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The keratinocytes of the skin are unique in being not only the primary source of vitamin D for the body, but in possessing the enzymatic machinery to metabolize vitamin D to its active metabolite 1,25(OH)2D. Furthermore, these cells also express the vitamin D receptor (VDR) that enables them to respond to the 1,25(OH)2D they produce. Numerous functions of the skin are regulated by 1,25(OH)2D and/or its receptor. These include inhibition of proliferation, stimulation of differentiation including formation of the permeability barrier, promotion of innate immunity, and promotion of the hair follicle cycle. Regulation of these actions is exerted by a number of different coregulators including the coactivators DRIP and SRC, the cosuppressor hairless (Hr), and β-catenin. This review will examine the regulation of vitamin D production and metabolism in the skin, and explore the various functions regulated by 1,25(OH)2D and its receptor.
The epidermis is the major source of vitamin D for the body. However, the keratinocytes within the epidermis are further capable of metabolizing the vitamin D to its active metabolite, 1,25(OH)2D. 1,25(OH)2D, acting through the vitamin D receptor (VDR), regulates epidermal proliferation in the basal layer (stratum basale) and promotes the sequential differentiation of keratinocytes as they form the upper layers of the epidermis. Loss of VDR or loss of the capacity to produce 1,25(OH)2D (CYP27B1 mutations/deletion) disrupts differentiation of the epidermis and results in hyperproliferation of the basal layers. The keratinocytes lining the outer layer of the hair follicle (the outer root sheath or ORS) also possess VDR. Loss of VDR function either by inactivating mutations or bioengineered deletions leads to loss of hair follicle cycling and alopecia. In this case, it is less obvious that the VDR requires 1,25(OH)2D for its activity in that deletion of CYP27B1 does not produce alopecia. VDR also functions as a tumor suppressor, a function seen in other epithelial tissues such as the colon, breast and prostate. As for hair follicle cycling, the role of 1,25(OH)2D in this tumor suppressor function is not clear. The specificity of VDR action within the skin for the different functions it regulates is attributed at least in part to the different coregulators that modulate its genomic actions. In the proliferating keratinocytes of the epidermis and hair follicle, the DRIP complex (vitamin D receptor interacting protein complex) also known as Mediator is the dominant coregulator. In the more differentiated keratinocytes of the epidermis, the SRC (steroid receptor coactivator) complexes (SRC 2 and 3) dominate VDR function. In the hair follicle, the coregulator hairless (Hr) plays an important role. For 1,25(OH)2D regulated VDR actions, Hr acts as a cosuppressor. But its interaction with VDR in regulating hair follicle cycling, a 1,25(OH)2D independent action of VDR, is less clear. In this review we will examine the production of vitamin D and its subsequent metabolism to 1,25(OH)2D, then review the different actions of 1,25(OH)2D and its receptor in the skin, emphasizing the many roles vitamin D signaling plays in regulating epidermal proliferation and differentiation, hair follicle cycling, and tumorigenesis.
Vitamin D3 is produced from 7-dehydrocholesterol (7-DHC) (figure 1). Although irradiation of 7-DHC was known to produce pre-D3 (which subsequently undergoes a temperature rearrangement of the triene structure to form D3), lumisterol, and tachysterol, the physiologic regulation of this pathway was not well understood until the studies of Holick and colleagues (Holick, et al. 1979, Holick, et al. 1980, Holick, et al. 1981). They demonstrated that the formation of pre-D3 under the influence of solar or UVB irradiation (maximal effective wavelength between 280–320) is relatively rapid and reaches a maximum within hours. UV irradiation further converts pre-D3 to lumisterol and tachysterol. Both the degree of epidermal pigmentation and the intensity of exposure correlate with the time required to achieve this maximal concentration of pre-D3, but do not alter the maximal level achieved. Although pre-D3 levels reach a maximum level, the biologically inactive lumisterol accumulates with continued UV exposure. Tachysterol is also formed, but like pre-D3, does not accumulate with extended UV exposure. The formation of lumisterol is reversible and can be converted back to pre-D3 as pre-D3 levels fall. At 0°C, no D3 is formed; however, at 37°C pre-D3 is rapidly converted to D3. Prolonged exposure to sunlight would not produce toxic amounts of D3 because of the photoconversion of pre-D3 to lumisterol and tachysterol as well as the photoconversion of D3 itself to suprasterols I and II and 5,6 transvitamin D3 (Webb, et al. 1989). Thus, stimulation of epidermal D3 production is a safe way to provide D3 to the body.
Melanin in the epidermis, by absorbing UV irradiation, can reduce the effectiveness of sunlight in producing D3 in the skin. This may be one important reason for the lower 25OHD levels in dark skinned individuals living in temperate latitudes (Bell, et al. 1985). Sunlight exposure increases melanin production, and so provides another mechanism by which excess D3 production can be prevented. The intensity of UV irradiation is also important for effective D3 production. The seasonal variation of 25OHD levels can be quite pronounced with higher levels during the summer months and lower levels during the winter in areas furthest from the equator. In Edmonton, Canada (52°N), for example, very little D3 is produced in exposed skin from mid-October to mid-April; Boston (42 °N) has a somewhat longer period for effective D3 production; whereas in Los Angeles (34 °N) and San Juan (18 °N) the skin is able to produce D3 all year long (Webb, et al. 1988). Peak D3 production occurs around noon, with a larger portion of the day being capable of producing D3 in the skin during the summer than other times of the year. Clothing (Matsuoka, et al. 1992) and sunscreens (Matsuoka, et al. 1987) effectively prevent D3 production in the covered areas. This is one likely explanation for the observation that the Bedouins in the Middle East, who totally cover their bodies with clothing, are more prone to develop rickets and osteomalacia than the Israeli Jews with comparable sunlight exposure.
Keratinocytes are not only capable of producing D3 but of metabolizing D3 via the vitamin D-25 hydroxylase (CYP27A) and 25OHD-1α-hydroxylase (CYP27B1) to its active metabolite 1,25(OH)2D3 (Bikle, et al. 1986a, Bikle, et al. 1986b, Lehmann, et al. 2001, Matsumoto, et al. 1991, Fu et al. 1997). Keratinocytes are the only cells in the body containing the entire pathway (Figure 1). Most of the circulating 1,25(OH)2D3 is produced by the kidney. However, the expression of CYP27B1 is higher in the keratinocyte than in any other cell including the cells of the proximal renal tubule. Presumably the 1,25(OH)2D3 produced in the skin is used for autocrine or paracrine purposes.
Parathyroid hormone (PTH) exerts a modest stimulation of 1,25(OH)2D production by keratinocytes. However, this involves a different mechanism than that resulting in stimulation of 1,25(OH)2D3 production by PTH in the kidney. The keratinocyte does not have a classic PTH receptor coupled to adenylate cyclase. Furthermore, these effects of PTH are not reproduced by cAMP or its membrane-permeable derivatives, suggesting that the actions of PTH may be operating through a mechanism independent of cAMP (Bikle, et al. 1986a). The effects of PTH are maximal after a 4-hr incubation of cells with these agents before adding substrate (25OHD3); that is, the effects are not immediate. In renal cells PTH exerts a more acute stimulation of 1,25(OH)2D3 production (Rasmussen, et al. 1972), and cAMP appears to play a second messenger role (Rost, et al. 1981). The mechanism by which PTH stimulates 1,25(OH)2D3 production in the keratinocyte remains unclear.
1,25(OH)2D3 negatively regulates its own levels within the keratinocyte. This negative feedback loop is similar to that observed in the kidney, but it differs from that seen in the macrophage, which lacks this feedback loop. In the keratinocyte, this feedback inhibition is not mediated by an effect on 1,25(OH)2D3 production but is due solely to induction of 25OHD 24-hydroxylase (CYP24A) that converts 25OHD3 and 1,25(OH)2D3 to 24,25(OH)2D3 and 1,24,25(OH)3D3, respectively (Xie et al. 2002b), and then on to further catabolic products. The exquisite responsiveness of CYP24A to 1,25(OH)2D3 in keratinocytes may explain why so little 1,25(OH)2D3 appears to enter the circulation from the skin when renal production of 1,25(OH)2D3 is intact.
The expression and activity of CYP27B1 changes with differentiation (Pillai, et al. 1988a). Enzymatic activity is greatest in the undifferentiated cells. Growing the cells in 0.1 mM calcium, which retards differentiation (Pillai, et al. 1988b), permits the cells to maintain higher activity than when they are grown in 1.2 mM calcium (Bikle, et al. 1989), although acute changes in calcium have little effect on 1,25(OH)2D3 production (Bikle, et al. 1986a). These observations in vitro are consistent with the finding that CYP27B1 expression is highest in the stratum basale of the epidermis in vivo (Zehnder, et al. 2001).
Both tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) stimulate 1,25(OH)2D3 production by keratinocytes (Bikle, et al. 1989, 1991b, Morhenn and Wood 1988, Pillai, et al. 1989) (figure 1). These cytokines are stimulated by ultraviolet light (Trefzer, et al. 1993) and barrier disruption (Wood, et al. 1994) and contribute to the increased CYP27B1 expression following such environmental stimuli (Loser and Beissert 2009, Schauber, et al. 2007).
The epidermis is composed of four layers of keratinocytes at different stages of differentiation (figure 2). The basal layer (stratum basale) rests on the basal lamina separating the dermis and epidermis. These cells proliferate, providing the cells for the upper differentiating layers. They are large, columnar cells forming intercellular attachments with adjacent cells through desmosomes. An asymmetric distribution of integrins on their lateral and basal surface may also regulate their attachment to the basal lamina and adjacent cells (Guo, et al. 1991, Marchisio, et al. 1991, Peltonen, et al. 1989). They contain an extensive keratin network comprising principally keratins K5 (58 kDa) and K14 (50 kDa) (Moll, et al. 1982). As these cells migrate outward from this basal layer, they acquire the characteristics of a fully differentiated corneocyte, which is eventually sloughed off.
The layer above the basal cells is the spinous layer (stratum spinosum). These cells initiate the production of the keratins K1 and K10, which are the keratins characteristic of the more differentiated layers of the epidermis (Eichner, et al. 1986). Cornified envelope precursors such as involucrin (Warhol, et al. 1985) also appear in the spinous layer as does the enzyme transglutaminase, responsible for the ε–(γ-glutamyl) lysine cross-linking of these substrates into the insoluble cornified envelope (Thacher and Rice 1985). The keratinocyte contains both the soluble (tissue, TG-C, or type II) and membrane-bound (particulate, TG-K, or type I) forms of transglutaminase. It is the membrane-bound form that correlates with differentiation and is thought to be responsible for the formation of the cornified envelope (Thacher and Rice 1985). The granular layer (stratum granulosum), lying above the spinous layer, is characterized by electron-dense keratohyalin granules. These are of two types (Steven, et al. 1990). The larger of the two granules contains profilaggrin, the precursor of filaggrin, a protein thought to facilitate the aggregation of keratin filaments (Dale, et al. 1985). The smaller granule contains loricrin, a major component of the cornified envelope (Mehrel, et al. 1990). The granular layer also contains lamellar bodies, lipid-filled structures that fuse with the plasma membrane, divesting their contents into the extracellular space where the lipid contributes to the permeability barrier of skin (Elias, et al. 1988). As the cells pass from the granular layer to the cornified layer (stratum corneum), they undergo destruction of their organelles with further maturation of the cornified envelope into an insoluble, highly resistant structure surrounding the keratin-filaggrin complex and linked to the extracellular lipid milieu (Hohl 1990). The outer layer of the epidermis provides not only a barrier to water loss (permeability barrier) but a barrier to invasion by infectious organisms via its expression of the innate immune system. In particular disruption of the barrier triggers the induction of defensins such as cathelicidin that provide the initial defense in killing such organisms (Hennings and Holbrook 1983). Calcium forms a steep gradient within the epidermis, with highest concentration in the stratum granulosum (Menon, et al. 1985). Disruption of the permeability barrier by removing the stratum corneum or extracting its lipids leads to a loss of this calcium gradient (Mauro, et al. 1998) resulting in increased lamellar body secretion but reduced expression of the genes for loricrin, profilaggrin, and involucrin (Elias, et al. 2002).
Both calcium and 1,25(OH)2D play important and interacting roles in regulating the differentiation process (figure 3). 1,25(OH)2D increases the expression of involucrin, transglutaminase, loricrin, and filaggrin and increases cornified envelope formation (Bikle, et al. 1991a, Bikle and Pillai 1993, Hawker, et al. 2007, Hosomi, et al. 1983, McLane, et al. 1990, Pillai and Bikle 1991, Smith, et al. 1986) while inhibiting proliferation. These actions are due at least in part to the ability of 1,25(OH)2D to increase intracellular calcium levels achieved by induction of the calcium receptor (CaR) (Ratnam, et al. 1999) and the phospholipases C (PLC) (Pillai et al. 1995) that are critical for the ability of calcium to stimulate keratinocyte differentiation (Tu, et al. 2001, Xie and Bikle 1999, 2001). The antiproliferative effects are accompanied by a reduction in the mRNA levels for c-myc (Matsumoto, et al. 1990) and cyclin D1 and an increase in the cell cycle inhibitors p21cip and p27kip. In addition, 1,25(OH)2D and its receptor regulate the processing of the long chain glycosylceramides that are critical for permeability barrier formation (Oda, et al. 2009) and induce the receptors, toll like receptor 2 (TLR2) and its coreceptor CD14, that initiate the innate immune response in skin (Schauber, et al. 2007). Activation of these receptors leads to the induction of CYP27B1, which in turn induces cathelicidin resulting in the killing of invasive organisms(Schauber, et al. 2006, Schauber, et al. 2007). Mice lacking the VDR or the enzyme (CYP27B1) producing its ligand 1,25(OH)2D show defective epidermal differentiation manifesting as reduced levels of involucrin and loricrin and loss of keratohyalin granules(Bikle, et al. 2006, Xie, et al. 2002a), decreased lipid content of the lamellar bodies leading to a defective permeability barrier (Oda, et al. 2009), and a defective response of the innate immune system to wounding (Schauber, et al. 2007).
The process of epidermal differentiation is sequential. 1,25(OH)2D and VDR regulate all steps from the control of proliferation in the SB, to the regulation of K1, K10, involucrin, and transglutaminase production in the SS, to the regulation of loricrin and filaggrin production in the SG, to the synthesis of lipids required for the permeability barrier in the SC, and to the development of the innate immune system(Bikle and Pillai 1993, Hawker, et al. 2007, Schauber, et al. 2007). How does this occur? Although CYP27B1 and VDR are found in highest concentration in the SB, they are both distributed throughout the epidermis(Milde, et al. 1991, Stumpf, et al. 1984, Zehnder, et al. 2001), so this does not provide an obvious explanation for the sequential induction of genes involved in the differentiation process. However, VDR requires the binding of coactivators to stimulate transcription. The two major coactivator complexes in the epidermis are DRIP (Mediator) and SRC (McKenna, et al. 1999, Oda, et al. 2003). We (Oda, et al. 2003) observed that in proliferating keratinocytes DRIP was the major coactivator complex binding to VDR, whereas the SRC complex dominated VDR binding in differentiated keratinocytes(Oda, et al. 2003, Oda, et al. 2007). These results are consistent with our finding that in the epidermis DRIP205 (Med1) is expressed in highest concentration in the SB and SS, whereas SRC3 is expressed in highest concentration in the SG(Oda, et al. 2007, Schauber, et al. 2008). The DRIP complex is anchored to VDR via DRIP205 (Rachez, et al. 1999, Rachez, et al. 2000). The SRC complex is anchored to VDR with one of three homologous proteins, SRC1, 2, and 3(Leo and Chen 2000), but only SRC2 and 3 are found in keratinocytes(Oda, et al. 2003). These coactivator complexes interact with the C terminal (AF2) domain of VDR following ligand binding via LxxLL motifs (NR boxes). They do not bind to VDR at the same time, competing as they do for the same region of the VDR(Rachez, et al. 2000). The SRC coactivators have 3 NR boxes, whereas DRIP205 has 2. Our recent studies (Teichert, et al. 2009) indicate that VDR binds most strongly to the 2nd and 3rd NR box of SRC1 and 2, the 3rd NR box of SRC3, and the 2nd NR box of DRIP205. Different nuclear hormone receptors differ in the affinity for the different NR boxes of the different coactivators suggesting some degree of specificity (Acevedo, et al. 2004). SRC recruits CREB-binding protein (CBP) or P300 and other histone acetyl transferases (HATs) and methyltranferases (MeTs) to the VDR resulting in a multisubunit complex(Christakos, et al. 2003). The HAT and MeT activity of the SRC complex is thought to destabilize the interaction between DNA and the histone core, enabling transcription to occur. The DRIP complex does not have HAT or MeT activity but functions, at least in part, through recruitment of RNA polymerase II to the transcription start site(Rachez, et al. 2000, Rachez and Freedman 2000). Some studies suggest that the order of coactivator binding to its nuclear hormone receptor is sequential with different kinetics, generally with SRC binding preceding and being required for DRIP binding(Acevedo, et al. 2004). Other studies indicate that the specificity of coactivator binding to VDR depends on the gene being regulated(Carvallo, et al. 2008, Issa, et al. 2002), the ligand being evaluated(Bouillon, et al. 2005), and the cellular context(Maeda, et al. 2002, Peleg, et al. 2003). Our data, summarized below, indicate that the sequential action of 1,25(OH)2D and its receptor on keratinocyte differentiation is due to the differential expression and distribution of these coactivators according to the differentiation status of the cell coupled with the selectivity of genes regulated by VDR for one or the other of the coactivator complexes.
DRIP205 is expressed in proliferating keratinocytes, and its expression decreases with differentiation, as the expression of SRC3 is increased(Oda, et al. 2003). Knockdown of DRIP205 using siRNA results in increased keratinocyte proliferation, similar to that seen by knocking down VDR itself, but knockdown of SRC3 does not show such an effect (Oda, et al. 2007). Inhibition of DRIP205 binding to VDR in proliferating keratinocytes blocks VDR transcriptional activity with a VDRE reporter construct, but such inhibition is not seen in differentiated keratinocytes(Oda, et al. 2003). However, this inhibition of transcriptional activity turns out to be gene specific. For example, knockdown of DRIP205 using siRNA methodology has a greater impact on keratins 1, 10, and involucrin expression than does knockdown of SRC3, although depletion of both coactivators profoundly reduces loricrin and filaggrin expression(Hawker, et al. 2007). On the other hand SRC3 knockdown, not DRIP205 knockdown, reduces glucosylceramide production and lamellar body formation similar to that of VDR knockdown(Oda, et al. 2009), and prevents 1,25(OH)2D induced cathelicidin expression(Schauber, et al. 2008). Thus, our hypothesis is that SRC facilitates the ability of VDR to regulate the more differentiated functions of the keratinocyte, whereas DRIP facilitates the ability of VDR to regulate proliferation and early keratinocyte differentiation, although some overlap in coactivator function is observed.
The hair follicle cycle is divided into three main stages: anagen, catagen, and telogen (figure 4). Anagen is the stage of hair follicle growth; catagen is the stage of regression; telogen is the resting stage. Only the proximal or dermal portion of the hair follicle cycles; the distal or epidermal portion does not. The duration of these stages in a given species varies from location to location on the body and between genders. Furthermore, there are two types of cycles: developmental and postnatal. The developmental cycle is initiated during embryogenesis. The follicle develops from specific regions of the epidermis called placodes. The follicle is induced to grow by its interaction with a collection of specialized mesenchymal cells in the dermis called the dermal papilla. Wnt signaling (β-catenin) appears to be necessary to maintain the ability of the dermal papilla to stimulate hair follicle growth (Kishimoto, et al. 2000, Shimizu and Morgan 2004). Following the developmental cycle, which leads to the initial coat of hair, the follicle undergoes repetitive cycling until senescence. The length of the hair is dependent on the duration of anagen. During this stage the follicle grows through the dermis into the subcutaneous tissue. As the follicle develops different cell layers appear. The outer root sheath (ORS) is a direct extension of the stratum basale, and separates the hair follicle from the surrounding connective tissue sheath (CTS). From outside in are found the companion layer, the three layers of the inner root sheath (IRS)--Henle's layer, Huxley's layer, cuticle of the IRS—and the hair shaft itself including the cuticle of the shaft, shaft cortex, and shaft medulla. Stem cells in the bulge are capable of generating all cells in the hair follicle and epidermis (Morris, et al. 2004). The keratins produced by the cells of the IRS and hair shaft differ from those expressed by epidermal keratinocytes (Langbein, et al. 2003). Of particular interest is these hair keratins have β-catenin/lef1 binding sites in their promoters that regulate their expression (Zhou, et al. 1995). Following anagen, the follicle enters catagen during which massive apoptosis occurs primarily in the cells of the proximal follicle (the dermal portion), and the hair shaft produced during anagen is generally shed. At the end of catagen the follicle enters telogen, the resting phase. Duration of telogen is highly variable. A new cycle then begins with anagen. The juxtaposition of the dermal papilla to the bulge is critical for this process to begin, and it is associated with increased proliferation of stem cells in the bulge with migration of cells from the bulge into the hair bulb to restart the growth of the hair follicle. The regulatory elements that control the transition from one stage to the next are not well understood.
Alopecia is a well-known part of the phenotype of many patients with mutations in their VDR (Hochberg, et al. 1985, Marx, et al. 1986), a syndrome known as hereditary vitamin D resistant rickets (HVDRR). Vitamin D deficiency per se or CYP27B1 mutations are not associated with alopecia, indicating that the regulation of hair follicle cycling requires VDR but not its principal ligand 1,25(OH)2D. VDR null mice develop their first coat of hair normally, but reinitiation of anagen following the first cycle or after depilation is impaired (Sakai and Demay 2000). Reconstitution of the VDR to the VDR null mouse skin using a keratinocyte specific promoter reverses the defect in hair growth without reversing the metabolic defects of skeletal growth retardation, hypocalcemia, and rickets otherwise associated with the VDR null condition (Chen, et al. 2001, Kong, et al. 2002). On the other hand, correction of the metabolic abnormalities with a high calcium diet prevents the rickets and hyperparathyroidism but does not prevent the alopecia (Li, et al. 1998). Furthermore, it is the lack of VDR in the keratinocyte as opposed to the dermal papilla that is critical. Dermal papilla cells obtained from either VDR null or wildtype mice can initially induce hair growth in a hair reconstitution assay when mixed with epidermal keratinocytes obtained from wildtype or VDR null mice, but if the hair grown with keratinocytes from VDR null mice is then depilated, anagen will not be reinitiated regardless of the source of dermal papilla cells (Sakai and Demay 2000).
Hr mutations in both mice (Panteleyev, et al. 1999) and humans (Ahmad, et al. 1998, Miller, et al. 2001) result in phenocopies of the VDR null mouse and some human VDR mutations, respectively, with regard to the morphologic changes observed in hair follicle cycling. The dissociation of the dermal papilla from the hair bulb by the end of catagen is thought to account for the failure to initiate the subsequent anagen in both Hr mutant and VDR null mice (Bikle, et al. 2006, Panteleyev, et al. 1999). The distal (epidermal) portion of the hair follicle including the sebaceous gland as well as the interfollicular epidermis is less impacted (Bikle, et al. 2006, Panteleyev, et al. 1999, Xie, et al. 2002). We have found VDR and Hr in the nuclei of keratinocytes in the stratum basale and ORS (Bikle, et al. 2006). However, we found little or no VDR in the IRS and hair bulb or cells of the dermal papilla and CTS, whereas we did find Hr in those locations (Bikle, et al. 2006). As will be discussed subsequently, deletion of the transcriptional domain of β-catenin results in a similar phenotype (DasGupta, et al. 2002, Huelsken, et al. 2001).
Hr has characteristics of a coregulator in that it resides in the nucleus; its structure contains a nuclear localization signal, a putative zinc finger, and three LXXLL motifs (Djabali, et al. 2001) like that found in coactivators that interact with nuclear hormone receptors such as VDR as well as ΦXXΦΦ motifs (Φ=hydrophobic amino acid) similar to regions in corepressors like SMRT and NCoR responsible for the binding of these corepressors to nuclear hormone receptors. In the brain, Hr has been suggested as a corepressor of the thyroid receptor (THRb) in that Hr can bind to THRb and inhibit its transcriptional activity (Thompson and Bottcher 1997). However, Hr does not appear to regulate thyroid hormone action in the keratinocyte (Engelhard and Christiano 2004). Rather, VDR appears to be the target (Xie, et al. 2006). Hsieh et al. (Hsieh, et al. 2003) demonstrated that Hr could bind to VDR in COS cells. They noted that Hr bound to VDR in the same region predicted for corepressor binding, and different from the C-terminal region to which coactivators bind. The region of Hr responsible for VDR binding contains one LXXLL motif, but also a ΦXXΦΦ motif. However, only mutations in the ΦXXΦΦ motif altered binding to VDR (Hsieh, et al. 2003). Furthermore, when we tested both motifs separately for their binding to VDR, the ΦXXΦΦ motif had the higher affinity regardless of the presence or absence of 1,25(OH)2D (Teichert, et al. 2009). We have shown that the endogenous VDR binds to endogenous Hr in keratinocytes (Xie, et al. 2006). Binding of Hr to VDR inhibited 1,25(OH)2D stimulation of a CYP24A1 (24-hydroxylase) promoter construct containing the vitamin D response element (VDRE) of this vitamin D target gene. Overexpression of Hr blocks the ability of 1,25(OH)2D to induce differentiation markers in keratinocytes, whereas inhibition of Hr expression enhances the stimulation by 1,25(OH)2D of these markers (Xie, et al. 2006). The Hr null animal demonstrates upregulation of differentiation markers in the epidermis (Zarach, et al. 2004) consistent with a corepressor role for Hr in vitamin D regulated epidermal differentiation. Antibodies to Hr enhance the binding of VDR to VDREs in vitamin D target genes in gel retardation assays (Xie, et al. 2006) suggesting that Hr binding to VDR blocks its binding to VDREs. 1,25(OH)2D displaces Hr from VDREs as it recruits the coactivators DRIP205 and SRC3 to these same VDREs (Xie, et al. 2006). Thus at least for 1,25(OH)2D stimulated actions of VDR, Hr is a cosuppressor.
Wnt signaling via activation of β-catenin has a complex role in VDR actions (figure 5). Wnt ligands bind to their seven-transmembrane Frizzled receptors and an LRP5 or LRP6 co-receptor leading to phosphorylation of disheveled (Dvl) resulting in disruption of the axin/APC complex and inhibition of the kinase activity of glycogen synthase kinase-3β (GSK-3β)), which otherwise phosphorylates the serine(s) within exon 3 of β-catenin facilitating its degradation by the E3 ubiquitin ligase. Thus wnt signaling increases the availability of β-catenin in the cytoplasm, which can then bind to transcription factors of the T-cell factor (TCF) and lymphoid enhancer factor (LEF) families to promote expression of genes such as cyclin D1 and c-myc (He, et al. 1998) important for proliferation. β-catenin also forms part of the adherens junction complex with E-cadherin where it may play an important role in keratinocyte differentiation (Xie and Bikle 2007). Tyrosine phosphorylation of β-catenin, as occurs after calcium administration to keratinocytes, promotes the binding of β-catenin and other catenins to the adherens junction complex (Bienz 2005, Xie and Bikle 2007) making it less available for transcriptional activity. Cells differ markedly in the components of the β-catenin signaling pathway utilized. This is well illustrated in the keratinocytes of the hair follicle and interfollicular epidermis (DasGupta, et al. 2002, Huelsken, et al. 2001). LEF1 is the dominant transcription partner for β-catenin in the dermal portion of the hair follicle, which has little E-cadherin. The epidermal keratinocyte, on the other hand, has little LEF1 but a lot of E-cadherin especially in the differentiated layers(Stenn and Paus 2001). Over expression and/or activating mutations in the β-catenin pathway lead to skin tumors, in this case pilomatricomas or trichofolliculomas (hair follicle tumors) (Chan, et al. 1999, Gat, et al. 1998, Xia, et al. 2006) indicative of the hyperproliferative response to β-catenin in these cells. Activating mutations of specific serines within exon 3, or deletion of exon 3, block phosphorylation of β–catenin by GSK-3β, phosphorylation which otherwise leads to its proteosomal degradation. As a result β-catenin levels increase in the nucleus where its transcriptional activity is exerted in association with members of the LEF/TCF family of transcription factors.
In colon cancer cells VDR has been shown to bind to β-catenin, and reduce its transcriptional activity in a ligand dependent fashion(Palmer, et al. 2001). Furthermore, in these cells 1,25(OH)2D has been shown to increase E-cadherin expression, such that β-catenin is redistributed from the nucleus to the plasma membrane where it forms a complex with E-cadherin and other catenins at adherens junctions (Shah, et al. 2003). However, the suppression of β-catenin signaling by 1,25(OH)2D does not necessarily require E-cadherin (Shah, et al. 2006). Rather β-catenin binds to VDR in its AF-2 domain, binding that enhances the ability of 1,25(OH)2D to activate the transcriptional activity of the VDR (Shah, et al. 2006) but blocks the transcriptional activity of β-catenin. Mutations in the AF-2 domain of VDR that block coactivator binding do not necessarily block β-catenin binding (Shah, et al. 2006). Whether β-catenin binding alters DRIP205 or SRC3 binding to this same region has not been determined. Palmer et al. (Palmer, et al. 2008) evaluated the interaction between VDR and β-catenin in transcriptional regulation in keratinocytes, and identified putative response elements for VDR and β-catenin/LEF in a number of genes. These interactions were either positive or negative, depending on the gene being evaluated. The hypothesis put forward is that genes in which the interaction is positive (ie. stimulated transcription) benefit from β-catenin acting as a coactivator for VDR on VDREs, whereas in situations where the interaction is negative (ie. suppression of transcription) VDR prevents β-catenin from binding to TCF/LEF required for transcription of those genes. We (Y Oda and D Bikle, unpublished) have found in keratinocytes that knockdown of VDR reduces E-cadherin expression and formation of the β-catenin/E-cadherin membrane complex resulting in increased β-catenin transcriptional activity, whereas 1,25(OH)2D administration has the opposite effect. This was associated with increased (with VDR and DRIP205 knockdown) or decreased (with 1,25(OH)2D administration) keratinocyte proliferation and cyclin D1 expression, respectively. Other studies suggest that VDR potentiates, not inhibits, β-catenin transcriptional activity. Cianferotti et al. (Cianferotti, et al. 2007) found a reduction in proliferation of keratinocytes in the dermal portion of the hair follicle (below the bulge) in VDR null mice, and no stimulation of proliferation when β-catenin was overexpressed in these cells in contrast to the stimulation of proliferation in control animals. Thus VDR/β-catenin interactions can be positive or negative, depending on the gene/cell/function being evaluated.
The skin is unique in being not only the source of vitamin D for the body but in being capable of producing and responding to the active metabolite of vitamin D, 1,25(OH)2D. 1,25(OH)2D and its receptor have many roles in the skin. Some of these roles-- induction of genes required for differentiation, suppression of genes involved with proliferation-- appear to require both 1,25(OH)2D and VDR and synergize with the actions of calcium. Other roles such as the regulation of hair follicle cycling require VDR but do not require 1,25(OH)2D. Different coactivator complexes including DRIP and SRC modulate the actions of VDR, and the choice of coactivator complex in many cases is gene specific. Regulation of proliferation is dependent on DRIP, whereas more differentiated functions including innate immunity and permeability barrier formation are SRC dependent. Hr is a coregulator with profound actions in hair follicle cycling. Although Hr blocks 1,25(OH)2D regulated VDR functions, its role in VDR regulated hair follicle cycling is less clear. β-catenin interactions with VDR function can enhance VDR induction of some genes, whereas VDR can suppress β-catenin induction of other genes. Many genes in the skin contain both putative VDREs and LEF/TCF sites. At this point we are a long ways away from understanding how 1,25(OH)2D and VDR regulate all the various functions in the skin that they impact. But what we have learned indicates that the skin is a fertile area for understanding the mechanisms by which vitamin D signaling regulates so many different physiologic processes.
The author acknowledges the administrative support of Teresa Tong, the scientific contributions of Zhongjian Xie, Yuko Oda, Arnaud Teichert, Sreekumar Pillai, Chialing Tu, Dean Ng, and Anita Ratnam, and the financial support of grants from the Veterans Administration, American Institute for Cancer Research (98A079), and the National Institutes for Health ((RO1 AR050023,PO1 AR39448).
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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It's a race to ring the bell! Can your eagle eye spot an item on your card that's also on your game board? Look hard, there's only one. Could it be the green race car, or the red ball? Once you find it, ring fast, and you win that round! Whoever spots the most objects wins the game. Includes 30 double-sided cards, 4 double-sided game boards, and a bell.
2 to 4 players
Ages 5+

subset: commoncrawl


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Jump long line cardigan with black sleeves and trim, 56% lambswool 31% acrylic 13%wool. A great style for winter to wear over anything.


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Business & Finance
Online shopping cart is the most feasible solution fitting in the competitive ecommerce environment. It has become a robust e-business solution that more and more business organizations operating online are taking too. Online shopping cart is a cost-effective Internet marketing application.
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What Is A Zero Entry Pool And How Much Does It Cost - The size of the pool is one of the foremost reason that will change the cost . If you will accommodate an extra space in the pool then the costing of the pool will automatically increase and will leverage and extra penny in your pocket.
What Is A Zero Entry Pool And How Much Does It Cost
The best advantage of having a #hiddenpool is that you can very easily get the pool in your homes into the similar area of the patio and use as and when required. The cost of hidden pools solely depends upon the size, design, customizability, packages offered by the contractor etc.


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hitRECord with Joseph Gordon-Levitt Live Tuesday September 20th 6pm at Amoeba Hollywood!
Joe presents and performs work from the new anthology, RECollectionVol. 1, a collection of hitRECord's work, featuring the contributions of 471 collaborators in film, art, music and writing - presented in a meticulously-designed cloth-bound piece of art.
A limited-edition hitRECord "LIVE AT AMOEBA" poster will be created for this event and given with purchase of RECollectionVol. 1 on the day of the event. While they last!
AND - tickets will be available on-site for the hitRECord Fall Formal - October 10th at The Orpheum (with NO service charge!).


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WOOOOOOOOO HOOOOOOOOOOOO!!!!!!!! Yessssssssss!!!!! My dad is a Hall of Famer!!!!!!!!!
Way too many NASCAR related things have made it on TMZ lately. Remember when we got all of our news from The Winston Cup Scene?
My mom just called me crying and now I'm crying and we're all crying. Amazing day for the family. Thanks for the messages everyone!
Qualified 9th. Woo hoo!!!! Way to go, Dad!!! You are simply awesome!


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ago92 days ago
2013 Ford Transit T260 125ps Swb with Optional Air Conditioning. Only 4900 Miles, backed up with Extensive Service History. Specification includes; Air Conditioning, Quickclear Heated Windscreen, Electric Windows, Factory Fitted Bulkhead, Ply Lining, CD Player with Aux Audio Input,, Twin Passenger Seat, and Side Loading Door. Flexible Finance Available. Please call Louis on 01730 82908001730 8290...(click to reveal full phone number) for more details
ABS, Air Bag, Immobiliser, Alarm, Central Locking, Remote Central Locking, Power Steering, Air Conditioning, Quick-Clear Screen, Stereo, Electric Front Windows, Trip Computer, CD Player, Height Adjustable Seat, Front Centre Armrest, Anti-Theft System, Head Restraints, Cloth Upholstery, Side Load Door, Ply-Lined, Dual Passenger Seat, Bulkhead, Barn Doors, Low Floor, Steering Wheel Audio Controls, Drivers Arm Rest, 6 - Speed, Aux Audio Input, Factory Fitted Bulkhead, EURO FIVE, Full Service History
ago2 days ago


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Is this attraction suitable for all ages?
Is this attraction pet friendly?
Would this be a good sunny day activity?
Would this be a good hot day activity?
Would this be a good cold day activity?
Is this an outdoor attraction or activity?
Do you recommend this attraction for luxury travellers?
Does this attraction provide visitors with a taste of the local culture?
Is this attraction exciting, unusual, or risky to visit?
Does this attraction require above average amounts of physical activity (long walks, climbs, stairs or hikes)?
Thanks for helping!
At the opposite end of Beverly to the minster and equally interesting.met a lovely lady quide who help us with the history ..
Much bigger inside than it looks from the outside. The building is a delight to walk round and the guide on duty was very helpful.
This is a gorgeous church and is architecturally very interesting. I was drawn to it and as it was open decided to pay a visit and I am glad I did. There is wonderful art work on the ceiling painted in 1446 that depicts the kings from before that time and is still vibrant and impressive. There is also the...
Our visit was sadly for a funeral.
What a beautiful place to lift the spirits. The vicar and her staff were friendly and contributed to a beautiful service.
This is a well kept historic church that may misidentify as The Minster due to its size.
The church is located only a few yards aware from the Town square known as...
Good old St Mary's Hey? it's a cool bit of History to add to the good old town of beverleys heritage.
St Mary's is truly wonderful. Visit when someone is there to take you round and explain what everything is and what it represents. Look out for the carved rabbit that is said to have inspired Lewis Carroll's White Rabbit. This church was built for the people of Beverley wher the Minster was for the Friary.
I can't be the only person who ( 40 years ago) turned up, spent time in the church and thought it wasn't very big for a minster. Then I found the other one! St. Mary's is a beautiful church with much to see and very friendly volunteers on duty.
An impressive church both inside and out I visited in the afternoon unfortunately the church was about to close so I was not able to take in all the beautiful architecture within. Would recommend a visit . The church is free to enter.
Went to lunchtime concert yesterday. Musicians were simply excellent - world class players!
Going in middle of the day gave us a chance to look round St Mary's Church. It is much larger than we had thought and with so many very beautiful features. Peaceful, spiritual and gorgeous! Highly recommended.
Don't just go to the minster - have a look here. Well worth it.
A lovely building which hosts concerts.
Own or manage this property? Claim your listing for free to respond to reviews, update your profile and much more.


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Rino Tod Financing
Rino Tod Llc, Limited Liability Company just submitted form D announcing $3.60 million equity financing. This is a new filing. Rino Tod was able to fundraise $3.60 million. That is 100.00% of the financing round. The total private offering amount was $3.60 million. The financing form was filed on 2016-10-19. The reason for the financing was: Affiliates of the Managers of the Company will be reimbursed $1,030,524 from the Offering proceeds for pre-closing construction and development expenses incurred by them on behalf of RINO TOD LLC..
Rino Tod is based in Colorado. The company's business is Commercial. The SEC form was submitted by Jason Kaplan Manager. The company was incorporated in 2014. The filler's address is: 3455 Ringsby Court, Suite 100, Denver, Co, Colorado, 80216. Kyle Zeppelin is the related person in the form and it has address: 3455 Ringsby Court, Suite 100, Denver, Co, Colorado, 80216. Link to Rino Tod Filing: 000168722416000002.
Analysis of Rino Tod Offering
On average, startups in the Commercial sector, sell 65.22% of the total offering size. Rino Tod sold 100.00% of the offering. Could this mean that the trust in Rino Tod is high? The average investment floor size for companies in the Commercial industry is $1.60 million. The total amount raised is 125.00% bigger than the average for companies in the Commercial sector. The minimum investment for this fundraising is set at $0. If you know more about the reasons for the fundraising, please comment below.
What is Form D? What It Is Used For
Form D disclosures could be used to track and understand better your competitors. The information in Form D is usually highly confidential for ventures and startups and they don't like revealing it. This is because it reveals amount raised or planned to be raised as well as reasons for the financing. This could help competitors. Entrepreneurs usually want to keep their financing a 'secret' so they can stay in stealth mode for longer.
Why Fundraising Reporting Is Good For Rino Tod Also
The Form D signed by Jason Kaplan might help Rino Tod Llc's sector. First, it helps potential customers feel more safe to deal with a firm that is well financed. The odds are higher that it will stay in the business. Second, this could attract other investors such as venture-capital firms, funds and angels. Third, positive PR effects could even bring leasing firms and venture lenders.
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Luby's Inc. narrowed its loss in the first quarter ended Dec. 16 on increased sales at its cafeteria, and its Fuddruckers and Cheeseburger in Paradise brands, the company reported Thursday. The San Antonio-based multi-concept and contract services provider reported a net loss of $1.6 million, or 6 cents per share, compared with a loss of $4.4 million, or 11 cents per share, in the same period last year. Revenue increased 39 percent, to $120.7 million, from $86.9 million in last ...
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Excerpt from The Martyr President: Our Grief and Our Duty The Gospel for toe pat from the 24th Chapter of Luke was read. These badges of mourning, in the Sanctuary to-day, direct our thoughts to the terrible tragedy which has rilled our city, our whole land, with sorrow. And though this be our Communion season, I feel that the improvement of this sad Providence furnishes the theme of discourse to-day. I am inadequate to the occasion My heart has been well nigh paralyzed by the startling Providence. I feel that I am in deep sympathy with you, and with the loyal heart of this entire land. Even treason will blush with shame at this assassination. I would prefer to be silent today - to commingle my tears with those of the stricken household - with the tears of the great American people. I would prefer to hear others speak - to be still, and suffer God alone to speak- but rebelliou and treason have culminated in the murder of our beloved and noble Chief Magistrate. This is not the time to be silent. I would be untrue to you, untrue to myself as a citizen of this great Republic, as an Ambassador of truth, a servant of Christ, untrue to the promptings of my own deeply moved heart, unworthy the confidence and love you have ever reposed in me, did I fail to speak forth the words of truth and soberness. This is resurrection day- the day upon which the Church, during all her history, commemorates the rising from the grave of Him, who, but the third day before, had been crucified. In this drapery we have combined here to-day the emblems of sorrow and of joy. Nature is putting on her Easter robes - the grass is beginning to spring forth, the buds to swell, the leaves are unfolding, and the trees are covered with their varied blooms. About the Publisher Forgotten Books publishes hundreds of thousands of rare and classic books. Find more at www.forgottenbooks.com This book is a reproduction of an important historical work. Forgotten Books uses state-of-the-art technology to digitally reconstruct the work, preserving the original format whilst repairing imperfections present in the aged copy. In rare cases, an imperfection in the original, such as a blemish or missing page, may be replicated in our edition. We do, however, repair the vast majority of imperfections successfully- any imperfections that remain are intentionally left to preserve the state of such historical works.
About J G ButlerSadly, at this time we can't provide you with information about the actual Writer J G Butler. Nevertheless does not mean we are unsuccessful on the variety. We question that you just assist us in this make a difference. If you have sparetime and want will certainly profoundly value should you give people the information. While receiving such suggestions and data via consumers regarding the The Martyr President Publisher J G Butler, we all initially the girl check. When all of us make certain that just about all correct, merely article it. Most of us understand why aid and also many thanks in advance.
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|J G Butler
|Forgotten Books
|Data Published
|27 September 2015
|Format Book
|PDF, Epub, DOCx, TXT
|Number of Pages
|20 pages
|Age +
|15 years
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text: We went on a friend's recommendation. Worth it. So many choices and many were not your usual fare. We arrived at about 2 pm on a weekday. There were two others dining. Service was attentive if a bit perfunctory. We had the recommended pepper salt squid. It came out with tentacles. Always a good sign. The body was not cut... More


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Written on: 21/03/2010 by markbt14 (7 reviews written)
Before the iPhone I never used anything but a Nokia. I hesitated for a while but it is true that once you have the iPhone it becomes your communication hub. The key points for me are its reliability (I have not had a single crash), accuracy and responsiveness of the touch-screen (even with my broad fingers), easier than I thought to carry in the pocket and its simplicity. Only downside is battery life but charging every night is a small price to pay for having a mobile office in your pocket. No longer do I switch on the laptop at home when I just want to check emails, or for something simple on the internet. Most of my CD collection is on the iPhone too. I would have no hesitation in recommending the iPhone.
As rated by our community of reviewers
" Good phone " Read More
" Good very still " Read More
" Terrible Customer Service " Read More
Written by Chrisgeorged
" New Version is best " Read More
Written by lettiecoker
" Best quality " Read More
Written by alvinacoates


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Sign up for NWRPCA's monthly newsletter, Northwest Pulse, and stay up-to-date on the latest community health center innovations and trends.
Northwest Regional Primary Care Association is a member organization that strengthens community and migrant health centers by leveraging regional power and resources on their behalf.
|Education and Training
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NWRPCA's Education and Training program is an educational home for all health center staff's professional development needs, including clinical, financial, operational, administrative, and governance topics. We offer three annual conferences a year, workshops on specific topics throughout the region, and distance learning opportunities. We also provide on-demand access to our Learning Vault, an online, extensive central hub that houses training and conference materials. NWRPCA's education partners include state primary care associations and the National Association of Community Health Centers.
Current Trainings
Trainings are offered through Conferences, Workshops, Webinars and eLearning. We offer our three cornerstone annual conferences: the Fall and Spring Primary Care conferences, and the Western Forum for Migrant and Community Health. We offer standalone intensive workshops on specific topics including management skills, corporate compliance, recruitment and retention, and UDS training. We also conduct live webinars and provide eLearning offerings such as pre-recorded webinars and online learning courses.
Submit an abstract to speak or email comments and suggestions to Sadie Agurkis, Education and Training Program Manager.
Learning Vault
The Learning Vault is a centralized place for all conference and training content. Inside the Vault you will find: Primary Care Conference and conference materials - including instructor presentations, support materials, and past conference select session audio and/or video recordings; pre-recorded webinars and workshops; and NWRPCA tutorials.
Speakers Bureau
The Speakers Bureau program helps to facilitate trainings to CHC staff in more diverse areas throughout the region. The Speakers Bureau is compiled of three opportunities: the Speaker Referral Service, Support Services for your training, and the Speakers Bureau Roadshow. The Speaker Referral Service helps connect CHCs who are looking for an expert to present on high priority topics. Through our Support Services, NWRPCA can assist you in development, marketing, logistics, and execution of your training. Lastly, with the Speakers Bureau Roadshow, NWRPCA is able to provide additional face-to face trainings throughout the year in more diverse locations within the region, making educational opportunities more accessible.
Sign up for NWRPCA's monthly newsletter, Northwest Pulse, and stay up-to-date on the latest community health center innovations and trends.
11/15/20162017 Western Forum for Migrant and Community Health
11/14/2016Open Enrollment Begins for Health Centers
11/14/2016Two-Dose HPV Vaccination Series Now Recommended for Adolescents, 11-14 Years
10/11/2016Honoring Two Northwest Health Center Leaders
10/10/2016Development Strategies to Build on Capital Projects, Expand Programs and Provide Care
11/16/2016 » 9/20/2017
Fundamentals of Governance Webinar Series
12/14/2016 » 12/15/2016
2016 UDS Training
1/11/2017 » 12/13/2017
Behavioral Health Webinar Series
1/23/2017 » 1/24/2017
Corporate Compliance Training
2/22/2017 » 2/24/2017
2017 Western Forum for Migrant & Community Health


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Harley Benton B-30NT-LH
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Harley Benton B-30NT-LH Acoustic Bass Series. Lefthanded Super Jumbo Cutaway Style, Spruce Top, Sapele Mahogany Body, Mahogany Neck, Rosewood Fingerboard, Dot Inlay, 22 Frets, 815mm Scale, Nut Width 42mm, Double-Action Trussrod, Rosewood Bridge, Cream Bindings, Chrome Diecast Tuners, 045-105 Strings, Integreted Pickup System with 4-Band EQ & Tuner. Color Hi-Gloss Natural.
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I love all the talk of the 'ethical dilemmas' of self-driving cars. As if there weren't ethical dilemmas to human-guided cars.
Phones don't need 'airplane mode,' they need 'driving mode.' wsj.com/articles/a-sim… @cfchabris
With blizzards, we suddenly get very precise counting of road deaths, without asking if those deaths are actually fewer than a 'normal' day.
The cost of car crashes represents a "tax of $784 on every man, woman, and child living in the U.S." theatlantic.com/business/archi…
Sudden ominous email from @nytimes warning writers not to engage in activities that might "undermine...the reputation of The Times."


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Try our thirst quenching Frozen Lemonade made with real lemon, sweetened and served icy cold. Available in both Original and Raspberry flavour
Cette limonade glacée disponible aussi à la framboise est tellement bonne et surtout rafraîchissante. L'hiver je dois avouer ne pas en consommer beaucoup,par contre l'été c'est LE moment de s'en procurer!
Really not a fan of this lemonade. It tastes of chemicals. It's pretty sweet. For the price, definitely not worth it. Save your money for an ice cap or a chocolate chill
If you're struggling in the hot summer sun, this will do the trick. I prefer a more natural flavor, but that can be difficult if you're on the road and there's no stops for miles. It still tastes good (but I put it on the side of tasting like a freezie). If you do give this to a child, snap the lid on tight (the lids always seem to fall off.) As I said, it tastes good, but I just prefer something else. :)
Y'a rien de meilleur qu'une bonne limonade glacé du Tim Horton! Très rafraîchissant et vraiment pas dispendieux. C'est bien meilleur lorsqu'on rajoute du yogourt grek à l'intérieur!
Nothing hits the spot on a scorching summer day than a lemonade from tim hortons. They mix it up fresh in front of you and the flavour is excellent. They offer these for a very cheap price.
Worst frozen lemonade on the market! It tastes like a cheap lemon hard candy was dissolved in some tap water and frozen. Very artificial flavored and no sour tang that makes real lemonade so appeaing, and so over sweetened it makes my teeth itch.
Great treat for summer, but not something you would want to be drinking every day. These are highly processed and have a lot of sugar. For the price they can't be beat, but you can make a healthier version at home.
This is an amazing treat on a very hot day. The raspberry one is even better. There is some down sides to these as it depends on who is making them and how much of the lemon they put in, have had many that are way way to sour or not lemon tasteing at all but the good thing is you can give it back to them and they will make you a new one.
This is a very tart lemonade and I dont have it too often. It is good though on a hot summer's day when you are really parched. It is so cold and refreshing!!
Definitely not one of the best lemonades I've tried. The artificial lemon flavor leaves something to be desired. If I had to get one, I'd go with the raspberry (if they still have it!)
These reviews are the subjective opinions of ChickAdvisor members and not of ChickAdvisor Inc.


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Thursday, May 12, 2016
The Cloudcast #251 - IT Tricks that SaaS services Forget
2 comments:
I think SaaS IT Tricks should be made known by all the providers and users. Proper integration of the service can help improve a lot of students from paper writing service Papersboard.com learn what is cloud SaaS integration is all about.ReplyDelete
Pavé Tile Co combines over forty years of expertise and passion to bring you an inspiring collection of crafted tiles sourced from cutting-edge designs from Europe and across the globe. Located at 339 Swan Street, Richmond, Melbourne 3121ReplyDelete
floor tiles melbourne
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Build a Website
This project has been awarded to eWestsiders for €1250 EUR.Get free quotes for a project like this
Project Budget€750 - €1500 EUR
Total Bids143
Project Description
Dear Freelancers,
we are business, which offers electro-surgical systems for minimally invasive surgery. We want to turn our existing website into an internationally accessible and professional website in at least 3 languages, with the option to extend the language panel in the future. Whilst we do need much help with the content, we do need support with the structure and multipedia. We are looking for the following qualities in our ideal website:
- Easy navigation
- Logical layout
- User friendliness
- Professional looking, especially since we are in the medical business
- Interactive, mainly accommodating of multimedia components such as YouTube and self-published videos
Here is our current website: [url removed, login to view]
Here are some website examples of our competitors, which we naturally want to surpass in user experience and quality:
[url removed, login to view]
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Howard Elliott Gold 22"e Accent Table in Bright Gold
Home > 1800lighting.com > Howard Elliott
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GREENSBORO, N.C. — Mercifully, Florida State's mediocre ACC season is over. It officially ended when time completely expired on the game clock and the Seminoles followed their battle-tested and road-weary coach into a shadowy tunnel. Unofficially, however, their 83-62 ACC Tournament quarterfinal defeat at the hands of North Carolina occurred much sooner.
FSU's Conference Season Ends with 83-62 Loss to UNC
From OrlandoSentinel.com
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Top Linksmain detailsbiographyby votesphoto galleryquotes
Filmographiesby yearby typeby ratingsby votesby TV seriesby genreby keyword
Did You Know?photo galleryquotes
Johnny Tran (Character)
from The Fast and the Furious (2001)
|Photos (See all 2 | slideshow)
|Related Videos (see all 2)
FilmographyEdit Credits
- Furious and Fast (2015) Played by Tony Dew
- The Fast and the Furious (2001) Played by Rick Yune
... aka "Fast and Furious" - Israel (English title) (imdb display title)
... aka "Wild Speed" - Japan (English title) (imdb display title)
Additional Details
Fun Stuff
Johnny Tran: [about Jesse who is driving away] Where's he going?
Dom: [sarcastic] He went to the car wash.
Johnny Tran: Whatever. Go fetch my car!
Dom: Go fetch your car? We're not on your block any more. You better watch who you talk to like that.
Johnny Tran: [as Dom walks away] TORETTO! TORETTO! SWAT came into my house, disrespected my whole family because somebody narc'd me out! And you know what? IT WAS YOU!
[Dom punches Tran and a brawl ensues]
Dom: I never narc'd on nobody! I never narc'd on nobody!
See more »
You may correct errors and omissions on this page directly. Clicking the 'Update' button will take you through a step-by-step process.


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Now from the get-go I want to make sure you know there's a difference between designing your own wedding cake, and making your own wedding cake. Both are possible, but there are considerations to make with the first if you are thinking about embarking on the second!
Cake decorating may not be as easy as you'd think; then again with practice it doesn't have to be that hard either. While making your own cake is a great way to make sure you get exactly what you want and keeps the wedding cake cost down considerably, do not underestimate the talent of your local baker or sugar artist.
Get Some Tips From the Experts
Forget Online Tools - Get Imaginative
While there are online tools that can let you play around with certain virtual looks, nothing is quite the same as real pictures. This also helps you to realize your vision more fully and open up your imagination. Wedding cakes nowadays can be whatever you want them to be and looking through cake design source magazines, online galleries, and cake decorators' websites you'll be buzzing with ideas.
Fancy a Novelty Cake?
Or you could decide to go down the fruit cake route and merely decorate up the cake into something more spectacular rather than using a shaped cake. The advantage of using fruit cake is that it lasts for ages so you can get the wedding cake completed weeks before the big day.
Fruit cakes don't have to stick to traditional looks; you could stack up some square or round cakes and add sugar dough to make it look like a fairytale castle for example.
Consider Ready-Made Options
So if you want to buy a few different sized store bought cakes that are ready iced, or you want to make the basic cakes yourself, then you can of course do that and use the customized elements to make it all your very own. This creates a really simple but elegant look that will be exactly what you want.
As you can see from this picture, even with a 3 tiered design, you still have options, such as either stacking regularly on top of each other, using cake pillars, or as here alternating the angle as each cake is placed - a simple idea that is really effective and totally doable by yourself.
Draw Up Your Design
Much as you would go into a hair salon with a picture for a new style you want, it pays to do this when visiting bakers too. Even if you don't have a photo, if you could draw something up, or go in with very definite ideas then this will help in coming up with a design that you really want.
If you also plan on making the cake yourself this can serve as a great reminder and a cheat sheet for when you are working. You can then work out what size each tier needs to be and so on, which is vital in knowing you have enough to feed everybody, and what amount of ingredients you need to buy.
Stay Away from Chocolate Cake
The art of chocolate is a whole different ball game to regular cake decorating so if you are thinking of doing this yourself I would say... don't. Putting finishing touches to a chocolate cake can only really be done on the day of the actual wedding and I think you could without that stress.
Even with a lot of practice the art of working with chocolate, and indeed molding chocolate is very difficult. So by all means come up with a design for a chocolate cake, and involve molded fans, swathes of chocolate fabric, chocolate roses, or even fruit, but make sure you get an expert to do the actual making. Be sure to take a look at their portfolio to make sure they have sufficient experience with chocolate work too.
Work Out How Much You Need
This is the trickiest part of designing your own cake as it's not all pretty pictures, and it's not all yummy smells -- this is where you need to get the calculator out!
Consider first how many guests you need to feed. Think about if you are also going to want to keep a tier for yourself, or if you want to send cake to any guests that were unable to make it.
As a guide, an iced fruit cake that is 10 inches square should serve around 90 guests; round cakes serve fewer guests (around 75 in this example).
Remember too that fruit cakes only require small portions to be cut (around 1 inch square slices), whereas sponge cakes require a bigger slice. A 10 inch square cake that is made of sponge would only serve 50 guests.
Make Dowels Your Friend
Ever wondered how those superb stacked cakes stay up and don't collapse on each other? Whether you use the direct stacked method, or you utilize cake pillars you need to make friends with dowels.
Dowels come in either wood, white plastic, or clear plastic to suit your needs. Stick them in the bottom tier of your cake (3 in a triangle formation for a circle cake, and 1 in each corner of a square cake but placed so the cake that goes on top will cover the holes - a few inches in).
Mark with a pencil where the top of the cake comes and remove the dowels. Cut the dowels and file as necessary. Replace into the cake and a cake board can now sit proudly on top, supported by the dowels underneath.
Now you know how to design your own wedding cake you can either go forth with your design to the cake decorator, or else get going on making your own! Just remember to leave plenty of time to get it all done. You are looking at around 3-4 months planning if you are doing it all yourself, but popular decorators may be booked up to a year in advance - Good Luck!


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Michael McDowell, a popular NASCAR driver took some time away from the social media before the busy racing began. He told his supporters on Facebook and Twitter that he would refrain from using social networking sites for thirty days as part of what he called a "social media fast." McDowell says he got the idea while attending a Bible study dealing with the distractions of life. He remembered that his young son had asked him to play while he was busy updating his status, and realized that his family was more important. Too help him avoid temptation; McDowell deleted social media apps from his phone. He says although he won't post any personal messages, daily Bible verses will continue to be automatically posted to his accounts during the 30 days off. He added, "For me, it's like it's become almost an addiction. It's something you almost have to do; you want to see what people are saying and you want to keep your fans up to date and you want to be engaged, but you don't realize how much time it actually takes."—Jim L. Wilson and Jim Sandell
Bible Study Leads NASCAR Driver to Take 'Social Media Fast', http://www.christainpost.com/news/bible-study-leads-nascar-driver-to-take-social-media-fast-88068, Accessed January 14, 2013.
Ephesians 5:15-16 (NIV) (15) Be very careful, then, how you live--not as unwise but as wise, (16) making the most of every opportunity, because the days are evil.


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For a second straight year, Aram Eisho has been crowned the country's best junior-aged defensive football player of the year.
The Hamilton Hurricanes' linebacker received the honour at the Canadian Junior Football League's award banquet on Friday. The 19-year-old was, of course, also named to the All-Canadian Team, along with one of his teammates.
Receiver Travis Steeves was named to the elite team.
Eisho finished the eight-game regular schedule with a rating of 156.5. His next closest defensive challenger scored 111. Eisho registered 44 tackles.
Steeves caught 56 passes for 655 yards, an average of 11.7 per reception. Nine of his catches were for touchdown for the Hurricanes who finished in second pace but were eliminated in the first round of playoffs.


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"Statue of Prince Eugene of Savoy" Eugene of Savoy Statue Tip by nicolaitan
Eugene of Savoy Statue, Budapest: 7 reviews and 14 photos
Entering the center courtyard of the Royal Castle, this imposing equestrian statue honors a 17th Century military commander who helped in liberating Hungary from the Ottoman Empire. French by birth and possibly an illegitimate son of Louis XIV, he became one of the Habsburg Empire's greatest generals and the defeat of the Turks one of his greatest triumphs.
Address: District I
Directions: On the top of Castle Hill (Varhegy). Funicular from Clark Adam ter (Buda bridgehead of the Chain Bridge), bus #16 from Deak F. ter, bus VAR from Moszkva ter. No cars allowed.
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Hamilton Hurricanes kicker, Chris Bartolomeo, has been named Special Teams Player of the Week by the Ontario Football Conference.
Chris earned the honours after a solid performance in the OFC Semi-Final game against the St. Leonard Cougars. He had 7 kick offs for 305 yards, his longest being a 51 yard boot, he was 2 for 2 on field goals totaling 32 yards, his longest coming from a 19 yard attempt, and Chris wBent 4 for 4 on extra point converts. Chris contributed 10 points to the Hurricanes win in their week nine playoff game, which advanced them to this Saturday's OFC Championship game.
The Hurricanes battle the Windsor AKO Fratmen for the OFC title Saturday at Windsor's Alumni Stadium. The champion will host the CJFL Championship on November 12th.


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BEST ENTRANCE: Uno's has their own parking area
LOCATION IN MALL: Located on the Exterior of Bangor Mall, adjacent from Macy's
Call (207) 947-5000 |
Get Driving Directions |
Visit Uno Pizzeria & Grill Website |
View Deals | View Store on Mall Map
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When the going gets tough, the tough gets takeout. Free Thin Crust when you buy one at https://t.co/GgfrBzWopP and… https://t.co/lZv7ZKU1So/p>
Uno Pizzeria & Grill
Did you know we have $5 takeout pizza?! Just buy a pizza and get a second for $5. It's high intensity training for your piehole.
And NOW...order online and get a free Chicago Thin Crust when you buy a pizza for takeout. Use promo code 5889!
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Free takeout Chicago Thin Crust when you buy any pizza ONLINE! https://t.co/Igz9ADQwwY and use code 5889!/p>
You're cooking for mothers, fathers, aunts, uncles and cousins this week. Let us cook for the kids today. FOR FREE.
Having people over for the game? Check out our family deals at unos.com and be the MVP.
Did U-No the Whole Hog Burger has over a pound of meat and four types of cheese???
Tomorrow is Monday already? We're feeling a vacation. Share your winter vacation plans with us!/p>
On National Pizza with the Works Day, we celebrate our Windy City Works pizza. And you should too. #pizzawiththeworksday #windycityworks
The winner of our Submit your Photo contest is Rick Reed and this great photo he submitted from Uno Pizzeria & Grill! We will send you a private message to find out where to send your gift card, congrats!
Fall baking is fun. But do you know what's more fun? When someone else does it for you. #browniebowlFTW… https://t.co/KueMz7jJ4d/p>
Don't make Friday harder than it has to be. Order online. Pick it up. You don't even have to talk to anyone!… https://t.co/kcGlEMtJtI/p>
To the city of Chicago, congratulations. Now it's time to celebrate like any Windy City native would!
It's sweet, it's spicy, it's National Sandwich Day!!
It's sweet, it's spicy, it's National Sandwich Day!! https://t.co/Y9AT5o5YO1/p>
Thirsty Thursday doesn't have to be at a premium, we've got Margaritas for $5. Celebrate another nearly conquered w… https://t.co/NStpNSgULn/p>
Its Wednesday at UNO. That means a big plate of delicious wings. We like 'em firey... Chicago Fire, that is. What's… https://t.co/0IKBjGVg2i/p>
Have you purchased your holiday gift cards? For every $25 you spend in gift cards at UNO, you get a $5 bonus. What's not to love about that?!
Happy Holiday Season! What's your favorite part of the holidays? #holidayseason/p>
Like this post and leave a comment to share with us your favorite Thanksgiving tradition for a chance to win an Uno's gift card!
Black Friday is for shopping, sales and snacks. Join us for drinks and apps and refuel! #blackfriday #unopizzeria https://t.co/oFMlrfO60o/p>
Did U-No the Whole Hog Burger has over a pound of meat and four types of cheese??? #meathead #holycow https://t.co/596HoxWj0L/p>
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Don't be a last minute shopper again. Instead reward yourself for getting it done early by getting $5 back when you buy $25 in Gift Cards!/p>
Make Monday guy's night with our draft specials, football on tv and great food. #mnf #unopizzeriaandgrill #guysnight
We had a great morning at the Boston VA Hospital, delivering 150 pizzas and visiting with Veterans and their families. Thanks to Mary Girard and her team for all they do, can't wait till next year!
The winner of our Election Day Submit your Photo contest is Jeanne King Matz! Thank you for sharing and for voting!!
Looking for an awesome football snack?! Our Cheesy Cheesy Cheesy Bread is perfect for sharing...or not. #cheesybread #footballsnacks #unosapps #unopizzeriaandgrill #bombdotcom
Happy Election Day! Today is the day you can make a difference in our country's future. We vote...MORE PIZZA. #pizzaforprez #electionday/p>
Because some days you just need a bowl of pasta. Our Tuscan Beef Ragout will do the trick.
Did you know you can order online at unos.com? Simple, easy and our system remembers your order history!
Join us for our Craft Beer Party tonight! Glass painting, trivia, prizes and our awesome craft beer selection. See you tonight! #unobeer
*Participating locations only
Craft beer party tonight at participating locations! Glass painting, trivia and prizes, 50 cent wings and more.… https://t.co/ovTtgn7wI3/p>
Who says Margaritas are a weekend thing? $5 dollars says you can have one tonight!
Its Wednesday at UNO. That means a big plate of delicious wings. We like 'em firey... Chicago Fire, that is. What's your favorite sauce?
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It's Black Friday and that means sales, stores and a hungry bunch of shoppers. Stop into Uno's and warm up and fuel up with our Spinach and Artichoke Deep Dip!
This Thanksgiving, we at Uno Pizzeria & Grill are thankful for our amazing staff, our hardworking management and most importantly, our loyal guests who make our jobs that much easier. Cheers to you!
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Government Narrowly Avoids Shutdown
The government was this close to shutting down last night but managed to reach an eleventh-hour (literally) compromise before the midnight deadline. House Speaker John "Smarmy" Boehner presented the laundry list of spending cuts and revisions and got Congress' positive response just before 11 p.m. What does this mean? It means that our government is still functioning -- for now -- and it means $38.5 billion in spending cuts.
Not so fast, though: the deal isn't quite final. What's really happening is that the House has agreed on an extension until April 15 to work out all the details. So we all have to stay tuned. This could conceivably turn sour in the next five days.
As we've discussed before, a government shutdown would have had some serious consequences for the country. We've avoided it for now, but what kind of changes and cuts (some of which Obama described as "painful" for Democrats, who agreed to about two thirds of the cuts Republicans wanted) can we expect in light of the new deal? And what should we be relieved is not happening?
- Government is still functional, or "functional."
- "Numerous studies" of the health care bill have been ordered. Uh oh.
- Federal funding for Planned Parenthood is safe. According to Politico, Obama and Biden went hard in the paint in terms of protecting that one.
- Repubs tried to get federal funding currently devoted to family planning and women's health converted to block grants for states (see a pattern here?). Didn't happen.
- Environmental Protection Agency funding = safe.
- According to Obama, some needed infrastructural projects will be delayed, and certain programs will be scaled down.
So the country is still kind of working. Key words being "kind of."
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Beverley, East Yorkshire, England Show on map
|Three-bedroom holiday home
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|From £205/€243.03/A$346.58/US$258.02/CA$340.87/CHF262.38/kr2,361.75/kr1,815.77/kr2,176.22/kr28,873/$4,166.67/$170,833/PEN879.83/NZ$359.84/R3,528.40/zł1,081.79/R$871.97/Kč6,591.64/RSD30,147 per 3 nights
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|2 bedroom static caravan
|5 x
|From £280/€331.95/A$473.37/US$352.42/CA$465.58/CHF358.38/kr3,225.81/kr2,480.07/kr2,972.40/kr39,437/$5,691.06/$233,333/PEN1,201.72/NZ$491.49/R4,819.28/zł1,477.57/R$1,190.98/Kč9,003.22/RSD41,176 per 7 nights
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Green Beans With Water Chestnuts
Total Time
Prep 10 mins
Cook 15 mins
Love those water chestnuts they spruce up so many dishes. Do not over cook the beans
Ingredients Nutrition
- 1 (227 ml) can water chestnuts, cut each in half
- 1 lb green beans, trimmed
- 1 medium onion, chopped
- 3 tablespoons butter or 3 tablespoons margarine
- salt
- 1⁄4 teaspoon mace
- Bring a pot of salted water to a boil, add beans and cook for 6-8 minutes.
- Melt the butter/margarine in a skillet, add onion and saute for 7 minutes, stirring.
- Stir in salt, mace and water chestnuts; saute 2 minutes.
- Add beans and saute until heated through.
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A nice change of pace that fancies up green beans (I steamed mine). The mace gives a nice hint of flavour to it and the novelty of water chestnuts is a treat.
I agree with you, Bergy....those water chestnuts really do jazz up many veggies. This a great example. I loved the bit of mace and the crunchiness of the water chestnuts mixed with the green beans. I had almost 1 1/2 lbs of beans, but kept all the other amounts the same. These will be a part of my holiday table! Thanx for posting!