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Review ARTICLE
7α, 25-dihydroxycholesterol-mediated activation of EBI2 in immune regulation and diseases
- 1Immunology Therapeutic Area, Janssen Pharmaceutical Research & Development, LLC, San Diego, CA, USA
- 2Neuroscience Therapeutic Area, Janssen Pharmaceutical Research & Development, LLC, San Diego, CA, USA
EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt's lymphoma cell line BL41 by Epstein–Barr virus (EBV) infection. After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand. In 2011 we and another group reported the identification of 7α, 25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2. A few subsequently published studies further elucidated how 7α, 25-OHC bound to EBI2, and how a gradient of 7α, 25-OHC could be generated in vivo and regulated migration, activation, and functions of B cells, T cells, dendritic cells (DCs), monocytes/macrophages, and astrocytes. The identification of 7α, 25-OHC as a G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a class of molecules which exert profound biological functions. Dysregulation of the synthesis or functions of these molecules is believed to contribute to inflammation and autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity, and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions for human diseases.
G protein-coupled receptors (GPCRs), through ligation and activation by cognate ligands, regulate key cellular functions including generation, homeostasis, activation, differentiation, proliferation, migration. Functional dysregulation of these receptors often lead to pathogenesis in many human diseases. Therefore these receptors represent a class of highly druggable targets, which counted for a significant number of top marketed drugs in recent years (Andrews et al., 2014). Among ~800 predicted GPCR genes, over 600 belong to a largest group of Rhodopsin-like family (Class A) and about half of which are believed to be liganded receptors. For this group liganded receptors, there are still ~100 GPCR whose cognate ligands have not been identified, which are of high interest for discovering novel biological mechanisms and potential drug targets. At Janssen, our past efforts have de-orphanized a number of these orphans including H3, H4 (Lovenberg et al., 1999; Liu et al., 2001, 2003, 2005, 2009; Hannedouche et al., 2011).
EBI2, aka, GPR183, was originally identified in Birkenbach et al. (1993) as one of main genes induced in Burkitt's lymphoma cell line BL41 by Epstein–Barr virus (EBV) infection. Gatto et al. (2009) and Pereira et al. (2009), two groups independently reported that the receptor played a key role in regulating B cell migration and responses, which prompted our interest and effort in looking for its endogenous ligand. Two years later, our group and the other (Hannedouche et al., 2011; Liu et al., 2011) independently discovered and reported the identification of 7α, 25-dihydroxycholesterol (7α, 25-OHC) as the endogenous ligand for EBI2. This was further supported by subsequent studies (Benned-Jensen et al., 2012; Zhang et al., 2012) detailing how 7α, 25-OHC binds and activates EBI2, and how the oxysterol is produced and how a gradient of 7α, 25-OHC is generated in vivo (Yi et al., 2012). Besides its role in regulating immune cell migration (Table 1), there were also published evidences linking EBI2 with human diseases, including type 1 diabetes (T1D; Heinig et al., 2010), multiple sclerosis (MS; Chalmin et al., 2015), and cancer cell proliferation (Benned-Jensen et al., 2011). Therefore EBI2 may represent a promising target for a number of indications such as inflammatory or autoimmune diseases, metabolism diseases, and cancer.
In this review, we describe our de-orphanization effort leading to the identification of 7α, 25-OHC, summarize published data related to EBI2 receptor function and in human diseases, and small molecule EBI2 modulators reported to date.
Role of EBI2 in B Cells Migration
Secondary lymphoid tissues such as spleen and lymph nodes consist of distinct functional compartments such as B cell follicles that surround a central T cells zone. In spleen, follicles are also surrounded by marginal zone where marginal zone innate B cells localize. Functional compartmentation of these tissues is controlled by spatial and temporal expression of chemokines by stromal or resident cells, and chemokine receptors by migratory lymphocytes including T cells, B cells, and DC. For example, naïve B cells express high level of CXCR5, home to follicles via gradient of CXCL13 produced by follicular stromal cells. Upon antigen encounter, activated B cells upregulate the expression of CCR7, and migrate toward T-B boundary in responding to CCL19 and CCL21 which are produced by cells within T cell zone. As B cells response progresses, differentiating B cells within germinal centers regulate expression of another receptor CXCR4, the receptor for CXCL12, which segregate B cells into light zone and dark zone, and also direct migration of plasma cells to splenic red pulp and bone marrow.
Gatto et al. (2009) and Pereira et al. (2009) two groups reported that EBI2 played a critical role in regulating B cell migration during immune activation. It appeared that naïve B cells express high level of EBI2, which was further upregulated upon B cell activation, and interestingly expression of EBI2 was significantly down-regulated in germinal center B cells. Employing B cells which were deficient or overexpressing EBI2, the authors demonstrated that increased expression of EBI2 directed activated B cell migration to outer follicular areas; and down-regulation of EBI2 was a prerequisite for migration into central follicular areas to form germinal centers. Although it appeared that EBI2 did not directly affect activation and proliferation of B cells, B cells deficient in EBI2 nonetheless led to defective antibody responses in vivo. These seminal findings clearly suggested EBI2 played a role in B cells migration. Therefore, together with CXCR5, CXCR4, and CCR7, EBI2 appeared to be another key chemotactic receptor to direct B cell migration and positioning within secondary lymphoid tissues. This notion was further demonstrated later by a study using compound knockout mice in which one, two or all three of receptors including CXCR5, CCR7, and EBI2 were knocked out (Gatto et al., 2011).
De-orphanization of EBI2
In 2011, we and another group (Hannedouche et al., 2011; Liu et al., 2011), independently identified 7α, 25-OHC as the endogenous ligand for EBI2 and demonstrated that the oxysterol functioned as a chemotactic molecule for B cell migration.
To identify EBI2 ligand, the two groups took similar approaches starting from detecting EBI2-specific activity in partially purified rat, porcine, or sheep tissue extracts, followed by chromatography–mass spectrometry (GCMS) and NMR methods to identify the active molecule as an oxysterol. While Hannedouche et al. (2011) directly showed the final purified activity as 7α, 25-OHC, we took a slightly different approach. Once we identified certain EBI2 active oxysterols such as 7α-OHC, 7β-OHC, and 25-OHC through GCMS and NMR, we acquired and tested a number of commercially available oxysterols. The results led us to speculate that 7α, 25-OHC was likely the most potent EBI2 agonist, which was confirmed using a synthesized compound. We then further showed that starting from extract of a single mouse spleen, the only significant activity which could be purified and detected co-migrated in GCMS with the synthetic 7α, 25-OHC, and the identity of the active purified fraction was further confirmed by NMR.
Both groups demonstrated that 7α, 25-OHC showed saturated binding to EBI2 in radioligand binding assays. 7α, 25-OHC was highly potent in binding and activating human EBI2 in cells (Figure 1; Kd 450 pM; GTPγS EC50 140 pM), and coupled to Gi/o proteins (e.g., inhibition of cAMP production IC50, 2 nM). Consistent with previously findings indicting a role of EBI2 in driving B cell migration, 7α, 25-OHC induced migration of mouse and human B cells in vitro, and interestingly T cells and DC as well, in an EBI2-dependent manner. In cells, ligation of EBI2 by 7α, 25-OHC induced receptor internalization and desensitization. Thus, pretreatment of mouse B cells with 7α, 25-OHC for 1 h in vitro rendered these cells refractory to migration induced by 7α, 25-OHC, and interestingly a few other chemokines such as CXCL12, CXCL13, and CCL19/21 as well.
FIGURE 1. Structures of selected E1312 agonists and antagonists, and their activities. Key compound activities and associated publications were listed.
Further experiments showed that the expression of EBI2 and also the two enzymes required for synthesis of 7α, 25-OHC biosynthesis, i.e., cholesterol 25-hydrxylase (Ch25H) and oxysterol 7α-hydroxylase (Cyp7B1) was highly modulated by inflammatory stimuli such as LPS in various immune cells such as B cells, T cells, and dendritic cells (DCs) in vitro as well as in vivo in mice. In a B cell adoptive transfer model, we showed that 7α, 25-OHC-pretreatment of B cells (therefore desensitized) reduced homing of these cells into follicles after adoptive transfer, suggesting EBI2 also plays a role in B cell homing to secondary lymphoid tissues.
To demonstrate the role of 7α, 25-OHC in vivo, we employed a model in which host mice were dosed with Clotrimazole, an anti-fungi compound with known Cyp7B1 inhibition activity which was shown to significantly reduce level of 7α, 25-OHC in vitro and in vivo. In comparison, Hannedouche et al. (2011) employed Ch25H KO mice as hosts which as expected were deficient in production of 7α, 25-OHC. In both models adoptively transferred wild-type B cells showed identical migration pattern as those for Ebi2-deficient B cells adoptively transferred into vehicle-treated or wild-type hosts. Thus, for example, our studies showed that adoptively transferred wild-type B cells migrated into and localized throughout splenic follicles in normal hosts; however, in Clotrimazole-treated hosts, a much greater percentage of transferred B cells was localized at the T-B boundary, presumably due to CCR7-dependent migration of these B cells and lack of EBI2-driven migration at the same time. In addition, Hannedouche et al. (2011) further showed that, as a functional consequence, plasma cell response in Ch25H KO mice was similarly defective as that in Ebi2-deficient mice.
A subsequent study by Yi et al. (2012) suggested that lymphoid stromal cells were the main Ch25H- and Cyp7B1-expressing cells and were responsible for production of 7α, 25-OHC in vivo. In addition, the group also demonstrated that the same cells were likely also responsible for degradation of 7α, 25-OHC by expressing HSD3B7 which converts 7α, 25-OHC into a 3-oxo derivative. Importantly, deficiency in any three of these enzymes affected B cell positioning in vivo, and resulted in defective T cell-dependent plasma cell response.
Taken together, the data from these studies clearly demonstrated that 7α, 25-OHC was the endogenous EBI2 ligand driving B cells migration, and modulating B cell antibody responses in vivo.
Binding of 7α, 25-OHC to EBI2
Since EBI2 is the first GPCR known to bind and be activated by an oxysterol, we carried out and later published (Zhang et al., 2012) a study to understand the molecular and structural basis for its ligand-dependent activation.
Using a site-directed mutagenesis approach, we generated mutated receptors that carried single amino acid substitutions. The pharmacological profiles of these mutant receptors were characterized by measuring receptor expression, radioligand binding, and receptor activation. Within the highly variable extracellular regions, we compared sequences from human, rat and mouse, and selected a number of conserved residues for mutagenesis study. This led to identification of Glu183 in ECL2, Ala-substitution of which resulted in significant reduction of ligand binding and ~50-fold potency reduction.
Transmembrane (TM) regions of GPCR are structurally conserved and the helical cores are thought to make up the ligand binding pocket. We aligned EBI2 TM sequences with those of GPCR with a defined ligand binding pocket, and selected key residues for mutagenesis analysis. Among key residues identified by these analyses, Arg87 (TM2) to Ala, or Trp and Asn114 to Ala resulted in diminished receptor binding and ~500 fold or more reduction in ligand potency. A number of other residues that showed reduced ligand binding and receptor function after Ala substitution included Tyr112 and Tyr116 of TM3; Leu197 of TM5; Tyr260, His216, and Ile264 of TM6; Val294 and M297 of TM7. Moreover, Ala substitution of Asp77 showed no effect on ligand binding, however, was found to severely reduce receptor activation suggesting the residue was important for receptor activation or signal transduction.
By examining various analogs of 7α, 25-OHC in EBI2-dependent assays, we showed that all three hydroxyl groups at 3′, 7′α, and 25′ were required for receptor binding and activation. Using a hybrid β2AR-CXCR4 structure as a template, we created a homology model for EBI2. Optimization of docking of 7α, 25-OHC into the putative ligand binding pocket of the EBI2 model structure suggested that residues Arg87, Asn114, and Glu183 interact with 7′α-, 25′-, and 3′-hydroxyl group respectively.
In addition, our analysis also suggested that Cys104 (ECL1) and Cys181 (ECL2) form the classic disulfide bond observed in many other GPCR, while Cys21 (N-terminal) and Cys280 (ECL3) may form a second disulfide bridge. This pattern of extracellular disulfide bridges appeared to be the same as in CXCR4. This proposed model of two disulfide bridges has important functional implications. Because of the Cys104-Cys181 link, ECL2 is brought close to the TM domain and may form a cap over the putative ligand binding site. As a result, Glu183 with ECL2 is positioned within the ligand binding domain, representing the best candidate forming interaction with 3′-hydroxyl group of 7α, 25-OHC. This notion was further supported by the inactivity of 7α, 27-dihydroxy-4-cholesten-3-one where a ketone interacting with the carboxylate would be energetically unfavorable.
Another group (Benned-Jensen et al., 2012) published a similar mutagenesis study around the same time. In that study, the authors focused on residues facing the main putative ligand binding pocket for mutagenesis analysis, which led to identification of four key residues required for 7α, 25-OHC binding: Arg87, Tyr112 and Tyr116, and Tyr260. These findings are consistent with what we reported. Docking modeling by these authors suggested a different model from ours, i.e., Y116 interacts with 3′-hydroxyl group, Y260 with 7′α-hydroxyl group, and Y260 directly or indirectly with 25′-hydroxyl group.
Together, these two studies started to shed some insights on how an oxysterol ligand could bind and activate a GPCR, which may potentially benefit discovery of novel EBI2 modulators.
Role of EBI2 in Immune Responses and Diseases
It is now clear that EBI2 plays important roles in modulating activation and controls migration of various immune cells (Table 1). The function of EBI2 in B cells in vivo appears to be largely dependent on directing B cell migration and positioning in secondary lymphoid tissues. As described above, EBI2 deficiency or deficiency in 7α, 25-OHC biosynthesis resulted in reduce plasma cell responses. In vitro, EBI2-deficient mouse B cells did not show overt deficiency in activation including proliferation or upregulation of cell surface marker such as CD86 (Gatto et al., 2009). Neither did we observe much effect with 7α, 25-OHC when added to B cell cultures (unpublished data). However, it was reported that B cells from transgenic mice with overexpression of human EBI2 showed enhanced antibody-induced proliferation (Benned-Jensen et al., 2011). Therefore, it remains a possibility that EBI2 ligation may directly affect certain aspect of B cell activation. To this end, it was speculated that dysregulation of EBI2 expression might contribute in B cell malignancies (Benned-Jensen et al., 2011, 2013). For example, EBI2 expression was increased in post-transplantation lymphoproliferative diseases (PTLDs; Craig et al., 2007). Therefore, it was proposed that an EBI2 antagonist might offer therapeutic benefit in blocking proliferation of EBV-transformed B cell lymphomas (Benned-Jensen et al., 2011, 2013).
In addition to B cells, EBI2 was also found to be expressed in T cells, and DC/monocytes (Hannedouche et al., 2011; Liu et al., 2011). These findings suggested that EBI2 may play key roles in regulating other immune cells. In vitro, 7α, 25-OHC clearly induced migration of mouse and human T cells and CD11c+ DC/monocytes. One recent report (Chalmin et al., 2015) showed that Ch25h deficiency led to significantly attenuated disease in mouse experimental autoimmune encephalomyelitis (EAE). a model of MS, The authors showed that there was a critical involvement for oxysterols in recruiting leukocytes into the inflamed central nervous system (CNS) and proposed that 7α, 25-OHC preferentially promoted EBI2-dependent migration of activated CD44+CD4+ T cells. In a related study (Wanke et al., 2014), using a novel reporter-knockin/knockout mouse model, the authors showed that pathogenic Th1 and Th17 cells expressed EBI2 within inflamed CNS, while Treg cells showed a bipartite expression. Using a transfer model of EAE, the authors showed that EBI2-deficient Th17 cell displayed a significantly delayed pathogenesis compared to wild-type Th17 cells. Taken together, these studies suggested EBI2-dependent migration of T cells might play a role in pathogenesis in autoimmune disease such as MS.
EBI2 also appeared to play an important role in controlling DC migration and homeostasis in mice. Two groups (Gatto et al., 2013; Yi and Cyster, 2013) independently reported that mouse splenic CD4+ DC highly expressed EBI2 and migrated in response to 7α, 25-OHC. In mice which were deficient in EBI2 or 7α, 25-OHC biosynthesis, there was a reduced frequency of splenic CD4+ DC number. The authors further showed that the deficiency was likely due to defective CD4+ DC migration as there was defective positioning of remaining CD4+ DC to marginal zone bridging channels and EBI2 did not affect development of DC or DC survival. As one of the main functions of CD4+ DC in the marginal zone bridging channels was to promote DC encounter of blood-borne particulate antigens, EBI2 deficiency in these specific DC led to defects in both activation of helper T cells and induction of antibody response to this type of antigens.
Expression of EBI2, Ch25H, and Cyp7B1 was found to be highly unregulated in a number of inflammatory diseases, including chronic rhinosinusitis (CRS; Hulse et al., 2013). Nasal polyps from CRS patients showed increased expression of EBI2 which was positively correlated with the expression of plasma cell markers (such as CD138 and B lymphocyte-induced maturation protein) in sinus tissue. Upregulation of Cyp7B1 was observed in inflamed joints in collagen-induced arthritis model (Dulos et al., 2004), a mouse model of rheumatoid arthritis (RA). The same findings applied to fibroblast-like synoviocytes obtained from RA synovial tissues (Dulos et al., 2005), which suggested that EBI2 might also play a role in RA. Interestingly, supporting this notion, the CYP7B1 inhibitor Clotrimazole was tested in RA and showed some efficacy (Wojtulewski et al., 1980).
Human primary macrophages were also reported (Preuss et al., 2014) to express EBI2, Ch25H, and Cyp7B1. In cultured monocyte-derived macrophages, LPS triggered a strong up-regulation of Ch25H and Cyp7B1 and a transient increase in EBI2 expression. Ligation of EBI2 in cultured macrophages led to calcium mobilization and cell migration. Culture supernatants of LPS-stimulated macrophages were able to activate EBI2 signaling indicating that these cells produced 7α, 25-OHC upon LPS-induction of Ch25H and Cyp7B1.
A genome-wide association study using both rat and human data published in Heinig et al. (2010) implicated EBI2 as a regulator of an interferon regulatory factor 7 (IRF)-driven inflammatory network (IDIN), which was associated with susceptibility of T1D. The human locus controlling IDIN was associated with the risk of T1D at a single nucleotide polymorphism rs9585056, which was also associated with increased EBI2 expression. siRNA knockdown of EBI2 in rat macrophages increased expression of Irf7 and IDIN genes. Another study (Chiang et al., 2013) demonstrated that EBI2 negatively regulated type I interferon (IFN) responses in plasmacytoid DC and CD11b+ myeloid cells. EBI2 deficiency led to increased production of type I interferon induced by TLR ligands in vitro as well as in vivo. Therefore, it will be interesting to explore whether dysregulation of EBI2 plays a role in pathogenesis of certain autoimmune disease such as lupus, Sjogren's syndrome in which type I interferon is implicated (Swiecki and Colonna, 2011). Oxysterols and oxysterol sensing receptors have been shown to modulate metabolism (Gill et al., 2008; Raychaudhuri and Prinz, 2010) and may play roles in metabolic disease such as diabetes, obesity, and dyslipidemia. The link between EBI2 and T1D suggested that EBI2 may also have a similar role.
One group (Rutkowska et al., 2015) recently showed that human and mouse astrocytes express EBI2 and the enzymes necessary for synthesis and degradation of 7α, 25-OHC. In astrocytes, EBI2 activation stimulates ERK phosphorylation, Ca2+ signaling and induces cellular migration. In addition, activation EBI2 prevents lysophosphatidylcholine (LPC)-induced demyelination in cerebellar slices. These results suggested that EBI2 is involved in glial cell function and modulation of this receptor may be beneficial in neuroinflammatory or neurodegenerative disorders.
EBI2 Modulators
As described above, it has been demonstrated that EBI2 serves as a key chemotactic receptor for B cells, T cells and DC, modulating both T cell and B cell response to blood-borne antigens. The expression of EBI2 and enzymes for 7α, 25-OHC is upregulated in inflammatory diseases, and dysregulation of EBI2 may contribute to B cell malignancies, and certain autoimmune diseases such as T1D, RA, lupus, and MS. Therefore it is of interest to discover and develop EBI2 modulators and test for their therapeutic potentials in preclinical models and in patients.
Simultaneous to discovery of 7α, 25-OHC as the endogenous EBI2 ligand, one group (Benned-Jensen et al., 2011) reported the identification and characterization of a small molecule inverse agonist, GSK682753A (Figure 1), which blocked the apparent constitutive activity of EBI2 receptor in a recombinant system. It was later (Benned-Jensen et al., 2013) shown that the compound was actually a potent EBI2 antagonist, blocking 7α, 25-OHC induced EBI2 activation in vitro. A number of compounds were also identified using a uHTS screen at the Sanford-Burnham Center for Chemical Genomics which inhibited 7α, 25-OHC-mediated β-arrestin recruitment (PubChem BioAssay ID: 651636).
Another group (Gessier et al., 2014) recently reported the identification of a small molecule agonist NIBR51 (Figure 1; hEBI2 EC50 ~2 μM) from screening about 100 K compounds in an EBI2-dependent recombinant assay. Using this agonist, the group rescreened the same library and identified a small molecule antagonists NIBR127 (Figure 1) which bind to EBI2 with high affinity (human EBI2 EC50 83 nM) and good potency in receptor activation (hEBI2 Ca2+ IC50 196 nM). A subsequent medicinal chemistry effort using NIBR127 as a starting point led to NIBR189 (Figure 1) with significant improved potency in EBI2 receptor activation (hEBI2 Ca2+ IC50 11 nM). Further pharmacological characterization suggested that NIBR189 was a potent and selective EBI2 antagonist with pharmacokinetic properties which should allow for in vitro and in vivo experiments. To this end, it was noted by the authors that much of initial testing was directed toward paradigms of autoimmune disorders. Because of the demonstrated activity of EBI2 in monocytes as described above, it was proposed by the authors to test the EBI2 antagonist in paradigms relevant for cardiovascular diseases (Gessier et al., 2014).
Concluding Remarks
The identification of 7α, 25-OHC as the endogenous EBI2 ligand uncovered a previously unknown role for oxysterols, a class of molecules which exert profound biological effects. Work published by a number of groups including ours in last few years showed that EBI2 and key enzymes in producing 7α, 25-OHC were highly regulated during inflammation, and might play key roles in pathogenesis of certain human diseases such as to inflammation and autoimmune diseases, neurodegenerative disease, cardiovascular diseases, cancers, as well as metabolic diseases such as diabetes, obesity, and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Andrews, S. P., Brown, G. A., and Christopher, J. A. (2014), Structure-based and fragment-based GPCR drug discovery. Chem. Med. Chem. 9, 256–275. doi: 10.1002/cmdc.201300382
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Benned-Jensen, T., Madsen, C. M., Arfelt, K. N., Smethurts, C., Blanchard, A., Jepras, R.,et al. (2013). Small molecule antagonism of oxysterol-induced Epstein–Barr virus induced gene 2 (EBI2) activation. FEBS Open Bio. 3, 156–160. doi: 10.1016/j.fob.2013.02.003
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Benned-Jensen, T., Norn, C., Laurent, S., Madsen, C. M., Larsen, H. M., Arfelt, K. N.,et al. (2012). Molecular characterization of oxysterol binding to the Epstein–Barr virus-induced gene 2 (GPR183). J. Biol. Chem. 287, 35470–35483. doi: 10.1074/jbc.M112.387894
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Benned-Jensen, T., Smethurst, C., Holst, P. J., Page, K. R., Sauls, H., Sivertsen, B.,et al. (2011). Ligand modulation of the Epstein–Barr virus-induced seven-transmembrane receptor EBI2: identification of a potent and efficacious inverse agonist J. Biol. Chem. 2011, 286, 29292–29302. doi: 10.1074/jbc.M110.196345
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Birkenbach, M., Josefsen, K., Yalamanchili, R., Lenoir, G., and Kieff, E. (1993). Epstein–Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors. J. Virol. 67, 2209–2220.
Chalmin, F., Rochemont, V., Lippens, C., Clottu, A., Sailer, A. W., Merkler, D.,et al. (2015). Oxysterols regulate encephalitogenic CD4(+) T cell trafficking during central nervous system autoimmunity. J. Autoimmun. 56, 45–55. doi: 10.1016/j.jaut.2014.10.001
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Chiang, E. Y., Johnston, R. J., and Grogan, J. L. (2013). EBI2 Is a negative regulator of type I interferons in plasmacytoid and myeloid dendritic cells. PLoS ONE 8:e83457. doi: 10.1371/journal.pone.0083457
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Craig, F. E., Johnson, L. R., Harvey, S. A., Nalesnik, M. A., Luo, J. H., Bhattacharya, S. D.,et al. (2007). Gene expression profiling of Epstein–Barr virus-positive and negative monomorphoic B-cell posttransplant lymphoproliferative disorders. Diagn. Mol. Pathol. 16, 158–168. doi: 10.1097/PDM.0b013e31804f54a9
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Dulos, J., van der Vleuten, M. A., Kavelaars, A., Heijnen, C. J., and Boots, A. M. (2005). CYP7B expression and activity in fibroblast-like synoviocytes from patients with rheumatoid arthritis: regulation by proinflammatory cytokines. Arthritis Rheum. 52, 770–778. doi: 10.1002/art.20950
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Dulos, J., Verbraak, E., Bagchus, W. M., Boots, A. M., and Kaptein, A. (2004). Severity of murine collagen-induced arthritis correlates with increased CYP7B activity: enhancement of dehydroepiandrosterone metabolism by interleukin-1beta. Arthritis Rheum. 50, 3346–3353. doi: 10.1002/art.20509
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Gatto, D., Paus, D., Basten, A., Mackay, C. R., and Brink, R. (2009). Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity 31, 1–11. doi: 10.1016/j.immuni.2009.06.016
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Gatto, D., Wood, K., and Brink, R. (2011). EBI2 operates independently of but in cooperation with CXCR5 and CCR7 to direct B cell migration and organization in follicles and the germinal center. J. Immunol. 187, 4621–4628. doi: 10.4049/jimmunol.1101542
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Gatto, D., Wood, K., Caminschi, I., Murphy-Durland, D., Schofield, P., Christ, D.,et al. (2013). The chemotactic receptor EBI2 regulates the homeostasis, localization and immunological function of splenic dendritic cells. Nat. Immunol. 14, 446–453. doi: 10.1038/ni.2555
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Gessier, F., Preuss, I., Yin, H., Rosenkilde, M. M., Laurent, S., Endres, R.,et al. (2014), Identification and characterization of small molecule modulators of the Epstein–Barr virus-induced gene 2 (EBI2) receptor. J. Med. Chem. 57, 3358–3368. doi: 10.1021/jm4019355
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Gill, S., Chow, R., and Brown, A. J. (2008). Sterol regulators of cholesterol homeostasis and beyond: the oxysterol hypothesis revisited and revised. Prog. Lipid Res. 2008, 47, 391–404. doi: 10.1016/j.plipres.2008.04.002
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Hannedouche, S., Zhang, J., Yi, T., Shen, W., Nguyen, D., Pereira, J. P.,et al. (2011). Oxysterols direct immune cell migration via EBI2. Nature 475, 524–527. doi: 10.1038/nature10280
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Heinig, M., Petretto, E., Wallace, C., Bottolo, L., Rotival, M., Lu, H.,et al. (2010). A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467, 460–464. doi: 10.1038/nature09386
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Hulse, K. E., Norton, J. E., Suh, L., Zhong, Q., Mahdavinia, M., Simon, P.,et al. (2013). Chronic rhinosinusitis with nasal polyps is characterized by B-cell inflammation and EBV-induced protein 2 expression. J. Allergy Clin. Immunol. 131, 1075–1083. doi: 10.1016/j.jaci.2013.01.043
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Liu, C., Eriste, E., Sutton, S., Chen, J., Roland, B., Kuei, C.,et al. (2003). Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein-coupled receptor GPCR135. J. Biol. Chem. 278, 50754–50764. doi: 10.1074/jbc.M308995200
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Liu, C., Kuei, C., Sutton, S., Chen, J., Bonaventure, P., Wu, J.,et al. (2005). INSL5 is a high affinity specific agonist for GPCR142 (GPR100). J. Biol. Chem. 280, 292–300. doi: 10.1074/jbc.M409916200
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Liu, C., Ma, X. J., Jiang, X., Wilson, S. J., Hofstra, C. L., Blevitt, J.,et al. (2001). Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow. Mol. Pharmacol. 59:420–426. doi: 10.1124/mol.59.3.420
Liu, C., Wu, J., Zhu, J., Kuei, C., Yu, J., Shelton, J.,et al. (2009). Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J. Biol. Chem. 284, 2811–2822. doi: 10.1074/jbc.M806409200
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Liu, C., Yang, X. V., Wu, J., Kuei, C., Mani, N. S., Zhang, L.,et al. (2011). Oxysterols direct B-cell migration through EBI2. Nature 475, 519–523. doi: 10.1038/nature10226
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Lovenberg, T. W., Roland, B. L., Wilson, S. J., Jiang, X., Pyati, J., Huvar, A.,et al. (1999). Cloning and functional expression of the human histamine H3 receptor. Mol. Pharmacol. 55, 1101–1107.
Pereira, J. P., Kelly, L. M., Xu, Y., and Cyster, J. G. (2009), EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460, 1122–1126. doi: 10.1038/nature08226
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Preuss, I., Ludwig, M. G., Baumgarten, B., Bassilana, F., Gessier, F., Seuwen, K.,et al. (2014). Transcriptional regulation and functional characterization of the oxysterol/EBI2 system in primary human macrophages. Biochem. Biophys. Res. Commun. 446, 663–668. doi: 10.1016/j.bbrc.2014.01.069
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Raychaudhuri, S., and Prinz, W. A. (2010). The diverse functions of oxysterol-binding proteins. Annu. Rev. Cell Dev. Biol. 26, 157–177. doi: 10.1146/annurev.cellbio.042308.113334
Rutkowska, A., Preuss, I., Gessier, F., Sailer, A. W., and Dev, K. K. (2015), EBI2 regulates intracellular signaling and migration in human astrocyte. Glia 63, 341–351. doi: 10.1002/glia.22757
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Swiecki, M., and Colonna, M. (2011). Type I interferons: diversity of sources, production pathways and effects on immune responses. Curr. Opin. Virol. 1, 463–475. doi: 10.1016/j.coviro.2011.10.026
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Wanke, F., Croxford, A. L., Heinen, A. P., Firmenich, S., Moos, S., Israel, N.,et al. (2014) Expression of the G-protein coupled receptor EBI2 in T cells is highly regulated and confers pathogenicity to myelin specific Th17 cells. J. Neuroimmunol. 275:211. doi: 10.1016/j.jneuroim.2014.08.566
Wojtulewski, J. A., Gow, P. J., Walter, J., Grahame, R., Gibson, T., Panayi, G. S.,et al. (1980). Clotrimazole in rheumatoid arthritis. Ann. Rheum. Dis. 39, 469–472. doi: 10.1136/ard.39.5.469
Yi, T., and Cyster, J. G. (2013). EBI2-mediated bridging channel positioning supports splenic dendritic cell homeostasis and particulate antigen capture. eLife 2:e00757. doi: 10.7554/elife.00757
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Yi, T., Wang, X., Kelly, L. M., An, J., Sailer, A. W., Gustafsson, J. A.,et al. (2012). Oxysterol gradient generation by lymphoid stromal cells guides activated B cell movement during humoral responses. Immunity 37, 535–548. doi: 10.1016/j.immuni.2012.06.015
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Zhang, L., Shih, A. Y., Yang, X. V., Kuei, C., Wu, J., Deng, X.,et al. (2012). Identification of structural motifs critical for Epstein–Barr virus-induced molecule 2 function and homology modeling of the ligand docking site. Mol. Pharmacol. 82, 1094–1103. doi: 10.1124/mol.112.080275
PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar
Keywords: EBI2, 7α, 25-OHC
Citation: Sun S and Liu C (2015) 7α, 25-dihydroxycholesterol-mediated activation of EBI2 in immune regulation and diseases. Front. Pharmacol. 6:60. doi: 10.3389/fphar.2015.00060
Received: 14 January 2015; Accepted: 09 March 2015;
Published online: 24 March 2015.
Edited by:Ye Fang, Corning Incorporated, USA
Reviewed by:Sunita Nair, Capita India Pvt. Ltd., India
Dominique Hess, Garvan Institute of Medical Research, Australia
Copyright © 2015 Sun and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Siquan Sun, Immunology Therapeutic Area, Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA firstname.lastname@example.com; Changlu Liu, Neuroscience Therapeutic Area, Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA firstname.lastname@example.com


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The Toronto Raptors have been using the slogan and hashtag #WeTheNorth to represent themselves all year long. It's sort of their calling card and motto and has grown in popularity throughout these NBA playoffs. After the Cleveland Cavaliers lost in Game 3 of the Eastern Conference Finals to the Raptors, Richard Jefferson made fun of the #WeTheNorth motto by saying this:
Richard Jefferson opens up with a tongue-in-cheek statement to the press: "We the South are going to be OK. We're going to be just fine"
— Dave McMenamin (@mcten) May 22, 2016
Jefferson is clearly just poking fun at the Raptors. No harm, no foul, but it will be entertaining to see how the Raptors will respond, if at all. Game 4 begins Monday night as both teams look to make a statement and get one game closer to reaching the NBA Finals.
The game will likely come down to who is mentally tougher and who makes the least amount of mistakes. It's hard to tell what the outcome may be because, in Game 3, Cleveland did not look like the team they were when they won 10 straight playoff games.
Cleveland must come out swinging if they wish to come closer to closing out the Raptors and moving on to the Finals for the second year in a row.

subset: commoncrawl


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ROME (Reuters) - A rescue deal that will allow Italy to inject up to 6.6 billion euros ($7.4 billion) into the country's fourth largest bank Monte dei Paschi di Siena
The Bank of Italy's Deputy Governor Fabio Panetta told a press briefing on Monday that Monte dei Paschi's bailout was a "a done deal."
At the same briefing, Chief Supervisor Carmelo Barbagallo said the EU Commission had only to formalize its approval but there were no doubts that, unlike regional rival Popolare di Vicenza and Veneto Banca, Monte dei Paschi would be able to tap state aid to remain in business.
Barbagallo said Monte dei Paschi would close a bad loan sale, a key plank of its rescue plan, thanks to the fact that banking industry bailout fund Atlante could now divert cash previously earmarked for the Veneto banks' soured debts to buy Monte dei Paschi's bad loans.
(Reporting by Stefano Bernabei, writing by Valentina Za)
(c) Copyright Thomson Reuters 2017. Click For Restrictions


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Overtime, you and your family accumulated a lot of belongings, either through gifts or your shopping spree. Some of these belongings are stored or get stuck somewhere in your house without you knowing it. This could take up space inside your residence, and when it is time to move, you may need to dispose some of this stuff, so you can have fewer things to pack and lighter load for your baggage and shipment.
If you don't know how to dispose these unnecessary belongings, here are some ideas from international moving companies in Dubai:
- Throw away unnecessary clutter
Some people have this habit of hanging on to things they acquire. Although some of them might have real sentimental value, most of these stuff are just eating up the space in your home and probably have no value. If you are moving to a new place and thinking of how you can squeeze in everything in your storage boxes, the first thing that you need to do is to dispose the useless belongings you have at home. You need to assess and evaluate which of your stuff have real use to you. Once you determine and categorize your things, you can simply throw away useless stuff. Do not feel bad about it. You can still purchase and acquire some in your new home.
- Do a yard sale
If you think throwing away the useless stuff is heartbreaking, then it would be best to let it go by making money out of it. Set up a garage or yard sale in your property and lined up those things that you think would be of use of someone else. Pre-loved items are quite popular to some people, given the condition of the items are still acceptable. They are less pricey than the new ones. Just price the items accordingly and announce that you will be having a yard sale in your place to draw out people.
- Give to your local charities
If there are still some stuff left to dispose, you can simply send them over to a local charity in your place. These charities are distributing these belongings to families and individuals who are in need of these stuff the most. You can lighten your load and also help those who are in need.
- Subscribe to a storage facility
If there are still some things left and you don't know where you can take them, it would be best to put them in storage in Dubai while you are thinking of how you can dispose these things.


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Cropped sweaters can't be any better for Los Angeles autumns. We don't experience much of a season change but you can definitely tell that the wind has a bit more of chill to it. We've been having cloudy skies and I can't be more excited for some colder weather! As much as I love being in the sun and at the beach, we need grey skies and rain. It also makes staying at home in a chunky sweater and a cup of coffee so much more worth while. I can't wait for these colder days so I can curl up with my cuddle buddy Corona. This sleeveless sweater is so cozy, it's perfect for this fall. Find it here:
Photography by Jeremy Lee: Check out his work here


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Hotels & Accommodation in Kwintsheul
Search Kwintsheul Hotels
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Best Kwintsheul Hotels
Kwintsheul overviewWhatever your interests are, Kwintsheul has something for you. Kwintsheul might not have well-known attractions within the city, but you won't need to venture far to find top places to visit like Oude Kerk and Nieuwe Kerk. In the surrounding area, popular sights include Binnenhof and Noordeinde Palace.
Where to stay in KwintsheulWhether you're planning a longer vacation or a weekend getaway, Kwintsheul has the right accommodation for you. You can shop as many as 347 deals for Kwintsheul accommodations on Hotels.com, some with discounts of up to 60%. We have room prices starting at 15 USD per night and here you'll find a breakdown of hotels by star rating in Kwintsheul as well as in the surrounding area:
- • 12 5-star hotels from 120 USD per night
- • 138 4-star hotels from 72 USD per night
- • 120 3-star hotels from 56 USD per night
- • 22 2-star hotels from 22 USD per night
How to get to KwintsheulFly into Rotterdam (RTM-Rotterdam The Hague), 8.5 mi (13.7 km) from the heart of Kwintsheul. Amsterdam (AMS-Schiphol) is the next closest major airport, 29.1 mi (46.8 km) away.
What to see around KwintsheulHere are some top sights in the surrounding area:
- • Oude Kerk (3.8 mi/6.1 km from the city center)
- • Nieuwe Kerk (4 mi/6.4 km from the city center)
- • Binnenhof (4.7 mi/7.6 km from the city center)
- • Noordeinde Palace (4.7 mi/7.6 km from the city center)
- • Panorama Mesdag (5 mi/8 km from the city center)
When to visit KwintsheulIf you're beginning to plan your vacation, you might be wondering when is the best time to visit. Here are the seasonal norms to help you decide when to go:
Seasonal temperature averages
- • January-March: 51°F day, 33°F night
- • April-June: 67°F day, 38°F night
- • July-September: 70°F day, 49°F night
- • October-December: 60°F day, 35°F night
- • January-March: 8.27 inches
- • April-June: 5.75 inches
- • July-September: 8.58 inches
- • October-December: 9.80 inches


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|Residing In
|Godfrey, IL USA
|Occupational Health Nurse/Ameren Missouri
| Maura, born 1981
Nicholas, born 1988
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It was great helping you celebrate your birthday early on Sanibel Island yesterday! Gorgeous day , good shelling, and two best friends celebrating. A friend couldn't ask for much more. Happy Birthday!
Posted on: Oct 07, 2014 at 8:42 AM
Can't wait to see you at the reunion! We'll have a mini-St. Mary's reunion and get caught up.....
welcome to the website! See you at the reunion.
welcome to the website!
Posted on: May 09, 2014 at 9:37 PM
You look terrific, lady!!!
Posted on: May 05, 2014 at 9:05 PM
Okay, I'm glad I joined this one. Welcome, everyone. I can't believe it's been 40 years myself. It will be great to see all of you!


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By Christiana Gokyo, Jos
Following the recent attacks on the people of Irigwe (Miango) community in Bassa local government council of Plateau State, which started on the 7th of September, 2017, killing about 20 people, as well as houses being burnt down, the community has condemned the attacks in strong terms.
Addressing a press conference in Jos by the community, Hon. Sunday Abdu expressed sadness over the attacks, while decrying the imposition of curfew in the area as having all but negative impact, since "the siege has continued till date."
He further explained that, the Fulani herdsmen do not respect the curfew, saying the curfew was only for the Irigwe people and not for the marauding herdsmen.
Hon. Abdu said it is painful to note that all this happened despite useful and timely information provided to security personnel, regarding movement and mode of operation of the assailants, the attacks have continued in sequence and stopped.
The spokesman urged the government to do the needful – that is, to stop these nightly attacks on their people, adding that curfew should not be used as a weapon of war on their people.
According to Abdu, "up till now, no attackers have been arrested or driven away, but only been seeing the security personnel only mounting check points and operating questionable card on and search operations for non existing weapons in our peoples homes."
He further explained that women and children are displaced, while feeding has become impossible in homes that accepted refugees, and their people cannot go to farm to harvest for fear of the attackers.
Hon Abdu maintained that "no aid agency, government or private organization has visited the community to provide relief materials; we are left at the mercy of our fate," and urged government officials, all relevant stakeholders to take practical steps at serving the people.
He said "the attacks took place in this Villages: Ncha, Hukke, Nkie Dongwro, Kpachudu, Nzhweruvo and Tafigana, Rikwe Chongu, Taegbe and Nkyie Doghwro."
On the other side of the coin, the Fulani cattle rearers have expressed dismay over the killings and beheading of six (6) innocent Fulani cattle rearers on Sunday, October 15, 2017, by the Irigwe militia in Kuri Village of Bassa Local Government Area of Plateau state.
The incident occurred at about 3pm on the fateful Sunday when the Fulani, while grazing their cattle at Kuri Village in Bassa LGA were attacked, slaughtered, beheaded and their heads carted away by the Irigwe militia.
A statement, signed and issued to newsmen in Jos, by chairman MACBAN plateau state chapter, Nura Muhammadu Abdullahi, noted that a total of forty (40) sheep, nine (9) cows were machete and killed, and a total of two hundred and thirty-two (232) herds of cattle belonging to the families of the deceased persons were rustled.
According to the statement, the incident was immediately reported to the Divisional Police Officer (DPO) of Bassa Local Government Area and Operation Safe Haven (OPSH), Sector 6, who visited the scene and confirmed the dead and burial.
The Irigwe community, while calling for government's intervention, said "We are peace loving people; therefore, we are calling on Plateau state Government and security operatives to investigate, fish out the killers and take necessary action that will stop future re-occurrence."


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Taylor Swift Gives A Taste Of Reputation On "Call It What You Want", Stream & Download Mp3
"Call It What You Want" available now. @applemusic
Pre-order #reputation: https://t.co/oExj2XFGvH pic.twitter.com/EWxoTpSzIT
— Taylor Swift (@taylorswift13) November 3, 2017
Taylor Swift has fulfilled her promised as she debutes a new track off the Reputation album, the new track was released at midnight Friday (Nov. 3). The song "Call It What You Want", is the fourth song from her upcoming album Reputation. Swift also promised that Reputation will be available everywhere on November 10th.
The song had earlier been teased by the The 27-year-old singer on Thursday (November 2), the snippet came with a type-written note previewing another batch of its lyrics: "Holding my breath/ Slowly I said/ 'You don't need to save me … But would you run away with me?'" followed by "Yes."
After teasing and subsequently dropping "Look What You Made Me Do" in August with mysterious snake videos, Swift has held up a promise she made in one of her Instagram posts: "There will be no further explanation.
It's about to go down, check out the new track below.
CIlCK lMAGE BEI0W T0 D0WNI0AD MUSlC


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STYLISH PENCIL PLEAT TAPE TOP LINED FLOWER PATTERN PAIR OF CURTAINS TERRACOTTA & BROWN COLOUR ( Brown Flower Curtains #3) Images Gallery
Context of STYLISH PENCIL PLEAT TAPE TOP LINED FLOWER PATTERN PAIR OF CURTAINS TERRACOTTA & BROWN COLOUR
TOPtop1 (top),USA pronunciation n., adj., v., topped, top•ping.
- the highest or loftiest point or part of anything;
- the uppermost or upper part, surface, etc., of anything.
- the higher end of anything on a slope.
- [Brit.]
- a part considered as higher: the top of the street.
- high gear of an automobile.
- tops,
- the part of a plant that grows above ground, esp. of an edible root.
- one of the tender tips of the branches or shoots of plants.
- the part of anything that is first or foremost;
beginning: Let's go over it from the top again.
- the highest or leading place, position, rank, etc.: at the top of the class.
- the highest point, pitch, or degree: to talk at the top of one's voice.
- a person or thing that occupies the highest or leading position.
- the best or choicest part: the top of all creation.
- a covering or lid, as of a container or vehicle.
- the head.
- any of various outer garments for the upper body, as a blouse, shirt, or sweater: a sale on cotton tops and shorts.
- [Naut.]a platform surrounding the head of a lower mast on a ship, and serving as a foothold, a means of extending the upper rigging, etc.
- [Chem.]the part of a mixture under distillation that volatilizes first.
- [Bridge.]
- the best card of a suit in a player's hand.
- (in duplicate bridge) the best score on a hand.
- [Sports.]
- a stroke that hits the ball above its center.
- the forward spin given to the ball by such a stroke.
- [Baseball.]
- the first half of an inning.
- the first three batters in the batting order.
- [Textiles.]
- a cluster of textile fibers, esp. tow, put on a distaff.
- a strand of the long wool fibers in sliver form, separated from noil by combing and wound into a large ball.
- a similar strand of rayon.
- [Jewelry.]crown (def. 27).
- blow one's top, [Informal.]
- to become enraged;
lose one's temper.
- to go mad;
become insane: He must have blown his top to make such a fool of himself.
- off the top of one's head, [Informal.]See head (def. 56).
- on top, successful;
dominant: to stay on top.
- on top of:
- over or upon.
- in addition to;
over and above.
- close upon;
following upon: Gale winds came on top of the floods.
- in complete control: on top of the problem.
- on top of the world:
- successful.
- elated: The success made her feel on top of the world.
- over the top:
- [Mil.]over the top of the parapet before a trench, as in issuing to charge against the enemy.
- surpassing a goal, quota, or limit.
- the tops, [Informal.]the most outstanding person or thing in ability, favor, etc.: As a friend, she's the tops.
- pertaining to, situated at, or forming the top;
upper: the top shelf.
- highest in degree;
greatest: to pay top prices.
- foremost, chief, or principal: to win top honors in a competition.
- to furnish with a top;
put a top on.
- to be at or constitute the top of.
- to reach the top of.
- to rise above: The sun had topped the horizon.
- to exceed in height, amount, number, etc.
- to surpass, excel, or outdo: That tops everything.
- [Theat.](in spoken dialogue) to reply in a voice of greater volume or higher pitch: King Henry must top the crowd noises in his St. Crispin's Day speech.
- to surmount with something specified: to top a sundae with whipped cream.
- to remove the top of;
prune: to top a tall tree.
- to get or leap over the top of (a fence, barrier, etc.).
- [Chem.]to distill off only the most volatile part of (a mixture).
- [Sports.]
- to strike (the ball) above its center, giving it a forward spin.
- to make (a stroke) by hitting the ball in this manner.
- to top-dress (land).
- [Obs.]to have coitus with (a woman).
- to rise aloft.
- top off:
- to climax or complete, esp. in an exceptional manner;
finish: They topped off the evening with a ferryboat ride at midnight.
- to fill (a partly full container) completely: to top off a gas tank.
- top oneself, [Chiefly Brit.]to kill oneself.
- top out:
- to finish the top of (a structure).
- to reach the highest level.
FLOWERflow•er (flou′ər),USA pronunciation n.
- the blossom of a plant.
- the part of a seed plant comprising the reproductive organs and their envelopes if any, esp. when such envelopes are more or less conspicuous in form and color.
- an analogous reproductive structure in other plants, as the mosses.
- a plant, considered with reference to its blossom or cultivated for its floral beauty.
- state of efflorescence or bloom: Peonies were in flower.
- an ornament representing a flower.
- Also called fleuron, floret. an ornamental piece of type, esp. a stylized floral design, often used in a line to decorate chapter headings, page borders, or bindings.
- an ornament or adornment.
- the finest or most flourishing period: Poetic drama was in flower in Elizabethan England.
- the best or finest member or part of a number, body, or whole: the flower of American youth.
- the finest or choicest product or example.
- flowers, (used with a sing. v.)a substance in the form of a fine powder, esp. as obtained by sublimation: flowers of sulfur.
- to produce flowers;
come to full bloom.
- to come out into full development;
- to cover or deck with flowers.
- to decorate with a floral design.
PATTERNpat•tern (pat′ərn; Brit. pat′n),USA pronunciation n.
- a decorative design, as for wallpaper, china, or textile fabrics, etc.
- decoration or ornament having such a design.
- a natural or chance marking, configuration, or design: patterns of frost on the window.
- a distinctive style, model, or form: a new pattern of army helmet.
- a combination of qualities, acts, tendencies, etc., forming a consistent or characteristic arrangement: the behavior patterns of teenagers.
- an original or model considered for or deserving of imitation: Our constitution has been a pattern for those of many new republics.
- anything fashioned or designed to serve as a model or guide for something to be made: a paper pattern for a dress.
- a sufficient quantity of material for making a garment.
- the path of flight established for an aircraft approaching an airport at which it is to land.
- a diagram of lines transmitted occasionally by a television station to aid in adjusting receiving sets;
test pattern.
- Metall. a model or form, usually of wood or metal, used for giving the shape of the interior of a mold.
- Numis. a coin, either the redesign of an existing piece or the model for a new one, submitted for authorization as a regular issue.
- an example, instance, sample, or specimen.
- [Gunnery, Aerial Bombing.]
- the distribution of strikes around a target at which artillery rounds have been fired or on which bombs have been dropped.
- a diagram showing such distribution.
- to make or fashion after or according to a pattern.
- to cover or mark with a pattern.
- Chiefly Brit. Dial.
- to imitate.
- to attempt to match or duplicate.
pat′tern•a•ble, adj.
- to make or fall into a pattern.
pat′terned, adj.
pat′tern•er, n.
pat′tern•less, adj.
pat′tern•like′, adj.
pat′tern•y, adj.
OFof1 (uv, ov; unstressed əv or, esp. before consonants, ə),USA pronunciation prep.
- (used to indicate distance or direction from, separation, deprivation, etc.): within a mile of the church; south of Omaha; to be robbed of one's money.
- (used to indicate derivation, origin, or source): a man of good family; the plays of Shakespeare; a piece of cake.
- (used to indicate cause, motive, occasion, or reason): to die of hunger.
- (used to indicate material, component parts, substance, or contents): a dress of silk; a book of poems; a package of cheese.
- (used to indicate apposition or identity): Is that idiot of a salesman calling again?
- (used to indicate specific identity or a particular item within a category): the city of Chicago; thoughts of love.
- (used to indicate possession, connection, or association): the king of France; the property of the church.
- (used to indicate inclusion in a number, class, or whole): one of us.
- (used to indicate the objective relation, the object of the action noted by the preceding noun or the application of a verb or adjective): the ringing of bells; He writes her of home; I'm tired of working.
- (used to indicate reference or respect): There is talk of peace.
- (used to indicate qualities or attributes): an ambassador of remarkable tact.
- (used to indicate a specified time): They arrived of an evening.
- [Chiefly Northern U.S.]before the hour of;
until: twenty minutes of five.
- on the part of: It was very mean of you to laugh at me.
- in respect to: fleet of foot.
- set aside for or devoted to: a minute of prayer.
- [Archaic.]by: consumed of worms.
CURTAINScur•tain (kûr′tn),USA pronunciation n.
- a hanging piece of fabric used to shut out the light from a window, adorn a room, increase privacy, etc.
- a movable or folding screen used for similar purposes.
- [Chiefly New Eng.]a window shade.
- [Theat.]
- a set of hanging drapery for concealing all or part of the stage or set from the view of the audience.
- the act or time of raising or opening a curtain at the start of a performance: an 8:30 curtain.
- the end of a scene or act indicated by the closing or falling of a curtain: first-act curtain.
- an effect, line, or plot solution at the conclusion of a performance: a strong curtain; weak curtain.
- music signaling the end of a radio or television performance.
- (used as a direction in a script of a play to indicate that a scene or act is concluded.)
- anything that shuts off, covers, or conceals: a curtain of artillery fire.
- a relatively flat or featureless extent of wall between two pavilions or the like.
- [Fort.]the part of a wall or rampart connecting two bastions, towers, or the like.
- curtains, the end;
death, esp. by violence: It looked like curtains for another mobster.
- draw the curtain on or over:
- to bring to a close: to draw the curtain on a long career of public service.
- to keep secret.
- lift the curtain on:
- to commence;
- to make known or public;
disclose: to lift the curtain on a new scientific discovery.
cur′tain•less, adj.
- to provide, shut off, conceal, or adorn with, or as if with, a curtain.
BROWNbrown (broun),USA pronunciation n., adj., -er, -est, v.
- a dark tertiary color with a yellowish or reddish hue.
- a person whose skin has a dusky or light-brown pigmentation.
- of the color brown.
- (of animals) having skin, fur, hair, or feathers of that color.
- sunburned or tanned.
- (of persons) having the skin naturally pigmented a brown color.
- do it up brown, [Informal.]to do thoroughly: When they entertain, they really do it up brown.
v.t., v.i.
brown′ish, brown′y, adj.
- to make or become brown.
- to fry, sauté, or scorch slightly in cooking: to brown onions before adding them to the stew. The potatoes browned in the pan.
- browned off, [Slang.]angry;
fed up.
- brown out, to subject to a brownout: The power failure browned out the southern half of the state.
brown′ness, n.
COLOURcol•our (kul′ər),USA pronunciation n., adj. v.t., v.i. [Chiefly Brit.]
- color.
See -or 1.
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text:
OSAMA bin Laden's son could be in charge of some of the biggest construction contracts at the 2022 World Cup.
Omar, 31, who attended terrorist training camps as a youngster and was once seen as his father's heir, could pocket millions from football's most treasured tournament.
The Saudi-born businessman is bidding for a string of engineering contracts including an underground rail service between stadiums in the capital city Doha.
He said: "We want to be involved in the Doha Metro and other high-speed rail projects in Qatar, as well as hydraulics and water treatment plants.
"There is a limited timeframe for projects in Qatar. It's all happening in the next 10 years, and we want to be involved as much as we can.
"We hope to be submitting proposals by the end of June."
Omar trained with al-Qaeda killers in his youth but turned his back on terrorism before September 11th.
And following the death of his father last year, Omar, speaking exclusively to The Sun in Qatar, said: "I loved him, he was my father."
He added: "I didn't agree with what he did - I only believe in peace - but that doesn't mean I couldn't love him as a father."


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Building Details
- Price Range$689,900 to $699,000
- Bedrooms
- Year Built
- Number of units
- Stories0
- SF Range0 to 0
- Average Price / Sq.Ft$0
- Average DOM2 day(s)
Want to know if it is the right time to sell your unit at Dickens Court?
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