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Publications (25)
Article: Impact of the Serum- & Glucocorticoid-inducible Kinase 1 (SGK1) on platelet dense granule biogenesis and secretion[Show abstract] [Hide abstract] ABSTRACT: Background Platelet secretion is critical to development of acute thrombotic occlusion. Platelet dense granules contain a variety of important hemostatically active substances. Nevertheless, biogenesis of platelet granules is poorly understood.ObjectivesSGK1 has been shown to be highly expressed in platelets and megakaryocytes, but its role in the regulation of platelet granule biogenesis and its impact on thrombosis has not been investigated so far.Methods and ResultsElectron microscopy analysis of platelet ultrastructure revealed significant reduction in number and packing of dense granules in platelets lacking SGK1 (sgk1-/-). In sgk1-/- platelets serotonin content was significantly reduced and activation-dependent secretion of ATP, serotonin and CD63 significantly impaired. In vivo adhesion after carotis ligation was significantly decreased in platelets lacking SGK1 and occlusive thrombus formation after FeCl3-induced vascular injury was significantly diminished in sgk1-/- mice. Transcript levels and protein abundance of dense granule biogenesis regulating GTPase Rab27b were significantly reduced in sgk1-/- platelets without affecting Rab27b mRNA stability. In MEG-01 cells transfection with constitutively active S422DSGK1 but not with inactive K127NSGK1 significantly enhanced Rab27b mRNA levels. Sgk1-/- megakaryocytes show significantly reduced expression of Rab27b and serotonin/CD63 levels compared to sgk1+/+ megakaryocytes. Proteome analysis identified 9 further vesicular transport proteins regulated by SGK1 which may have an impact on impaired platelet granules biogenesis in sgk1-/- platelets independent of Rab27b.Conclusions The present observations unravel SGK1 as a novel powerful regulator of platelet dense granule biogenesis, platelet secretion and thrombus formation. SGK1 is at least partially effective by regulating transcription of Rab27b in megakaryocytes.This article is protected by copyright. All rights reserved.
Article: Extracellular Cyclophilin A Activates Platelets Via EMMPRIN (CD147) and PI3K/Akt Signaling, Which Promotes Platelet Adhesion and Thrombus Formation In Vitro and In Vivo[Show abstract] [Hide abstract] ABSTRACT: Cyclophilin A (CyPA) is secreted under inflammatory conditions by various cell types. Whereas the important role of intracellular CyPA for platelet function has been reported, the effect of extracellular CyPA on platelet function has not been investigated yet. Inhibition of extracellular CyPA through a novel specific inhibitor MM284 reduced thrombus after ferric chloride-induced injury in vivo. In vitro extracellular CyPA enhanced thrombus formation even in CyPA(-/-) platelets. Treatment of isolated platelets with recombinant CyPA resulted in platelet degranulation in a time- and dose-dependent manner. Inhibition of the platelet surface receptor extracellular matrix metalloproteinase inducer (cluster of differentiation 147) by an anticluster of differentiation 147 monoclonal antibody significantly reduced CyPA-dependent platelet degranulation. Pretreatment of platelets with CyPA enhanced their recruitment to mouse carotid arteries after arterial injury, which could be inhibited by an anticluster of differentiation 147 monoclonal antibody (intravital microscopy). The role of extracellular CyPA in adhesion could be confirmed by infusing CyPA(-/-) platelets in CyPA(+/+) mice and by infusing CyPA(+/+) platelets in CyPA(-/-) mice. Stimulation of platelets with CyPA induced phosphorylation of Akt, which could in turn be inhibited in the presence of phosphoinositid-3-kinase inhibitors. Akt-1(-/-) platelets revealed a markedly decreased degranulation on CyPA stimulation. Finally, ADP-induced platelet aggregation was attenuated by MM284, as well as by inhibiting paracrine-secreted CyPA without directly affecting Ca(2+)-signaling. Extracellular CyPA activates platelets via cluster of differentiation 147-mediated phosphoinositid-3-kinase/Akt-signaling, leading to enhanced adhesion and thrombus formation independently of intracellular CyPA. Targeting extracellular CyPA via a specific inhibitor may be a promising strategy for platelet inhibition without affecting critical functions of intracellular CyPA. © 2014 American Heart Association, Inc.
Article: Functional characterization and anti-cancer action of the clinical phase II cardiac Na+/K+ ATPase inhibitor istaroxime: in vitro and in vivo properties and cross talk with the membrane androgen receptor[Show abstract] [Hide abstract] ABSTRACT: Sodium potassium pump (Na+/K+ ATPase) is a validated pharmacological target for the treatment of various cardiac conditions. Recent published data with Na+/K+ ATPase inhibitors suggest a potent anti-cancer action of these agents in multiple indications. In the present study, we focus on istaroxime, a Na+/K+ ATPase inhibitor that has shown favorable safety and efficacy properties in cardiac phase II clinical trials. Our experiments in 22 cancer cell lines and in prostate tumors in vivo proved the strong anti-cancer action of this compound. Istaroxime induced apoptosis, affected the key proliferative and apoptotic mediators c-Myc and caspase-3 and modified actin cystoskeleton dynamics and RhoA activity in prostate cancer cells. Interestingly, istaroxime was capable of binding to mAR, a membrane receptor mediating rapid, non-genomic actions of steroids in prostate and other cells. These results support a multi-level action of Na+/K+ ATPase inhibitors in cancer cells and collectively validate istaroxime as a strong re-purposing candidate for further cancer drug development.
Article: 1,25( OH)(2) vitamin D-3-dependent inhibition of platelet Ca2+ signaling and thrombus formation in klotho-deficient mice[Show abstract] [Hide abstract] ABSTRACT: Platelets are activated by increased cytosolic Ca2+ concentration ([Ca2+]i) following store-operated calcium entry (SOCE) accomplished by calciumrelease-activated calcium (CRAC) channel moiety Orai1 and its regulator STIM1. In other cells, Ca2+ transport is regulated by 1,25(OH)2 vitamin D3 [1,25(OH) 2D3]. 1,25(OH)2D3 formation is inhibited by klotho and excessive in klotho-deficient mice (kl/kl). The present study explored the effect of klotho deficiency on platelet Ca2+ signaling and activation. Platelets and megakaryocytes isolated from WT and kl/kl-mice were analyzed by RT-PCR, Western blotting, confocal microscopy, Fura-2-fluorescence, patch clamp, flow cytometry, aggregometry, and flow chamber. STIM1/Orai1 transcript and protein levels, SOCE, agonist-induced [Ca2+]i increase, activation-dependent degranulation, integrin αIIbβ3 activation and aggregation, and thrombus formation were significantly blunted in kl/kl platelets (by 27-90%). STIM1/Orai1 transcript and protein levels, as well as CRAC currents, were significantly reduced in kl/kl megakaryocytes (by 38-73%) and 1,25(OH) 2D3-treated WT megakaryocytes. Nuclear NF-kB subunit p50/p65 abundance was significantly reduced in kl/kl-megakaryocytes (by 51-76%). Transfection with p50/p65 significantly increased STIM1/Orai1 transcript and protein levels in megakaryocytic MEG-01 cells (by 46-97%). Low-vitamin D diet (LVD) of kl/kl mice normalized plasma 1,25(OH)2D3 concentration and function of platelets and megakaryocytes. Klotho deficiency inhibits platelet Ca2+ signaling and activation, an effect at least partially due to 1,25(OH)2D3-dependent down-regulation of NF-kB activity and STIM1/Orai1 expression in megakaryocytes.
Article: Acid Sphingomyelinase Regulates Platelet Cell Membrane Scrambling, Secretion, and Thrombus Formation[Show abstract] [Hide abstract] ABSTRACT: Platelet activation is essential for primary hemostasis and acute thrombotic vascular occlusions. On activation, platelets release their prothrombotic granules and expose phosphatidylserines, thus fostering thrombin generation and thrombus formation. In other cell types, both degranulation and phosphatidylserine exposure are modified by sphingomyelinase-dependent formation of ceramide. The present study thus explored whether acid sphingomyelinase participates in the regulation of platelet secretion, phosphatidylserine exposure, and thrombus formation. Collagen-related peptide- induced or thrombin-induced ATP release and P-selectin exposure were significantly blunted in platelets from Asm-deficient mice (Smpd1(-/-)) when compared with platelets from wild-type mice (Smpd1(+/+)). Moreover, phosphatidylserine exposure and thrombin generation were significantly less pronounced in Smpd1(-/-) platelets than in Smpd1(+/+) platelets. In contrast, platelet integrin αIIbβ3 activation and aggregation, as well as activation-dependent Ca(2+) flux, were not significantly different between Smpd1(-/-) and Smpd1(+/+) platelets. In vitro thrombus formation at shear rates of 1700 s(-1) and in vivo thrombus formation after FeCl3 injury were significantly blunted in Smpd1(-/-) mice while bleeding time was unaffected. Asm-deficient platelets showed significantly reduced activation-dependent ceramide formation, whereas exogenous ceramide rescued diminished platelet secretion and thrombus formation caused by Asm deficiency. Treatment of Smpd1(+/+) platelets with bacterial sphingomyelinase (0.01 U/mL) increased, whereas treatment with functional acid sphingomyelinase-inhibitors, amitriptyline or fluoxetine (5 μmol/L), blunted activation-dependent platelet degranulation, phosphatidylserine exposure, and thrombus formation. Impaired degranulation and thrombus formation of Smpd1(-/-) platelets were again overcome by exogenous bacterial sphingomyelinase. Acid sphingomyelinase is a completely novel element in the regulation of platelet plasma membrane properties, secretion, and thrombus formation.
Article: Differential Effects of Dehydroepiandrosterone and Testosterone in Prostate and Colon Cancer Cell Apoptosis: The Role of Nerve Growth Factor (NGF) Receptors[Show abstract] [Hide abstract] ABSTRACT: Tumor growth is fostered by inhibition of cell death, which involves the receptiveness of tumor to growth factors and hormones. We have recently shown that testosterone exerts proapoptotic effects in prostate and colon cancer cells through a membrane-initiated mechanism. In addition, we have recently reported that dehydroepiandrosterone (DHEA) can control cell fate, activating nerve growth factor (NGF) receptors, namely tropomyosin-related kinase (Trk)A and p75(NTR), in primary neurons and in PC12 tumoral cells. NGF was recently involved in cancer cell proliferation and apoptosis. In the present study, we explored the cross talk between androgens (testosterone and DHEA) and NGF in regulating apoptosis of prostate and colon cancer cells. DHEA and NGF strongly blunted serum deprivation-induced apoptosis, whereas testosterone induced apoptosis of both cancer cell lines. The antiapoptotic effect of both DHEA and NGF was completely reversed by testosterone. In line with this, DHEA or NGF up-regulated, whereas testosterone down-regulated, the expression of TrkA receptor. The effects of androgens were abolished in both cell lines in the presence of TrkA inhibitor. DHEA induced the phosphorylation of TrkA and the interaction of p75(NTR) receptor with its effectors, RhoGDI and RIP2. Conversely, testosterone was unable to activate both receptors. Testosterone acted as a DHEA and NGF antagonist, by blocking the activation of both receptors by DHEA or NGF. Our findings suggest that androgens may influence hormone-sensitive tumor cells via their cross talk with NGF receptors. The interplay between steroid hormone and neurotrophins signaling in hormone-dependent tumors offers new insights in the pathophysiology of these neoplasias.
- [Show abstract] [Hide abstract] ABSTRACT: Thrombin activates pore forming channel protein Orai1 resulting in store operated Ca(2+) entry (SOCE) with subsequent Ca(2+)-dependent release of platelet granules, activation of integrin αIIbβ3, adhesion, aggregation and thrombus formation. Platelets lack nuclei and are thus unable to modify protein abundance by transcriptional regulation. Nevertheless, they still contain pre-mRNA and mRNA and are thus able to express protein by stimulation of rapid translation. Platelet translation is sensitive to phosphoinositide-3-kinase (PI3K) and actin polymerization. The present study explored whether platelet activation via thrombin modifies Orai1 protein abundance. According to RT-PCR platelets contain pre-mRNA and mRNA encoding Orai1. Activation with thrombin (0.1 U/ml) results in a significant decline of pre-mRNA, which is, according to Western blotting and confocal microscopy, paralleled by a marked and statistically significant increase of Orai1 protein abundance. The increase of Orai1 protein abundance is insensitive to inhibition of transcription with actinomycin (4 μg/ml), but is significantly blunted by inhibition of translation with puromycin (100 nM) and by inhibition of PI3K with wortmannin (100 nM) or LY294002 (25 μM). In conclusion, activation of platelets stimulates the translational expression of Orai1, thus augmenting platelet Ca(2+) signaling.
- [Show abstract] [Hide abstract] ABSTRACT: Chorea-acanthocytosis (ChAc), a lethal disease caused by defective chorein, is characterized by neurodegeneration and erythrocyte acanthocytosis. The functional significance of chorein in other cell types remained ill-defined. The present study revealed chorein expression in blood platelets. As compared to platelets from healthy volunteers, platelets from patients with ChAc displayed a 47% increased globular/filamentous actin ratio, indicating actin depolymerization. Moreover, phosphoinositide-3-kinase subunit p85 phosphorylation, p21 protein-activated kinase (PAK1) phosphorylation, as well as vesicle-associated membrane protein 8 (VAMP8) expression were significantly reduced in platelets from patients with ChAc (by 17, 22, and 39%, respectively) and in megakaryocytic (MEG-01) cells following chorein silencing (by 16, 54, and 11%, respectively). Activation-induced platelet secretion from dense granules (ATP release) and α granules (P-selectin exposure) were significantly less (by 55% after stimulation with 1 μg/ml CRP and by 33% after stimulation with 5 μM TRAP, respectively) in ChAc platelets than in control platelets. Furthermore, platelet aggregation following stimulation with different platelet agonists was significantly impaired. These observations reveal a completely novel function of chorein, i.e., regulation of secretion and aggregation of blood platelets.-Schmidt, E.-M., Schmid, E., Münzer, P., Hermann, A., Eyrich, A.-K., Russo, A., Walker, B., Gu, S., Müller vom Hagen, J., Faggio, C., Schaller, M., Föller, M., Schöls, L., Gawaz, M., Borst, O., Storch, A., Stournaras, C., Lang, F. Chorein sensitivity of cytoskeletal organization and degranulation of platelets.
- [Show abstract] [Hide abstract] ABSTRACT: Glycopeptides, such as vancomycin, are powerful antibiotics against methicillin-resistant Staphylococcus aureus. Balhimycin, a glycopeptide antibiotic isolated from Amycolatopsis balhimycina, is similarly effective as vancomycin. Side effects of vancomycin include triggering of platelet apoptosis, which is characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine exposure at the cell surface. Stimulation of apoptosis may involve increase of cytosolic Ca(2+) activity, ceramide formation, mitochondrial depolarization and/or caspase activation. An effect of balhimycin on apoptosis has, however, never been reported. The present study thus tested whether balhimycin triggers platelet apoptosis. Human blood platelets were treated with balhimycin and cell volume was estimated from forward scatter, phosphatidylserine exposure from annexin V-binding, cytosolic Ca(2+) activity from fluo-3AM fluorescence, ceramide formation utilizing antibodies, mitochondrial potential from DiOC(6) fluorescence, and caspase-3 activity utilizing antibodies. As a result, a 30min exposure to balhimycin significantly decreased cell volume (⩾1μg/ml), triggered annexin V binding (⩾1μg/ml), increased cytosolic Ca(2+) activity (⩾1μg/ml), stimulated ceramide formation (⩾10μg/ml), depolarized mitochondria (⩾1μg/ml) and activated caspase-3 (⩾1μg/ml). Cell membrane scrambling and caspase-3 activation were virtually abrogated by removal of extracellular Ca(2+). Cell membrane scrambling was not significantly blunted by pancaspase inhibition with zVAD-FMK (1μM). In conclusion, balhimycin triggers cell membrane scrambling of platelets, an effect dependent on Ca(2+), but not on activation of caspases.
- [Show abstract] [Hide abstract] ABSTRACT: Background/Aims: Side effects of vancomycin, a widely used antibiotic, include thrombocytopenia. The vancomycin-induced thrombocytopenia has been attributed to immune reactions. At least in theory, thrombocytopenia could result in part from the triggering of apoptosis, which results in cell shrinkage and cell membrane scrambling with subsequent phosphatidylserine exposure at the cell surface. The cell membrane scrambling could be initiated by a signaling involving increase of cytosolic Ca(2+) activity, ceramide formation, mitochondrial depolarization and/or caspase activation. Vancomycin has indeed been shown to trigger neutrophil apoptosis. An effect of vancomycin on platelet apoptosis has, however, never been tested. The present study thus explored the effect of vancomycin on platelet activation and apoptosis. Methods: Human blood platelets were exposed to vancomycin and forward scatter was utilized to estimate cell volume, annexin V-binding to quantify phosphatidylserine (PS) exposure, Fluo-3 AM fluorescence to estimate cytosolic Ca(2+) activity ([Ca(2+)](i)), antibodies to quantify ceramide formation and immunofluorescence to quantify protein abundance of active caspase-3. Results: A 30 minutes exposure to vancomycin (≥1 µg/ ml) decreased cell volume, triggered annexin V-binding, increased [Ca(2+)](i), activated caspase 3, stimulated ceramide formation, triggered release of thromboxane B(2), and upregulated surface expression of CD62P (P-selectin) as well as activated integrin α(llb)β(3). Annexin V-binding and upregulation of CD62P (P-selectin) and integrin α(llb)β(3) was significantly blunted by removal of extracellular Ca(2+). Annexin V-binding was not significantly blunted by pan-caspase inhibitor zVAD-FMK (1 µM). In conclusion, vancomycin results in platelet activation and suicidal platelet death with increase of [Ca(2+)](i), caspase-3 activation, cell membrane scrambling and cell shrinkage. Activation and cell membrane scrambling required the presence of Ca(2+), but not activation of caspases. Conclusion: Vancomycin exposure leads to platelet activation and apoptosis.
Article: Rapid activation of FAK/mTOR/p70S6K/PAK1-signaling controls the early testosterone-induced actin reorganization in colon cancer cells[Show abstract] [Hide abstract] ABSTRACT: Actin cytoskeleton reorganization initiated by testosterone conjugates through activation of membrane androgen receptors (mAR) has recently been reported in colon tumor cells. This mAR-induced actin reorganization was recognized as a critical initial event, controlling apoptosis and inhibiting cell migration. The present study addressed the molecular signaling regulating the rapid actin remodeling initiated upon testosterone-induced mAR activation in Caco2 colon tumor cells. We report early phosphorylation of the Focal Adhesion Kinase (FAK), followed by substantial early phosphorylation of mammalian target of rapamycin (mTOR), S6 kinase (p70S6K) and the actin regulating p21-activated kinase (PAK1). Pharmacological inhibition of FAK-sensitive phosphatidylinositide-3-kinase (PI-3K), a known element of mAR-signaling, fully abrogated the testosterone-induced actin reorganization and the activation of mTOR, p70S6K and PAK1. Similarly, inhibition of mTOR blocked p70S6K and PAK1 phosphorylation and actin remodeling. Pretreatment of the cells with the intracellular androgen receptor (iAR) antagonist flutamide or silencing iAR through siRNA did not influence mTOR phosphorylation and actin reorganization, indicating specific mAR-induced testosterone effects that are independent of iAR signaling. In conclusion, we demonstrate for the first time a new mAR-governed pathway involving FAK/PI-3K and mTOR/p70S6K/PAK1-cascade that regulates early actin reorganization in colon cancer cells.
Dataset: Supplementary Material[Show abstract] [Hide abstract] ABSTRACT: Arithmetic means ± SEM (n = 10) of Annexin-V positive cells (%) after 30 min exposure to platelet buffer in the absence (0) and presence of 50 and 1000 ng/ml monomeric PGN (mPGN) and ionomycin 10 μM as a positive control. ***p < 0.001 indicates statistically significant difference to value in the absence of mPGN (one-way ANOVA). Each experiment included ionomycin 10 μM as positive control. b Arithmetic means ± SEM (n = 10) of Fluo-3AM staining for platelets stimulated 5 minutes without (0) and with monomeric mPGN (50 and 1000 ng/ml) and ionomycin 10 μM as a positive control. **p < 0.01 and ***p < 0.001 shows significant increase in Fluo-3AM fluoresecence due to Ca2+-influx (one-way ANOVA). Each experiment included ionomycin 10 μM as positive control. c Arithmetic means ± SEM (n = 8) of DiOC6 (MCF) in FACS analysis reflectin mitochondrial membrane potential of platelets following a 30 min exposure to platelet buffer in the absence (0) and presence of mPGN (50 and 1000 ng/ml), and ionomycin 10 μM as a positive control. **p < 0.01 shows significant decrease in mitochondrial membrane potential (one-way ANOVA). Each experiment included ionomycin 10 μM as positive control. d Arithmetic means ± SEM (n = 10) of the % human platelets with caspase-3 activation (%) following a 30 min exposure to platelet buffer in the absence (0) and presence of mPGN (50 and 1000 ng/ml) and ionomycin 10 μM as a positive control. ***p < 0.001 indicate statistically significant difference in comparison to the value of control (one-way ANOVA). Each experiment included ionomycin 10 μM as positive control
Article: The Inflammatory Chemokine CXC Motif Ligand 16 Triggers Platelet Activation and Adhesion Via CXC Motif Receptor 6-Dependent Phosphatidylinositide 3-Kinase/Akt Signaling[Show abstract] [Hide abstract] ABSTRACT: Rationale: The recently discovered chemokine CXC motif ligand 16 (CXCL16) is highly expressed in atherosclerotic lesions and is a potential pathogenic mediator in coronary artery disease. Objective: The aim of this study was to test the role of CXCL16 on platelet activation and vascular adhesion, as well as the underlying mechanism and signaling pathway. Methods and results: Reverse-transcriptase polymerase chain reaction, Western blotting, confocal microscopy, and flow cytometry revealed that CXCL16-specific receptor, CXC motif receptor 6, is highly expressed in platelets. According to flow cytometry and confocal microscopy, stimulation of platelets with CXCL16 induced platelet degranulation, integrin α(IIb)β(3) activation, and shape change. CXCL16 increased Akt phosphorylation (Thr(308)/Ser(473)), an effect abrogated by phosphatidylinositide 3-kinase inhibitors wortmannin (100 nmol/L) and LY294002 (25 µmol/L). The phosphatidylinositide 3-kinase inhibitors and Akt inhibitor SH-6 (20 µmol/L) further diminished CXCL16-induced platelet activation. CXCL16-mediated platelet degranulation, integrin α(IIb)β(3) activation, and Akt phosphorylation were blunted in platelets lacking CXCL16-specific receptor CXC motif receptor 6. CXCL16-induced platelet activation was abrogated in Akt1- or Akt2-deficient platelets. CXCL16 enhanced platelet adhesion to endothelium in vitro after high arterial shear stress (2000(-s)) and to injured vascular wall in vivo after carotid ligation. CXCL16-induced stimulation of platelet adhesion again was prevented by phosphatidylinositide 3-kinase and Akt inhibitors. Apyrase and antagonists of platelet purinergic receptors P(2)Y(1) (MRS2179, 100 µmol/L) and especially P(2)Y(12) (Cangrelor, 10 µmol/L) blunted CXCL16-triggered platelet activation as well as CXCL16-induced platelet adhesion under high arterial shear stress in vitro and after carotid ligation in vivo. Conclusions: The inflammatory chemokine CXCL16 triggers platelet activation and adhesion via CXC motif receptor 6-dependent phosphatidylinositide 3-kinase/Akt signaling and paracrine activation, suggesting a decisive role for CXCL16 in linking vascular inflammation and thrombo-occlusive diseases.
Article: Translational regulation of the serum- and glucocorticoid-inducible kinase-1 (SGK1) in platelets[Show abstract] [Hide abstract] ABSTRACT: Activation of platelets by thrombin opens pore forming channel protein Orai1 with subsequent store operated Ca(2+) entry (SOCE) and Ca(2+) dependent platelet granule release, integrin α(IIb)β(3) activation, adhesion, aggregation and thrombus formation. Orai1 and thus SOCE as well as platelet activation are up-regulated by the serum- and glucocorticoid-inducible kinase-1 (SGK1), which transcriptionally regulates Orai1 expression in megakaryocytes and thus determines Orai1 protein abundance in mature, circulating platelets. As platelets are devoid of nuclei, they are unable to modify protein abundance by regulation of transcription. However, they contain mRNA and thus could express novel protein by stimulation of protein translation. Translation is sensitive to actin polymerization and phosphoinositide-3-kinase (PI3K). Translational regulation of SGK1 expression has never been described before. The present study thus explored whether thrombin regulates SGK1 expression in platelets. As a result, according to RT-PCR mRNA encoding SGK1 is present in circulating platelets and significantly decreased by activation of platelets with thrombin (1 U/ml). The protein abundance of SGK1 is significantly enhanced by thrombin treatment, an effect significantly decreased by inhibition of translation with puromycin (100 nM) but not by inhibition of transcription with actinomycin (4 μg/ml). The increase of SGK1 protein abundance is blunted by inhibition of PI3K with wortmannin (100 nM) or LY294002 (25 μM), and by disruption of the cytoskeleton with cytochalasin B (1 μM). In conclusion, activation of platelets with thrombin stimulates the translation of SGK1.
- [Show abstract] [Hide abstract] ABSTRACT: Peptidoglycan (PGN), a component of bacterial cell wall and belonging to "Microbe-Associated Molecular Patterns" (MAMP) triggers host reactions contributing to the pathophysiology of infectious disease. Host cell responses to PGN exposure include apoptosis. Bacterial infections may result in activation of blood platelets and thrombocytopenia. The present study explored, whether HPLC-purified fractions of PGNs from Staphylococcus aureus 113 triggers apoptosis of platelets. To this end platelets were exposed to PGN fractions and annexin-V binding determined to depict cell membrane scrambling, DiOC6 fluorescence to estimate depolarization of mitochondrial potential, Fluo-3AM staining for intracellular Ca(2+) activity ([Ca(2+)](i)) and immunofluorescence to quantify protein abundance of active caspase-3. As a result, a 30 min exposure to monomeric fraction (mPGN) (≥50 ng/ml) was followed by annexin-V binding, paralleled by increase of [Ca(2+)](i), mitochondrial depolarization, caspase-3 activation and integrin α(IIb)β(3) upregulation. The annexin-V binding was significantly blunted by anti-TLR-2 antibodies, in absence of extracellular Ca(2+), and by pancaspase inhibitor zVAD-FMK (1 μM). In conclusion, PGN triggers apoptosis of platelets in activation-dependent manner, characterized by mitochondrial depolarization, caspase-3 activation and cell membrane scrambling.
- [Show abstract] [Hide abstract] ABSTRACT: Recent observations pointed to the ability of platelets to migrate and thus to invade the inflamed vascular wall. Platelet migration could be stimulated by stromal cell-derived factor-1 (SDF-1), an effect dependent on phosphatidylinositide-3-kinase (PI3K) and paralleled by activation and phosphorylation of Wiskott-Aldrich syndrome protein (WASP). Migration is inhibited by vinculin, which is similarly regulated by phosphorylation. PI3K-sensitive kinases include the serum- and glucocorticoid-inducible kinase 1 (SGK1). The present study explored whether SGK1 modifies WASP and vinculin phosphorylation in murine platelets and participates in the regulation of platelet migration. Platelets were isolated from gene-targeted mice lacking SGK1 (sgk1(-/-)) and from their wild type littermates (sgk1(+/+)). Platelet migration stimulated with SDF-1 was significantly less pronounced in sgk1(-/-)platelets than in sgk1(+/+) platelets. Moreover, SDF-1 significantly induced WASP phosphorylation, an effect again reduced in platelets lacking SGK1. Phosphorylation of vinculin was significantly enhanced in sgk1(-/-)platelets and was significantly reduced following treatment of platelets with Ca(2+) chelator BAPTA. Immunohistochemical analysis of in vivo experiments in intestinal vessels after vascular inflammation revealed that transmigration of platelets into inflamed vessel walls was significantly less pronounced in sgk1(-/-)than in sgk1(+/+) mice. In conclusion, SGK1 is a powerful regulator of platelet migration.
Article: Cyclophilin A affects inflammation, virus elimination and myocardial fibrosis in coxsackievirus B3-induced myocarditis[Show abstract] [Hide abstract] ABSTRACT: Extracellular cyclophilin A (CyPA) and its receptor Extracellular Matrix Metalloproteinase Inducer (EMMPRIN, CD147) modulate inflammatory processes beyond metalloproteinase (MMP) activity. Recently, we have shown that CyPA and CD147 are upregulated in patients with inflammatory cardiomyopathy. Here we investigate the role of CyPA and CD147 in murine coxsackievirus B3 (CVB3)-induced myocarditis. CVB3-infected CyPA(-/-) mice (129S6/SvEv) revealed a significantly reduced T-cell and macrophage recruitment at 8 days p.i. compared to wild-type mice. In A.BY/SnJ mice, treatment with the cyclophilin-inhibitor NIM811 was associated with a reduction of inflammatory lesions and MMP-9 expression but with enhanced virus replication 8 days p.i. At 28 days p.i. the extent of lesion areas was not affected bei NIM811, whereas the collagen content was reduced. Initiation of NIM811-treatment on day 12 (after an effective virus defense) resulted in an even more pronounced reduction of myocardial fibrosis. In conclusion, in CVB3-induced myocarditis CyPA is important for macrophage and T cell recruitment and effective virus defense and may represent a pharmacological target to modulate myocardial remodeling in myocarditis.
Article: Serum- and glucocorticoid-dependent kinase-1-induced cell migration is dependent on vinculin and regulated by the membrane androgen receptor[Show abstract] [Hide abstract] ABSTRACT: The serum- and glucocorticoid-dependent kinases 1-3 (SGK1-3) are downstream effectors of phosphatidylinositol 3-kinases, implicated in various cell responses including colon cancer tumorigenesis in mice. Here, we investigated the role of SGK1 in the regulation of cell motility. Using Caco-2 colon tumor and HEK293 embryonic kidney cells, we report that transfection with the constitutively active SGK1 mutant (SGK1-SD) significantly enhanced cell motility. The cell-adhesion protein vinculin was effectively dephosphorylated in SGK1-SD-transfected cells. Treatment of the cells with phosphatase inhibitors restored vinculin phosphorylation and inhibited cell migration, indicating a significant role for vinculin phosphorylation in SGK1-induced motility. SGK1-SD-enhanced cell motility was inhibited by activation of membrane androgen-binding sites (mAR) via testosterone-conjugates in both cell lines, whereas intracellular androgen receptor (iAR)-silencing and flutamide treatment revealed that these effects were clearly independent of the interaction of SGK1 with the classical androgen receptors (iAR). More importantly, mAR activation restored vinculin phosphorylation in SGK1-SD-transfected cells, whereas silencing of vinculin fully reversed the mAR-induced inhibition of the migratory capacity, implying that this protein is directly involved in cell motility regulation by SGK1 and mAR. This study indicates for the first time that SGK1 regulates cell migration via vinculin dephosphorylation, a mechanism that is controlled by mAR function.
Article: Chorein-sensitive polymerization of cortical actin and suicidal cell death in chorea-acanthocytosis[Show abstract] [Hide abstract] ABSTRACT: Chorea-acanthocytosis is an inevitably lethal genetic disease characterized by a progressive hyperkinetic movement disorder and cognitive and behavioral abnormalities as well as acanthocytosis. The disease is caused by loss-of-function mutations of the gene encoding vacuolar protein sorting-associated protein 13A (VPS13A) or chorein, a protein with unknown function expressed in various cell types. How chorein deficiency leads to the pathophysiology of chorea-acanthocytosis remains enigmatic. Here we show decreased phosphoinositide-3-kinase (PI3K)-p85-subunit phosphorylation, ras-related C3 botulinum toxin substrate 1 (Rac1) activity, and p21 protein-activated kinase 1 (PAK1) phosphorylation as well as depolymerized cortical actin in erythrocytes from patients with chorea-acanthocytosis and in K562-erythrocytic cells following chorein silencing. Pharmacological inhibition of PI3K, Rac1, or PAK1 similarly triggered actin depolymerization. Moreover, in K562 cells, both chorein silencing and PAK1 inhibition with IPA-3 decreased phosphorylation of Bad, a Bcl2-associated protein, promoting apoptosis by forming mitochondrial pores, followed by mitochondrial depolarization, DNA fragmentation, and phosphatidylserine exposure at the cell surface, all hallmarks of apoptosis. Our observations reveal chorein as a novel powerful regulator of cytoskeletal architecture and cell survival, thus explaining erythrocyte misshape and possibly neurodegeneration in chorea-acanthocytosis.
Article: The serum- and glucocorticoid-inducible kinase 1 (SGK1) influences platelet calcium signaling and function by regulation of Orai1 expression in megakaryocytes[Show abstract] [Hide abstract] ABSTRACT: Platelets are activated on increase of cytosolic Ca2+ activity ([Ca2+](i)), accomplished by store-operated Ca2+ entry (SOCE) involving the pore-forming ion channel subunit Orai1. Here, we show, for the first time, that the serum- and glucocorticoid-inducible kinase 1 (SGK1) is expressed in platelets and megakaryocytes. SOCE and agonist-induced [Ca2+](i) increase are significantly blunted in platelets from SGK1 knockout mice (sgk1(-/-)). Similarly, Ca2+ -dependent degranulation, integrin α(IIb)β3 activation, phosphatidylserine exposure, aggregation, and in vitro thrombus formation were significantly impaired in sgk1(-/-) platelets, whereas tail bleeding time was not significantly enhanced. Platelet and megakaryocyte Orai1 transcript levels and membrane protein abundance were significantly reduced in sgk1(-/-) mice. In human megakaryoblastic cells (MEG-01), transfection with constitutively active (S422D)SGK1 but not with inactive (K127N)SGK1 significantly enhanced Orai1 expression and SOCE, while effects reversed by the SGK1 inhibitor GSK650394 (1μM). Transfection of MEG-01 cells with (S422D)SGK1 significantly increased phosphorylation of IκB kinase α/β and IκBα resulting in nuclear translocation of NF-κB subunit p65. Treatment of (S422D)SGK1-transfected MEG-01 cells with the IκB kinase inhibitor BMS-345541 (10μM) abolished SGK1-induced increase of Orai1 expression and SOCE. The present observations unravel SGK1 as novel regulator of platelet function, effective at least in part by NF-κB-dependent transcriptional up-regulation of Orai1 in megakaryocytes and increasing platelet SOCE.


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In this session, Chango will present the findings of a new study conducted with Digiday to better understand how brands and agencies are incorporating programmatic practices into their strategies. The findings will reveal the scope of marketers that have adopted the programmatic approach, as well as insight into the specific marketing goals for which they are leveraging the approach and seeing the greatest impact. Furthermore, the results also provide an understanding of how data-driven marketers plan to refine and update their programmatic efforts in the upcoming year.

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- 2015 Winner -
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Download our exclusive free hat patterns, including Tiny Clanger,
ABBA and our adorable Owl, and help raise money for Age UK.
Once you've knitted your hats, pop them in an envelope (along with your name, address and number of hats knitted), and send them to innocent by Friday 11th December. They'll put them on their smoothie bottles and you'll be able to admire your handiwork (and others) in stores across the country from February 2016.
For every hatted bottle sold, 25p is donated to Age UK.
Send your hats to:
The Big Knit 2015, innocent drinks, 342 Ladbroke Grove, London, W10 5BU


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Why are you REALLY surfing internet dating websites test.
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in my little fantasy world, all women love surfers. so here is a challange to you ladies, to actually date one. the questions are based on real life e...
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Hi! And welcome to The Joe Satriani Test Test. Joe deserves the title of the greatest guitarist of all time... Hope you enjoy the test!
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The FA said in a statement on Tuesday that the Uruguayan international has accepted a charge of violent conduct but "has denied the FA's claim that the standard punishment of three matches is clearly insufficient for this offence".
The incident in Sunday's 2-2 Premier League draw at Anfield was not seen by match officials and is being retrospectively reviewed.
An Independent Regulatory Commission will hear the case on Wednesday. The player has already apologised to Serbian defender Ivanovic and been fined by his club.
Suarez, who scored an injury-time equaliser following the bite midway though the second half, received a seven-game ban from the Dutch FA for biting an opponent while playing for Ajax Amsterdam in 2010 shortly before he joined Liverpool.
The 26-year-old, Liverpool's top scorer in the league this term with 23 goals, served an eight-match ban for racially abusing Manchester United's Patrice Evra last season.
Uruguay captain Diego Lugano issued a statement supporting Suarez, a key member of the team fighting for a berth at the 2014 World Cup in Brazil.
"All of us who compete at a thousand revs and maximum adrenalin are prone to some mistakes," Lugano said on his personal website. "Luis is the most competitive of all. He made a mistake and said sorry.
"In the same way that a defender makes a mistake going for the attacker's leg instead of the ball or when coaches, referees, journalists or even directors make mistakes without the adrenalin of competition.
"The (Uruguay) squad support him because you see people's quality in everyday things. The people who work with him like, respect and protect him, as much in Uruguay as Holland or England. That's the most important thing in life."
The Uruguayan Football Association (AUF) is also defending Suarez from punishment by world soccer's ruling body FIFA for punching Chile defender Gonzalo Jara in a South American World Cup qualifier in Santiago last month.
FIFA opened an investigation after Argentine referee Nestor Pitana missed the incident when Suarez and Jara, who also plays for Championship side Nottingham Forest, tussled at a corner.
The AUF said Suarez reacted to provocation from Jara.
- Sports & Recreation
- Soccer


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Contact Information
This Is Northfield CVB205 3rd St W Ste B
Northfield, MN 55057
(507) 645-5604 (Phone)
(800) 658-2548 (Toll Free)
Region: Southern
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Come visit the scenic river town of Northfield for an unforgettable getaway. Come for an event — stay for the experience!
From the Defeat of Jesse James Days to the Bridge Chamber Music Festival to a summer-long Riverwalk Market Fair each Saturday, Northfield has an appreciation for history, music and the arts!
Historic downtown, Riverwalk Market Fair, Shops, Art Galleries, Museum & History Tours, Goodsell Observatory, Carleton's Japanese Garden, Cowling Arboretum, St. Olaf's Norwegian-American Historical Association, Cannon River Wilderness Area, Big Woods State Park, Performing and Visual Arts, St. Olaf, Carleton College, Northfield Historical Society, Defeat of Jesse James Days, Northfield Arts Guild
Cross-Country/Skate Skiing and Hiking at the Arboretums, Canoeing, Kayaking and Fishing on the Cannon River, Geocaching at Nerstrand Big Woods State Park, Snowmobiling, Skating, Disc Golf, Biking, Golf & Skydiving
Stay at a cozy B&B, historic inn, or hotel and enjoy fine dining options.
www.visitingnorthfield.com 1-800-658-2548
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Cemetery Stories
Call: (507) 645-9268
Watch and listen as history comes alive and tells it's story at the Northfield Historical Society's Cemetery Stories.
Tours will run October 8, 4:20–8 p.m. You can reserve your spot by calling the society at 507-645-9268, buying online at northfieldhistory.org, or by stopping by the Scriver Building at 408 Division Street.
Defeat of Jesse James Days
Call: 507-645-5604
Toll Free: 800-658-2548
Northfield, Minnesota's annual Defeat of Jesse James Days is a wild and wooly community festival that revolves around one of the most dramatic episodes of the Old West, the Great Northfield, Minnesota Bank Raid of 1876.
Held each year on the weekend after Labor Day, it celebrates the courage of a town that defied Jesse James and the James-Younger Gang and won. Horses thunder down the historic main street and bullets fly during the many authentic bank raid re-enactments that tell this amazing story. It is street theater at its best.
In addition, the celebration features professional rodeo, Northfield Arts Guild Riverfront Fine Art Festival, car shows, parades, great music, great food and plenty of activities for the family. Four days of non-stop fun, history and fellowship in an idyllic, historic river town worthy of a Norman Rockwell canvas.
Defeat of Jesse James Days captures the excitement and the pageantry of a mini state fair, the perfect punctuation to the summer season.
Malt-O-Meal Originals: An Exhibition of Firsts
Call: (507) 645-9268
Nearly one hundred years ago, John S. Campbell formed the Campbell Cereal Company with one goal in
mind: to create a delicious and easy-to-prepare hot wheat breakfast cereal. He called his cereal Malt-O-
Meal. To this day, Malt-O-Meal cereal is still manufactured in Northfield's historic Ames Mill.
The company is full of historic "firsts" like Campbell's wildly successful hot cereal. This exhibition showcases a number of examples of original Malt-O-Meal achievements from throughout the company's history. Thanks to the generosity of Campbell's family, the Northfield Historical Society will ensure that the stories of Malt-O-Meal and its connection to the community of Northfield can be told for years to come.
Outlaw Run
408 Division St
Northfield, MN 55057
Call: (507) 645-9268
Toll Free: (800) 658-2548
Get your bikes, Riders, it's time for the Outlaw Run Motorcycle Ride! The Northfield Historical Society invites you to saddle up for the 8th Annual Outlaw Run.
The event promises a great motorcycle ride through southeastern Minnesota, stops to slake your thirst and satisfy your hunger and games to play.
The Northfield Historical Society will be offering FREE tours of the Jesse James Bank Raid site during registration.
Rice County Steam and Gas Engines Show
Highway 3
Dundas, MN 55019
Call: (612) 816-3131
Annual flea market/swap meet, consignment auction and Barta Pedal Tractor Pull. Steam & Gas tractor exhibits.
-Antique tractors
-Horse drawn wagon rides
-Grain threshing
-Blacksmithing & Much More!
Riverfront Fine Arts Festival
Call: 507-645-8877
Produced by the Northfield Arts Guild the second weekend in September in conjunction with the Defeat of Jesse James Days. Well over 65 Minnesota fine artists display and sell their work along the beautiful Cannon River.
Riverwalk Market Fair
Division and 4th Street
Northfield, MN 55057
Call: (800) 658-2548
Toll Free: (800) 658-2548
Riverwalk Market Fair is a Saturday open-air market located on Bridge Square in historic downtown Northfield.This one-of-a-kind European-style market is open Saturdays from June through October. Each Saturday features a different combination of organic and sustainably grown produce from local farmers, artisan foods, seasonal flowers and a juried selection of the region's top art and fine crafts including ceramics, art works, prints, photography, glasswork, textiles, wearable art, garden sculpture and hand-crafted jewelry.
Studio Art Tour
Call: (507) 645-5604
The Studio ARTour is a co-operative venture among a group of artists in the areas around Farmington, Northfield, and Faribault. We open our studios to the public on the third weekend in October (in 2016: Oct 14,15 &16) and invite you to come out and see where and how we work.
The range of work is amazing; weaving to welding, glass to gemstones, clay to carving – and paper in between. Whether you are a long-time collector, or are just looking for something unique, the studio tour is a perfect way to shop for fine art, and best of all the tour is free!
Winter Walk
205 3rd St W Ste B
Northfield, MN 55057
Call: (507) 645-5604
Toll Free: (800) 658-2548
In the heart of the holiday season, an event takes place that draws crowds from near and far. Steaming cups of hot cocoa, the sounds of hooves clippity-clapping along the streets, and candles flickering in the breeze, creates a magically and can't miss one-night festival.
Winter Walk is set to take place on the evening of December 18, in downtown Northfield. Visitors can wander through our unique shops and enjoy beautifully decorated storefront window displays. There will be horse-drawn carriages ready to take you for a short ride, carolers strolling through downtown along with thousands of twinkling lights to guide your path! Old and young alike enjoy viewing the model train display located in the lower level of the Archer House River Inn & Suites – or watching the performance of the NAGCracker (Nutcracker) at the Northfield Arts Guild.
Santa Claus and his elves will be making an appearance as well as Frosty the Snowman and Rudolf the Red-nosed Reindeer! We hope you will join us, as we usher in the holiday season with this fun and festive event.
Voted Best Holiday Event in 2013, 2014 & 2015 by SoMinn Scene Magazine!


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10 stories you might have missed: Robert Pattinson and Kristin Stewart skipping the Oscars
Plus 'Gasland,' Lady Gaga and 'Glory Days' 'Dark Knight' and more
<< Prev Next >>
Next gallery »The stars walk the 2011 Independent Spirit Awards red carpet
« Previous galleryWho should play Whitney Houston's role in 'The Bodyguard' remake?
Jenna Elfman eyes TV return on ABC's 'Bad Mom' pilot
Her last several attempts at primetime comedy haven't been especially successful, but Jenna Elfman may be making a pilot return at the home of her biggest success.
According to Deadline.com, Elfman is in negotiations to play the lead in ABC's single-camera pilot "Bad Mom," created by Sharon Horgan.
Elfman's last ABC comedy, "Dharma & Greg" ran for five seasons and 119 episodes, earning her a Golden Globe win and three Emmy nominations. Her subsequent CBS comedies "Courting Alex" and "Accidentally on Purpose" ran for eight and 18 episodes respectively.
Photo Credit: AP


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- Report: #1037013
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Complaint Review: Management Assist INC
Management Assist INC2626 E Commercial Blvd. Ste 4, Fort Lauderdale, Florida United States of America
Management Assist INC Thomas Decker Unprofessional, unethical and doesn't serve the client's best interests Fort Lauderdale, Florida
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This report was posted on Ripoff Report on 03/22/2013 09:22 AM and is a permanent record located here: http://www.ripoffreport.com/r/Management-Assist-INC/Fort-Lauderdale-Florida-33308/Management-Assist-INC-Thomas-Decker-Unprofessional-unethical-and-doesnt-serve-the-client-1037013. The posting time indicated is Arizona local time. Arizona does not observe daylight savings so the post time may be Mountain or Pacific depending on the time of year.
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Discover the designer Stacy Adams selection at Belk. Explore our amazing Stacy Adams collection and enjoy our first class customer service and terrific free shipping deals. Shopping for designer names are a popular thing to do because it is known that these brands can be trusted for their quality and styling choices. Whether you're shopping for yourself or buying a gift for a holiday, birthday, or other special occasion, you'll find this Stacy Adams assortment appealing. Still not sure which items to choose? Our online buying guides and customer reviews make it easy to find the right item, and our simple, secure ordering process makes shopping a true pleasure. There are many places to find designer brands. However, to find the best Stacy Adams assortment with fantastic designs and superior quality, shop at Belk.


text: Sunshine Award 21 Monday Apr 2014 Posted by laurenparadis in Miscellaneous ≈ 8 Comments Tags10things, facts, factsaboutme, fun, sunshineaward Cassi from Davis To Dixie nominated me for the Sunshine Award. How nice.🙂 What is the Sunshine award: In Cassi's words it is basically: to recognize "bloggers who positively and creatively inspire others in the blogosphere". So what did I have to do? 1. Display the Award Certificate on your blog. 2. Announce your win with a post and thank the blogger who nominated you. 3. Post 10 interesting things about yourself. 4. Nominate some fellow deserving bloggers for the award. 5. Link your nominees in the post and let them know about their nomination with a comment. 10 Things About Me: 1. I couldn't sleep alone until I was a teenager. 2. I hated peanut butter as a child and now I can't get enough! 3. I was more confident with my image/weight at 13 than I am now. 4. I miss high school. 5. My mom is my best friend. 6. Relax Riesling is my favorite wine. 7. But I like beer more. 8. I work out 5 days a week, and have fun on the weekends. 9. I am loving almond butter more and more. 10. I wear too much black. So if I nominate you, you will have to do the same! Good luck and congrats.🙂 My nominees: 1. Lizzie Fit 2. A Dash Of Meg 3. Diary Of An Ex Sloth 4. The Real Life RD 5. The Little Honey Bee Share this:PinterestFacebookTumblrLinkedInGoogleTwitterLike this:Like Loading... Related


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Monster Turbine Pro Copper In-Ear Headphones
" I was selected to review these headphones in exchange for honest review, that review follows: I have used a lot of different headphones of varying prices and have been enjoying the Monster Turbine Pro Copper headphones ever since I received them. In short, they are now my IEMs of choice. Before even listening to the headphones, I was impressed by the packaging and the way I could..." --schalliol
Aurisonics Rockets Solo Precision Micro-Dynamic Noise Isolating In-Ear Headphones
"The Aurisonics Rockets was purchased by me from Hifiheadphones UK in their big clearance of Aurisonics items after it was official the Fender has now acquired Aurisonics. At the time of this review they were available from Amazon at $249:http://www.amazon.com/Aurisonics-Precision-Micro-Dynamic-Isolating-Headphones/dp/B00NP9ZML0 I'm not in any way affiliated with Aurisonics. About..." --peter123
Aurisonics ASG-2.5 Generic Fit Digital-Hybrid In-Ear Monitors in Polished Red
"Aurisonics ASG 2.5 – initial impressions I have recently picked a pair of the Aurisonics ASG-2.5 in one of the many closeout sales that are going on due to their acquisition/merger with Fender, and these are my initial impressions after burn-in and a solid week of listening. I'm still pretty new to this whole review/impressions thing, so please take it all with a pinch of salt –..." --Jackpot77
Aurisonics ASG-1PLUS
"Inspired by my great experience with the Aurisonics Rockets I caved in and bought the ASG-1PLUS as well as it was said by many that they we're the ones of the higher tier Aurisonics offerings being most similar to the Rockets. The Aurisonics ASG-1PLUS was purchased by me as an open box unit from Hifiheadphones UK. At the time of this review they were available from Amazon at..." --peter123
Miles Davis Trumpet High Performance In-ear Headphones
"Sound is neutral with a slight mid bass tilt. Highs and lows are well extended. Sound stage is large for an iem. The bass has some impact without being boomy. The treble is clear without roughness. Don't pull hard on the cable. The strain relief is not strong. Hold the Trumpet by the "mouthpiece" end when handling them. If you have the..." --Merfolk
Monster Turbine Pro Gold In-Ear Headphones
" Well, this has been quite the turn of events! I had auditioned a full-sized Monster headphone, which I felt rather negative about, but the Turbine Pro Gold (TPG from here on) caught me quite off guard. Overall, the TPGs are excellent sounding, have superior build quality to many earbuds and IEMs I've owned/seen and offer a wide array of tips for fitted comfort, so let's explore what makes..." --Landis
Aurisonics Harmony
"Intro: The Aurisonics Harmony is the top of the line earphone of the Aurisonics Bravo line, with models focused on bringing great sound at great value. The Harmony features 2 BAs and a single dynamic configuration, and is said to be their most balanced model. This item is bought by myself with no relation to Aurisonics. I paid AUD$800 and they retail for MSRP USD$499. ..." --Antihippy
Aurisonics AS-2
" Synopsis: The Aurisonics AS-2 is a high-end custom-fit in-ear stage monitor with a lively, rich sound. It has a unique, crossover-free design that allows its 15mm dynamic driver and two special balanced armatures to work together seamlessly. With an adjustable bass port system, the AS-2 provides a real bass energy in just the amount you want. Combined with a lush midrange and an accurate,..." --Kunlun
iBeats Headphones with ControlTalk From Monster® - In-Ear Noise Isolation - Black
"So I'm relatively new to the world of high end headphones, and I've started by experimenting with over the ear cans, I'll move onto IEMs eventually, but I feel like these guys get a bad rap. As for what I like, I like to listen to my electronic music, so the bright (and not overshadowed) highs and thumpy bass make for a good, enjoyable time. I wish the mids were as present, but this is..." --AtomikSound
Aurisonics ASG-2
" Introduction The ASG-2 is Aurisonics' second (official) foray into the world of iems. The guys over at Aurisonics cater primarily to the music professional crowd, and their products are generally tuned for stage use. Their original ASG-1 was a perfect example of this, with its ability to present vocals in a way that made it seem as if the notes were rolling off your own..." --eke2k6


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Women's Health
Vaginal Self-Examination (VSE)
A vaginal self-examination is a way for a woman to look at her vulva and vagina. A vaginal self-examination may help you better understand your body, the changes that take place during the menstrual cycle, and any problems that may need medical attention.
The best time to do a vaginal self-examination is between your menstrual periods. A vaginal self-examination should not replace a regular pelvic examination by your doctor.
Why It Is Done
A vaginal self-examination can be done to:
- Help you learn more about your body and what is normal for you.
- Help you check for vaginal sores, abnormal discharge, or other problems, such as genital warts.
How To Prepare
To do a vaginal self-examination, you will need:
- A small flashlight or good lighting in the room.
- A handheld mirror with a long handle.
Choose a time when you are not having a menstrual period. Do not use vaginal creams or douches before doing the examination.
How It Is Done
Take off your clothes below the waist. Have the mirror and flashlight where you can easily reach them. Wash your hands. Sit on the floor, a bed, or a couch and support your back with pillows. Bend your knees, place your feet near your bottom, lean slightly backward, and spread your knees apart so your genital area can be seen.
Hold or prop the mirror in front of your genital area. Look at the:
- Outer and inner fleshy lips of the vulva (called the labia).
- Bump of tissue covered by a hood of skin at the front of the labia (called the clitoris). The clitoris is the main area that is stimulated during sexual activity.
- Opening of the urethra where urine drains from your body.
- Opening of the vagina.
- Opening of the anus.
Have the light reflect off the mirror so you can clearly see your vaginal area. Then use your fingers to spread apart the vaginal lips. Adjust the light and mirror until you can see into the vagina. You should be able to see the reddish pink walls of the vagina, which have small folds or ridges known as rugae.
Look at your vaginal discharge. A normal discharge usually is clear to cloudy white, smells slightly acidic (like vinegar), may be thick or thin, and changes a little throughout the menstrual cycle. To learn more, see the topic Fertility Awareness.
WebMD Medical Reference from Healthwise
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Editors' Note: Clicking on the Download Now (Visit Site) button above will open a connection to a third-party site. Download.com cannot completely ensure the security of the software hosted on third-party sites.
Adobe PPD Files: Hewlett-PackardFree
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Confused? You won't be, after the next episode of "Soap!"
Er, HBT Daily. Sorry.
Confused? You won't be, after the next episode of "Soap!"
Er, HBT Daily. Sorry.
A woman from Camden County in New Jersey has filed suit against the Milwaukee Brewers after being struck by a foul ball during batting practice two years ago at Miller Park, Jeff Goldman of NJ.com reports. According to her lawsuit, she suffered an orbital fracture to her left eye socket, nerve and iris damage, and a concussion.
The woman, Dana Morelli, was in the second row behind third base along with her fiancee and his son when she was struck by the foul ball. She had to remain in a dark room in Milwaukee before being able to safely travel home. (Sensitivity to light is a common symptom of a concussion.)
Fan safety has become a hot button topic recently. This past December, Major League Baseball issued safety recommendations but ultimately left it up to each ballpark to decide by how much to extend the netting.
Earlier this month, Phillies infielder Freddy Galvis fouled off a pitch that struck a fan. After the game, he clamored for the Phillies to increase protective netting at Citizens Bank Park to extend to the seats behind the dugout, where the fan was hit. Another fan was hit the next day and Galvis threw up his hands in frustration. While fans and owners seem to mostly be against netting, the players seem to be for it.
The Cardinals have placed starter Mike Leake on the 15-day disabled list, retroactive to August 22, with shingles. Which: ugh. Anyone I've ever known who has had it wouldn't wish it on their worst enemy.
Leake was diagnosed with the virus last week and had to be scratched from his scheduled start Saturday versus the Athletics. There is no timetable for Leake's return. Leake is 9-9 with a 4.56 ERA in 25 starts for the Cardinals. Poor dude.


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Browsing SPS Articles by Author "REITER, Herbert"
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Title:Desperately Seeking Politics: Political attitudes of participants in three demonstrations for worker's rights in Italy Author(s):DELLA PORTA, Donatella; REITER, HerbertDate:2012Citation:Mobilization: An International Quarterly, 2012, Vol. 17, No. 3, pp. 349-361Type of Publication:ArticleSeries/Report no.:[COSMOS]Abstract:Social conflicts tend to take different forms. This article compares three demonstrations on issues of social justice in Italy: a traditional Labor Day demonstration, a march supporting a general strike called by the largest ...
Title:Protesta transnazionale e controllo Author(s):DELLA PORTA, Donatella; REITER, HerbertDate:2006Citation:Questione giustizia, 2006, 4, 717-739Type of Publication:Contribution to book


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The wounds of 2012 were still fresh when Auburn's seniors came together early this year. More of them than not had played two years earlier in Glendale, Ariz., when Auburn won the national championship. And they had seen it all fall apart, culminating in a 3-9 record last season.
Click here for the original story.
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text:
Saturday, 8 December 2007
"Says" or "sayeth"? The Lord doesn't "say." The Lord "sayeth." And there's the indispensable rest: "I will repay." "Vengeance is mine, " sayeth the Lord. "I will repay."
Tolstoy liked the sentiment, and found it an apt epigraph for "Anna Karenina." He uses the Church Slavonic version -- "az vozdam" for "I will repay" -- rather than the KJV in English. Can't imagine why. Foreigners -- what can you do with them?
Posted on 12/08/2007 1:37 PM by Hugh Fitzgerald
8 Dec 2007
Mary Jackson
Quite right. God, as I have said many times, is nothing if not old fashioned. From my article a while back: God spake and He smote - He did not do podcasts.


text:
- Report: #323934
Report - Rebuttal - Arbitrate
Complaint Review: BatteryJunction.com
BatteryJunction.com11 Bokum Road Unit B Essex, Connecticut U.S.A.
BatteryJunction.com Mail Order Battery Rip Off Essex Connecticut
*Author of original report: Smoke Detector Worked With Batteries Purchased Locally
*UPDATE Employee: The complaints are unjustified.
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I put the batteries in my smoke detector and within a week it started beeping. I called the security company out and they said the batteries were weak. I emailed BatteryJunciton.com to let them know I'd be sending the batteries back and they said they could not offer a refund. Here is a direct quote from their email to me. " If an item does not meet with your satisfaction for any reason, you are welcome to return it." However they refused to offer me a refund. I told them if they didn't refund my money I'd post negative feedback about them on the internet and dispute the charge on my credit card. They reluctantly agreed to refund my money.
I went to the post office to mail the batteries back and sent them certified mail which cost $3.00. To my surprise I received an email from them stating they had credited my credit card $3.20. I paid them $11.46 for the batteries. They told me that they don't refund shipping costs. So, I paid them a total of $14.46 for two batteries and received $3.20 back which leaves me in the negative $11.26. First of all it is wrong to make me pay shipping to return defective merchandise to them but to also charge me $8.26 to mail two tiny batteries is a rip off. There is no way it could have cost them that much to mail the batteries since I sent them certified mail for $3.00. I will NEVER do business with this company again. BEWARE.
Orlando, Florida
This report was posted on Ripoff Report on 04/05/2008 12:56 PM and is a permanent record located here: http://www.ripoffreport.com/r/BatteryJunctioncom/Essex-Connecticut-06426/BatteryJunctioncom-Mail-Order-Battery-Rip-Off-Essex-Connecticut-323934. The posting time indicated is Arizona local time. Arizona does not observe daylight savings so the post time may be Mountain or Pacific depending on the time of year.
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#1 Author of original report
Smoke Detector Worked With Batteries Purchased Locally
AUTHOR: Larry - (U.S.A.)
SUBMITTED: Monday, February 08, 2010POSTED: Monday, February 08, 2010
This company was not as friendly and quick as they claim they were in their rebuttal to provide me with a refund or I would not have needed to file the complaint here. When I received new batteries which I purchased locally the smoke detector worked fine.
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#2 UPDATE Employee
The complaints are unjustified.
AUTHOR: Customer Service Battery Junction - (U.S.A.)
SUBMITTED: Wednesday, July 09, 2008POSTED: Wednesday, July 09, 2008
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i need to install WordPress in a website currently already onlin. I need to create a maintenance page to display to users, when i delete old file and install the wordpress in the server. How do I install wordpress and to hide the process for users with a maintenance page?
Thanks for all!


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- Report: #884093
Report - Rebuttal - Arbitrate
Complaint Review: CCP SOLUTIONS
CCP SOLUTIONS18 BEADEL ST Brooklyn, New York United States of America
CCP SOLUTIONS owe our church $20,000 Brooklyn, New York
*UPDATE Employee: Libelous intent
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This report was posted on Ripoff Report on 05/17/2012 10:20 AM and is a permanent record located here: http://www.ripoffreport.com/r/CCP-SOLUTIONS/Brooklyn-New-York-11211/CCP-SOLUTIONS-owe-our-church-20000-Brooklyn-New-York-884093. The posting time indicated is Arizona local time. Arizona does not observe daylight savings so the post time may be Mountain or Pacific depending on the time of year.
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#1 UPDATE Employee
Libelous intent
AUTHOR: ccp response - (United States of America)
SUBMITTED: Wednesday, June 20, 2012POSTED: Wednesday, June 20, 2012
All of our customers are contracted with in writing and obligations, service and support fulfilled upon with dignity, respect and the highest degree of personal and professional ethics. We have an extraordinary level of customer retention, one of the highest in our industry, and many of our customers have been with us for more than 20 years.
If there is any customer in the future who has any question or concern...you already have our corporate package with at least 12 phone numbers and email addresses to connect with for resolution.
** While I am certain this rebuttle will illicit further libel from the person responsible for these attacks...We at CCP will not participate in this cyber bullying arena.
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I spend the vast majority of my time solo, often at odd hours when there's not many people on. Hence the most important aspect of a class is that it has to be capable of soloing as much open world 'group' stuff as possible. At the same time, I enjoy the occasional fractal or dungeon so I'd like to play something that's somewhat desirable in groups.
The main two classes I've been looking at are the Reaper and the Herald. I have an old power based necro at 80 and I'm loving both reapers shroud and the GS. However, I remember necro being relatively poor for group play due to bad sustained AoE, low damage, and very little relevant support. From what I hear, the damage is now at least competitive and the AoE seems to have been fixed by having a cleaving power weapon. Unfortunately it still seems like it's lacking damage support. Were the changes enough to make necro desirable for groups?
As for Herald, I've leveled one up to 40 and am enjoying it so far. I like the resource management gameplay and both the support and damage potential seem to be insane. My only concern is that I'm struggling with champions and other group stuff. Since it's been a very long time since I've leveled anything, I'm not sure if that's just because I'm under-geared or inexperienced or if the class in just inherently worse at soloing stuff then the reaper.
I'd greatly appreciate an advice. Sorry for the long post.
- Is the reaper desirable in groups?
- How is the herald at soloing 'group' stuff in the open world?


text:
Police blotter: Cowpens man arrested on burglary, robbery charges from 2 different incidents
Published: Thursday, December 20, 2012 at 3:15 a.m.
Last Modified: Friday, December 21, 2012 at 2:25 a.m.
Spartanburg County Sheriff's Office
A Cowpens man has been arrested on burglary and robbery charges stemming from two separate incidents.
Eddie Ricardo Oglesby, 42, of 1134 Bunche Lane, has been charged with armed robbery, grand larceny and second-degree burglary, according to arrest warrants.
On Oct. 11, investigators believe that Oglesby went into a Plainview Drive home in Spartanburg and took various household items valued between $2,000 and $10,000, a warrant states.
Oglesby also is accused of taking money from a man at knifepoint in an incident on Nov. 27, according to another warrant.
Oglesby remained at the Spartanburg County Detention Facility on Thursday on a $50,000 bond.
Reader comments posted to this article may be published in our print edition. All rights reserved. This copyrighted material may not be re-published without permission. Links are encouraged.


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The Long Long Journey
Wednesday, July 28, 2010
I have been looking at my weight loss journey as a really long rode trip. In my head, I have analogies for all sorts of things that play in this scenario. My ego, my super ego, and my id are all taking a road trip together (psychology major-based on Sigmund Freud's parts of the psyche) and our destination is really my goal weight. My ego, which is the rational part of my psyche, has been driving throughout most of this journey. The id, which is the pleasure seeking part of the psyche, has wanted chocolate and other things throughout the whole trip, and keeps asking �are we there yet�. She is like a very whiney child. The ego gives in sometimes and has let the id have small portions of what she wants because we all need to be happy. The super ego, which is the moralistic part, always points out that the small piece cake is still going to take us off schedule. She sometimes insists that we spend extra time working out to make up for it. A few times we listened to her, and we did not stop for gas, even though we really needed it. We were stuck at the side of the rode not going anywhere for 3 weeks because we did not have enough fuel to move forward (although it felt like the engine was still running). Sometimes, she makes us feel bad for not being on schedule. The ego keeps driving and looks for ways to balance everyone's needs.
There are those times that I have been stuck in traffic. I am doing everything right, but I am not moving..., or I am just moving so slow that it feels like I am not moving. I know if I just stay in my car going the right way, then I will get there. I occasionally had to find an alternative route, but usually the traffic just clears up and I start moving again.
Then there are those times that I lose my way. That darn id wanted to stop for food or drinks or the super ego had us run out of gas, and then I get on the freeway going the wrong direction. As soon as I realize that I am going the wrong way, I look for an offramp so I can turn myself back around. I am not �starting over�. Starting over implies that I am back at the beginning, and dismisses the part of the journey that I have already traveled. I just lost some time. It puts me behind schedule, but I know I do not give up. It's was just a short detour. I am sure we have all gotten on the freeway in the wrong in direction. How many of us go, �oh well, maybe I should just go home�..., no, you just get off and go back the correct direction. No big deal..., but you do lose time. Those stops can kill time too, but you know you need to eat and fuel up, or else there is no energy for the drive.
Sparkpeople is like a really good map..., maybe even GSP. It will help you get there, but you still have drive. Oh.., and the friends I have made on sparkpeople are a bit like having auto club. They have been quite helpful on the journey and are there when you need them.
Well, I am way off schedule right now. I was suppose to be there about four to six months ago. I have taken a big detour lately, and I have gotten a little lost the last few months. I think I might have even let the id drive for a while. I know I haven't check the map as often, and the weather has been a bit stormy. I lost and gained part of 13 pounds several times now. I think the ego was tired and needed a short break (she has been dealing with bigger things). On this half of the journey, our speed limit seems to be slower than it was in the beginning of the trip. At first, I lost 8-12 pounds a month, and two years later (and 160 pounds lighter) I think I am only capable of about 5 a month. So, this 13 pounds is probably going to take me a few months just to get back to where I was. I am ready to get back on that rode and tell that id to be quite for a while. My husband, who has been unemployed for the last six months, is suppose to start a new job next week. Maybe I can keep the id happy with some new clothes or cute shoes, like putting on a DVD for a child. I haven't been able to give the id much these days, and think that's why we have to keep stopping for food. Often, she will shut up, if she knows she is getting something out of it or is distracted. My super ego has been distracted with issues pertaining to money, time, and work, so she hasn't speaking up much when we are off track on food. Either way, I need to get back on the rode in the right direction with the ego back at the wheel. Balance needs to be restored. I will reach my destination. Hopefully..., soon, but until then, I will just enjoy the ride. Oh look, a rainbow!!!
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I always love reading your blogs, Jeannie- so full of insight! Thank you for sharing.. I know the rest of your journey is going to be amazing.
2208 days ago
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My SparkPage
Wonderful blog! My tranny keeps slipping, so I am having trouble keeping it in gear....
2209 days ago
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Thanks for sharing your journey with us.
2210 days ago
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I love your analogies!!!
2217 days ago
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You're so awesome!
2218 days ago
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What a GREAT blog! You've got it!
2218 days ago
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This whole thing would be so much easier without an id, huh?
2218 days ago
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You sure have some great insights and similes in this blog. I really like the comparison of traveling correcting navigation errors.
I think that you have done an amazing job with your juggling act and trying to keep your family moving forward during trying times. Now, you can move forward on your journey to health.
2219 days ago
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