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This article summarizes perspectives on how reactive oxygen species (ROS) and redox signaling mechanisms participate in regulating vascular smooth muscle function that have resulted from our studies over the past 25 years in areas including oxygen sensing and the regulation of cGMP production by soluble guanylate cyclase (sGC) that were presented in the Robert M. Berne Distinguished Lectureship at the 2008 Experimental Biology Meeting. It considers mechanisms controlling the activity of sources of ROS including Nox oxidases and mitochondria by physiological stimuli, vascular diseases processes, and metabolic mechanisms linked to NAD(P)H redox and hypoxia. Metabolic interactions of individual ROS such as hydrogen peroxide with cellular peroxide metabolizing enzymes are viewed as some of the most sensitive ways of influencing cellular signaling systems. The control of cytosolic NADPH redox also seems to be a major contributor to bovine coronary arterial relaxation to hypoxia, where its oxidation functions to coordinate the lowering of intracellular calcium, whereas increased cytosolic NADPH generation in pulmonary arteries appears to maintain elevated Nox oxidase activity, and relaxation to hydrogen peroxide, which is attenuated by hypoxia. The sensitivity of sGC to nitric oxide seems to be regulated by thiol and heme redox systems controlled by cytosolic NADPH. Heme biosynthesis and metabolism are also important factors regulating the sGC system. The signaling pathways controlling oxidases and their colocalization with redox-regulated systems enables selective activation of numerous regulatory mechanisms influencing vascular function in physiological processes and the progression of aging-associated vascular diseases.
- guanylate cyclase
- Nox oxidases
- oxygen sensing
- redox signaling
reactive oxygen species (ROS) are now known to have many important roles in the control of vascular function. If we look back to the field that existed before realizing contributions of ROS to vascular regulation, the work of two individuals stands out as having a tremendous impact on our own work and the field as we know it today. Early studies by Fridovich (24, 25) on agents that altered an oxygen-dependent reduction of cytochrome c by xanthine oxidase evolved into the discovery of the enzyme superoxide dismutase (SOD) that metabolizes superoxide generated by this enzyme (43) and a modeling of the biological properties of superoxide biosynthesis and metabolism. The initial interests of Chance in detecting how enzymes such as catalase metabolize peroxide (14) evolved into developing an integrated understanding of many key aspects of cellular peroxide metabolism that included areas such as how the redox status of components of the mitochondrial electron transport chain influence ROS generation (15). While the existence and importance of NAD(P)H oxidases or Nox oxidases in vascular regulation is a relatively new area of investigation, early studies recognized the major importance of microsomal NAD(P)H oxidase activities as cellular sources of peroxide in tissues such as the liver (9, 27). Currently, there is substantial evidence that Nox oxidases and mitochondria are significant sources of ROS generation in vascular smooth muscle (3, 35, 41, 70, 74). In addition, the endothelium can be a source of these and additional enzymes such as nitric oxide synthase, xanthine oxidase, cyclooxygenase, and cytochrome P-450, which can potentially generate and/or release ROS in amounts that have a major influence on the control of vascular function (39, 55). Early studies by groups lead by Kontos (38) and others showing how endogenously produced ROS can regulate microvascular contractile function contributed to developing the evolving field of how these systems regulate blood flow in a diversity of physiological and pathophysiological processes (40, 55). A major source of the variability in vascular regulation seen in arteries and veins, and the microcirculation of different organ systems during the progression of aging and disease processes, originates from changes in ROS and their interactions with systems controlling endothelial mediator release and vascular function. An early hypothesis for the mechanism of pulmonary hypoxic vasoconstriction by Archer and Weir (6) highlights initial thoughts on ways the modulation of ROS by changes in oxygen tension could influence cytosolic NAD(P)H redox in a manner that regulates thiol redox-controlled systems such as potassium channels. Our current understanding of how redox-regulated systems are organized to control signaling remains rather incomplete, and it is an evolving field of science. This article provides a concise overview of some of the known ways the metabolism of ROS and function of key cellular redox control mechanisms potentially result in interactions with signaling systems that control vascular function. Perspectives on ROS-redox signaling gained from our work in areas including oxygen sensing and the regulation of cGMP production by soluble guanylate cyclase (sGC) in vascular smooth muscle are emphasized in the context of where they are potentially contributing factors to physiological regulation and the progression of aging-associated vascular disease.
Cellular Generation and Metabolism of ROS
There appears to be a basal rate of production of ROS in essentially all cells from oxidases such as Nox oxidases and components of the mitochondrial electron transport chain, and many types of physiological and pathophysiological stimuli can cause acute increases in the rates of ROS production by influencing the activities of the oxidases that are expressed. Most oxidases begin the production of ROS by donating an electron to oxygen to generate superoxide anion (O2•−), and this electron often originates from cellular systems utilizing reduced pyridine nucleotides such as NADPH and/or NADH as the electron donors. In the absence of superoxide metabolizing systems, the rates of superoxide production by oxidases in cells will probably generate concentrations of superoxide in the nanomolar range based on the known levels of oxidase activities that are present in biological systems and the spontaneous rate of reaction of superoxide with itself, which generates hydrogen peroxide (H2O2) and oxygen. The amounts of different forms of SOD thought to be present in intracellular regions should lower the levels of superoxide into the picomolar concentration range (25). Based on the apparent rates of generation of peroxide and its metabolism by key scavenging systems, including glutathione peroxidase and catalase, peroxide levels in the cytosolic region of cells are thought to be in the low nanomolar concentration range (15). While superoxide reacts with nitric oxide (NO) three to four times faster than it reacts with SOD, this reaction only becomes a significant biological regulatory factor when superoxide levels rise or when NO levels are very high and approach the concentrations of SOD that are present. This reaction of NO with superoxide generates peroxynitrite (ONOO−), a reactive molecule that causes the modification of multiple other biological molecules and key sites on proteins potentially involved in their regulation. Initially, hydroxyl radical was thought to be a key regulatory species generated from reactions of peroxide with ferrous iron (Fe2+) and from the decomposition of peroxynitrite (61). However, because of the extreme chemical reactivity of hydroxyl radical, its importance in biological regulation seems to have been questioned, and evidence for alternative reactions of peroxide and peroxynitrite has evolved. For example, the reaction of peroxide with metal sites on proteins such as heme or bound iron is more likely to be involved in biological regulation. In addition, reactions associated with nitric oxide oxidation generating other reactive radicals such as nitrogen dioxide (·NO2) and carbonate radical are potential contributing factors in responses initially thought to result from peroxynitrite formation.
Mechanisms for Interactions of ROS with Cellular Signaling Systems
The relatively low intracellular concentrations of superoxide because of the presence of SOD may limit its direct interactions with signaling systems. However, regulation resulting from superoxide generation may originate from either the efficient formation of peroxide by SOD or as a result of its interaction with NO (see Fig. 1), and perhaps other targets that superoxide readily reacts with. Some of the most efficient ways peroxide can interact with signaling systems appear to result from the consequences of its enzymatic metabolism by proteins including catalase, glutathione peroxidase, and peroxiredoxins. Early observations documented that exposure of microvascular preparations to peroxide elicited responses that were often dominated by prostaglandin (PG)-mediated mechanisms (64, 75). These observations and studies on cyclooxygenase evolved into recognizing the important role of peroxide metabolism by the heme peroxidase reaction of this enzyme in the physiological stimulation of prostaglandin generation (42). Variation in activities of PGH2-metabolizing enzymes that are present in different segments of the circulation in normal and pathophysiological states seems to be a major contributor to the expression of both prostaglandin-mediated contractile and relaxing responses to conditions that expose vascular tissue to peroxide. We observed that, although catalase was metabolizing peroxide, it was able to stimulate sGC either with purified enzymes or under conditions present in pulmonary arteries that were associated with relaxation to peroxide (11, 12, 18). It is well established that the glutathione peroxidase reaction generates oxidized glutathione (GSSG) while it metabolizes peroxide and that GSSG is a substrate for enzymes that appear to regulate the redox status of thiols on proteins in ways that have potential regulatory roles (23, 72). The metabolism of peroxide by peroxiredoxins is usually linked to the generation of oxidized thioredoxin thiols, and thioredoxin reductase/thioredoxin systems are well established as regulators of protein thiol redox sites that often have important regulatory roles. For example, the status of these cellular thiol redox systems in subcellular regions potentially influences signaling systems through enzymatic reactions such as glutaredoxin and protein disulfide isomerases, which reversibly modify the redox of protein thiol groups in a manner dependent on the localized ratio of cofactors such as reduced glutathione (GSH) to GSSG. Although there are many hypotheses assuming peroxides interact with signaling systems by directly reacting with thiol groups presumably in their more reactive anionic form, the slow rates that have been reported for these reactions suggest alternative processes may be involved. One possibility is that protein-binding interactions might put the catalytic site of oxidases together with thiols in a manner that exposes them to the high concentrations of peroxide needed to drive direct reactions of peroxide with thiols. Alternatively, it could be hypothesized that catalysts such as transition metals might promote peroxide reactions with reactive protein thiol groups. Oxidized forms of NO, including peroxynitrite and nitrogen dioxide, have chemical properties that are potentially involved in regulation through their reactions with protein sites such as thiols and tyrosine, unsaturated fatty acids, and other molecules (GSH, tetrahydrobiopterin, etc.) that these species readily react with (60). Most of the other known direct chemical reactions of superoxide, peroxide, and other ROS with targets linked to signaling systems have rates suggesting they would not be very significant or selective at the concentrations of these species potentially present in cells under biological conditions. However, there is evidence for distinct subcellular localizations for oxidases that may enable signaling systems colocalized with the oxidases to be exposed to very high concentrations of ROS (16, 35).
An extremely important, but rather poorly understood, aspect of signaling by ROS is that there are specific signaling mechanisms regulating the activities of the different oxidases in cells, and there is likely to be selective activation of redox-regulated signaling systems that are localized to the subcellular regions of the oxidases being regulated. For example, Griendling and colleagues (35) initially documented that Nox1 and Nox4 had specific subcellular localizations in vascular smooth muscle cells and suggested this was an important factor in determining the signaling processes that these ROS-generating systems were involved in. An endoplasmic reticulum localization of Nox4 in endothelium has recently been shown by the Keaney group (16) to be essential for observing its ability to inhibit protein tyrosine phosphatase 1B in epidermal growth factor receptor (EGFR) signaling. Thus, while a molecule such as hydrogen peroxide could influence the function of many different signaling systems, there will be selective regulation of specific cellular functions as a result of the unique ways each oxidase-generating peroxide is controlled by biological processes and colocalized with redox-regulated signaling systems.
Cytosolic NAD(P)H Redox Metabolic Control Mechanisms
Pathways of glucose metabolism and aspects of mitochondrial function are potentially major regulators of cellular redox control through their influence on the redox status of NADPH and NADH [or ratios of reduced NAD(P)H to oxidized NAD(P)+] in subcellular regions (see Fig. 2). The major source of NADH generation in the cytosolic region appears to be glyceraldehyde 3-phosphate dehydrogenase in glycolysis. However, the efficiency of mitochondrial shuttles and the equilibrium-like behavior of the lactate dehydrogenase reaction generally function in the direction of removing cytosolic NADH and keeping the cytosolic NAD(H) system primarily in its oxidized NAD+ form. In contrast, most studies suggest cells maintain greater levels of NADPH than NADP+ in subcellular regions such as cytosol and mitochondria. It is generally thought that glucose-6-phosphate dehydrogenase (G6PD) and phosphogluconate dehydrogenase, the subsequent enzyme in the pentose phosphate pathway (PPP) of glucose metabolism, are the primary sites generating NADPH in the cytosolic region of vascular tissue. An observation consistent with this interpretation is evidence that inhibitors of G6PD promote the oxidation of NADPH in vascular smooth muscle (28). Whereas the control of cytosolic NADPH by a variety of biosynthetic enzymes, oxidases, and enzymes maintaining thiol redox which consume NADPH is not well understood, it is likely that the activities of these enzymes determine their influence on NADPH redox in subcellular regions.
Interactions of Cytosolic NAD(P)H Redox with Vascular Signaling Systems
A variety of regulatory systems are influenced by NAD(P)H redox in a manner that could potentially be important in the control of vascular function. The key roles of NADPH as both a source of vascular ROS generation and as a controller of the redox status of thiol redox systems involved in peroxide metabolism and oxidant-associated signaling suggest that the control of NADPH redox in cytosolic-linked cellular regions will be a major factor in the expression of signaling and responses that are observed. Because both NADH and NADPH appear to be substrates for Nox oxidases, the availability of these electron donors for superoxide generation can influence ROS-regulated signaling. We first recognized the potential importance of cytosolic NADH as a substrate for vascular Nox oxidases as a result of discovering that lactate increased superoxide and caused a peroxide-mediated relaxation in endothelium-removed bovine arteries (53, 59). Our emphasis in studying the role of substrates for Nox oxidases may have initially been biased toward focusing on NADH because measurements of superoxide generation using high concentrations of lucigenin could have contained a redox cycling artifact enhancing NADH-derived superoxide production compared with NADPH. However, our subsequent studies in coronary arteries developed by Gupte et al. (28) with inhibition of NADPH generation by G6PD detected a decrease in superoxide and peroxide release from bovine coronary arteries, suggesting that NADPH was normally the primary substrate supporting Nox oxidase activity.
Studies on the mechanism of a ROS-independent relaxation that resulted from inhibition of G6PD evolved into the realization that cytosolic NADPH oxidation appears to function as a coordinator of multiple mechanisms that lower intracellular calcium (28, 32). Some of the systems that seem to have roles in the relaxation of bovine coronary arteries when cytosolic NADPH oxidizes include stimulation of calcium uptake by the sarco(endo)plasmic reticulum calcium ATPase pump and the opening of voltage- and calcium-regulated potassium channels. Inhibition of G6PD also promotes oxidation of glutathione and has actions similar to the thiol oxidant diamide in promoting relaxation through what appears to be a thiol redox-regulated mechanism of controlling calcium influx through both voltage-regulated calcium channels and other receptor-regulated calcium channels (28, 36). Figure 3 shows some of the ways cytosolic NADPH oxidation potentially coordinates the lowering of intracellular calcium. However, the poorly understood interactive nature of systems regulating calcium around the sarcoplasmic reticulum and evidence for potential redox regulation of most calcium and potassium channels makes it difficult to sort out which redox-regulated sites are most important. Oxidation of cytosolic NADPH also appears to inhibit nitric oxide-elicited stimulation of sGC and vascular relaxation through thiol and heme redox-associated mechanisms that are discussed below. Thus, as nitric oxide-elicited relaxation becomes impaired, cytosolic NADPH oxidation appears have an important role in additional processes promoting vasodilation through coordinating multiple mechanisms of lowering intracellular calcium.
The control of thiol redox on proteins is thought to be an important component of the redox regulation of multiple signaling systems. Thiol redox changes involve processes such as the formation of sulfenic acids, S-nitrosated thiols, S-nitrated thiols, disulfide formation between protein cysteine thiols or with glutathione to form S-thiolated or S-gluthionated adducts with protein cysteines, and the disruption of iron-sulfur or zinc sulfur centers (23, 60, 61, 72). NAD(P)H and thiol redox potentially influence key sites regulating calcium reuptake and release from the sarcoplasmic reticulum, channels involved in capacitive- and voltage-regulated calcium influx across the plasma membrane, ion channels controlling membrane potential, and contractile-enhancing systems that participate in controlling vascular smooth muscle force generation. The role of NADPH in influencing redox effects of peroxide metabolism by glutathione peroxidase and peroxiredoxins is potentially a major route for ROS to interact with thiol redox-associated signaling. NADPH is used by glutathione reductase and thioredoxin reductase reactions to metabolize peroxide through its role in maintaining glutathione and thioredoxin in their reduced forms. Oxidation of the glutathione and thioredoxin systems is thought to be a key cofactors in controlling the status of thiol sites on proteins that are involved in redox regulation of their function through their actions in controlling sites undergoing thiol oxidation or S-thiolation. The reversible or chemical equilibrium-like behavior of NADPH-dependent enzymes, including glutathione and thioredoxin reductases controlling the thiol redox status of the glutathione and thioredoxin systems, is likely to be an important contributing factor in the localized redox control of proteins involved in cellular signaling. Although the balance in subcellular regions between metabolic production of NADPH and its consumption by oxidase, peroxidase, thiol-reducing, and other metabolic systems could be hypothesized to be a major factor in determining which signaling processes are regulated, minimal consideration has been given to the interactive properties of these redox systems. Thus the influence of vasoactive stimuli on the interactive balance between peroxide metabolism and thiol redox control systems linked to NADPH redox in subcellular regions should be considered for its potential role as a key factor in determining how specific signaling systems are regulating vascular function.
Influence of Hypoxia on Cytosolic NADPH Redox and Basal Levels of ROS are Potentially Major Factors in Vascular Oxygen-Sensing Mechanisms
Mechanisms involving changes in ROS and redox have been key components of most current hypotheses for linking the sensing of changes in oxygen tension to the regulation of vascular tissue (54, 69, 74). However, substantial controversy currently exists regarding the role of ROS and redox changes in modulating contractile function elicited by exposing the vascular smooth muscle of pulmonary and systemic arteries to hypoxia. For example, in pulmonary arteries, there is evidence for hypoxia promoting vasoconstriction through either decreasing or increasing vasoactive ROS derived from mitochondrial and/or Nox oxidase sources. In systemic arteries, hypoxia has been reported to increase mitochondrial ROS, and to elicit relaxation through oxidative redox changes in systems such as cytosolic NADPH and/or thiol redox regulation of potassium channels that are either ROS-dependent (44) or ROS-independent (32, 49, 52).
Our recent studies in bovine calf coronary and pulmonary arteries have provided evidence supporting potential explanations for the origins of some key controversies in this field. Initially, the studies of Mohazzab-H et al. (52) found that hypoxia seemed to lower superoxide detected by lucigenin chemiluminescence and peroxide based on its ability to convert methanol to formaldehyde by endogenous catalase in precontracted endothelium-denuded coronary arteries, and Nox-type oxidases dependent on NAD(P)H appeared to be the major source of basal superoxide in this vascular segment. However, the relaxation of these arteries to hypoxia did not appear to involve superoxide-derived ROS such as hydrogen peroxide (49, 52). Recent work by Gao and Wolin (26) has provided evidence that we can detect hypoxia-eliciting increases in mitochondrial superoxide detected by mitosox in coronary arteries. Surprisingly, when the arteries are contracted with 30 mM KCl, they show decreases in mitochondrial superoxide. In addition, inhibition of mitochondrial electron transport in bovine coronary arteries under normoxic conditions with probes such as rotenone and antimycin increases mitochondrial superoxide, but these treatments do not decrease force generation or mimic the effects of hypoxia (26, 28). Superoxide and/or hydrogen peroxide from extramitochondrial sources that appear to be Nox oxidases also seem to be decreased by hypoxia in the absence or presence of contraction (26, 52). Our studies suggest that increases in superoxide detected by mitosox are observed when hypoxia or mitochondrial electron transport inhibitors raise mitochondrial NAD(P)H redox above the basal level, and this was observed to be associated with mitochondrial membrane hyperpolarization (26). However, when the arteries are exposed to 30 mM KCl, the increased intracellular calcium release and/or metabolic stress associated with contraction alters the balance of processes controlling mitochondrial NAD(P)H redox in a manner that prevents the increase caused by hypoxia, and these conditions are associated with a decrease in superoxide (26). Thus differences in experimental conditions such as the absence or presence of force generation could be factors in influencing if mitochondria in vascular smooth muscle show increases or decreases in superoxide or ROS generation under hypoxic conditions.
Studies by Gupte and Wolin (32) have provided evidence for a key role of hypoxia in promoting relaxation of bovine coronary arteries through a metabolic stress (see Fig. 3) that decreases the activity of the G6PD reaction of the PPP, and this seems to promote the oxidation of cytosolic NADPH and relaxation through the coordination of calcium-lowering processes regulated by this system. Because ATP levels are maintained under hypoxia, the metabolic stress does not seem to be related to a deficiency in energy metabolism. Pulmonary arteries maintain higher levels of NADPH and G6PD [but not glucose-6-phosphate (G-6-P)], and this seems to prevent hypoxia from causing cytosolic NADPH oxidation and relaxation (30, 31). Interestingly, pyruvate inhibits relaxation and changes such a lowering of G-6-P and NADPH elicited by hypoxia, suggesting that a metabolic stress on glycolysis or process promoting NADPH oxidation could be a key factor (32). Because hypoxia lowers endogenous pyruvate, a mitochondrial-dependent metabolic pathway of pyruvate linked to maintaining cytosolic NADPH redox could be a fundamental process in the mechanism of sensing hypoxia by coronary arteries (26). Thus a metabolic impairment of the ability of mitochondrial-associated pathways of pyruvate metabolism to maintain cytosolic NADPH by the G6PD reaction of the PPP appears to be an oxygen-sensing mechanism that regulates the relaxation of coronary arteries by hypoxia.
Early studies by Burke and Wolin (11–13) developed evidence for a hypothesis that hypoxia promoted vasoconstriction of bovine calf pulmonary arteries through removing a peroxide-dependent relaxing mechanism, where a suppression of cGMP signaling seemed to be a contributing factor to the response that was observed. Although this seemed to be an alternative to the initial redox hypothesis for hypoxic pulmonary vasoconstriction of Archer et al. (4, 6) linking hypoxia to removing a ROS-dependent hyperpolarization depressing force through a loss of ROS-mediated oxidation of cytosolic NAD(P)H and thiol redox systems maintaining the opening of potassium channels, subsequent work is providing evidence that components of both hypotheses may be important contributing factors. The detection of NAD(P)H oxidases as major sources of superoxide-derived peroxide in bovine pulmonary arteries led us to consider the oxygen dependence of Nox oxidases as the oxygen sensor for hypoxia (50, 53). In contrast, the influence of mitochondrial inhibitors on responses of rat pulmonary arterial smooth muscle to hypoxia promoted consideration of mitochondrial sources of ROS as key contributors to the redox hypothesis (4, 44). Although it is possible that either source of ROS generation could be important, our studies in bovine pulmonary arteries have led us in the direction of considering Nox4 as the dominant oxygen-regulated source of ROS linked to force regulation by hypoxia. Studies of Gupte et al. (30) have provided evidence that Nox2 and Nox4 are the major forms of this oxidase present in the smooth muscle of bovine pulmonary arteries. Our group and Archer and Weir have evidence from studies using pharmacological probes (1) and knockout mice (5) suggesting that, while Nox2 may be an important source of ROS in the pulmonary vasculature, the oxidants generated by this oxidase system do not seem to be a significant contributing factor to vasoconstriction elicited by hypoxia. We hypothesize that Nox4 is the important source of peroxide influencing hypoxic vasoconstriction in bovine pulmonary arteries based on recent work developed by Ahmad et al. (1, 2) suggesting that pharmacological or small-interfering RNA inhibition of Nox4 activity and increasing Nox4 expression by organ culture with transforming growth factor-β influences the magnitude of contractions to hypoxia in a manner consistent with a role for changes in ROS generation by this oxidase (Ahmad M and Wolin MS, unpublished observations). In contrast, while mitochondrial inhibitors including rotenone and antimycin decrease superoxide in bovine arteries (1) in a manner similar to changes seen in the rat pulmonary vasculature (4, 44), we find that these inhibitors do not alter the magnitude of contraction to hypoxia in the bovine pulmonary arteries. Gupte and colleagues (31) have observed that hypoxia increases NADPH in rat pulmonary arteries under conditions where contraction is observed, suggesting that a contributing factor could also be removal of relaxing mechanisms controlled by cytosolic NADP/NADPH redox. For example, increasing cytosolic NADPH redox could result in the closing of potassium channels and/or lowering intracellular calcium. Because decreased NADPH consumption by Nox oxidases and the metabolism of peroxide are components of the hypotheses for hypoxic pulmonary vasoconstriction being discussed, much of the evidence on the response of pulmonary arterial smooth muscle to hypoxia being considered here seems to be converging on what appears to be a signaling mechanism involving hypoxia decreasing a peroxide-controlled NADPH redox-regulated relaxing mechanism.
sGC and cGMP Signaling are Major Targets of Regulation by ROS and Cytosolic NADPH Redox
Many redox systems seem to regulate sGC- and/or cGMP-associated signaling systems designed to coordinate processes involved in vascular smooth muscle relaxation. As discussed previously, it is well established that superoxide anion attenuates sGC stimulation by NO as a result the efficiency of the diffusion-controlled reaction between these two free radical species. Our studies by Cherry et al. (17) and Omar et al. (58) developed evidence for the important role of Cu,Zn-SOD activity in protecting the stimulation of sGC by NO from being impaired by the basal levels of superoxide generated in pulmonary and coronary arteries, respectively. Peroxide generated from the scavenging of superoxide by Cu,Zn-SOD derived from sources including Nox oxidases (11–13, 49, 52, 53) seems to be able to stimulate sGC activity when it is metabolized by catalase. However, several factors can make it difficult to observe relaxation responses through this mechanism. Relaxation to peroxide is readily inhibited by both superoxide and NO through their ability to inhibit catalase (11, 18, 51). It addition, peroxide can also simultaneously stimulate contractile-enhancing mechanisms such as those activated by stimulation of extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase, which seems to promote a functional antagonism of relaxation (56, 57). Peroxynitrite and nitrogen dioxide can interact with thiols in a manner that generates donors of NO, and the release of NO over time can promote a prolongation of relaxation (22). In addition, peroxynitrite appears to be able to oxidize the heme of sGC from its ferrous (Fe2+) NO-binding form to its ferric (Fe3+) form, which seems to be resistant to participating in stimulating sGC activity, and potentially associated with a loss of heme and the degradation of sGC (63). Thus the levels of NO and individual ROS and NO-derived species in the proximity of sGC are likely to determine how the production of cGMP by this enzyme is regulated.
Our more recent studies by Gupte and Mingone have provided evidence that cytosolic NADPH redox also has an important role in controlled thiol and heme redox systems, which have a major influence on the ability of NO to stimulate sGC through mechanisms that are shown in Fig. 4. It is well established that NO stimulates cGMP production by binding the ferrous (Fe2+) heme of sGC (19, 71, 76). Recent studies suggest that the heme of sGC is readily oxidized to its ferric (Fe3+) form under vascular pathophysiological conditions associated with impaired NO stimulation of sGC (63). Our studies have detected a cytosolic NADPH redox-controlled methemoprotein reductase activity that appears to have an important role in maintaining the heme of sGC in its ferrous oxidation state (33). When inhibitors of G6PD cause oxidation of cytosolic NADPH associated with increased GSSG, it appears that an enzymatic reaction utilizes GSSG to promote what appears to be a thiol redox-mediated inhibition of sGC activation by NO in a manner that does not appear to inhibit the basal sGC (46). Interestingly, peroxide has been shown to cause a thiol oxidation-mediated dimerization of cGMP-dependent protein kinase (PKG) associated with its activation and relaxation of coronary arteries (10), and recently reproduced these observations in the bovine pulmonary arteries studied in our laboratory (Neo BH and Wolin MS, unpublished observations). Thus cytosolic NADPH redox also appears to have important roles in regulating the vascular function through altering the sensitivity of sGC to NO through its influence on thiol and heme groups of sGC. In addition, redox regulation of PKG could be a contributing factor or alternative mechanism for oxidant-elicited vascular relaxation.
Pathways controlling the biosynthesis of heme and its metabolism by heme oxygenase (HO) also have a major influence on the generation of cGMP by sGC. Heme biosynthesis is obviously needed to maintain the availability of heme for its role in enabling NO to bind and stimulate sGC. The biosynthetic precursor to heme, protoporphyrin IX, is an activator of sGC that is thought to function through replacing the heme on sGC in a manner that reproduces interactions elicited by NO (76), such as the loss of a heme iron-histidine coordination associated with stimulation of cGMP production (71). Recently developed drugs designed to stimulate sGC through the protoporphyrin IX binding appear to be resistant to some of the oxidant processes that impair sGC regulation in disease models that impair NO-mediated vascular relaxation through this system (63). Although exposure of vascular tissue to δ-aminolevulinic acid can cause the accumulation of protoporphyrin IX in amounts that stimulate sGC and promote relaxation (47), there is an absence of evidence that this activator of sGC accumulates under physiological conditions in amounts that regulate vascular function. The HO reaction also seems to regulate sGC through several potential mechanisms. There is evidence that its product carbon monoxide is a stimulator of sGC at micromolar concentrations and an inhibitor of NO stimulation of sGC; however, we have not been successful in finding evidence for these effects in our studies on bovine arteries (45). Generation of biliverdin and bilirubin by the HO reaction seems to have antioxidant-like actions that could have effects on systems regulating sGC (73). In addition, our recent studies suggest that the induction of heme oxygenase-1 (HO-1) can impair sGC regulation by NO under conditions where it depletes heme in vascular smooth muscle. The induction of HO-1 also seems to lower superoxide through increasing the expression of the extracellular form of SOD, and this may have an important beneficial role in restoring NO-mediated responses in diseases such as diabetes (65). Thus heme metabolism has multiple interactions with redox processes that regulate the activity of sGC.
Stimuli of Vasoconstriction Can Function Through Promoting Oxidant Signaling
There is some evidence that many agents or stimuli associated with promoting vasoconstriction also cause the generation of ROS. The generation of ROS as a result of ANG II (AT) stimulating the AT1 receptor on vascular smooth muscle is one of the most-studied systems. Griendling and colleagues (62) have documented that stimulation of the AT1 receptor initially promotes a p47phox stimulation of Nox oxidase activity in rat aortic smooth muscle cells. The peroxide generated by this pathway appears to further stimulate Nox oxidase activity by activating Src kinase, which promotes a EGFR transactivation of phosphatidylinositol-3-kinase, which is linked to rac binding to Nox oxidase. Our studies by Richard Oeckler on a stretch-induced enhancement of force generation in bovine coronary arteries associated with a p47phox-mediated activation of superoxide generation by Nox oxidase resulted in evidence for a peroxide-mediated Src kinase-EGFR transactivation of ERK MAP kinase in the response observed (57). This mechanism was also observed in bovine pulmonary arteries, and it could be activated by increased lactate, which was presumably functioning through increasing the availability of cytosolic NADH for utilization as a substrate for Nox oxidase (56). We have observed in collaborative work by Ungvari et al. (66) that acute increases in luminal pressure are also a direct stimulus for increasing superoxide in both endothelium and vascular smooth muscle of rat femoral arteries. Studies by Gupte et al. (29) on a contraction of bovine coronary arteries elicited by the phorbol 12,13-dibutyrate activator of protein kinase C has resulted in the detection of a p47phox kinase activation of Nox2, suggesting that the activation of this system could be an important factor in the action of contractile agents that function through stimulating protein kinase C. Webb and colleagues (37) have provided evidence that Rho kinase may also be an important factor in regulating the mechanisms of contraction elicited by ROS. We suspect that the subcellular colocalization of signaling and spilling over of oxidant stress into other subcellular regions will be major factors in determining the regulation of signaling systems in responses that are observed. It is likely that differences in expression of components regulating oxidases and the actions of ROS on signaling systems influencing endothelial mediator release and vascular force are major contributors to regional differences in vascular regulation, and changes associated with vascular disease processes.
ROS and Redox Controlled Signaling Mechanisms are Potentially Major Factors in Aging-Associated Vascular Diseases
Studies published in the literature provide an extensive documentation of roles for changes in ROS and the function of redox-regulated systems in cardiovascular diseases associated with aging. Our laboratory has gained much insight into how ROS and redox controlled signaling mechanisms are potentially involved in aging and aging-associated cardiovascular diseases (e.g., hypertension, heart failure, diabetes) as a result of collaborations with colleagues at our institution, including Gabor Kaley, Thomas Hintze, Akos Koller, Zoltan Ungvari, Alberto Nasjletti, and others we have published with. Although the scientific literature has provided extensive documentation for increased superoxide generation functioning to attenuate endothelial regulation of vascular smooth muscle relaxation by nitric oxide in aging-associated vascular diseases and the ability of the endothelium to generate vasoactive levels of hydrogen peroxide, there appear to be many additional aspects of ROS and redox regulation in these diseases that remain to be defined. Models for each disease have provided evidence for different aspects of processes increasing oxidant production in the endothelium and vascular smooth muscle. In addition, the Harrison group (55) has highlighted the potential importance of a feedforward mechanism where the initial activation of Nox oxidases by pathophysiological mediators such as ANG II promotes the activation of other oxidases. Each major ROS-generating system shown in the endothelium of the model in Fig. 5 has ways of being activated by oxidants derived from superoxide and NO to produce further increases in ROS. For example, peroxynitrite oxidizes tetrahydrobiopterin and uncouples NO synthase (55); xanthine oxidase activity is increased by multiple oxidant-linked processes, including p38 MAP kinase activation, thiol oxidation, and oxidant-stimulated proteolysis (8); oxidants activate ROS production by cyclooxygenase (COX) by a combination of promoting release of its substrate arachidonic acid and by oxidizing the heme of COX to a form that promotes prostaglandin biosynthesis and oxidant generation by its peroxidase reaction (38, 42), and oxidant conditions are also known to promote mitochondrial superoxide generation (34). In addition, Nox oxidases have previously discussed roles for oxidants in their activation of superoxide production. Because PGI2 synthase is readily inactivated by peroxynitrite through a tyrosine nitration reaction, oxidant stress of vascular disease processes is often associated with a shift from PG-mediated relaxation responses by PGI2 to constrictor responses elicited by the accumulation of PGH2 (77). Increases in hormones such as ANG II, cytokines, pressure in the vasculature, turbulence of blood flow (shear), and metabolic stresses such as elevated glucose and low-density lipoprotein all have the ability to increase ROS in the vessel wall in a manner that is generally associated with alterations in endothelial regulation of vascular function.
Although some aspects of the effects of increased oxidant production in vascular smooth muscle have been studied, we believe that many aspects of the regulation that exists remains to be defined. Aging itself and models of hypertension, diabetes, and elevated angiotensin appear to increase Nox oxidase activity in vascular smooth muscle (7, 20, 21, 62, 66–68). In addition, some of these disease models also seem to be associated with increased mitochondrial oxidant production. While some disease models show a superoxide-mediated impairment of NO-mediated vascular smooth muscle relaxation, there are additional systems regulating vascular function that are likely to be influenced by the observed increases in oxidants. Systems such as NAD(P)H redox and ROS-linked signaling mechanisms associated with oxygen sensing, regulating sGC/PKG, and other relaxant and contractile mechanisms, are also likely to be contributing factors to changes in vascular regulation related to aging. For example, Gutterman and colleagues (48) have shown that diabetes impairs the relaxation of human coronary arterioles to hypoxia. However, the processes responsible for this change remain to be defined. Because evidence is emerging for subcellular colocalization of specific pathways of oxidase activation and redox-controlled signaling mechanisms regulated by oxidase activation, it is likely that each metabolic stress or pathophysiological condition has unique ways of influencing adaptive regulation through the diversity of oxidant-signaling mechanisms discussed in this article. While we have emphasized acute responses influencing the control of vascular force, it is important to emphasize that many processes, including inflammatory responses and remodeling of the vessel wall, are also regulated by the time-dependent function of many of the ROS redox-signaling mechanisms we have considered. Thus factors regulating redox and oxidant signaling are likely to be major determining aspects in the progression of vascular adaptation and pathophysiology seen in aging and vascular disease processes.
Recent studies from the author's laboratory have been funded by National Institutes of Health Grants HL-31069, HL-43023, and HL-66331.
- Copyright © 2009 the American Physiological Society


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Rumor: 12.9-inch "iPad Pro" to incorporate Force Touch, USB-C connector, other changes
Date: Monday, May 4th, 2015, 08:41
Category: Hardware, iPad, iPhone, Rumor
A source close to the story has stated that Apple is indeed working on a larger 12.9-inch iPad. The upcoming iPad, commonly referred to as the "iPad Pro", is rumored to incorporate a number of changes including a Bluetooth stylus accessory with pressure sensitivity, support for Force Touch input, and a USB-C connector.
Its expected arrival date is currently unknown.
The source stated that Apple is expected to include an NFC radio within the new 12.9-inch iPad. While tap-to-pay functionality in an iPad is unlikely, the inclusion of NFC could allow for an "iPad Pro" to serve as a payment receiving terminal for Apple Pay.
The inclusion of NFC could also allow for simplified pairing with accessories, such as the new stylus said to be in the works.
The source also indicated that the jumbo-sized iPad will sport a new touchscreen with improved touch latency. It was said that this will improve the experience when used with a new Apple-built Bluetooth stylus.
The screen itself will also reportedly sense pressure from fingertips, as Apple is said to be planning to bring its Force Touch input to the 12.9-inch iPad. AppleInsider was first to report in February that Apple's next-generation iPhone, referred to colloquially as the "iPhone 6s," will also feature the Force Touch input that is currently available on the Apple Watch and latest MacBooks.
It's currently unknown as to whether the rumored iPad's USB-C port will replace the primary port or be included as a new, second port. Cases based on allegedly leaked "iPad Pro" designs have included spaces for two port openings, leading to speculation that Apple could potentially include both USB-C and Lightning, or offer docking capabilities in two different orientations.
The source also stated that the upcoming iPad will feature a next-generation A-series processor to replace the current high-end iPad Air 2 features an A8X processor that is a beefed-up variant of the A8 chip found in the iPhone 6 and iPhone 6 Plus.
Stay tuned for additional details as they become available.
Via AppleInsider
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Plugin ucm domain manager PHP Scripts Add ons
Export domains to csv manager 06/01/2014 first release upgrade instructions the plugin has an automatically upgrade function too. Delete) import domains from csv export domains client to csv automatically upgrade function automatically upgrade function the plugin has an automatically upgrade function too. Please ensure the latest version of ultimate client manager (lite or pro) has been purchased & installed before using addon this plugin. Upload the crm plugin_domain folder into your websites includes folder to finishing the installation choose the settings >. Modify & delete do
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You'll always hear me say how important it is to start with a clean, well-lit photo. I simply cannot stress this enough. Editing is really about embellishing and creating artistic effects, not about magically transforming a poorly shot photo. Here I've started with a gorgeous photo from Melody White Studios. It's shot beautifully, in even flat light and properly exposed. If you prefer a very light and simple edit, try using only Dull to Dazzling or Bland to Brilliant for a simple punch and call it good. Or, to create more stunning drama, follow the simple steps outlined below and in the video to see how you can easily customize the layers inside of Dull to Dazzling to add in extra oomph, matte haze, and richer color to your photos. It's deceptively simple!
The edits I choose to do for these blueprints are intended to inspire and educate my action customers on what is possible to achieve when using my actions. Editing is entirely subjective.
Photo courtesy of Melody White Studios.
Photo Editing Blueprint.
1. Lavish 100%, mask Matte Haze layer slightly off the face.
2. Dull to Dazzling 100% Customized inside layers as such.
- Warmth layer turned off.
- Airy Haze layer 100% then duplicated and copy layer set to 43%
- Light layer turned off.
- Dark layer on and increased to 93% masked off skin where it got too dark.
- Dazzling Richness layer was masked off eyes to bring back light and detail.
3. Eye-citement 100% masked on with a low opacity brush over the iris of the eyes to add in sparkle.
4. Mulberry 60% to add in pink tone to the edges. Masked almost completely off the skin.
5. Cosmic Ray 66% to add in blue to the shadows of the edges. Masked almost completely off the skin and hair.
1. The actions in the SIMPLE set of the Creative HeART Collection are packed with powerful layers that are begging to be customized. Many times you can simply play one of these 3 actions and using only the layers inside the action, create a beautiful complete edit. They are robust all-in-one actions that save you time and energy. Add in your favorite tone and be done!
2. Experiment with combining multiple tones. You may come up with a look that's all you and totally custom. For more tones, try those in the Botanical Blends Collection.


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pricing on the internet
From The New Palgrave Dictionary of Economics, Online Edition, 2013
Edited by Steven N. Durlauf and Lawrence E. Blume
Back to topBack to top
While many conjectured that the information-rich and frictionless nature of online markets would result in marginal cost pricing, this has proved not to be the case. Price dispersion online is ubiquitous. The main reason is that price discovery occurs through platforms that have an incentive to ensure that prices are dispersed so that information is valuable. We survey models of platform pricing and trace the impact of their decisions downstream to e-retailers. Finally, we highlight the connection between empirical findings and theory predictions for e-retail pricing.
Back to topBack to top
See Also
- auctions (experiments);
- auctions (theory);
- Bertrand competition;
- electronic commerce;
- Hotelling, Harold (1895–1973);
- internet and the offline world;
- location theory;
- online platforms, economics of;
- price dispersion;
- product differentiation;
- search theory (new perspectives);
- search theory;
- two-sided markets;
- Vickrey, William Spencer (1914–1996)
How to cite this article
Baye, Michael R. and John Morgan. "pricing on the internet." The New Palgrave Dictionary of Economics. Online Edition. Eds. Steven N. Durlauf and Lawrence E. Blume. Palgrave Macmillan, 2013. The New Palgrave Dictionary of Economics Online. Palgrave Macmillan. 22 November 2017 <http://www.dictionaryofeconomics.com/article?id=pde2013_P000379> doi:10.1057/9780230226203.3895


text: I really would like to be a childminder, but when I was trying to find a property to rent, I couldn't find any. Sowhy I am just a nanny, but I didn't givce up. Any suggestion how could I find a property where the landlord is not agains to do my childcare business? I am thinking for long term! Unfortunately I don't have the chance to buy an own flat:(


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In a blog post on the company's site, Sony Computer Entertainment's American president Jack Tretton said that the 160 GB PS3 will now be $249, and the 320 GB version will be $299. The price cut is effective immediately in the United States and Europe. In Japan, the cheaper price will kick in on August 18.
Adding that the PS3 is fairly future-proof — ahem, Nintendo — Tretton also pointed to the PS3 titles coming up including Uncharted 3.
"The new price will make the PS3 more accessible than ever before, so there's never been a better time to join PlayStation Nation," Tretton wrote.
Now that Sony has joined Nintendo Co.'s price-cut party, all eyes are on Microsoft. If the company slashes the price of its Xbox console soon, it could probably sway college students on the fence about how exactly they want to outfit their dorm rooms.
Related stories:
More technology coverage from The Post
Microsoft is discontinuing the glossy Xbox


text: サービス アーティスト 見せる お問い合わせ Eduardo Fernandez, Эдуардо Фернандес,Sergei Molchanov Artists Management - IAMA Russian member, Opera, ballet, piano, violin, conductor, choreographer, dancer, bass, baritone, tenor, soprano, mezzo-soprano, counter tenor, alto, Produced, classical music Eduardo Fernandez www.eduardo-fernandez.com Winner of 9 International and National piano competitions Considered by Fanfare magazine as Alicia de Larrocha's King-in-waiting, his interpretation of Spanish music has been prized and recognized several times, being winner of the Extraordinary Prize of the Fundacion Guerrero and the Manuel de Falla Award in Granada. He has performed in broadcast for TVE, RNE, RAI and France Musique. After the success of his first recording for Warner, Suite Iberia by Albeniz, he has just released his next recording for Centaur dedicated to the opus 117, 118 and 119 by Brahms. "The flood of expression that he threw at us, this boy, with his hands, completely out of the ordinary, made us, his public, watch in amazement. And we experienced one of these moments of magic that may surprise you when you least expect it" E. Cedena, ABC, Spain Download Bio Eduardo Fernandez was born in Madrid on 16 May, 1981. Education Eduardo started to play piano at the age 4 with his grandfather His formal studies included: 1989 - 1997 – Conservatorio Profesional de Alcala de Henares (prof. Carmen Aguirre) 1997 - 1999 – Real Conservatorio Superior de Madrid (prof. Almudena Cano) In addition, he graduated in chamber music, accompaniment and clarinet, and he finished his post-graduate degree in piano with honours from Fundacion Guerrero Eduardo participate in master-classes of Esteban Sanchez, Dmitri Bashkirov, Galina Egyazarova, Joaquin Achucarro, Vassily Lobanov, Boris Berman, Nadine Wright, John O'Conor, Tibor Szasz Competitions 1999 – Premio "Fundacion Guerrero" of RCSMM. Madrid, Spain – I Prize 2000 – II Concurso Nacional de Piano "Gerardo Diego". Soria, Spain – I Prize 2001 – "Premio Matrimonio Luque". Madrid, Spain – I Prize 2002 – II Concurs Internacional de Piano "Vila de Capdepera". Capdepera, Spain – I Prize 2003 – XVIII Premi de Musica "Ciudad de Manresa". Manresa, Spain – I Prize 2004 – I Concurso Internacional de Piano "Anton Garcia Abril". Teruel, Spain – I Prize 2004 – II Concurso de Piano "Seiler". Valladolid, Spain – I Prize 2004 – XIV Concurso Nacional de Piano "Manuel de Falla". Granada, Spain – I Prize 2005 – XIII Concurso Internacional de Piano "Rotaract Palma de Mallorca". Palma de Mallorca, Spain – I Prize Major performances 2005 – Auditorio Manuel de Falla. Granada. Spain. Solo Recital. 2006 – Palau de la Musica. Barcelona. Spain. Mozart piano concerto 17 with Orquestra Nacional Classica d'Andorra (conductor Marzio Conti) 2007 – Teatro de la Zarzuela. Madrid. Spain. Solo recital "Scherzo cycle". 2008 – Auditorio de Cuenca. Spain. Rachmaninov 3rd piano concerto with Cuenca Philharmonic (conductor Luis Carlos Ortiz) 2008 – Auditorio Manuel de Falla. Granada. Spain. Solo Recital 2009 – Great Hall of the Teatro Real. Madrid. Spain. Madrid Symphony Orchestra (conductor Joan Cervero) 2009 – Teatro de la Zarzuela. Madrid. Spain. Zarzuela with his own piano transcriptions 2009 – Teatro 1 de Mayo. Santa Fe. Argentina. Beethoven 1st piano concerto with Santa Fe Symphony Orchestra (conductor Roberto Montenegro) 2010 – Auditorio Nacional. Madrid. Spain. Solo recital. 2010 – Teatro 1 de Mayo. Santa Fe. Argentina. Falla Nights in the garden of Spain. Santa Fe Symphony Orchestra (conductor Jose Miguel Rodilla) 2010 – Universidad de Valparaiso, Chile. Solo Recital 2010 – Festival Rafael Orozco, Cordoba, Spain. Solo Recital 2011 – Saint Petersburg Philharmonia, Russia. Solo Recital 2011 – Juan March Foundation, Madrid, Spain. Solo Recital with his own piano transcriptions 2011 – Auditorio Cuenca, Spain. Solo Recital with his own piano transcriptions 2011 – Auditorio Nacional, Madrid, Spain. Two recitals 2011 – Shanghai Oriental Art Center, China. Solo recital 2011 – Yangzhou Concert Hall, China. Solo recital 2011 – Guangzhou Tianhe Concert Hall, China. Solo recital 2011 – Piano aux Jacobins, Toulouse, France. Solo recital 2011 – Auditorio Nacional. Madrid. Spain. Solo recital 2012 – Filarmonicii Oltenia, Craiova, Romania. Solo recital 2012 – Filarmonicii Oltenia, Craiova, Romania. Rachmaninov 3rd piano concerto with Oltenia Philharmonic (conductor Leonard Dumitriu) 2012 – Auditorium CML, Luxembourg. Solo recital 2012 – National Centre for the Performing Arts, Mumbai, India. Solo recital 2012 – Great Hall of Kiev Philharmonic, Ukraine. Solo recital 2012 – Great Hall of Kishinev Philharmonic, Moldova. Solo recital 2012 – Casa de America, Madrid, Spain. Recording for TVE 2013 – Palacio de Cibeles, Madrid, Spain. Solo recital 2013 – Auditorio Nacional, Madrid. Spain. Solo recital 2013 – Palacio Real, Segovia, Spain. Solo recital International Tours 2009 – Denmark 2009 – Estonia 2009 – Argentina 2010 – Austria 2010 – Argentina and Chile 2011 – China CDs Albeniz: Iberia Suite (2010, Warner) Brahms: Piano Pieces opus 117, 118, and 119 (2013, Centaur) Repertoire Фото Видео/Аудио Get the Flash Player to see this player.


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About the Mag
Known as "the bible of the sport," SURFER Magazine has been the foremost authority on surf culture since its founding in 1960. Every issue is packed with award-winning photography, provocative interviews, and travel features to the world's most exotic surf locales.
In This Issue
Japan is for Trustfunders
Finding great surf in the Land of the Rising Sun requires money, patience, and guidance. Just ask Dan Malloy. He's been trying to score in Japan for a decade.
Land of the Rainbow Serpent
Protected by distance (and its locals), Kalbarri remains an oasis in the vast, West Australian desert.
Sand on the Wind
A tall tale from Africa's longest left.
Anarchy and A-Frames
In Nigeria, squalor and sublimity exist side by side.
Highway to Helsinki
Kalle Carranza's unlikely path from Mainland Mexico to the shores of Finland.


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Quotes for Dance Teachers
Young dancers are training at a very vulnerable time in their lives... So train the whole person, not just the dancer.
It is more important who they are as people and only then is it important who they are as dancers.
If their feet aren't in the right place, at least their hearts are.
Let us first teach little children to breathe, to vibrate, to feel, and to become one with the general harmony and movement of nature. Let us first produce a beautiful human being, a dancing child.
Good dancers are made, not born.
A dance teacher helps their students find the song in their heart, the beat in their feet and a passion for life.
I will make an average man into an average dancer, provided he be passably well made. I will teach him how to move his arms and legs, to turn his head. I will give him steadiness, brilliancy and speed; but I cannot endow him that fire and intelligence, those graces and that expression of feeling which is the soul of true pantomime.
Correction does much, but encouragement does more. Encouragement after censure is as the sun after a shower.
The teacher doesn't teach, not really. The teacher offers stimulation and ways in which the person can educate himself or herself. At best the teacher wakes up that person and makes a person hungry.
A teacher must possess many qualities – firmness and softness, patience and perseverance and sturdiness... But above all is love for children, desire to train them up, all of them, both week and strong. And, creativity in one's approach to one's task is also above all...
To dance is to share – to share is to teach.
Just like it is rare to get a good guru, it is equally rare for gurus to get a good disciple. Every performer is not an able guru and vice-versa. Not everyone has the kind of patience required for teaching.
The mediocre teacher tells. The good teacher explains. The superior teacher demonstrates. The great teacher inspires.
Try to respect the student's spiritual feeling and intelligence. A human being is in your hands. If you don't love your students, it's better you don't teach. Give the truth always.
It is the supreme art of the teacher to awaken joy in creative expression and knowledge.


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- Johnny Esfeller
- Story
Nick Bollettieri to be inducted into the United States Professional Tennis Association Hall of Fame
Tomorrow at a special ceremony in Orlando, Fla., IMG Academy's own Nick Bollettieri, the legendary tennis coach that helped develop 10 World No. 1 players, in addition to a multitude of world-class players during his career, will be inducted into the United States Professional Tennis Association Hall of Fame.
Bollettieri remarked, "There are many outstanding professionals that belong to the USPTA that deserve this award as well. I accept this award, but I also acknowledge all the work done by other pros to make the USPTA what it is today."
Founded in 1927, USPTA is the world's oldest and largest association of tennis-teaching professionals. Induction into the Hall of Fame is the Association's highest honor afforded any person, national or international, living or deceased. Inductees have demonstrated exemplary service to the tennis-teaching profession. Inductees must have momentous international and/or national tennis industry or teaching service, be well known by name to teaching professionals in the country in which they reside.
Bollettieri developed numerous champions at the collegiate and professional levels, but his accolades are not limited to his proven coaching method. Bollettieri created a paradigm shift among player development when he founded the world's first fulltime residency and boarding program specializing in sports training in 1978. Now known as IMG Academy, that institution has grown to nearly 500 acres encompassing eight sports, and continues to develop student-athletes on and off the field.
connect with us & get a guide
Contact Us
Bradenton, FL 34210
Fill out the form below and we'll be in touch soon!
Request a brochure
We offer downloadable brochures about our boarding school, youth camps, adult programs, team training and pro/collegiate training in multiple languages.
Visit Us
Are you interested in touring the IMG Academy campus? Fill out the form below to submit a tour request and we will be in touch soon to confirm your request.


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Read about recent events, essential information and the latest related news.
Remember Me
11/2/2017Updated Food for Thought Calendar - Next Lunch is Nov. 14th!
10/5/2017Food for Thought Calendar Now Available!
12/14/2017TAHP Holiday Networking Reception
12/15/2017TAHP Medical Directors Forum: Driving Health Care Quality: Part 1
1001 Congress Avenue, Suite 300 | Austin, Texas 78701 | Phone: (512) 476-2091 | Email Us: firstname.lastname@example.com


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Simple String plugin
Visit Publisher Site
Simple String plugin Hosting Promo
Simple String is a plugin which allows you to sell hyperlinked ad string on your WordPress website. You don�t have to pay any comission fee to ad networks, because now you can work directly with advertisers. It�s really easy: install the plugin and start making more money today!Visit publisher site: Simple String plugin
Listing Details
- Version:
- 1.28
- Filed in:
Plugins / Wordpress Plugins / Ad Management / Banner Rotators
- Submitted on:
- Last Updated:
- Oct 16, 2011
- Publisher:
- Ivan Churakov Other listings by this publisher
License & Pricing Information
- License Type:
- Commercial
- Price:
- Additional Info:
- Commercial License
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For the special mom / grandma, this beautiful adoption necklace speaks the words that you've had in your heart for so long - "I wished for you."
• sterling silver
• 1" name bar will be personalized with up to 9 characters
• your choice of a Swarovski birthstone or pearl in a variety of colors
• option to personalize the back of either/both charms with a date/name/message
Further customize your necklace by adding another initial/name charm and/or stone.
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To see a stone chart: stone chart
To see a chain chart: chain chart
please allow 7 days for your custom made jewelry to ship
see the FAQS for more information and for rush options


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Perak Mentri Besar Datuk Seri Dr Zambry Abd Kadir has won his suit against the PKR over a defamatory article published by Suara Keadilan.
Senior assistant registrar Noordura Mohamed Din on Monday allowed the application by Dr Zambry to enter judgment against all the defendants in his RM100mil suit.
Dr Zambry's lawyer Firuz Hussein Ahmad Jamaluddin said it was a judgment on liability in respect of a major part of his client's claim against the defendants.
Damages are to be assessed.
Dr Zambry had on Feb 25 filed the suit against PKR president Datuk Seri Dr Wan Azizah Wan Ismail, her deputy Datuk Dr Syed Husin Ali and two others over the article published by the party's monthly newspaper.
In his statement of claim, Dr Zambry said Suara Keadilan had published and circulated an article titled "Zambry disyaki pengganas gagal masuk ke Amerika Syarikat" (Zambry denied entry to US on suspicion of being a terrorist) in its Dec 29, 2009 - Jan 5, 2010 edition which contained defamatory words.
Dr Zambry claimed the words meant that he was suspected of being a terrorist and was unfit to be the Mentri Besar of Perak.
The defendants in their statement of defence stated that an apology titled "Mohon Maaf Dr Zambry" and withdrawal of the said article was published in Suara Keadilan in its March 30 - April 5 edition.


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High Ridge, missouri vegetarians, vegans and raw foodist events and singles dating
is a 26 year old, Buddhist female.
Living in High Ridge, missouri
Veggie/vegan diet.
I've been a vegetarian for a little over 10 years now, and recently (2 months ago), I made the switch to vegan. I love animals, and as a zookeeper at the Saint Louis Zoo, I get the privilege of working with cool animals all the time! I volunteer with a few organizations in my free time. I love to run, hike, kayak, crochet, and read. I try to live each day with a purpose and a positive attitude. I am a very goal-oriented person.
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Kst is a fast real-time large-dataset viewing and plotting tool with built-in data analysis functionality. It contains many powerful built-in features and is expandable with plugins and extensions. It features powerful keyboard and mouse plot manipulation, a large selection of built-in plotting and data manipulation functions (such as histograms, equations, and power spectra), built-in filtering and curve fitting capabilities, a convenient command-line interface, a powerful graphical user interface with non-modal dialogs for an optimized workflow, support for several popular data formats, extended annotation objects similar to vector graphics applications, and high-quality export to bitmap or vector formats,
|Science Scientific Visualization visualisation data analysis KDE Qt
|GPL GPLv2 GPL v2 GPL v2 Or Later
|Operating Systems
|Linux GNU/Linux BSD
|KDE 4.x Qt
Release Notes: This release adds a data-fixed annotation object, support for Matlab's .mat file format for strigns, matrices, vectors, and scalars, a beta version of Python scripting, Drag-and-Drop support, improved printing to vector formats, and optional antialiasing. There have been also a number of bugs and crashes fixed in various areas, including shared axis boxes.
Release Notes: This release brings a redone automatic plot layout algorithm, the ability to change a scalar value directly in the scalar selection combo box, and as-you-type search in combo boxes (vector selection). There are also some user interface enhancements and bugfixes.
A Fluent OpenStack client API for Java.
A TWiki appliance that is easy to use and lightweight.


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Davenport, IA 52801
1854 Avenue Of The Cities Moline, IL
3523 Eastern Ave # 1 Davenport, CA
I have been to Camera Corner several times in the past couple years. The employees there are very attentive and really do know what they are talking about. They are always eager to answer any questions I may have. However, it can be a bit on the expensive side.4


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Gypsy Sally's Presents a FREE show in our Vinyl Lounge!
Reed Turchi
Wed, May 10, 2017
Doors: 5:30 pm / Show: 7:30 pmVinyl Lounge at Gypsy Sally's
This event is 21 and overhttps://www.gypsysallys.com/event/1442518/
Reed Turchi
As low-down and lonesome as the Blues may be, listening to the song—or playing it—is nevertheless cathartic, hard-won resilience washes away despair. The despair isn't entirely removed, however; rather, like a long-handled broom, it is left leaning in the corner. And, of course, the work of composing new Blues music, is also an act of research and preservation. As with any folk tradition, one must reach back to the deepest roots. There one finds not singularity, but rich variety, styles and tunings and riffs that have blended together to be, ultimately, inseparable. And, yet, when the right player and the right voice perform the right songs, the result is wholly singular. That is how one working within a tradition makes an original contribution. And that is how I hear this fine record. Reed Turchi has delivered an original, unvarnished interpretation of a long musical tradition. Tallahatchie taps the sacred and profane roots behind it to make those mysterious, conflicted energies vital all over again. Such renewal keeps the art alive, and this record is as alive as a whippoorwill singing from a midnight hillside.
Venue Information:
Vinyl Lounge at Gypsy Sally's
3401 K Street NW
Washington, DC, 20007
Vinyl Lounge at Gypsy Sally's
3401 K Street NW
Washington, DC, 20007


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Fall Floral Street Style 2011
Look of the Day: Fittingly Floral
With pretty florals and cool Fall layers, Fab reader postgradchic's look is perfectly suited to her surroundings. We love how she tempers a bright floral print with a moody palette and seasonal suede on her boots and jacket. It's a masterful exercise in Autumn layers, and a photo shoot made sweeter by the gorgeous natural backdrop.
Congrats to postgradchic!
Everyone else, submit your looks, and we might feature you on FabSugar!


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The Bendigo Family History Group conducts a monthly meeting on the third Saturday of each month, except for December & January.
The meeting commences with Business at 2 pm and a Guest Speaker commences around 2.10 pm.
Meetings are held at Bendigo Goldfields Library room 1, entrance in Hargreaves St
The meeting program usually includes a talk by a speaker on a subject associated with family history, genealogy or a related subject. There is an opportunity to socialise with other attendees over light refreshments.
Meetings are not exclusively for members, members of the public are most welcome. A gold coin donation is accepted.
January - No meeting
February 18th - speaker Janet McCalman, author, Vandemonians of Bendigo Janet is a published author of three award winning books.
March 18th - speaker Carolyn Morrisey, British Military Records & Family History Carolyn is a member of AIGS Council and the coordinator of Regional and Interest Groups.
April 22nd - speaker Jennifer McNeice, Australian Military Exemption Courts 1916 Jennifer is a member of the Genealogical Society of Victoria and SAG. A local historian and writer, conducting advice and workshops to other researchers.
May 20th - speaker Dianne Packer, Starting German Research Dianne has developed a particular interest in searching records from The Netherlands, Germany, Italy, Ireland and Great Britain. How and where to access German civilian records will be explored.
June 17th - speakers Patricia Ibbotson & Pam Keown The Boys of Tragowel Patricia & Pam have researched and written a book on the above lads of Tragowel who went to war. They will share their experience while engaged in producing their book.
July 15th - speaker Vivien Newton on Using Find my Past, Ancestry and other online resourses, Viv is a Senior Librarian and has many years experience assisting people with Family and Local Research in Bendigo.
August 19th - speaker Lyn Thorne Irish Records in 2017 Lyn is currently a volunteer library assistant and member of the research team and records management at the AIGS in Blackburn. Her talk will cover the newly available Irish records and how to access them.
September 16th - Topic of discussion Brick walls - Running into & Demolishing them.
October 21st - Speaker Mike Butcher Love Revisited the builder/architect Robert Love and St Paul's Cathedral of Bendigo. His great grandson and his research on family.
November 18th - Speaker Dr Rebecca Kippen " What killed the Convicts ? causes of mortality of convicts transported to Van Diemena Land" Dr Kippen is Associate Professor of Demography in the school of Rural Health Monash University, Bendigo. Her research includes life course analysis of Tasmanian Convicts, Victorian Aborigines, and Word War one veterans.
December No Meeting


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Going from the Mt Washington Valley region of Maine/NH, all the way down to the "Horse Capital of the World, Marion County" in Central Florida in April 2014, was quite a change to say the least! Photo ops, in a totally new and intriguing area of this very large and varied state, are slowly presenting themselves to me as I adjust to this brand new environment and much warmer weather!! I look forward to this new photographic chapter of my life!
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Wednesday March 5, 2014
San Francisco, CA (Current Weather Conditions)
Caption: that lasted just a couple of minutes..luckily I glanced out the kitchen window at the right moment..the setting sun looked amazing just as an intense snow squall moved in over the mountains beyond the treeline..then it was gone behind low gray clouds..
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As October creeps to a close, the Holiday season is fast approaching. Faster than we'd like to admit, really. But this is also an exciting time for publishers; not only because it's the most profitable time of the year, but also a time to roll out and test your well-planned campaigns and strategies for your consumers.
But the traditional trends in shopping and consumer habits have radically changed in a relatively short period of time. Shoppers are smarter and savvier than they were before;
|• they have the wealth of the world's knowledge at their fingertips
|• they have the resources to research and compare prices like never before (including blogs, and alerts)
|• they're mobile as they shop—no need to be tied down to a desktop
With E-commerce channels predicting a 13% growth in Holiday sales for this 2016 Holiday season—similar to the growth experienced in 2015 (CJ Affiliate, 2016)—publishers know that their key to success lies in their own hands… and maybe taking a tip or two from the OPM Pros team.
After careful thought, consideration, strategizing, and overall analysis, the 'Pros have put together a definitive guide on how our affiliates can succeed in this year's peak-week.
Timing is everything
Like most things in life, timing is everything. Knowing when to roll out promotions—or knowing when to hold back—is a tricky game where the stakes are high, and the rewards even higher. Though difficult to anticipate, implementing strategic timing in your placements and marketing campaigns is an integral part of your success for the 2016 peak-season.
Not convinced? Here's some quick numbers about our Peak-Days, courtesy of Adobe
|• Black Friday is the fastest growing online sales day to date
|• Cyber Monday is the largest online sales day (Refer to point 1)
|• Thanksgiving Day is the biggest mobile sales day
Time your messages to your community: Generate interesting topics or native content that begins a conversation. It's a noisy online world out there, so make sure your community is hearing, and identifying with you!
Now that you've got your reader's attention, it's time for affiliates to start digging into shopping patterns. Look at the trends from previous years and see if you're optimizing your website and products to attract the right kind of traffic.
For example, in most cases shoppers who are looking for beauty products tend to begin their purchasing during the last week of October and into the first week of November, whereas those shopping for electronics, like FitBits or mobile phones (which also happen to be some of the most sought after gifts during peak-week) begin their shopping (or browsing) only in the first and second week of November. Scheduling your campaigns and targeting this community should reflect this trend.
Shipping strategy; timing, timing, timing!
For a client, there's nothing worse than placing all your holiday orders and realizing they won't come in on time. Creating a Shipping Calendar for your customers and community is a great way to add value to your business, and helps your shoppers keep on track. It's also cost-effective for you to push products that will actually reach your customers on time, rather than dedicate resources to products that won't make the cut.
Our 'Pro Tip: Make sure your schedule is foolproof. Set reminders, notifications, and tiered-deadlines to make sure your products get to your customers on time!
Mobile friendly is the make-or-break factor
Knowing how and where your customers shop is just as important to your success as timing is. In a recent study conducted by CJ Affiliate Network, it was noted that over 29% of shoppers in the US use their smartphone or tablet when making a purchase, and in Canada, that number is as high as 35%. That's a lot of people making purchases on devices that aren't tied to their home or desk. Optimizing your mobile websites has never been more important than it is now.
Thanks again to Adobe Digital, consumers spent a whopping $1.73 billion dollars last year (2015) during Thanksgiving Day alone. That's a 25% increase from the year before, and a similar forecast is expected for the 2016 Holiday season.
|• Make sure your campaigns and sales are displaying properly on mobiles! Test, test, test!
|• How's your load time? According to Google, 53% of mobile sites visited are abandoned if pages take longer than 3 seconds to load (Sampled 11.8k global mWeb homepage domains 2016)
Capitalize on your trust & trends
There's a lot of competition out there, but not matter the size of your competitors, you have something unique: you have the trust of your community. Their loyalty is what supports your program; these customers shop with you because they trust your products, and trust that they're getting the best deal.
Giving something back to the community is a way to reinforce their loyalty.
|• Send out your own product reviews to customers
|• Prepare guides that indicate special selling points or offers, or that promote things of interest to your community (for example, which products are express shipped, or have full guarantees, etc.)
|• Make sure you're staying on top of trends, and market your products following those guidelines. (Ex. Many gift givers are opting on giving "experiences" rather than "things." Knowing this, craft a story around the product you have)
|• Offer what your customers want, not what they don't want: according to CJ Affiliate, promotions that involved in-store pick up fared better than promotions with indicated free shipping.
Post-Holiday Strategy
Though peak-week has yet to begin, making sure you have a complete strategy that'll outline your post-mortem is crucial. Whether it's strategizing your way out of overstock, or seeing what the most popular items were, these are all tools that'll allow you to keep track of what your customers want, and capitalize on emerging trends.
Whether you're an industry vet or a timid newbie, don't stress about the upcoming Holiday madness. Getting organized and following OPM Pros' advice is sure way to lead you to your most successful Cyber Weekend ever!


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The easiest way to drive traffic to a music website is to give away free downloads. It's what every music fan wants, and what dedicated fans spend a majority of their time searching for on the Internet. They hear a song they like on a new podcast, go look up the track list, and then search the name of the song and add Zippyshare to the end of it. Or Hulkshare, or whatever their preferred method may be.
If our only goal was to get as much traffic as quickly as possible, then we would simply upload these ripped MP3's (which can be low quality) to a third party hosting site and then make them available for download on our site. This would probably get our name out into the Interweb's quicker and allow us to build our social following faster and with less time/effort.
The core founding team of Only The Beat thought long and hard about what our mission was when we started this site. Why we wanted to do it, what our goals were, and how we could help shape the future of the music industry, as many of us were, and currently are, involved in all aspects of the nightlife/entertainment/music industry. There are obvious con's to giving away pirated music, like meeting your idol and introducing yourself, "Hi, I'm Daniel, I run xyz.com and we give away your music for free!"...The reaction you get is, well, less than thrilling. I know from experience. Not many people who put their heart and soul, blood, sweat and tears into producing music to put food on the table enjoy hearing that you just give away their tediously crafted works of art for free. But hey, their feelings don't affect you on a daily basis, so for the sake of a good conversation, let's be insensitive and look past that.
It's not about stealing $1.29 from an artist. There is a much bigger issue confronting the music industry that has been turned on its head since the introduction and really, the acceptance on a mass level, of peer 2 peer sharing. Or simply the Internet for the matter. The initial reaction that we all witnessed was the large record labels frantically attempting to control an element that they had seen as their main source income since their establishment. And rightfully so! We are witnessing it right now on a much larger scale with the use of fossil fuels. We know there are other sources of energy we could be harnessing, but there are too many people with too much power making too much money on oil consumption. Political rant over, yet the concept still applies. Only in the case of the music industry, unlike oil, a tangible product, the internet has allowed the users to take control, and the distribution of wealth in the industry now goes to those who work the hardest to be recognized as experts in their fields and know how to use the tools at their disposal (social media, Soundcloud, etc.) to market themselves most effectively and efficiently.
In the music blogosphere, one has to make a choice: are we going to give away pirated music on our site, or not. There's really no gray area. Even if you hosted a pirated track for a limited time and then delete the post, it's still traceable down the line (the Internet never forgets!). Not to mention, regardless of disclaimers, you won't be taken seriously as a legitimate business if you are doing something unethical and technically illegal, however awesome it is. Again, our goal is to help influence the music industry. And when the time comes for us to speak up, we want to have a legitimate say in the future of its paradigm.
Do we think that artists should give away their music for free? Absolutely. It's pretty clear that there isn't any real money in selling music, and it's silly to continue to focus on something that you can't control. Simply put, people are going to steal your music. Hell, the next generation of music lovers is going to question why we ever even paid for music! And some artists are starting to get smart. They realize that the real money is in the shows, getting booked. Building one's brand to the point where they can get paid tens of thousands of dollars for a single show (think artists like Tiesto or Armin. I think I'd be happy just to get $1000 for a gig). But instead, there are people who have been around long enough to remember what that taste of money was like when the Internet didn't allow people to download music for free. And those same people are scared by the power the Internet has given consumers. So they perpetuate the inevitable. I don't know about you, but I've never heard of an EDM artists putting out an album on Beatport and becoming an overnight sensation. But an EDM artist who releases an entire album for free? Well, we've seen quite a few of those over the last 3 years haven't we? (cough, Skrillex, cough)
It's pretty clear that the most important thing to do is to get one's music into the hands of their fans and/or potential fans, and let it spread as far and wide as quickly as possible. If the music is good, the people will share it, and the booking agents and promoters will beat a path to your door. The counter argument to this could be, "Well it's only $1.29 a song, that's not too much to ask." But for a niche audience (EDM is really still considered niche!) with a demographic that sits in the range of 18 to 24 years old, it is really hard to ask this economically stressed group to take a risk and spend the money, especially when they know how to get it for free. In under a minute. If you don't initially agree with this, think back to a time in your life when you spent $15.99 on a CD and it was a complete dud. Pissed you off, didn't it?
In conclusion, we live in an experience driven economy, where the norms of music acquisition and consumption have already changed. I'm not saying that every track an artists produces should be given away for free... but what about giving away the first half of an album for free, perhaps in return, creating a sense of security for the consumer when it comes to the second half of the purchase. I don't claim to have all the answers (yet) but I don't see things moving backwards as technology only continues to move forwards either. In the meantime, we will continue to support artist discovery and the purchasing of their music. I just hope this sheds some light on an issue that we can begin to discuss more openly and with more intelligence. And on that note, I'd like to say thank you for supporting our blog! Please, let me know what you think in the comments section below.
This video does a pretty good job summing things up.


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As European heavy transport and crane rental companies become increasingly concerned about safety during the delivery and erection of onshore wind turbines, leading industry figures are calling on developers and turbine manufacturers to join them in discussions about how standards can be raised and major incidents avoided.
The move is being led by the European Association for Abnormal Road Transport and Mobile Cranes, or ESTA, with support from the European Materials Handling Federation, or FEM.
"Just a few years ago, using large cranes to the maximum of their capabilities was not seen every day. Now it is commonplace, and we have all read about or seen accidents involving very large cranes, especially when used to erect wind turbines," said ESTA Director Søren Jansen.
Industry experts privately estimate that there are two accidents a month, and fear the situation will get worse.
Jansen added the industry is facing a lot of challenges in this sector when erecting the wind turbines due to the increase of hub heights, and the size and weight of the turbines.
"What's more, turbine manufacturers are now talking about hub heights up to 200 meters or ever higher," he said.
Ground conditions, quality of access roads and manufacturer's requirements, which vary from firm to firm, also present challenges for transport companies.
"ESTA will be lobbying for common standards among the turbine manufacturers regarding ground conditions, access roads and their transportation requirements," said ESTA President David Collett.
"We are convinced that such common standards will not just improve safety but result in efficiencies that will benefit the entire supply chain, including the developers and turbine manufacturers themselves," Collett said.
An ESTA and FEM Experts Summit focused on the subject is scheduled in Hamburg, Germany on Feb. 23, 2017. Called "New challenges in on-shore wind farm construction – safety, productivity and the supply chain," the one-day conference and reception will feature industry speakers from across the sector.
The organizers hope the summit will lead to the development of a new best practice guide that will raise standards, boost productivity and reduce the number of accidents. For more information, visit www.estaeurope.eu/summit.
Photo: Wind farm near Lisewo, Poland


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Event Information
Date and Time
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On-line registration for this event will close at 5pm, Tues 6 December.
Please email: email@example.com
or ring: 024 7647 8772 to enquire about late availability.
Opportunities for beef and lamb in a post-Brexit landscape will be addressed at the 2016 AHDB Beef & Lamb Stakeholder Seminar.
The event, which is aimed at stakeholders and industry partners, will feature headline speakers including Paul Clayton from the US Meat Export Federation (USMEF), discussing the opportunities for UK beef and lamb on the American market, and David Wagstaff from Noble Foods, who will focus on the importance of innovation and creating a successful brand.
Gwyn Jones, chair of Responsible Use of Medicines in Agriculture (RUMA, will speak about the challenges presented by anti-microbial resistance (AMR) and there will be presentations from AHDB head of exports Peter Hardwick, looking at post-Brexit options for trade, and sector strategy director Laura Ryan, who will give an overview of the organisation's strategic direction for the next three years.
Conference programme
0930 Registration and breakfast refreshments
1030 Welcome and Introduction from the Chair, Adam Quinney, Chairman of AHDB Beef & Lamb
- Peter Hardwick, AHDB Head of Exports, 'Brexit implications for industry'
- David Wagstaff, President & COO, Noble Foods 'Product differentiation: excellence in marketing'
- Gwyn Jones, RUMA Chairman 'Antimicrobial resistance and the challenge facing the beef and lamb sector'
Panel and Q&A with morning speakers
Conference lunch and AHDB trade and consumer displays
- Phil Hadley, Head of Global Supply Chain Dvt, AHDB Beef & Lamb, 'Meat quality'
- Paul Clayton, Senior VP Exports Service, USA Meat Export Federation, 'US market and opportunities'
- Laura Ryan, Sector Strategy Director, AHDB Beef & Lamb 'AHDB Beef & Lamb Strategy'
Panel and Q&A with afternoon speakers
1600 Chair's summary and close
Tea and coffee will be available for delegates, before departure
Date and Time
Crowne Plaza (Stratford-upon-Avon)
United Kingdom
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