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Toll-like receptor (Tlr) 4 is a lipopolysaccharide (LPS) receptor that contributes to the regulation of intestinal cell homeostasis, a condition that is altered in the intestines of cystic fibrosis mice. Herein, we assessed whether Tlr4 genotype influences cystic fibrosis intestinal disease by producing and phenotyping 12-wk (adult)- and 4-day (neonate)-old mice derived from BALB cystic fibrosis transmembrane conductance regulator, Cftr+/tm1Unc and C.C3-Tlr4Lps-d/J (Tlr4−/−), progenitors. Intestinal disease was assayed through mouse survival, crypt-villus axis (CVA) length, cell proliferation, bacterial load, bacterial classification, inflammatory cell infiltrate, and mucus content measures. Of the 77 Cftr−/− (CF) mice produced, only one Cftr/Tlr4 double-mutant mouse lived to the age of 12 wk while the majority of the remainder succumbed at ∼4 days of age. The survival of CF Tlr4+/− mice exceeded that of both CF Tlr4+/+ and Cftr/Tlr4 double-mutant mice. Adult CF mice presented increased Tlr4 expression, CVA length, crypt cell proliferation, and bacterial load relative to non-CF mice, but no differences were detected in Tlr4+/− compared with Tlr4+/+ CF mice. The double-mutant neonates did not differ from Tlr4+/+ or Tlr4+/− CF mice by intestinal CVA length or bacterial load, but fewer Tlr4+/− CF neonates presented with luminal mucus obstruction in the distal ileum, and the intestinal mast cell increase of CF mice was not evident in double-mutant neonates. We conclude that Tlr4 deficiency reduces the survival, but does not alter the intestinal phenotypes, of extended CVA or increased bacterial load in BALB CF mice.
- cystic fibrosis
- survival
- toll-like receptor-4
- intestinal obstruction
cystic fibrosis (CF) is the most common, fatal, autosomal recessive disease of Caucasians with an incidence of 1 in 2,500 newborns in this population (6). Although it is well documented that the basic defect in CF lies in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, exactly how the encoded epithelial chloride-ion channel deficiency leads to the varied CF symptoms, including intestinal disease, is unclear. The intestinal disease is presumed to be due to reduced water secretion and increased mucus accumulation in this organ, which results in the development of meconium ileus in 10–15% of CF newborns (48) and distal intestinal obstruction syndrome episodes in 25% of CF adults (45).
Several mouse models have been made to investigate the complex CF phenotype (7), and, since most Cftr-deficient mice suffer from intestinal goblet cell hyperplasia, mucus accumulation, and crypt dilation, which ultimately lead to lethal obstruction (7, 15), these mice have been used as a model of clinical meconium ileus. One approach toward elucidating the mechanism leading to intestinal disease in CF mice has been to cross the mice with others deficient in specific physiological pathways such as NHE3 a sodium/hydrogen ion exchanger that alters intestinal content fluidity (2) or chloride channel ClCa3 (47) to determine whether such deficiencies alter the CF disease course.
Toll-like receptors (Tlr), which are expressed on innate immune and epithelial cells and coordinate an immune response when bound by ligands, have been investigated as modifiers of cystic fibrosis lung disease (1, 26), but the potential influence of such receptors on cystic fibrosis intestinal disease has not been studied. Rakoff-Nahoum et al. (37) showed that recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis, and, given that both intestinal homeostasis (4) and gram-negative bacterial content (31), which contain the Tlr4 ligand, are altered in the intestine in CF mice, we hypothesized that mutations in Tlr4 would alter the CF intestinal phenotype. Supporting this hypothesis, we have shown Tlr4 expression to be increased in the intestines of BALB × C57BL/6 F2 Cftr-deficient mice (4) as were components of its signaling pathway CD14 and Ly96 and genes of lipid metabolism, a pathway for which there is cross talk with Tlr4 signaling (10). In addition, the intestinal phenotype of the F2 CF mice featured both increased proliferation and less apoptosis in crypts compared with wild-type mice. These changes are consistent with the influence of increased Tlr4 signaling on the CF intestine, since Tlr4-deficient mice, when challenged with dextran sodium sulfate, have been shown to develop colitis with decreased proliferation and increased apoptosis (11). A deficiency in this gene, in CF, could therefore spare the proliferation and apoptosis alterations in the intestine. Alternatively, a deficiency of Tlr4 in CF could leave the mouse unable to mount an adequate inflammatory response to the increased bacteria, which would result in increased disease such as occurs in the development of sepsis (33).
Using the mutation in Tlr4 originally identified in C3H/HeJ mice (36), which renders the gene product nonfunctional, herein to investigate the hypothesis that Tlr4 genotype alters the CF intestinal phenotype we bred and phenotyped a population of Cftr/Tlr4 double-mutant mice and their littermates. We demonstrate that the survival of CF mice is dependent on Tlr4 genotype but that the histology and bacterial load of surviving mice are not. Characterization of a population of 4-day-old mice suggests this survival difference to be affected by mucous and mast cell levels in the intestine.
To create Cftr/Tlr4 double-mutant mice in one genetic background, we bred C.C3-Tlr4Lps-d/J mice obtained from Jackson Laboratories (Bar Harbor, ME), which have the C3H/HeJ point mutation in Tlr4, in the BALB background (44), with BALB Cftrtm1UNC mice and genotyped the offspring for Cftr (4) and the C3H/HeJ-derived Tlr4 donor region (44). Congenic BALB Cftrtm1UNC mice, which had previously been generated by backcrossing the original Cftrtm1UNC mice to BALB/c mice for 20 generations (20), were used in these studies. Cftr/Tlr4 double mutants and littermate controls were then derived from Cftr/Tlr4 double-heterozygous and Cftr+/−/Tlr4−/− parents. Cftr and Tlr4 are on separate chromosomes (www.informatics.jax.org); therefore, these genes segregated independently. Mice were maintained on Colyte from the age of 21 days until death at 12 wk of age (19). Neonatal mice were similarly generated through timed matings of the parental mice and killed at 4 days of age. All mice were housed in microisolator cages in a Specific Pathogen Free room and handled according to the standard husbandry of the animal facility at the Meakins-Christie Laboratories of McGill University. The mice were cared for under a protocol approved by the McGill University Animal Care Committee in accordance with the regulations set by the Canadian Council on Animal Care.
Mice were killed by carbon dioxide exposure at the age of 12 wk, and their total body weight was recorded. At dissection, the entire small intestine was removed and flushed with PBS and a mucolytic agent (10 mM dithiothreitol), the contents were collected, and a 10- to 15-cm portion of the terminal small intestine was fixed in 10% buffered formalin and submitted for standard histological processing. Also at dissection, a 1-cm portion of the terminal ileum was removed and immediately homogenized in 1 ml of Trizol reagent (Sigma) and stored at −85°C. Neonatal mice were decapitated at 4 days of age, and their entire small intestine was fixed and processed. Swiss roll paraffin-embedded sections (5 μm) were stained with hematoxylin and eosin, and the crypt-villus axis (CVA) length was measured. The entire depth of the crypt and the length of the villus were measured only from complete and intact CVAs using image analysis of the histological sections (Olympus BX51, Image-Pro Plus 5.1; Media Cybernetics). Goblet cells and mast cells were detected using Periodic acid-Schiff (PAS) and toluidine blue staining, respectively. Goblet cells were quantified per intact CVAs and mast cells per high-power field (HPF) from an average of 20 random sections viewed at ×200. The mucus obstruction was measured as the area filled by mucus plugs in PAS-stained sections using image analysis. All sections were scored by an observer blinded to mouse genotype.
To assess the numbers of proliferating cells, macrophages, and T and B lymphocytes and the expression of Tlr4, paraffin tissue sections (5 μm thick) were immunostained with antibodies directed against proliferating cell nuclear antigen as used previously (4), F4/80 (MCA497R), CD3 (MCA1477; AbD Serotec), CD20 (sc-7735; Santa Cruz Biotechnology), and Tlr4 (ab47093; Abcam), respectively, using antigen retrieval treatment as in Ref. 4. Blinded scoring of an average of 25 CVAs/mouse was performed and presented as the average number of positively stained cells per CVA or per HPF. The F4/80 expression in the mucosa was recorded as the percentage of stained tissue area in the entire measured area, since single cells were difficult to delineate.
Quantitative real-time PCR.
RNA was extracted according to the manufacturer's (Sigma) instructions from 1 cm of the distal ileum collected at dissection. cDNA was generated, and relative quantification of Cftr and Tlr4 was completed with Assays-on-Demand TaqMan probes using the Applied Biosystems' 7500 Real Time PCR System as in Haston et al. (18).
Bacterial load measurement and classification.
DNA was extracted from 100 mg of the intestinal contents using a Stool DNA Kit (Qiagen), and the bacterial load contained was quantified by real-time PCR amplification of the 16S (small ribosomal subunit gene) as in Refs. 30 and 35. A standard curve relating the number of bacteria present to the amount of DNA was created by extracting and quantifying DNA from suspensions of Escherichia coli of known colony-forming units per milliliter. For classification, equal amounts of DNA extracted from the intestinal contents of CF and non-CF mice, grouped by Tlr4 genotype (n = 3–5/group), were pooled as has been used by others (31). From each pool, the 16S rDNA gene was amplified in a PCR reaction using universal primers, cloned into the pDRIVE vector (QIAGEN), transformed into TOP10 cells, and incubated on LB agar plates overnight at 37°C. Sixty colonies from each pool were selected, and the plasmid DNA was purified and submitted for sequencing with the M13F and M13R plasmid primers. BLASTN analysis was used to identify the taxonomic group of each clone, based on its sequence.
The bacterial load of 4-day-old mice was determined by counting the number of colony-forming units evident on agar plates (LB Agar, Lennox L Agar; Invitrogen) incubated with serial dilution of the entire intestinal homogenate (tissue in 5 ml of cold sterile PBS) at 37°C for 24 h.
Phenotypic data analysis.
Tests for differences in mouse weight, gene expression, and ileal morphology between groups were done by Student's t-test or by ANOVA in the case of multiple groups. Survival curves were generated by using the Kaplan-Meier method and were compared by the log-rank test.
Survival of Cftr-deficient mice is dependent on Tlr4 genotype.
To determine the effect of Tlr4 genotype on cystic fibrosis intestinal phenotype, a population of mice was bred from a cross of Cftr+/− and Tlr4+/− or Tlr4−/− progenitors. Of a total of 302 mice produced, 77 were homozygous for the Cftr mutated allele. The survival of these CF mice was dependent on Tlr4 genotype, as shown in Fig. 1, where double-mutant mice (Cftr−/−Tlr4−/−) showed lower survival compared with that of Tlr4+/+ or Tlr4+/− CF mice, and only a single double-mutant mouse survived to 12 wk of age. The majority of the Cftr/Tlr4 double-mutant mice succumbed at ∼4 days of age (Fig. 1). In addition, Tlr4+/− CF mice showed greater survival to 12 wk of age than that of either Tlr4−/− or Tlr4+/+ CF mice. Of the non-CF littermate control mice, including 72 Tlr4−/− mice, a small percentage succumbed at an early age, and the survival of these mice was independent of Tlr4 genotype (P = 0.10; data not shown).
Seventeen CF mice (16 females) lived to the age of 12 wk, and, at this age, the CF female mice were smaller than the non-CF mice [CF, 17.9 ± 0.78 (SE) g; non-CF, 22.1 ± 0.28 g; P = 0.0002], in agreement with previous data of this strain (17), but no difference in body weight by Tlr4 genotype in CF (P = 0.4) or non-CF mice (P = 0.1) was evident (data not shown).
Ileal expression of Tlr4 is increased in BALB Cftr-deficient mice.
To determine whether the ileal expression of Tlr4 is altered in 12-wk-old BALB CF mice, as it is in (BALB × B6) F2 CF mice (4), real-time PCR analysis was performed. As depicted in Fig. 2A, CF mice had higher expression levels of Tlr4 compared with levels in non-CF mice, and the expression of Tlr4 was not altered by the Tlr4 mutation in CF (P = 0.44) or non-CF (P = 0.11) mice, as has been shown in C3H/HeJ mice (36). The expression level of Tlr4 did not differ between Cftr+/+ and Cftr+/− mice (P = 0.15, data not shown); thus, the data of these groups were combined in Fig. 2. Second, the expression level of Cftr was greater in non-CF mice than in CF mice, and this difference was independent of Tlr4 genotype (Fig. 2B).
We used immunohistochemistry to confirm the increased expression of Tlr4 in the CF intestine and to identify the cells expressing this protein. As shown in Fig. 2C, Tlr4 staining was evident in mononuclear cells in lamina propria and submucosa with faint staining in enterocytes and epithelial crypt cells. Quantification of this staining revealed the number of Tlr4-positive mononuclear cells to be increased in the CF mice compared with non-CF littermates, as shown in Fig. 2D. This increase in the number of Tlr4-positive cells was evident for both Tlr4+/+ and Tlr4+/− CF mice, as shown in Fig. 2D.
Intestinal phenotypes unaltered by Tlr4 haploinsufficiency in 12-wk-old CF mice.
We (4) and others (9, 14, 24, 41) have shown the intestinal phenotype of Cftr-deficient mice to include an extended CVA and increased proliferation compared with non-CF mice. To determine whether this phenotype was evident in BALB CF mice and was influenced by Tlr4 haploinsufficiency, histological measures were completed. Comparison of the intestinal phenotypes demonstrated CVA length and proliferative cell number to differ between BALB CF and non-CF mice but not to be affected by Tlr4 haploinsufficiency either in CF or non-CF mice, as shown in Fig. 3, A–D. CVA length and cell proliferation counts did not differ between Cftr+/+ and Cftr+/− mice (P = 0.17 and P = 0.34, respectively; data not shown); thus, the data of these groups were combined in Fig. 3.
Next, bacterial loads in the small intestines were recorded to determine whether Tlr4 genotype influenced this phenotype. As shown in Fig. 3E, and in agreement with Norkina's (31) report of C57BL/6J CF mice, more bacteria colonized the small intestine of 12-wk-old CF mice compared with that of non-CF littermates, but no difference in bacterial counts was found in mice grouped by Tlr4 genotype.
To determine whether the intestinal bacterial composition differed among animals grouped by Cftr and Tlr4 genotype, species identification was completed by sequence analysis. As shown in Table 1, the bacteria in the intestines of non-CF, Tlr4+/+ mice was 68% gram positive and 32% gram negative. In Tlr4 haploinsufficient and insufficient non-CF mice, the percentage of gram-negative bacteria increased to 47 and 62%, respectively. In contrast to non-CF Tlr4+/+ mice, the bacteria in the intestines of CF/Tlr4+/+ mice were 60% gram negative while in CF/Tlr4+/− mice the gram-negative proportion of 42% is similar to that of non-CF, Tlr4+/− mice (47%). The predominant gram-positive bacterial classification identified in both CF and non-CF mice was Lactobacillales, whereas gram-negative bacteria were Bacteriodales in non-CF mice and β-Proteobacteria in CF mice.
Finally, Shang et al. (40) reported transgenic mice created with the Tlr4 gene constitutively active in the intestinal epithelium to have increased B cell numbers in the proximal region of this tissue compared with control mice. Because Tlr4 was of higher expression in CF mice, we investigated the presence of intestinal B cells in our 12-wk-old CF and non-CF mice. The numbers of CD20 positive cells did not differ in mice grouped by CF status, and this result did not depend on Tlr4 genotype (data not shown).
Phenotypic assessment of Cftr/Tlr4 neonates.
Because Cftr/Tlr4 double-mutant mice had low survival to the age of 12 wk, we assessed the influence of Tlr4 genotype on the intestinal phenotype of CF mice at the age of 4 days. A population of mice was bred from a cross of Cftr+/− and Tlr4+/− or Tlr4−/− progenitors, and, of the 166 mice produced, 42 were homozygous for the Cftr mutated allele, which is consistent with expected Mendelian ratios. CF mice, independent of Tlr4 genotype, had lower body weight compared with non-CF mice (CF, 2.1 ± 0.08; non-CF, 3.5 ± 0.05, P < 0.0001).
To determine whether phenotypic alterations are present in the intestines of Cftr/Tlr4 double-mutant neonates, which might account for their reduced survival to 12 wk of age, we measured the CVA length, bacterial content, goblet cell count, intestinal mucus obstruction, and inflammatory infiltration of this tissue. Histological assessment of the intestine revealed the distended phenotype of CF mice to be evident at this age, as shown in Fig. 4, A and B, but that the greater crypt depth in CF mice was not dependent on Tlr4 genotype (P = 0.81). Similarly, the intestinal bacterial load in the neonates revealed higher counts for the CF mice compared with non-CF littermates, and this was independent of Tlr4 genotype in CF (P = 0.28) and non-CF (P = 0.58) mice, as shown in Fig. 4C.
Inflammatory cell phenotyping revealed the number of CD3+ cells to be greatest in the small intestine of Cftr/Tlr4 double mutants, but no statistically significant differences in lymphocyte count by Cftr genotype (P = 0.15 by t-test) or Tlr4 genotype within CF mice (P = 0.22 by ANOVA) were evident (Fig. 5A). As shown in Fig. 5B, and in agreement with previous reports on adult CF mice (8, 32), the number of mast cells was increased in the small intestine of CF compared with non-CF mice (P = 0.025 by t-test), and, within the CF mice, the double knockouts had the fewest mast cells (P = 0.068 by ANOVA, P = 0.033 compared with Tlr4+/+ CF). An increase of mucosal F4/80+ cells was evident in the non-CF compared with the CF mice (P = 0.016 by t-test), but no difference in this phenotype by Tlr4 genotype was observed within the CF mice (P = 0.64 by ANOVA) (Fig. 5C). The findings in submucosal macrophages, however, did not reveal a significant difference in cell numbers by either Cftr or Tlr4 genotype (P = 0.33 by ANOVA) (Fig. 5D).
Goblet cell hyperplasia is a feature of CF intestinal disease in mice (41), and our assessment of the neonates showed this trait to be evident in the proximal intestine of CF mice (P = 0.003), independent of Tlr4 genotype (ANOVA, P = 0.50), whereas, in the distal half, which includes the terminal ileum, the number of goblet cells did not differ by CF status (P = 0.46; Fig. 6A). Most CF neonates also had histological evidence of dilated mucus-filled crypts and the accumulation of mucus material in intervillous spaces and in the intestinal lumen, while a few presented with a nonobstructed ileum (Fig. 6B). By Tlr4 genotype, the incidence of intestinal obstruction was eight of nine double mutants: 5/5 Tlr4+/+ CF mice and 3/6 Tlr4+/− CF mice. To assess whether the obstructed area was dependent on Tlr4 genotype, we measured the total obstructed area in the ileum of PAS-stained sections of these mice. As expected, CF mice had a greater obstructed area compared with the level in non-CF, and we observed a nonsignificant decrease in the affected area of CF Tlr4+/− compared with CF Tlr4 homozygous mice (Fig. 6C).
In this work, we show the CF intestinal disease traits of extended CVA, goblet cell hyperplasia, and greater bacterial load to be present in the BALB Cftrtm1UNC model of cystic fibrosis and that these changes are evident in 4-day-old CF neonates. By creating and analyzing a population of mice carrying Cftr and/or Tlr4 mutations, we demonstrate the survival of CF mice to be altered by mutations in Tlr4, where, specifically, the incidence of lethality was increased in Tlr4 homozygous mutant CF mice while survival was enhanced in Tlr4 heterozygous CF mice. Finally, our studies revealed the level of Tlr4 expression to be increased in the intestinal tissue of adult BALB CF mice but that haploinsufficiency of Tlr4 did not alter the CVA length, crypt proliferation, or bacterial content in these adult CF mice.
In this population, the survival of CF mice with the Tlr4+/+ genotype agrees with that reported for the original Cftrtm1UNC mouse model (41) by both the early wave of perinatal lethality and in that ∼46% of mice survived to weaning. In contrast, the CF mice with homozygosity for the Tlr4 mutation succumbed to early lethality in this study, whereas the greater survival to 12 wk of age of Tlr4+/− CF mice was associated with perinatal deaths in only 25% of the population. The mechanisms contributing to this enhanced (for Tlr4+/− CF mice) or reduced (for Tlr4−/− CF mice) survival were most likely Tlr4-dependent development of mucus obstructions and a reduced inflammatory response in double-mutant mice, respectively, since extensive analysis of the intestinal disease of 4-day-old CF and Cftr/Tlr4 mutant mice revealed no differences in CVA length or in intestinal bacterial content between double-mutant and CF mice. In particular, for the histologically evaluated neonates, only four CF mice, three of which were of the Tlr4+/− genotype, did not have evidence of complete mucus plugging of the intestinal lumen. Given that manipulations that reduce the mucus in the CF intestine increase the survival of these mice (2, 47) and that the administration of LPS, a Tlr4 ligand, can reduce mucus levels in the lung (38), we speculate that the improved survival of Tlr4+/− CF mice is due to a reduction in intestinal mucus. Elucidation of the mechanism that reduces mucus in Tlr4+/−, but not Tlr4+/+, CF mice, if such exists, will require additional study. Further analysis of the intestinal disease of 4-day-old CF mice revealed a decrease in mast cell infiltration in Tlr4−/−, compared with the level in Tlr4+/+, CF mice. The reduced mast cell infiltration in the double-mutant mice, which may be due to the deficiency in Tlr4 signaling (23, 46) coupled with the reduced inflammatory response of Tlr4-deficient mast cells (42), could result in an inadequate immune response to the gram-negative bacterial burden in the intestines of CF mice (31), such as occurs in sepsis (42), and thus the reduced survival of the Cftr/Tlr4 double-mutant mice.
Established functions for Tlr4 include initiating an innate immune response to bacterial challenge, which ultimately decreases tissue bacterial load (43) and, in the intestine, signaling to maintain epithelial cell homeostasis (37); however, in this CF model, neither the epithelial cell proliferation nor the amount of luminal bacteria was altered by mutant Tlr4. That intestinal bacterial load was not dependent on functional Tlr4 has been reported for related animal models of ileitis and colitis (21, 25) and distinguishes Tlr4 function in this tissue from that in a systemic response where bacterial levels are related to Tlr4 genotype (3, 29, 43). Second, the influence of Tlr4 on intestinal cell homeostasis and disease phenotype in challenge models is not obvious, since the deficiency has been shown to increase (11, 12, 37) or to lessen (21, 25, 27) disease. Regarding the latter, Leaphart et al. (27) reported C3H/HeJ mice to be spared necrotizing enterocolitis due to reduced apoptosis and increased proliferation compared with the levels in wild-type mice. Despite carrying the same C3H/HeJ mutation in Tlr4, the crypts of our Cftr/Tlr4 mutant mice did not display altered levels of apoptosis or proliferation relative to CF Tlr4+/+ animals. The absence of a Tlr4 effect on proliferation/apoptosis in the CF intestine may have occurred, since the level of injury in CF is not of the order of that in the induced colitis models or may indicate this Tlr4-regulated tissue response does not contribute to CF intestinal disease.
An assessment of the intestinal bacteria species revealed both Tlr4 genotype- and CF status-dependent profiles to exist in these mice. In detail, sequencing and BLASTN analysis of the 16S rDNA gene in the intestinal contents of the BALB non-CF, Tlr4+/+ mice revealed the majority of the bacteria to be gram positive, in agreement with findings of Hasegawa et al. (16) who used a similar technique to define the bacterial species present in the small intestines of C57BL/6 (Tlr4+/+) mice. In their study, however, the predominant gram-positive bacteria detected was Erysipelotrichales, and these were not detected in the current work. Compared with the Tlr4-sufficient mice, non-CF mice of the Tlr4+/− or Tlr−/− genotype had an increased proportion of gram-negative bacteria in their small intestines, reflecting their deficiencies in the innate immunity receptor for gram-negative bacteria. In CF mice, we observed not just a shift from gram-positive to gram-negative bacteria but a profound overgrowth of certain bacteria that are detected in small numbers in the control group. This shift and overgrowth agrees with the report of bacterial content in the intestines of C57BL/6 CF mice by Norkina et al. (31). The gram-negative bacteria in the intestines of BALB CF mice were principally classified as β-proteobacteria, a class that includes bacteria known to infect the lungs of CF patients, Burkholderia cepacia (28), while Bacteroidales were of increased proportion in the intestines of Tlr4 genotype-matched non-CF mice. Because commensal bacteria function to supply nutrients to the host, aid in digestion, and can contribute to the development and regulation of the immune system (22, 39), these changes in flora may contribute to the disease phenotype of CF mice. Whether such changes contributed to the altered survival of CF mice by Tlr4 genotype is not evident, since bacterial phenotyping was completed in mice surviving to 12 wk of age only.
In this work, we confirmed our previous finding of higher levels of Tlr4 expression in the ileal tissue of CF mice (4) and extended this work to show this increase to be due in part to greater numbers of Tlr4-positive cells in the lamina propria in CF mice relative to control. The localization of Tlr4-positive cells to the intestinal lamina propria in mice has been reported previously (13, 34) as has increased Tlr4 expression levels in the intestinal diseases of necrotizing enterocolitis (27) and inflammatory bowel disease (5), indicating a similarity in tissue response across syndromes. Despite the increased expression of intestinal Tlr4 in CF mice, we did not detect an increase in intestinal B lymphocytes as was reported by Shang et al. (40) for mice with the Tlr4 gene constitutively active in the intestine, although in their work this increase was evident in the proximal small intestine, and here we evaluated the more distal intestine. Nevertheless, we report B cell numbers in the intestine to be unaltered in CF mice.
In summary, the results of this study show the increased expression and presence of Tlr4 in the CF mouse small intestine and, significantly, that functional interruption of this protein (through mutation) severely reduced the survival of CF mice. Despite evidence of Tlr4 mutations altering tissue bacterial levels and intestinal cell homeostasis, neither of these traits was identified as Tlr4 dependent in the CF intestine, rather the reduced survival of Cftr/Tlr4-deficient mice was associated with decreased mast cell numbers. Finally, we also showed the CF newborn mouse to acquire an almost immediate small intestinal bacterial overgrowth, crypt elongation, and mucus accumulation compared with non-CF neonates, resembling the phenotypes found in CF adult mice.
This study was supported by a grant from the Canadian Cystic Fibrosis Foundation (to C. K. Haston), Fonds de la Recherche en Sante Quebec, and a Research Fellowship by the Consejo Nacional de Ciencia y Tecnología of Mexico (to J. C. Canale-Zambrano).
No conflicts of interest are declared by the authors.
- Copyright © 2010 the American Physiological Society


text:
Credibility in Engineering Education
This work addresses a joint effort by educators in engineering and speech communication at a technological university to explore the influences the educator has on the quality of the educational experience. The results presented represent initial research into the complex area of teaching style and credibility in engineering education.
Recommended Citation
S. L. Murray and A. A. Daniel, "Credibility in Engineering Education," Proceedings of the ASEE Annual Conference (1995, Anaheim, CA), vol. 1, pp. 1160-1162, American Society for Engineering Education (ASEE), Jan 1995.
Meeting Name
ASEE Annual Conference (1995: Jun. 25-28; Anaheim, CA)
Engineering Management and Systems Engineering
Second Department
Psychological Science
Keywords and Phrases
Information dissemination; Problem solving; Societies and institutions; Speech communication; Teaching; Technical presentations; Technology; Total quality management; Credibility; Engineering educators; Engineering work force; Foreign competition; Students; Twenty first century approaches; Engineering education
International Standard Serial Number (ISSN)
Document Type
Article - Conference proceedings
Document Version
File Type
© 1995 American Society for Engineering Education (ASEE), All rights reserved.
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Tender shrimp, garlic, and olives make this Mediterranean Shrimp Pasta light and flavorful. This simple dinner dish takes less than 30 minutes.
Pasta has always been a staple in our house. If you took a peek into my pantry at this very moment, you'd find no less than five different boxes of noodles. Many of them partially used and most almost empty.
I've loved pasta for as long as I can remember, and Kale shares that same affection. Poor John got tired of having pasta early on during our first year of marriage. It is relatively inexpensive, so we ate it several nights a week. Needless, to say he doesn't eat it often now.
In an effort to add some variety and flavor to our pasta dishes, John worked on some recipes. We rarely purchase jarred spaghetti sauce or have plain marinara. When we decide to have pasta, we add various herbs, spices, vegetables, and sauces. This Mediterranean Shrimp Pasta is the product of one of those recipes.
Make the Pasta:
Cook the pasta according to directions on the box. I like to use long pasta like spaghetti, linguine, or angel hair. Cook until al dente and drain reserving half a cup of pasta water. Set the pasta aside.
Make the Sauce:
Heat olive oil in a saucepan over medium heat. Add the garlic, salt, and red pepper flakes. Cook for 1 minute until the garlic is tender and becomes fragrant. Add the shrimp and cook about 1 to 2 minutes on each side. Shrimp will become translucent and slightly pink. It's important not to overcook the shrimp because it will come rubbery.
Remove from heat and add the cooked pasta and chopped olives to the sauce and shrimp. Toss ingredients together to combine. Add reserved pasta water one tablespoon at a time if pasta is too dry. Serve immediately and enjoy!
Want more pasta recipes? Try our Smoky Chipotle Chicken Pasta or Penne Alla Vodka.
If you like this recipe, please leave us a comment and rate the recipe card. You can also find us on Facebook, Pinterest, Twitter and Instagram searching for Berly's Kitchen!
- 1 pound of long pasta (Similar to angel hair, cooked and drained with some of the pasta water reserved.)
- 1 pound of shrimp, cleaned and deveined
- 4 Tablespoons olive oil
- 3 cloves of garlic, minced
- 1 1/2 teaspoon of salt
- 1/2 teaspoon red pepper flakes
- 5-6 green olives, chopped
Cook pasta according to package directions. Drain and reserve about 1/2 cup of the pasta water.
Heat olive oil in a saucepan over medium heat.
Add garlic, salt, and red pepper flakes to the pan.
Cook for 1 minute until garlic is tender and fragrant.
Add the shrimp and cook for 1 to 2 minutes on each side. Shrimp will become translucent and pink when done.
Remove from heat and add the cooked pasta and olives and toss with garlic mixture to combine.
Add reserved pasta water a tablespoon at a time if the pasta is too dry.


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Check out some options how vcard files might be converted to nbu format.
If you are looking for a way to import vCard contacts to your Nokia Phone, you do not need to convert them to NBU backups - and you probably cannot anyway. You can import the VCF to the phone using Bluetooth and opening them from inbox. A faster solution would be to import the *.vcf files into Outlook and then to sync it with the phone using Nokia PC Suite.
Unfortunately, there is no detailed software record in the database for this conversion.
Additional links: vcard file extension details, nbu file extension details
Back to conversion search


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Bronze Greek knob & plate set. Set includes one pair of knobs with one pair of back plates. Knob matches doorknob N241990 and has the same fluted leaf pattern with floral center and concentric dotted design on outside edge. These knobs were made by Sargent in 1905. They are part of L-112 Bullis group.
The dimensions are: Knob 2 in. diameter, plate 9.375 in. H x 2.625 in. W, Set is 2.5 lbs
**NOTE: Before purchasing directly through PayPal, please inquire about item availability and please wait for invoice to be emailed to you BEFORE paying directly. Often, an item has been sold quickly & not taken off yet or shipping prices have to be adjusted. Thank You!
Your source for Architectural Antiques & Altered Antiques
Industrial, altered antiques, doors, hardware, farm tables, tin mirrors and panels and mantels.


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Template >> Website - BeautifulMag Blog PSD Template 190618 by TastyThemes @ CreativeMarket
File Size: 38.82 MB; Requirements: Adobe CS6+; Layered: Yes.
BeautifulMag is aimed at people who want to create professional blog and online shop.
List of All PSD Files .
- Main Page.psd
- Main Page with banner.psd
- FAQ.psd
- Gallery Boxed V1.psd
- Gallery Full Width V1.psd
- Contact.psd
- Contact with map.psd
- Author Posts view.psd
- Authors page.psd
- Registration & Login page.psd
- Blog - Single Post.psd
- Shop.psd
- Shop - Catalog.psd
- Shop - Categories.psd
- Shop - Category Product.psd
- Shop - External&Affiliate Product.psd
- Shop - Grouped Product.psd
- Shop - Variable Product.psd
- Shop - Virtual Simple Product.psd
- Cart is currently empty.psd
- Cart.psd
- 404.psd
Support .
In the archive You will find a full detailed documentation about How to Customise PSD Files in Photoshop, What fonts I used for the template and where you will find it. Also you can find general documentation about "How to Customise PSD Template" on our support http://tastythemes.org/
IMPORTANT!!! - All Images are from different resources and they are not included to PSD files.
Keywords: psd, template, blog, commerce, design, website.


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In "A Certain Sparkle," Gayle Keck participated in a traditional grape harvest in Champagne. Here she shares some tips for enjoying a bottle of bubbly—including chilling, opening and tasting.
The French typically drink champagne as an aperitif, before meals. No need to save it for a special occasion! As Madame Lily Bollinger, of the famous champagne-making family once said, "I only drink champagne when I'm happy, and when I'm sad. Sometimes I drink it when I'm alone. When I have company, I consider it obligatory. I trifle with it if I am not hungry and drink it when I am. Otherwise I never touch it—unless I'm thirsty."
Most champagnes are a blend of wine from different grapes (the classic ones are pinot noir, pinot meunier, and chardonnay) and component wines from different years. Unlike with other wines, vintages are only declared in exceptional years, so don't feel that you always have to drink vintage champagne—there are many fine non-vintage options, too.
By law, French champagnes must spend a minimum of 15 months maturing in producers' cellars after bottling. Of that, at least 12 months is "maturation on the lees," when sediment formed by dead yeast cells decomposes and imparts its flavor to the wine. Vintage champagnes are cellared for at least three years. But some producers age their wines much longer—seven years, nine years, and more. As champagnes age, they tend to take on a golden hue and a toasty bouquet, and the bubbles become more delicate.
The recommended temperature for serving younger champagnes is 46 degrees. Vintage and mature bottles should be served at 50 degrees. If champagne is chilled too much, you'll miss out on delicate flavors and aromas. Cool it in the fridge for 3-4 hours or in a bucket of ice and water for 15-20 minutes.
To open a bottle of bubbly, after removing the wire cage or "muzzle," grasp the end of the bottle in one hand and the cork in the palm of the other hand. Twist the bottle and then tilt the cork slightly to release pressure from the bottle.
Experts say a tulip-shaped glass (filled only halfway) is perfect for tasting champagne. That shape lets bubbles form and rise, but also provides you a chance to take in the wine's aromas. Flutes are a good second choice. The old-school wide "coupes" don't do justice to a good champagne, despite being big on glamour. Experts also recommend that you clean your glasses with only warm water and let them air-dry. Soap residue and towel lint can impact the bubbles.
When you pour a glass of champagne, here's the proper way to appreciate it:
Look: Admire the bubbles and the color. It should be bright, and anywhere from nearly colorless (younger champagnes) to golden (older bottles).
Aromas: Swirl the wine in the glass and inhale. The aromas are divided into five groups, flowers, fruits, vegetables, dried fruit, and "indulgent delicacies."
Taste: Take a sip and let it roll around in your mouth (professionals swish it around in their mouths as aggressively as you might rinse after brushing your teeth). What do you taste? Green apple, citrus, tropical fruits, vanilla, toast, and nuttiness are common notes that you might discern—but there's a vast number of nuanced elements that a trained palate can tease out. Consider the weight or viscosity of the wine, too.
Finish: After you swallow, contemplate the aftertaste that lingers on your palate. The longer the finish, the better the quality of the wine.
For more tips on choosing, serving, and enjoying champagne, visit the Champagne Bureau's websites (http://www.champagne.us/ and http://www.champagne.fr).
Photo by Marie Hennechart.


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Lamaze Play House Gym
The Lamaze Play House 3-1 Gym supports your child through their early stages of development. This fun and colourful play mat has play modes including "lay and play", "tummy time" and "sit and play". Perfect for role-playing. Plus, the play house is soft and reversible which means more activities and adventures to stimulate their body and mind as they grow.
- Lamaze kids' early development
- Design: Play House Gym
- Colour: Multi
- Soft side walls to avoid bumps
- Musical flower for on-the-go fun!
- Easy set-up, storage and portability
- Cushioned playmat perfect for tummy time
- Weight: 1.8kg
- 3 x AAA batteries required
- Materials: N/A
- Dimensions (approx. cm):
- 77.5 (W) x 91.5 (L) unfolded
- 53 (H) with toy bar
- Country of origin: N/A


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Posting in General Chat thread. 11/11/2017it has been noted that too many Members are posting messages in the General Chat area instead of the correct Forums. Any messages posted in the General Chat area that are not General Chat will be deleted without warning and offenders may recieve warning points if repeated instances are seen from that Member. There are plenty of different Club areas that encompass 99% of Ford related posts, please select and use the correct one. If anyone is not sure of which area to post something then feel free to P/M myself or other Senior Staff for guidance. The Moderating Staff are having to spend far too much time chasing this problem instead of maintaining the other areas of the forum.
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About as400
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Ford Model
Focus Ghia 2.0tdci
Ford Year
UK/Ireland Location
as400 reacted to a post in a topic: Eve, It's Time For A Face Lift (mk2 Focus Zetec Climate 2.0)
as400 reacted to a post in a topic: Eibach Pro Kit on 2.0tdci
as400 started following MAF Warning Light P0101, Eibach Pro Kit on 2.0tdci, Front Suspension Clanking? and and 3 others
Eibach Pro Kit on 2.0tdci
as400 posted a topic in Ford Focus ClubLooking at getting a set for £100 from EBAY Any idea what a local garage would charge to fit these?...how long would it take? Are these plug and play or does anything else need to be bought?...I saw a post previously where someone on this forum had these little bolts also to correct camber?...are these necessary?...the car is running standard 16" alloys. Is it advisable to get tracking/alignment checked after dropping the car by 30mm with these?
Front Suspension Clanking?
as400 posted a topic in Ford Focus ClubWhen I go over a bump the front end of my car sounds like a bag of spanners. Just had a major service at Halfords and nothing was picked up, not sure if they even test drive it. Are they all like that Sir?...or could there be something loose? How noisy is yours when you go over a speed bump etc? Car has done 77K and is standard 2.0tdci Ghia as far as I know
zorba-01 reacted to a post in a topic: Water On Drivers Side Floor: Blocked A/C Outlet?
Mmmm I'll have another poke around tomorrow when its light. Got so fed up of the wet thick heavy sound proofing I have cut it mostly out as well as half of the poor quality carpet. This is meant to be a cheap interim run around car as my A6 got written off by a Muslim asleep at the wheel due to fasting for Ramadan so I don't mind hacking it up a bit. Actually quite impressed with the torque from the 2.0tdci engine, have plans to lower it a tad and get a remap with EGR delete as work is a 100 mile round journey, getting 43mpg without driving like Miss Daisy.
Cheers Russ...I can see this one?...is there another?....think i did see a drip of water come out while i was photographing it actually!...I guess over time it could have built up, the soundproofing foam is quite soaked.
Water On Drivers Side Floor: Blocked A/C Outlet?
as400 posted a topic in Ford Focus ClubNoticed an area of wetness on the drivers front floor area only. Checked coolant level and it was fine so am guessing its a blocked A/C outlet tube. But running the A/C still produces the usual dripping under the car so guess that's OK. This is drivers side only nowhere else. Any ideas? Thanks for any advice.
How To Top Up Steering Fluid?
as400 posted a topic in Ford Focus ClubWhen car is stationary I hear a drone when turning the steering wheel. Had a look at what I'm guessing is the power steering bottle and couldn't see any fluid moving around. But what a crazy location!...how do you access it to top it up? Ah forget that, that pic is of the Brake/clutch fluid reservoir. So where can you monitor the level on a 55 plate Focus?....the handbook says "no fluid level checks necessary" for 1.8/2.0 l Duratec-HE, 2.5 l Duratec-ST and Turbo diesel engines" How does that work?
as400 reacted to a post in a topic: Inner Wheel Arch Rubbing Noise On Turning?
trailertrash reacted to a post in a topic: MAF Warning Light P0101
Inner Wheel Arch Rubbing Noise On Turning?
as400 replied to as400's topic in Ford Focus ClubFocus MK2 2006 2.0tdci Ghia. Regular 16" wheels non lowered.
MAF Warning Light P0101
as400 replied to as400's topic in Ford Focus ClubIn the end took the car back to Halfords along the lines of "seems a bit coincidental the light came on after you serviced it"...etc... They offered a free diagnostic check....only to discover the MAF had "worked loose"....maybe because I had had the engine area detailed they suggested? I just laughed and drove off.
Inner Wheel Arch Rubbing Noise On Turning?
as400 posted a topic in Ford Focus ClubCar just had a 'major' service at Halfords, I mentioned I could hear a rubbing plasticky type noise coming from the off side wheel arch area when turning sometimes. Just sounds like the wheel is rubbing against something on the inner side. Not really a wheel bearing mechanical grinding noise. Have had a look under and can't really see anything amiss. Anyone any ideas? or had anything similar?
as400 changed their profile photo
MAF Warning Light P0101
as400 posted a topic in Ford Focus ClubJust bought a 2006 2.0tdci Focus, took it to Halfords autocentre for a major service+cambelt change, got it home to find an engine warning light suddenly on. Ran a diagnostic check with my £5.99 OBD11 scanner to get a P0101 $07E8 Mass or Volume Air Flow A Cicuit Range/Performance message Could this have been caused by anything they did?..maybe something not properly connected Car runs fine.
Focus 2006 Remote Operation
as400 posted a topic in Ford Focus ClubWhen I use the remote to lock my Focus 2006 the doors lock but there are no confirmation indicators flashing or cheep cheep noise and I get paranoid if the car is locked or not! Can I set the remote to produce a visual or auditory confirmation of operation?
Picked up a Focus 1.6TDCi Zetec Climate today
as400 replied to hawker's topic in Ford Focus ClubPrice sounds about right to me as long as there's nothing wrong with it. I got a 06 plate 1.8 tdci focus ghia this week also with 92k, one owner from new full ford service history 12 months tax and mot. The car is mint and feels tight for £5650. Looking around it seemed about right, probably could have got it cheaper at auction but it has 3 months warranty and Im chuffed with it.


text:
- Please select a date to see the proper prices!
- Meal can be requested on the spot
Best offer
70.17 € / person / night, no meal
Description of the accommodation:
Rooms, services Hotell Gässlingen Skanör med Falsterbo is glad to host the guests of RevNGo.com for some pleasant days in Sweden. The guests of the hotel may stay in 29 nicely furnished, comfortable rooms in Skanör med Falsterbo. The hotel is offering you freshly prepared fine local meals in its restaurant every day. Car parking possibility is available nearby. Nearby bike rental opportunities will provide an excellent chance to spend your leisure time actively. The bar has excellent atmosphere for a relaxed evening talk or a personal meeting. You may secure your valuables in the safe. You can browse the Internet via wireless connection (WiFi) available at the hotel. You can find the exact list of services provided by Hotell Gässlingen Skanör med Falsterbo (including those for extra fees) and the exact equipment of the rooms on the information sheet below.
Payment Credit card guarantee or advance bank card payment may be necessary for finalizing your reservation, depending on the exact room, date and price.
Arrival, opening hours The earliest arrival time is 15:00, the latest time to leave the rooms is 11:00. The personnel speaks Swedish and English.
Hotell Gässlingen Skanör med Falsterbo rooms Rooms
- Please select a date to see the proper prices!
Accommodation services
Free WiFi in shared places
Bike rental at the accommodation
- Finnish sauna
- Jacuzzi
- Pool (Outdoor - seasonally open)
Pet friendly (150 €/night), Bar, Elevator, Safe deposit box
Own restaurant
Bathrobe, Hairdryer
General Policies
On Saturday and Sunday: 7:00 - 20:00


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Upcoming Events
We work and Play in Downtown Yankton. Check out upcoming events at The Sandbox + Downtown Yankton.
Our Memberships
The Sandbox understands not every member is the same... Therefore we provide a variety of options.
Check out our Blog
Highlighting coworking. Highlighting members. Highlighting the cool people and things happening near and far.


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Ruth Hamilton
Listed by Coldwell Banker Linwood Re/Littleton
A lovely, well kept and maintained property that is within walking distance to town, yet at the end of the street to allow for privacy. At one time this home was a single family that has been very nicely turned into two separate apartments. The home is owner occupied and they have had a very good rental history since they have owned the home. The owners have done some extensive remodeling to make this home comfortable and easy to take care of. The first floor offers a large front foyer, two bedrooms, living room, kitchen, mudroom and laundry area and a full bath. The second floor offers an oversized master bedroom, living room and kitchen, dining room, office or den, plus an extra large full bath and laundry area, and a nice deck to sit out and enjoy your meals, or just sit and relax and look over the nicely landscaped yard. Owner will be leaving most of the furniture and other items. There is also a large attic area that is broken up into 4 sections. The large 2 bay garage gives you lots of room for a work shop and equipment and cars. Property is just a short distance to 3 ski areas, 5 golf courses, and all the other four season activities that this area offers.
Date Showings Begin:
Delayed Showing: Unknown


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Product Code: RDS206
Availability: In Stock
Length: 13.5"
Width: 0.75"
Height: 10"
L*W*H (in inches): 13.5*0.75*10
Closure: CFC zipper
Compartments: 1
Hardware: Metal
Color: Dark Brown
Material / Fabric: Buff Grain PU
The Valeria is a dark brown Buff grain PU laptop sleeve. It gives you a neat, rich elegant leather look and is comfortable and functional with good cushioning, foam padding and twill lining. The Valeria comes with a concealed reverse zipper.
Write a review
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By ERIK SANDBERG-DIMENT
Published: January 13, 1987
AS a writer, I am interested in word processors. And as a curmudgeon of the old school, I have yet to find a word-processing package that truly suits me. According to certain members of my family, in fact, the reason I periodically aspire to add geese to our farm menagerie is solely to assure myself of a steady supply of quill pens. Although this is the type of hyperbole with which our teen-agers frequently confront me - I just happen to like fresh goose on St. Martin's Day - I cannot deny that my writing is done on narrow-lined yellow paper, the last upgrade in my production style having occurred some 20 years ago when I gave up leaky fountain pens for smeary ballpoints.
Word processing, for which I currently use WordPerfect, does indeed save time at the final editing stage. Without it, furthermore, I would not be able to transmit finished copy to this newspaper by modem, a vast improvement over dictating my columns by telephone or mailing in typed manuscripts. But as a composing tool, a typewriter or computer keyboard has never been to my liking. I'm by nature a napkin-scribbling note taker, working on as many as 20 or 30 different pads at once and writing by association. You can't write that way with a word processor, even a trendy one with an outline processor. So for all the convenience that word processing offers in editing and communications, it doesn't help me at all in composition, and one of my basic rules of personal computing is, if the machine doesn't do the job better and more conveniently, then don't use it. Advent of Hypertext
I know full well that there are still other closet nonword-processing writers out there, for I've spoken with many of them, furtively, far from the hum of dot matrix printers. Yet even these last holdouts may surrender once hypertext overtakes personal computing.
The word ''hypertext'' was coined way back in 1965 by Ted Nelson, an early, self-styled visionary and enfant terrible of personal computing, who envisioned, in essense, the computerization of everything ever written and to be written. He called the idea the Xanadu Project, to be released in 1979, then '80, then '81 . . . .
I remember my own disbelief regarding the scheme. The project as he envisioned it seemed too massive to be undertaken. And even if such a venture were feasible, the complexity of organizing it all into hypertext seemed to me beyond reckoning. In Project Xanadu, all data would be electronically connected to all other related data, so that, for instance, on reading about the caves in Plato's ''Republic,'' one could instantly move to spelunking, stalagmites, isolation-induced psychic moods or Schopenhauer's feelings on the subject - if he had any. Working by Association
Always one to give credit where credit was due, Mr. Nelson invariably began discussions of the Xanadu Project by mentioning of Vannevar Bush, Roosevelt's science adviser, who had first presented the basic idea of hypertext, in an article entitled ''As We May Think.'' The basic premise of his argument was that the books, files and forms constituting the information systems of the time were based on a rigid hierarchical model, the most obvious embodiment of which was the library. Dr. Bush's point was that such a hierarchical arrangement does not reflect the way in which we think. The human mind works by association, leaping from thought to thought, following an intricate trail of conceptual relationships having no immediately obvious structure.
Dr. Bush also observed that there is a design carryover from earlier to later technologies. Thus it happens that word processors produce pages the same size as those produced by standard typewriters, even though there is no technological reason for it. By contrast, the standard printout utilized by mainframes and minicomputers is much larger. Their data output was not considered typed copy, so it did not seem necessary to make it conform to the 8 1/2-by-11 dimensions of manuscript format. The most practical page size was adopted.
Dr. Bush visualized an improved data storage format he called memex, whereby authors and readers alike could build associative trails through a maze of published material. Another Approach
By and large, the computerization of data has not led to anything resembling such a system. Our data bases still mimic the hierarchical structure of the card catalogue, our word processors follow the standard manuscript format and even our so-called free-form outline processors are essentially just expanded electronic versions of a book's table of contents. Conceptually, they all mimic the storage of information on paper.
This doesn't mean that the provocative notions of memex and hypertext have gone unheeded. Douglas Englebart, developer of the computer mouse, devised a memexlike system for mainframe computers several decades ago, and Xerox, that innovate nonmarketeer, recently produced a similar system, inappropriately enough called Notecards.
Another avid advocate of the hypertext approach is Dr. Peter Brown, professor of computer science at the University of Kent in Britain, whose work in the field has been transformed into a product called Guide ($134.95 for the Macintosh Plus or the 512k Mac from Owl International, Bellevue, Wash. 98007, 206-747-3203).
Although not as all-encompassing as hypertext may eventually become, Guide does offer writers an associative, multilayered, tool for putting words to screen. Combining graphics with textual capabilities, it suggests some truly intriguing possibilities. Writing with Guide, however, takes some getting used to. What with one on-screen thought leading to another, and another or another two or three, it's all too easy to become lost in the electronic maze while one is learning to deal with the associative clutter.
I will continue this discussion next week, if I can locate the various weighty, cogent thoughts I filed away deep down among the many layers of Guide.


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So, we just got a review of our new CD A Year With The Very Most (which I'll be talking about in more detail later) from a blog in Germany. I always love reviews in non-English languages because it gives me an excuse to read the mangled English produced by Google Translate. Here's the funniest mangled review I've read in a long time.
Here's the original (which is quite complimentary, thankfully).
And here's Google's translation:
indiecater records for the specific ideas that are used. we went end of last year with the candy claws on virtual world tour, so we were in the same year the band to accompany the very most of their seasonal travel. because for each of the four natural wonder in the year they had at hand, the circular matching ep spring (summer, autumn, winter). It was now obvious, this song collection on a cd together and publish, including a "bonus tracks again. formerly offered as a download only eps can now, on a cd bundled to provide as physical tonträger shelf ins. 22.01.10 since yesterday is the "a year with the very most" good piece titled on indiecater relate to. The band from boise, idaho, convinces tunes primarily with saving, with two big and vocal harmony. the stylish arrangement, in part, each song concept, yet persuaded any doubters. is the twee-pop, or even quite large? who wanted to draw boundaries set, who compare it with belle and sebastian? the very most have developed a very own style that pulls from a growing self-confidence as well as to the collection of unbound label, and by marketing and detachment from any drawer mentality. rem just a sore. The cd can be heard on indiecater in full before we proceed to purchase, then, the cat in a bag somewhere gibts. The bonus track is actually a lake called the cover "kite"! buy and be happy!
Oh, man. "Is the twee-pop, or even quite large?" Well, that, my friend, is a question that mankind has been wrestling with for ages.
Thanks to das klienicum for the nice review, and thanks to the good folks at Google for providing a laugh while giving me, perhaps, the gist of what was in the review.


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The eighteenth century was a time of expansion, forming the hinge between the old world and the new for, by its end, change was not only detectable, it was also seen to be irreversible.
These specially commissioned chapters, written by experts in the field, address all the major issues in Europe's political, economic, religious, cultural, and international history.
Compendious, ingormed, instructive, readable and easy to handle...high overall standards...Tim Blanning and his colleagues have done justice to the fraught, fantastic times they have had to grapple with.


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The Nordic Countries Express, September 2013
Able to focus on the sightseeing experience
I would recommend Nordic Visitor to anyone who wants to travel in Scandinavia. My husband and I were able to focus on the sightseeing experience knowing that all of our accommodations and transportation between cities were taken care of. We received all of the materials we needed and our travel consultant marked our hotels and train stations on maps to assist us in new cities. I can't say anything negative about the experience.


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Sleeper Trailer (2012)
"Love is a dangerous thing..." 03 October 2012 Horror, Action 87 mins
Enigmatically silent, and driven by love, the man known as Resnik was imprisoned for butchering another man and kidnapping the young girl at the heart of his obsession, Kelly. For the safety of his fellow inmates, Resnik was only ever allowed to wake, eat and exercise alone, after dark, he learned to like it. Now having escaped during a midnight transfer, Resnik is headed back to Moonlight Bay, and Detectives Raynor and Molloy have only 12 hours to stop him before the sun goes down, and the carnage begins, again. Written by Anonymous (IMDb.com).
Watch the official Sleeper 2012 trailer in HD below or find more Sleeper videos on Vidimovie.


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Drivers and transit users struggled with a slow commute after a fresh layer of snow blanketed the city.
CBC meteorologist Jay Scotland said that while Tuesday's snowfall wasn't massive, it was enough to make things difficult for drivers.
"We're not talking about major snow for the GTA, but we are talking about more in the way of nuisance snow, just a few centimetres is all it takes to snarl traffic," he said.
The Toronto area saw some five centimetres of new snow on Tuesday. Flurries are expected to continue into the evening according to Environment Canada.
Roads were slippery enough to cause problems during the Tuesday morning commute. A driver slid into a fire hydrant at the corner of Jarvis Street and King Street early Tuesday. The accident caused water flood the intersection, creating a mess that took two hours to clear.
Brush up on your winter driving tips/prep here! 'Cause winter's not going anywhere for a while: http://t.co/gcDyTaJCkt— Joan Chang (@cbcjoanchang)
December 17, 2013
To encourage thoughtful and respectful conversations, first and last names will appear with each submission to CBC/Radio-Canada's online communities (except in children and youth-oriented communities). Pseudonyms will no longer be permitted.
By submitting a comment, you accept that CBC has the right to reproduce and publish that comment in whole or in part, in any manner CBC chooses. Please note that CBC does not endorse the opinions expressed in comments. Comments on this story are moderated according to our Submission Guidelines. Comments are welcome while open. We reserve the right to close comments at any time.
Note: The CBC does not necessarily endorse any of the views posted. By submitting your comments, you acknowledge that CBC has the right to reproduce, broadcast and publicize those comments or any part thereof in any manner whatsoever. Please note that comments are moderated and published according to our submission guidelines.


text: Does anyone carry their Glock in a holster at a GSSF shoot? I know the slide has to be locked back to carry in a holster so I was considering carrying my G34 racegun in my CR speed rig. At the very least I think I should have my mag pouches on so I will have them handy before I start a stage. Can you carry your Glock in a holster outside of the designated safe areas? I really want to be sure I don't get disqualified for a rule infraction so any advice on this would be highly appreciated. Can you have all your mags loaded while they are in your range bag or should you wait until you are about to be on deck before you load them?


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2017-18 Clatsop Community College Scholarship Competition is closed.
Please click here for CCC scholarship instructions, application login and available scholarships.
The 2017-18 CCC Scholarship Competition is closed. The competition closed April 14, 2017. After the close of the competition, the CCC Scholarship Committee will review submitted applications. Only complete scholarship applications will be reviewed. Recipients of CCC scholarships will be notified of the scholarship competition results the week of May 15th.
Oregon Student Access Commission (OSAC) scholarships. March 1, 2017 is the deadline for more than 450 OSAC scholarship opportunities. You don't need to be a merit scholar or have financial need to apply. Apply early in the year with one easy online application at www.oregonstudentaid.gov.
A special note of thanks to our scholarship donors. They have made a difference in the lives of our students. Their generosity has lessened the economic burden on our students and provided access to education.
This site lists scholarships available at Clatsop Community College. Let it be a tribute to those who actively invest in the future of our students. Thank you for your support.
If you would like to invest in the future of a student by opening a new scholarship opportunity, please contact the Clatsop Community College Foundation at 503-338-2306.All scholarship donations are tax deductible.
Questions concerning scholarships should be directed to:
Director of Financial Aid
Clatsop Community College
1651 Lexington Avenue,
Astoria, Oregon 97103


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About Newreg.co.uk
NewReg.co.uk the UK's strongest personalised number plates brand are perhaps one of the best examples of premium domain marketing. The first number plates dealer to sell on line, New Reg started using ecommerce back in 1996; they were probably one of the very first websites to use the internet commercially in the UK.
.com or .co.uk
Well established as a .com by 1998, and an age before the dotcom bubble even started to swell, New Reg traded over 80% of all sales via their website before the millennium. Ten years later and New Reg had a dilemma, do they stick with their .com image or move to the TLD for their UK market place. As a UK only supplier, the Directors believed that changing to the .co.uk Domain suffix was appropriate.
Taking advice from Domains.co.uk, New Reg secured and commenced trading on the UK TDL suffix, forwarding the .com and removing all duplication. In the last three years New Reg have significantly improved turnover, perhaps a sign that using a .co.uk Domain to do business in the UK is the right way to go!


text: I'm an SVU fan, an it's the stories that draw me in. Let me throw it out there, I'm not much of an original L&O fan...(Although, Angie Harmon, Carey Lowell, Alana de la Garza were pretty interesting...lol...and it's cool seeing Anthony Anderson in a serious role). Anywho, if either Stabler (usually called 'Un-stabler') or Olivia were to leave, they can easily do something different. There is still Fin, there is still Munch...and, like the original L&O, they can bring new blood into the picture... Now that Jeff Goldblum is joining the Criminal Intent cast, I'm now going to have to catch up with that show. (I never really watched the show in it's entirety). Side-question: I came into an episode where the ADA Casey Novak portrayed by Diane Neal was being carted away in custody. What happened? (Wiki gives a light description, but if someone could elaborate).


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Call on J&J for your Luxury Transportation needs
- Business travel
- Corporate events
- Weddings & rehearsals
- Bachelor/bachelorette parties
- Casino trips
- Religious/school/university/athletic events
- Family reunions
- Black-tie affairs
- Package delivery
- Hourly occasions, full-day events and multi-day tours
- Other occasions
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Ask A Service Tech at Woody's Automotive Group!
Check engine light on? Car making a funny noise? Not sure what to do? Ask A Service Tech at Woody's Automotive Group!
Have a question? We've got answers!
Woody's Automotive Group is proud to be an automotive leader serving the Kansas City, MO area. Please fill out this short form and we will gladly help you with all of your automotive needs.
Contact Information


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Now that the feast-heavy holidays are over and Old Man Winter has arrived over much of the country, restaurants will use special promotions, gift cards, and even a reduction in customers' taxes to help heat up first-quarter sales.
The quarter, which typically stretches from Jan. 1 to March 31, has long been considered a tricky period for restaurants given the lack of major holidays and the cold weather that makes potential diners stay home.
"Traditionally, January an
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LOUISVILLE — The Fourth of July is often celebrated with dazzling displays of fireworks, but emergency physicians with Jewish Hospital, a part of KentuckyOne Health, encourage individuals to take precautions to stay safe while enjoying Independence Day.
According to the National Fire Protection Association (NFPA), in 2010 more than 8,500 people were treated in emergency rooms for firework-related injuries.
PIONEER VILLAGE - Despite an economic downturn over the past couple of years, the city of Pioneer Village appears to be in fine shape financially.
PIONEER VILLAGE - Ash Group LLC now has expanded to north Bullitt County.
SHEPHERDSVILLE — Patrick Myers knows that his Apex physical therapy clinics are not associated with big-time medical companies.
SHEPHERDSVILLE - Five local students have earned scholarships through the Farm Bureau.
Rachel Thacker, a senior at Bullitt Central High School; Jessica Carver, Carly Coulter and Christopher Blake Laytham, all seniors at Bullitt East High School; and Forrest Miller, a senior at North Bullitt High School, are the 2012 recipients of college scholarships from Farm Bureau.
Thacker received a $1,000 Bullitt County Farm Bureau Young Farmers Scholarship while Carver, Coulter, Laytham and Miller each received a $2,000 Bullitt Count Farm Bureau Scholarship.
HEBRON ESTATES - A few years ago, North Bullitt's Michael Dowell wanted to be a basketball player.
Years ago if you had some kind of disease it was difficult to treat because they did not have the medicine to treat it with.
LEBANON JUNCTION - You have some old limbs you need to get rid of at your home. You don't want to wait until your garbage hauler makes his rounds next week. So, you decide to burn it.
SHEPHERDSVILLE — A former Shepherdsville city employee who was indicted for not returning property as required will not go to trial until August.
HEBRON ESTATES - The students in the Hebron Presbyterian Church Sunday School class will hear some exciting stories over the next few weeks.
Copyright © 2017
The Pioneer News Online is your source for local news, sports, events and information in Bullitt County and Shepherdsville, KY, and the surrounding area.


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PBO again at odds with feds over budget details
Parliamentary Budget Office wants more information on lapsed program spending projections, but forecasts a higher surplus than Finance Department ahead of the next election.
Details, details: Assistant Parliamentary Budget Officer Mostafa Askari, left, and Finance Minister Jim Flaherty. Mr. Askari says there's not enough information on the impact of lapsed spending and ongoing budget cuts on government services. The PBO's latest report also says that the feds are keeping EI premiums artificially high.
More Stories In This Section
Politics This Morning: Grey Cup comes to Centre Block; Notley speaks at Economic Club; Petitpas Taylor participates in Facebook Live 'coffee break'
Hill Life & People


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Traveling Luck for Hopkins Ranch, Nevada, United States
Where is Hopkins Ranch?What's around Hopkins Ranch?
Wikipedia near Hopkins Ranch
Where to stay near Hopkins Ranch
The timezone in Hopkins Ranch is America/Whitehorse
Sunrise at 06:36 and Sunset at 16:14. It's light
Latitude. 41.1928°, Longitude. -114.8792° , Elevation. 1789m
Weather near Hopkins Ranch; Report from Wildhorse Reservation / Elko, NV 25.2km away
Weather :
Temperature: 27°C / 81°F
Wind: 11.5km/h South
Cloud: Sky Clear
Weather :
Temperature: 27°C / 81°F
Wind: 11.5km/h South
Cloud: Sky Clear
Satellite map around Hopkins Ranch
Loading map of Hopkins Ranch and it's surroudings
Geographic features & Photographs around Hopkins Ranch, in Nevada, United States
- spring(s);
- a place where ground water flows naturally out of the ground.
- Chicken Spring (2.4km)
- Town Creek Spring (2.5km)
- Town Creek Spring (4.5km)
- Cottonwood Spring (4.7km)
- Bishop Flat Spring Number Forty (6.8km)
- Winchell Spring (7.8km)
- Bishop Spring (8.6km)
- Twelvemile Spring (9.4km)
- Chicken Seep Spring (10.3km)
- Quilici Spring (10.9km)
- Summit Springs (10.9km)
- Wilson Spring (11km)
- Hot Springs (11.1km)
- Threemile Spring (11.4km)
- Hot Spring (11.6km)
- Independence Springs (12.4km)
- Cricket Spring (13.1km)
- Hot Spring (13.2km)
- Local Feature;
- A Nearby feature worthy of being marked on a map..
- Hopkins Ranch (0km)
- Town Creek (0.4km)
- Single Tree Ranch (5.8km)
- Cedar (9.9km)
- Kaw (11.9km)
- Independence Station (12.4km)
- Moor Interchange (13.1km)
- Anthony (13.8km)
- Wells Indian Colony (14km)
- Wells District Ranger Office (14.5km)
- US93/East Wells Interchange (14.7km)
- well;
- a cylindrical hole, pit, or tunnel drilled or dug down to a depth from which water, oil, or gas can be pumped or brought to the surface.
- Wood Ranch Well Number Fifty Three (2.3km)
- Weeks Well (8.9km)
- Town Creek Well (9.4km)
- Bishop Flat Well (13km)
- Ralphs Well (13.1km)
- Wrights Well (13.5km)
- stream;
- a body of running water moving to a lower level in a channel on land.
- Johnson Creek (10.6km)
- Cricket Creek (12km)
- Willow Creek (12.4km)
- Town Creek (13.6km)
- school;
- building(s) where instruction in one or more branches of knowledge takes place.
- Ruby Valley Elementary School (14.2km)
- Wells Elementary School (14.3km)
- Wells High School (14.5km)
- mountain;
- an elevation standing high above the surrounding area with small summit area, steep slopes and local relief of 300m or more.
- Oxley Peak (5.4km)
- Cedar Peak (6.3km)
- Wells Peak (7km)
- gap;
- a low place in a ridge, not used for transportation.
- Cedar Pass (12km)
- Moor Summit (12.2km)
- valley;
- an elongated depression usually traversed by a stream.
- Bishop Creek Canyon (11.1km)
- Indian Hollow (11.2km)
- flat;
- a small level or nearly level area.
- Town Creek Flat (10.9km)
- airport;
- a place where aircraft regularly land and take off, with runways, navigational aids, and major facilities for the commercial handling of passengers and cargo.
- Harriet Field (10.7km)
- building(s);
- a structure built for permanent use, as a house, factory, etc..
- Wells City Hall (14.3km)
- meteorological station;
- a station at which weather elements are recorded.
- Wells (13.4km)
- swamp;
- a wetland dominated by tree vegetation.
- Humboldt Wells (12.6km)
- post office;
- a public building in which mail is received, sorted and distributed.
- Wells Post Office (13.7km)
- reservoir(s);
- an artificial pond or lake.
- Bishop Creek Reservoir (9km)
- dam;
- a barrier constructed across a stream to impound water.
- Bishop Creek Dam (9km)
- park;
- an area, often of forested land, maintained as a place of beauty, or for recreation.
- Wells City Park (14.7km)
Wikipedia entries close to
Hopkins Ranch
- Wells Municipal Airport airport airport
- Wells, Nevada city city o
- Angel Lake city city o
- Greys Peak mountain mountain k
- East Humboldt Range city city o
- East Humboldt Wilderness city city o
- Humboldt Peak (Nevada) mountain mountain k
- Pequop Mountains city city o
- Hidden Lakes, Nevada city city o
- Soldier Lakes, Nevada city city o
- Robinson Lake, Nevada city city o
- Cold Lakes, Nevada city city o
- Pilot Peak (Nevada) mountain mountain k
- Lamoille, Nevada city city o
- Verdi Lake, Nevada city city o
- Verdi Peaks mountain mountain k
Airports close to Hopkins Ranch
Wendover(ENV), Wendover, Usa (106.5km)


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To protect your passions as well as your wellness, you need to make sufficient preparation for the times when cooling repair work has to carried out in your residence. It excels to understand the fundamentals concerning cooling You must constantly be a proficient about air-conditioning if you anticipate to go over the repair procedures with the service technician you intend to employ. Keep in mind that employed workers will certainly always check out the task from their perspective and will certainly always follow the manner in which will certainly make it easier for them to complete their task.Click here now for More About AC repair Aiken.
As the proprietor of your home, you have to watch out for its interests and also the rate of interest of individuals living there. When you plan out the information of the fixing with your technician, you will need some expertise about the technicians of air-conditioning to comprehend exactly what he is proposing to do and for you to be able making counter proposals of your own for lessening the disruption that the fixings will certainly create for people in your home.
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STV Big Cheese Mega Sonic Scatter-Cat Gun
Barcode: 5036200126320
Product Code: STV632
£21.29(£17.74 exVAT)
The STV Big Cheese Mega Sonic Scatter-Cat Gun from STV Big Cheese.
STV have produced the well known Defender brand of pest control systems and devices for a wide range of unwanted guests in and around your home or work place.
The STV632 sonic repeller gun with laser-light sighting repels cats, dogs, squirrels and other nuisance animals without harm.
This trigger action and laser-light sighting gun will give off a ultra sonic sound that only animals can hear.
The mega sonic scatter unit can effectively target animals up to 20 metres away, and help you to protect flower beds and plants from unwanted pests. This STV632 is ultra sonic and there will be no disturbance to neighbours.
Technical Question?
If you have technical questions regarding this product please fill in this Enquiry form.
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Singomakers On Air Music MULTiFORMAT
Category: Software
Singomakers On Air Music MULTiFORMAT | 1.18 Gb
Singomakers are very proud to present "On Air Music sample collection. Based on super-hits which are holding 1 spots on Spotify, Apple Music and radio stations all over the world! We took some great tracks as a reference from Kygo, Kriss Kross Amsterdam, Cheat Codes, The Chainsmokers, Eva Simmons, VINAI, Coldplay, Mike Posner, Robin Schulz, Dante Klein and more!
This 1.46 Gb sample pack is full of professionally designed samples at 105 BPM, including 150 One Shots, 60 Melody Loops, 40 Bass Loops, 30 Vocal Loops, 70 Drum Loops, 30 Drum Fills, 20 FX & Noise Loops, 100 Midi Files, 230 Rex2 Files, 50 Sound FX and 5 Sampler Patches!
If you are searching for melodies and sounds designed specially to fit the popular tracks currently on the Radio and Spotify - this sample collection is the one for you.
On Air Music is available for download as Full Zip (Wav files), Apple Loops, Ableton Live pack, Reason Refill and separate formats like Wav & Midi Loops, One Shots & Sound FX and more!
Home Page - http://www.loopmasters.com/genres/25-House/products/5340-On-Air-Music
Mirror Links


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Sexy Girls Diary - Laura and Dou : Make me yours
Description:Sexy Girls Diary - Laura and Dou : Make me yours , sexy skirt and dancing
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Vandread Episode 1 English Subbed
You are watching Vandread Episode 1 English Subbed from the Vandread Anime Show. Watch or Download Vandread Episode 1 MP4 English Sub and other episodes of Vandread Streamed for Free.
"Boy Meets Girl"
Stream Vandread Episode 1
Episode Summary: The male planet of Tarak commemorates the launch of a new battleship, Ikazuchi. Hibiki attempts to steal a vangard onboard the ship but is captured. A female pirate raids the ship and ends up capturing Hibiki, along with Bart, Duero, and half the ship.


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Walgreens (est. 1901)
[33.5432859539847, -111.905641257763] walgreen, photo, print, drug, store, beauti, suppli, conveni, perfum, pharmaci, milk, bread, egg, cigarett, magazin, coffe, candi, gum, cosmet, flu, shot, western, union, monei, transfer
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Refill your prescriptions, shop health and beauty products, print photos and more at Walgreens. Pharmacy Hours: M-F 9am-9pm, Sa 9am-6pm, Su 10am-6pm
American Express, Discover, Visa, Cash, MasterCard, Check, Android Pay, and Apple Pay gladly accepted
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Phantom Glass makes all kinds of screens for electronic devices, and now it seems they're adding the Switch to their roster. When asked on Twitter if they had any plans for Switch screens, they confirmed their plans and asked people to stay tuned. We'll bring you more details when they come in.
I got the tempered glass product from caseology, it went on super well and has been great. They have an updated 2.0 version now for some reason, not sure what they could have changed
Today's VIP
Joined: January 2017


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Flu Tightens Its Hold On The Nation
Wochit Headline News - January 13, 2017
com reports that The pace of flu activity continues to quicken across the United States, and probably hasn't peaked yet. That's the assessment of the U.S.
Centers for Disease Control and Prevention, which is urging the most vulnerable -- the very young, the elderly, the chronically ill and pregnant women -- to get their flu shots before it's too late.
Right now, the heaviest flu activity is occurring along the East and West Coasts..


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Sticky Bead Mat
Bead Addiction
Ideal for keeping beads and findings right where you want them! One side is indented with U-channels like a traditional bead board to arrange jewelry pieces before stringing and the other side is flat. Both sides are marked with measurements in both inches and centimeters. When the mat starts to gather dust or debris, simply rinse it with water and let it dry. It will refresh and become as sticky as when it was new! Double-sided: two different work surfaces! Surface feels sticky but leaves NO residue! Keeps small beads & parts in place Great for jewelry making & crafts Rinse and dry to refresh sticky surface
Large Measures 8-3/4 x 12-1/8 inches"
Small Measures 3-1/4 x 5-1/2 inches


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Next Show
Past Shows
Misha Cross
May 27, 2016 06:00 PM PDT (60 min.)Amarna Miller
Mar 16, 2017 12:30 PM PDT
FIRST VRCAM SHOW 180º3D - 60FPS OF THE HISTORY!
More than 6000 people with Amarna Miller in the first live VR cams in 180º 3D – 60fps of the history!
Who We are?
We are the team of VirtualRealPorn.com, the very first website with VR Porn, always working in improving the Porn Experience for the maximum immersion.
What We do?
VirtualRealCams is our new and awesome project for bringing you the best VR Pornstars to your VR headset in real time. You'll feel our girls as you were there! 180 degrees of head movement freedom in Stereoscopic 3D
- Oculus DK2 or Oculus Rift with Oculus Runtime 1.3+
- HTC Vive compatibility using Steam VR
- Windows PC
- Internet connection
- VirtualRealCams app
- We are working in new versions for Android, Gear VR and iOS
- More pornstars
- More shows
- Stay tuned!


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Years & Years singer Olly Alexander wants to encourage people to be open about their sexuality.
The new video for the band's song 'Desire' celebrates sex in the LGBT community and Olly revealed the concept of the video came from their wish to highlight "other sexualities and identities that are well deserving of some shiny pop video love".
He explained in an open letter on Facebook: "Most of the pop videos I've seen that have any male and female interaction are usually centred around a romance, and that's great, I am all for romance, but let's face it there are a lot of other sexualities and identities that are well deserving of some shiny pop video love.
"I've been wanting to make a video with some of my queer family for a long time and 'Desire' felt like the right time to do it. Every Y&Y video has some similar elements that run through it: magical worlds, symbolism, pretty lights and this time I wanted sex added into that mixture.
"I wanted the video to feel sexy. Everyone has a different definition of what they find sexy, so why do we so often get given one version of what sexy is time and time again? Is there a rulebook for men and women on how to feel sexy or what sexy is? For me, whoever it is, two women, two men, a group of gender-queer people, it's all cute. It can all be a positive and a joyful expression of sexiness and sexuality, you don't have to be a specific gender to enjoy it.
"So yeah, gay people have sex, and it's not just gay people, it's all kinds of people! All these non-straight people, they're out there, having sex! Sex, between two consenting adults, can be a healthy, positive, safe and enjoyable thing (sic)."
Olly also cited his teenage influences as women including Madonna, Destiny's Child, Alanis Morisette, Britney Spears and Whitney Houston who "asserted and acknowledged their sexuality in varying and different ways and to me they were ways that felt powerful".
He explained: "They were singing about men and I wanted to sing about men. They were seductive and sensual in their videos - I wanted to be seductive and sensual in my videos (and believe me I made a lot of these kind of home videos). They were so much more interesting to me than the majority of male musicians whose Type A macho masculinity felt completely un-relatable."


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When he was young, Jimmy met a boy in a playground.
As the years passed, Jimmy grew older...but the boy did not.
Set in a haunted playground, The Red Boy explores the boundaries between parents and children, women and men, and the living and the dead.
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A solid story with solid narration
- Daltha Dolanch
A mysterious boy in Jimmy's life
I was offered a copy of this book in audio format from the narrator in exchange for an honest review.
It seems the boy in the red sweater has always been at the playground; before Jimmy was born, during his childhood and when he became a grownup. The mysterious red boy, who knows the future and is incessantly looking for bones in the ground.
This book seems composed by short stories, being each one a stage in Jimmy's life. Seasons and years pass by, but the red boy is the constant in this story. The book is just over three hours, and due to its construction, we know little about the characters, but despite their short appearances they were really well constructed, and the dialogs are vivid and feel natural.
I would like to comment that the fact that Jimmy's son is called James got me confused a couple of times. I think a more different name would have worked better here.
The only drawback is how short this story is. I wish I had more time to better know the characters, and especially the boy in the red sweater. We get a glimpse of why he is there looking for bones, but I would have wished to know more.
The book is narrated by Tanya Eby and Neil Hellegers, but not in the usual way of having the male narrator doing male voices, and the female narrator doing female voices. Each narrator took turns to narrate each chapter, which felt weird and in my opinion, make the book to lose continuity. This feeling could be because their styles and postproduction were very different, although I really liked both narrators. I especially enjoyed Eby's clarity and Hellegers' ability to express the characters' emotions.
It was a good book but I would have liked for Camp to have expanded the story and tell us more about the characters. The story and the character building were very promising. In the end it seemed more like a campfire story.
- Lomeraniel


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GraphicRiver Power Solution Proposal Template 10906506
Category: Print Template | Comment: ( 0 )
GraphicRiver Power Solution Proposal Template 10906506
Print Template \ Stationery \ Proposals & Invoices
Proposal \ Business \ Project \ Website \ Template \ Swiss \ Simple \ Layered
Print Template - Power Solution Proposal Template 10906506 by alimran24 @ GraphicRiver
Print Template \ Stationery \ Proposals & Invoices
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Keywords: business, business proposal, catalog, clean, folio, innd, layered, modern, project, project proposal, proposal, proposal template, simple, swiss, template, website, website proposal.


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The first logo
Before the organization was founded, two of the founding members had already created a logo. When a friend and I joined the effort, we decided to change the logo and make it "friendlier," because we didn't want the organization to look "techy" or threatening. Bright colors and cute shapes a la Google were the name of the game.
The first change
When I recruited my friend Chloe from The Daily, we got a huge fillip in terms of design talent. In coming up with this logo, I iterated with her at her workstation. My inspiration for this shape was the "accordion book," which I was creating as part of my English class. The idea of something opening up easily was my inspiration. Chloe agreed and came up with this beautiful design while I sat there. Ultimately, we let this go, as the logo, though beautiful, was too wide for most contexts and too color dependent. In Black and white, the many-dimensional nature of the design would be lost. We decided that a square or a box would be most appropriate.
The first box
This was a very early version of the logo I sketched out using pen and color pencils. Chloe and I went back and forth a few times with ideas over text. This one looked too much like a disposable toilet, but it got some parts across clearly. It was less color dependent, a lot more compact, and gave the idea of a technical subject "giving up" its secrets easily and in an accessible manner.
Iteration over email
The process continued over email, with Chloe running with the idea of the box and creating several different prototypes. As you can see, I was with her every step of the way, offering my suggestions and criticisms. We were close to done with the logo.
The final logo
This logo went off one of the ideas in the previous iteration. The big new idea here was the "peeling back" of the box of tech holding its secrets, thus highlighting the process and hinting at the result.
Coupled with a snazzy slogan we brainstormed on, the process was complete.
Creating the posters
While we were iterating the logo, an earlier version served as the lynchpin of our poster designs. I wanted to look at people from various walks of life who had spoken about tech as an important part of the modern world. I was also intent on having some ethic diversity in our outreach, because reaching minority students was a priority of ours. My initial idea was to have a "posterize" effect, but Chloe demonstrated that it didn't work. Thus, we moved to a flatter effect and chose the layout of the posters.
Using the logo
Here I am in the center holding the banner with the DubsTech admin and the first cohort of students in Winter quarter, 2016.


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A proposal with detailed plans is circulating in Kahnawake that would bring a hotel, water park and casino to the territory. Lee Thomspon's name is on the document as the backer of the multi-million dollar entirely privately funded project. It would be nearly 221 000 square feet and include an 800 room hotel that would be built on the land adjacent to the old Maddie's place. In the document, Thomspon says the project would bring in $100 million dollars a year to the community and create 1500 jobs. K103 News has reached out to organizers who have said they will be prepared to speak on Tuesday.
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text:
3XL & 4XL available in Black, French Navy and White only
XS available in White and French Navy only
Prices listed exclude VAT
Available Options:
Chest Size:XS (34-36)S (36-38)M (38-40)L (40-42)XL (42-44)2XL (44-46)3XL (46-48)4XL (48-50)
Colour:AppleBlackWhiteBottle GreenBright RoyalCandy PinkClassic RedFrench NavyFuschiaLight OxfordLimeOrangePurpleSkyTurquoiseYellow
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Web design by Masonhost


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Service Update 2+
FSX Voice Control: 2.3
FSX Button Control: 2.4
FS9 Voice and Button Control: 2.2
See the FS2Crew Support Forum at Avsim.com for the Change Log.
P3D Version 3 users: Please read this thread for very important information.
This update is NOT built into the main installer, so all users (Voice and Button Control, FSX and FS9) should install it.
• Released: 22 January 2014
• Requirements: FS2Crew iFly 737NG Edition (Voice or Button Control)
• Built into Main Installer: No
Download (Approx 3.6 MB)
VERY IMPORTANT: If you do not have the VS2010 end user runtimes installed, you must download and install the VS2010 End-User Runtimes or you may get a CTD when you run the update.
Please read this thread in the FS2Crew Support forum for the Change Log. Many of the "Button Control" button/joystict assigments were changed in V2.3 to match those used in the NGX version.
You must read this thread carefully!