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Cancers 2011, 3(1), 198-212; https://doi.org/10.3390/cancers3010198
Abstract: Small heterodimer partner (SHP, NR0B2) is a unique orphan nuclear receptor that contains the dimerization and a putative ligand-binding domain, but lacks the conserved DNA binding domain. SHP exerts its physiological function as an inhibitor of gene transcription through physical interaction with multiple nuclear receptors and transcriptional factors. SHP is a critical transcriptional regulator affecting diverse biological functions, including bile acid, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology. Recently, we and others have demonstrated that SHP is an epigenetically regulated transcriptional repressor that suppresses the development of liver cancer. In this review, we summarize recent major findings regarding the role of SHP in cell proliferation, apoptosis, and DNA methylation, and discuss recent progress in understanding the function of SHP as a tumor suppressor in the development of liver cancer. Future study will be focused on identifying SHP associated novel prooncogenes and anti-oncogenes in liver cancer progression and applying the knowledge gained on SHP in liver cancer prevention, diagnosis and treatment.
1. Introduction
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide [1]. Chronic viral hepatitis associated liver cirrhosis, non-alcoholic steatohepatitis (NASH), ethanol consumption, hereditary diseases (α1 antitrypsin deficiency, hemochromatosis), and exposure to hepatotoxins (aflatoxin) represent the major risk factors for HCC development [2]. Apoptosis is a distinct form of cell death characterized by organized nuclear and cellular fragmentation that occurs in all organs and tissues. As in all other sites, a certain degree of hepatocyte apoptosis is characteristic of a healthy liver [3]. Indeed, in recent years it has become clear that development and progression of HCC are associated in particular with both defective apoptosis and increased cell proliferation. Specifically, tumor cells often show alterations in genes regulating the apoptotic machinery. However, the precise molecular mechanisms of apoptosis regulation involved in hepatocarcinogenesis are still poorly understood.
Nuclear receptors (NRs) are a unique family of transcription factors (TFs) that are being recognized as key regulators of multiple functions in almost all aspects of mammalian development, metabolism and physiology [4]. In recent years, accumulating evidence suggests that dysfunction of NR signaling leads to a wide spectrum of proliferative, reproductive, and metabolic diseases, including obesity, diabetes, and cancers. Small heterodimer partner (SHP, NR0B2) is a unique NR distinct from other conventional NRs in both its structure and function [5]. The presence of a putative ligand-binding domain (LBD) classifies SHP as a member of the NR family, although the endogenous ligand has not been identified. Importantly, the absence of the classical DNA binding domain (DBD) makes SHP an atypical NR, exerting its regulatory function through protein-protein interactions with other NRs and TFs. Since its discovery in 1996, SHP has been identified as a key transcriptional regulator affecting diverse biological functions, including bile acid, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology [6]. Recently, we and others have found that SHP is an epigenetically regulated transcriptional repressor that suppresses the development of liver cancer in both humans and mice [7-9]. In this review, we will summarize major findings in the field regarding the role of SHP in cell proliferation, apoptosis, and DNA methylation, and discuss recent progress in understanding the function of SHP as a tumor suppressor in the development of liver cancer.
2. SHP Structure and Expression
SHP gene resides on chromosome 1 at 1p36.1 in humans and chromosome 4 and 5 in mouse and rat, respectively. The genomic structure of SHP consists of two exons, with a single intron spanning approximately 1.8 kilobases in humans and 1.2 kilobases in mouse [10]. The SHP gene is detected in a variety of tissues. In the mouse, SHP is predominantly expressed in the gallbladder and liver, and at lower levels in the brainstem, cerebellum, adrenal, pancreas, stomach, duodenum, jejunum, ileum, colon, kidney, ovary, testis, and heart [11]. In humans, SHP mRNA has been detected in the liver, heart, pancreas, kidney, spleen, small intestine, adrenal gland and stomach [10,12,13].
Accumulating evidence shows that many NRs and TFs can target the SHP promoter and regulate SHP gene expression. They include steroidogenic factor-1 (SF-1), liver receptor homologue-1 (LRH-1), farsenoid X receptor (FXR), c-jun, hepatocyte nuclear factor 4α (HNF4α), estrogen receptor-related receptor γ (ERRγ), E2A gene products (E47, E12 and E2/5), liver X receptor α (LXRα), estrogen receptor α (ERα), sterol regulatory element binding protein 1c (SREBP-1c), adaptor protein (AP1), pregnane X receptor (PXR), the core circadian component CLOCK-BMAL1, peroxisome proliferator-activated receptor γ (PPARγ), and upstream stimulatory factor-1 (USF-1) [12,14-26].
SHP is an unusual orphan member of the NR family. A classical NR contains five major functional domains: the N-terminal ligand-independent transactivation domain, the DBD, hinge region, the C-terminal LBD, and the ligand-dependent transactivation domain. However, SHP contains a putative LBD domain, but lacks the conserved DBD [5]. SHP interacts with other NRs or TFs through two functional LXXLL-related motifs (also called NR-boxes), which are located in the putative N-terminal helix 1 of the LBD and in the C-terminal region of helix 5. SHP generally represses the transcriptional activities of its target genes. SHP has been shown to bind directly to a variety of NRs, including SF-1, LRH-1, HNF4, HNF6, ERRs, LXRs, PPARs, GR, ERs, TRβ, RARα, FXR, PXR, CAR, AR, NGFI-B (Nur77) and RXRs (the common heterodimerization partner for many NRs). SHP also interacts with several TFs and co-regulators such as ARNT, BETA2/NeuroD, C-jun, Jun D, C/EBPα, Foxo1, HNF3, NF-κB, Smad3, P53, BAF155, BAF57, Brm, EID1, G9a, HDAC1, HDAC3, HDAC5, HDAC6, mSinA, SMRT, SIRT1, CBP/p300, and SRC-1. To date, three distinct transcriptional repression mechanisms for SHP have been identified. SHP represses NR or TF mediated transactivation by competition for coactivator binding to NR, recruitment of SHP-associated corepressors, and inhibition of DNA binding. SHP can utilize these three inhibitory steps alternatively or sequentially in a cell type and target gene specific manner. Although generally a repressor of gene transcription, SHP has also been found to activate NF-κB and up-regulate the transcriptional activity of PPAR [13,27]. SHP modulates gene transactivation or suppression by recruiting mSin3A/HDAC corepressors, class III histone deacetylase SIRT1, G9a methyltransferase, and Swi/Snf–Brm chromatin remodeling complex [28-31].
3. SHP and Apoptosis
Apoptosis is a distinct form of cell death characterized by organized nuclear and cellular fragmentation. It can be executed via two fundamental pathways: (i) the intrinsic mitochondrion-dependent pathway; or (ii) the death receptor (DR)-mediated extrinsic mitochondrion-independent pathway [32]. The intrinsic pathway is triggered by a variety of stressors and is mediated through the release of pro-apoptotic proteins that activate caspase enzymes from the mitochondria. The permeability of the mitochondrial membrane is tightly controlled by the balance of activity between pro- and anti-apoptotic members of the Bcl-2 superfamily proteins. Upon membrane permeabilization, cytochrome c and the pro-apoptotic protein smac/Diablo are able to translocate from the intermembrane space of the mitochondria into the cytosol. Cytochrome c then interacts with the adapter protein Apaf-1, dATP, and caspase-9 to subsequently activate caspase-3, leading to cell death [33]. The extrinsic pathway begins outside the cell through the activation of specific proapoptotic receptors on the cell surface. It is mediated through binding of specific molecules known as pro-apoptotic ligands to their death receptors, including CD95 (Fas/APO-1), TNF-R1, and the TRAIL receptors DR4 and DR5 [34]. Ligand binding results in direct cleavage and activation of procaspases-8 to further activate executor caspase-3, 6, and/or 7, thereby converging on the intrinsic pathway.
SHP is a pleiotropic regulator, influencing expression of multiple target genes involved in diverse biological processes, including regulation of metabolic pathways, stress and inflammatory response, detoxification, cellular adhesion and differentiation, and cell cycle control [35]. Recently, we and others have found that SHP contributes to regulation of apoptosis pathways.
3.1. SHP Functions in Apoptosis
In an early study, SHP was shown to have a negative crosstalk with Nur77 during anti-Fas antibody (CH11) mediated apoptosis of hepatic cells [36] (Figure 1). Nur77 is an orphan nuclear receptor that has been identified in apoptosis of a variety of cell types, including hepatocytes. In prostate and lung cancer cells, upon apoptotic stimuli, Nur77 translocates from the nucleus to the cytoplasm where it targets mitochondria to induce cytochrome c [37,38]. In these cells, the apoptotic effect of Nur77 does not require its transcriptional activity or DNA binding, whereas the interaction of Nur77 with the Bcl-2 apoptotic machinery converts Bcl-2 from a protector to a killer [39]. In contrast, in liver cells, the transactivation function of Nur77 plays a critical role in the regulation of the Fas/FasL-induced apoptotic pathway. SHP was shown to bind the coactivator CBP, thereby releasing the coactivator from Nur77, resulting in repression of the transcriptional function of Nur77. Consistent with this, expression of SHP decreased, whereas antisense SHP enhanced, the transcriptional activity of Nur77 in human liver cancer HepG2 cells. Further, SHP was not detected in the interferon γ (IFNγ)/CH11-sensitive liver cancer SNU354 cells, whereas it was significantly expressed in the IFNγ/CH11-resistant HepG2 cells. Moreover, SNU354 cells stably expressing SHP became resistant to IFNγ/CH11-induced apoptosis. From these observations, SHP has been proposed to play a protective role in Nur77 mediated apoptosis in liver.
Another recent study shows that SHP expression was increased during monocytic differentiaton through c-Jun and p65 mediated transcriptional activation of the SHP promoter [40]. Interestingly, SHP protected differentiated monocytic cells from etoposide-induced cellular apoptosis through the induction and cytoplasmic sequestration of p21WAF1. Cytoplasmic p21 has been demonstrated to exert biological effects distinct from those of nuclear p21 [41]. p21 functions as a cell cycle brake in the nucleus and as an inhibitor of apoptosis in the cytoplasm. This study indicates that SHP participates in the monocytic differentiation program and contributes to the acquisition of resistance to apoptosis by inducing cytoplasmic localization of p21.
In contrast to these two studies about the anti-apoptotic function of SHP, we and others have demonstrated that SHP is an active component of apoptosis signaling [42-47]. The adamantyl-substituted retinoid-related (ARR) compounds 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) and 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) are effective inducers of apoptosis of malignant cells both in vitro and in vivo. Although numerous potential mechanisms have been proposed for how these compounds exert this effect, the precise mechanism by which ARR induces apoptosis remains unclear. An exciting recent observation is that AHPN and 3-Cl-AHPC are SHP ligands and induce apoptosis in human leukemia cell lines HL-60R and KG-1, and the breast carcinoma cell line MDA-MB-468 through their binding to SHP [43]. The binding of ARRs to SHP consequently promotes the formation of a corepressor complex containing Sin3A, nuclear receptor co-repressor (N-CoR), histone deacetylase 4, and histone shock protein (HSP90). This protein complex in turn binds to the c-myc promoter and inhibits its transcription. Knockout of SHP and knockdown of Sin3A compromise the proapoptotic activity, indicating that formation of the SHP-Sin3A complex is essential for the ability of ARRs to induce apoptosis. In addition, the correlation between ARRs binding to SHP and the induction of apoptosis strongly suggests that SHP functions as the receptor through which the ARRs exert apoptotic activity. However, the mechanism by which binding of ARRs to SHP modulates the SHP-Sin3A complex remains to be delineated. Nevertheless, the loss of SHP or Sin3A expression had little effect on ARR inhibition of cellular proliferation, suggesting that ARR mediated growth inhibition and apoptosis seem to involve separate pathways [48]. Continued study showed that induction of c-Fos and c-Jun expression as well as NF-kappaB activation by ARRs were SHP-dependent and may be essential for ARR mediated apoptosis [45]. A more recent in vivo and in vitro study found that the human acute myelogenous leukemia cell line FFMA-AML and TF (v-SRC) cells displayed resistance to standard retinoid (including trans-retinoic acid, 9-cis-retinoic acid, and the synthetic retinoid TTNPB) induced apoptosis but showed sensitivity to 3-Cl-AHPC and AHPN mediated apoptosis. Detailed experiment showed the decreased expression of the antiapoptotic proteins (cellular inhibitor of apoptosis 1 and X-linked inhibitor of apoptosis protein) and phospho-Bad, and the activation of the NF-kappaB canonical pathway [46]. Interestingly, knockdown of SHP in these AML cells blocked 3-Cl-AHPC and AHPN mediated induction of apoptosis. Overall, these results provided evidence that SHP has important functions in ARR induced apoptosis.
Recently, we used a series of in vivo and in vitro experimental approaches to demonstrate that SHP is a critical component of mitochondrial apoptotic signaling and mediates the proapoptotic effects of AHPN [47]. We found that SHP overexpression in mouse HCC Hepa-1 cell was sufficient to induce apoptosis and also enhanced greatly the apoptotic effects of TNF-α and AHPN [47]. We also observed that SHP activated apoptotic signaling in mouse hepatocytes, as evidenced by the decreased number of apoptotic hepatocytes in SHP-/- livers, and the increased apoptosis in hepatocyte-specific SHP-transgenic (STG) mice. The STG mice were also hypersensitive to Fas-induced hepatocyte apoptosis. Interestingly, both AHPN and AHPC were able to activate SHP gene transcription via LRH1 and induce apoptosis in human liver cancer Huh7 cells. Of particular interest in these studies are the observations that a competition exists between AHPN and HNF4α to traffic SHP between mitochondria and the nucleus, and that SHP interacts with Bcl-2 in mitochondria to induce cytochrome c release. Bcl-2 normally functions as an anti-apoptotic protein by inhibiting the effect of pro-apoptotic proteins. Upon mitochondrial localization, SHP interacts with Bcl-2 and disrupts the Bcl-2/Bid complex, resulting in activation of apoptosis. We are currently in the process of further delineation of endogenous signaling molecules that are involved in SHP mitochondrial targeting. Interestingly, we also observed a feedback loop in which Bcl-2 decreased SHP protein stability (Zhang, Y.X. and Wang, L., manuscript in preparation). Perhaps the most exciting result from these studies is the discovery that induction of SHP by oral administration of AHPN serves as a potent inhibitor of in vivo implanted peritoneal pancreatic tumor growth. Therefore, our findings suggest the intriguing possibility of manipulation of SHP in the treatment of hepatic and other gastrointestinal cancers.
MicroRNAs (miRNAs, miRs) are recently discovered small 21-23 nts noncoding RNAs that repress the expression of their target genes primarily by a post-transcriptional mechanism. MiRNAs participate in the regulation of many cellular processes including apoptosis, and alteration of their expression is frequently observed in cancers. Recently, we identified a novel "dual inhibitory" cascade regulation governing the activation of miR-206 gene transcription by SHP, which involves ERRγ, YY1, and AP1 (c-Jun and c-Fos) [49]. A promising observation is that expression of miR-206 markedly induces apoptotic cell death and blocks the anti-apoptotic activity of Notch3. Thus, SHP also activates apoptosis through the regulation of miR-206 expression and function.
3.2. FXR Functions in Apoptosis
Nuclear receptor FXR, a SHP transcriptional activator, is best known for regulating the homeostasis of cholesterol and bile acids, but its role as a mediator of apoptosis has been increasingly recognized in various types of cells [50-54]. The earlier studies have described the use of FXR agonists as enhancers of apoptosis in ovarian cancer cells and in vascular smooth muscle cells [50,53]. However, it remains unknown how FXR activation induces apoptosis. Based on our studies, a possible explanation is that FXR activation induces SHP gene transcription which in turn induces apoptosis. One study demonstrates that exposure of hepatic stellate cells (HSCs) to 6-ethyl chenodeoxycholic acid (6-ECDCA), a FXR ligand, increases SHP expression. This then causes an inhibition of Jun D binding to the consensus element in the tissue metalloproteinase inhibitor (TIMP-1) promoter, resulting in TIMP-1 transcriptional inhibition, and also enhances the sensitivity of HSCs to proapoptogenic stimuli [51]. This study established that FXR ligands may be beneficial in treatment of liver fibrosis. Swales et al. reported that FXR is present in human breast cancer MCF-7 and MDA-MB-468 cells, and that activation of FXR by high concentrations of its ligands activates SHP gene transcription and induces cell apoptosis [52]. Thus, this study suggests the possibility of manipulating FXR and SHP in the treatment of breast cancer. FXR is abundantly expressed in the liver and the lower digestive tract. In the human colon, the expression of FXR has been reported to progressively decrease in the sequence normal mucosa – adenoma – adenocarcinoma [55]. In addition, reactivation of FXR in the intestine and colon cancer cells results in induction of apoptosis [54]. Therefore, from a therapeutic standpoint, the above results provided evidence that strategies aimed at inducing FXR/SHP expression to activate apoptosis might be useful in treating liver fibrosis, breast and liver cancer.
In contrast, FXR has been demonstrated to play a protective role in inhibiting liver cell apoptosis induced by nutritional withdrawal [56]. FXR activation by CDCA (50 μM/L) and GW4064 (2 μM/L) suppresses serum deprivation-induced apoptosis in human liver cancer HepG2 cells by activating the ERK1/2 MAPK pathway. Moreover, FXR-/- mice showed enhanced liver cell apoptosis induced by starvation, suggesting a protective role of FXR in maintaining normal liver physiology. This study is consistent with the observation that guggulsterone, a potent antagonist of FXR, induced apoptosis in a Barrett's esophagus-derived cell line [57]. Because guggulsterone also acts as a steroid receptor ligand, this study cannot exclude the possibility that apoptosis is induced by other mechanisms not involving FXR. At present, it is unclear whether those incongruities of SHP and FXR functions in apoptosis could potentially reflect differences in the surrounding microenvironment, tissue specific effects, or different technologies employed in the studies.
4. SHP and Liver Cancer
NRs have been implicated in the initiation and progression of a wide variety of cancers. Prostate cancer has been linked to the androgen receptor, bone cancer to the nor-1 receptor, colon cancer to PPARγ, breast cancer to estrogen receptors, and leukemias to nur77. Due to their important physiologic functions in cancers, NRs and their regulated critical genes are emerging targets for molecular diagnosis and cancer therapeutics. For instance, by competing with endogenous estrogen, anti-estrogenic drugs have been successfully applied in the treatment of breast cancers that have excess estrogen receptor activity. Our recent studies have demonstrated that SHP has potent tumor suppressive functions in HCC via inhibition of cellular growth and activation of apoptosis [7,8,47].
4.1. SHP and Cell Proliferation in HCC
In an initial study, we showed that SHP negatively regulates cellular growth and the deletion of SHP results in enhanced hepatocyte proliferation [8] (Figure 2). SHP-/- mice developed spontaneous HCC at 12 to 15 months of age, which is associated with massive hepatocyte proliferation and increased cyclin D1 expression. Conversely, cell proliferation is completely reversed in hepatocyte specific SHP transgenic mice. Consistent with the in vivo observation, enhanced proliferation and increased cyclin D1 expression were observed in SHP-/- embryonic fibroblasts. SHP was further shown to repress cyclin D1 gene transcription through LRH-1. We also discovered that the immortal SHP-/- fibroblasts displayed characteristics of malignant transformed cells and formed tumors in nude mice. Of particular note, this study revealed a unique role for SHP in mediating cell growth through repression of cyclin D1, thereby providing a novel molecular link between SHP and liver cancer. Interestingly, Smith et al. demonstrated recently that sodium taurocholate (NaTC) decreases intestinal tumor formation in APC Min/+ mice. This effect is mediated through the activation of FXR and suppression of cyclin D1 by SHP, resulting in reduced epithelial cell proliferation [58].
4.2. Epigenetic Silencing of SHP in HCC
The expression of SHP is markedly diminished in human HCC compared with the normal surrounding liver tissue because of SHP promoter hypermethylation [7]. We further demonstrated that methylation occurred more frequently in the six sparsely distributed CpG orphans in the SHP proximal promoter than in the exonic CpG island of the SHP gene. Of particular interest, we discovered that methylation of the six CpGs in vitro blocked LRH-1 binding and transactivation of the SHP promoter by recruiting methyl-CpG binding proteins and co-repressors. In contrast, the normal surrounding tissues had fewer methylated CpGs in this region. Therefore, methylation of the six CpGs appeared to be critical for maintaining normal SHP promoter activity and played a major role in silencing SHP during HCC progression. Consistent with the tumor suppressor functions of SHP, overexpression of SHP inhibited human HCC foci formation, arrested HCC tumor growth in xenografted nude mice, and increased the sensitivity of HCC cells to apoptotic stimuli. Overall, this study suggests that CpG hypermethylation is an important mechanism in SHP gene silencing and the loss of SHP expression might be a critical epigenetic event in the development of liver cancer.
In line with our observations, a more recent study revealed that SHP is a good prognostic factor in HCC [9]. Notably, by using genomic approaches, this study identified several cell cycle genes that are regulated by SHP in liver cancer, including CDK4, MCM5, EXOCS1, CCNB1, BUB3, and BCL2L2. The poorer survival of liver cancer patients with low expression of SHP might be due to higher proliferation of cancer cells.
4.3. SHP and Epigenetic DNA Methylation in HCC
Global changes in DNA methylation status as well as changes in methylation patterns of individual genes are characteristic properties of a wide variety of tumor cells. Both DNA hypomethylation and hypermethylation are associated with cancer [59]. Hypomethylation of specific proto-oncogenes and hypermethylation of tumor-suppressor genes contribute to a selective growth advantage of the cancer cells and may therefore represent one of the multiple steps leading to malignancy [60]. For instance, hypomethylation of proto-oncogenes such as c-fos, c-myc, Ha-ras and Ki-ras genes has been observed particularly in human liver cancer. Conversely, early hypermethylation changes appear to involve p15 (INK4B) and p16 (INK4A) in cirrhosis, and p16 (INK4A) in HCC [61].
In mammalian cells, DNA methylation occurs by adding a methyl group to the 5-carbon position of the cytosine residue in the CpG dinucleotide, which is catalyzed by the family of DNA methyltransferases including DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L. DNMT1 maintains DNA methylation during replication by copying the methylation pattern of the parent DNA strand onto the newly synthesized strand. DNMT2 only has weak DNA methylation ability in vitro and appears to be involved in methylation of RNA. DNMT3A and DNMT3B are responsible for de novo DNA methylation. DNMT3L is expressed during gametogenesis and establishes maternal genomic imprinting. Despite the important roles of DNMTs in liver cancer formation, how the expression of these genes is regulated remains poorly understood. Our recent study identified SHP as a transcriptional repressor of DNMT1 expression. This raises the question whether aberrant DNA methylation exists and contributes to the development of HCC in SHP deficient conditions. We combined a genome wide analysis of DNA methylation and gene expression to compare the differential methylation status of a comprehensive set of genes in normal liver vs. SHP-/- liver. We found that promoter DNA methylation is aberrantly distributed in the SHF-/- genome compared with normal liver genome (Zhang, Y.X. and Wang, L., manuscript in preparation). Therefore, the loss of SHP function appears to be correlated with epigenetic changes, which might contribute to the development of liver cancer.
5. Perspective
SHP is a unique member of the nuclear receptor superfamily in both its structure and function. The fact that SHP acts as a critical transcriptional coregulator in diverse metabolic processes provides a potential means to develop SHP targeted therapeutics for several metabolic diseases. Of particular interest is the observation that manipulation of SHP through the synthetic ligands ARRs induces apoptosis and inhibits tumor growth in vivo. This raises the possibility of developing synthetic agonists that activate SHP selectively as therapeutics for liver fibrosis and cancer. Major challenges for future research are to delineate the ARR binding pocket in the SHP molecule, characterize those motifs that are critical for binding, determine whether endogenous SHP ligands exist, and develop more efficacious and selective synthetic SHP ligands for pharmaceutical applications. The identification of SHP in the mitochondria opens new doors for future investigation of the endogenous signaling molecules that initiate SHP mitochondrial targeting. SHP protein stability was increased in the AHPN induced apoptosis pathway, and it would be interesting to determine whether the stability of SHP is crucial in regulating other pathways such as lipid and glucose metabolism.
6. Conclusions
Studies by us and others provide strong evidence that SHP functions as a tumor suppressor in the development of liver cancer by inhibiting cell proliferation and inducing apoptosis. Of particular note, the loss of SHP results in genome wide aberrant DNA methylation, which may have implications for investigation and treatment of liver cancer. Although much work still remains to be completed, we are excited by the prospects of applying SHP as a new diagnostic, therapeutic and preventive agent for liver cancer. In this context, it is of particular interest to identify SHP associated novel pro-oncogenes and anti-oncogenes.
YZ is supported by T32CA093247 Multidisciplinary Cancer Research Training Program (MCRTP). This work is in part supported by NIDDK R01 080440 to L.W.
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Hemera Contemplative Fellowships for Health Care Professionals (CFHP)
Health care professionals can receive financial support to attend our retreats, thanks to the Hemera Contemplative Fellowships for Health Care Professionals (CFHP) Program. The fellowship is intended to encourage less-experienced meditators to attend a retreat for the first time, as well as extending support to experienced retreatants. CFHP support can be available for residential meditation retreats of any length up to a month.
Applicants must meet these requirements:
- working full-time in a health care field
- working directly with clients or overseeing other healthcare professionals
Level of Support
You may apply for one fellowship per year. The level of support varies based on retreat experience level, past fellowship support, and need:
- 100% funding for anyone new to retreat practice (no more than a prior weekend retreat).
- 50% plus additional need-based funding, for anyone with prior retreat experience.
Community of Fellows
Part of the long-term vision of the Hemera CFHP Program is to build a community of fellows, both online and in person. By accepting Hemera Fellowship funding, you agree to allow your contact information to be shared with the Hemera Foundation, and to fill out a survey about your retreat experience and the impact it has on your work.
How to Apply
Participants must first apply to our retreat, and be accepted, before applying for a Hemera fellowship.
Next, visit the Hemera Slideroom site and submit your application for a Hemera CFHP fellowship.
- Note that there will be a $5.00 application fee.
- Be sure to select Dharma Drum Retreat Center on your Hemera application.

subset: commoncrawl


text: A short description of "Duplexing, Frequency Division Duplexing, Time Division Duplexing" Duplexing In wireless communication system, it is often desirable to allow the subscriber to send simultaneously information to the base station while receiving information from the base station. This effect is duplexing. Frequency Division Duplexing FDD provides two distinct bands of frequencies for …Read More »


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Scotch Thistle
Onopordum acanthium
Family: Asteraceae
Other Common Names: cotton thistle, woolly thistle
Weed class: B
Year Listed: 1988
Native to: Europe and Asia
Is this Weed Toxic?:
not known to be
Legal listings:
WA Quarantine list, WAC 16-752
Why Is It a Noxious Weed?
Scotch thistle is a problem in rangeland. Infestations of Scotch thistle reduce forage production and virtually prohibit land utilization for livestock. Dense stands of the large, spiny plants exclude animals from grazing and access to water.
How would I identify it?
General Description
Scotch thistle is a branched, biennial or annual with a broadly winged stem that can grow up to 8 feet or more in height and 6 feet in width.
Flower Description
Plants flower in mid-summer. The globe-shaped flower heads are borne in groups of 2 or 3 on branch tips. Flower heads are up to 2 inches in diameter, with long, stiff, needle-like bracts at the base. Flowers range from dark pink to lavender.
Leaf description
Leaves are up to 2 feet long and 1 foot wide, are covered with sharp yellow spines and have a gray-green appearance from being covered with a thick mat of cotton-like or woolly hairs.
Stem description
Stems have vertical rows of prominent, spiny, ribbon-like leaf material or wings that extend to the base of the flower heads.
Fruit Seed Description
Seeds are smooth, slender, and plumed.
Where does it grow?
Scotch thistle will grow in wet meadows and pastures as well as dry pastures and rangelands. It may also be found alongside streams and rivers. Please click here to see a county level distribution map of Scotch thistle in Washington.
How Does it Reproduce?
Scotch thistle reproduces by seed. Each plant can produce 8,400 to 40,000 seeds.
How Do I Control It?
General Control Strategy
Establishing a dense well-maintained pasture is effective in preventing a Scotch thistle infestation.
Mechanical Control
Small areas can be dug out. Mowing has limited effectiveness for controlling Scotch thistle, usually only prevents seed production.
Biological Control
Goats will graze Scotch thistle, preventing seed production.
Herbicide Control
Please refer to the PNW Weed Management Handbook, or contact your county noxious weed coordinator.
For More Information
See our Written Findings for more information about Scotch thistle (Onopordum acanthium).
Thurston County NWCB Fact Sheet on Scotch thistle
Franklin County NWCB Fact Sheet on Scotch thistle
Stevens County NWCB Fact Sheet on Scotch thistle
Whatcom County NWCB Fact Sheet on Scotch thistle
Pierce County NWCB Fact Sheet on Scotch thistle
Lincoln County NWCB Brochure on Scotch thistle


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The SIGGRAPH 2002 Art Gallery celebrates the creative spirit by taking a look "behind the scenes" at the process of creating digital and electronic fine art. This year, the gallery highlights the process that generates the work, demonstrating how the digital artist creates.
Attendees experience the innovative examples of two-dimensional, three-dimensional, interactive, and installation work submitted by the international computer graphics community. Some works represent traditional forms such as print or sculpture while others push the boundaries of Web communication and interactive spaces.
Through sketches, diagrams, video documentation, Web documentation, and discussions, more than 70 artists reveal the magic behind their work. The artworks show excellence in innovation and artistic talent, document creative thought, illustrate the working process, and explain the use of the computer or electronics in the piece. The six papers place process in a theoretical and cultural context.
In a new collaboration, the Art Gallery and the Studio feature seven artists in working studio, where they create art using Studio facilities. The goal is to make the creative process visible. Attendees watch the work develop, talk with the artists, and (perhaps) make art themselves.
Working Artists
Art Gallery Committee
Complete documentation of the SIGGRAPH 2002 Art Gallery: SIGGRAPH 2002 Electronic Art and Animation Catalog


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Excited, nervous, strong, prepared, slightly unsure of how the day is going to go - I guess I'm feeling it all.
We have put in thousands upon thousands of miles in preparation for August 24, 2014. And I'm not just talking about the past 21 weeks of our training plan that we have completed. When Mike and I started the couch-to-5K program back in April 2011, we knew we were going to attempt an Ironman someday.
We have raced almost 70 times since our first 5K, all while knowing we were working toward the 140.6 mile victory lap. We have endured long training days in the fall, winter, spring and summer getting in our swims, rides and runs. Sometimes alone, sometimes just the two of us and sometimes with friends and family.
Celebrating one like minded person with other like minded people
Our love of this lifestyle has brought people with like mindsets into our lives. True friends, the kind that feel like they have been a part of your life forever, even though they haven't. It has also shown us who truly cares about us, who will be there for us no matter what and who supports us while we pursue "crazy" things like an Ironman.
This love of ours has brought us closer together. The one person I know I can always count on is Mike. He is there with me, pursuing the same dream that I am working my hardest to accomplish. To me that is the best part. It wouldn't be the same without him.
So. That someday, is really not all that far away anymore.
I can't predict what the future holds. I know we are ready. Is it going to hurt? Yes. Is it going to be tough? Yes.
Is it going to be worth it? Damn right it is.


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Geographic Information System Map: Green Initiatives at Drury
This Geographic Information System map features the green initiatives on Drury University campus, highlighting four landscapes that were restored into environmentally-friendly spaces. The four restoration sites include Sunderland Hall, Kellogg Green, Burnham Circle, and HPER Rain Garden all of which encompass one or more of the performance objectives of aesthetic, financial, environmental, and functional that falls under the philosophy of Drury Grounds.
The GIS map includes the previous condition of the space, the restoration objectives, the restoration process, and the ecological and financial benefits of restoring the site.
How to Use: Click on the green shapes to view more information about each restoration site.


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- News
- Sports
- Police Beat
- Opinion
- Community
- Obits
- Lifestyle
- The Forecaster
- MaineJobs
- Directory
Gallivan launches Acadia
Park app for iPhone, iPad
YARMOUTH — Kerry Gallivan of Yarmouth, founder of Chimani, LLC, has developed and launched the Chimani Acadia app, a comprehensive guide to Acadia National Park for the iPhone and iPad.
The app, now available for purchase on iTunes, is designed to work off-line without any cell phone connection and is an all-in-one guide to Acadia National Park.
In addition to general and operational park information, the Chimani Acadia app includes over 300 points of interest, and features a custom-made GPS-enabled map, a 35-minute audio tour of the Park Loop Road, projected sunrise/sunset data, projected tidal data, schedules for the Island Explorer shuttle bus and an updated list of the park's Ranger-led events.
For more information, please visit chimani.com, or search iTunes using key words "Chimani Acadia."
Unum, Sea Dogs team up
to honor local teachers
PORTLAND — Unum and the Maine Coalition for Excellence in Education teamed up with the Portland Sea Dogs to honor nine local teachers as the Unum Teachers' Hall of Fame "Starting 9."
The "Starting 9" is an event sponsored by Unum to recognize educators across the state for their dedication and service to students.
Local teachers nominated for the "Starting 9" are Andrew Lupien of South Portland High School and Judy Stanhope of Scarborough High School.
The manager of this year's "Starting 9" is the Maine Teacher of the Year, Kevin Grover of Lunt School in Falmouth.
The celebration was held at Hadlock Field on June 19, where each teacher received a personalized Sea Dogs jersey, $500 award, Sea Dogs tickets, and the opportunity to throw out a ceremonial first pitch during the on-field presentation prior to the game.
UNE to house Maine-
Harvard research center
PORTLAND — University of New England's Center for Community and Public Health will serve as the new home of The Maine-Harvard Prevention Research Center.
The MHPRC works with local and statewide partners to conduct research, education and training aimed at reducing obesity, improving nutrition and increasing physical activity for children and adults.
Over the next year, the MHPRC will evaluate Maine's first-in-the-nation law to prohibit junk food advertising in school.
It will also expand its current worksite wellness initiative, a collaborative with Harvard-based researchers to develop new obesity research and policy initiatives, and expand a child care center physical activity and nutrition program.
The Center for Community and Public Health is located on UNE's Portland campus.
Florence House up for
affordable housing award
PORTLAND — Avesta Housing's Florence House has been nominated as a finalist in the 2010 Readers' Choice Award of the Affordable Housing Finance magazine.
Affordable Housing Finance magazine readers can vote for the overall winner at housingfinance.com from July 16 through Aug. 13.
Florence House is a $7.7 million supportive housing development that uses modern technologies and sustainable design features including a geothermal heating and cooling system, solar water pre-heat, and heat recovery systems. It provides independent apartments, safe haven spaces and emergency beds to homeless individuals in Portland.
Avesta Housing is the first affordable housing developer from Maine to be named a finalist for this award.
New Ventures
Portland designer Hannah Tarkinson, along with Sonya Tomlinson and Kelly McGinty, have opened the doors to their fashion studio, Ponomo, at the State Theater building on 142 High St., Suite 307 in Portland. Ponomo features original jewelry, handbags, and accessories crafted from re-purposed and reconstructed vintage materials.
The Chebeague Island Inn re-opened May 14 under the new ownership of the Prentice family of Yarmouth. The Inn will continue to offer a quintessential coastal Maine experience, revitalized with an updated interior decor, expanded amenities and a new restaurant. For reservation and rate information, visit chebeagueislandinn.com or call 846-5155.
The Creative Portland Corporation has launched a new website, LiveWorkPortland.org, dedicated to growing the creative economy and supporting creative entrepreneurs of Portland. A unique feature of the website is multimedia interviews with nationally recognized individuals who have chosen to live and/or locate their creative business in Portland.
Camp Ketcha in Scarborough is expanding its school year program offerings with a new preschool program to begin in fall 2010. The Hearth and Home Montessori Preschool program will be a morning preschool from 9 a.m. to noon, with a choice of two, three or five sessions. The affordably priced program will enroll up to 14 children and will have 2 teachers. For more information or to set up a time to meet the lead teacher, please call Camp Ketcha at 883-8977 ext. 107 or visit campketcha.org/montessori.
Mexicali Blues has opened an additional location in the Old Port across the street from its current location at 9 Moulton St., Portland. The new store will be devoted to showcasing its gemstone and sterling silver jewelry. The original store will continue to offer responsibly imported clothing, jewelry, and decor, with newly installed dressing rooms, shelving units and displays.
Heron Point Gallery, located at the corner of Middle and Market Streets in the Old Port, has been joined by jeweler Dan Dostie as a gallery partner. Dostie has closed his Milk Street location and brings an extensive collection of gold and silver jewelry. The Gallery will continue to showcase glass art by Bonnie Faulkner, and also welcomes three new gallery associate artists, Stephen Lanzalotta, Avery Pierce, and Abbigail Hinds-Aldrich.
The Scarborough Economic Development Corporation, SEDCO, has launched its new website, ScarboroughEconomicDevelopment.com. IC Solutions of Scarborough designed and completed the website to enable better communication to and between Scarborough businesses. Highlights of the new SEDCO website are a searchable database of business properties for sale or lease, and a searchable, interactive business directory.
Sidebar Elements
Johnny Rockets is now open in downtown Freeport's Village Station. The restaurant, known for it's hand-dipped shakes, burgers, fries, barstools jukeboxes, and dancing waitstaff, is open daily from 10 a.m. until 9:30 p.m. Free parking is available in the attached underground garage. This is the first Johnny Rockets franchise to open in Maine. A second franchise is scheduled to open in the Maine Mall food court in mid-July.


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Title: Per Rege Et Lege
Location: Bridge End, Leeds
Camera: Panasonic Lumix GF1 / 20mm EF f/1.7
Notes: Recovery day after Think Visibility. We had a leisurely breakfast at the hotel and then a pleasant walk along the canal finding some geocaches on the way back to the car park before the drive home. This is the Leeds City crest on one of the old Victorian bridges, given a bit of photoshop treatment.
One Year Ago: Day #796
Two Years Ago: Day #431
Three Years Ago: Day #66
Day #1161
Title: Per Rege Et Lege
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Lately, rings. I can't stop thinking about them, searching for them, studying them, fixing them, photographing them. They are my jewelry muse for the moment. I am still stocking other things (really, I am!) but mostly . . . rings.
Thursday, May 15, 2014
Rings, more rings, still more rings
Posted by Jean Jean Vintage at 3:30 PM
5 comments:
- darchocoffee said...
the last one *U*
- May 16, 2014 at 5:45 AM
- Ana said...
OMG! This pieces are so beautiful, I'm totally in love with them. I found this awesome page when I can buy jewels like this :) http://www.certifiedjewelry.com/shop
- July 9, 2014 at 5:27 PM
- Debashis Sharma said...
So much prettier in person. Very petite and beautiful, understates but simply gorgeous. The picture is nice but we have a million times better antique jewelry .
If you don't mind please have a look to my jewelry collection! hope you like it too!
- December 27, 2014 at 9:31 AM
- Iski Uski said...
Diamond Jewellery Online Shopping India in 2016 with the latest jewellery design from the our online jewellery store.
- October 15, 2016 at 4:31 AM
- RockRushIndia said...
Nice post. Buy rings online.
- January 30, 2018 at 6:30 AM
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Drapes can be subtle and quiet, I really like that look, or they can command a little attention. I really don't like for my drapes to command too much attention. I like for them to blend into the background of a room and add some softness to windows, not dominate the window.
In the living room of my last house I had some really pretty beige and white plaid drapes that I loved. They gave just enough pattern to the room, yet they didn't dictate what other pattern I was using. These stayed with the house at the new owners request. I think she liked them as much as I did.
See how they add just a touch of pattern and texture with a slight shimmer to the fabric. They don't scream at you, they just add interest in a really quiet way.
The family room in that house had quite a few different treatments too. At one point I was into a little more farmhouse style, so I went with checks. These were fun and so economical. They are tablecloths. How easy is that.
Then I changed my style to a little more transitional and put up some soft camel and white tiny stripe drapes with some grasscloth textured roman shades
The master bedroom got a fun diy pair of made-over Ikea drapes. These were so easy and matched the shams on the bed. This is just two different widths of grosgrain ribbon sewed down the side. (You can buy great grosgrain ribbon at Walmart for $1 a spool)
I plan on using simple linen panels for our new house living room, but I think I will embellish them a little with some trim down the side of the panels. There are scores of great pictures of trim on drapes. I love this tone on tone. It looks elegant to me and doesn't scream at you at all.
Ribbon trim is definitely a favorite. Super simple and tone on tone could be used again.
I was looking on line and found some really fun ones that I loved at a etsy shop called shopofembellishments. There are your normal greek key trim and lots of different ribbon treatments, but this shop had a few unusual things.
Embellished lace. Isn't this different.
All of these are 2" wide or wider and are sold by the yard anywhere from $4 to $8 per yard. I think that is really reasonable for all this detail.
Hobby Lobby has this 2 1/4" soft beige and white greek key trim that I have used before on lamp shades. It would be gorgeous to trim out my drapes too.


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For this week, in addition to the Facebook post assignment I mentioned in class:
How do you think you might go about deciding what goes into an MVP?
How do you think you could apply basic entrepreneurial principles such as those we discussed and you read about in an established media organization?
Name one other thing you found interesting or relevant from the readings.


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About Merrilee Webb
Merrilee Webb is the owner of, and incredible talent behind Reading Keyboard Music.
Merrilee earned Bachelor and Masters degrees in Music Education from Brigham Young University Provo where she was selected as the "Most Outstanding Musician" in 1983.
She learned to play the piano using the Reading Keyboard Music method when she was only 5 years old and studied piano with Reid Nibley at Brigham Young University. Merrilee has spent her career as a music educator. In addition to piano, she also teaches and conducts men's, women's and mixed choirs. She teaches music theory and even guitar.
Merrilee has taught at Brigham Young University Hawaii, where she successfully used the RKM method to teach hundreds of students from all over the world to play the piano. She is currently an Assistant Professor of Music at Dixie State College in St. George Utah.
She has also served as Associate Director for "Young Americans" and owns the Infinity Business Ventures Recording Studio.
I just want to share the gift of music with the entire world! -Merrilee Webb
What students have to say about Merrilee and the "Learning to Play" program.
Merrilee didn't just teach me how to play the piano. I learned so much about music and the commitment to finish something I had started – which, sadly, was a new concept for me.
Merrilee, our teacher, is so fun that I didn't realize how much I was learning while I laughed.


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Gang Chen, PhD
Assistant Professor
About Professor Chen
Gang Chen is Assistant Professor at the Rockefeller College of Public Affairs and Policy, University at Albany, SUNY. Chen's research interests include state and local budgeting and finance, public pension management, fiscal stress management, and comparative public administration. He received a Ph.D. degree in Public Administration from the University of Nebraska at Omaha in 2013. Chen's work has been published in several English and Chinese academic journals, including Public Budgeting & Finance, Administration & Society, Journal of Public Budgeting, Accounting & Financial Management, Municipal Finance Journal, and Journal of Public Administration (China). Before coming to the U.S., Chen studied at Sun Yat-sen University, China, where he received his Master and Bachelor degrees in Public Administration. At Rockefeller College, Professor Chen teaches PAD 316 Methodological Tools for Public Policy, PAD 501 Public and Nonprofit Financial Management, PAD 505 Data Models and Decisions, and PAD 642 Public Budgeting.
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Students participate in more than 200 student clubs and honor societies, and enjoy a busy calendar of campus events.


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Retail Sales Teammate
Company Overview
We Promise to Care
We understand that we offer more than just car service. We rescue people from bad days and we offer solutions for difficult situations. We are people of integrity and we believe that fundamental honesty is the keystone of our business. We are committed to doing the hard work necessary to earn the loyalty of our teammates and our customers by providing a positive experience every time. We are proud and passionate to represent the brand of Bridgestone. Every day, in every store, with every teammate and every customer….We promise to care!
Our Purpose: To be the most trusted provider of automotive care in every neighborhood we serve.
Bridgestone Retail Operations, LLC employs over 22,000 teammates in North America and operates more than 2,200 company-owned stores. Our locations include Firestone Complete Auto Care, Tires Plus, Hibdon Tires and Wheel Works.
Apply today to learn more about why Bridgestone Retail Operations is the right place to build your career!
Position Summary
An energetic position to provide customer needs in person and on the phone. Use your communication skills to explain warranty options, establish time commitments between technicians and customers, checkout procedures and promotion of products and services.
Job Responsibilities of Retail Sales Teammate
Responsibilities include presenting tire products and automotive service to customers while developing retail merchandizing skills in order to provide professional, timely and courteous customer service. Additionally you will learn to:
- Demonstrate a high level of energetic responsiveness to every customer, on the phone or in the store.
- Listen closely to each customer's needs, document and determine the best possible response and solution.
- Communicate accurately with customer service manager and technicians to establish time commitments that meet Firestone standards and exceed customer requirements.
- Use company documents to communicate clearly with customers and co-workers in ensuring exceptional customer care.
- Follow proper exit procedures: explain all warranties and options to all customers, thank them and display appreciation for their business.
- Step up to duties as assigned.
This is a fast paced position that will have daily exposure to serving our customers.
- At least 1 year of Retail Sales Experience.
- Valid driver's license required.
- Pre-employment drug test, physical exam and background check required.
- A college degree is preferred.
Benefits, Privileges and Growth Opportunities
- We offer over 31 Benefits and Privileges to include medical, dental, vision, 401k, cash balance retirement plan and more.
- We are An Equal Opportunity Affirmative Action Employer, in fact, "One of our strengths is found in our commitment to serve a diverse customer population with diverse teams of teammates."
- Over 100 years of success is an indication of the stability our workforce enjoys.
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D Marie
First of all, I love animals and can't stand people that hurt animals!!!
There, that's now out of the way!!! ;-)
People always tell me I have an eye...loved photography since I was a little girl, so I am now a
freelance photographer...shoot nature, landscapes, architecture and animals...
traveled a lot, moved a lot, different states, different countries and enjoyed all places!!!
I also draw, paint, and write poetry.
Love laughter and of course shopping!!! :-)
Life without any art form would be boring and sad!!!
© by Dawn M. Becker
- 5,504 Affection
- 113,056 Photo Views
- 156 Followers
- 75 Following
- Milwaukee, WI, USA


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|Wishes for the New Year | 2013 Edition
Categories: Latest News
Posted: January 3, 2013
by Ted Greenberg
Welcome to Lucky Number Thirteen. After the way 2012 ended, I think we are all hoping for a little more luck, joy and happiness. Last year, I set out a number of resolutions, 12 in fact, — some of them (looking at you #4) that I was better at keeping than others (sad to say #8 did not happen). This year, in honor of 2013, I am making 13 wishes — things I hope will come true. Not just for me, but for the world.
13. That Scarlett Johansson is amazing in Cat on a Hot Tin Roof. Of course, if she isn't, that won't bother me one bit.
12. That the New York Giants regain their swagger and at least make a playoff run next season.
11. One of Mascot's marriages has long term appeal. And by "long term," I mean lasting longer than 60 minutes.
10. Mother Nature is nice to my beloved city. Post-Sandy, we need some luck in this regard.
9. Likewise, the 2013 ING New York City Marathon can happen. And as many people who trained for the 2012 edition get to run.
8. If I do not see Wicked on Broadway, I will at least read the book which inspired the musical.
7. I know I drive a cab at the end of my show for fun and because it's an iconic symbol for the Big Apple. But, after all the recent subway deaths, I'm concerned for my fellow New Yorkers and audience members. Here's to no more subway fatalities in 2013.
6. That all of the froyo, ice cream and frozen sweet treat stores (16 Handles, Red Mango, Pinkberry, Ben & Jerry's) all make it through the summer. Who doesn't love a little sweet, cold dessert in the middle of a sweltering summer?
5. That I watch the Polar Bear Run next New Year's Day. No way in hell I'm getting in that ice cold water, but I will cheer on others. Perhaps with the e Mascot in tow.
4. Have the Mascot enter the July 4th Hot Dog Eating Contest. How many do you think he will eat?
3. Support my favorite local businesses like Milk & Cookies, which has been so great to my show Ted Greenberg's The Complete Performer.
2. That you see my show sometime in 2013. If you do, you'll understand what I mean about the Mascot's marriages. What else are you doing 10:00 pm on a Saturday night?
1. That Kim Kardashian and Kanye West name the "Kimye" baby after me. Kinda. In keeping with the 'K' naming tradition, how about KED? It rhymes with Ted, and like the brown-haired beauty I know about short marriages, having racked up one myself.
Tags: 2013 wishes, comedy, resolutions


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This blog post came out of nowhere!
I have been making notes on what to write about for weeks now and nothing seemed to stick long enough to make me want to open the browser. But this! This kinda annoyed me and it's only because I wrote about the campaign before and loved the initial idea.
So excuse me while I take a moment from procrastinating with reading unrelated articles, when I should be writing, to further pack my time with stuff that I really should not be doing right now.
And yes! I am going to be using a lot of these body-less heads during this post because that's what I am writing about today. EMOJIs and EMOTICONS!
Not just in general, but pertaining to the new Always Emoji ad from their #LikeAGirl campaign. Now as I mentioned before, I covered the #LikeAGirl campaign a year ago on this blog and I was all for it. I don't pay much attention to the idiots who use my gender to insult someone and then expect me to think it's just a joke but younger girls are subject to this. I know because I was a young girl once. Girl jokes sucked for me then and it will probably suck for the girls now too.
Now the original ad (which you can find in the link above) and a few others that were made after them were very enlightening.
However this new one…
I know this is a social campaign for monetary gain but my face actually looked a lot like this after ward.
I am confused. Always has given me some cute girls, musing about getting more characters on a chat system that are distinctly female like them and not male. I am sorry but I checked half the emoticons on my phone that they called and you just CANNOT tell if it is male or female. Many of them are ambiguous where gender is concerned.
Now if they want new ones, fine. I have no problem with that. Go ahead and ask. It is a service and we are the customers.
But why try to make it into this humongous social injustice that are tying girls confidence down? When did emojis and emoticons become a statement of identity? Do girls and young women really find themselves sad and disheveled in a corner seriously doubting their self worth because they can't find a female lawyer emoji or lady bicycle emoji to send to their friends to express themselves?
Yes, I am using a lot of emoticons! Emojis and emoticons are fun! Even my own mother uses them! Just today she sent me this one!
And then I sent her back this one!
Emojis and emoticons are great quick ways to express yourself because sometimes you don't always need words (or have time for them) and nothing is wrong with liking them. However, this whole Always Emoji campaign is honestly just making more out of something than it really is.
How do we say it on Twitter?
I have never once noticed that the girl/lady emoji wore pink! Ne-ver. If I had been randomly asked I would have drawn a complete blank. Never gave it a second thought. Why? Because it's not important! Who cares? I almost feel ridiculous for writing a whole blog post about this!
Because emoticons DO NOT validate my existence. They never did and they never will. And if they validate yours or your child's existence you probably need to sit down and think over your life and more importantly your parenting strategies.
Here. Want some weighty social injustice to get your girls AND boys behind? This is a Much Much Much Much More Important Gender Inequality Issue
– Written by Travesaou
Copyright © 2010-2016 Critics May Lie All Rights Reserved


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A rising mobile game unfolds for gamers and makes its presence felt online. Last Day on Earth: Survival is a zombie survival game. Survivors are driven by one goal: to stay alive as long as they can. This is all about survival and there is no place left for friendship, love, and compassion. When the apocalypse comes, you can't rely on someone except yourself and your weapon.
This mobile is from Kefir! Studios. The game is currently in the early stages of BETA. With its early stage of development, Last Day on Earth: Survival is a deep game. Literally, the player is left alone to survive and has to deal with it unless there is Last Day of Earth: Survival hack.
The Choice to Hack
Playing a game with the use of a hack depends on you. There is only one option to take. So, there's nothing to complicate. But of course, beware of scams. You might compromise your game account if you are not extra careful. Don't be a prey to the scam hounds out there. You can hack the Last Day on Earth Survival in a lot of ways. You can directly buy game accounts, which would shave some dollars off to your savings. Wait here is the best option. Just click last day on earth survival hack. You can trust the tool without spending much time and effort. The efficiency level of the tool is considerably high. You can use this without much complications and get all the resources that you want in an instant. For those who have made up their minds, don't take so much time and be one of those gamers who are currently benefitting from our tool. Just read on.
The Basics of the Game
In playing the game, you become a survivor. As a survivor, you have to shelter yourself with a strong base, calmness, and craftiness. You have to build a strong base to protect your life and belongings from the attacks of the zombies and other players. You have to place traps on strategic locations to take captives and teach them a lesson for having stolen from you. You have to keep on improving your skills and craft more weapons to knock heads off, virtually.
Survival Experience
You don't trust in this game. You find yourself suited against zombies and other players who want to steal your resources. You have to show domination and control in this post- apocalyptic world. Aside from zombies and other players you also have to deal with other difficulties. These include wild animals, hunger, thirst and cold. These difficulties could easily end your life faster than a walking dead army. You also have to survive by hunting animals and prepare food over a campfire. You don't have water supply so be ready with your rain catcher. You also have to face the need to kill other players for survival.
Other Possibilities
This game affords you other experiences, which you would surely enjoy. You can freely search for abandoned military bunkers. Find and take any resources you could have and use your well – crafted vehicle to roam around the ruins of the city. You can travel to distant regions and build shelter there or anywhere else. Join a clan and claim territories with them. In this way you can make others work for you.
Wait! Don't you think you need a hack?


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Have you ever wondered the creativeness behind any branded company's logo? It has always been a challenging job for designers to come up with innovative logos for the company. Our list of top 10 hidden messages in famous brand logos may help you fill with loads of unknown information about branded company's logo.
You may also like: "25 Stunningly Beautiful Libraries Around the World"
10. Adidas
Adidas is a reputed sports clothing and shoe manufacturer in the world that originally had three stripes as its logo. The current logo is manifested to be the three slanted stripes which resemble a triangle shape. The three black stripes with the white space signify the mountain and obstacles respectively, that people need to overcome.
9. Amazon
Amazon's logo seems pretty simple with an arrow from letter "A" to "Z" at first glance. It represents the diverse varieties among Amazon's product. The arrow from letter "A" to "Z" symbolizes a visible smiles delivered to their customers.
8. Pepsi
Pepsi being the most trusted soft drinks brand in the world, decided to invest millions of dollars on their new logo with tri-color of red, white and blue within a circle. The circle symbolizes the globe and the tri- color represents the Earth's geodynamics, magnetic field, and Pythagoras. It also resembles the American Flag due to its intentional colors implemented.
7. Google
Google's logo comprises of four primary colors being broken intentionally by a secondary color green. Google wanted their designers to implement great deal of message behind the logo, the different colors on the logo signifies that Google is not a company that "plays by the rules" provided the broken pattern represents the playfulness.
BMW's logo is a mixture of blue and white color alternately fixed in a circle of four quadrants. The white color signifies the propelling blade against the blue sky. BMW provided a major role in manufacture of aircraft engine during World War II which led to the emergence of this logo.
5. Mercedes-Benz
Mercedes-Benz's logo resembles something like a wheel's spokes but has a confidential meaning behind it. It represents a tri-star which manifests its dominance over land, sea and air.
4. McDonald's
McDonald's logo being the most recognized one in the world, with two arches in its logo allegedly considered as a letter "M". In 1960s McDonald's discussed a new logo with their design partners of two golden arches, which unconsciously would be recognized by customers as "symbolism of nourishing breasts".
3. FedEx
FedEx's logo looks pretty simple but seems very tricky in terms of hidden meaning. The space between orange letters "E" and "X" forms an arrow pointing forward which represents an aspiration over their speed and forward thinking.
It is not just the punch of lines passing through IBM's logo. The white lines passing through the IBM's logo resembles an equal sign at the lower right corner which represents equality.
1. Toyota
Toyota's logo is the trickiest out of all listed here. The three ellipses signify the heart of customer, the heart of the product and the heart of technological process in the company's logo.


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Our School App Stay connected on the go...
Latest News
London Air Ambulance VIsit - #behindeverygreatcity
Ms Wildish organised a brilliant event for years 7 and 8 on 18th January introducing the dynamic and vital work of the crew of the London Air Ambulance Service. As part of the visit, students were advised about the different careers paths that individuals took, what a typical day might look like and what areas they should think about when considering their own careers. The session was topped off by a series of thought provoking and insightful questions by our students. We were delighted to have so many active and inspriring women sharing their roles - as paramedics, drs. and fire fighters. We hope the event continues to empower our students to really consider their future ambitions - anything is possible!
Thank you also to local MP Catherine West who came along to support the #behindeverygreatcity initiative launched by the Mayor Sadiq Khan.


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What is the dose of clopidogrel and how often should I take it?
- The usual dose of clopidogrel is one 75mg tablet taken once a day.
- Some people may be asked to take a single higher dose of 300mg or 600mg for their first dose - follow the instructions given by your doctor.
- You can take your clopidogrel tablet at any time of day, but try and always take it at the same time because this will help you to remember it.
Should I take clopidogrel with or without food?
- It doesn't matter. You can take your clopidogrel tablet either with or without food, on a full or empty stomach. Swallow it with a drink.
What should I do if I miss a dose?
- If you forget to take your clopidogrel tablet at your usual time take it as soon as you remember, as long as it's not more than 12 hours late. If you are more than 12 hours late taking a dose, leave out the missed dose and just take your next dose as usual when it is due. Do not take a double dose to make up for a missed dose.
How long do I need to take clopidogrel for?
- This depends on why your doctor has prescribed clopidogrel. Some people may need to take it for a few weeks or months, while others may need to keep taking it every day on a long-term basis. Always follow the instructions given by your doctor.
- What is clopidogrel used for and how does it work?
- What should I know before taking clopidogrel?
- What are the possible side effects of clopidogrel?
- Can I take other medicines with clopidogrel?
Last updated: 14.03.2017


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New York's Xi'an Famous Foods
Xi'an Famous Foods is beneath the Manhattan Bridge near the corner of East Broadway and Forsyth, next to where the original Saigon Bakery used to be (for banh mi trivia experts). There's as much room for customers as there is for one more person to squeeze into the last car of a Brooklyn-bound L at 1st Ave during rush hour. Stake out the tiny metal counter in the corner, or have a spot to eat nearby in mind. Hint: there are two Starbucks within about eight blocks.
Of course, the dish that put the "Famous" in Xi'an Famous Foods is the incredible Asian cumin spiced lamb "burger" on flat bread. The muttony, powerful, cumin-flavored meat totally delivers on its reputation. The pork "burger" will make you forget about David Chang's Momofuku buns (for a moment). They're spectacular and are 50 cents less then the lamb at $2.00 and $2.50, respectively.
For the thrill seeker, there's the Spicy and Tingly Lamb Face Salad. The cold, fatty, spicy meat has just enough greens mixed in to be put in that category. The Lamb Treasure's Soup (exactly what you think), and the Stewed Lamb Spine and Rib are also not for the faint of heart. The noodles in the Stewed Lamb Spine Hand-Pulled Noodles in Soup are amazing, and the soup gets better and better as you reach the bottom. If they run out of the lamb spine, try the pig spine— it's delicious too. Wash it all down with sour Hawberry tea made from the fruit of the Chinese Hawthorne tree and you'll think you're in Xi'an City instead of New York City.


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|Me before getting my skin stretched out.
|Me before getting my skin stretched out.
Amen, my sister.ReplyDelete
I think we probably appreciate boobs a lot more than these jackasses.Delete
I ended up making the mistake of commenting on their video and getting into an argument with their supporters. then I remembered I am a strong, intelligent woman and I turned off the notifications. because seriously, dumb as rocks.ReplyDelete
You're braver than me. Youtube commenters are pretty much the worst of the worst, especially since it's a dudebro channel. I could teach them how to pick up ladies - stop being douchebags.Delete
yeah, you tell 'em, lara. beautiful truth - they'll probably never "get it", just hope they don't have to have it slammed into their faces if ever it's their moms, sister, dads, brothers or THEM who ever have to face this horrible disease first hand, up close and personal. then see how much fun their asinine pranks infringe on the dignity and sensitivity of people they care about. totally dumb asses.ReplyDelete
This is great! You are great! Thank you!ReplyDelete
You are awesome!!ReplyDelete
I'll tell ya, Lara, between you & the splendidly snarky Erin Gloria Ryan's response to these execrable dudes in Jezebel (and her fabulous phrase 'metastatic douchebaggery'), I think you've pretty much nailed how most of us feel.
xoxo, Kathi


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Organization Search Results
Organizations within 20.0 miles of Ashburn, VA, USA
Displaying 1 - 10 of 1010
- Sort by Distance
- Sort by Name
- Sorted by Date Updated
Since 1967, Disabled Sports USA has focused on one goal: To improve the lives of wounded warriors, youth and adults with disabilities by providing sports and recreation opportunities. Disabilities...
ROCKVILLE, MD | ( No Reviews)
Interest Areas: Children & Youth, People with Disabilities, Sports & Recreation, Veterans & Military Families
Updated: 5/8/19 , Distance: 18.32 miles away
SCORE Test Account
SCORE, America's premier source of free and confidential small business advice for entrepreneurs and small businesses, is a nonprofit resource partner with the U.S. Small Business...
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Herndon, VA | ( No Reviews)
Interest Areas: Community, Education & Literacy, Employment, Veterans & Military Families, Women
Updated: 5/6/19 , Distance: 7.17 miles away
Maison Chance USA is a non-profit organization and is organized exclusively for charitable, educational and cultural purposes, more specifically the mission of Maison Chance USA is to provide the...
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ARLINGTON, VA | ( No Reviews)
Interest Areas: Advocacy & Human Rights, Children & Youth, Community, Health & Medicine, People with Disabilities
Updated: 5/3/19
National Wildlife Federation
The National Wildlife Federation was born in 1936 to use education and cooperation as a catalyst for uniting groups and their members -- from hunters and anglers to gardeners and outdoor...
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Reston, VA | ( 1 reviews)
Interest Areas: Animals, Children & Youth, Community, Education & Literacy, Environment
Updated: 5/1/19 , Distance: 10.57 miles away
Golden Dreams Therapeutic Riding
We are a nonprofit organization specializing in therapeutic riding for children with disabilities
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Middleburg, VA | ( 1 reviews)
Interest Areas: Animals, Children & Youth, People with Disabilities, Sports & Recreation
Updated: 4/29/19 , Distance: 14.12 miles away
We are a nonprofit Creative Reuse Center, our space is a dedicated donation and retail center for gently used or pre-owned arts & crafts materials. We aim to provide the community with low cost...
Paeonian Springs, VA | ( No Reviews)
Interest Areas: Arts & Culture, Children & Youth, Community, Environment
Updated: 4/26/19 , Distance: 10.07 miles away
Nourish Now collects surplus food from dedicated food donor partners including restaurants, grocers, caterers, and more throughout the D.C. metro area. After packaging donations, Nourish Now...
ROCKVILLE, MD | ( No Reviews)
Interest Areas: Children & Youth, Community, Crisis Support, Homeless & Housing, Hunger
Updated: 4/26/19 , Distance: 19.17 miles away
Reiki Outreach Services for Elders, Inc.
ROSE is an organization comprised of Reiki Practitioners who have a passion for bringing the gentle yet powerful healing properties of Reiki to Elders in the community and in elder-centric...
Fairfax, VA | ( No Reviews)
Interest Areas: Health & Medicine, People with Disabilities, Seniors
Updated: 4/25/19 , Distance: 16.41 miles away
Adventist HealthCare is a faith-based, not-for-profit organization whose Mission is "to extend God's care through the ministry of physical, mental and spiritual healing" throughout...
GAITHERSBURG, MD | ( No Reviews)
Interest Areas: Children & Youth, Community, Employment, Health & Medicine, Veterans & Military Families
Updated: 4/19/19 , Distance: 16.15 miles away
The WGB Store is filled with wonderful clothing, accessories, shoes and more for our clients that are currently in shelters or transitional programs. We open the second Saturday of each month or by...
STERLING, VA | ( No Reviews)
Interest Areas: Children & Youth, Crisis Support, Women
Updated: 3/23/19 , Distance: 4.81 miles away


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121 players / 183 plays
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by evonyrocksme
First published on 13th November, 2015
An epic adventure of two best friends, one of which is kidnapped. The other, a silhouette named Kai, ventures to save his taken polar bear friend. Score is reversed, like golf, the lower your score, the better!
183 total plays
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Our users:
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Connecticut Landscape Construction
Serving West Hartford, Newington, Wethersfield, Avon, Farmington, & Simsbury, CT
Our landscape construction crews build and install hardscape features that will compliment your overall landscape and the softscape (the flowers, shrubs and trees) features of the property. We work closely with you to design these features to your specifications and offer suggestions on design and various options on materials to meet your budget and acheive your desired look.
Where heavy machinery is needed our mini-excavation equipment often does the trick. Mini-excavators and skid-steer tractors fit into tighter spaces and between buildings while minimizing disturbanaces outside the areas being worked on. They also save time and expense on labour and manage the heavier lifiting and soil movement.
Walkways and Driveways
Walkways and driveways are a functional aspect of your landscape that can be designed to also complement the aesthetic appearance of your property and how it interacts with your green areas. Various surfacing options are available from crushed gravel, concrete, natural stone such as flagstone, and man made bricks and stone pavers.
Patio surfaces make for usefull areas of your landscape as places for entertaining, eating, barbequing or just plain relaxing on a chair in the sunshine. Patios can be surfaced with a range of materials from stone to conrete or even wood. Let us help design and then construct the type of patio you want in your yard.
Retaining Walls
Retaining walls hold back earth to keep it from eroding and collapsing. They can be placed in a step format with planting areas in between each level to make for an attractive landscape feature. Retaining walls can be constructed from a wide range of materials such as large natural stones and boulders, man made bricks and blocks, as well as presure treated lumber.
Arbors, Trellises and Pergolas
An arbor over a walkway or a sun trellis or pergoal over a patio, or part of a patio make for wonderfully attractive landscape features. They add a touch of classic architecture to your garden areas and provide space for hanging baskets or climbing plants for a verticle component to your landscape. We can design and construct the perfect feature for your garden.
Decorative Stone Work
There are lots of options for the use of stone in your landscape. Walkways and paito surfaces can use flagstone, Interlocking brick pavers or cobblestones that come in a wide variety of styles and colors. Large natural boulders can be used for smaller, stepped, retaining walls or as stand alone features in a planting bed. Retaining walls can also be constrcuted with various types of bricks or concrete blocks.
Contact Us Today to about building elegant features in your landscape. Residential or Commercial.