurt | 4 star hotelfrom $106
InterCityHotel Frankfurt AirportInnenstadt, Frankfurt | 4 star hotelfrom $72
- Good Location to Airport
- Very basic hotel
- Decent airport hotel
Kempinski Hotel Frankfurt GravenbruchGraf Zu Ysenburg und Buedingen Platz 1, Frankfurt | 5 star hotelfrom $118
Mercure Hotel & Residenz Frankfurt MesseInnenstadt, Frankfurt | 4 star hotelfrom $72
RAMADA Hotel Frankfurt-MesseNied, Frankfurt | 4 star hotelfrom $65
Lindner Congress Hotel FrankfurtFrankfurt Am Main West, Frankfurt | 4 star hotelfrom $86
Novotel Frankfurt CityInnenstadt, Frankfurt | 4 star hotelfrom $55
Ibis Frankfurt City MesseInnenstadt, Frankfurt | 2 star hotelfrom $55
NH Frankfurt CityInnenstadt, Frankfurt | 4 star hotelfrom $87
- Good hotel
- Excellent hotel all around
- Fab hotel
Holiday Inn Express Frankfurt-MesseGutleutviertel, Frankfurt | 3 star hotelfrom $68
Motel One Frankfurt-NiederradInnenstadt, Frankfurt | 2 star hotelfrom $79
Dorint Hotel Frankfurt-NiederradFrankfurt Am Main Süd, Frankfurt | 4 star hotelfrom $75


text:
Quality Assurance,POC,Telemarketer,Lead Generator,Appointment Setter
Philippines - Last active: 1 month ago - Tests: 2
*Technical Support Specialist for D-Link Home Products - Provides excellent Technical and Customer experience - Solve issues/concerns with their networking devices - Went extra mile helping customers connect their 3rd party devices to their network devices Spent almost 2 years as a Customer Service Representative (Outbound Sales) handling; * Financial Account (Mortgages) * Surveys (UK products and services and Auto Insurance) * Education (US citizens for getting a Masteral, for 2nd coursers and College transferees) * Credit card pull-out account (travelling agency and baby products and services) * Appointment setting (for people who qualify for a heart scan within United States, merchant accounts and for advertising) I've also done some Social Bookmarking and set appointments for Americans for a one on one interview with our manager for Bankers, merchant accounts and advertising. * VA for an Amazon seller and is in charge of his promotions and any customer related services * Supervisor for Data gathering campaign * Lead Generator for big tech companies in US
Manual and Automation tester(Web Applications/Android Apps)
Australia - Last active: 5 days ago - Tests: 4 - Portfolio: 3
Priya is an manual tester form Melbourne,Australia specialized in functional,usability and compatibility testing of web applications and mobile applications. A quick learner, adaptable, self motivated, team player, quality minded, focused, reliable committed and able to work independently. I have been working as a QA Engineer over 3 years. I have been testing and managing the web applications or software products which gave me a great knowledge and experience in creating test-plans and test-cases, implementing any kind of testing. I possess excellent understanding of Software Quality Assurance, SDLC, STLC and bug life cycle processes. My professional experience believes in providing high quality testing deliverable in reasonable span of time and cost. My Core Skills and Experiences are following : • 3 years of experience in testing Web based applications and Mobile Applications • ISTQB foundation level Certified Tester • Proficient with preparing and executing test cases • Experienced in HP Quality Center,Jira,Zendesk • Good Knowledge of all stages of SDLC,STLC and bug life cycle • Good knowledge of Agile methodology including Scrum and Kanban • Knowledgeable in Automation Tools HP UFT and Selenium IDE • Sound working knowledge of different methodologies Agile ,V and Waterfall • Good analysis and problem solving skills • Excellent communication, organization and presentation skills Types of testing 1.Black box testing 2.Functional 3.Accessibility(content testing for spelling,grammar,font color and size validation against W3C standard,error messages validation) 4.Usability 5.Integration 6.Front end testing 7.Back end testing 8.Trouble shooting and performing root cause by studying error logs 8.Compatibility testing on platforms/browsers/devices 9.Localization 10.Exploratory 11.Regression testing Tools Test management and defect tracking tool:HP Quality center 10 Test Automation tool HP UFT 12 Test Automation Tool Selenium IDE sites tested 1.www.yeeepie.com.au 2.www.webjet.com.au 3.www.zuji.com.au 3.www.moodmedia.com 4.etrust admin antivirus Environment * Asus Laptop * HTC Desire 300,Sony Xperia ion * Microsoft surface pro 2 * IPad Mini 2 * Browsers:Google Chrome(38.0),Internet Explorer (8/10/11),Safari,Firefox(34) * Operating systems:Windows XP/7/8/8.1, IOS (7.1.2),Android (4.1.2,4.0.4) Access to high speed and reliable cable broadband internet connection with speed of 35 Mbps Access to emulators and Virtual box for other operating systems and devices. I work well under pressure and always meet the deadlines and have strong communication and problem solving skills. Available full time AEST more than 20 hours per week, also.With the above skills and experience would like positively contribute towards the project.Looking forward to hear from potential clients and establish long term relationship with the clients.
Reviews, Blogs , Article writing, Data Entry
United States - Last active: 6 days ago - Tests: 2 - Portfolio: 2
I am a self-motivated worker with excellent administrative, clerical, writing, and web skills. I have worked in making paper worker from spec sheets, running new product for the company,lead in quality, retail management, data entry, customer service, and clerical positions. I type 45+ words per minute and I pay particular attention to spelling and grammar. I am proficient with Microsoft Word, Excel, and PowerPoint. I have extensive experience conducting research on the internet, writing papers, and leading group projects. I am looking for any opportunity to use these skills in a productive way. I have a strong sense of responsibility and I value a strong work ethic. I learn quickly and am always willing to learn something new.
Software QA/Testing Professional
India - Last active: 8 days ago - Tests: 3
• Over 9 years of experience in Software Testing and additionally 3 years of Non-IT experience in Financial Audits. • ITIL V3 Certified. • Worked onsite at Melbourne during the User Acceptance Testing Phase for BUPA Australia • Received merit award for excellent performance in testing client requirements and applications • Received Circle of Excellence Award as part of BT-Spine Project, Mastek Ltd • Team Lead with knowledge of L3 plans (using MPP), Estimation, Test Strategy and Planning. • Knowledge of Software Testing Life Cycle, understanding different types of testing. • Domain experience in Healthcare, Insurance, Telecom, Financial Accounting & Budgeting • Expertise in functional Black Box and White Box Testing • Proficiency in Designing, Reviewing, Executing Test Cases and Recording test results. • Core competency in analyzing requirements for Coverage and Traceability • Experience in Manual Testing, Automation Tools and Development • Basic German Language competency
- Software Testing
- Software QA Testing
- Manual Test Execution
- Database testing
- Black Box Testing
- Functional testing
- Penetration Testing
- Regression testing
- Usability testing
- User acceptance testing
- Technical Documentation
- Test Case Design
- Web Testing
- HP Quality Center
Associated with: TEAM360, TheQACorps
Management Graduate | Experienced tester | Computer Science Engineer
France - Last active: 1 month ago - Tests: 1
I'm a recent Management graduate with a Computer Science Engineering background. I have 16 months of experience as Strategy Analyst with MNCs. Previously I have worked with an Indian MNC for 2 years as a Tester. Since then, I have always aimed to perfect everything I had my hands on. Hence, I'm here to help you deliver your products and projects with 100 % quality meeting the requirements specification. I have complete knowledge of SDLC and during my previous experience, I used HP Quality Center as the Test Management tool.
Expert in Office and Online Jobs
Philippines - Last active: 2 days ago - Tests: 2 - Portfolio: 1
My experience is my strength to work professionally.
Master of Business Administration in Systems and IT
India - Last active: 4 days ago - Tests: 33 - Portfolio: 10
I have overall 15+ years Information Technology experience and worked on many platforms and programming languages and well versed with latest technologies. I am committed to client benefit and growth by contributing my sincere efforts and talent. I have started working as freelancer- remote worker in 2008 and successfully contributed my services to the global clients with good feedback reviews. I have strong skill set to perform below activities:- 1) Expert in Tableau, Excel VBA and Qlikview to develop Reporting Dashboard 3) Expert in Administration, Installation and configuration of opensource tools - Word press, Jenkins 6) Website Development using Word Press on any Web Host Platform. I also have experience in the below areas as well: Data Warehousing, Data Mining, Jasper Reports, MYSQL, HP QC/ALM, HP PPM, Opensource Application assessment, PostGres, cPanel, SQL, CA Clarity, TOAD for Oracle, IBM Jazz, IBM Urban I am sincere, Hardworking and quick learner. I believe in "count the efforts only when it add the value to your business". So, I expect the return only when its worth and add value to your business.
Groups: BigCommerce
Associated with: Soluscopic solutions - Mturk Team, Emerging Tech Skills Group
Quality Assurance,admin support,web research
India - Last active: 08/21/2014 - Tests: 4 - Portfolio: 2
Seeking challenging assignments to help small businesses and entrepreneur. I'm a goal oriented person and have an outstanding personality. And to be able to satisfy my clients and my employer at my best.Operations person with ability to understand needs and quality parameters and implement time bound solutions.
Manual & Automated Software Tester/ Data Entry
United States - Last active: 4 days ago - Tests: 3 - Portfolio: 3
I am a Software QA engineer with 10 years of experience. I am seeking opportunities to test applications from the ground up for you or your business. I am well versed in .. ✔ Testing Domains:- Travel and Hospitality, e-learning, Insurance, Retail, Manlog, CRM, Media etc ✔ Types of testing :- Smoke, Sanity, Black Box, Functional, Regression, System Integration, Build Verification Testing, Compatibility-Cross and Backward (OS/Browser), User Acceptance Testing, Database Testing, Mainframe testing etc ✔ QA methodology and processes:- CMMI, ISO, Agile Scrum best practices,waterfall model, V- model etc. ✔ QA Tasks:- Analyze, Review and Assess user requirements, Specifications and models for testability - Test Scenario, Test Case, Test Plan, Test Strategies, Test Traceability Matrix, Gap Analysis,Conduct quality assurance on product updates at planned intervals. Creating lessons learnt document on projects ending Risk Management, Mitigation and Contingency Planning, Help develop strategy for growth, including resource needs, automated testing etc. ✔ Bug Reporting tools:-Notepad, Wordpad, MS word, MS Excel, JIRA, Bugzilla, QC, Issue Tracker,Trello ✔ Test Case Management Tools:- Test Director, Quality Center, Rational Clearcase ✔ Test Automation Tools :- QTP, Selenium Webdriver, Silk Test, Rational Robot ✔ Version Control System :- Microsoft Visual SourceSafe, Perforce, MS Sharepoint ✔ Database:- SQL Server, MySQL, Sybase, DB2 Mainframe, Oracle ✔ Operating Systems to test:- Windows 2000/Xp/Vista/Win7, Mac, Linux ✔ Browsers to test:- Chrome, Firefox, IE, Safai ✔ Experience in proof-reading the content, checking links, spell check, checking layout on mobile/tablet/desktop, giving feedback etc ✔ Gadgets available for Testing :- iPod Touch, Anroid phone and Tablet
Experienced Consultant with Project and Product Management Experience
United States - Last active: 1 day ago - Tests: 1
I am new to Upwork, but I am an experienced management consultant and entrepreneur with a 10+ year record of meeting/exceeding objectives in multiple business environments within the federal government and private sector. On the consulting side, I leverage strong business acumen and subject matter expertise to help clients improve operational efficiency and outcomes through business transformation planning and implementation, increasing productivity by developing and leading high performance teams, optimizing business processes and workflows, and developing strategic relationships with client and consulting leadership. I've helped my clients move from vision and strategy to implementation and follow through. I am PMP and Six Sigma Green Belt certified. On the entrepreneurship side, I am the founder and product manager for a pre-launch startup, launching fall 2015. I've been a project manager, business analyst, systems analyst, program manager, product manager, quality assurance tester, financial analyst, marketing manager, swim coach, and board member. I'm looking to give back to the community and help others out as I've been helped out over the last 10 years or so.


text:
Can You Profit From Patriotic Portfolio Investing?
July 3 (Bloomberg) - Bloomberg's Julie Hyman examines returns of companies that do business solely in the United States compared to multi-national corporations. She speaks on "In The Loop."
Most Recent Videos
Does Apple TV Need a Revamp?
11:07 - Homebrew VC Partner Hunter Walk, Technalysis Founder Bob O'Donnell and IDC Chief Research Officer Crawford Del Prete discuss Apple to unveil a new TV box this fall and the future of Apple's streaming service. They speak with Bloomberg's Emily Chang on "Bloomberg West." (Source: Bloomberg)


text:
Marseilles, France
Marseilles, France News
Local news for Marseilles, France continually updated from thousands of sources on the web.
Where New York meets West Africa
Wednesday Jul 22 | Cornish Guardian | Comment?
Charles Aznavour says 'Affairs? I'd rather go to Ikea'
Friday Jul 17 | Daily Mail | Comment?
Rabies Postexposure Prophylaxis for Travelers Injured by Nonhuman...
Thursday Jul 16 | Centers for Disease Control and Preve... | Comment?
'Terrorist' attack on French military foiled: Minister
Wednesday Jul 15 | Channelnewsasia.com | Comment?
France blasts: Foul play suspected as 'electronic device' found at the scene
Wednesday Jul 15 | Russia Taday | Comment?
Iran Nuclear Agreement: Black Mark or Gold Star for Obama?
policy 454
Same Sex Marriage: It's Officially Legal
Legislation 858
The 29 Worst Celeb Wardrobe Malfunctions Of 2014
Criminal intent seen in petrochemical fire on French Bastille Day
Tuesday Jul 14 | AlertNet | Comment?
Criminal intent seen in French petrochemical fires - source
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Bravo! Residents are turning 100, serving our country and otherwise achieving great things
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Comment TL;DR (Score 1) 109 109
Because a bad update on the phone won't cause a high speed fiery wreck.
"Oh crap, my battery's exploded and my smartphone's caught fire!" *throws phone*
"I'm not afraid of dying, I just don't want to be there when it happens." -- Woody Allen


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So you went on a date last night. Should you text them today?
The NFL has officially hired its first female coach
Guess who's coming to The Voice?
Mmmmmonday: Try these amazing Asian-inspired dishes
Amp up your August with these sweet end-of-summer ensembles
ALERT: Forget everything you thought you knew about washing your hair
Pulled a muscle? Get some relief with these five fixes
Sneak a peek at our August/September issue starring Dove Cameron!
GL's Exclusive Look at Sunday's Best Friends Whenever
More Friends = More Fun
GL Tweets !
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26 Comments | Add Yours
by Pinkkatie1999 on 5/19/2012 12:32:14 PM
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by username0000 on 1/12/2012 8:19:34 PM
Hey Girlies! Love to write songs? Then join my club 'Sassy Songwriters'! It's a great club for songwriters to hang out and share their ideas! Also come to get advice, feedback on Ur songs, and just to have a good time with other songwriters! I would love to see U there!(:
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925 Merritt Blvd
Baltimore, MD 21222
Whether you're just packing up the groceries or helping a friend move to a new house with box after box of belongings, having a vehicle that can accommodate your packing needs is incredible advantageous. The subcompact 2016 Honda Fit hatchback is coming soon and will answer all your cargo needs while also offering a gorgeous style and true driving fun. Take a look below to see how the 2nd Row Magic Seat can either fold up or down to give you two different cargo space configurations depending on your needs. We think you're going to like it:
In our experiences at Norris Honda, we've learned there are two types of car owners. First, there are the neat freaks, the ones who keep their car looking, feeling, and even smelling the same way it did the day they drove it off our lot. Then, there are the polar opposites. Their backseats are covered in peanuts shells and there are french fries on the floor. But sometimes, that can't be helped, especially…
We're always looking for "more" out of life, and the good news is, you'll find that here at Norris Honda in Baltimore, MD. For the family on the go, the one that wants to feel close even when they're away, the new Honda Odyssey is pleased to meet you, and waiting within our new inventory. Check it out.
Named a Top Safety Pick by the Insurance Institute for Highway Safety, the Honda…
At Norris Honda, we know Beltway-area drivers are on-the-go people who want a vehicle as versatile and ready-to-perform as they are. That?s why we can't wait for the Spring 2015 debut of the all-new Honda HR-V, the brand's newest mini-crossover. The HR-V is set to debut as the most fuel-efficient conventionally powered vehicle in the midsize SUV class. The HR-V will be available in three trims, each of which are powered by a 1.8 liter gasoline engine capable of an EPA-estimated fuel rating of 32 MPG. This efficiency, combined with the super-versatile interior, is bound to…
For the first half of the year, the Honda Accord is once again America's most popular car, while the Honda CR-V is the best-selling SUV, a position the SUV has held for the past decade. The record sales numbers and other information were collected from new-vehicle retail registration data from IHS Automotive, a data publishing company. Honda predicts that, if sale trends continue, the company will repeat their 2013 full-year results as a top?
Need something new for 2014? Norris Honda in Baltimore MD has a suggestion for drivers in the greater Washington DC area that are in search of a new car. The model we?re talking about is the 2014 Honda Accord.
One of our favorite things about this model is that you can get it in different styles.
One of our most popular models at Norris Honda is the famous Honda Civic. If you live in the greater Baltimore, MD area we recommend stopping into our dealership at 925 Merritt Blvd Baltimore, MD 21222 for a test drive.
This stylish sedan comes in a variety of different gray shades, blue or beige. You can look over color choices in the showroom page of our site. There you can choose from a variety of?


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2004 Volkswagen Jetta in Casper, WY
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2004 Volkswagen Jetta GLS TDi Review
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"A good option for a socially conscious driver whose bank account is a little bloated."
My friend Amy recently lent me her 2004 biodiesel-powered Jetta for the afternoon. This was the first diesel vehicle I had ever driven, but I had an idea of what to expect—lots of low end torque, a narrow power band, and a loud rumbling engine. I was pleasantly surprised. Volkswagen has done a good job of tuning the engine to keep it more...
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Innovation in Ireland →
Founder, Young Inventors
Partner, Third Rock Ventures
Managing Partner at Pappas Ventures
Co-Founder, BuddyTV
CEO of Zero Locus
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Chairman, CEO, & Founder, Alexandria Real Estate Equities
September 30, 2015 ·
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The God of Small Things
By Arundhati Roy
(Random House Trade, Paperback, 9780812979657, 333pp.)
Publication Date: December 16, 2008
List Price: $16.00*
* Individual store prices may vary.
Shop Local
Enter your zip code below to find indies closest to you.
"Dazzling . . . as subtle as it is powerful."
–Michiko Kakutani, The New York Times
"[The God of Small Things] offers such magic, mystery, and sadness that, literally, this reader turned the last page and decided to reread it. Immediately. It's that hauntingly wonderful."
–USA Today
"The quality of Ms. Roy's narration is so extraordinary–at once so morally strenuous and so imaginatively supple–that the reader remains enthralled all the way through."
–The New York Times Book Review
"A novel of real ambition must invent its own language, and this one does."
–John Updike, The New Yorker
"Outstanding. A glowing first novel."
"Splendid and stunning."
–The Washington Post Book World


text:
Recent News
August 4, 2015
NAA Industry Insider: Vacancy Rates Hit 30-Year Low
July 31, 2015
Rental Vacancy Rate Hits 30-Year Low
July 21, 2015
NAA Named 2015 Azbee Award Finalist
There is no doubt the multifamily industry is in an upswing right now, evident with sharply increased new construction numbers and continued growth to average rents. So when Axiometrics vice president of research Jay Denton sat down with Gables Residential REIT Vice President Donna Summers to discuss the Top 10 Submarkets at the 2013 Apartment Revenue Management Conference, it was no surprise the impact that new construction, desirability and rent growth were having on markets and submarkets. What was surprising was the impact optimized pricing practices (or lack thereof) have had on markets across the country.
"Dallas, Atlanta and Houston boast 50 to 70 percent of assets using revenue management," said Denton. "When evaluating the performance comparison of markets and their submarkets, there is a significant correlation between revenue management adoption and the ability to push rents, maintain occupancy and minimize concessions, even in a downturn."
More specifically, when comparing revenue management to traditional pricing performance in the Atlanta/Fulton submarket, Denton found price optimization practices solidly in the lead. When looking at effective rents from January 2010 to July 2013, Axiometrics' data showed revenue managed pricing not only started out at a higher rate but also doubled traditional pricing increases and added an additional $300 more per month to effective rents. Furthermore, occupancy at traditionally priced communities saw significant fluctuations between 91 and 95 percent while revenue managed communities held steady at roughly 95 percent.
Denton also detailed how REITs are outperforming the nation on effective rent growth. "They are doing it right," said Denton. "They are operating in the right MSAs, in the right submarkets and using revenue management." On average, REITs are outperforming the nation and trending between 1-2% higher in effective rent growth.
Additional Axiometric findings included:
For your own closer look at the data, download the Top 10 Submarkets presentation.
This information was presented at the 2013 Apartment Revenue Management Conference.
Learn about the multifamily industry, why NAA is a leader and how We Lead the Way Home.


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List all words ending with balsamed
Only the word balsamed was found, nothing longer.
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text:
Str. Aroneanu nr. 8
View the venue listing
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Johnny D, Negru, Zotist, Funk-E, M.N.T.S.
Ara Events presents Underground Session 002 @ Sunrise Lounge Iasi
Str. Aroneanu nr. 8 (Ciric Complex) / Friday 11 March from 22:00
The spring is coming!
We are back as we promised! With the second party from the Underground Session series.
For this party that is much expected, by you and also by us, we have prepared for the ladies with snowdrops flowers, trinkets for everyone, new dance sneakers and a lot of good mood.
So for the first time in Moldova we have invited the german originally from Eritrea: Johnny D! Joining him will mix: Negru, Zotist, Funk-E and M.N.T.S. with an live act premiere!
Given the rapid rise in recent years the young artist Johnny D, both in terms of music production and DJing, has become one of the names that do not need no introduction. Releasing productions at labels like Oslo, Cecille, 8bit and Deep Vibes.
Like all the big names successfully managed to create their unique and unmistakable style, combining impulsive rhythms with elements of percussions and vocal samples.
Full Line-up:
.: JOHNNY D :. (Oslo Records, Livet, Frankfurt)
.: NEGRU :. (Cécille, Rekids, Soweso, Sunrise, Bucharest)
.: FUNK-E :. (Resident Zoo Project Ibiza, Bucharest)
.: ZOTIST :. (12HDM, Zebra Events, Sunrise, Bacau)
.: M.N.T.S. :. (Live Act, GreelPound, Bucharest)
Video teaser: http://www.youtube.com/watch?v=JgteEeJ4Gpw
After-Party starting from 08:00 AM, the location and the line-up will be announced soon.
Tickets: 20 Ron before 00:00 and 30 Ron after 00:00.
The Access will be open from 22.00.
Persons under 18 years old are not allowed!
You are not allowed to get out of the location until 01:00 if so another entry fee will be payed..
Go on http://www.araevents.ro and you can win invitations to this event.
The Guestlist is available from 22:00 till 00:00.
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Microsoft Type Cover Keyboard/Cover Case (Flip) for Tablet - Black
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Product Information for Lenovo ThinkPad T420 14" LED Core i5 2.50GHz 4GB DDR3 SDRAM 500GB HDD DVD-Writer 64-bit Windows 7 Professional Black Laptop
Highlights for Lenovo ThinkPad T420 14" LED Core i5 2.50GHz 4GB DDR3 SDRAM 500GB HDD DVD-Writer 64-bit Windows 7 Professional Black Laptop
- Screen Size:14"
- Processor Type:Core i5
- Standard Memory:4 GB
- Hard Drive Capacity:500 GB
Marketing Information
Rock-solid reliability. Blazing-fast performance. Clever manageability tools. We pack a lot of intelligent features into every ThinkPad laptop so you get more out. More productivity, more cost savings, more IT headache busting. That's why a ThinkPad investment isn't just smart. It's pure genius.
Battery Information
Built-in Devices
Display & Graphics
General Information
I/O Expansions
Input Devices
Package Contents
Security Features
Green ComplianceYes
Green Compliance Certificate/AuthorityEnergy Star
Network & Communication
Physical Characteristics
Power Description
Processor & Chipset