text:
Inhibition of protein geranylgeranylation induces apoptosis in synovial fibroblasts
- Alison M Connor1,
- Stuart Berger1,
- Aru Narendran2 and
- Edward C Keystone3Email author
DOI: 10.1186/ar1968
© Connor et al.; licensee BioMed Central Ltd. 2006
Received: 23 February 2006
Accepted: 4 May 2006
Published: 14 June 2006
Statins, competitive inhibitors of hydroxymethylglutaryl-CoA reductase, have recently been shown to have a therapeutic effect in rheumatoid arthritis (RA). In RA, synovial fibroblasts in the synovial lining, are believed to be particularly important in the pathogenesis of disease because they recruit leukocytes into the synovium and secrete angiogenesis-promoting molecules and proteases that degrade extracellular matrix. In this study, we show a marked reduction in RA synovial fibroblast survival through the induction of apoptosis when the cells were cultured with statins. Simvastatin was more effective in RA synovial fibroblasts than atorvastatin, and both statins were more potent on tumor necrosis factor-α-induced cells. In contrast, in osteoarthritis synovial fibroblasts, neither the statin nor the activation state of the cell contributed to the efficacy of apoptosis induction. Viability of statin-treated cells could be rescued by geranylgeraniol but not by farnesol, suggesting a requirement for a geranylgeranylated protein for synovial fibroblast survival. Phase partitioning experiments confirmed that in the presence of statin, geranylgeranylated proteins are redistributed to the cytoplasm. siRNA experiments demonstrated a role for Rac1 in synovial fibroblast survival. Western blotting showed that the activated phosphorylated form of Akt, a protein previously implicated in RA synovial fibroblast survival, was decreased by about 75%. The results presented in this study lend further support to the importance of elevated pAkt levels to RA synovial fibroblast survival and suggest that statins might have a beneficial role in reducing the aberrant pAkt levels in patients with RA. The results may also partly explain the therapeutic effect of atorvastatin in patients with RA.
Rheumatoid arthritis (RA) is a chronic inflammatory disease causing progressive joint destruction, deformity and disability. The pathogenesis of the rheumatoid joint involves hyperplasia of the synovial lining cells, mononuclear cell infiltration and new blood vessel formation within the synovium as well as the destruction of cartilage and underlying bone as a consequence of pro-inflammatory cytokines and proteases [1]. Much of the pathology is thought to be driven by cytokines, particularly tumor necrosis factor α (TNF-α) [2].
Synovial tissue consists primarily of two distinct cell types: the macrophage-like synoviocytes and synovial fibroblasts. The synovial fibroblasts are important in all aspects of the pathogenesis of arthritis. Hyperplasia of the synovial lining in RA is due primarily to increases in the number of synovial fibroblasts. Although the reason for this increase is currently unknown, impaired apoptosis or senescence has been proposed to explain their increased numbers [3].
The RA synovial fibroblast response to the macrophage-derived cytokines TNF-α and IL-1 includes elevated expression of adhesion molecules, cytokines and chemokines. RA synovial fibroblasts also secrete angiogenesis-promoting molecules such as vascular endothelial growth factor A and several proteases, including matrix metalloproteinases, aggrecanases and cathepsins, that mediate extracellular matrix degradation [4].
TNF-α is capable of signaling both cell-survival and cell-death signals. The response of a cell to TNF-α depends on specific adaptors and downstream signaling molecules [5]. The addition of TNF-α to RA synovial fibroblasts results in resistance to apoptosis and hence to increased survival as well as proliferation [6]. Recent reports have indicated that it is possible to reverse the survival response of RA synovial fibroblasts to TNF-α by inhibiting the translocation of nuclear factor κB to the nucleus [7], or ectopically expressing TIMP (tissue inhibitor of metalloproteinases) 3 [8]. The ability to reverse resistance of fibroblast-like synoviocytes (FLS) to apoptosis could represent an important therapeutic target in arthritis [9].
Statins, competitive inhibitors of hydroxymethylglutaryl (HMG)-CoA reductase, were initially designed as inhibitors of cholesterol synthesis [10]. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, a rate-limiting step in cholesterol biosynthesis. However, statins seem to have anti-inflammatory effects that cannot be accounted for by their lipid-lowering abilities. These include the suppression of proinflammatory cytokine and chemokine production, immunomodulation and the downregulation of endothelial cell activation [11, 12]. As a consequence of these properties, statin therapy has been examined in several chronic immune-mediated inflammatory diseases including experimental autoimmune encephalomyelitis and arthritis. The statin simvastatin has been shown to exhibit a therapeutic effect in the collagen-induced arthritis (CIA) model of RA [13]. It was thought to exert its effect through decreasing the viability of T helper type 1 cells and attenuating the interaction of T cells with macrophages. In contrast with these results, another study showed that neither atorvastatin nor rosurvastatin had a beneficial effect on the mouse CIA model of arthritis. The results of simvastatin could be accounted for by severe side effects [14]. Nevertheless, atorvastatin was found to have a therapeutic effect in patients with RA as well as beneficially influencing inflammatory markers [15].
Some of the beneficial effects of statins can be explained by the fact that the inhibition of mevalonate synthesis by statins also prevents the synthesis of other intermediates along the cholesterol biosynthetic pathway. These include the isoprenoid intermediates geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP), which are required for the prenylation of many cellular proteins such as the small GTP-binding proteins Ras, Rho and Rac [16]. Isoprenylation enables the insertion of these proteins into the cellular membrane, where they function in intracellular signal transduction pathways [17]. It is significant that statins have also been shown to induce apoptosis, mediated by inhibition of the synthesis of FPP and GGPP [18–20].
Because reduced apoptosis of synovial fibroblasts in RA is thought to be a cause of synovial hyperplasia, statins could theoretically reduce joint damage by interfering with synovial fibroblast survival. The aim of the present study was therefore to determine whether statins could substantially reduce RA synovial fibroblast survival and whether one statin would be particularly effective. Our data suggest that simvastatin is significantly more effective than atorvastatin at decreasing the viability of RA synovial fibroblasts, particularly in the presence of TNF-α. This contrasts with the viability of synovial fibroblasts derived from patients with osteoarthritis (OA), in whom no differential effect of the statins was observed. The decreased viability of RA synovial fibroblasts with statins was shown to be mediated by the inhibition of membrane-associated geranylgeranylated proteins and was associated with decreased pAkt levels.
Materials and methods
Synovial tissue
The protocol for patient consent and the use of human tissues was approved by ethics review committees at both the University Health Network and St Michael's Hospital. All tissue was obtained with patient consent.
Cell culture
Synovial fibroblasts were isolated from synovial tissues of patients with RA or OA removed at the time of arthroplasty, as described previously [21]. Cells were maintained in Opti-MEM supplemented with 4% fetal bovine serum and 1% antibiotic-antimycotic (Life Technologies, Rockville, MD, USA) and were cultured at 37°C in a humidified chamber containing 95% air, 5% CO2. Synovial fibroblasts were used at passages 2 to 4. Unless indicated otherwise, cells used for Western blots were plated at 105 cells per well in a six-well plate for 48 hours before initiation of experiments.
Effect of statins on cellular viability
Stock solutions of lovastatin (Sigma-Aldrich, Oakville, Ontario, Canada) and atorvastatin (Toronto Research Chemicals, North York, Ontario, Canada) were prepared in dimethylsulfoxide (DMSO). Cerivastatin (Toronto Research Chemicals) was prepared in PBS and simvastatin (Calbiochem, La Jolla, CA, USA) was activated and neutralized in accordance with the manufacturer's directions. Recombinant human TNF-α was purchased from R&D Systems Inc. (Minneapolis, MN, USA). GGPP and FPP, sodium 3-(1-(phenylamino-carbonyl)-3, 4-tetrazolium)-bis (4-methoxy-6-nitro) benzenesulfonic acid hydrate (XTT), and phenazine methosulfate (PMS) were obtained from Sigma-Aldrich. Synovial fibroblasts (n = 6 RA, n = 6 OA) were plated in 100 μl at a concentration of 3 × 104 cells/ml in a 96-well plate. Before treatment with statin or carrier control, they were cultured for 24 hours in the presence or absence of 10 ng/ml TNF-α. Statins were then added to the wells and cells were continued to be cultured for the duration indicated in the figure legends. Where indicated, synovial fibroblast cultures were supplemented with 5 μM FPP or 5 μM GGPP at the time of statin addition [22]. Cellular viability was determined by the XTT assay on quadruplicate wells [23]. XTT (1 mg/ml; 50 μl) and 1 μl of 1.25 mmol (PMS) were added to each well and plates were cultured for a further 4 hours. Colour development was measured at 490 nm with a reference wavelength of 650 nm.
Phase partitioning
RA synovial fibroblasts were incubated for 72 hours with 3 μM simvastatin in the presence or absence of 5 μM FPP or 5 μM GGPP. Integral membrane proteins were extracted by Triton X-114 as described [24]. In brief, 200 μl of lysis solution (10 mM Tris-HCl pH 7.4, 150 mM NaCl, 1.0% Triton X-114) was added to each well of a six-well culture plate and incubated on ice for 30 minutes. Samples were scraped from the plate and overlaid on a sucrose cushion. After a 3-minute incubation at 30°C they were centrifuged at 300 g for 3 minutes to separate the phases. The upper aqueous phase was rinsed twice; then Triton X-114 and buffer were added to the aqueous and detergent phases, respectively, to yield equal volumes and approximately the same salt and detergent concentration in both fractions. Samples were separated on a 12% SDS-polyacrylamide gel. Fractionated proteins were transferred to a poly(vinylidene difluoride) membrane (Immobilon-P; Millipore Corp, Bedford, MA, USA). Membranes were blocked for 1 hour in blocking buffer (10 mM Tris pH 7.5, 2.5 mM EDTA, 100 mM NaCl, 0.1% Tween 20) containing 3% gelatin, and then probed with anti-RhoA (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) or anti-Rac1 (BD Biosciences, Mississauga, Ontario, Canada) for 1 hour. After being washed, membranes were incubated with a goat anti-mouse IgG conjugated to horseradish peroxidase secondary antibody (Sigma-Aldrich) for a further 1 hour, and bands were revealed by enhanced chemiluminescence (ECL; Amersham Pharmacia Biotech, Baie d'Urfe, Québec, Canada).
Cell Death Detection ELISA
Cytoplasmic histone-associated DNA fragments associated with apoptotic cell death were determined quantitatively with the Cell Death Detection ELISAPLUS (Roche Molecular Biochemicals, Mannheim, Germany). Cells were plated at 1.5 × 104 cells per well in a 24-well plate and treated for 72 hours with DMSO or with 3 or 10 μM lovastatin in the presence or absence of 5 μM FPP or 5 μM GGPP as indicated. Cells were lysed with 200 μl of lysis buffer; 20 μl was then added to the microtiter plate followed by 80 μl of immunoreagent. After incubation for 2 hours at room temperature, the plate was washed and developed with ABTS (2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)) solution. Each experimental condition was performed in duplicate.
TUNEL (TdT-mediated dUTP nick end labelling) staining of synovial fibroblasts
RA synovial fibroblast apoptotic nuclei were detected by a TdT-FragEL DNA fragmentation kit in accordance with the manufacturer's directions (Oncogene Research Products, Cambridge, MA, USA). Cells were plated at 2 × 104 per chamber of a two-well chamber slide and treated for 72 hours with DMSO or 10 μM lovastatin in the presence or absence of 5 μM FPP or 5 μM GGPP as indicated in the figure legends. After TUNEL staining, cells were counterstained with hematoxylin. This was performed on two different lines.
Analysis of phosphorylated proteins
RA synovial fibroblasts were treated with DMSO or 3 μM lovastatin for 48 hours and subsequently cultured for 15 minutes with 10 ng/ml TNF-α or 2 ng/ml IL-1 (R&D Systems Inc, Minneapolis, MN, USA). Cells were then rinsed twice with PBS and lysed in 20 mM Tris pH 7.5, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 mM β-glycerolphosphate, 0.5 μg/ml leupeptin, 0.2 mM phenylmethylsulphonyl fluoride. Protein concentrations were determined by the micro bicinchoninic acid (BCA) protein assay kit (Pierce, Rockford, IL, USA) to enable comparable sample loading on a 12% SDS-polyacrylamide gel. SDS-PAGE was performed as described for the phase partitioning. pJNK (Thr183/Tyr185), pERK and pAkt (Ser473) antibodies were obtained from Cell Signaling Technology (Beverly, MA, USA). Prehybridization and hybridization were performed in accordance with the manufacturer's protocol. Blots were scanned and band intensities were measured with the UN-SCAN-IT version 5.1 software (Silk Scientific, Orem, UT, USA). Relative amounts of protein were expressed as multiples of the solvent control.
Blots were stripped between probings with Re-Blot-Plus (Chemicon International, Inc., Temecula, CA, USA).
To confirm the involvement of geranylgeranylated proteins in FLS survival and pAkt expression, siRNA for Rac1 (target sequence 5'-AACCGGTGAATCTGGGCTTAT-3') was transfected into RA synovial fibroblasts (n = 3) plated at 6.0 × 104 cells per well of a six-well plate or 3 × 103 cells per well of a 96-well plate, at an siRNA to RNAiFect Reagent (Qiagen Inc., Mississauga, Ontario, Canada) ratio of 1:4.5. In preliminary experiments, a non-silencing control siRNA labeled with Alexa Fluor 488 was monitored by fluorescence microscopy. The conditions used in this study resulted in a cell transfection efficiency of greater than 95%. The medium was changed 18 hours after transfection. XTT assays were performed and cell lysates were prepared 96 hours after transfection as described above.
Results are presented as means ± SD. Significant differences between groups were analysed by using a two-tailed unpaired Student t test; p < 0.05 was considered statistically significant.
Statins decrease synovial fibroblast viability
Statins decrease the viability of TNF-α-stimulated synovial fibroblasts
Because TNF-α is an important driver of RA pathology, we investigated the effects of statins on TNF-α-stimulated proliferation of synovial fibroblasts. Preliminary time-course experiments ranging from 24 to 96 hours (not shown) revealed that similarly to non-treated synovial fibroblasts, those pretreated with TNF-α exhibited decreased viability in a time-dependent manner. As depicted in Figure 3, both statins were able to decrease the viability of TNF-α-stimulated RA synovial fibroblasts (n = 6). In TNF-α-stimulated RA synovial fibroblasts, simvastatin caused a marked reduction in synovial fibroblast viability compared with atorvastatin both at 3 μM (35 ± 11% versus 67 ± 13%, respectively; p = 0.0008) and at 10 μM (2 ± 5% versus 23 ± 6%, respectively; p = 8 × 10-5). Reduced RA synovial fibroblast viability was observed in TNF-α-stimulated cells compared with unstimulated cells at 10 μM for both simvastatin (p = 0.003) and atorvastatin (p = 0.02). As with unstimulated OA synovial fibroblasts, simvastatin reduced the viability of TNF-α-stimulated OA synovial fibroblasts (n = 6) to a greater extent than atorvastatin, but no statistically significant differences were observed at 3 μM. In contrast with RA synovial fibroblasts, there were no differences between TNF-α-stimulated and unstimulated OA synovial fibroblasts with either statin at 3 μM or 10 μM. There was a significant difference in reduction in viability between TNF-α-stimulated RA synovial fibroblasts compared with OA synovial fibroblasts at 10 μM, both with simvastatin (p = 0.02) and with atorvastatin (p = 0.007). These differences were not explained by differences in the degree of stimulation of OA and RA synovial fibroblasts to TNF-α (p = 0.72 for the atorvastatin control; p = 0.33 for the simvastatin control). Taken together, these results show that although TNF-α stimulates OA and RA synovial fibroblasts equally, RA synovial fibroblasts show a further decrease in viability in the presence of statins.
Geranylgeranylpyrophosphate restores the viability of RA synovial fibroblasts in the presence of statins
Geranylgeranylated proteins are redistributed to the cytoplasm in the presence of statins
Reduced RA synovial fibroblast viability with statins results from apoptosis
The Akt survival pathway is inhibited by statins in RA synovial fibroblasts
siRNA-directed inhibition of Rac1 reduces RA synovial fibroblast viability and pAkt levels
We have shown that statins decrease RA synovial fibroblast viability in a concentration-dependent and time-dependent manner. Simvastatin is significantly more effective than atorvastatin at inhibiting RA synovial fibroblast survival. Similar differences in the efficacy of different statins have been reported previously in tumor-specific apoptosis [28]. The difference between simvastatin and atorvastatin was even greater in cells preactivated with TNF-α. Although both statins also decreased OA synovial fibroblast survival, there was no significant difference between them in their ability to reduce survival. Moreover, they were not significantly more effective in reducing OA synovial fibroblast survival in the presence of TNF-α. Taken together, these data suggest that in RA synovial fibroblasts, statins are inhibiting TNF-α regulated synovial fibroblast survival, enabling TNF-α to function as an apoptotic signal rather than as a survival signal. Our results demonstrated that all of the statins examined seem to exert their effects in a similar manner through the inhibition of a geranylgeranyl pyrophosphate intermediate, resulting in a loss of membrane-associated geranylgeranylated proteins and a subsequent reduction in viability of synovial fibroblasts. All statins consist of a dihydroxyheptanoic group that mimics mevalonate, but they have different chemical substituents elsewhere on the molecule that can lead to differences in their efficacy [29]. It is therefore possible that differences in the efficacies of the statins on RA synovial fibroblast viability result from differences in the molecules other than the dihydroxyheptanoic group. These differences account for differences in the bioavailability of the statins and the active metabolites generated by the cytochrome P450 family of enzymes [30].
As far as we are aware, this is the first report to implicate geranylgeranylated proteins in synovial fibroblast viability. The presence of this pathway in both OA and RA synovial fibroblasts suggests that it is a constitutive pathway in synovial fibroblast biology. However, the inhibition by GGPP of the statin effect on TNF-α-stimulated RA synovial fibroblasts suggests that in RA synovial fibroblasts, TNF-α is signaling through the same pathway that is required for their overall viability and that this pathway requires a functional geranylgeranylated protein. This pathway differs in RA synovial fibroblasts compared with OA synovial fibroblasts, as demonstrated by the significant difference in the effect of statins between TNF-α-stimulated and non-stimulated RA synovial fibroblasts not seen with OA synovial fibroblasts.
The data in this study also show that the statins affect the Akt pathway in RA synovial fibroblasts. Previous studies have demonstrated that synovial tissue obtained from patients with RA expresses higher levels of pAkt than that derived from patients with OA [31]. It was also demonstrated that elevated pAkt levels account for the anti-apoptotic response of synovial fibroblasts to both TNF-α and transforming growth factor-β, suggesting that elevated pAkt might contribute to the establishment of synovial hyperplasia observed in patients with RA [31, 32]. The phosphoinositide 3-kinase/Akt pathway is being increasingly recognized as playing a major role in synovial fibroblasts. It is used in response to TRAIL (TNF-related apoptosis-inducing ligand) [33], the transmission of IL-18 signals leading to VCAM (vascular cell adhesion molecule) expression [34] and the production of IL-6 and IL-8 stimulated by IL-17 [35]. The results presented in the present study lend further support to the importance of elevated pAkt levels to synovial fibroblast survival and suggest that statins might have a beneficial role in reducing the aberrant pAkt levels in patients with RA.
Experiments with siRNA technology implicated Rac1 in synovial fibroblast survival. Additional experiments are currently under way to determine whether other geranylgeranylated proteins contribute to synovial fibroblast survival. We also demonstrated decreased levels of pAkt in these cells. These data suggest that a survival signal is propagated in synovial fibroblasts via a membrane-associated geranylgeranylated protein, Rac1 with subsequent pAkt activation. These data are consistent with other studies of Rac1-regulated Akt resulting in an anti-apoptotic signal [36–38].
The results of this study have several implications for the therapeutic use of statins in patients with RA. In the TARA study of patients with RA, atorvastatin significantly improved the swollen joint count, C-reactive protein, erythrocyte sedimentation rate, fibrinogen, soluble intercellular adhesion molecule 1 (sICAM1) and IL-6 [15]. Because synovial fibroblasts synthesize sICAM1 and IL-6 it is possible that the decreased level observed results in part from atorvastatin-driven decreased synovial fibroblast viability. If this were so, our studies suggest that simvastatin might be more effective than atorvastatin in patients with RA. Previous investigation demonstrated that the administration of simvastatin in a CIA model resulted in decreased proliferation of T cells, but it was not reported whether this resulted from apoptosis [13]. There is the possibility that the effect of statins might be cell type specific, a concept supported by differential effects of statins on human lung fibroblasts, human atrial myofibroblasts, and lymphoma tumour cells compared with human pancreatic islets and microglia [19, 39–42].
Our results show that the pathway affected by statins in RA synovial fibroblasts is also a TNF-α anti-apoptotic pathway. We are currently dissecting these pathways with a view to discerning new therapeutic targets for RA.
Statins attenuate the insertion of geranylgeranylated proteins into the plasma membrane with a resultant decrease in viability and increased apoptosis of synovial fibroblasts. A significant difference in the efficacy of simvastatin from that of atorvastatin was observed in both activated and non-activated RA synovial fibroblasts but not OA synovial fibroblasts, suggesting a fundamental difference in their intracellular signaling pathways. The intracellular redistribution of geranylgeranyl proteins resulting from treatment with statin is correlated with decreased activation of Akt, a pathway previously identified as being anti-apoptotic in synovial fibroblasts. These results suggest that statins, particularly simvastatin, might have a beneficial role in reducing aberrant pAkt levels in the synovial fibroblasts of patients with RA, with the resultant decrease in synovial hyperplasia.
= collagen-induced arthritis
= dimethylsulfoxide
= fibroblast-like synoviocytes
= farnesylpyrophosphate
= geranylgeranylpyrophosphate
= hydroxymethylglutaryl
= interleukin
= osteoarthritis
= phosphate-buffered saline
= rheumatoid arthritis
- siRNA:
= short interfering RNA
- TNF-α:
= tumor necrosis factor-α
- XTT = sodium 3-(1-(phenylamino-carbonyl)-3:
4-tetrazolium)-bis (4-methoxy-6-nitro) benzenesulfonic acid hydrate
= TdT-mediated dUTP nick end labelling.
We thank Dr E Bogochfor providing surgical samples and Ms K Griffith Cunningham for coordinating the tissue collections. This study was funded by The Younger Foundation.
Authors' Affiliations
- Firestein GS: Evolving concepts of rheumatoid arthritis. Nature. 2003, 423: 356-361. 10.1038/nature01661.View ArticlePubMedGoogle Scholar
- Feldmann M, Brennan FM, Foxwell BM, Taylor PC, Williams RO, Maini RN: Anti-TNF therapy: Where have we got to in 2005?. J Autoimmun. 2005, 26-28. 10.1016/j.jaut.2005.09.006.Google Scholar
- Mor A, Abramson SB, Pillinger MH: The fibroblast-like synovial cell in rheumatoid arthritis: akey player in inflammation and joint destruction. Clin Immunol. 2005, 115: 118-128. 10.1016/j.clim.2004.12.009.View ArticlePubMedGoogle Scholar
- Davis LS: A question of transformation: the synovial fibroblast in rheumatoid arthritis. Am J Pathol. 2003, 162: 1399-1402.PubMed CentralView ArticlePubMedGoogle Scholar
- Gupta S, Gollapudi S: Molecular mechanisms of TNF-alpha-induced apoptosis in aging human T cell subsets. Int J Biochem Cell Biol. 2005, 37: 1034-1042. 10.1016/j.biocel.2004.08.013.View ArticlePubMedGoogle Scholar
- Youn J, Kim HY, Park JH, Hwang SH, Lee SY, Cho CS, Lee SK: Regulation of TNF-alpha-mediated hyperplasia through TNF receptors, TRAFs, and NF-κB in synoviocytes obtained from patients with rheumatoid arthritis. Immunol Lett. 2002, 83: 85-93. 10.1016/S0165-2478(02)00079-2.View ArticlePubMedGoogle Scholar
- Zhang HG, Huang N, Liu D, Bilbao L, Zhang X, Yang P, Zhou T, Curiel DT, Mountz JD: Gene therapy that inhibits nuclear translocation of nuclear factor κB results in tumor necrosis factor alpha-induced apoptosis of human synovial fibroblasts. Arthritis Rheum. 2000, 43: 1094-1105. 10.1002/1529-0131(200005)43:5<1094::AID-ANR20>3.0.CO;2-V.View ArticlePubMedGoogle Scholar
- Drynda A, Quax PH, Neumann M, van der Laan WH, Pap G, Drynda S, Meinecke I, Kekow J, Neumann W, Huizinga TW, et al: Gene transfer of tissue inhibitor of metalloproteinases-3 reverses the inhibitory effects of TNF-alpha on Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. J Immunol. 2005, 174: 6524-6531.View ArticlePubMedGoogle Scholar
- Pope RM: Apoptosis as a therapeutic tool in rheumatoid arthritis. Nat Rev Immunol. 2002, 2: 527-535. 10.1038/nri846.View ArticlePubMedGoogle Scholar
- Endo A: The origin of the statins. Atheroscler Suppl. 2004, 5: 125-130. 10.1016/j.atherosclerosissup.2004.08.033.View ArticlePubMedGoogle Scholar
- Palinski W, Tsimikas S: Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis. J Am Soc Nephrol. 2002, 13: 1673-1681. 10.1097/01.ASN.0000018400.39687.8C.View ArticlePubMedGoogle Scholar
- Blanco-Colio LM, Tunon J, Martin-Ventura JL, Egido J: Anti-inflammatory and immunomodulatory effects of statins. Kidney Int. 2003, 63: 12-23. 10.1046/j.1523-1755.2003.00744.x.View ArticlePubMedGoogle Scholar
- Leung BP, Sattar N, Crilly A, Prach M, McCarey DW, Payne H, Madhok R, Campbell C, Gracie JA, Liew FY, McInnes IB: A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol. 2003, 170: 1524-1530.View ArticlePubMedGoogle Scholar
- Palmer G, Chobaz V, Talabot-Ayer D, Taylor S, So A, Gabay C, Busso N: Assessment of the efficacy of different statins in murine collagen-induced arthritis. Arthritis Rheum. 2004, 50: 4051-4059. 10.1002/art.20673.View ArticlePubMedGoogle Scholar
- McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N: Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004, 363: 2015-2021. 10.1016/S0140-6736(04)16449-0.View ArticlePubMedGoogle Scholar
- Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature. 1990, 343: 425-430. 10.1038/343425a0.View ArticlePubMedGoogle Scholar
- Resh MD: Regulation of cellular signalling by fatty acid acylation and prenylation of signal transduction proteins. Cell Signal. 1996, 8: 403-412. 10.1016/S0898-6568(96)00088-5.View ArticlePubMedGoogle Scholar
- Guijarro C, Blanco-Colio LM, Ortego M, Alonso C, Ortiz A, Plaza JJ, Diaz C, Hernandez G, Egido J: 3-Hydroxy-3-methylglutaryl coenzyme A reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res. 1998, 83: 490-500.View ArticlePubMedGoogle Scholar
- van de Donk NW, Schotte D, Kamphuis MM, van Marion AM, van Kessel B, Bloem AC, Lokhorst HM: Protein geranylgeranylation is critical for the regulation of survival and proliferation of lymphoma tumor cells. Clin Cancer Res. 2003, 9: 5735-5748.PubMedGoogle Scholar
- Bifulco M: Role of the isoprenoid pathway in ras transforming activity, cytoskeleton organization, cell proliferation and apoptosis. Life Sci. 2005, 77: 1740-1749. 10.1016/j.lfs.2005.05.017.View ArticlePubMedGoogle Scholar
- Scott BB, Weisbrot LM, Greenwood JD, Bogoch ER, Paige CJ, Keystone EC: Rheumatoid arthritis synovial fibroblast and U937 macrophage/monocyte cell line interaction in cartilage degradation. Arthritis Rheum. 1997, 40: 490-498.View ArticlePubMedGoogle Scholar
- Crick DC, Andres DA, Waechter CJ: Novel salvage pathway utilizing farnesol and geranylgeraniol for protein isoprenylation. Biochem Biophys Res Commun. 1997, 237: 483-487. 10.1006/bbrc.1997.7145.View ArticlePubMedGoogle Scholar
- Roehm NW, Rodgers GH, Hatfield SM, Glasebrook AL: An improved colorimetric assay for cell proliferation and viability utilizing the tetrazolium salt XTT. J Immunol Methods. 1991, 142: 257-265. 10.1016/0022-1759(91)90114-U.View ArticlePubMedGoogle Scholar
- Bordier C: Phase separation of integral membrane proteins in Triton X-114 solution. J Biol Chem. 1981, 256: 1604-1607.PubMedGoogle Scholar
- Perez-Sala D, Mollinedo F: Inhibition of isoprenoid biosynthesis induces apoptosis in human promyelocytic HL-60 cells. Biochem Biophys Res Commun. 1994, 199: 1209-1215. 10.1006/bbrc.1994.1359.View ArticlePubMedGoogle Scholar
- Deshpande SS, Angkeow P, Huang J, Ozaki M, Irani K: Rac1 inhibits TNF-alpha-induced endothelial cell apoptosis: dual regulation by reactive oxygen species. FASEB J. 2000, 14: 1705-1714. 10.1096/fj.99-0910com.View ArticlePubMedGoogle Scholar
- Sanlioglu S, Luleci G, Thomas KW: Simultaneous inhibition of Rac1 and IKK pathways sensitizes lung cancer cells to TNFalpha-mediated apoptosis. Cancer Gene Ther. 2001, 8: 897-905. 10.1038/sj.cgt.7700394.View ArticlePubMedGoogle Scholar
- Wong WW, Tan MM, Xia Z, Dimitroulakos J, Minden MD, Penn LZ: Cerivastatin triggers tumor-specific apoptosis with higher efficacy than lovastatin. Clin Cancer Res. 2001, 7: 2067-2075.PubMedGoogle Scholar
- Mason RP, Walter MF, Day CA, Jacob RF: Intermolecular differences of 3-hydroxy-3-methylglutaryl coenzyme areductase inhibitors contribute to distinct pharmacologic and pleiotropic actions. Am J Cardiol. 2005, 96: 11F-23F. 10.1016/j.amjcard.2005.06.008.View ArticlePubMedGoogle Scholar
- Schachter M: Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005, 19: 117-125. 10.1111/j.1472-8206.2004.00299.x.View ArticlePubMedGoogle Scholar
- Zhang HG, Wang Y, Xie JF, Liang X, Liu D, Yang P, Hsu HC, Ray RB, Mountz JD: Regulation of tumor necrosis factor alpha-mediated apoptosis of rheumatoid arthritis synovial fibroblasts by the protein kinase Akt. Arthritis Rheum. 2001, 44: 1555-1567. 10.1002/1529-0131(200107)44:7<1555::AID-ART279>3.0.CO;2-M.View ArticlePubMedGoogle Scholar
- Kim G, Jun JB, Elkon KB: Necessary role of phosphatidylinositol 3-kinase in transforming growth factor beta-mediated activation of Akt in normal and rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2002, 46: 1504-1511. 10.1002/art.10314.View ArticlePubMedGoogle Scholar
- Miyashita T, Kawakami A, Tamai M, Izumi Y, Mingguo H, Tanaka F, Abiru S, Nakashima K, Iwanaga N, Aratake K, et al: Akt is an endogenous inhibitor toward tumor necrosis factor-related apoptosis inducing ligand-mediated apoptosis in rheumatoid synovial cells. Biochem Biophys Res Commun. 2003, 312: 397-404. 10.1016/j.bbrc.2003.10.141.View ArticlePubMedGoogle Scholar
- Morel JC, Park CC, Woods JM, Koch AE: A novel role for interleukin-18 in adhesion molecule induction through NF κB and phosphatidylinositol (PI) 3-kinase-dependent signal transduction pathways. J Biol Chem. 2001, 276: 37069-37075. 10.1074/jbc.M103574200.View ArticlePubMedGoogle Scholar
- Hwang SY, Kim JY, Kim KW, Park MK, Moon Y, Kim WU, Kim HY: IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-κB- and PI3-kinase/Akt-dependent pathways. Arthritis Res Ther. 2004, 6: R120-128. 10.1186/ar1038.PubMed CentralView ArticlePubMedGoogle Scholar
- Nishida K, Kaziro Y, Satoh T: Anti-apoptotic function of Rac in hematopoietic cells. Oncogene. 1999, 18: 407-415. 10.1038/sj.onc.1202301.View ArticlePubMedGoogle Scholar
- Murga C, Zohar M, Teramoto H, Gutkind JS: Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-κB. Oncogene. 2002, 21: 207-216. 10.1038/sj.onc.1205036.View ArticlePubMedGoogle Scholar
- Gonzalez E, Kou R, Michel T: Rac1 modulates sphingosine 1-phosphate-mediated activation of phosphoinositide 3-kinase/Akt signaling pathways in vascular endothelial cells. J Biol Chem. 2006, 281: 3210-3216. 10.1074/jbc.M510434200.View ArticlePubMedGoogle Scholar
- Tan A, Levrey H, Dahm C, Polunovsky VA, Rubins J, Bitterman PB: Lovastatin induces fibroblast apoptosis in vitro and in vivo. A possible therapy for fibroproliferative disorders. Am J Respir Crit Care Med. 1999, 159: 220-227.View ArticlePubMedGoogle Scholar
- Contreras JL, Smyth CA, Bilbao G, Young CJ, Thompson JA, Eckhoff DE: Simvastatin induces activation of the serine-threonine protein kinase AKT and increases survival of isolated human pancreatic islets. Transplantation. 2002, 74: 1063-1069. 10.1097/00007890-200210270-00001.View ArticlePubMedGoogle Scholar
- Porter KE, Turner NA, O'Regan DJ, Balmforth AJ, Ball SG: Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA. Cardiovasc Res. 2004, 61: 745-755. 10.1016/j.cardiores.2003.11.032.View ArticlePubMedGoogle Scholar
- Bi X, Baudry M, Liu J, Yao Y, Fu L, Brucher F, Lynch G: Inhibition of geranylgeranylation mediates the effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors on microglia. J Biol Chem. 2004, 279: 48238-48245. 10.1074/jbc.M405442200.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


text:
Can a vegan person get a good meal at this restaurant?
Does this restaurant have parking?
Is this restaurant good for special occasions?
Can a gluten free person get a good meal at this restaurant?
Is this restaurant romantic?
Is this restaurant good for business meetings?
Is this restaurant good for lunch?
Is this restaurant good for dinner?
Is this restaurant good for breakfast?
Does this restaurant offer delivery?
Thanks for helping!
The spring rolls were unbelievable, I would go back just for them. The price was reasonable and the staff very friendly. If you are in this area it is worth checking out.
Relaxing and inviting music greeted us as we walked in.The restaurant may look small but the food was great. My daughter and husband came with me. The spring rolls, clay pot eggplant, and lemongrass chicken in the banana leaf were marvelous and overall it was great!
Thank you Amira for taking time to review Laugh Cafe. We appreciate your comments.
The service here was slow. We waited quite a long time for our meals and we were the only customers in the restaurant. In fact, we almost left as we had to get to our tour at a certain time.
However, the food was decent and they are an NGO organisation (although I am not sure where the money goes...
Thank you for your review. The NGO details are available at the front of the menu. MAD Indochina has been working in SE Asia for more than ten years.
Laugh cafe was set up to train young Vietnamese in how to run a restaurant. We teach then English, restaurant and kitchen management, hygiene and safety, cooking, and service and presentation...
This is a great little cafe. The food is delicious and cheap. It is also away from all the city noise. I wish we were here longer so we could go back and have another meal here. ^^The wontons and coconut cakes were amazing. The staff is also kind and helpful.
We went here on our last day in Hoi An for lunch. We were actually headed somewhere else, which turned out to be closed, so we stopped in here as it looked promising. Overall, we were pleased with our choice - the food was good, and the prices were reasonable. The service was fine, though nothing special. This is a...
The food here is just as good as the places in the main town center, but a quarter of the price. I think it's definitely worth it to get out of the crazy toursity section and come here for a meal.
Located on a side street a few blocks outside of the Old City is this great little café. The menu has a good selection of simple Asian and Western dishes. The veggie omelette tastes even better when stuffed into the accompanying crispy, freshly baked banh mi (bread). The Boss looks serious and non-talkative, but we'll cut him some slack... it's...
I bought a mango shake- it was delicious- not too sweet but could definitely taste the mango. Pleasant staff.
Food is pretty good and the staff is so nice and friendly. We liked it a lot to stay here.
And I don't like that TripAdvisor is telling me now that I have to Tltext more about a restaurant. Lovely TripAdvisor, it's my decission and my opinion how much I want to share or talk about something.
Please accept this.
Just enjoyed a nice relaxing breakfast, perfectly cooked eggs and really fresh bread. Friendly service and good prices, a little out of the main tourist roads which meant less noise and hawkers. Worth a visit and supports local charity.
Own or manage this property? Claim your listing for free to respond to reviews, update your profile and much more.
When do you do your next cooking class?
I stay right now in your Restaurant and enyoing coffee and fruit salad.
I am in hoi an in August and want to check the price of a private cooking class for me and my wife. Also is it best to book online or call in during our stay to gaurantee the lessons availability.
what time are you open till at night ?
See all questions

subset: commoncrawl


text:
Ginger Cookies
|1⁄2 Cup (8 tbs)
|Brown sugar
|1⁄2 Cup (8 tbs)
|1⁄2 Cup (8 tbs)
|Unbleached white flour
|1⁄2 Cup (8 tbs)
|Whole wheat flour
|1 Cup (16 tbs)
|Soy flour
|1⁄4 Cup (4 tbs)
|Brewer's yeast
|2 Tablespoon
|Non-fat dry milk powder
|1⁄2 Cup (8 tbs)
|1⁄4 Teaspoon
|Baking soda
|2 Teaspoon
|Ground ginger
|3 Teaspoon (Or To Taste)
|Ground cinnamon
|1 Teaspoon
|Wheat germ
|1⁄4 Cup (4 tbs)
|Brown sugar
|1⁄4 Cup (4 tbs)
1. Preheat the oven to 350 degrees.
2. Cream the butter and 1/2 cup sugar together until light and fluffy. Beat in the molasses and egg.
3. Sift together the unbleached white flour, whole wheat flour, soy flour, yeast, dry milk, salt, baking soda, ginger, and cinnamon.
4. Stir the sifted dry ingredients into the creamed mixture. Stir in the wheat germ. Mix until the ingredients are well blended.
5. Form the dough (it's fairly soft) into balls the size of a walnut. Roll in sugar and place 2 inches apart on an oiled baking sheet.
6. Bake for about 15 minutes, or until lightly browned and the tops are crackled. Cool on a wire rack.
Recipe Summary
Rate It
Nutrition Rank
Nutrition Facts
Serving size: Complete recipe
Calories 3222 Calories from Fat 942
% Daily Value*
Total Fat 110 g168.7%
Saturated Fat 61.3 g306.5%
Trans Fat 0 g
Cholesterol 468 mg156%
Sodium 3711.7 mg154.7%
Total Carbohydrates 504 g167.9%
Dietary Fiber 35.4 g141.7%
Sugars 276.2 g
Protein 84 g168.7%
Vitamin A 62.6% Vitamin C 7%
Calcium 130.8% Iron 177.1%
*Based on a 2000 Calorie diet


text:
This project received 12 bids from talented freelancers with an average bid price of $908 USD.Get free quotes for a project like this
Project BudgetN/A
Total Bids12
Project Description
Need about 50 000 upload adult xxx videos mp4. or flv. format without any ads on video. Only Freelancers with experience in adult industry.
Skills Required
Looking to make some money?
- Set your budget and the timeframe
- Outline your proposal
- Get paid for your work
Hire Freelancers who also bid on this project
Looking for work?
Work on projects like this and make money from home!Sign Up Now
- Forbes
- The New York Times
- Time
- Wall Street Journal
- Times Online


text:
Jump Main Menu. Go directly to the main content (Acces key S)
Languages block
End of languages block
Utilities block
End of utilities block
You are in:
Start of main content
He holds an Electronic Superior Engineering Degree from the University of Navarra.
Along his professional career he has hold different posts in companies like GKN Automotive International (1987-1998) where he held the post of CEO in the United States and General Director of the Group for America, among others. Likewise he was Deputy General Director to the Chairman of Alcatel España (1998-1999), General Director of Operations in Europe in GKN Automotive Internacional (1999-2001) and Deputy Chairman in CIE Automotive, where he previously held the posts of Chief Executive Officer (2002-2010) and Executive Deputy Chairman (2010-2011).
Currently he is Independent Director in Bankoa-Credit Agricole. Likewise he is Director in the Board of Directors of APD (Asociación para el Progreso de la Dirección) and member of the Strategic Committee of CEIT.
Technical Engineering Degree from the Bilbao School of Engineering. He is the Chairman of ENCE Energía y Celulosa, Viña Izadi and Foresta Capital. Director of GRL Aceite and First Deputy Chairman of Cartera Industrial Rea.
He holds an Industrial Metallurgic Engineering Degree and an Economics Degree from the University of País Vasco. Chairman of the Board of Directors of Giroa (Grupo Veolia) and member of the Patronato and of the Strategic Board of the Centro de Estudios e Investigaciones Técnicas de Gipuzkoa (CEIT).
She holds a Degree in Economics and Business from the Universidad Autónoma of Madrid and completes her training as post graduated at ICEA, IESE and Centro de Estudios Financieros. She is Compliance Chief Officer at Iberdrola.
He holds a Degree in Telecommunications Engineering from the Polytechnic University of Madrid. He is "Ad Honorem" Professor and permanent member of the Royal Academy of Engineering. Nowadays he is advisor of Telefónica and member of some of the Telefonica's subsidiaries, as well as member of the Board of Directors of Indra Sistemas and ENCE Energía y Celulosa.
State's Attorney. Holds a Degree in Law from the Universidad Pontificia Comillas (ICADE). Currently he is the Director of Global Legal Services of Regulation and Corporate Issues in the Iberdrola Group.
Electronic Techinal Engineer by the University of Mondragón. He has hold different posts in companies like Cipresi, Fagor Electrónica and Mondragón Corporación, in which he held, among others, the posts of Deputy Chairman and Chairman of the General Board. He is Director of VISCOFAN.
Degree in Industry Engineering from the University of Navarra with a specialization in Industrial Organization and completed his studies with a Master in Business Administration in the IESE. Throughout his professional career he held different posts in the private and public sector, among others he was General Director of Sodena (Sociedad de Desarrollo de Navarra) and Assistant to the Chairman of Grupo Cementos Portland Valderrivas. Currently he is member of the Board of the Consultora Altair and founding partner of Tangle Research.
Civil Engineer by the Polytechnic University of Valencia and Program of Development of Senior Management in the Management School of IESE Business School (University of Navarra). Along his professional career he has hold different posts in Hidroeléctrica Española and in the Iberdrola group, as well as posts in the Board of Directors of several companies. Until February 1, 2016 he held the post of general director of Networking Business of the Iberdrola group.
She studied at the Complutense University of Madrid, where she obtained a degree in Economic Sciences with a specialty in Economic Theory.
He holds a Master's in Electrical Engineering from the Escuela de Armería in Eibar, and a Master's in Human Resources from CEREM.
He holds a Law Degree from the Complutense University of Madrid. Over the last few years, he has performed the tasks of Director of or Secretary to the Board of Directors, among other positions, in the following companies: Audiovisual Española 2000, S.A., Construcciones Sarrión and Rodríguez-Quiroga Abogados.
End of main content


text:
The manuscript, named after a line from a news story about a fire at a circus, was rejected by publishers and confined to a filing cabinet for decades. Now, for the first time, this legendary collaboration between two of the 20th century's most influential writers is being released. Both a fascinating piece of American literary history and an engrossing, atmospheric novel, it brings to life a shocking murder at the dawn of the Beat Generation.
Walk the Beat with Jack Kerouac and William S. Burroughs.
©2008 the Estate of Jack Kerouac and the William S. Burroughs Trust; (P)2008 Blackstone Audio, Inc.
"Pre-Beat Lit, instant classic!"
I was skeptic... lost book? Burroughs and Kerouac? Does the phrase "too good to be true" come to mind. Yet, to my delight, this could turn out to be one of my favorite pieces of midcentury counter-culture lit. Jack and William take turns with chapters, allowing a really neat multi-perspective view of the controversial plot. Ray does a great job reading, as usual. The epilogue is a great treat, the true story behind the novel.
"Not a great story."
Put into the context of a biography written many years before the characters/authors of the Beat Generation, this story is interesting.
As a stand alone piece, the story is not very good.
I have a passion for all things science, music, and outdoors. I am also a "crazy dog lady."
historical, shocking, honest
The movement between chapters made it impossible to stop listening.
I felt like I was listening to the authors telling their story.
Dare I say this may be my favorite Kerouac?
"I tried."
I wish I had read the other reviews before I bought this. It's awful. I can't even finish it and I ALWAYS finish any book I've started. It just makes no sense; it's very difficult to follow along.
Report Inappropriate Content
If you find this review inappropriate and think it should be removed from our site, let us know. This report will be reviewed by Audible and we will take appropriate action.


text:
Celebrating Local Higher Education Missouri has long been known for quality higher education. Continuing that tradition, it was recently announced that Missouri State University – West Plains was ranked sixth in the Best Community College category for the 2013 Washington ...Read More »
Republican Women's Club Welcomes Special Guests To Aug. 20 Meeting
The Douglas County Republican Women's Club met on Aug. 20 at 5 p.m. Karry Davis, Douglas County Clerk, was the guest speaker. She gave a summary of her duties which include sending out forms to all schools and other entities ...Read More »
Douglas County Republicans Will Host Meeting On What's Happening In Jefferson City
The Douglas County Republican Committee is presenting a public forum about what is happening in Jefferson City. The meeting will be held at 7 p.m. Thursday, Sept. 5, at Ava Victory Academy. Admission to this educational event is free of ...Read More »
Congressman Jason Smith: Park Service Rescinds Permit Requirements For River Baptisms
On Thursday, Aug. 22, one day after it was made public that the Ozark National Scenic Riverways would restrict baptisms in some Missouri streams, Congressman Jason Smith announced the Park Service had reversed course and would no longer require permits ...Read More »
Smith Report 8.22.2103
Work-A-Day Tour Proves Washington Does Not Have the Answers Last week I spent time working various jobs throughout our Eighth Congressional District on a Work-A-Day Tour. My goal in touring the district and working local jobs was to meet new ...Read More »
Cong. Jason Smith Seeks Answer on Baptism Permits
SALEM – Congressman Jason Smith sent a letter to Ozark National Scenic Riverways Superintendent Bill Black seeking answers on news that the Ozark National Scenic Riverways will now require a permit and 48-hour notice before baptisms can occur in riverways. ...Read More »
Missouri Natural Gas Bills On The Way Up? Half-Billion in Surcharges Waiting on Gov. Nixon's Desk
JEFFERSON CITY, Mo. – Gov. Jay Nixon vetoed five bills last week, but one that remains on his desk is of concern to the Consumer Council of Missouri and AARP Missouri. It's a natural gas surcharge bill that allows utilities ...Read More »
Missouri Chamber Deeply Disappointed With Gov. Nixon's Veto of Unemployment System Reforms, Feels The Veto Is Completely Political
On July 2, Gov. Nixon vetoed House Bill 611, legislation containing provisions that would keep Missouri in compliance with federal mandates and protect money that is critical to Missouri's unemployment insurance system. The legislation also contains a provision that would ...Read More »
Governor Nixon Signs Senate Bill 1 And Secures Workers' Comp Reforms After Years Of Impasse
Employers will be facing significantly less financial and legal liability as a result of Senate Bill 1, which Gov. Nixon signed into law today. At the same time, hundreds of injured workers will now receive the benefits they are due. ...Read More »
Smith Report: 6.20.2013
At the end of my first week representing Missouri's Eighth Congressional District in the United States House of Representatives I filed legislation to add a Balanced Budget Amendment to the U.S. Constitution. For the last several months I have talked ...Read More »


text:
Read Family Circus Chapters 1-4 Hentai Manga Online Manga Info :
rewrite,english,big breasts,family circus
Description:Mama Consoling her son who attempted suicide because he cannot get a girlfriend
love this comic
just so much awesomeness!!!!
omg I died from laugher at the ending after the "next Morning" nurse goues like "'da fuck?" omg I'm dead from laugher
i have a little sister that looks alot likr her she's in middle school now and she says boys are asking her out what should i do? T~T
Awesome 🙂 I hope there's more chapters after this one ^ ^ some doujin series gets you hooked :p
lol yaya for wincest XD
yeah, I get that error as well. High res will have to do 😛
IF this is how they treat us in hell Then I'm glad that I have a space in hell with my name on it…
wow . . .mikan . . .
No better education than the real thing.
Fuck yeah.
nice artwork and colouring but short~ X(
The 7th one came out. Hasn't been translated yet though.
The mother of the girl needs to die
Ah, I missed this one. I'm 8 months late.
i thnik they should make more karin dojins ecxept add more machi cuz she's awesome too
looks good to me, lol. First download ftw, I suppose =] Thanks much
rotfl at hermit crab


text:
Although it has been three years since the financial crisis began, there will be a decade of higher unemployment and lower home prices, a new study finds. The study, conducted by husband and wife economists Vincent and Carmen Reinhart, looks at past economic crises, such as the Great Depression and the 1973 oil shock, and the state of the economy 10 years before the crisis, the year it hit and 10 years later. Ten years after downturns, unemployment historically remains "significantly higher," median housing prices are 10% to 15% lower, and per-capita GDP growth is also much lower than it was before the crisis, the study says.
Full Story:NPR.org


text:
Lil Kim's New Mixtape is Here: Listen"It always seems like it's a time every year when everyone's either playing my music or paying homage with some of my most iconic looks."
Drake's 'Summer Sixteen' Gets Lil' Kim RemixLil' Kim brings a sharp tongue to her version.
Lil Kim Drops New Remix Track, Promises New AlbumKim drops some overtly sexual rhymes like these were her Hardcore days.
Diddy To Drop Free 'MMM' MusicThe release will feature collaborations with Lil Kim, French Montana, Future and Wiz Khalifa.
Strangest Celebrity Baby Names of 2014These celebrities stepped out with some of the strangest names for their kids for 2014
Lil Kim Remixes Beyonce's 'Flawless'Ah, rivalries. What fun.
Iggy Azalea's 'Fancy' Breaks Chart Record for Female RappersIt doesn't take a chart to know that Iggy Azalea's smash single "Fancy," featuring Charli XCX on the hook, is massive.
Hot Right Now - Kim Talks Booty Selfie And Kanye, Miley Dresses As Lil Kim For Halloween, Rihanna Gets Hand TattooKim Kardashian was on The Tonight Show last night with Jay Leno talking about her weight gain during pregnancy and her infamous booty selfie she took a few weeks ago.
Beyonce & Andre 3000 Cover Amy Winehouse For 'Great Gatsby' Soundtrack
[PHOTO] Lil' Kim's Plastic Surgery Leaves Her Unrecognizable
Lil Kim Rep Denies Queen Bee's Drake Diss: "Please Disregard The Nonsense"A representative for Lil Kim is walking back statements that had her criticizing Young Money rhymer Drake for his alleged role in last Wednesday's bottle-throwing incident with Chris Brown.
The Notorious B.I.G. Remembered


text:
I went on a garden tour today called Inside the Garden Gate. Interesting
to see what other people do. What really surprised me was at least half of
the 7 gardens grew Purple Loosestrife quite proudly. And Chameleon Plant
and almost every one. Yikes! Another odd thing I noticed at one home was
she had about 10 of those stone benches around the property and not one you
could sit on. She used the to put pots on. Hidden wat in the back ( I
like to see work areas) by the compost heap was a broken down skinny piece
of wood shaped into a bench. The only place to sit. odd.
> [Original Message]
> From: Donna <email@example.com>
> To: <firstname.lastname@example.com>
> Date: 6/21/2003 9:55:08 AM
> Subject: [CHAT] Hum.......
> So what is everyone doing this weekend.... figuring since it is so
> quiet, everyone must be having great weather and busy in the garden....
> or something...
> I have a meeting in a few minutes, then out of here myself. May hit a
> few nurseries on the way home. I have a few holes in the garden that
> need something, well that's my excuse for shopping for more plants and I
> am sticking to it!:)
> Donna
> ---------------------------------------------------------------------
> To sign-off this list, send email to firstname.lastname@example.com with the
> message text UNSUBSCRIBE GARDENCHAT
To sign-off this list, send email to email@example.com with the
message text UNSUBSCRIBE GARDENCHAT


text:
Added to Cart
Kogan 1800W Portable Induction Cooker
Extended Care Options
Kogan 1800W Portable Induction Cooker
Faster, safer cooking
See delivery information
Enjoy delicious food anywhere with this portable cooker that utilises magnetic induction technology to cook your meals faster.
- Cook food 25 – 50% faster
- Use for camping, boating, in apartments or as an extra cooktop
- Stay safe with no open flame
- Enjoy quick, precise temperature adjustment
The Kogan 1800W Portable Induction Cooker provides a simple, fast and energy efficient way of cooking all your meals. Instead of a flame or traditional heating element, the Induction Cooker uses a high frequency magnetic field to heat the cooking vessel. This method, as well as being extremely quick, is also safe, since there is no open flame.
Unlike regular electric stovetops, the heat is distributed evenly, and temperature adjustments occur rapidly, so your food can be cooked to perfection.
- Super fast induction technology
- Energy efficient
- Safety overheat protection
- Rapid temperature adjustment
- Even heating
- Easy to clean
- Timer
- LED display
NOTE: Flat based conductive cookware such as iron, cast iron or carbon steel cookware is necessary for use with this cooktop. Only cookware made of such ferromagnetic materials will work with this item.
This Product is offered and supplied by Dick Smith pursuant to the Terms and Conditions.
Frequent searches leading to this pageportable cooker inductioninduction cookerportable induction cookerinduction cooker portable1101400107879
Related CategoriesAppliances - Air ConditionersAppliances - Air HumidifiersAppliances - Air PurifiersAppliances - Bundle & Save!Appliances - Carpet & Steam CleanersAppliances - Coffee MachinesAppliances - Cooking AppliancesAppliances - DishwashersAppliances - FansAppliances - Food Mixer AttachmentsAppliances - Food PreparationAppliances - FridgesAppliances - HeatersAppliances - Irons & Garment SteamersAppliances - Jewellery CleanersJuicersKettlesMicrowavesOutdoor AppliancesOutdoor Fridges/FreezersOvens & CooktopsPizza OvensScales (Kitchen)Steam Mop Refill PadsToasters & GrillsVacuum Cleaner AccessoriesVacuum CleanersWashing Machines & Dryers


text:
Women's apparel retailer J.Jill goes public
Online sales for J.Jill are growing and hit $228 million for the 12 months ended Oct. 29.
Women's apparel retailer J.Jill goes public
Online sales for J.Jill are growing and hit $228 million for the 12 months ended Oct. 29.
Sycamore Partners buys The Limited for $26.75 million
The apparel chain filed for bankruptcy in January and closed its e-commerce site and stores.
Sign up for IRNewsLink and get daily reports delivery to your inbox. Sign Up Now
Sponsored by 2013 Social Media 300
1 - 8 of 8 Results
Marketers are learning new ways to optimize e-mail and pay-per-click campaigns. When it comes to social networks and mobile, it's all new.
Posted 12/29/2009Internet RetailerPost a comment
The e-commerce director is a fixture in retail organization charts. But Sears is among the first to have an m-commerce chief.
Posted 05/29/2009Internet RetailerPost a comment
When it comes to getting as close as possible to customers, tiny text messages hit the bull's-eye.
Posted 12/29/2008Internet RetailerPost a comment
Related Content:Footwear Return Rate
In addition to launching a mobile retail site at m.QVC.com, QVC Inc. is trumping almost all of the small but growing number of retailers in m-commerce by offering a text message purchasing program.
Posted 09/30/2008Internet RetailerPost a comment
A handful of m-commerce sites and services are employing a strategy that encourages shoppers to access mobile offerings while in stores.
Posted 12/31/2007Internet RetailerPost a comment
Mobile mini-shopping mall seeks maximum revenue from minimal effort
Posted 06/01/2007Internet RetailerPost a comment
Outdoor gear and apparel retailer Moosejaw Mountaineering has launched a mobile shopping site that enables shoppers to browse, compare prices and purchase merchandise using any mobile phone or handheld device. The retailer also lets customers receive order-tracking information on their mobile devices.
Posted 06/01/2007Internet RetailerPost a comment
Transactional e-mails can build relationships and increase sales with well-designed promotional messages, Silverpop Systems Inc. research says.
Posted 02/01/2007Internet RetailerPost a comment


text:
by: be1ay • 114
All Android applications categories
All Android games categories
by: be1ay • 114
This application will help you to store data about your salary in a convenient form. Selecting the year and then a month you can write or see the salary for the selected month. The program also calculates the salary for the year and the calculation of average salary per month.
Tags: salary , salary packages , salary range , salary package , google salary , salaries packages in , salary in , salaries , salary package in
Users review
from 114 reviews
Download Salary
Free - V184.108.40.206.6 - 250K
More actions


text:
SQLSaturday is a free training event for Microsoft Data Platform professionals and those wanting to learn about SQL Server, Business Intelligence and Analytics. This event will be held on Jul 12 2014 at Patrick Hays Learning Center, 2700 Gateway Oaks Drive, Suite 2600, Sacramento, California, 95833, United States
Register Now!
The Sacramento SQL Server User Group is hosting our third SQLSaturday this year!When:Saturday, July 12, 2014, 7:30 AM to 5:30 PMWhere:Patrick Hays Learning Center2700 Gateway Oaks Drive, Suite 2600Sacramento, CA 95833What:SQLSaturday is a training event for SQL Server professionals and those wanting to learn about SQL Server. Admittance to this event is free, but we do charge a lunch fee of $8.00 so that we can provide a lunch. Please register soon as seating is limited, and let friends and colleagues know about the event.Schedule:Click here to see the schedule for this event.
We are pleased to offer two pre-conference seminars on Friday, July 11, 2014. Chose either Kalen Delaney's "What the Hekaton!?" or Stacia Misner's "SSRS Rookie to Rockstar!". Each pre-con is a full day of training available for purchase via the Eventbrite links below.
When:Friday, July 11, 2014, 8:30 AM to 4:30 PMWhere:Patrick Hays Learning Center2700 Gateway Oaks Drive, Suite 2600Sacramento, CA 95833What:What the Hekaton!? A Whole Day on a Whole New Way to Think About Data Management. SQL Server Hekaton, Microsoft's new In-Memory table technology being shipped as part of SQL Server 2014, will completely change the way you think about data management. As a DBA, you'll need to analyze your memory and storage needs completely differently. All Hekaton data is always stored in memory, and the data stored on disk is basically just a REDO log used to regenerate the contents of your memory-optimized tables. In this full-day seminar, Kalen Delaney (a SQL Server MVP for over 20 years) will show you the in-memory architecture for your Hekaton data and indexes, and discuss what gets written to disk during checkpoints, as well as what gets logged. She will explain how the recovery process recreates your Hekaton tables. Finally, she'll go into detail on just what it is that makes Hekaton so much FASTER!For more information, or to register to join us for this precon event, please click here:
When:Friday, July 11, 2014, 8:30 AM to 4:30 PMWhere:Patrick Hays Learning Center2700 Gateway Oaks Drive, Suite 2600Sacramento, CA 95833What:Join this introduction to SQL Server Reporting Services, designed specifically for report developers who have no prior experience with the product, and learn how to use the development tools effectively, how to present and enhance data in a report, and how to create dynamic reports. Even if you have some experience with Reporting Services, this session will explore aspects that aren't intuitive or well-documented, helping you expand your skills and make the most of this powerful reporting tool.For more information, or to register to join us for this precon event, please click here:
To register for SQLSaturday #312 in Sacramento on July 12, 2014, click here:
Jim Murphy
Jonathan Amen
Jason Horner
Mickey Stuewe
Angel Abundez
Steve Wake
Kevin Boles
Randy Knight
Andrew Nakamura
Michael Fal
SQL Saturday Sacramento 2016 (#540) will be held on July 23, 2016. Call for speakers and attendee registration is now open!
Speaker Steve Wake mentioned us in his blog: http://blog.wakebi.com/2014/05/june-presentations.html
SQL Solutions Group speaker info: http://www.sqlsolutionsgroup.com/events/sqlsaturday-312-sacramento/
SQL Solutions Group event sponsor press release: http://www.sqlsolutionsgroup.com/sql-solutions-group-sponsors-sacramento-sqlsaturday-event/
Blog post by speaker Mitch Bottel: http://mitchespitch.com/2014/06/13/coming-soon-sql-saturday-312/
Contact the Organizer
Glenn Burnett


text:
For an ideal user experience, please update your flash player. Click here to download the latest version of Adobe Flash.
You have 4000 characters left.
You reached the maximum length of this message (4000 characters).
what a classy woman
Very talented. Liked her for many years. // Pstrik, leavin
She is great. Somehow I am not though. Was nice to meet her. Wont forget her. P
Thanks babe - great!
sory. where r u from?
hot women... nice...
A long time keeper that always was respectful to me. She looks awesome. But I never looked for that. She is a clever and fun person I respect. //Patrik
You reached the maximum length of this message(4000 characters).
The site contains sexually explicit material. Enter ONLY if you are at least 18 years old and agree to our cookie rules.
18 U.S.C. 2257 Record-Keeping Requirements Compliance Statement
This site is owned and operated by Duodecad IT Services Luxembourg S.à.r.l.
© 2017 LivePrivates.com - All Rights Reserved!


text:
DJ/producer Gunnar Stiller has seen Berlin transform considerably over the last couple of decades, soaking in influence as well as helping shape its development as a musical force, becoming a fixture of the city's scene along the way. Whether playing in clubs around the world such as Panorama Bar in Berlin, Studio 80 Amsterdam, Glow Bangkok and Agwa in Sydney or producing his own tracks for respected labels like Upon.You Records, Clap Your Hands or Voltage Musique, Stiller's technique is deep in character, an outward-reaching combination of techno and house with his trademark funk-tinged basslines.
View the full artist profile
Open You
Open You (Layo & Bushwacka! remix)
Track unavailable


text:
The Oscars and Beyond: An...
Make Up For Ever: You've built up an enviable career as a makeup artist, working with some of the biggest names in Hollywood and on some...Read more
Make Up For Ever: You've built up an enviable career as a makeup artist, working with some of the biggest names in Hollywood and on some...Read more
I remember my first red. Up until then, I had always played around with a pinkish brown color palette that could sometimes veer towards a light brick red. But...Read more
Jabe arrived in Paris from his native Guadeloupe when he was just sixteen. Launching himself into the world of makeup after a foray into painting, Jabe's work has been featured in Vogue...Read more
The energy is electric. Every inch of the narrow hallways that wind behind the stage are hung with huge feathered headpieces and crystal and sequin-encrusted costumes. Dancers and dressers...Read more
Dany Sanz, Founder, Artistic Director of MAKE UP FOR EVER, and confirmed observer of the world around her, recently shared another of her favorite inspiring things...Read more
Having been at MAKE UP FOR EVER for 11 years, four of them behind the counter at the MAKE UP FOR EVER store, Ludovic is now part of the inner sanctum. Dany Sanz...Read more
Part 1: Driving & Thinking Every morning I drive from my home in Chatou to my other home in Paris, the MAKE UP FOR EVER offices. It would take an hour if I took...Read more
Many years ago I was asked by Muriel Hermine, a French champion synchronized swimmer, to create a line of makeup that would stay on underwater for her...Read more
Make up for ever: in looking at some of your work, we see you use shadow as much as light. what do light and dark each convey in your photos and how do you juxtapose them to achieve...Read more


text:
Black artists have filled all top 10 spots on this week's American Billboard singles chart for the first time.
Nine of the 10 are rappers, while the number one is "Baby Boy", a track from the R&B singer Beyonce Knowles and the reggae star Sean Paul. Other artists include P Diddy and Black Eyed Peas. The clean sweep shows the popularity of rap among teenagers.
Silvio Pietroluongo, who manages Billboard's Hot 100 Singles chart, said: "We went back through our lists to the mid-1990s, when R&B was the hot thing. But even then there were always some pop and rock acts as well."
The DJ Mike Anthony told BBC Radio Five Live: "It was just a matter of time." He attributed the rise of black music to the boom in the video music industry."There are so many new avenues out there, we had drum-n-bass, then UK garage, which affected the youth - and it's the youth that lead the way."
Experts said part of the reason for the dominance of rapwas that it was a musical form where singles still showed signs of commercial life.
- More about:
- Artists
- Billboard.com
- Music


text:
Going into Thursday's Golden Globe nominations announcement, certain films and stars were expected to get their due with a number of nods, such as critic favorites "The Butler" and "Saving Mr. Banks." But one thing is for sure — those films weren't favorites among the Hollywood Foreign Press Association.
Disney's "Saving Mr. Banks" failed to get any notice in the best drama category, and supporting actor Tom Hanks was nowhere to be seen — expect, of course, in the best actor category for his title role in "Captain Phillips." The lone honor for the film went to best actress contender Emma Thompson.
While some were no doubt surprised to see Oprah Winfrey shut out of the best supporting actress category hot on the heels of her SAG Awards nomination for her work in "Lee Daniels' The Butler," she was in good company among "The Butler" snubs. The Globes also ignored the film in the best drama roundup, and lead actor Forest Whitaker (who made SAG's leading man list) didn't make the cut either.
As for that supporting actress category, Winfrey arguably wasn't even the biggest oversight there. Octavia Spencer certainly would have been a worthy inclusion for her role in the 2013 Sundance fave "Fruitvale Station," a film that failed to get Golden Globe recognition across the board.
Another expected name that proved to be a Globes no-show was that of late actor James Gandolfini. His work in his posthumous release, "Enough Said," has been the subject of steady Oscar buzz, but didn't rank a nod this time — even though co-star Julia Louis-Dreyfus made list for her part in the romantic comedy.
Jaap Buitendijk / Fox Searchlight
2014 Golden Globe nominations
"12 Years a Slave" and "American Hustle" both received seven nods, while "Wolf of Wall Street" received two. See what other films and television shows were recognized.
2014 Golden Globe nominationsof
'12 Years a Slave' -
Chiwetel Ejiofor stars as Solomon Northup in "12 Years A Slave," which earned seven nominations, including best drama, actor for Ejiofor, supporting actress, supporting actor, director and othersAP / AP
2014 Golden Globe nominationsof
'American Hustle' -
"American Hustle," starring Jennifer Lawrence, received seven nods as well, including best actress for Lawrence, best comedy or musical, supporting actor and actress, and more.Columbia Pictures / Columbia Pictures
2014 Golden Globe nominationsof
'Captain Phillips' -
Tom Hanks starred with Somali immigrants, including Barkhad Abdi, in "Captain Phillips," based on a 2009 hijacking in the Indian Ocean. The film was nominated for four Golden Globes, including best drama and actor for Hanks.AP / AP
2014 Golden Globe nominationsof
'Gravity' -
"Gravity," starring Sandra Bullock, received four nominations, including best drama and actress.AP / AP
2014 Golden Globe nominationsof
'Nebraska' -
"Nebraska" received five nominations, including best comedy or musical, actor for Bruce Dern (left), actress, director and more.AP / AP
2014 Golden Globe nominationsof
'Inside Llewyn Davis' -
"Inside Llewyn Davis" received three nominations, including best actor in a comedy or musical for star Oscar Isaac and best comedy or musical.CBS FIlms / CBS FIlms
2014 Golden Globe nominationsof
'Philomena' -
"Philomena," starring Judi Dench and Steve Coogan, received three nominations: best drama, actress for Dench, and screenplay for Coogan.The Weinstein Company / The Weinstein Company
2014 Golden Globe nominationsof
'Blue Jasmine' -
Woody Allen's "Blue Jasmine," starring Cate Blanchett, earned two nods: drama actress for Blanchett, and supporting actress.Sony Pictures / Sony Pictures
2014 Golden Globe nominationsof
'Saving Mr. Banks' -
Walt Disney (Tom Hanks) shows Disneyland to "Mary Poppins" author P.L. Travers (Emma Thompson) in Disney's "Saving Mr. Banks." Thompson was nominated for best actress.Disney Enterprises, Inc. / Disney Enterprises, Inc.
2014 Golden Globe nominationsof
'All Is Lost' -
Robert Redford barely speaks in his role as an unnamed sailor battling the sea in "All Is Lost," which earned the star a best actor nod. The film was also recognized for its score.Roadside Attractions / Roadside Attractions
2014 Golden Globe nominationsof
'Dallas Buyers Club' -
Matthew McConaughey lost 50 pounds to portray Ron Woodroof, who was diagnosed with AIDS in 1985, in the film "Dallas Buyers Club." The film received two nods: best actor for McConaughey, and supporting actor for Jared Leto.AP / AP
2014 Golden Globe nominationsof
'Mandela: Long Walk to Freedom' -
Idris Elba, seen here with Riaad Moosa, plays Nelson Mandela in the biographical film "Mandela: Long Walk to Freedom." The film received three nods, including best actor for Elba.AP / AP
2014 Golden Globe nominationsof
'Wolf of Wall Street' -
Leonardo DiCaprio lives the good life as stockbroker Jordan Belfort in "Wolf of Wall Street," which received two nominations, including best comedy or musical, and actor for DiCaprio.AP / AP
2014 Golden Globe nominationsof
'August: Osage County' -
Julianne Nicholson, Meryl Streep and Margo Martindale are seen in a scene from "August: Osage County," which received two nods, including comedy or musical actress for Streep.AP / AP
2014 Golden Globe nominationsof
'Labor Day' -
"Labor Day" received a best actress nod for star Kate Winslet.AP / AP
2014 Golden Globe nominationsof
'Her' -
"Her" received three nominations, includiing best comedy actor for Joaquin Phoenix.Warner Bros. Pictures / Warner Bros. Pictures
2014 Golden Globe nominationsof
'Frances Ha' -
"Frances Ha" was nominated for best actress in a comedy or musical for star Greta Gerwig, right.AP / AP
2014 Golden Globe nominationsof
'Rush' -
"Rush" received two nods: best supporting actor for Daniel Bruhl, and best drama.Universal Pictures / Universal Pictures
2014 Golden Globe nominationsof
'Before Midnight' -
"Before Midnight" scored a best comedy or musical actress nod for star Julie Delpy.AP / AP
2014 Golden Globe nominationsof
'Breaking Bad' -
AMC's "Breaking Bad,' about a chemistry teacher turned drug kingpin, received three nods, including actor for star Bryan Cranston (pictured), supporting actor for Aaron Paul, and best TV drama series.
2014 Golden Globe nominationsof
'Downton Abbey' -
PBS' "Downton Abbey" received a nod for best TV drama.AP / AP
2014 Golden Globe nominationsof
'House of Cards' -
Netflix's political drama "House of Cards," starring Robin Wright and Kevin Spacey, received four nods, including: actor and actress for Spacey and Wright, and best series.AP / AP
2014 Golden Globe nominationsof
'Masters of Sex' -
Showtime's freshman series "Masters of Sex" received two nominations: best actor for star Michael Sheen, and best drama.Showtime / Showtime
2014 Golden Globe nominationsof
'Scandal' -
Kerry Washington plays fixer Olivia Pope in ABC's "Scandal," and received a best actress nomination for her work.AP / AP
2014 Golden Globe nominationsof
'The Big Bang Theory' -
Jim Parsons received a nod for his portrayal of Sheldon Cooper on CBS sitcom "The Big Bang Theory." The show was also nominated for best comedy.CBS / CBS
2014 Golden Globe nominationsof
"Girls" -
HBO's "Girls," starring Lena Dunham, was nominated for best comedy and best actress for Dunham.Getty Images / Getty Images
2014 Golden Globe nominationsof
'Parks and Recreation' -
Amy Poehler plays Leslie Knope on NBC's sitcom "Parks and Recreation." The show received two nods: best actress for Poehler, and best comedy.AP / AP
2014 Golden Globe nominationsof
'Veep' -
Julia Louis-Dreyfus was nominated for her work as Selina Meyer on HBO's comedy "Veep." The actress was also nominated for best actress for her work in the comedy film "Enough Said."AP / AP
2014 Golden Globe nominationsof
'House of Lies' -
Don Cheadle is nominated for best actor in a comedy series for his role as Marty Kaan in Netflix's "House of Lies."AP / AP
2014 Golden Globe nominationsof
'American Horror Story: Coven' -
Jessica Lange was nominated for her work as witch Fiona on FX's "American Horror Story: Coven." The show also received a nod for best miniseries.FX / FX
2014 Golden Globe nominationsof
"The Michael J. Fox Show" -
Michael J. Fox received a best comedy actor nod for his new NBC sitcom, "The Michael J. Fox Show."NBC / NBC
2014 Golden Globe nominationsof
'The Blacklist' -
NBC's freshman drama "The Blacklist" received a nomination for best actor for star James Spader.NBC / NBC
2014 Golden Globe nominationsof
'The Good Wife' -
CBS drama "The Good Wife" received three nods, including best actress Julianna Margulies, supporting actor and best drama.CBS / CBS
2014 Golden Globe nominationsof
'Behind the Candelabra' -
HBO's "Behind the Candelabra" scored four nods, including best actors for stars Michael Douglas, left, and Matt Damon.HBO / HBO
2014 Golden Globe nominationsof
'Brooklyn Nine-Nine' -
Fox's freshman sitcom "Brooklyn Nine-Nine" received two nods: best comedy and best actor for star Andy SambergFOX / FOX
2014 Golden Globe nominationsof
'Orange Is the New Black' -
Netflix's "Orange Is the New Black" snagged a best actress nod for star Taylor Schilling, left.Netflix / Netflix
2014 Golden Globe nominationsof
'Ray Donovan' -
Showtime's "Ray Donovan" received two nods: best actor for Liev Schreiber (pictured) and supporting actor.Showtime / Showtime
2014 Golden Globe nominationsof
'Nurse Jackie' -
Showtime's "Nurse Jackie" snagged a best actress nod for star Edie Falco.Showtime / Showtime
2014 Golden Globe nominationsof
'Modern Family' -
ABC's "Modern" family received two nominations: best comedy, and best supporting actress for Sofia Vergara.ABC / ABC
2014 Golden Globe nominationsof
'Arrested Development' -
Netflix's "Arrested Development" earned a best comedy actor nod for star Jason Bateman.Netflix / Netflix
The snubs weren't the only shockers in the mix on Thursday. Just as notable the Golden Globes oversights were the unexpected inclusions.
While Sally Hawkins deserved her place on the supporting actress list for her part in the Woody Allen dramedy "Blue Jasmine," it's a nod that few predicted, especially given the wealth of potential contenders in that category, including Winfrey's aforementioned expected appearance.
And while "Blue Jasmine" didn't make find a spot in the best drama nominations, Ron Howard's racing drama "Rush" did. "Rush's" Daniel Bruhl also surprised with his best supporting actor nod — as he did the day before with a SAG honor.
British offering "Philomena" was another shocker in the best drama roundup, nabbing a spot that seemed ripe for "Jasmine" or "Dallas Buyers Club" (though "Dallas" lead Matthew McConaughy and supporting star Jared Leto made the grade in the acting categories).
Of course, the biggest surprises still lie ahead — the winners and losers. See who walks away with the awards when the 71st Annual Golden Globe Awards air Jan. 12 on NBC.


text:
We recommend using a modern web browser such as Google Chrome or Microsoft Edge with their default settings.
One of the challenge points on the Better World Books 2017 Reading […]
Babatunde Lawal
Hello, I'm an eBook!
ATTENTION: This item is an eBook. It can be read on iOS, Android, MAC and PC's with a supported eReader. It is not a physical book. eBooks are available via download immediately after you've checked out.
Shipped from other seller
Libro Co. Italia srl
Art features prominently in the culture of the Yoruba, a people numbering more than 25 million and subdivided into different kingdoms in Nigeria and adjacent regions. It both enriches life and is used to venerate and influence deities. The exceptional quality of Yoruba art from ancient times to the present is an expression of the complexity of Yoruba life. This new book explores the archaeological and historical evidence that suggests that by the beginning of the second millennium, many Yoruba kingdoms had become major urban centers with highly developed economic, cultural, political, and religious institutions. Drawing on field observations, contextual analyses, oral sources, and published materials, this book offers insight into the poetics and dynamics of Yoruba art and belief that the "beautiful" or "well-made" generates a special power that commands attention.
Our best deal on used books 3 for $10 and just $3 each additional book. Shop and Save
Gift Certificate = Happy Friend + Books donated to families in need. Make Someone Happy »
We match every book you purchase with a book donation. Learn more »
Sign up now to get news, sales and special promotions!
Manage Subscriptions
© Better World Books (BetterWorldBooks.com)
- All Rights Reserved Deals | Terms of Use | Privacy Policy | Copyright | Legal


text:
FiltersShow / Hide
- All Events
- Rock & Pop
- Acoustic
- Alternative
- Americana
- Indie
- Metal
- Pop
- Punk
- Rock
- Rock & Roll
- Tribute Bands
- Dance & Urban
- Ambient
- Electronic
- Experimental
- Hip-Hop
- Reggae
- Modern RnB
- Ska
- Jazz, Blues & Soul
- Big Band
- Blues
- Classic RnB
- Easy Listening
- Gospel
- Jazz
- Soul
- Swing
- Folk, Roots & World
- Celtic
- Country
- Folk
- Latin
- World
- Classical
- Brass
- Choral
- Classical
- Decades
- 50s
- 60s
- 70s
- 80s
- 90s
- Comedy
- Theatre & Arts
- Shows & Events
- Cinema
- Festivals
- Venue Week
- All Tickets
- My Tracked Artists
- Latest Tickets
- Free Events
- Special Tickets
- Disabled Access Venues
- Festival Offers
- Anywhere In The UK
- Location: Anywhere in the UK
Radius: ... miles
Sat 16th Feb
Best In Live Comedy
@ The Glee Club, Oxford
Featuring: Gary Delaney, Danny McLoughlin, Eddy Brimson, David Trent
This event has been and gone!
Catch the next one:
Check out the info below for future tour dates, and track them to receive alerts when they tour near you
Best In Live Comedy : Gary Delaney, Danny McLoughlin, Eddy Brimson, David Trent
Please note that the artists appearing may be subject to change.
Gary Delaney
Gary Delaney is a razor sharp one-liner comedian, who is widely regarded as being the most quotable comic on the circuit. The high quantity of stand out gags leaves the audience struggling to remember them all. He regularly plays all the big clubs including The Comedy Store, Highlight, Jongleurs, Komedia, Glee, Rawhide, The Frog and Bucket, Hyena, Baby Blue, The Stand, Comedy Café, Lee Hurst's Backyard, Banana Cabaret and headlines at clubs throughout the UK.
Gary is a regular guest on Mock The Week and has also appeared on Dave's 'One Night Stand', Comedy Central's 'Comedy Blue' and on Channel 4's 'Robert's Web' as well as Radio 4's 'Loose Ends' and Radio 2's 'Russell Kane's Whistle-Stop Tour'. His debut show 'Purist' was a big hit at the Edinburgh Festival in 2010, selling out every night and receiving many four and five star reviews.
'Gary Delaney has more quality jokes in this hour than many comics have in their entire careers… Quite brilliant' (The Scotsman).
'I laughed and I laughed and I laughed! A master craftsman' (The Times)
'Taut, brilliant one-liners. Delaney was worth the price of admission alone' (Chortle)
'... Razor sharp one-liners' (The Daily Telegraph)
'Quickfire material of the very highest quality is pretty much guaranteed from the
fast-thinking Delaney, a master of the deadpan one-liner... Expect a cavalcade of brilliantly inventive puns' (The Guardian).
Gary Delaney tour dates
Danny McLoughlin
With an amiable, confident stage presence and a well written set, Danny delivers material with more than just an immediate pay-off line, preferring to take the joke one or two steps further.
Confident enough to take a risk on stage he does so not to the detriment of the audience, keeping them laughing along or hanging on every word.
A bright future surely awaits.
'McLoughlin's main weapon is his audacity: he's so bold he can recite an advertising jingle and still get plenty of laughs' (Chortle).
Danny McLoughlin tour dates
Eddy Brimson
Eddy Brimson is one of the UK circuit's most in demand headline acts and works regularly with leading clubs both in this country and overseas.
Having made many TV appearances including Eastenders, Absolutely Fabulous, The Thin Blue and Casualty, he has also featured in TV adverts such as Snickers and Bacardi Breezer.
'The crowd love him' (The Guardian)
'... one of the most fascinating comedians on the circuit...' (Funhouse Comedy)
'There must be a school of comedy in the British Isles, if such a school exists, Eddy
Brimson would have been top of the class' (Sydney Sunday Herald).
Eddy Brimson tour dates
David Trent
Former teacher and 'deadpan multimedia-ist'. He was nominated for the prestigious Edinburgh Comedy Award in 2012 for his debut solo show Spontaneous Comedian. David offers up high energy commentary on celebrity culture and topical news stories using projection and an extremely effective frenetic style of video editing.
'A creator of bold, category-defying comedy' (The Stage)
'His performances are intense, fearless and original' (LondonIsFunny)
'One of the most talked-about people in comedy right now' (The Guardian)
'His meticulous deconstruction and righteous exasperation makes him a master of the genre...' (Chortle)
'Perfect comedy' (Three Weeks).
David Trent tour dates
Track this event
- Event has been added to your calendar
- Any important updates will be sent to your email address
- Add to your personal Ents24 calendar
- Sync with iCal, Outlook and others
- Receive important updates
Venue Facts
Venue: The Glee Club
Website: glee.co.uk/oxford
Phone: 0871 472 0400
Disabled Bookings: 0121 693 2248
→ Oxford 3 min walk


text:
Published on
Anca Mosoiu, Josh Visick, and Sonja London discussed their experience running WordPress businesses at the February 2014 East Bay WordPress Meetup. These slides formed the background to a discussion that ranged from Scott Berkun's The Year Without Pants (about working at Automattic) to basics of any business (entity choice, taxes, insurance, contracts), to the varying ways to make money from an open-source product (hosting, sales of plugins, sales of themes, training, development, and design). The presenters all have services businesses.


text:
There is my dream.
The sun is too mean.
If only I could.
I swear that I would.
I try to fly.
Too short of the sky.
What to do?
Here comes the blue.
Changing are days.
Yet another May.
Someone be mine.
Come now, it's time.
I need a ladder.
To stop "badder".
© Copyright 2017 parkelis. All rights reserved.
Status: Finished
Genre: Action and Adventure
Book / Young Adult
Book / Children Stories
Poem / Romance
Paste the link to picture in the entry below:
Paste the link to Youtube video in the following entry:
Cannot annotate a non-flat selection. Make sure your selection starts and ends within the same node.
An annotation cannot contain another annotation.
There was an error uploading your file.


text:
To embed, copy and paste the code into your website or blog:
[author: Emily Tsai]
The long fight between China's regulatory agencies for the private equity (PE) and venture capital (VC) industry has finally been concluded. By a notice on Division of Duties in Private Equity Fund Administration promulgated by the State Commission Office for Public Sector Reform ("SCOPSR") on June 27, 2013 ("Notice"), the China Securities Regulatory Commission ("CSRC") is designated as the sole regulator of China's PE and VC industry.
The CSRC is authorized by SCOPSR to carry out appropriate regulation over the PE and VC industry, in an effort to protect the interest of investors.
"Initial public offerings are a main exit way for companies with investments from PE and VC companies, and the CSRC is at an appropriate position to regulate them," said an industry insider.
The sector was previously regulated by the CSRC and the National Development and Reform Commission ("NDRC"), causing disunified and unstable regulatory framework. In fact, there has not been any legislation clarifying the corporate nature of PE/VC firms. NDRC requires mandatory registration of PE firms, while the registration of VC firms is voluntary. The criteria in differentiating between the two however, is merely the registered name of the entity, or the general description of its registered business scope. The lack of comprehensive and systematic definition has thus led to the confusing regulatory regime of the industry.
Further adding to the confusion, in February, the CSRC released a notice stating that PE and VC firms may engage in public and private fund management businesses, which may be implemented on June 1. However, the NDRC later promulgated a regulation in March stipulating that PE and VC companies are not allowed invest in public-offered funds.
In order to clarify the situation and standardize the administration of the industry, China's legislators tried earlier to include PE/VC regulatory provisions into the 2012 revisions of the PRC Securities Investment Fund Law – a controversial move which ended up with the joint petition of 25 PE/VC industry associations to oppose the proposal. By the time of the third draft in December, 2012, the relevant provisions were removed from the proposal. As a result of the compromise, no legislation was passed regarding the regulation of the industry and the chaos continued, until June when the Notice announced the CSRC as the sole regulator.
Under the new administrative system, the NDRC is designated to compile policies and measures for the development of PE and VC industry as well as jointly set investment criteria for PE and VC funds with related government departments.
The SCOPSR also calls for the CSRC and the NDRC to establish a "working mechanism based on coordination and collaboration and the transparency of information".
Many industry players welcome the move, agreeing that as the country's top economic planning agency, the NDRC should focus more on macro issues and reduce intervention in details.
Liu Jianjun, director of CSRC's Department of Fiscal and Financial Affairs, a regulatory arm responsible for the PE and VC sector, was transferred to the CSRC's fund department last month.
The CSRC will establish a regulatory department for the PE and VC industry before long, said an industry insider, adding that Liu will head the department and core function of the department is to implement regulation on the PE and VC industry.
See more »
DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.
© Sheppard Mullin Richter & Hampton LLP
Your first step to building a free, personalized, morning email brief covering pertinent authors and topics on JD Supra:
Sign up to create your digest using LinkedIn*
JD Supra provides users with access to its legal industry publishing services (the "Service") through its website (the "Website") as well as through other sources. Our policies with regard to data collection and use of personal information of users of the Service, regardless of the manner in which users access the Service, and visitors to the Website are set forth in this statement ("Policy"). By using the Service, you signify your acceptance of this Policy.
JD Supra collects users' names, companies, titles, e-mail address and industry. JD Supra also tracks the pages that users visit, logs IP addresses and aggregates non-personally identifiable user data and browser type. This data is gathered using cookies and other technologies.
The information and data collected is used to authenticate users and to send notifications relating to the Service, including email alerts to which users have subscribed; to manage the Service and Website, to improve the Service and to customize the user's experience. This information is also provided to the authors of the content to give them insight into their readership and help them to improve their content, so that it is most useful for our users.
JD Supra does not sell, rent or otherwise provide your details to third parties, other than to the authors of the content on JD Supra.
If you prefer not to enable cookies, you may change your browser settings to disable cookies; however, please note that rejecting cookies while visiting the Website may result in certain parts of the Website not operating correctly or as efficiently as if cookies were allowed.
Users who opt in to receive emails may choose to no longer receive e-mail updates and newsletters by selecting the "opt-out of future email" option in the email they receive from JD Supra or in their JD Supra account management screen.
JD Supra takes reasonable precautions to insure that user information is kept private. We restrict access to user information to those individuals who reasonably need access to perform their job functions, such as our third party email service, customer service personnel and technical staff. However, please note that no method of transmitting or storing data is completely secure and we cannot guarantee the security of user information. Unauthorized entry or use, hardware or software failure, and other factors may compromise the security of user information at any time.
If you have reason to believe that your interaction with us is no longer secure, you must immediately notify us of the problem by contacting us at firstname.lastname@example.com. In the unlikely event that we believe that the security of your user information in our possession or control may have been compromised, we may seek to notify you of that development and, if so, will endeavor to do so as promptly as practicable under the circumstances.
Except as otherwise described in this privacy statement, JD Supra will not disclose personal information to any third party unless we believe that disclosure is necessary to: (1) comply with applicable laws; (2) respond to governmental inquiries or requests; (3) comply with valid legal process; (4) protect the rights, privacy, safety or property of JD Supra, users of the Service, Website visitors or the public; (5) permit us to pursue available remedies or limit the damages that we may sustain; and (6) enforce our Terms & Conditions of Use.
In the event there is a change in the corporate structure of JD Supra such as, but not limited to, merger, consolidation, sale, liquidation or transfer of substantial assets, JD Supra may, in its sole discretion, transfer, sell or assign information collected on and through the Service to one or more affiliated or unaffiliated third parties.
This Website and the Service may contain links to other websites. The operator of such other websites may collect information about you, including through cookies or other technologies. If you are using the Service through the Website and link to another site, you will leave the Website and this Policy will not apply to your use of and activity on those other sites. We encourage you to read the legal notices posted on those sites, including their privacy policies. We shall have no responsibility or liability for your visitation to, and the data collection and use practices of, such other sites. This Policy applies solely to the information collected in connection with your use of this Website and does not apply to any practices conducted offline or in connection with any other websites.
We reserve the right to change this Policy at any time. Please refer to the date at the top of this page to determine when this Policy was last revised. Any changes to our privacy policy will become effective upon posting of the revised policy on the Website. By continuing to use the Service or Website following such changes, you will be deemed to have agreed to such changes. If you do not agree with the terms of this Policy, as it may be amended from time to time, in whole or part, please do not continue using the Service or the Website.
If you have any questions about this privacy statement, the practices of this site, your dealings with this Web site, or if you would like to change any of the information you have provided to us, please contact us at: email@example.com.
Already signed up? Log in here
Back to Top
Explore 2016 Readers' Choice Awards
Copyright ©


text:
This is the login panel
TCA Scholarship
Since 1973, Truckload Carriers Association has been helping students associated with the truckload industry reach their dreams. Our Scholarship Fund awards up to $6,250 per year to full-time college students. Much of our program's support comes from within the truckload family—companies and individuals who are committed to our community's future.
Winners have been announced! Click on Meet the Recipients link below.
Interested in applying for 2017? Application to open in the Spring.
Prior Recipient Video Archives


text:
This website uses cookies to give you the best, most relevant experience. Using this website means you're Ok with this. You can change which cookies are set at any time - and find out more about them - by following this link.
For the second year in a row, Carrefour and its "Retail Lab" will be partnering Viva Technology in Paris between 15 and 17 June. Once again, start-ups working alongside major groups – one of the key factors behind the success of the first edition – will play a central role in the event, thanks to
Carrefour has been a pioneer in food quality for 25 years and is continuing its work with four new initiatives. A programme to accelerate the adoption of organic farming practices, working alongside producers: as the leading general distributor of organic products in France, Carrefour is introducing
Carrefour Spain, is incorporating compressed natural gas trucks in its fleet to carry out deliveries of e-commerce orders together with home delivery vans with the same characteristics. These vehicles reduce nitrogen oxide (Nox) emissions by up to 99% and the level of particles emitted by 95%
2016 Sales: €85.7bn Very good performance +3.3% in the full year and +3.5% in Q4 (ex petrol)
Fifth consecutive year of like-for-like sales growth and the best yearly performance over the period, at +3.0%: Relevance of our...