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Mutations in the human GJB2 gene, which encodes connexin26 (Cx26), underlie various forms of hereditary deafness and skin disease. While it has proven difficult to discern the exact pathological mechanisms that cause these disorders, studies have shown that the loss or abnormal function of Cx26 protein has a profound effect on tissue homeostasis. Here, we used the Xenopus oocyte expression system to examine the functional characteristics of a Cx26 mutation (G45E) that results in keratitis-ichthyosis-deafness syndrome (KIDS) with a fatal outcome. Our data showed that oocytes were able to express both wild-type Cx26 and its G45E variant, each of which formed hemichannels and gap junction channels. However, Cx26-G45E hemichannels displayed significantly greater whole cell currents than wild-type Cx26, leading to cell lysis and death. This severe phenotype could be rescued in the presence of elevated Ca2+ levels in the extracellular milieu. Cx26-G45E could also form intercellular channels with a similar efficiency as wild-type Cx26, however, with increased voltage sensitive gating. We also compared Cx26-G45E with a previously described Cx26 mutant, A40V, which has an overlapping human phenotype. We found that both dominant Cx26 mutants elicited similar functional consequences and that cells coexpressing mutant and wild-type connexins predominantly displayed mutant-like behavior. These data suggest that mutant hemichannels may act on cellular homeostasis in a manner that can be detrimental to the tissues in which they are expressed.
- connexin
connexins have been implicated in a variety of hereditary human diseases including deafness and skin disease (1, 42, 44). The most common connexin-related disease is genetic deafness [sensorineural hearing loss (SNHL)], which can be nonsyndromic or syndromic when associated with skin disorders and other ectodermal abnormalities, such as palmoplantar keratoderma, Vohwinkel syndrome, Bart-Pumphrey syndrome, or keratitis-ichthyosis-deafness syndrome (KIDS) (13, 30). In most cases, SNHL is due to a mutation in the GJB2 gene that encodes connexin26 (Cx26), although mutations in other connexins also have been described (27). Functional analyses of specific Cx26 mutations associated with syndromic and nonsyndromic SNHL have been conducted to decipher the molecular mechanisms underlying these different disorders. Autosomal recessive hearing loss without skin involvement (nonsyndromic) is often due to a simple loss of channel function altering cochlear intercellular communication (5, 43, 46). The lack of skin involvement in these cases suggests that loss of Cx26 function alone is not detrimental for the development and function of the epidermis. Thus, it has been hypothesized that mutant connexins resulting in syndromic SNHL associated with skin disorders must acquire novel activities compared with wild-type Cx26 channels to alter the epidermal differentiation.
Connexins are the basic subunits of a gap junction channels and consists of four membrane-spanning domains with two extracellular loops and cytoplasmic NH2 and COOH termini. Six connexins oligomerize within the cell membrane to form a hemichannel, or one-half of an intercellular channel. A complete gap junction channel arises from the alignment of two hemichannels from adjacent cells in the extracellular space, creating a direct communication pathway between cytoplasms of neighboring cells (18). It was once believed that hemichannels must remained in a closed state until they were aligned with another hemichannel from an adjacent cell, but recent studies (16, 35) have suggested that hemichannels may play important roles in maintaining homeostasis under different physiological conditions.
If hemichannels play a role in normal physiology, it is possible that some connexin mutations may result in abnormal hemichannel activity that could contribute to disease pathology. This idea has been supported by studies of connexin mutations causing syndromic deafness associated with skin disease. One recently described example is the A40V mutation of Cx26, which is linked to a severe form of KIDS (25). A40V is located within the first extracellular domain of Cx26, a region in which multiple Cx26 mutations linked to syndromic deafness have been found (29). Injection of A40V cRNA into Xenopus oocytes resulted in a disorganization of cell pigmentation followed by cell death. Moreover, the induction of large membrane currents not seen in wild-type Cx26-expressing oocytes suggested the presence of aberrant A40V hemichannel activity (25), leading the authors to conclude that constitutively active hemichannels could contribute to the pathophysiology of this mutation.
Functional evaluation of additional KIDS mutations in Cx26 would help determine if aberrant hemichannel activity is a general pathological mechanism for this syndromic disorder. Here, we report the functional characteristics of a Cx26 mutation (G45E) that was observed in two previously described infants with a rare fatal form of KIDS. The children harboring the G45E mutation in GJB2 had congenital deafness, hyperkeratosis of the skin, and recurrent severe skin infections, which eventually lead to septicemia and death within the first year of life (14, 17, 21). Using an in vitro expression assay, we show that Cx26-G45E hemichannels display a significant increase in membrane current flow that results in cell death. Elevated Cx26-G45E hemichannel currents can be attenuated by increased extracellular Ca2+ levels that prevent cell death. Moreover, when oocytes are cultured in high Ca2+, we demonstrate that Cx26-G45E can assemble into functional intercellular channels with coupling levels identical to those observed for Cx26. While the intercellular conductance was nearly identical, the voltage gating properties of Cx26-G45E and wild-type Cx26 gap junction channels displayed significant differences, further indicating a fundamental change in channel gating due to this mutation.
Molecular cloning.
Human wild-type Cx26 was cloned into the BamHI restriction site of the pCS2+ expression vector for functional experiments in Xenopus laevis oocytes. Mutant Cx26-G45E was prepared by site-directed mutagenesis. Wild-type Cx26 was amplified by PCR using primers 5′-TGT TGT GGA TCC ATG GAT TGG GGC ACG CTG CAG ACG-3′ and 3′-CTG CTC ATC TTC CCA CAC CTC CTT TGC-5′ as well as 5′-AAG GAG GTG TGG GAA GAT GAG CAG GCC GAC-3′ and 3′-TGT TGT GGA TCC TTA AAC TGG CTT TTT TGA CTT CCC AGA-5′ and gene splicing by the overlap extension method (20) to create the glycine to glutamic acid substitution. Following amplification, G45E was initially cloned into pBlueScript and sequenced on both strands prior to being subcloned into the pCS2+ expression vector for Xenopus laevis expression experiments. Mutant Cx26-A40V was directly amplified from patient genomic DNA as previously described (25).
In vitro transcription, oocyte microinjection, and pairing.
Human Cx26, A40V, and G45E were linearized using the NotI restriction site of pCS2+ and transcribed using the SP6 mMessage mMachine RNA protocol (Ambion, Austin, TX). Adult Xenopus females were anesthetized with ethyl-3-aminobenzoate methanesulfonate, and the ovarian lobes were surgically removed and digested for 1.5 h in a solution containing 50 mg/ml collagenase B and 50 mg/ml hyaluronidase in modified Barth's (MB) medium without Ca2+. Stage V–VI oocytes were collected and injected first with 10 ng of antisense Xenopus Cx38 oligonucleotide to eliminate endogenous connexins (2, 4). The aforementioned antisense oligonucleotide-treated oocytes were then injected with wild-type Cx26, A40V, or G45E cRNA transcripts alone or a combination of wild-type and mutant Cx26 at a 1:1 ratio (total concentration of 5 ng/cell in all cases) or H2O as a negative control. cRNA-injected oocytes were then cultured in Ca2+-free MB medium or MB medium with elevated Ca2+ (2 mM CaCl2). For measurements of gap junctional conductance, the vitelline envelopes were removed in a hypertonic solution (200 mM aspartic acid, 10 mM HEPES, 1 mM MgCl2, 10 mM EGTA, and 20 mM KCl; pH 7.4), and oocytes were manually paired with the vegetal poles apposed in MB medium with elevated Ca2+.
Preparation of oocyte samples for Western blot analysis and quantification.
Oocytes were collected in 1 ml of buffer containing 5 mM Tris (pH 8.0), 5 mM EDTA, and protease inhibitors and lysed using a series of mechanical passages through needles of diminishing caliber. Extracts were centrifuged at 1,000 g at 4°C for 5 min. The supernatant was then centrifuged at 100,000 g at 4°C for 30 min. Membrane pellets were resuspended in SDS sample buffer (2 μl/oocyte), and samples were separated on 15% SDS gels and transferred to nitrocellulose membranes. Blots were blocked with 5% BSA in 1× PBS with 0.02% NaN3 for 1 h and probed with a polyclonal Cx26 antibody at a 1:500 dilution (Zymed Laboratories, San Francisco, CA) followed by an incubation with alkaline phosphatase-conjugated anti-rabbit secondary antibody (Jackson ImmunoResearch Laboratories, West Grove, PA). Band intensities were quantified using Kodak 1D Image Analysis software (Eastman Kodak, Rochester, NY). Values from three independent experiments were normalized to the mean value of band intensity of the wild-type Cx26 sample.
Electrophysiological recording of hemichannel currents.
Macroscopic recordings of hemichannel currents were recorded from single Xenopus oocytes using a GeneClamp 500 amplifier controlled by a personal computer (PC)-compatible computer through a Digidata 1320 interface (Axon Instruments, Foster City, CA). pCLAMP 8.0 software (Axon Instruments) was used to program stimulus and data collection paradigms. To obtain hemichannel current-voltage curves, cells were initially clamped at −40 mV and subjected to 5-s depolarizing voltage steps ranging from −30 to +60 mV in 10-mV increments. To test the effect of added Ca2+ on hemichannel currents, cells were transferred between 35-mm dishes containing MB media without Ca2+ or MB media supplemented with either 2 or 4 mM CaCl2. Hemichannel currents were recorded within 1–2 min of oocyte transfer.
Dual whole cell voltage clamp.
Gap junctional coupling between oocyte pairs was measured using the dual whole cell voltage-clamp technique (36). Current and voltage electrodes (1.2 mm diameter, omega dot, Glass Company of America, Millville, NJ) were pulled to a resistance of 1–2 MΩ with a horizontal puller (Narishige, Tokyo, Japan) and filled with solution containing 3 M KCl, 10 mM EGTA, and 10 mM HEPES (pH 7.4). Voltage-clamp experiments were performed using two GeneClamp 500 amplifiers controlled by a PC-compatible computer through a Digidata 1320A interface (Axon Instruments).
For measurements of junctional conductance (Gj), both cells in a pair were initially clamped at −40 mV to eliminate any transjunctional potential (Vj). One cell was then subjected to alternating pulses of ±20 mV while the current produced by the change in voltage was recorded in the second cell. The current delivered to the second cell was equal in magnitude to the junctional current (Ij), and Gj was calculated by dividing the measured current by the voltage difference as follows: Gj = Ij/(V1 − V2), where V1 and V2 are the voltages in the first and second cells, respectively.
To determine voltage gating properties, Vjs of opposite polarity were generated by hyperpolarizing or depolarizing one cell in 20 mV steps (range = ±120 mV) while clamping the second cell at −40 mV. Currents were measured at the end of the voltage pulse, at which time they approached steady state (Ijss). Macroscopic conductance (Gjss) was calculated by dividing Ijss by Vj (normalized to the values determined at ±20 mV) and plotted against Vj. Data describing the relationship of Gjss as a function of Vj were analyzed using Origin 6.1 software (Microcal Software, Northampton, MA) and fit to a Boltzmann relation of the following form: Gjss = (Gjmax − Gjmin)/{1 + exp[A(Vj − V0)]} + Gjmin, where Gjmax (normalized to unity) is maximum conductance, Gjmin is the residual conductance at large values of Vj, and V0 is the Vj at which Gjss = (Gjmax − Gjmin)/2. The constant A = nq/kT and represents the voltage sensitivity in terms of gating charge as the equivalent number (n) of electron charges (q) moving through the membrane, k is the Boltzmann constant, and T is the absolute temperature. To analyze channel closure kinetics, the initial 1,000 ms of current decay were plotted against time and fit to a monoexponential function to determine the time constant (τ) using Origin 6.1.
G45E induces gap junction hemichannel currents in single Xenopus oocytes.
The G45E mutation in the GJB2 gene results in a single amino acid substitution in the first extracellular domain of Cx26 and causes KIDS, with a reported lethal outcome in two unrelated infants. To identify the functional consequences of mutation G45E, wild-type Cx26 and Cx26-G45E were expressed in Xenopus oocytes. Initially, single cells were subjected to depolarizing voltage pulses and membrane currents were recorded (Fig. 1). Control oocytes (H2O injected) displayed negligible current flow over a range of voltages from −30 to +60 mV. Cx26-injected cells exhibited larger outward currents than control cells, confirming previous reports (15, 34) of low levels of hemichannel activity. In contrast, oocytes expressing the G45E mutation displayed currents of much greater magnitude in response to depolarization than either control or Cx26-injected cells. Thus, expression of G45E correlated with a markedly decreased plasma membrane electrical resistance, suggesting that G45E formed hemichannels that were functionally distinct from wild-type Cx26.
To quantitatively compare hemichannel currents produced by G45E and Cx26, mean Imss values were plotted as a function of membrane potential (Fig. 2). Control oocytes displayed small currents at all voltages tested. Cx26-injected cells were initially indistinguishable from controls but showed greater current magnitudes at higher voltages with a maximum current approximately fourfold higher than control at the largest voltage tested (+60 mV, P < 0.05 by Student's t-test). G45E-expressing oocytes had much greater membrane currents than either H2O- or Cx26-injected cells at all tested voltages. At +60 mV, the G45E membrane current was 30-fold higher than control cells and more than 7-fold greater than Cx26-injected cells (P < 0.05). This statistically significant increase in membrane current may result from G45E forming hemichannels that are either fixed in the open configuration or gate open more easily than wild-type Cx26, leading to much greater ionic flux.
G45E induces cell death that can be rescued by elevated extracellular Ca2+ levels.
We (25) have previously shown that another dominant Cx26 mutation associated with KIDS and the follicular occlusion triad (A40V) produced abnormal hemichannel currents when expressed in Xenopus oocytes and eventually led to lysis and death of the injected cells. Numerous studies (9, 28) have shown that increased extracellular Ca2+ suppresses gap junction hemichannel activity. Hence, if Xenopus oocytes expressing Cx26 mutants A40V and G45E die as result of abnormal hemichannel activity, this outcome may be prevented in the presence of increased Ca2+ levels. To test if Cx26-G45E indeed can affect cell viability in a Ca2+-dependent manner, oocytes were cultured in medium in the presence or absence of Ca2+ (Fig. 3). Control and Cx26-expressing oocytes remained healthy as indicated by visual inspection when incubated in MB medium without Ca2+ (Fig. 3, A and B). In contrast, cells injected with G45E displayed pigment disorganization and blebbing of the ooplasm into the culture medium within 8 h (Fig. 3C), which preceded lysis and cell death within 12–24 h. Incubation of G45E-injected cells in MB media supplemented with ≥2 mM extracellular Ca2+ rescued this phenotype and preserved cell viability (Fig. 3D). These data suggested that the increased Ca2+ level suppressed G45E hemichannels and maintained cell viability.
If the addition of Ca2+ preserved cell viability by suppressing hemichannel activity, then whole cell membrane currents should be greatly reduced in elevated Ca2+. To test this idea, we measured hemichannel currents from G45E- and A40V-expressing cells in media containing 0, 2, or 4 mM Ca2+ (Fig. 4). Oocytes expressing G45E in the absence of extracellular Ca2+ produced large outward currents that were reduced by 2 mM Ca2+ and further reduced by 4 mM Ca2+ (Fig. 4A). To quantitate these findings, Imss values of G45E oocytes in the presence and absence of Ca2+ were plotted as a function of voltage. The addition of 2 and 4 mM Ca2+produced a significant decrease in current flow at all tested voltages, with the maximum voltage displaying a greater than twofold decrease at 2 mM Ca2+ and a sixfold decrease in hemichannel current in 4 mM Ca2+. In addition, the threshold of voltage activation was shifted to more positive potentials with increased Ca2+ concentration (Fig. 4B).
Like G45E, the A40V Cx26 mutation has been previously shown to induce hemichannel-mediated cell lysis and death (25); however, the ability of elevated Ca2+ to rescue A40V had not been tested. To determine whether elevated Ca2+ could also suppress A40V activity, we measured membrane currents from A40V hemichannels in the presence and absence of elevated extracellular Ca2+. In the absence of Ca2+, A40V-injected oocytes produced large currents similar to those observed in G45E cells (Fig. 4C). The addition of Ca2+ to the media produced a dramatic reduction in hemichannel current flow consistent with the results observed in G45E cells. Again, quantitation of Imss values revealed a significant decrease in hemichannel activity in the presence of Ca2+ and a positive shift in the threshold of voltage activation (Fig. 4D). This decrease in current flow was detected at all voltages tested, with the maximum decline being twofold in 2 mM Ca2+ and fourfold in 4 mM Ca2+ at +60 mV. Taken together, these data indicate a significant reduction in the number of active hemichannels with the elevation of extracellular Ca2+ for both G45E and A40V and that these two mutations share similar functional properties.
G45E and A40V may contribute to cellular pathology through abnormal hemichannel activity; however, wild-type Cx26 also induced low levels of hemichannel current, and the differences in current magnitude between the wild type and mutants could have resulted from different levels of protein expression in each condition. To examine the levels of connexin protein expressed in oocytes, we performed Western blot analysis with cell extracts from control (H2O injected) and Cx26-, G45E-, and A40V-injected cells (Fig. 5). Antibodies for Cx26 failed to detect protein expression in control cells but readily detected expression of Cx26, G45E, and A40V following injection of their respective cRNAs (Fig. 5A). To quantify expression levels, we measured the band intensities of G45E and A40V and compared them to the value obtained for Cx26 (Fig. 5B). Cx26, G45E, and A40V were all expressed in equal amounts, and thus the differences in hemichannel current magnitude were not due to the relative overexpression of mutant protein.
Previous reports have described the G45E mutation as dominant in the Caucasian population; however, this mutation has also been linked to recessive deafness in some Asian populations (26). Given the conflicting nature of these data, we performed experiments to examine the impact of the mutant allele on wild-type Cx26 function. To test for dominant activity, we injected oocytes with both wild-type Cx26 and G45E in a 1:1 ratio and measured hemichannel currents in the absence and presence of elevated extracellular Ca2+. Oocytes coexpressing G45E and wild-type Cx26 displayed large membrane currents similar to those observed with expression of G45E alone (Fig. 6A). The large membrane currents seen in coinjected oocytes were reduced with the addition of 2 mM Ca2+ in a manner also consistent with the results from cells only expressing the G45E variant of Cx26. Quantitation of Imss values revealed a significant decrease in membrane current with the addition of Ca2+, displaying a threefold decrease at the maximum voltage tested (Fig. 6B).
Given that oocytes injected with A40V exhibited properties similar to G45E, we also examined the dominance of A40V by coinjecting cells with A40V and wild-type Cx26. Oocytes expressing A40V in conjunction with wild-type Cx26 again displayed large membrane currents that were reduced by the addition of 2 mM Ca2+ (Fig. 6C). Again, quantitation revealed a significant decrease with the addition of calcium with a threefold difference at a membrane potential of +60 mV (Fig. 6D). Together, these data show that both G45E and A40V exhibited dominant, Ca2+-sensitive hemichannel activity when coexpressed with wild-type Cx26.
G45E also forms gap junction channels in paired Xenopus oocytes.
We and others (5–7, 24, 38, 41, 45) have previously shown that not all disease-causing mutations in Cx26 result in the complete loss of gap junction channel activity. The ability to rescue viability in cells expressing G45E with elevated extracellular Ca2+ allowed us to examine its ability to form intercellular channels using the dual cell voltage-clamp technique in paired oocytes (Fig. 7). After G45E or Cx26 cRNA injection, oocytes were paired and incubated in medium with 2 mM Ca2+. H2O-injected cells were used as negative controls. Wild-type Cx26 formed functional channels with Gj that was 20-fold higher than background levels recorded in control pairs. Oocyte pairs injected with G45E also had a mean conductance 20-fold higher than the background level and indistinguishable from wild-type Cx26 (P > 0.05). Thus, the G45E mutation retained the ability to form functional gap junction channels when hemichannel activity was suppressed by elevated extracellular Ca2+.
G45E intercellular channels have altered voltage gating properties.
The ability of G45E to form functional gap junction channels in elevated extracellular Ca2+ allowed its voltage gating properties to be compared with wild-type Cx26 channels. Although the macroscopic conductance measurements were indistinguishable, we found that the voltage gating properties of Cx26 and G45E channels were markedly different. Figure 8 shows the gap junctional currents (Ij) for wild-type Cx26 and G45E recorded for a series of different Vjs. Cx26 currents were consistent with previous data showing an asymmetric decay at higher voltages with greater closure for positive Vjs (Fig. 8A) (2, 24). In contrast, G45E gap junctions exhibited a more symmetric current decline in response to Vjs of either polarity (Fig. 8B). In addition to the increased symmetry, G45E currents decayed more rapidly than wild-type Cx26. For example, at Vj = −120 mV, G45E currents decayed with a mean τ value of 0.19 ± 0.05 s (n = 6), whereas Cx26 currents decayed six times slower with a mean τ value of 1.15 ± 0.38 s (P < 0.05, n = 5).
To analyze the equilibrium voltage gating properties, Gjss values were normalized, plotted against Vj, and fitted to a Boltzmann equation (Fig. 8C). This analysis revealed that for Cx26, V0 (which corresponds to the midway point between Gjmax and Gjmin) was asymmetric with values of 99 and −117 mV for positive and negative Vjs, respectively (Table 1). Conversely, V0 values for G45E channels were more symmetrical and much lower, with positive and negative V0 values of +56 and −61 mV. These data demonstrate that, in addition to increased hemichannel function, the magnitude and kinetics of the voltage gating properties of gap junction channels made from G45E differed quantitatively from those of wild-type Cx26.
We also tested for a dominant impact of G45E on wild-type Cx26 in gap junction channels between paired oocytes (Fig. 9). Cell pairs coinjected with equal amounts of wild-type Cx26 and G45E cRNA were able to form functional gap junctions that exhibited significantly increased conductance compared with H2O-injected negative controls (Fig. 9A) but were not statistically different from the coupling levels in oocyte pairs injected with Cx26 or G45E alone (see Fig. 7). An examination of the voltage-induced current decay revealed that coinjected pairs displayed voltage gating properties more like those of gap junctions composed of G45E alone rather than Cx26 alone. Specifically, the voltage sensitivity of the currents was more symmetrical than Cx26 with faster gating kinetics (Fig. 9B). Analysis of the equilibrium voltage gating properties confirmed that coinjected cell pairs were dominated by G45E-like behavior (Fig. 9C). The equilibrium properties of cell pairs coexpressing G45E and Cx26 were deduced from a Boltzmann fit and found to be nearly identical to those of pairs injected with G45E alone (Table 1). These data showed that the voltage gating properties of gap junction channels made from an equal mixture of Cx26 and G45E did not differ markedly from those composed of G45E alone and suggested that G45E exerted a dominant gating phenotype on wild-type Cx26.
Numerous studies have linked mutations in the GJB2 gene to syndromic deafness associated with skin disease. In the case of KIDS, all pathogenic mutations cluster in regions coding for the first extracellular domain and the NH2-terminal of Cx26, implying common functional defects. In the present study, we showed that the G45E and A40V mutant forms of Cx26 produced greatly increased hemichannel activity that ultimately led to cell death. This severe phenotype could be rescued by elevated extracellular Ca2+, which allowed Cx26-G45E intercellular channels to be evaluated. G45E mutant gap junction channels also displayed significantly altered voltage-sensitive gating. These findings are consistent with the hypothesis that aberrant hemichannel activity might be a common feature of some KIDS mutations and may contribute to severe epidermal pathology in these cases.
While the rare fatal form of KIDS has been associated with Cx26-G45E in two unrelated Caucasian patients (14, 17, 21), it has also been linked to recessive nonsyndromic deafness in some Asian populations. In a large study of Japanese patients with nonsyndromic SNHL, G45E was detected in 16% of the GJB2 disease alleles (26). Among Japanese patients, G45E was classified as a recessive allele as it was always present homozygously or as compound heterozygotes with other GJB2 mutations in deaf individuals. In addition, it was never detected in control individuals or classified as causing syndromic deafness associated with skin disease (12, 26).
Our data are consistent with a dominant gain of function for G45E, which rapidly killed Xenopus oocytes through aberrant hemichannel activity. Further support for the cellular lethality of Cx26-G45E comes from a report of hemichannel activity in transfected HEK-293 cells that appeared while this article was being written (37). Stong et al. (37) reported that Cx26-G45E expression facilitated dye uptake, resulting in apoptosis within 24 h of cell transfection, and cell death could be rescued by increasing the extracellular Ca2+ concentration. Thus, in two different functional expression systems, Cx26-G45E led to aberrant hemichannel formation and cell lysis, functional properties that we show were shared by a second severe KIDS mutation in GJB2, Cx26-A40V. To date, the A40V mutation has only been associated with KIDS and the follicular occlusion triad (25).
Nine connexin genes, including Cx26, are expressed during epidermal morphogenesis, and gap junctional communication plays an important role in keratinocyte growth and differentiation (8, 22). Mutations in Cx26 are the leading cause of hereditary deafness, which can be associated with a variety of skin diseases (23, 31–33, 40).The presence of Cx26 mutations in syndromic and nonsyndromic deafness suggests that different functional consequences of distinct mutations may correspond to unique pathological states. For example, many nonsyndromic mutations in the GJB2 gene have resulted in altered protein trafficking, loss of channel function, or alteration of channel permeability, without causing cell death (43, 46). In contrast, we and others (25, 37) have shown that two separate KIDS mutations exhibited lethal hemichannel activity that may have contributed to both hearing loss and the epidermal pathology. Further support for this aberrant hemichannel hypothesis comes from studies of mutations in the GJB6 gene (which encodes Cx30) causing hidrotic ectodermal dysplasia (HED). Two HED-associated Cx30 mutants, G11R and A88V, induced cell death in Xenopus oocytes, which could have resulted from the presence of functional hemichannels, an idea supported by the detection of large voltage-activated currents in single oocytes expressing mutant proteins that were not seen in cells injected with wild-type Cx30 (10). Furthermore, transfected cells expressing the mutant channels had a two- to threefold higher ATP leakage than control cells, suggesting that ATP release through unregulated hemichannels may play a role in the HED phenotype (10). In addition to causing cell depolarization and death, hemichannels could induce the release of metabolites into the extracellular space in the epidermis and influence the regulation of keratinocyte growth and differentiation.
Extracellular Ca2+ plays an important role in normal epidermal differentiation, regulating cell proliferation, terminal differentiation, and cell-to-cell adhesion. In addition, altered Ca2+ regulation has been implicated in the pathogenesis of some epidermal diseases (3, 11, 19, 39). An increase in the extracellular Ca2+ concentration is thought to drive the developmental switch from keratinocyte proliferation to terminal differentiation by providing a reservoir of Ca2+ that influences intracellular Ca2+-dependant signaling processes. However, it is not known if this developmentally regulated rise in extracellular Ca2+ achieves concentrations sufficiently high to inhibit G45E or A40V mutant hemichannels. While we have not tried other hemichannel blockers, future studies may identify novel treatment strategies seeking to modulate epidermal Ca2+ concentrations pharmacologically or seeking novel blocking agents that specifically act on Cx26 hemichannels.
This work was supported by National Institutes of Health Grants DC-06652 and EY-13163 (to T. W. White).
We thank Gülistan Meşe for critically reading the manuscript.
↵* D. A. Gerido and A. M. DeRosa contributed equally to this work.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2007 the American Physiological Society


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From the undeniably Courrèges cuts and colours, to the '60s cloned hair and make-up, there was no denying the love at Moschino this morning.
Tom Pecheux committed to a full wattage lashes and white eyeliner ("The lashes would have been lost against black," he explained) with a totally retro glossy coral lip. "I usually hate to heavily reference the past," explained Pecheux. "But if you're going to do it then you may as well take it the whole way."
Clearly an attitude that Sam McKnight channeled for the big backcombed updos, too. "Its Lana del Ray meets Raquel Welsh, the whole look is so Courrèges. Ok, its not a beauty look we're going to replicate religiously although, there was something pretty fabulous about the opaque white nails but in terms of tapping into the fun, energetic, spirited vibe of Moschino, the makeup and hair were spot on.

subset: commoncrawl


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Common Phrases We All Secretly Hate
I can't stand when people say "it is, what it is." Is it really? Gee thanks.
Here are other phrases that drive people crazy.
Feel free to add yours in the comment section below.
"Everything happens for a reason."
"If it's meant to be, it's meant to be."
"I mean…"
"To be frank…"
"Just sayin'."
"At the end of the day…"
"Same difference."
"Do what you love."
"Let me tell you something.".
"I apologize if I made you feel that way."
"My bad."
"Sorry I'm not sorry."
"No worries."
"Chill out."
"Work hard, play hard."
"Give 110 percent."


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Spotlight & Review - All For Love by Susanne Matthews - @jandsmatt #FiveStars #Romance
Bethany-Kris Bragdon
This is my stop during the blog tour for All for Love by Susanne Matthews. This blog tour is organized by Lola's Blog Tours. The blog tour runs from 26 may till 8 June, you can view the complete tour schedule on the website of Lola's Blog Tours.
All for Love
By Susanne Matthews
Genre: Contemporary Romance
Age category: Adult
Publisher: Anaiah Press
Release Date: May 26, 2015
To overcome your fear, you must first face it.
Someone is out to destroy Greg Simmons and everyone he has ever loved. After an accident leaves his teenage daughter depressed and distraught, Greg will do anything to make her happy again.
Olivia Marshall lost both her fiancé and her cousin in a deadly avalanche. She has vowed never to set foot on a ski hill again. But now, working as a bodyguard with Anderson Security, Olivia must face her greatest fears to save Greg and his daughter.
Something about Olivia's determination strikes a chord in Greg, but will she be the salvation he needs, or will he be her destruction?
You can find All for Love on Goodreads
You can buy All for Love here:
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Jack rubbed the back of his neck. "Right. Well, if you're determined to do this, Veronica has the guest room all set up for you in the apartment until you leave for the chalet near Scranton at the end of the week. Do you have everything you'll need?"
"I have to pick up ski equipment, but the rest is in the truck Tim provided. By the way, what did your operative have to say about all this?"
Greg watched the color seep into Jack's face. Obviously, the mighty Livy wasn't as happy with the situation as Veronica had said she'd be. He frowned.
"Nothing yet, but she'll be fine. Don't worry. You'll meet her shortly. We've got a great cover story established for you both."
Greg gawked, and fought not to lose his temper. Something in Jack's voice told him things were definitely not fine. "She doesn't know yet, does she?" His voice conveyed his irritation. "It's too late to back out now and come up with another plan."
Jack ran his hand through his hair, disarranging it. Greg could see the man was worried, and it didn't calm his own unsettled nerves. Lord, this has to work.
"I know. Believe me, I know." Jack's frustration was evident. "I expected her early yesterday, but her plane was delayed because of bad weather. I couldn't speak to her about this over the airport phone. Veronica's convinced we have nothing to worry about. She says she won't let us down, and since my wife knows her better than anyone, I'll have to take her word for it. Livy's been after me for assignments with more meat to them, and she won't find anything more exciting than this cloak and dagger business. That's what's bothering me. Not only am I convinced this plan is full of holes, not knowing who's behind the threats makes it almost impossible to eliminate them. You're still convinced it's personal and not political?"
"I am, and the note proves it. For what it's worth, you don't have to worry about me. I'll play my part. Marrying a stranger is the last thing I want, but I'll do what I must for my daughter. Let's hope your woman is as good as you say she is and as agreeable as Veronica believes."
About the Author:
Susanne Matthews grew up as an avid reader of all types of books, but always with a penchant for happily ever after romances. In her imagination, she travelled to foreign lands, past and present, and soared into the future. Today, she has made her dreams come true. A retired educator, she now gets to spend her time writing, so she can share her adventures with her readers. She loves the ins and outs of romance, and the complex journey it takes to get from the first word to the last period of a novel. As she writes, her characters take on a life of their own, and she shares their fears and agonies on the road to self-discovery and love.
Susanne lives in Cornwall, Ontario with her husband. She has three adult children and five grandchildren. When she isn't writing, she enjoys reading, chatting on the Internet with her writer friends, and hearing from her readers.
You can find and contact Susanne here:
- Website
- Goodreads
- Amazon
- Google+
There is a tour wide giveaway for the blog tour of All for Love. These are the prizes you can win:
- 2 $10 gift cards (US Only)
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Bethany-Kris's Review of All For Love
****Five out of Five Stars****
Greg Simmons, a famous author constantly looking over his shoulder, has lost everything he holds dear ... except his daughter. A tragic accident took away his daughter's mother, leaving him to raise the girl who blames him for her mother's death alone. But, someone is out to get Greg and destroy what he haves left, but he's not willing to give it up. For his daughter, he'll do anything to keep her safe safe. Even marrying a complete stranger--for real--to keep up the facade.
Olivia Marshall has also lost those she was close to in a terrible skiing/avalanche accident. Her once promising career in competitive skiing ended that day and she vowed to never get back on the slopes again. Her new job as a bodyguard to Greg Simmon's daughter will put her front and center to her greatest fears again, but she's nothing if not determined. Can these two make it through together, and alive?
Susanne Matthews tells a great story and All For Love was no exception in my case. She has yet to fail me with her romantic suspense's. I would say All For Love was a little different from her norm, considering there is a bit more religious undertones to this one. It was done without being a focus or overbearing, so I didn't mind. It wasn't the overall story teller, but rather, pieces of the character's persona that was important to them as a person.
Nonetheless, Mrs. Matthews keeps a reading turning the page, wanting to know what comes next, who is behind it all, and why. I read this book in two sit-downs (I only break for life, you know). Greg will tug at your heartstrings with his love and devotion. Olivia with tug,too, but she also makes the reader want to cheer for her throughout the novel. Sometimes, you just want to hug them, too.
Descriptive writing that makes the reader believe they're a part of the action, seeing the book through the character's eyes, a great plot, and awesome characters makes All For Love one of my favorite Matthews novels yet ...
Then again, I've said that before. Until the next one.
Labels: Blog Tour, Book Tour, Review, Romance, Romantic Suspense, Spotlight, Susanne Matthews |
2 Responses
Susanne Matthews Says:
Thank you for the wonderful review and for having me on your blog today. I love dropping by!
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Very welcome! Thanks for stopping by!
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Peters uses rap, poetry to share positive messages
BEMIDJI – It took getting tagged by his high school wrestling coach for showing up high for a meet to get Ryan Peters to take a good look at the direction of his life.
Surrounded by classmates in a middle-class neighborhood and school, Peters wondered how his life took the turn it did when he was 10 years old and already addicted to drugs and alcohol.
Peters was born in Michigan, but grew up in Mound, Minn., near Wayzata.
He grew up in a single parent household with his mother, Teresa Jones, a strict Southern Baptist. Ryan said that he was a kid who hid his addictions from his mother.
Drugs and alcohol were abundant in his surroundings and everyone did them, so even at 10, it was the norm, he said.
However, when Jones found out about her son's addictions, she took care of the situation immediately.
"I got into a little bit of trouble when I was 17 and was sent to a treatment facility (a youth recovery program) in South Dakota," Ryan said. "It was halfway through my junior year. I didn't want to go back to Mound so I came here to Evergreen House, which turned out to be my only option."
Ryan attended Bemidji High School, danced and sang with Vocalmotive and packed three years of high school learning into two. Ryan was ready to leave Evergreen House when his "godparents," as he calls them, stepped into the picture.
"The folks at Calvary Lutheran Church were good to me," he said. "Deb and Paul Ericsson asked me to stay with them – that was awesome because I really didn't want to go back home.
"I love the guy, he's the father I never had and I know how to push his buttons."
Ericcson gets a little teary when talking about Ryan, and said he and his wife knew they couldn't let Ryan go home after all the progress he made in recovery.
Ryan also pointed to others in his life that helped him, including his girlfriend, Amanda, and the rapper Tupac Shakur. Ryan said the rapper's poetry gave him hope for the future.
Perhaps Tupac's words: "Everybody's at war with different things. I'm at war with my own heart sometimes," helped Ryan see that his downtimes were shared by many other youth.
When Ryan entered Bemidji High School, he used his interpersonal skills to see the way around those students who might get him back on the wrong track. That helped Ryan to stay sober and he "hung out" with kids he probably wouldn't have in his past.
Ryan is clean for four years now and attends alcohol anonymous meetings twice a week. He hopes to restart AA meetings on the campus of Bemidji State University, where he is a resident assistant at Oak Hall.
"It's who you know – who you hang with – that can get you into trouble," Ryan said.
His major in criminal justice is an avenue for him to work with troubled youth along with his love of music. Ryan plans to work as a counselor in the future and knows some of the students he's working with as an RA at BSU welcome his input. He is proud of being chosen from among 200 candidates who applied for the position.
"When kids come in from Northwest Juvenile Center, they don't want to only hear from the older guys," said Ryan. "The kids look at them like, 'You have no idea of what I'm going through,' because we're from different generations.
"I feel as though they will listen to someone their own age. I try to use the whole rapping thing to like 'lure them in.'"
And Ryan now is sending his own positive messages to audiences in Bemidji. As a representative for his record label, Aurora Borealis, Ryan books gigs at the VFW in downtown Bemidji to appreciative audiences.
Last June, during the Bemidji Book Festival, Ryan won second prize at the Poetry Slam for his Christian rhymes.
Now he prefers to talk of his poetry in terms of giving a positive message to anyone and all who need courage to succeed or just overcome the unforeseen events that can cloud an otherwise bright future.


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The Latest: Vatican flag flying outside United Nations
The Vatican flag is flying for the first time at the United Nations
The Vatican flag is flying for the first time at the United Nations
Federal prosecutors say seven people from Ohio and West Virginia have been charged in a heroin trafficking operation.
John Carroll Catholic High School student Nick Bertani crafted a giant art installation for his art class of Pope Francis.
A group of parishioners gathered early Friday morning to load up two buses and head to Philadelphia to see Pope Francis.
The latest weather forecast for Youngstown, Ohio and surrounding areas.
A Wellsville man is accused of burning his house to the ground early Wednesday.
A storm has heavily damaged at least 10 homes but apparently caused no injuries when it struck near Charleston, South Carolina.
A juvenile brandished what a resident thought was a firearm after being asked not to trespass on the resident's yard.
A judge has reduced the sex offender status of a former high school football player found delinquent in the rape of a 16-year-old girl.
Jason Kipnis hit a leadoff homer, Carlos Santana connected for a three-run shot.
The latest weather forecast for Youngstown, Ohio and surrounding areas.
Two people were taken to the hospital following a later afternoon crash in Beaver Township.
Community Connectors is part of Gov. Kasich's program, which provides a grant to give juniors and seniors internship opportunities.
David Engler made the announcement Thursday night during a Republican gathering in Beaver Township.
Jose Morales, one day away from retiring, and his son, also named Jose, four years into a career.
Congressman Tim Ryan said he hopes that the pope's message will encourage Congress to work together in pursuing a culture of care.
Holy Wooder, was already a hit with happy hour crowds when the seminary hosting Pope Francis this weekend called to say it wanted some, too.
Both Jesuit schools said it is the first time they have rescinded an honorary degree.
The jackpot is currently more than $1 million.
Alvarez hit a go-ahead, three-run homer in the eighth inning, and the Pirates earned their 10,000th win since joining the National League.
At an evening prayer service in St. Patrick's Cathedral, Francis thanked American nuns for their strength and courage.
A van overloaded with 24 people headed to a factory overturned on an interstate in Indiana on Thursday, killing one passenger.
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A robust and bawdy battle of the sexes, this ever popular comedy captivates audiences with outrageous humor as Katharina, the shrew, engages in a contest of wills–and love–with her bridegroom, Petruchio. Their boisterous conflict is set off against a more conventional romantic plot involving the wooing of Katharina's lovely and compliant sister, Bianca. Rich with the psychological themes of identity and transformation, the play is quintessentially lighthearted,… (more)
Publisher: Modern Library (September 14, 2010)
Format: EPUB
File size: 3.2 MB
Protection: DRM
Language: English


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Kathryn Scott - Live Worship At Focusfest CD
by Kathryn Scott;
Rated 4 stars by our customers!
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Price and PurchaseOffer price: £12.99 Free UK Delivery Go to Basket
If you're buying for a church, school or business, why not Buy Now Pay Later?Find Out More
Kathryn Scott - Live Worship At Focusfest CD
Full Product Description
They have two daughters and have recently set up a worship internship within the church.
It is an established fact that in the church world-wide, women make up the majority of our congregations. However, women are often not released to serve and contribute effectively to the life of the church.
Focusfest Women's Conference was founded in 1993 and has become Northern Ireland's largest event for Christian women, drawing women of all ages together from different denominations, backgrounds and locations. The desire of Focusfest's heart is that Focusfest will be a tool for equipping and mobilising women of all ages to make a difference in their world. Imagine a group of women, young and old, who know their true worth and purpose in God, reaching out and showing God's love to those they encounter everyday!
Kathryn Scott - Live Worship At Focusfest CD was published by Integrity Music Europe in September 2008 and is our 20197th best seller. The ISBN for Kathryn Scott - Live Worship At Focusfest CD is 5034646997825.
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Got a question? No problem! Just click here to ask us about Kathryn Scott - Live Worship At Focusfest CD.
What songs are on this album please?
The full track listing is as follows:
1. Holy
2. Our God Saves
3. Everlasting God
4. I Belong
5. I Love You Lord
6. No Turning Back
7. All People That On Earth Do Dwell
8. I Have Decided To Follow Jesus
9. Hope Of The Nations
10. Hosanna
11. Worthy
12. From The Inside Out
13. At The Foot Of The Cross
14. Nothing But The Blood
15. There Is A Redeemer
Details for Kathryn Scott - Live Worship At Focusfest CD
|Integrity Music Europe (September 2008)
|Product Code
|Page last updated
|17th August 2017


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Release Date: 2012 |
Album Rating: 4.0A short review for a short album. Seriously you guys should give this a chance. It's pretty
impressive, and the worst case scenario is you loss twenty minutes of time.
Stream: aarontrinkner.bandcamp.com
Album Rating: 4.0I seem to have forgotten how to link something in a comment.. can anyone help me out?
Are you this guy? Or his brother or something?
Album Rating: 4.0you didn't even read the first paragraph : ( it says i'm his twin brother
Album Rating: 4.0I USED TO BE FAMOUS!
I started writing reviews again for the new mewithoutyou one. And now i'm in college and I have so
much more time to write. So I do
Whoops, yeah, I skimmed the review and started at the bold. Listening now though.
I'm going to trust you on this one bro.
Album Rating: 4.0Thank you. You'll like it. It's not bad. I'm probably overselling it (he is my brother) But i remember not enjoying a lot of his early music. But these four tracks are pretty good
sounds pretty interesting
acoustic music is really hit or miss with me :/
Album Rating: 4.0only one song is purely acoustic. The first one. It's my personal favorite song. But the last two are electric.
so is that you in the album art?
and besides Aids's hyperbolic review of an album he played in is featured right now so everything goes
Album Rating: 4.0Yeah, It's me and my cousin at Cornerstone festival.
And I haven't even read that review yet. I'm surprised at how I haven't been bashed for him being my brother yet. I guess people don't care lol
Album Rating: 4.0You know what i wanted to say but forgot to mention it? all of this was recorded in a bedroom using a 97 windows computer. Seriously blows my mind every time i listen to this. It doesn't sound that lo-fi
Your brother has quite a nice voice.
Album Rating: 4.0I think so too lol
it's pree cool
Album Rating: 4.0Finally! Another rating!!
Bands: A B C D E F G H I J K L M N O P Q R S T U V W X Y Z


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Advanced Micro Devices will pull back the curtain a little more on its first quad-core processor the week of Feb. 12. At the International Solid State Circuits Conference in San Francisco, which kicks off Feb. 11, the company's engineers will demonstrate new technology that will make AMD's first quad-core chip more power-efficient than previous dual-core processors. The quad-core AMD Opteron processor, which goes by the codename "Barcelona," is scheduled to be released later this year. It will compete against Intel's quad-core Xeon 5300 series, which the company released last November.
AMD, which is based in Sunnyvale, Calif., believes that its engineers have developed a better, "native" quad-core design, which allows four, x86 processing cores on a single piece of silicon. By comparison, Intel's quad-core processor ties two dual-core chips onto a single piece of silicon. In addition, Intel and AMD have each poured money and resources into technologies that ease the power consumption and heat generation of their processors. At this week's conference, AMD will show its quad-core processor's power efficiency. Specifically, engineers have improved on the company's PowerNow technology, which can increase or reduce the amount of power to the chip depending on the demand.
View: The full story
News source: eWeek


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Click here to view this resume
A resume is often the first interaction you have with a potential employer. No matter how experienced you are, if your resume is poorly written you have less of a chance at getting an interview than someone with fewer skills who has a better crafted resume. This Certified Nursing Assistant resume sample will show you some common mistakes to avoid.
Whoever reviews your resume is trying to envision how you will fit into their organization. If you are changing careers, your resume must convey how your past experience fits into your future career plans. The summary here should not be about teaching, but rather, how teaching skills are transferable to nursing skills. If you have two parallel careers, which not so unusual these days, emphasize the one in which you are trying to get a job with your resume. Some people have more than one resume written for this very reason; different jobs require a different emphasis on your skills and background.
Your Highlights Should Emphasize Relevant and Hard Skills
Many character traits, or soft skills are listed here under highlights, but most of these would fit better in the summary paragraph. You highlights should list skills by relevance and importance. In this example, working with young children should not be a highlight if your only nursing experience was with the elderly. Hard skills like typing and record keeping should be listed first as they are easily measured and are transferable from one career to the other. Pay attention to format; highlights should be in table form, without bullets, and balanced so that each column has a near equal number of phrases.
This should be presented as bullets and as be as specific as possible. This resume is far too vague. Mention how many words per minute you can type, for instance, or how many records you maintain every month. If you listed skills in your highlights, they should show up in your experience section as well to demonstrate how they are applied. Think about what you do all day and jot down what comes to mind; if you have to, take a notebook to work and write down what you do when you do it. No matter how routine your work may seem, you can easily create a list of 5 to 10 bullets with specific tasks and duties.
Youve probably heard many times that a resume should never be longer than a page. Thats not always true, but your resume should definitely never be less than one page. If it looks like you have nothing to say about yourself, you will come across as lacking ambition or interest in the job you apply for. It is always possible to go into more depth about what you did in your previous jobs, or what your various skills are.
Missing Information
At some point this person had to have received a nurses certificate but this is not mentioned in the education section. Before you write a resume, give careful thought to each section and jot notes on what you need to include so you dont forget anything important. If necessary, ask a co-worker or friend to go over your list with you to help you remember or see yourself from a different point of view. Additionally, this resume shows an employment gap. If you are out of work for more than 30 days you should indicate what you were doing; list volunteer or community activities if you had no paid work during that time. Are you ready to write your own exceptional Certified Nursing Assistant resume? Use the tips from this sample to draft your resume with QuintCareer's resume builder.


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By JOANNA KAKISSIS
Published: November 11, 2007
The aromatic resin from the mastiha, or lentisk, tree on the Greek island of Chios has flavored potions, sweets and cosmetics in the eastern Mediterranean for thousands of years. In more recent times, entrepreneurs have been transforming the fresh burst-of-sweet, hint-of-bitter sap known in Greece as mastiha into a boutique brand for these healthy-chic times.
The mastihashops, run by Mediterra, an outgrowth of the Chios Gum Mastic Growers Association, use mastiha in almost everything: chewing gum, coffee, candy, pasta, ouzo and shampoo. There are 11 mastihashops in Greece, 1 in Cyprus and 2 in Jeddah, Saudi Arabia. A store will open in New York next month, and there are plans to expand in Europe and Asia.
Pinar Akkaya, a customer from Istanbul, grew up eating mastiha in Turkish custard creams and loukoumi (known outside Greece as Turkish delight). At the busy central Athens mastihashop near Syntagma Square, she admired the nostalgic packaging -- with 1960s black-and-white images of a vanished Mediterranean culture. Indeed, mastiha has made the rounds in history. Hippocrates studied its medicinal effects, and Roman nobles used toothpicks made from the tree's wood to whiten their teeth. Mastiha became a Mediterranean and Middle East delicacy in the 14th century, when the Genoese, who occupied Chios, exported it to Marseille, Beirut, Tehran, Odessa and Constantinople. In modern times, mastiha imbues the Turkish ice cream called dondurma and custard creams in Syria and Lebanon.
Mastic trees, cultivated in southern Chios, begin to produce resin after about five years. Most of the product is exported, mainly to Arab countries, where it is sold in chewy crystals or powder in bazaars.
At the shop in downtown Athens, mastihashop chewing gum ranges from about 90 euro cents to 2.40 euros, about $1.33 to $3.50, at $1.47 to the euro; toothpaste goes for 4.40 euros; and body butter for 12.60 euros. In the five years since the first shop opened in Chios, the company has grown steadily, said Stylianos Gerazounis, business development manager for Mediterra.
The mastihashop in central Athens (30-210-363-2750; www.mastihashop.com) is at Panepistimiou and Kriezotou Streets, near Syntagma Square.


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Book of Days
ok of Days, by Lanford Wilson, is set in Dublin, Missouri - a town "so beautiful in the spring it could break your heart." As the town's own Saint Joan searches for the truth, Dublin's soul is revealed and America's fate is in the balanc
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PROVO — He's the last of the Reynolds.
Houston Reynolds is the caboose in a train of brothers and a father who made careers playing on the offensive line at BYU.
This Reynolds, a junior, is slated to play center and guard and is coming off shoulder surgery in the offseason. In fall camp so far, Houston Reynolds has battled some sore shins but is expected to don pads and get after it this week.
If you think about it, it's pretty unusual to play major college football, have a shot at a pro career, become a professional coach and then have one son after another not only play college football, but start and play major roles.
That's what's transpired with BYU assistant head coach Lance Reynolds and his progeny.
His oldest son, Lance Jr., started as a center during the John Beck era. In an unfortunate twist of paperwork, he did not get an extra year of eligibility due to an injury and never played his senior season as Beck's center. He now works for Zion's Bank near University Mall.
His second son, Dallas Reynolds, who started almost his entire BYU career, is back with the Philadelphia Eagles this fall and is in his fourth year in the NFL. He is currently running with the second team on the Eagles' offensive line, sometimes getting a shot with the first team.
The third son, Matt Reynolds, signed as a free agent with the Carolina Panthers after not getting drafted this past spring. According to his father, he's going through a typical rookie camp, not knowing what to expect, although he has seen time with the first and second team.
Matt Reynolds had a chance to put his name in for the NFL draft after his junior year but decided to return as a senior. He was very disappointed on draft day when nobody called his name.
"We talked about the possibility of that happening in the days leading up to the draft," said coach Reynolds. "So we were prepared, if that happened, but it was still a very long and painful day for Matt (Reynolds). He was very disappointed.
"You see it every year, somebody sitting by the phone on draft day and the call doesn't come. What happens, happens and you have no control over it, so you can't worry about it. You have to make it anyway, whether you are drafted or not."
Getting drafted is about respect and realizing what people think of you. "But in the end, you have to put the lid on the garbage can and forget about it and go out and play," said the father.
With Houston Reynolds, BYU's offensive line has another in a group of well-trained, smart players who understands the game and what it takes to play at a major college level.
Houston Reynolds is 6-foot-2, 296 pounds, and although he underwent shoulder surgery this winter, he has regularly benched 400 pounds with that shoulder this summer.
"If we can just keep that dude healthy, he's a good player. He's explosive, really powerful and a real stout guy, but he's had some injury problems and we're hoping he can get over that and get on," said his dad, Lance. "If that happens, he'll be a good player. He started the bulk of the season before he hurt his shoulder last season."
Like his brothers before him, he's a gentleman, a respected teammate and a very coachable player. And like all of them, he's humble.
He wears the Reynolds' brand very well.
The father is in his 29th year coaching at BYU, his 33rd year in the profession if you count Snow College. He sees this year's Cougar team as a group made of talent and experience.6 comments on this story
"We need a few more stand-up, grit-your-teeth, nothing-stands-in-your-way type guys to step forward," Lance Reynolds said. "When they get tired, we'll see who stands up and who fades, but right now they are experienced, older guys and we have a returning quarterback, which is always great news."
In the group he coaches, Reynolds has Devin Mahina out with a broken arm, but the rest of his tight ends are healthy. "We are certainly a mile ahead of where we were a year ago. We started in a bad place, then had a lot of injuries."
Reynolds said the Cougars have healthy and experienced backs, wideouts, linemen and tight ends — and that wasn't the case a year ago.
"We've got to make it to the dance with everybody there, and then we might have a chance to be pretty good," said coach Reynolds.
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Stanley Kubrick was an American film director, screenwriter, producer, cinematographer and editor who did most of his work as an expatriate in the United Kingdom. He is regarded as one of the greatest filmmakers of all time. His films, typically adaptations of novels or short stories, are noted for their "dazzling" and unique cinematography, attention to details to achieve realism and an inspired use of music scores. Kubrick's films covered a variety of genres, including war, crime, romantic and black comedies, horror, epic and science fiction. Kubrick was also noted for being a perfectionist, using painstaking care with scene staging and working closely with his actors.
Starting out as a photographer in New York City, he taught himself all aspects of film production and directing after graduating from high school. His earliest films were made on a shoestring budget, followed by one Hollywood blockbuster, Spartacus, after which he spent most of the rest of his career living and filming in the United Kingdom. His home at Childwickbury Manor in Hertfordshire became his workplace where he did his writing, research, editing and management of production details. This allowed him to have almost complete artistic control, but with the rare advantage of having financial support from major Hollywood studios.
A film is -- or should be -- more like music than like fiction. It should be a progression of moods and feelings.
Quotes, by Stanley Kubrick
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A film is -- or should be -- more like music than like fiction. It should be a progression of moods and feelings.
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Public invited to 'listening series' to decide funding
What do you want to accomplish with history funds from Minnesota's Legacy Amendment over the next 20 years?
The Minnesota Historical Society (MHS) will ask Northern Minnesotans that question at two listening sessions on Friday, Dec. 14, in the Detroit Lakes Library.
The first session, from 10:30 a.m. to noon, is open to people currently working in the history field. The second listening session, from 1 to 2:30 p.m., is open to the general public. The Detroit Lakes Library is located at 1000 Washington Ave, Detroit Lakes.
The Clean Water, Land and Legacy Amendment was approved by Minnesota voters in November 2008. One of the Amendment's four funds, the Arts and Cultural Heritage Fund (ACHF), supports the preservation of Minnesota's history and cultural heritage. Many millions of ACHF dollars will be invested in Minnesota history over the 25-year life of the Legacy Amendment.
"We have an unprecedented opportunity to shape how history looks in the future," said Matt Hill, MHS Arts and Cultural Heritage Fund Manager. "We encourage Minnesotans to make history by giving a voice to this process. What do you want to accomplish with Legacy history funds?"
To participate, please RSVP to Nancy Franke Wilson at 763-360-3875 or firstname.lastname@example.com.
MHS is holding five listening sessions throughout Minnesota in December. To learn about current MHS initiatives funded by the Legacy Amendment's Arts and Cultural Heritage Fund, please visit legacy.mnhs.org.
This event is made possible by the Legacy Amendment's Arts and Cultural Heritage Fund through the vote of Minnesotans on Nov. 4, 2008.
The Minnesota Historical Society is a non-profit educational and cultural institution established in 1849. The Society collects, preserves and tells the story of Minnesota's past through museum exhibits, libraries and collections, historic sites, educational programs and book publishing. Using the power of history to transform lives, the Society preserves our past, shares our state's stories and connects people with history.


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Dozen utility poles brought down in rainstorm knock out power in Yonkers
YONKERS - Thursday's nights rainstorms brought down a dozen utility poles in Yonkers, knocking out power to thousands.
Firefighters say the storm's strong wind gusts most likely brought down the poles. Most of the outages are on Yonkers and Ridgewood avenues, where most of the poles came down. Con Edison crews are now on the scene, working through the night to restore power.
Elsewhere, drivers say they have had to take things slow on the roads because of the large puddles and flooding.
Earlier Thursday evening, an Amtrak train was stranded on the tracks for three hours between Rye and Greenwich. Wires on two northbound tracks came down, causing the delay. Amtrak officials say another train was brought in to bring the passengers to Stamford, Connecticut.


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Kids Sofa
If you're looking for a quality kids' couch or bean bag, you've come to the right place!
The HipKids online store stocks an awesome range of children's furniture. These smartly designed kids' sofa chairs are suitable for a range of activities, such as reading, playing video games, watching television and napping.
Featuring durable materials and a solid construction, our collection of kids' sofa chairs meets Australian Safety Standards while also being a stylish addition to your home.
In addition to sofa chairs and couches, we also sell kids' bean bags and funky floor cushions in a variety of colours and designs.
Sit Back and Relax
Your child will love having their very own sofa! Sourced from the best furniture manufacturers in the world, HipKids' sofa chairs are built to endure the demands of everyday life. Our team handpick each one of our products, and quality workmanship is a key feature across the entire range. Our collection of kids' couches and sofas is suitable for children of all ages.
Our collection of kids' sofa chairs boasts clever design details such as:
- Water-resistance – you won't have to worry if playtime gets a little messy. These sofa chairs are easy to wipe down and some styles are suitable for outdoor use.
- Bright colours – from neutral shades to bright jewel tones, nearly all products in the range are available in a number of different colours.
- Practicality – HipKids' sofa chairs come with an assortment of handy features, such as cup holders, footrests, carry handles and washable covers.
Our Story
HipKids is a family-owned business based in Melbourne. We have been providing inspirational children's furniture since 2006, delivering unique and beautifully designed products to families all over Australia. If you'd like to see any of our products in person, don't hesitate to pay us a visit at our showroom!
We cannot guarantee that all the products in our online range will be available to purchase in store, but you can check whether we have a certain item in stock by contacting us


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Expert Orange County (O.C) SEO Consulting Services
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Orange County California (O.C) Business Resources & Information
Orange county located in southern California near Los Angeles county and is home to Disneyland. The county has 34 incorporated cities (see below). The county seat is in Santa Ana. Population: 3,010,232.
- Orange County
- U.S. Census Bureau Economic Statistics for Orange County
- Orange County Chamber of Commerce
- Orange County Business Council
- South Orange County Chambers of Commerce
- Orange County Small Business Development Center
- TriTech Small Business Development Center
- OCTANe – fueling Inovation in Orange County
- Life Coach Training Orange County, CA
- Life Coach Training
- What is Life Coaching
Orange County is a county in California. Its county seat is Santa Ana. As of the 2010 census, its population was 3,010,232, making it the third most populous county in California, behind Los Angeles County and San Diego County and the second most populous in the Greater Los Angeles Area after Los Angeles County. It is the sixth most populous county in the United States as of 2009 while at the same time is the smallest area-wise county in Southern California, being roughly half the size of the next smallest county, Ventura. The county is famous for its tourism, as the home of such attractions as Disneyland and Knott's Berry Farm, as well as several beaches along its more than 40 miles of coastline. (WikiPedia)


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As I understand it, summer break from schools originally came about because we were — at the time — a mostly agrarian society. That is, lots of folks lived out in the country, on the farms, and kid were needed to work the fields during the growing and planting seasons.
Hence, the three or so months off during the summer. It's become institutionalized and now most parents couldn't conceive of a summer that didn't include kids home out of school.
The thing of it is, we couldn't have designed a better skill-destroying, demotivational tool had we been trying. Seriously.
For most kids, the summer consists of sleeping as long as possible, doing as little as possible and thinking as few times as possible. All of which makes for a serious degredation of all the skills and knowledge picked up with all that hard work during the school year. And, to top it off, teachers must waste time at the beginning of the school year to reteach stuff that students learned the year before.
Which is why I come to you dudes with a novel suggestion. Why not put aside an hour or so a day, or however long you can afford, and have your little dude or dudette sit down and do some age-appropriate, grade-appropriate math problems? The best time to start this is now, when the school year is fresh in their minds and they're still used to doing work that breaks them out in a mental sweat.
I know most parents break out in the mental sweats and shakes when contemplating math problems, but I've got an easy answer for you here and it doesn't involve you having to create hard math problems all by your ownself.
That's what Google is for. A quick surf through the search engine and I found many, many sites that offer a whole mess of free math worksheets that you can download, print and use, or even sites that offer on-line, immediate response math worksheets on the computer. If they're not completely free, most of them offer a 30-day free trial offer.
There's a reason that websites offer this 30 days free. They hope you'll sign up for the paid subscription at the end. There's nothing wrong at all with signing up, using the service for 30 days and then moving on to a different site at the end of the trial period. For instance, Adapted Mind is a math learning site that offers such a trial offer. It definitely looks like a good place to start.
For instance, I found a site called School Express and, truly, I love this place. Not only are there free worksheets on subjects from etiquette to math for grades 1-9 that you can download already made, but the site also offers you the chance to create your own worksheets. I went ahead and made a word search. I simply typed in nine or so words off the top of my head, hit submit and — violá — there it was. Ready to be printed and used.
School Express offers 17,000 free worksheets. Subjects include reading, science, critical thinking, kindness to animals (I dunno. It's there.), social studies, sudoku and more. Definitely worth checking out.
Math Mammoth also offers something upwards of 300 free worksheets. You'll need to give the site your e-mail address, confirm that it's yours and then you'll get a massive download of free worksheets all in one go. There's some more stuff on the site, but the free load of worksheets is, I think, the important thing.
There you go, dudes. It took me all of two minutes to find all this stuff.
It's a great idea. I honestly think it's something that each child needs to do over the summer. Keeping their brains limber and used to work can't be anything but good for the little dudes and dudettes.


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Nationwide recall: Healthy Choice Chicken and Rice Soup
CHARLESTON, S.C. (WCIV) -- The U.S. Department of Agriculture's Food Safety and Inspection Service (FSIS) announced a nationwide recall of microwave soup.
Officials said ConAgra Foods is recalling about 54,673 pounds of chicken noodle soup products because of misbranding and undeclared allergens.
While the product was made with wheat and eggs the microwave soup bowls were sold with a "Healthy Choice Chicken with Rice" soup label, which doesn't not declare the allergens.
The products subject to recall bear the label: {}
- 14-oz. microwave bowls of "Healthy Choice Chicken with Rice" soup bearing the establishment number "P-770" inside the USDA Mark of Inspection and the Best By date of "JUN092015" stamped on the bottom of the bowl.
The products were made Dec. 16, 2013 and shipped to retail stores nationwide. They were also sent to the Dominican Republic, Jamaica and Puerto Rico.
The problem was reported to the firm by consumers who discovered chicken noodle soup in mislabeled bowls. FSIS and ConAgra said they haven't gotten any reports of adverse reactions from eating the soup but anyone concerned about a reaction should contact their doctor. {}{}{}{}{}{}{}{}{}
Anyone with questions about the recall should call the ConAgra Foods hotline number at: (800) 289-6014.


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You can count on one finger the mothers who play gigs costumed as a monstrous cross between a fly and a witch, surrounded by musicians dressed as bald-wigged characters from a horror movie (one lucky keyboardist even had a dagger embedded in his back). It's no surprise that Karin Dreijer Andersson, aka Fever Ray, was apparently told by her husband that her music is too unsettling to be heard by their two children.
And yet her group's look, which was complemented by dim purplish lighting and a cat's-cradle of green laser beams, paled alongside the suffocating properties of the sound.
Dreijer Andersson, whose day job is as half of cult Swedish electronic duo the Knife, reportedly intends to wind up Fever Ray after this brief tour. If so, she's going out with a bang – no, make that a distorted clang. Here, the music was the aural equivalent of wading through something dank and viscous, with Dreijer Andersson's half-submerged vocals providing a humanish touch. The first few numbers set the scene: illuminated mainly by a dozen lampstands that rendered the musicians blurry silhouettes, Fever Ray droned through If I Had a Heart and Concrete Walls, icy and aloof.
For all the iciness, there was a beating heart in there: the wavering synth note that pierced Seven sounded vulnerable; so did the keyboardist who, on a cover of Peter Gabriel's Mercy Street, created his own beat by clapping his hands. Dreijer Andersson, too, had moments when her hands dangled awkwardly, reminding you there was a human under the witchy robes. But these glimpses of normality did little to break the spell. When they left after Coconut, not having said a word to the audience all night, mesmerised fans shuffled out without even calling for an encore.


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Okay I have an array set up which is:
int number[30];
and the array is filled using random numbers. Now my question is how would i go about finding the highest value in the array with its array number. Its really boggling my mind and im sure its probably some simple function.
Anyways any help would be greatly appreiciated!


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Shambush! theater troupe gathered 300 volunteers in Stanmer Park, Brighton, England, on Saturday to re-enact Kate Bush's pop promo "Wuthering Heights."
The event called "The Ultimate Kate Bush Experience," was part of the Brighton Festival Fringe, where Shambush! aimed to set a new world record for the number of Kate Bush look-a-likes performing the hit song in one place.
Shambush! describe themselves as:
...a ludicrous troupe of performers. Shambush! specialise in creating immersive, theatrical encounters, performance spaces and nonsensical events.
Brighton's main newspaper The Argus reported on the event:
The bizarre sight of hundreds of men and women in red dresses, long black wigs and bright lipstick took many visitors to Stanmer Park on Saturday by surprise.
The Fringe event, organised by performance group Shambush, saw fans of the 80s icon spend the sunny afternoon practicing the dance moves before breaking the record.
More pictures and video from The Argus here.
Hire Shambush! for your event here and follow on Facebook here.
Below is a video of rehearsals for "The Ultimate Kate Bush Experience."
With thanks to Norn Cutson!


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KAZAKHSTAN, Russia, Dec. 20 (UPI) -- The head of Russia's Federal Space Agency said Sunday nuclear engine-powered spacecraft would be finalized by 2012.
Anatoly Perminov said financing for the space program in the next nine years would require at least $580 million, RIA Novosti reported.
Perminov previously had said development of Megawatt-class nuclear space power systems for cosmonaut-manned spacecraft would be crucial if Russia is to maintain its competitive edge in the world's space theater, including exploration of Mars and the moon, the newspaper said.
The president of the Russian Academy of Cosmonautics and head of the Keldysh research center, Anatoly Koroteyev, said the development of new propulsion systems and energy-mass efficient energy supplies is the major scientific and technical problem in sending manned missions to the Moon and Mars.
The current Russian space industry is clearly incapable of setting up a permanent base on the moon or of achieving an independent manned mission to Mars, Koroteyev said.


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JScript Editor ExtensionsFree
Contains a number of extensions for the JScript editor in Visual Studio 2010.
Visual Studio
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Fantastic A description of how to implement region on the main page would be great:
This is must have extension for Java Script developers who are used to C#/VB code. I needed something like this badly.
This is great a addition to my personal view of the "king of IDEs". It's one of those "why haven't other tools done this, its so mind numbingly obvious" pet peeves, that finally gets resolved...by Visual Studio no less!
Great extension. Only things missing now are #region and better intellisense for /// on doc comments. Anyway, deserves a 5 stars.
very good!
It's a wonderful addition in visual studio, I was using re-sharper 6.0 which has some nice Javascript re-factor feature, I definitely appreciate this kind of improvement and hope to see this extension with more and more feature in future versions.
For those people wanting a 'collapse all' feature. Simply press ctrl + m + a. This will collapse everything but if you've got 100's of JS functions like myself you'll find it useful!
Very helpful. Good work!
Very nice and thank you for this. If possible, it would nice to see this added as a feature:
I was waiting for this all my life!
I hope that these extensions alongside with JSEnhancements will be integrated in VS.NET 2012.
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Salute & Serve event a success in Charlotte
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The inaugural Salute & Serve Our Nation's Heroes event – featuring the efforts of The American Legion, Soldier's Wish and the HISTORY channel – was a big success at Charlotte Motor Speedway in North Carolina over the weekend.
More than 400 tickets to the HISTORY 300 NASCAR Nationwide Series race were given to servicemembers and veterans. A soldier who has completed four tours of duty in Afghanistan was, along with his family, given a VIP experience while attending the Coke 600 Sprint Cup Series race. And two North Carolina National Guardsmen were guests in the HISTORY Channel's VIP suite for the HISTORY 300 and were given a behind-the-scenes tour of NASCAR. Medal of Honor recipients also were honored for their service with a special tasting provided by HISTORY's Cross-Country Cookout.
Stars from several HISTORY programs, including Rick Dale from "American Restoration" and Willy Robertson from "Duck Dynasty," were at the track over the weekend. Soldier's Wish Executive Director Rick Bauer was on hand, as was Peter Gaytan, executive director of the Legion's Washington office. Gaytan shared the Legion's message and asked those in attendance to thank those currently serving in the U.S. Armed Forces. "Through Soldier's Wish and The American Legion, we can say 'thank you' to those who have served and those currently serving," said Gaytan.
The American Legion and Soldier's Wish had a tent at the Charlotte Speedway where people could nominate a servicemember or veteran to have a wish granted; more than 1,000 nominations were submitted.
North Carolina Legionnaires – including National Executive Committeeman Jerry Hedrick and Department Adjutant Frank Stancil – were on hand to pass out hundreds of Legion brochures and answer any questions about the Legion.
Several more Salute & Serve Our Nation's Heroes events are planned for the remainder of the summer. They include:
June 6-9 – CMA Music Festival; Nashville, Tenn.
June 25 – HISTORY New York City Event
July 6-7 – Summerfest; Milwaukee
July 20 – Chicago
July 29-31 – Oshkosh Airventure; Oshkosh, Wis.
Aug. 4-6 – Sturgis Motorcycle Rally; Sturgis, S.D.


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"Cheryl kicks Ash," was The Sun's banner headline last week. "Beauty (that's The X Factor judge 26-year-old Cheryl Cole) dumps rat footie star hubbie" (that's multi-millionaire philandering Chelsea footballer Ashley Cole). You have to have a heart of neo-Georgian stone not to laugh.
And those chuckling at this splendiferous tabloid soap opera (Ashley, by the way, reportedly blames his marriage woes on Cheryl's mother, Joan, moving into the couple's £6 million pile) will be the grand Surrey estate agents as another Oxshott footballer's mansion bounces onto the market.
"Other agents in the country get instructed because of death and debt, in Oxshott it is divorce," said Charles Davenport, a partner with Knight Frank.
Oxshott is estimated to be the most expensive village in England. It has about 6,000 residents, many of them celebrities including the tennis star Andy Murray, the publicist Max Clifford and a football team of multi-millionaire soccer stars, among them England captain John Terry who earlier this year was, like Ashley, accused of "playing away". The leafy suburb with its private roads is sandwiched between the A3 and M25, which Savills estate agency calls the country's "wealth corridor". It is 35 minutes from central London (less, obviously, in a Lamborghini) and there is not a single family house for sale on its Crown Estate for much under £2 million.
The latest mansion to come on the market is Amberleigh House, which has a guide price of £5.25 million. It is a seven-bedroom red-brick pile built two years ago that is every Wag's dream. It has electric, wrought-iron gates, a twinned Doric column portico, scores of sash windows and a blocked paved drive and parking area with garaging for four cars (two of which are specifically designed for the mandatory large, black, smoked-window Range Rover Sport with personalised number plates).
Inside are a grand entrance hall, family room, games room, gymnasium, and indoor swimming pool. It typifies the 21st century Oxshott vernacular style.
In 1885, Oxshott was, as it had been for centuries, a hamlet of pig farmers living on ancient hunting land owned by the Crown. However, the arrival of the railway changed it overnight. The hamlet developed a high street containing three shops – a draper's, tobacconist and set of tea rooms – and a rapidly growing community of comfortably off commuters living in newbuild mock Tudor homes on land that had been released by the Crown Estate.
"I remember it as a typical genteel Surrey village with a Cullen's, a Mac Fisheries, a butcher and a cobblers," says art gallery owner Martin Riley who lived there as a child and whose parents sold the family's four-bedroom detached home in 1968 for £12,000. ''Then it was an unremarkable place populated by the professions, City men and a few farm workers.''
Now the high street has 12 shops that include four estate agents, three interior stores and the Clay Salon and Spa that describes itself as a ''blissful sanctuary of tranquillity''. And those shops serve rows of homogenous multi-million-pound houses, commonly owned by twentysomething footballers and thirtysomething fund managers mostly sited on ''The Crown'', as the main patrolled estate is known locally.
Each property is built on half-acre or so, separated from the others by red-brick walls and swathes of evergreen foliage.
"There are no listed houses in Oxshott," says Charles Davenport of Knight Frank. "There are one or two Georgian houses and a handful of Victorian houses and the rest are modern."
Today the old mock Tudor manor houses that were built in the Fifties are being pulled down faster than a centre forward in the penalty box. So, too, are the detached houses from the Sixties, Seventies, Eighties and even the Nineties. They are making way for neo-Georgian pads that would sit comfortably in the soap opera Dynasty.
These new homes follow a formula. Behind the usual fortified electronic gates and CCTV lies the formal side that includes a large marble-floored hall that opens onto a rarely used guest sitting room and a modern dining room with the 12-seat table commonly already set in case, I presume, Roman Abramovich drops by. Then there is the informal part with a huge "family room" with a state-of-the-art kitchen and huge plasma screen television.
Upstairs the master suite (with his and her bathrooms) is as big as the chairman's box. The walls are cream, except in the children's rooms where it is pink for girls and blue for boys. The fitted carpets are in anonymous colours and there is no boot-room (golf and footie are the preferred activities).
This bland opulence does not, however, seem to bring much cheer. All the local estate agents who market the houses like designer handbags will gleefully tell you that Oxshott is "divorce central". After a tour of everything it has to offer, it is difficult not to conclude that it is in many ways a security-obsessed corner of our green and pleasant land where the red-top tabloids can happily graze.
1 A modern chandelier hanging from a high coffered ceiling in a capacious cream hall.
2 Crestron Control System (allows you to control home cinema, television, video, audio player, curtains, security and temperature from touch pads in every room).
3 A family room with a Mark Wilkinson kitchen (with a granite-topped island), Miele or Sub-Zero fridge, pair of Gaggenau cookers and a wine room (cellars are very non-footballer).
4 A Runco home cinema, Wi-Fi in every room, a gymnasium and games room (full of football memorabilia).
5 Comfort cooling (drops temperature by a few degrees rather than full air-conditioning).
6 Lutron lighting system with different intensities and dimming capacities (it can cost £20,000 a room).
7 At least one 50in wall-mounted touch-screen plasma television (plus smaller plasma screens in every room, including the shower).
8 A Whirlpool chromotherapy bath (that uses air and water jets) and a hot tub.
9 Underfloor heating (including the upstairs floors and the garage).
10 Indoor, underground swimming pool, preferably with a large football club crest set in the tiles.
The northern equivalent of Oxshott, where many Manchester United players live, is the Wilmslow/Alderley Edge/Hale triangle in Cheshire.
Local estate agents say 10 per cent of homes priced more than £500,000 go to players or those connected to the big northern clubs.
Ryan Giggs, Rio Ferdinand, Sir Alex Ferguson, cricketer Andrew Flintoff and Slade frontman Noddy Holder live there. So does Wayne Rooney, who lives in a six-bedroom mansion nick-named Rooney Towers that is neo-Georgian and includes a pink swimming pool.