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Publications (113)356.87 Total impact
Article: Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in vivo.[Show abstract] [Hide abstract]
ABSTRACT: Previous data demonstrate that Bexarotene (Bex), an RXR agonist, reduces soluble and insoluble amyloid-β (Aβ) in Alzheimer's disease (AD)-transgenic (Tg) mice either via increasing the levels of mouse apolipoprotein E (apoE) or increasing ABCA1/ABCG1-induced apoE lipoprotein-association/lipidation. However, while the mechanism of action of RXR agonists remains unclear, a major concern for their use is human (h)-APOE4, the greatest AD genetic-risk factor. If APOE4 imparts a toxic gain-of-function, then increasing apoE4 may increase soluble Aβ, likely the proximal AD neurotoxin. If APOE4 imparts a loss-of-function, then ABCA1/ABCG1-induced lipidation of apoE4 may be beneficial. In novel EFAD-Tg mice (overexpressing h-Aβ42 with h-APOE), levels of soluble Aβ (Aβ42 and oligomeric Aβ (oAβ)) are highest in E4FAD-hippocampus (HP) > E3FAD-HP > E4FAD-cortex (CX) > E3FAD-CX, while levels of lipoprotein-associated/lipidated apoE have the opposite pattern (6-months, M). In E4FAD-HP, short-term RXR agonist treatment (Bex or LG100268; 5.75-6M) increased ABCA1, apoE4 lipoprotein-association/lipidation and apoE4/Aβ complex, decreased soluble Aβ and increased PSD95. In addition, hydrogel delivery, which mimics low sustained release, was equally effective as gavage for Bex and LG in lowering soluble Aβ with APOE4. RXR agonists induced no beneficial effects in the E4FAD-HP in a prevention protocol (5-6M), and increased soluble Aβ levels in E3FAD-CX and E4FAD-CX (5.75-6M), likely the result of systemic hepatomegaly. Thus, RXR agonists address the loss-of-function associated with APOE4 and exacerbated by Aβ pathology--low levels of apoE4 lipoprotein-association/lipidation. Further studies are vital to address whether RXR agonists are an APOE4-specific AD therapeutic and the systemic side effects that limit translational application.The Journal of biological chemistry. 09/2014;
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ABSTRACT: Endocrine-resistant breast cancer is a major clinical obstacle. The use of 17beta-estradiol (E2) has re-emerged as a potential treatment option following exhaustive use of tamoxifen (TAM) or aromatase inhibitors although side effects have hindered its clinical usage. Protein kinase C alpha (PKCalpha) expression was shown to be a predictor of disease outcome for patients receiving endocrine therapy and may predict a positive response to an estrogenic treatment. Here, we have investigated the use of novel benzothiophene selective estrogen mimics (SEMs) as an alternative to E2 for the treatment of TAM-resistant breast cancer. Following in vitro characterization of SEMs, a panel of clinically relevant PKCalpha-expressing, TAM-resistant models were used to investigate the antitumor effects of these compounds. SEM treatment resulted in growth inhibition and apoptosis of TAM-resistant cell lines in vitro. In vivo SEM treatment induced tumor regression of TAM-resistant T47D:A18/PKCalpha and T47D:A18-TAM1 tumor models. T47D:A18/PKCalpha tumor regression was accompanied by translocation of ERalpha to extranuclear sites, possibly defining a mechanism through which these SEMs initiate tumor regression. SEM treatment did not stimulate growth of E2-dependent T47D:A18/neo tumors. Additionally, unlike E2 or TAM, treatment with SEMs did not stimulate uterine weight gain. These findings suggest the further development of SEMs as a feasible therapeutic strategy for the treatment of endocrine-resistant breast cancer without the side effects associated with E2.Molecular Cancer Therapeutics 09/2014; · 5.60 Impact Factor
Article: SERMs attenuate estrogen-induced malignant transformation of human breast epithelial cells by upregulating detoxification of oxidative metabolites.[Show abstract] [Hide abstract]
ABSTRACT: The risk of developing hormone-dependent cancers with long-term exposure to estrogens is attributed both to proliferative, hormonal actions at the estrogen receptor (ER), and chemical carcinogenesis elicited by genotoxic, oxidative estrogen metabolites. Non-tumorigenic MCF-10A human breast epithelial cells are classified as ER(-) and undergo estrogen-induced malignant transformation. Selective estrogen receptor modulators (SERMs), in use for breast cancer chemoprevention and for post-menopausal osteoporosis, were observed to inhibit malignant transformation, as measured by anchorage-independent colony growth. This chemopreventive activity was observed to correlate with reduced levels of oxidative estrogen metabolites, cellular ROS, and DNA oxidation. The ability of raloxifene, desmethylarzoxifene (DMA), and bazedoxifene to inhibit this chemical carcinogenesis pathway was not shared by 4-hydroxytamoxifen. Regulation of Phase 2 rather than Phase 1 metabolic enzymes was implicated mechanistically: raloxifene and DMA were observed to upregulate sulfotransferase (SULT 1E1) and glucuronidase (UGT 1A1). The results support upregulation of Phase 2 metabolism in detoxification of catechol estrogen metabolites leading to attenuated ROS formation as a mechanism for inhibition of malignant transformation by a subset of clinically important SERMs.Cancer Prevention Research 03/2014; · 4.89 Impact Factor
Article: Novel Analogues of Chlormethiazole are Neuroprotective in Four Cellular Models of Neurodegeneration by a Mechanism with Variable Dependence on GABAA Receptor Potentiation.[Show abstract] [Hide abstract]
ABSTRACT: Chlormethiazole (CMZ), a clinical sedative/anxiolytic agent, did not reach clinical efficacy in stroke trials despite neuroprotection demonstrated in numerous animal models. Using CMZ as a lead compound, neuroprotective methiazole (MZ) analogues were developed, and neuroprotection and GABAA receptor dependence were studied. Eight MZs were selected from a novel library, of which two were studied in detail. Neuroprotection, glutamate release, intracellular calcium and response to GABA blockade by picrotoxin were measured in rat primary cortical cultures using four cellular models of neurodegeneration. GABA potentiation was assayed in oocytes expressing the α1 β2 γ2 GABAA receptor. Neuroprotection against a range of insults was retained even with substantial chemical modification. Dependence on GABAA receptor activity was variable: at the extremes, neuroprotection by GN-28 was universally sensitive to picrotoxin, while GN-38 was largely insensitive. In parallel, effects on extracellular glutamate and intracellular calcium were associated with GABAA dependence. Consistent with these findings, GN-28 potentiated α1 β2 γ2 GABAA function, whereas GN-38 had weakly inhibitory effect. Neuroprotection against moderate dose oligomeric Aβ1-42 was also tolerant to structural changes. The results support the concept that CMZ does not contain a single pharmacophore, rather that broad-spectrum neuroprotection results from a GABAA -dependent mechanism represented by GN-28, combined with a mechanism represented in GN-38 that shows the least dependence on GABAA receptors. These findings allow further refinement of the neuroprotective pharmacophore and investigation into secondary mechanisms that will assist in identifying methiazole-based compounds of use in treating neurodegeneration.British Journal of Pharmacology 10/2013; · 5.07 Impact Factor
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ABSTRACT: Breast cancer remains a significant cause of death in women, and few therapeutic options exist for estrogen receptor negative (ER (-)) cancers. Epigenetic reactivation of target genes using histone deacetylase (HDAC) inhibitors has been proposed in ER (-) cancers to resensitize to therapy using selective estrogen receptor modulators (SERMs) that are effective in ER (+) cancer treatment. Based upon preliminary studies in ER (+) and ER (-) breast cancer cells treated with combinations of HDAC inhibitors and SERMs, hybrid drugs, termed SERMostats, were designed with computational guidance. Assay for inhibition of four type I HDAC isoforms and antagonism of estrogenic activity in two cell lines yielded a SERMostat with 1-3 μM potency across all targets. The superior hybrid caused significant cell death in ER (-) human breast cancer cells and elicited cell death at the same concentration as the parent SERM in combination treatment and at an earlier time point.ChemMedChem 08/2013; · 2.84 Impact Factor
Article: An NO Donor Approach to Neuroprotective and Procognitive Estrogen Therapy Overcomes Loss of NO Synthase Function and Potentially Thrombotic Risk.[Show abstract] [Hide abstract]
ABSTRACT: SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) ARE EFFECTIVE THERAPEUTICS THAT PRESERVE FAVORABLE ACTIONS OF ESTROGENS ON BONE AND ACT AS ANTIESTROGENS IN BREAST TISSUE, DECREASING THE RISK OF VERTEBRAL FRACTURES AND BREAST CANCER, BUT THEIR POTENTIAL IN NEUROPROTECTIVE AND PROCOGNITIVE THERAPY IS LIMITED BY: 1) an increased lifetime risk of thrombotic events; and 2) an attenuated response to estrogens with age, sometimes linked to endothelial nitric oxide synthase (eNOS) dysfunction. Herein, three 3(rd) generation SERMs with similar high affinity for estrogen receptors (ERα, ERβ) were studied: desmethylarzoxifene (DMA), FDMA, and a novel NO-donating SERM (NO-DMA). Neuroprotection was studied in primary rat neurons exposed to oxygen glucose deprivation; reversal of cholinergic cognitive deficit was studied in mice in a behavioral model of memory; long term potentiation (LTP), underlying cognition, was measured in hippocampal slices from older 3×Tg Alzheimer's transgenic mice; vasodilation was measured in rat aortic strips; and anticoagulant activity was compared. Pharmacologic blockade of GPR30 and NOS; denudation of endothelium; measurement of NO; and genetic knockout of eNOS were used to probe mechanism. Comparison of the three chemical probes indicates key roles for GPR30 and eNOS in mediating therapeutic activity. Procognitive, vasodilator and anticoagulant activities of DMA were found to be eNOS dependent, while neuroprotection and restoration of LTP were both shown to be dependent upon GPR30, a G-protein coupled receptor mediating estrogenic function. Finally, the observation that an NO-SERM shows enhanced vasodilation and anticoagulant activity, while retaining the positive attributes of SERMs even in the presence of NOS dysfunction, indicates a potential therapeutic approach without the increased risk of thrombotic events.PLoS ONE 01/2013; 8(8):e70740. · 3.53 Impact Factor
Article: Quinone-Induced Activation of Keap1/Nrf2 Signaling by Aspirin Prodrugs Masquerading as Nitric Oxide.[Show abstract] [Hide abstract]
ABSTRACT: The promising therapeutic potential of the NO-donating hybrid aspirin prodrugs (NO-ASA) includes induction of chemopreventive mechanisms and has been reported in almost 100 publications. One example, NCX-4040 (pNO-ASA), is bioactivated by esterase to a quinone methide (QM) electrophile. In cell cultures, pNO-ASA and QM-donating X-ASA prodrugs that cannot release NO rapidly depleted intracellular GSH and caused DNA damage; however, induction of Nrf2 signaling elicited cellular defense mechanisms including upregulation of NAD(P)H:quinone oxidoreductase-1 (NQO1) and glutamate-cysteine ligase (GCL). In HepG2 cells, the "NO-specific" 4,5-diaminofluorescein reporter, DAF-DA, responded to NO-ASA and X-ASA, with QM-induced oxidative stress masquerading as NO. LC-MS/MS analysis demonstrated efficient alkylation of Cys residues of proteins including glutathione-S-transferase-P1 (GST-P1) and Kelch-like ECH-associated protein 1 (Keap1). Evidence was obtained for alkylation of Keap1 Cys residues associated with Nrf2 translocation to the nucleus, nuclear translocation of Nrf2, activation of antioxidant response element (ARE), and upregulation of cytoprotective target genes. At least in cell culture, pNO-ASA acts as a QM donor, bioactivated by cellular esterase activity to release salicylates, NO(3)(-), and an electrophilic QM. Finally, two novel aspirin prodrugs were synthesized, both potent activators of ARE, designed to release only the QM and salicylates on bioactivation. Current interest in electrophilic drugs acting via Nrf2 signaling suggests that QM-donating hybrid drugs can be designed as informative chemical probes in drug discovery.Chemical Research in Toxicology 10/2012; · 3.67 Impact Factor
Article: Design and synthesis of neuroprotective methylthiazoles and modification as NO-chimeras for neurodegenerative therapy.[Show abstract] [Hide abstract]
ABSTRACT: Learning and memory deficits in Alzheimer's disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described that uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABA(A) receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen-glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for restoration of synaptic function in hippocampal slices from AD-transgenic mice, reversal of cognitive deficits, and brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together, the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD.Journal of Medicinal Chemistry 07/2012; 55(15):6784-801. · 5.61 Impact Factor
Article: Selective estrogen receptor modulator (SERM) lasofoxifene forms reactive quinones similar to estradiol.[Show abstract] [Hide abstract]
ABSTRACT: The bioactivation of both endogenous and equine estrogens to electrophilic quinoid metabolites has been postulated as a contributing factor in carcinogenic initiation and/or promotion in hormone sensitive tissues. Bearing structural resemblance to estrogens, extensive studies have shown that many selective estrogen receptor modulators (SERMs) are subject to similar bioactivation pathways. Lasofoxifene (LAS), a third generation SERM which has completed phase III clinical trials for the prevention and treatment of osteoporosis, is currently approved in the European Union for this indication. Previously, Prakash et al. (Drug Metab. Dispos. (2008) 36, 1218-1226) reported that similar to estradiol, two catechol regioisomers of LAS are formed as primary oxidative metabolites, accounting for roughly half of the total LAS metabolism. However, the potential for further oxidation of these catechols to electrophilic o-quinones has not been reported. In the present study, LAS was synthesized and its oxidative metabolism investigated in vitro under various conditions. Incubation of LAS with tyrosinase, human liver microsomes, or rat liver microsomes in the presence of GSH as a trapping reagent resulted in the formation of two mono-GSH and two di-GSH catechol conjugates which were characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Similar conjugates were also detected in incubations with P450 3A4, P450 2D6, and P450 1B1 supersomes. Interestingly, these conjugates were also detected as major metabolites when compared to competing detoxification pathways such as glucuronidation and methylation. The 7-hydroxylasofoxifene (7-OHLAS) catechol regioisomer was also synthesized and oxidized either chemically or enzymatically to an o-quinone that was shown to form depurinating adducts with DNA. Collectively, these data show that analogous to estrogens, LAS is oxidized to catechols and o-quinones which could potentially contribute to in vivo toxicity for this SERM.Chemical Research in Toxicology 05/2012; 25(7):1472-83. · 3.67 Impact Factor
Article: Furoxans (1,2,5-oxadiazole-N-oxides) as novel NO mimetic neuroprotective and procognitive agents.[Show abstract] [Hide abstract]
ABSTRACT: Furoxans (1,2,5-oxadiazole-N-oxides) are thiol-bioactivated NO-mimetics that have not hitherto been studied in the CNS. Incorporation of varied substituents adjacent to the furoxan ring system led to modulation of reactivity toward bioactivation, studied by HPLC-MS/MS analysis of reaction products. Attenuated reactivity unmasked the cytoprotective actions of NO in contrast to the cytotoxic actions of higher NO fluxes reported previously for furoxans. Neuroprotection was observed in primary neuronal cell cultures following oxygen glucose deprivation (OGD). Neuroprotective activity was observed to correlate with thiol-dependent bioactivation to produce NO(2)(-), but not with depletion of free thiol itself. Neuroprotection was abrogated upon cotreatment with a sGC inhibitor, ODQ, thus supporting activation of the NO/sGC/CREB signaling cascade by furoxans. Long-term potentiation (LTP), essential for learning and memory, has been shown to be potentiated by NO signaling, therefore, a peptidomimetic furoxan was tested in hippocampal slices treated with oligomeric amyloid-β peptide (Aβ) and was shown to restore synaptic function. The novel observation of furoxan activity of potential therapeutic use in the CNS warrants further studies.Journal of Medicinal Chemistry 03/2012; 55(7):3076-87. · 5.61 Impact Factor
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ABSTRACT: S-Nitrosothiol (RSNO) formation is one manner by which nitric oxide (•NO) exerts its biological effects. There are several proposed mechanisms of formation of RSNO in vivo: auto-oxidation of •NO, transnitrosation, oxidative nitrosylation, and from dinitrosyliron complexes (DNIC). Both free •NO, generated by •NO donors, and S-nitrosocysteine (CysNO) are widely used to study •NO biology and signaling, including protein S-nitrosation. It is assumed that the cellular effects of both compounds are analogous and indicative of in vivo •NO biology. A quantitative comparison was made of formation of DNIC and RSNO, the major •NO-derived cellular products. In RAW 264.7 cells, both •NO and CysNO were metabolized, leading to rapid intracellular RSNO and DNIC formation. DNIC were the dominant products formed from physiologic •NO concentrations, however, and RSNO were the major product from CysNO treatment. Chelatable iron was necessary for DNIC assembly from either •NO or CysNO, but not for RSNO formation. These profound differences in RSNO and DNIC formation from •NO and CysNO question the use of CysNO as a surrogate for physiologic •NO. Researchers designing experiments intended to elucidate the biological signaling mechanisms of •NO should be aware of these differences and should consider the biological relevance of the use of exogenous CysNO.Antioxidants & Redox Signaling 02/2012; 17(7):962-8. · 8.20 Impact Factor
Article: The naphthol selective estrogen receptor modulator (SERM), LY2066948, is oxidized to an o-quinone analogous to the naphthol equine estrogen, equilenin.[Show abstract] [Hide abstract]
ABSTRACT: o-Quinone forming estrogens and selective estrogen receptor modulators (SERMs) have been associated with carcinogenesis. LY2066948, a novel SERM in development by Eli Lilly for the treatment of uterine fibroids and myomas, has structural similarity to the equine estrogen equilenin present in hormone replacement formulations; both contain a naphthol group susceptible to oxidative metabolism to o-quinones. LY2066948 was synthesized and assayed for antiestrogenic activity, and in cell culture was confirmed to be a more potent antiestrogen than the prototypical SERM, 4-hydroxytamoxifen. Oxidation of LY2066948 with 2-iodoxybenzoic acid gave an o-quinone (t(1/2)=3.9 ± 0.1h) which like 4-hydroxyequilenin-o-quinone (t(1/2)=2.5 ± 0.2 h) was observed to be exceptionally long-lived with the potential to cause cytotoxicity and/or genotoxicity. In model reactions with tyrosinase, the catechol metabolites of LY2066948 and equilenin were products; interestingly, in the presence of ascorbate to inhibit autoxidation, these catechols were formed quantitatively. Tyrosinase incubations in the presence of GSH gave the expected GSH conjugates resulting from trapping of the o-quinones, which were characterized by LC-MS/MS. Incubations of LY2066948 or equilenin with rat liver microsomes also gave detectable o-quinone trapped GSH conjugates; however, as observed with other SERMs, oxidative metabolism of LY2066948 mainly occurred on the amino side chain to yield the N-dealkylated metabolite. CYP1B1 is believed to be responsible for extra-hepatic generation of genotoxic estrogen quinones and o-quinone GSH conjugates were detected in equilenin incubations. However, in corresponding incubations with CYP1B1 supersomes, no o-quinone GSH conjugates of LY2066948 were detected. These studies suggest that although the naphthol group is susceptible to oxidative metabolism to long-lived o-quinones, the formation of these quinones by cytochrome P450 can be attenuated by the chemistry of the remainder of the molecule as in the case of LY2066948.Chemico-biological interactions 01/2012; 196(1-2):1-10. · 2.46 Impact Factor
Article: Hops (Humulus lupulus) inhibits oxidative estrogen metabolism and estrogen-induced malignant transformation in human mammary epithelial cells (MCF-10A).[Show abstract] [Hide abstract]
ABSTRACT: Long-term exposure to estrogens including those in traditional hormone replacement therapy (HRT) increases the risk of developing hormone-dependent cancers. As a result, women are turning to over-the-counter (OTC) botanical dietary supplements, such as black cohosh (Cimicifuga racemosa) and hops (Humulus lupulus), as natural alternatives to HRT. The two major mechanisms which likely contribute to estrogen and/or HRT cancer risk are: the estrogen receptor-mediated hormonal pathway; and the chemical carcinogenesis pathway involving formation of estrogen quinones that damage DNA and proteins, hence initiating and promoting carcinogenesis. Because, OTC botanical HRT alternatives are in widespread use, they may have the potential for chemopreventive effects on estrogen carcinogenic pathways in vivo. Therefore, the effect of OTC botanicals on estrogen-induced malignant transformation of MCF-10A cells was studied. Cytochrome P450 catalyzed hydroxylation of estradiol at the 4-position leads to an o-quinone believed to act as the proximal carcinogen. Liquid chromatography/tandem mass spectrometry analysis of estradiol metabolites showed that 4-hydroxylation was inhibited by hops, whereas black cohosh was without effect. Estrogen-induced expression of CYP450 1B1 and CYP450 1A1 was attenuated by the hops extract. Two phenolic constituents of hops (xanthohumol, XH; 8-prenylnaringenin, 8-PN) were tested: 8-PN was a potent inhibitor, whereas XH had no effect. Finally, estrogen-induced malignant transformation of MCF-10A cells was observed to be significantly inhibited by hops (5 μg/mL) and 8-PN (50 nmol/L). These data suggest that hops extracts possess cancer chemopreventive activity through attenuation of estrogen metabolism mediated by 8-PN.Cancer Prevention Research 01/2012; 5(1):73-81. · 4.89 Impact Factor
Article: Effects of aromatase inhibition versus gonadectomy on hippocampal complex amyloid pathology in triple transgenic mice.[Show abstract] [Hide abstract]
ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia among the elderly with women exhibiting a higher risk than men for the disease. Due to these gender differences, there is great interest in the role that estrogens play in cognitive impairment and the onset of the classic amyloid and tau lesions in AD. Human and rodent studies indicate a strong association between low brain aromatase, sex hormone levels, and beta amyloid deposition. Therefore, the effects of depleting both circulating and brain estrogen levels, through gonadectomy and/or treatment with the aromatase inhibitor, anastrozole, upon hippocampal AD-like pathology in male and female 3xTgAD mice were evaluated. Liquid chromatography-mass spectrometry revealed anastrozole serum levels of 10.19 ng/mL and for the first time brain levels were detected at 4.7 pg/mL. Densitometric analysis of the hippocampus revealed that anastrozole significantly increased Aβ- but not APP/Aβ-immunoreactivity in intact 3xTgAD females compared to controls (p<0.001). Moreover, anastrozole significantly increased the number of Aβ- compared to APP/Aβ-positive hippocampal CA1 neurons in intact and gonadectomized female mice. Concurrently, anastrozole significantly reduced the APP/Aβ plaque load in 9 month old female 3xTgAD mice. These data suggest that anastrozole treatment differentially affects select amyloid species which in turn may play a role in the extraneuronal to intraneuronal deposition of this peptide.Neurobiology of Disease 09/2011; 45(1):479-87. · 5.62 Impact Factor
Article: NO-SSRIs: Nitric Oxide Chimera Drugs Incorporating a Selective Serotonin Reuptake Inhibitor.[Show abstract] [Hide abstract]
ABSTRACT: Hybrid nitrate drugs have been reported to provide NO bioactivity to ameliorate side effects or to provide ancillary therapeutic activity. Hybrid nitrate selective serotonin reuptake inhibitors (NO-SSRIs) were prepared to improve the therapeutic profile of this drug class. A synthetic strategy for use of a thiocarbamate linker was developed, which in the case of NO-fluoxetine facilitated hydrolysis to fluoxetine at pH 7.4 within 7 hours. In cell culture, NO-SSRIs were weak inhibitors of the serotonin transporter, however, in the forced swimming task (FST) in rats, NO-fluoxetine demonstrated classical antidepressant activity. Comparison of NO-fluoxetine, with fluoxetine, and an NO-chimera nitrate developed for Alzheimer's disease (GT-1061), was made in the step through passive avoidance (STPA) test of learning and memory in rats treated with scopolamine as an amnesic agent. Fluoxetine was inactive, whereas NO-fluoxetine and GT-1061 both restored long-term memory. GT-1061 also produced antidepressant behavior in FST. These data support the potential for NO-SSRIs to overcome the lag in onset of therapeutic action and provide co-therapy of neuropathologies concomitant with depression.ACS Medicinal Chemistry Letters 09/2011; 2(9):656-661. · 3.31 Impact Factor
Article: Benzothiophene Selective Estrogen Receptor Modulators Provide Neuroprotection by a novel GPR30-dependent Mechanism.[Show abstract] [Hide abstract]
ABSTRACT: The clinical benzothiophene SERM (BT-SERM), raloxifene, was compared with estrogens in protection of primary rat neurons against oxygen-glucose deprivation (OGD). Structure-activity relationships for neuroprotection were determined for a family of BT-SERMs displaying a spectrum of ERα and ERβ binding affinity and agonist/antagonist activity, leading to discovery of a neuroprotective pharmacophore, present in the clinically relevant SERMS, raloxifene and desmethylarzoxifene (DMA), for which submicromolar potency was observed for neuroprotection. BT-SERM neuroprotection did not correlate with binding to ER nor classical ER activity, however, both the neuroprotective SERMs and estrogens were shown, using pharmacological probes, to activate the same kinase signaling cascades. The antiestrogen ICI 182,780 inhibited the actions of estrogens, but not those of BT-SERMs, whereas antagonism of the G-protein coupled receptor, GPR30, was effective for both SERMs and estrogens. Since SERMs have antioxidant activity, ER-independent mechanisms were studied using the classical phenolic antioxidants, BHT and Trolox, and the Nrf2-dependent cytoprotective electrophile, sulforaphane. However, neuroprotection by these agents was not sensitive to GPR30 antagonism. Collectively, these data indicate that the activity of neuroprotective BT-SERMs is GPR30-dependent and ER-independent and not mediated by antioxidant effects. Comparison of novel BT-SERM derivatives and analogs identified a neuroprotective pharmacophore of potential use in design of novel neuroprotective agents with a spectrum of ER activity.ACS Chemical Neuroscience 05/2011; 2(5):256-268. · 3.87 Impact Factor
Article: Inhibition of amyloidogenesis by nonsteroidal anti-inflammatory drugs and their hybrid nitrates.[Show abstract] [Hide abstract]
ABSTRACT: Poor blood-brain barrier penetration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been blamed for the failure of the selective amyloid lowering agent (SALA) R-flurbiprofen in phase 3 clinical trials for Alzheimer's disease (AD). NO-donor NSAIDs (NO-NSAIDs) provide an alternative, gastric-sparing approach to NSAID SALAs, which may improve bioavailability. NSAID analogues were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (1) analogues were obtained with enhanced anti-inflammatory and antiamyloidogenic properties compared to 1, however, esterification led to elevated Aβ(1-42) levels. Hybrid nitrate prodrugs possessed superior anti-inflammatory activity and reduced toxicity relative to the parent NSAIDs, including clinical candidate CHF5074. Although hybrid nitrates elevated Aβ(1-42) at higher concentration, SALA activity was observed at low concentrations (≤1 μM): both Aβ(1-42) and the ratio of Aβ(1-42)/Aβ(1-40) were lowered. This biphasic SALA activity was attributed to the intact nitrate drug. For several compounds, the selective modulation of amyloidogenesis was tested using an immunoprecipitation MALDI-TOF approach. These data support the development of NO-NSAIDs as an alternative approach toward a clinically useful SALA.Journal of Medicinal Chemistry 03/2011; 54(7):2293-306. · 5.61 Impact Factor
Article: Photochemical reactions of thiols with organic nitrates � Oxygen atom transfer via a thionitrate[Show abstract] [Hide abstract]
ABSTRACT: Nitroglycerin is an organic nitrate that has been used in the clinical treatment of angina for 130 years, yet important details of its mechanism of action remain unanswered. The biological activity of nitrates suggests that they are bioactivated to NO via a three-electron reduction. The involvement of free or bound protein thiols in this reduction has often been proposed. To examine the involvement of thiyl radicals in such a process, the photochemical generation of benzenethiyl radical from thiol and disulfide precursors was studied in the presence of isopropyl nitrate. Analysis of reaction products and kinetics led to the conclusion that photolysis of the nitrate to NO2 dominated the observed photochemistry. Formation of sulfonothioate and NO as products, and trapping of NO2 by 4-chlorophenol, indicated a mechanism involving oxygen atom transfer from N to S via a thionitrate intermediate. The results of the study did not indicate a rapid reaction between thiyl radical and organic nitrate. Despite weak nitrate absorption of light >300 nm and a relatively high BDE for homolysis to give NO2, the photochemistry under thiyl-generating conditions was driven by nitrate photolysis to NO2. A novel nitrate, containing a phenyl disulfanyl group linked to nitrate groups, did not undergo photolysis to NO2 or generate sulfonothioate, but did yield NO. These observations suggest that reaction between thiyl radicals and nitrates leading to NO release is a viable pathway, but it is subservient to other competing reactions, such as photolysis, in the case of IPN, and reaction with thiolate, in the case of the novel nitrate.Canadian Journal of Chemistry 02/2011; · 0.96 Impact Factor
Article: Organic nitrates, thionitrates, peroxynitrites, and nitric oxide: a molecular orbital study of the (X = O, S) rearrangement, a reaction of potential biological significance[Show abstract] [Hide abstract]
ABSTRACT: The rearrangement of organic thionitrate to sulfenyl nitrite potentially mediates the release of nitric oxide from organic nitrates, such as nitroglycerin, in the presence of thiol. The biological activity of these nitrovasodilators is proposed to result from release of nitric oxide in vivo. The thionitrate rearrangement bears analogy to the rearrangement of peroxynitrous acid to nitric acid, which has been proposed to mediate the biological toxicity of nitric oxide and superoxide. In this paper, the two concerted rearrangement processes and competing homolytic reactions are explored using molecular orbital calculations at levels up to MP4SDQ/6-31G*//MP2/6-31G*. Examination of structure and energy for all conformers and isomers of RSONO2 (R = H, Me), models for organic thionitrates and their isomers, demonstrates that structures corresponding to thionitrates and sulfenyl nitrates are of similar energy. Free energies of reaction for homolysis of these compounds are low (ΔG0 < 19 kcal/mol), whereas the barrier for concerted rearrangement is large (ΔG≠(aq.) = 56 kcal/mol). The larger barrier for concerted rearrangement of peroxynitrous acid to nitric acid (ΔG≠(aq.) = 60 kcal/mol) again compares unfavourably with homolysis (ΔG0 < 11 kcal/mol for homolysis to NO2 or •NO). The transition state structures, confirmed by normal mode and intrinsic reaction coordinate analysis, indicate that considerable structural reorganization is required for concerted rearrangement of the ground state species. These results suggest that concerted rearrangement is not likely to be a viable step in either biological process. However, rearrangement via homolysis and radical recombination may provide an energetically accessible pathway for peroxynitrous acid rearrangement to nitric acid and rearrangement of thionitrate to sulfenyl nitrite. In this case, NO2 will be a primary product of both reactions. Keywords: thionitrate, nitric oxide, peroxynitrite, nitrovasodilator, nitrate.Canadian Journal of Chemistry 02/2011; 73(10):1627-1638. · 0.96 Impact Factor
Article: Synthesis, structure, and hydrolysis of esters of strained and unstrained N-phosphonylureas[Show abstract] [Hide abstract]
ABSTRACT: Compounds 1–5 were prepared to compare reactivity patterns of cyclic and acyclic phosphonylurea esters. The rates and products of reactions of phosphonylurea esters (1–3) with hydroxide in aqueous acetonitrile were analyzed. In these compounds the phosphonate moiety is in a strained five-membered ring, which also contains the ureido group. Structural determination of 1 by X-ray crystallography indicates that the five-membered ring is planar and the internal ring angle at phosphorus is 93.1°. The endocyclic N—C—N angle of the ureido group is 111°. The compounds undergo hydrolysis in alkaline aqueous acetonitrile at 35 °C with a rate about 106 times that of analogues (4, 5) in which the phosphonate group is exocyclic to the ureido ring. Compound 1 undergoes alkaline hydrolysis (k = 9.0 × 103 M−1 s−1) to release the phenoxy group to give 6. The hydrolysis of alkyl esters 2 (k = 2.4 × 104 M−1 s−1)and 3(k = 1.3 × 103 M−1 s−1) leads to cleavage of the endocyclic P—N bond, producing 7 and 8 respectively. The exocyclic alkyl esters (4 and 5) also cleave at the P—N bond with respective rate constants of 6.5 × 10−3 M−1 s−1 and 4.4 × 10−2 M−1 s−1. The data are consistent with a mechanism in which hydroxide adds to 1 to form a pentacoordinate phosphorus intermediate with the phenoxy group in an equatorial position and the ureido ring in apical and equatorial positions (with nitrogen apical). The departure of the urea group is slower than pseudorotation of the intermediate and expulsion of phenoxide. In the isomerized intermediate, phenoxy is apical but the methylene group of the ring, which has low apicophilicity, must also be apical. Reactions of 2 and 3, which have more basic oxygen leaving groups, occur with P—N cleavage because expulsion from the isomerized intermediate in those cases is not sufficiently fast. These results fit reaction patterns at phosphorus that are determined by ring strain and electronegativity of ligands. Contributions from effects due to antiperiplanar interactions between bonding and nonbonding electrons are not detected.Canadian Journal of Chemistry 02/2011; 65(8):1838-1844. · 0.96 Impact Factor
Top Journals
University of Illinois at Chicago
Chicago, Illinois, United States
- • Department of Medicinal Chemistry and Pharmacognosy
- • College of Pharmacy
Queen's University
Kingston, Ontario, Canada
- • Department of Chemistry
- • Department of Pharmacology and Toxicology
University of ChicagoChicago, Illinois, United States


text: Report: Hollywood Hypersexualizes Hispanics on the Big Screen Print article Send a Tip by Breitbart News 6 Aug 2014 post a comment A new report suggests Hollywood can't shake that "fiery Latina" stereotype. The film industry's diversity problems are well documented. People of color are under-represented in several key areas, from major screen roles to behind the scenes. A report completed by experts at USC's Annenberg School paints a bleak picture regarding Hispanic representation on the big screen, according to Indiewire.com. Not only do Hispanics get less film roles than other minority groups despite their rising numbers, they're more likely to be sexualized on screen. [Dr. Stacy L.] Smith and her colleagues Marc Choueiti and Dr. Katherine Pieper surveyed the 100 top-performing films of the past seven years (2007-2013) and found that the numbers of black and Asian characters are more or less commensurate with 2010 U.S. census data.... Hispanics are dramatically underrepresented and hypersexualized. In contrast to the representative numbers on black and Asian characters, only 4.9% of speaking characters in the years surveyed were Hispanic. Compare that to the 16.3% of the US population that is Hispanic -- and the fact that Latino moviegoers buy 25% of all theater tickets -- and the numbers are appalling. Even worse, Hispanic women on screen are the most likely (37%) to be partially or fully naked among all women. Black and Asian women were the least likely to be sexualized (23.5% and 18.2%). White women stood at 31.9%. Interestingly, Hispanic men were also the most likely to be sexualized among all the male racial groups.

subset: commoncrawl


text:
Business type: Software ×
Employees number: 11-100 ×
Industry: Construction & Construction Materials ×
Location: USA ×
ISB Global Limited
based in London, UNITED KINGDOM
ISB Global is a leading Business Software & Systems Consultants. We specialise in the implementation of software solutions for the Recycling, Waste Management and Energy markets.ISB Global is an SAP Business Partner, with specific expertise in the integrated business management software, SAP Business One. Our solutions are designed to add value with innovative mobility, ...
ifu Hamburg GmbH
based in Hamburg, GERMANY
We provide software and services for integrated implementation according to our clients` technical, environmental and economic needs. Our strength is the integration of knowledge from various players and disciplines operating in an information system. The combination of process, product, company and industry perspective allows the analysis of entire systems while ...
Enviance, Inc.
based in Carlsbad, CALIFORNIA (USA)
Enviance is the leading provider of Environmental ERP software. Our solutions have been developed, tested and proven by serving the world's leading corporations and government organizations. As the world business community faces increasing sustainability challenges, Enviance Environmental ERP enables organizations to measure, manage, report environmental performance and ...
based in Madison, WISCONSIN (USA)
dynaQ was created to reduce the effort required to conduct an data collection activties, product reports/metrics, and manage nonconformance/corrective actions. From the beginning, dynaQ was designed around three fundamental improvement objectives: Save Time, Save Money, and Improve Results.
based in London, UNITED KINGDOM
Ecometrica is passionate about clear, correct, and meaningful environmental management that helps businesses meet their sustainability challenges, reduce costs, and increase overall performance. We help our clients measure their environmental impacts, from carbon, energy, paper, waste and water management all the way through to full supply chain accounting. We have global ...
based in Longmeanygate, UNITED KINGDOM
Welcome to Sevron – your solution to transforming the way you keep on top of Health & Safety regulations, whatever size your company is. By focusing on your exact needs, our expert team of professionals has developed a radical new way of managing the minefield of Risk Assessments, COSHH assessments and Safety Data Sheets – creating a unique, affordable and practical ...
based in London, UNITED KINGDOM
Sustainability Software ExpertiseA progressive and innovative developer of sustainability software, with a focused specialisation in designing clear, simplified solutions for the most complex problems, Accuvio, has, in the short five years since its establishment, become a market leader in the sustainability software sector in the UK.The founders, an energetic team with ...
EHS Insight
based in Houston, TEXAS (USA)
StarTex Software is the company behind EHS Insight, the premier Environmental, Health, Safety, Competency, Compliance, and Audit software solution. StarTex Software was founded in 2009 with the goal of delivering the most usable, highest performing, and visually appealing software possible. StarTex Software LLC is a subsidiary of Petrotechnical Data Systems, a 20 year ...
Titan Cloud Software Company, LLC
based in Brentwood, TENNESSEE (USA)
Titan offers the petroleum industry`s most powerful cloud software--the solution used by the largest c-stores, commercial fleet, and petroleum marketers in the world. This software protects your valuable underground storage tank (UST) and above ground storage tank (AST) assets by enabling proactive management of all regulatory and operational risks. Its full array of ...
EcoIntense GmbH
based in Berlin, GERMANY
With offices in Germany and the U.S. EcoIntense (founded 2007) is the leading specialist for HSE management software solutions. Our 100% web-based software solution EcoWebDesk complies with ISO 14001, ISO 50001 and OHSAS 18001. EcoWebDesk is the one-stop shopping solution for organizations providing data consistency, streamlined processes, real time information as well as ...


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Stewart Cink
Video Results
McGlad to be there: Svoboda, MacKenzie lead
final round. It'll be interesting to see if those two can hang on to the lead. Someone else to keep an eye on. Stewart Cink shot 63 on Saturday. He has not won since the Open championship. Could he be a factor on Sunday? I think he could
Low rolling in Vegas:: Cink , Laird tied at top
afternoon we did. Martin Laird and Stewart Cink posting the 64's. Peter early ..... said to look at Martin Laird and Stewart Cink and just be able to check their ..... other half of the field tomorrow. Stewart Cink , Martin Laird looking to back
Golfing World: Walk the course with Colin Montgomerie
incident in Wales 2010, was the Molinari brothers. That they came down, to the last hole. I think it was against Stewart Cink and Matt Kuchar I believe. And one of them was gonna go for it in two. And I said no no no no no no no. Don't go
On the Clock: Should captain's picks be moved?
Will Gray and Jay Coffin get 40 seconds 'On the Clock' to debate the hottest Ryder Cup topics, including the U.S. Team they feel was the most outmatched
Nicklauses headline field at PNC Father/Son
2012 with a new title sponsor. The 36-hole scramble event will be played at the Ritz-Carlton Golf Club. Stewart and Connor Cink are the defending champions. Here are the teams: Steve/Sam Elkington Nick/Matthew Faldo Raymond/Robert Floyd Hale/Steve
Stat attack!: WGC-HSBC Champions preview
Woods 25 18 Ernie Els 9 2 Phil Mickelson 8 2 Rory McIlroy 8 1 Jim Furyk, Sergio Garcia 8 0 Ian Poulter 7 2 Justin Rose, Stewart Cink , Vijay Singh 7 1 Retief Goosen 7 0 One final thought: Adam Scott and Bubba Watson are among those players making
McGladrey taking multiple-course trend to East Coast
taken me years to get the formula just right.'' CINK 'S COMPANY: Stewart Cink hasn't won a tournament in more than five years ..... Everybody who's ever started in a PGA Tour event.'' Cink has gone 30 straight events since his last top 10
Stat attack!: CIMB Classic preview
3 MC DNP DNP Graham DeLaet T-7 T-39 DNP DNP Billy Horschel T-11 DNP MC DNP Sergio Garcia T-11 DNP DNP DNP Stewart Cink T-11 DNP T-33 T-32 Players with top finishes in the 2014-15 season who are in the CIMB field Player 2015 FedEx
McGladrey participants scrambling to reach Malaysia
have plenty of company on that private flight to New York, as Brendon de Jonge (T-2), Will MacKenzie (T-2) and Stewart Cink (T-32) had to miss their flights out of Jacksonville, Fla., because of late tee times. It will be a particularly long
MacKenzie, Svoboda share McGladrey lead
him. He hit his approach into the water on the par-5 15th for a bogey. Henley had a 68 and was one shot behind. Stewart Cink shot a 63 and was among those just three shots behind. Nine players were within four of the lead.
Svoboda, MacKenzie share McGladrey lead
12), Russell Henley (-11), Stewart Cink (-9), Chris Kirk (-9), Andrew ..... victory come Sunday. Round of the day: Cink hasn't won since his triumph at ..... 7-under 63 in the third round. Cink began on the back nine and birdied
Azinger's Ryder Cuppers: Pods put up points
going to happen like it did," said Stewart Cink , who played his fourth of five Ryder ..... a clearly defined game plan," Cink said. "Just like if you went to ..... scenes," Weekley said. While Cink added, "His system was [worth a point
Putnam, Knox share Shriners lead at Summerlin
outside the projected cut line. Biggest disappointment: Stewart Cink came out of the gates quickly with a first-round 64 to ..... but the former Open champ struggled mightily in Round 2. Cink made a quadruple-bogey 8 on No. 11, his second hole
Cink , Laird share early lead at Shriners
veterans share the lead: Leaderboard: Stewart Cink , (-7), Martin Laird (-7 ..... leaderboards at TPC Summerlin, but Cink later joined the fray. Several players ..... bogey-free 64. Best of the rest: Cink began slowly with seven straight pars
Lyle comeback continues with opening 66 in Vegas
15 of 18 greens in regulation at TPC Summerlin, and the score put him in an early tie for fourth, two shots behind Stewart Cink and Martin Laird. Beginning on No. 10, Lyle played his first six holes in even par before reeling off three straight
2014-2015 PGA TOUR Season Kicks Off On Golf Channel with Frys.com Open
Grande Lakes Resort in Orlando, Fla. – will wrap 2014 with a 20-team field made up of defending champions Stewart and Connor Cink , and 19 more of the game's greatest golfers and their son or daughter. Golf Channel and NBC will carry the two days of coverage
Golfing World: Matt Kuchar - Ryder Cup 2014
McIlroy and McDowell 1 up at the 16th, Kuchar rolled in a birdie to make it all square. And after a sensational birdie from Cink on the 17th, the pair sealed the match 1 up on 18 to give Kuchar his first Ryder Cup win In the singles Kuchar faced formerbirdie to make it all square. And after a sensational birdie from Cink on the 17th, the pair sealed the match 1 up on 18 to give Kuchar his first Ryder Cup win In the
Golfing World: Thomas Bjorn – Ryder Cup 2014
Next up in Golfing World's Ryder Cup profile series is Thomas Bjorn, who has never yet tasted defeat in the famous event as member of Team Europe.
Golfing World: Sergio Garcia - Ryder Cup 2014
Nicholson and David Toms in the Saturday foursomes. The only point Garcia lost that week came when he met an informed Stewart Cink in the Sunday singles. That didn't matter though as Europe went on to win by a record nine points. He will undoubtedlyonly point Garcia lost that week came when he met an informed Stewart Cink in the Sunday singles. That didn't matter though as Europe went on to win by a record nine points. He will undoubtedly
Golfing World: Henrik Stenson - Ryder Cup 2014
an automatic spot on Ian Woosnam's team in 2006. And impressed in the opening afternoon's foursomes. Pleasing Stewart Cink and David Toms, alongside David Howell. The Swede was teamed with Padraig Harrington in Saturday morning's fourWoosnam's team in 2006. And impressed in the opening afternoon's foursomes. Pleasing Stewart Cink and David Toms, alongside David Howell. The Swede was teamed with Padraig Harrington in Saturday morning's four balls. But this chip in
Golfing World: Rory McIlroy - Ryder Cup 2014
scoreboard. The first time two Northern Irishmen have been partnered in a Ryder Cup match. They met Open winner, Stuart Cink and Matt Kuchar. In front of strong home support, they. The pair started well but found themselves one down headinghave been partnered in a Ryder Cup match. They met Open winner, Stuart Cink and Matt Kuchar. In front of strong home support, they. The pair started well but found themselves one down heading into the
Watson's captain's picks want redemption in Scotland
Brandt Snedeker (No. 13) and Dustin Johnson (No. 15); while Corey Pavin went with Tiger Woods (No. 12), Stewart Cink (No. 14) and Rickie Fowler (No. 20). Even Paul Azinger, the maverick who overhauled the selection system
Players divided on 54-hole cut in playoffs
brought up at the first Player Advisory Council meeting of the 2014-15 season at the Frys.com Open. While PAC member Stewart Cink agreed with Brown's assessment – "That's the way we've done it all year. I don't see why we shouldn't keep
Azinger's insight into the 2014 U.S. Ryder Cup team
he said. "I didn't pick (Campbell). They had three players they could have picked. (Steve) Stricker, Stewart Cink and Ben Curtis picked Chad Campbell. They were invested in him and Campbell was so invested in them." If the U.S


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There's nothing like a good old fashion understatement to undermine the visceral reaction and emotional content of a statement. Never the less, I will lead with the proverbial understatement: Finding a good iPhone case is a challenge!
Some would disagree (another gross understatement 1), but the Iphone remains the iconic symbolence of the modern era and the most popular mobile amongst the hip, chic, happening, artistic, and the style conscious (as Apple products have been for decades). From the beautiful UI of iOS 8 to the thoughtful physical design of the hardware (though the iPhone 6 was quite a big step backward in that regard) the design remains iconic. People eagerly wait for the launch of the new models and are ready to pay almost any price for it.


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What turns a woman on? - Best ways to satisfy any woman
Men are very visual when it comes to being aroused sexually while women are a little more complex and are turned on in other ways. Here are a few examples.
Womens ears are extremely sensitive and a few licks and gentle kisses can really get her worked up.
A well groomed man who obviously takes pride in the way he looks is another. All women seem to fancy a man in uniform.
Self confidence is a huge turn on to a woman, the amount of not so handsome guys who are choc full of confidence who are with a stunner is unreal.
Compliments are also a huge turn on to women, not rude ones just things like your hair looks amazing or wow you look hot in those jeans.
Those are all non sexual things that turn a woman on, so what will turn a woman on in bed and make her beg you for more?
Cunnilingus (oral sex) when given well leads to the most powerful orgasms women can possibly have. I say when given properly for a reason because there is a right and wrong way to do oral sex.
The wrong way is to dive in and go on a licking frenzy, all this will do is put her off cunnilingus for a very long time.
The right way to give a woman an oral sex orgasm is to lick her vagina gently until she gets more and more aroused. Then when she starts to get louder with her pleasure moans move on to her clitoris. You must remember that her clitoris is hyper sensitive so be careful.
Flick it with your tongue and in a minute or two your woman will orgasm.
That's what turns a woman on sexually.
Discuss this Article
Tips to help you give your woman an orgasm Here are 10 tips to increase the chances she'll reach climax
Find and stimulate the G spot - The G-spot is a zone that feels like the roof of your mouth and is located about 2 inches inside....
How To Lick A Woman Better Orgasms For Women Multiple Orgasms
Positions To Make Her Orgasm Women's Orgasm How To Lick A Woman
How To Lick A Woman Best Way To Pleasure A Women Better Orgasms For Men
The Female Orgasm Multiple Orgasms How To Lick A Woman
Free Orgasms How To Give A Woman An Orgasm How To Lick A Woman
How to lick a womans vagina and give her an orgasm-Tips to lick a womans vagina
Do you want to learn about Make Woman Orgasm Review? Would you expect to learn more regarding the credibility of Holly Liv? Or is Make Woman Orgasm Scam or authentic product? You will find the answers within this honest review!
Luckily for women, they can encounter different sorts of orgasms and of course as you may have heard women can also have multiple orgasms. While this may be true, many women will go for years without experiencing an orgasm with their lover. That being said, here are the top 10 tips make sure your woman enjoys bountiful orgasms:
Erectile dysfunction can interfere with a man's quality of life. Stress may be the culprit, and finding ways to manage it is an important element of penis care.
What are the best techniques men can use in any setting to hide an erect penis? Find out here.
Dry penile skin can have some surprising causes. Here are just some of the issues that can lead to a parched, itchy penis.
There are countless products for men who want to improve their performance in the bedroom; however, sometimes, sex enhancement is best achieved through these lifestyle changes.
Men with reduced penis sensation may be skipping these three essential penile care steps.
This surgery isn't right for everyone, but some adult men have reason to pursue a circumcised penis.
Sex can be highly satisfying no matter what a man's penis size. This guide helps men learn the best positions for what they're packing.
A man doesn't have to be bored with his solo play routine to try new things. Check out these inventive masturbation techniques.
Delaying your ejaculation is easy if you use pills or creams but these things don't come cheap and they are a repeat purchase. So the best way to last longer in bed for men is not to use pills but to embark on a natural ejaculation trainer.
This article will focus on natural ways to prevent early ejaculation rather than the products that you can purchase. The reason being that I don't believe that spraying a numbing agent or applying a numbing cream to your penis can have no harmful side effects.
If there is one thing about having sex that most men would like to improve it is their sexual stamina. Early orgasms plaque millions of men but it is quite simple to last longer in bed. Here are two ways to stop early orgasm and last longer in bed for men.
Men love to boast about how good they are in bed and how long they can last for but next time you hear a guy telling someone about his huge amounts of sexual stamina don't take what he says to seriously. You see up to 65% of men lack the ability to stop ejaculating to fast during intercourse, so the chances are that the boasters are liars. If you find that you ejaculate before your partner has a chance to reach her climax then read on for these tips on how to stop ejaculating to fast while...
One of the main causes of men ejaculating too fast is not a hyper sensitive penis but simply an over active brain. Lasting longer during intercourse is not hard as long as your mind is right. An example is that your lover looks hot and you really want sex with her so you keep looking at her and getting yourself all worked up.
There are tons of ways for guys to last longer in bed from delay sprays to natural exercises that give you full ejaculatory control. It's ever more important to be able to outlast a woman in bed because the modern woman demands a guy who can cater for her sexual needs. Here are two tips on having more sexual stamina.
This article will give you 2 tips on how to stop from ejaculating too fast during intercourse. Before we get started though let's get one thing straight and that is no matter how fast you are ejaculating you do not have a problem. This is simply because of the time difference that it takes men and women to reach orgasm.
Stopping ejaculation isn't as hard as you may think, in fact if you follow a plan of action you will be lasting longer within a few days. Here are three ways of stopping ejaculation that will stop you asking, how do I last longer in bed?


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Potted Nevis Pine Pre-lit Christmas TreeItem # HN-VKR469
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text:
Car shredder in Benton Township unlikely after vote
Updated: 01/26/2010 - The Benton Township Planning Commission on Monday night voted against recommending a permit for Randy's Recycling to build a shredder along Paw Paw Avenue.
Updated: 01/26/2010 - The Benton Township Planning Commission on Monday night voted against recommending a permit for Randy's Recycling to build a shredder along Paw Paw Avenue.
Updated: 01/26/2010 - The New Paris community is looking for a man who has been breaking into about a dozen of its businesses the last few months.
Posted: 01/25/2010 - A team of Berrien County doctors and nurses pretty much dropped everything once they heard about the quake. Within 48 hours they were on a private jet on the way to Port Au Prince
Updated: 01/26/2010 - In December, Indiana's governor announced that state payments to local school districts would be cut by $300-million.
Posted: 01/25/2010 - The South Bend Medical Foundation is donating $10 to the Red Cross International Response Fund for every person that donates blood during the month of February.
Updated: 01/27/2010 - It reportedly happened early Saturday morning on the northwest side of campus, no specific location was given.
Updated: 01/26/2010 - The trial of Kristina Byers-Escobedo started Monday afternoon.
Updated: 01/25/2010 - The Boeing 737 had about 90 people aboard when it left the airport in Beirut, Lebanon early Monday.
Updated: 01/25/2010 - The blaze broke out around 4 a.m. Monday near the intersection of North Brookfield and Humbolt streets.
Updated: 01/25/2010 - A snowmobiler is badly injured after getting his pants caught during a race on Syracuse Lake Saturday morning.
Posted: 01/25/2010 - The local sports bars were busy Sunday as the Colts took on the Jets to try to make their Super Bowl dreams come true.
Updated: 01/24/2010 - Two weeks ago Newscenter 16 talked to Mobile EMS employees who were frustrated about bouncing checks. On Jan. 15, the company closed its doors – and since then, former employees say they're owed tens of thousands of dollars.
Updated: 01/25/2010 - Lindsay Schrader scored eight of her 16 points during a 14-2 Irish run as 5th-ranked Notre Dame rallied to beat West Virginia 74-66 at Purcell Pavilion to improve to 17-1.
Posted: 01/24/2010 - Elkhart Mayor Dick Moore is back from the U.S. Conference of Mayors in D.C. and he's ready to get to work.
Updated: 01/25/2010 - Four-time MVP Peyton Manning threw three touchdown passes and the Indianapolis Colts rallied from an 11-point, first-half deficit to beat the New York Jets 30-17 in the AFC championship game.
Posted: 01/24/2010 - It's been 32 years since the worst recorded blizzard in Michiana history hit the area. To reflect on the anniversary of when the storm began, which is tomorrow, Captian Chuck Steele of the South Bend fire department and Ed Friend, former Captain of the South Bend Police Department.
Updated: 01/24/2010 - Police in Lake County busted a massive drug operation this week and brought in 1,500 pounds of marijuana with a street value of $1.2 million.
Updated: 01/23/2010 - Tim Abromaitis scored 30 points and Luke Harangody picked up his 60th career double double as Notre Dame snapped a 2-game losing streak with an 87-77 win over rival DePaul Saturday at Purcell Pavilion.
Updated: 01/23/2010 - You may not know much about it, but if you love the arts, it's right up your alley, and right in your backyard.
Posted: 01/23/2010 - Police in Niles need your help find a man who held up a business Friday.
Posted: 01/23/2010 - Penn beat St. Joe in a battle of NIC unbeatens. Riley also stayed undefeated in conference play. Warsaw remains the leader in the NLC.
Posted: 01/22/2010 - Two Warsaw residents spend a week helping people in Haiti in dire need of medical attention, food, and water.
Posted: 01/22/2010 - Friday, 80 Haitian orphans arrived in Miami to be greeted by their adoptive families.
Updated: 01/26/2010 - Have you ever wondered how much energy you're wasting in your home? This may be your chance to find out.
Posted: 01/22/2010 - "Well, I think it's a disaster for our democracy and for the American people," said Elkhart County Democratic Party Chairperson Shari Mellin. "I think it just puts legislative seats up for sale basically."


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After these three random dudes at the store had their impromptu jam session captured by a passerby, the Internet is waiting to see what'll come next.
For the Wilsons of Dallas, taking pictures was a family affair. Today the mother is a successful photographer and her boys are hot Hollywood commodities. Here's a look at Laura Wilson's personal album.
May 1, 1996 | by Anne Dingus | Feature
Play about two male penguins raising a chick not allowed in the district's elementary schools.
November 15, 2012 | by Ross Dubois
Whose idea was it to install a Playboy sculpture in Marfa?
October 14, 2013 | by Francesca Mari
Bert Long comes to Houston's Contemporary Arts Museum by way of the Fifth Ward, the Marines, haute cuisine—and the Prix de Rome.
February 1, 1992 | by Michael Ennis | Art


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1972 Volvo 1800ES - Only 2 years production in this body style Mileage believed to be approximately 110k - past mechanical limits on odometer Recent respray... More
P1800E 1970 completely restored This car if a fine example of what can be done on a full restoration and how well it will hold... More
Excellent Condition Volvo XC70 Cross Country AWD Wagon. VERY Clean. Motor just replaced with 2007 motor with 6 month/6,000 mile warranty. New Turbo. All... More
Volvo 1966 122S, 2,500 miles on rebuilt B20 engine, SU carbs, overdrive transmission, IPD cam, IPD sport exhaust. New paint, new front windshield, nice... More
VOLVO: 1972 1800ES, excellent body, new tires, exhaust, one owner since 1987, well maintained, nicer 1968 gauges, automatic, runs and drives excellent, 85,000 miles,... More
Volvo 2007 S80, V8, awd, 37,500 mi, electric silver, off-black leather interior, non-smoker, one owner, climate pkg, navigation, front & rear park assist, adaptive... More
VOLVO: 1969 P1800S coupe, white with red leather, an exceptional example, must see. Hyman Ltd, 314-524-6000, MO; www.hymanltd.com... More
VOLVO: 1961 P1800 Jensen, VIN 1386, historical model in excellent condition, red with light interior, $24,500. 717-921-2644, 717-645-4723, PA.... More
VOLVO: 1968 P1800, maroon with black interior, sitting many years, excellent original car to restore, for $6,950. Beverly Hills Car Club Inc, 310-975-0272, FAX:... More
VOLVOS: 1963-1968 122S station wagon project cars, 20 to choose, various colors/conditions. Details: 717-921-2644, 717-645-4723, Carlisle, PA.... More
VOLVO: 1964 PV544 Sport, restored in 2007, little used since, very clean floor pan, very good paint, chrome, interior, excellent mechanicals, perfect compression, sway... More
VOLVOS: 122 coupe project cars, 1964-1968, 10 available, inside storage last 25 years, $1,850-$5,000. Susquehanna Spares, 717-921-2644, 717-645-4723, PA.... More
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text:
Samsung Galaxy Tab S 8.4: 4G Android tablet is easy to swallow
If by the size of its TV ad campaign shall ye know it, then the Galaxy Tab S is clearly a Very Big Deal to Samsung. I get the impression the Tab S range is Sammy's most determined effort yet to convince people that its Android tablets are not just better than anyone else's, but better also than Apple's iPad alternatives. …
Whither Nexus 8
I will want to replace my Mk1 Nexus 7 soon. The battery is tired and doesn't hold much charge. The case has been dropped once too often. I've coveted a friend's Nexus 10, but it's too heavy to hold one handed for long. The rumours of a Google Nexus 8 have gone quiet. Perhaps I'll have one of these instead.
Re: Whither Nexus 8
You appear to be living the same life as me.
Where indeed is the next iteration of the Nexus 7/8? Fed up with charging my Mk1 every night.
Re: Whither Nexus 8
Ditto, my first gen Nexus 7 is still in pretty good nick, bar a creaky edge to the screen, but it's always had those image persistence issues that some units had, and the speakers are pathetic, and the lack of a card slot has occasionally irked me when traveling. If there was a cheaper, wifi-only version of this Samsung, preferably without the Samsung bloat (dream on I guess), I'd buy it right now, but I'm not quite sold on it as it is.
Re: Whither Nexus 8
I also had a first gen Nexus 7 and was patiently waiting for the Nexus 8 to materialise when the Tab S made it's appearance. I took the plunge and bought a white Tab S 8.4 and haven't been disappointed for a moment. The screen is great, battery life good and with a 64GB SD card has plenty of storage for movies, books and music.
The only downside is the bloatware. Really Samsung, why do you do this to your customers?
After rooting, disabling some apps, freezing those that won't be disabled and installing Google Now launcher it is even better. The screen was worth it over the Nexus 8 vapourware if it ever gets released.
Re: Whither Nexus 8@ FartingHippo
"Where indeed is the next iteration of the Nexus 7/8? Fed up with charging my Mk1 every night."
Replace the stuffing battery then. £21 off Amazon, flip the back off using mobile phone disassembly tools, £10 or less from any mobile phone accessory seller (mind that bottom bit of the case around the speaker, that's fragile), unplug the battery connector, peel the battery off the double sided sticky, push in the new one, click, click, clickety-click and Bob's your uncle.
Bl00dy techies! "The battery's worn out so I'd better buy a new one"
Re: Whither Nexus 8@ FartingHippo
I don't have this device though my personal track record attempting procedures like this has me confident I'd break the device in the process.
I am glad my note3 has a user replacable battery will probably get near the 1 year anniversary of owning it.
Re: Whither Nexus 8@ FartingHippo
"Replace the stuffing battery then".
I did consider that. My problem is, I don't know how to tell angels from crooks on Amazon, eBay etc. The last two phone batteries I bought on-line were useless. One wasn't even new as claimed -- an old one with a half-hearted attempt to polish out some scratches.
Re: Whither Nexus 8@ FartingHippo
"I don't have this device though my personal track record attempting procedures like this has me confident I'd break the device in the process."
But you tried in the past, and that's far more important than failing. And if the device is virtually unusable to the point of wanting to replace it, what have you got to lose?
I'd agree designing for user replaceable batteries is a far preferrable consumer outcome, and that's how I select my phones, but there's times when you can't get everything you want, and in that case the shed approach must be tried.
Re: Whither Nexus 8@ FartingHippo
You can send it away and have the battery done for £30 with a guarantee on the work.... worth a go at that price I'd have thought.
My current car - which I bought last year, and it's a bit of a dud and I'm pissed off with it - needs about £1200 of work doing to it (tyres, inlet manifold, cambelt) so I considered replacing it with something newer/nicer. But apart from the newer/nicer carrot, I'm thinking why trade in and spend an additional £8000 on a new (s/h, always) car so I can save £1200? Doesn't quite add up!
Re: Fed up with charging my Mk1 every night
Me too. I got rather more iPad-ish battery life out of it by crippling some of the more annoying spoogeware, and going into advanced Wifi settings to switch of Wifi when asleep. Massive battery boost - 3-4 days between charges now, with moderate use (even films) at the loss of live notifications. Luckily my appointments still chime at me though...
Edited to add that the battery is not apparently failing so a replacement, as has been suggested elsewhere, will not do very much. What *did* kill it was the last OTA update, which ladled so much google crapware that the battery life went straight down the crapper. Hence the un-installing / crippling of most of it.
Re: Whither Nexus 8
You can pick the WiFi-only version up from Currys for £319. However, consider the Samsung Galaxy S Pro. This has a full set of RGB pixels (rather than pentile) and is not that much different to the 'S'. Indeed, I was rather annoyed when the 'S' came out so soon and was prepared to get one - but my 'Pro' is still a superb unit. Slightly bigger and heavier - but not by much - with a (still) great display. Yes, the blacks are slightly blacker on the Amoled 'S' - but the 'Pro' is no slouch and is a lot cheaper. Incidentally, I did check the screen quite closely on the 'S' as they have demo units at Currys. I'm sure you can see the pentile matrix - but you have to get *close*. In reality, the reviewer is correct. It really makes no difference. Incidentally, some 'Pro' users complain the screen is not as sensitive as the 'S' - they may be slightly correct but I have had no real issues with this.
Re: Fed up with charging my Mk1 every night
Sounds like a trip to http://get.cm is in order...
Re: Whither Nexus 8@ FartingHippo
A bigger problem with the mk1 is its insistence on only charging at 500ma (net charge rate 50mA) when used with anything other than its own specific charger.
Sounds like an impressive little tablet, although I would never want an LTE version myself,
i've never understood having multiple mobile contracts for multiple devices, I have one on my phone and tether anything I need to use, even with the higher price to allow tethering it works out much cheaper than having multiple mobile contracts..
Or you could get a second sim for your existing contract?
nice idea
unfortunately I am not aware of any networks here in the UK that support two sims on one contract let alone one number unless it is some kind of business plan.
I think EE did
but then they charge you £15 from memory - so you may as well get a cheapie sim-only sim.
It's also a phone!
I bought one and found that it is actually a telephone as well (as helpfully mentioned in this article) - unfortunately the data plan I bought is data-only as those were the only options presented to me by Carphone Warehouse. If you want to make and receive phone calls on this bear this in mind. You can still use SMS though (at least on EE you can). I don't think I'd "feel like a spanner" as it would be quite funny in a 'mines bigger than yours' kind of way. Reminds me of the Trigger Happy TV sketch with the oversized Motorola brick.
Re: It's also a phone!
I felt like a total tool using the Nokia 8110, so I doubt I'd feel particularly comfortable holding an 8 inch slab to my ear!
Re: It's also a phone!
It's Dom Joly time! I can imagine putting this huge fondleslab to your ear and going "HELLO!" very loudly :-)
Re: It's also a phone!
Alternatives to Dom Joly mode:
Bluetooth headset.
Wired heardphones with mic.
I would never buy a tablet device with cellular radio, that was unable to make calls and send sms.
Why would I want something that big, and STILL have to carry a phone?
Re: It's also a phone!
...because otherwise you'd need to carry a Bluetooth headset, Bluetooth headphones with mic or wired headphones with mic?
Re: It's also a phone!
Plus you can always just use a handsfree or headphones to avoid the channeling-Dom-Joly look.
One of those nifty bluetooth/plugin retro telephone handsets might be the thing!
Can you remove all trace of this plus Twitter and any other Social Media application from it or is it like the last Samsung device I had where you couldn't even stop the Facebook application without rooting the device. Even then it would somehow restart and try to connect to its Mothership even if you were in Flight Mode.
If my fairly simple requirement is possible then I might be tempted to buy one otherwise, Samsung you can take a hike.
Re: Facebook
Upvote - it's not just Facebook and not just Samsung. Why oh why oh why do manufacturers insist on pre-loading apps (ok, I could live with that) but then not letting you uninstall ones you have absolutely no need of.
Re: Facebook
As far as the manufacturers are concerned "everyone" wants these apps installed, and unfortunately those of us that actively don't want them are a statistically irrelevant minority. Plus it wouldn't surprise me in the slightest if there were incentives from the likes of Facebook to said manufacturers. Nexus devices don't have Twitter or Facebook preinstalled, however being Google devices you end up with a non-removable Google+ app instead.
The only real answer if you want total control is a custom ROM.
Re: Facebook
I'm not sure if you can remove the mentioned apps, but it should be fairly easy to deactivate them.
Then they won't show up in the apps list, and they will be prevented from starting, so apart from the storage space used, it's pretty much the same as removing them.
@ KjetilS - good point
I'd forgotten about disabling apps - just checked on my Nexus and you can indeed disable Google+ or any other of the bundled Google stuff, though it does give you a dire warning that this might break other functionality.
Re: Facebook
I was under the impression that as long as you don't create an account (facebook, twitter etc) you won't be bothered with it. I don't use twitter and my Note3 hasn't once bugged me about that and facebook or linked-in didn't say a peep until i created an account for them on my phone.
Re: Facebook
Easiest solution: save £££ by not buying a tablet, and get an A5 diary and a nice pen :)
Cinema mode...
... if that was the only reason to now like an AMOLED display, then why not activate it on earlier models? GS3 has had the 'Movie' option for ages, which banishes the garish 'Standard' colour balance for something far less eye-watering...
8.4 and 10.5
There's no 10.1 guys
"For comparison, the Snapdragon 801-powered Galaxy S5 scores just over 3,000. Only the GPU lets the side down a bit, it's just not up with the latest Adreno components in terms of outright performance, though this isn't a failing you'll ever notice in use."
I don't understand what you are saying here. The benchmark figures quoted above this seem to suggest the Tab S is faster at 3D (9326 compared with 8812) and only 23 point slower at 2D (1601 compared with 1624). Seems that the RAM is quite a bit slower though.
If it's as fast as my SGS5 in real use, I'll be very happy.
Re: Confused
When I ran a few dedicated graphics benchmarks like GFXBench 2.7 the Tab S 8.4 didn't perform as well as the Snapdragon 801 Galaxy S5. I didn't go into greater detail in the review because frankly it's a bit irrelevant. Sorry for any confusion.
Storage costs aren't always commutable
quote from the article: "Decent 128GB cards can be had for under £80 these days, proving that Apple is really taking the proverbial with its storage costs."
In-device flash storage is normally vastly overprovisioned compared to removable memory cards, so I would not be comfortable saying that a 16GB MicroSD would be identical to the 16GB internal memory on the Tab, or that a 128GB MicroSD is identical to the internal memory on a top of the range iDevice.
Having said that, I'd always prefer to have removable (i.e. replaceable) storage for high churn data like storing music or video, because changing the MicroSD when it finally dies is both easy and cost-effective, and they are also easily transferable between devices. Nice to see Samsung keeping MicroSD support as a differentiator from their competitors (including the Nexus range, not just Apple).
Oh, and the way to tell Apple is taking the mickey with internal storage costs is by spotting that they have the same surcharge to double the memory, regardless of the actual increment; 16 to 32GB costs the same as 64 to 128GB (+£80 for the iPad), so the £160 it costs to go from 16 to 64GB (+48GB) doesn't add up to the £80 it costs to add another 64GB to it.
Re: Storage costs aren't always commutable
I recently discovered another good reason for removable storage. Until the last Android update I could connect my phone by USB to my Linux computer and mount the storage as a disk device. Now it's something called a media device, the contents of which are inaccessible from my oldish Linux. The only solution, incredibly, seems to be to remove the memory card from the phone and mount it via a USB card adapter.
Re: Storage costs aren't always commutable @ Kubla Cant
My Mint 17 box mounts my Android 4.4.4 phone as a media device, which has 2 sub-directories, "Internal storage" and "SD card". These can be accessed identically to the USB HD that was detected by earlier versions of Android.
Re: Storage costs aren't always commutable
Settings -> Storage -> Menu -> USB computer connection -> Mass storage (UMS)
Re: Storage costs aren't always commutable
There's no such setting on my phone..
And after the kitkat update ate the ability to have an app write to anywhere I told it to on the (external) SD card, I'm left with either using the irritatingly non-syncable MTP to copy things across one directory at a time, or having to unmount and remove the SD card every time I want to copy something straight to, for example, /ExtSdCard/Music/ instead of being able to just press a button or two on my phone and have it all happen automatically courtesy of cheetahsync, or airdroid.
If this carries on, my next phone will probably be the first one without removable storage since the K750i...
Re: Storage costs aren't always commutable @ Kubla Cant
Accessed identically, with the advantage that the device can still access it at the same time.
@Kubla Cant - MTP instead of USB HDD mode
Yeah, this was really off-pi... um, off-putting. I have an HTC One X with fixed internal storage: no SD card.
I managed to work out (with difficulty) how to make Kubuntu on my PC communicate using MTP, but I'm stuffed when it comes to the car: I used to be able to connect with USB and play podcasts, music, etc. from the phone. Now the car headunit just reports "Media Error".
Re: Storage costs aren't always commutable
Yeah, you need to access it through MTP. If for example you have KDE, you can fetch kio-mtp and access it through dolphin using mtp:///
Re: Storage costs aren't always commutable
have you tried switching the phone from MTP (Media Device) to PTP (Camera) in the USB options? That should in theory work like a normar external storage device.
Re: Storage costs aren't always commutable @ Kubla Cant
I dare say that my Mint system will mount my Android 4.4.4 phone too, once I've set aside the time to upgrade to the latest Mint version. But all I wanted to do was copy a few new music files to the phone, not perform major system maintenance.
No such settings - you must be imagining it (or perhaps we have different phones).
@everybody else
Yes, yes, yes. I know there are solutions. I even know what some of the solutions are. I'm just irked to encounter a further example of ill-defined indirection layers on top of well-understood computer features. The incomprehensible "Libraries" in Windows 7 are another.
What's the point of the 4G?
What's the point of paying a large premium for a 4G enabled tablet plus the hassle & added expense of a phone plan that covers the extra SIM when the phone in your pocket can be tethered?
Re: What's the point of the 4G?
Convenience, battery life, better aerial/signal, network redundancy to name but 4 reasons.
Re: What's the point of the 4G?
Depending who you are with and what plan you are on, it's not always possible to tether via your phone.
Re: What's the point of the 4G?
I find I use my tablet both as a hotspot and for surfing especially when abroad. In such cases having one that takes a SIM is pretty useful. The bigger battery makes it more suitable for tethering than a phone.
Re: What's the point of the 4G?
4G no longer has a higher premium than 3G on most networks
Elephant in the room
Is the battery replaceable??
(Everything else sounds great, although dual sim would be nice).
In light of the GCHQ revelations, I am surprised El Reg hasnt removed all the other icons.
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'SNL' Star Seth Meyers Gets Engaged to Alexi Ashe
Congrats to Seth Meyers! The 'Saturday Night Live' alum and future 'Late Night' host and his longtime girlriend Alexi Ashe are engaged!
Congrats to Seth Meyers! The 'Saturday Night Live' alum and future 'Late Night' host and his longtime girlriend Alexi Ashe are engaged!
Sketch dumped for being unfunny.
Casey Battersix is quite the hot commodity on SNL's version of 'The Voice.' Buttersix, played by host Melissa McCarthy, is being fawned over by Adam Levine (Bill Hader), Usher (Jay Pharoah), Shakira (Kate McKinnon) and Blake Shelton (Jason Sudeikis) after a hilarious performance of 'Don't Mess With My Toot Toot.'
How do we know if that was the REAL Macklemore anyway? You can dress anybody up in a flashy red suit and have them memorize the song. I wanted a LIVE performance, that's why they call it Saturday Night LIVE!
Justin Timberlake has some pretty damn good PR people.
After announcing his new album 'The 20/20 Experience,' it seems like you can't go anywhere without being slapped in the face with an appearance by JT. Grammys, pre-Super Bowl concert, Brit Awards, we could go on and on. We're surprised he hasn't shown up in our shower yet.
Continuing the Timberlake saturation, it's been announced that he will host and perform on 'Saturday Night Live' on March 9, and will perform for a full week (March 11-15) on 'Late Night With Jimmy Fallon.'
Truth said in jest?
Adam Levine's episode continues to go viral!
Latest Saturday Night Live Digital Short going viral!
I'm still jealous I didn't get to go...
Rihanna made an appearance on Saturday Night Live and the staff & producers were less than pleased. Apparently she called in sick to the dress rehearsal. Ooops!
106.1 KISS-FM and USI are very proud to be bringing you Mike Posner and special guest Karmin, to the USI Springfest stage at the PAC on April 14th! You've likely heard Karmin's new single on KISS-FM. It's called Brokenhearted.
I though I would give you a sneak peek into what
I'll be honest, I bailed on SNL late last season, so I didn't see Lindsay notorious appearance on this weekend's "Saturday Night Live."


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Sao Paulo, Brazil
Av. Ibirapuera, 2577 - Moema, Sao Paulo, CEP 04029-200, Brazil – Show map
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Outdoor Pool (all year), Grounds
Fitness Center
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Restaurant, Bar
WiFi is available in all areas and is free of charge.
Private parking is available on site (reservation is not needed) and costs BRL 8 per day.
Room Service, Shuttle Service (surcharge), Airport Shuttle (surcharge), 24-Hour Front Desk, Express Check-in/Check-out, Baggage Storage, Laundry, Dry Cleaning, Ironing Service, Daily Housekeeping, Meeting/Banquet Facilities, Business Center
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I requested a room with wood floors, I hate dirty carpets and my request was granted. Very good breakfast buffet and staff. Very comfortable bed and good linens. Windows that open so you can get fresh air in.
the carpet in the hallways were very dirty.
The site
Bathroom well lit Good shower Bed and pillows were great Room without carpet was much cleaner
WiFi Price on Thursday night was double Friday and Saturday night.
Bed was comfortable Room was quiet
Wifi was inconsistent
Room wasn't vacuumed. Air conditioning didn't work. WiFi was awful. Traffic noise even while at 6th floor.
Staff (including parking)
Price (like everything in Brazil)
People were very friendly
Clean, helpful staff, fair breakfast
I was double billed for my stay. When I raised it on check-out I was advised it was an error and it would be reversed, 3 days later - no refund yet
Staff; room is big; clean;
Location is not close to subway
we have to wait more than 30 min to check out as they didn't have staff enough todo this
A big shopping mall was at walking distance.
It's a bit far to get to paulista avenue or even to get to metro/subway station.
breakfast was good
noisy, no difference between standard and luxury rooms.
The smell of dirty carpet
staff helpful good location parking easy good wifi
breakfast too simple
location close to bus stop
more staff that can speak fluent english
good decent location, friendly staff.
wifi not consistent.
Internet Service was epileptic
Internet didn't work from my room.
The room was smelling and we asked 4 times to change it but received no response.
The towels could be better
The pool was not clean and there was not possible to order any beverage because no one worked on the pool bar. There are constant noise due to the heavy trafic of airplanes landing nearby.
The Staff was quite helpful in that we are English speaking. They went out of their way to accommodate us! The location was excellent - close to restaurants etc. Breakfast buffet was good
Shower stall needs a thorough cleaning - some mold on the tiles clearly visible
The room is cool.
The breakfast until 10:30 am so early in holidays.
I have stayed that hotel for business. they dont give or issue to invoice for my cost at hotel.they told me would send by email later on but they dont. I have called many time for asking invoice and asked to them if possible send to me by fax they hold me on the phone such a long time and told me that they could not send a fax only email. Im still waiting invoice by email !!!!!!
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- The internet: who's in and who's out
1st August 2014 marks 15 years since Eldis first registered its internet domain name eldis.org. So how has the internet changed over that 15 year period and who have been the winners and losers as a result? This timeline uses International Telecommunication Union statistics and other research to highlight some the key developments in global internet use and looks at how the world has changed since that day in August 1999.
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text:
Rihanna in Social Media War With Chris Brown's Girlfriend Karrueche Tran
We think Rihanna is firing more shots at Chris Brown's girlfriend over Twitter than she does at aliens in 'Battleship!' What's the latest on the embroiled, entangled trio?
We think Rihanna is firing more shots at Chris Brown's girlfriend over Twitter than she does at aliens in 'Battleship!' What's the latest on the embroiled, entangled trio?
Apple officials announced today the details on the eagerly awaited new iPad.
When you're tweeting or posting on Facebook, you're probably not thinking about the Department of Homeland Security. But as it turns out, it may very well be thinking about you.
Fresh off the Harvard launch of her Born This Way Foundation, Lady Gaga has yet another reason to celebrate. No, it's not her birthday either. That's later this month, on March 28, when she turns 26. Right now, Gaga can throw her paws up and dance around the room because she has just notched 20 million Twitter followers. Make that 20,096,127 people are reading her tweets, as of press time.
Human tutors are usually good teachers — but what if a computer program could do the same thing, right down to identifying students' emotions and boredom levels?
Admit it, you've seen you're number of friends drop and it eats away at you as you think, "Who unfriended me?!"
Read on Facebooker ... we have answers.
Love him or hate him, one thing is for sure: Chris Brown isn't going away anytime soon, and the singer continues to be a subject of debate following his Grammy appearance and win last month.
Forget Batman — there is a new vigilante prowling the city streets. His mission? To silence noisy cell phones in public places. His weapon? A cell phone jammer, the latest trend in hot gadgets.
Would you want to ride a roller coaster whose sheer force has been ripping the limbs off of crash test dummies? Or one that has been described by a fighter pilot who was given a preview as "gut-wrenching"? Visitors to Thorpe Park in England will have to make that decision in a couple weeks when The Swarm roller coaster opens to the public.
You may not be able to search for your own Tweets on Twitter after a week, but a marketing research company in the UK can now search all the Tweets Tweeted since January of 2010. This is possible because Twitter just sold Datasift the right to sort through them.


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|lar01jokaSee portfolio
|Image reference
|Descriptive Category
|Abstract Sign/Symbol
|Lifestyles Celebrations Life Events
["alphabet","black","border","business","buy","cash","circle","commerce","concept","coupon","day","design","discount","economy","friday","gift","happy","holiday","icon","illustration","isolated","limit","market","off","percent","percentage","price","promotion","purchase","reduction","round","sale","save","shop","shopping","signs","text","type","vintage","white"]alphabet black border business buy cash circle commerce concept coupon day design discount economy friday gift happy holiday icon illustration isolated limit market off percent percentage price promotion purchase reduction round sale save shop shopping signs text type vintage white See all keywords
The vector illustration "black friday's icon" from lar01joka is available on Fotolia under a Royalty Free license from 1 credit (Credit from $0.74).
Available in AI/EPS and JPEG formats, this vector file may be downloaded for all kinds of professional uses. The V and XV files are delivered in AI/EPS. To modify this file, vector editing software such as Adobe Illustrator, Freehand, or CorelDRAW is required. JPEG files are available in different resolutions (up to 3,873 x 3,873 pixels in 300 DPI).
The author of this picture, lar01joka also has 127 images in the same series.
To download this vector file, you can buy Fotolia credits or purchase a subscription plan and benefit from the amazing price of $0.19 per image.
The V and XV licenses are vector files (AI, EPS).
To modify this file, vector editing software such as Adobe Illustrator, Freehand, or CorelDRAW is required. All other licenses are JPEG files.