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Bile acids from duodenogastric reflux promote inflammation and increase the risk for gastro-oesophageal cancers. FXR (farnesoid X receptor/NR1H4) is a transcription factor regulated by bile acids such as CDCA (chenodeoxycholic acid). FXR protects the liver and the intestinal tract against bile acid overload; however, a functional role for FXR in the stomach has not been described. We detected FXR expression in the normal human stomach and in GC (gastric cancer). FXR mRNA and protein were also present in the human GC cell lines MKN45 and SNU5, but not in the AGS cell line. Transfection of FXR into AGS cells protected against TNFα (tumour necrosis factor α)-induced cell damage. We identified K13 (keratin 13), an anti-apoptotic protein of desmosomes, as a novel CDCA-regulated FXR-target gene. FXR bound to a conserved regulatory element in the proximal human K13 promoter. Gastric expression of K13 mRNA was increased in an FXR-dependent manner by a chow diet enriched with 1% (w/w) CDCA and by indomethacin (35 mg/kg of body weight intraperitoneal) in C57BL/6 mice. FXR-deficient mice were more susceptible to indomethacin-induced gastric ulceration than their WT (wild-type) littermates. These results suggest that FXR increases the resistance of human and murine gastric epithelial cells to inflammation-mediated damage and may thus participate in the development of GC.
- bile acid
- chenodeoxycholic acid (CDCA)
- farnesoid X receptor (FXR)
- keratin
- gastric cancer
- stomach
Overexposure to bile acids leads to damage of GI (gastrointestinal) epithelia. For example, patients with recurrent heartburn are at increased risk of oesophageal cancer [1]. Chronic inflammation upon duodenogastric reflux of bile acids, e.g. after gastric resection, is an important risk factor for GC (gastric cancer) [2–5]. Efficient detoxification mechanisms, some involving members of the nuclear receptor superfamily [6], counteract the detrimental actions of excess bile acids on GI organs.
FXR (farnesoid X receptor/NR1H4) is nuclear receptor and transcription factor activated by physiological bile acids [6,7] including CDCA (chenodeoxycholic acid) and DCA (deoxycholic acid). FXR suppresses the de novo synthesis of bile acids in the liver and promotes excretion and enterohepatic circulation of conjugated bile acids [8]. Previous studies in FXR-deficient mice have suggested a beneficial role for FXR against cholestasis [7] and colitis [9]. FXR facilitates liver regeneration, supports the differentiation of the intestinal epithelium and promotes antibacterial defence in the GI tract [7]. In contrast, FXR-deficiency exacerbates hepatic [7] and intestinal [9] inflammation and promotes carcinogenesis in mice [10]. These results corroborate the idea that FXR acts as a protective factor in the liver and the GI tract.
Aberrant FXR expression or function has also been detected in human adenocarcinomas of the colon [11], breast [12], prostate [13] and oesophagus [Barrett's IM (intestinal metaplasia)] [14]. These findings pointed to either causative or protective roles for bile acids and/or FXR in the pathogenesis of these tumour types. FXR mRNA variants have been identified in normal stomach tissue of humans and mice [15,16]; however, a functional role for gastric FXR has not yet been defined. We therefore have evaluated the role of bile-acid-activated FXR on cell survival of human and mouse gastric epithelial cells. The results of the present study indicate that FXR increases the resistance to inflammation-induced cell damage accompanied by the up-regulation of protective target genes, such as K13 (keratin 13).
Tumour specimens were obtained by surgical resection from GC patients and processed according to standard methods [17]. TMAs (tissue microarrays) were then generated. GC was classified histologically into D-T (diffuse-type), I-T (intestinal-type) and undifferentiated types according to the Lauren classification [17a]. IM-T (IM-type) was assessed within I-T tissue specimens. Tissue sample collection of human GC specimens was approved by the Ethics Committees of the Technische Universität München and the Charité Berlin. Written informed consent was received from the patients used in this study.
Animal studies
WT (wild-type) and FXR (Nr1h4/UniProtKB/Swiss-Prot number Q60641)-KO (knockout) mice (strainB6; 129XFVB-Nr1h4-tm1Gonz/J, Jackson Laboratory) were maintained on a pure C57BL/6 background. Male mice (4-weeks-old) received a chow diet (Altromin) containing 1% (w/w) CDCA (Chemos) (n=5 per group and genotype). Experimental gastric ulceration (n≥6 per group and genotype) was performed with Indo (indomethacin) as described previously [18]. Animal housing and experiments were performed in agreement with the ethical guidelines of the Technische Universität München and the Ludwig Maximillians Universität München, and were approved by the appropriate government authorities.
Cell culture and WB (Western blotting)
HEK (human embryonic kidney)-293, hepatoma HepG2 and the GC cell lines AGS, NCI-N87, SNU1, SNU5, KATOIII (A.T.C.C.), MKN7 and MKN45 (Japan Cell Bank) were cultivated as described previously [17]. Stable AGS clones were generated [17] upon transfection with full-length human FXRα1 cDNA (GenBank® accession number NM_001206977.1) in pTarget (AGS/FXR) or pTarget EV (empty vector) (AGS/EV) respectively. SDS/PAGE (12% gel) and WB of cell and tissue lysates (25 μg of protein per gel lane) were performed as described previously [17].
The anti-FXR (H-130; Santa Cruz Biotechnology) and anti-K13 (NCL-K13; Novocastra) antibodies were used for IHC (immunohistochemistry) and WB. Anti-FXR (clone A9033A; R&D Systems), anti-(cleaved caspase 8) (Asp391) (18C8) and anti-(cleaved caspase 3) (Asp175) (Cell Signaling Technology), anti-(cleaved PARP) [poly(ADP-ribose) polymerase] (Asp214) (7C9; Cell Signaling Technology) and anti-β-actin (clone AC-74; Sigma) were used for WB.
Sections from paraffin-embedded tissues (3 μm) were stained (1:100, FXR H-130) as described previously [19]. Cryosections (10 μm) were stained (1:50, K13) following antigen retrieval using pepsin digestion and the Vectastain® Mouse-on-Mouse kit (Vectorlabs). The TMAs were subjected to an automated staining protocol and quantitatively evaluated by an expert pathologist.
DNA constructs
The FXR-RE (responsive element) reporter plasmid consists of the human BSEP (bile salt export pump) promoter driving the luciferase gene in pTK-luc (FXR-RE-luc) [20]. The human K13 promoter (GenBank®accession number AF049259, 1–525 bp) containing a putative FXR site (RARE2) was subcloned into pGL3-basic-luc (Promega) (RARE2-WT-K13p-luc) [21]. A second plasmid (RARE2-MUT-K13p-luc) was constructed, in which the ACTGGGTGGGGCTCA (RARE2) element in the human K13 promoter was deleted using the QuikChange® kit (Stratagene). The 1428 bp full-length human FXR cDNA (476 amino acids, α1 splice variant with additional four amino acids MYTG; GenBank® accession number NM_001206977.1) [16] was inserted into pTarget (Promega). SiGENOME SMARTpool siRNA (short interfering RNA) against human FXR and K13 was from Dharmacon. Knockdown efficiency was verified by RT (reverse transcription)–qPCR (quantitative PCR) and WB, and varied between 40 to 80%. PCR products for human FXRα1/2 (GenBank® accession numbers NM_001206977.1 and NM_001206978.1) and FXRα3/4 (GenBank® accession numbers NM_001206993.1 and NM_001206992.1) mRNA variants [22] (Supplementary Table S1 at http://www.BiochemJ.org/bj/438/bj4380315add.htm) were purified from agarose gels (Invitrogen) and confirmed by sequencing (GATC).
RT–PCR and qPCR
Reactions were performed as described previously [19]. CT-values were normalized to CT values of β2-microglobulin and compared with 'no template' controls (CT>36).
DNA microarrays
AGS/FXR and AGS/EV cells were treated for 16 h with 100 μM CDCA. cRNAs were produced as described by the manufacturer (One-Cycle cRNA labelling kit; Affymetrix) and hybridized to GeneChip® Human Genome Arrays (HG U133 Plus 2.0; Affymetrix) [20]. Gene sets (Supplementary Table S2 at http://www.BiochemJ.org/bj/438/bj4380315add.htm) were identified using the DAVID Bioinformatics resource (http://david.abcc.ncifcrf.gov).
ChIP (chromatin immunoprecipitation) and EMSA (electrophoretic mobility-shift assay)
ChIP and EMSA were performed using oligonucleotides (Supplementary Table S1) as described previously [20].
Cell viability assays
Colorimetric MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assays were performed according to the manufacturer's instructions (Roche Diagnostics). Flow cytometry was done on cells grown to confluency in six-well plates and treated with TNFα (tumour necrosis factor α; 100 ng/ml) (Roche) and CHX (cycloheximide; 20 μg/ml) for 6 h. Floating and adherent cells were harvested into PBS and collected by centrifugation [200 g for 4 min at room temperature (20 °C)]. Annexin and PI (propidium iodide) double staining was performed according to the manufacturer's protocols (Roche) and was analysed on a FACScalibur device (BD Biosciences).
Results are expressed as means±S.E.M. from at least five animals per group and genotype or three independent cell experiments. P values were calculated using Graphpad Prism 4 software with one-way ANOVA for mice, Student's t test for cells and Wilcoxon signed-rank test for patient data.
Expression of FXR in human GC tissues and cell lines
To assess the expression of FXR protein (NR1H4/UniProtKB/Swiss-Prot number Q96RI1) in human GC, IHC on tissue microarrays was performed using a rabbit polyclonal FXR antiserum [13,23,24] (Figure 1A). In tissues from healthy individuals, FXR was found in the nuclei of cells of the non-neoplastic foveolar epithelium from gastric glands. In a series of GC specimens (n=70), consisting of both I-T and D-T GC, FXR was undetectable (score 0 on the Lauren classification) in 32 cases (46%), showed moderate expression (score 1+) in 31 cases (44%) and strong expression (score 2+) in seven cases (10%) in the tumour cells. FXR was most prominently expressed (score 2+) in six out of the seven specimens of I-T GC which contained regions of IM, as evident by translucent goblet cells, and was localized both in the nucleus and the cytoplasm. FXR was detected by WB in gastric tissue lysates as a ~56 kDa band similar in size to that detected in normal human liver using a mouse monoclonal antibody [14,25] (Figure 1B). Collectively, these data indicated that FXR is expressed in the normal human stomach and in GC.
In humans [16] and rodents [15], two major FXR mRNA variants α1/2 and α3/4 have been identified that result in divergence in the N-terminal region of the protein (Figure 2A) [22]. In addition, the α1 and α3 variants contain a four-amino-acid (MYTG) insertion of unknown function [22]. We amplified the human full-length FXRα1/2 mRNA with a forward primer specific for exon 1 and the truncated ΔFXRα1/2 transcript with a primer specific for exon 3 that contains the start codon (GenBank® accession numbers NM_001206977.1 and NM_001206978.1). Human FXRα3/4 mRNA was detected by an exon 3a-specific primer (GenBank® accession numbers NM_001206993.1 and NM_001206992.1) [16]. A common reverse primer against exon 4 was applied for all RT–PCRs, and all PCR products were confirmed by DNA sequencing. We detected full-length FXRα1/2 mRNA in human hepatoma HepG2 cells. FXRα3/4 mRNA was detected in the human GC cell lines MKN45 and SNU5. None of the other human GC cell lines (AGS, SNU1, N87, KATOIII and MKN7) expressed either full-length FXRα1/2 mRNA or α3/4 mRNA; however, the ΔFXRα1/2 mRNA was detectable in all GC lines. Consistent with the results obtained from the PCR analyses, a ~56 kDa FXR protein was observed in SNU5 (Figure 2B, lane 3) cells as compared with protein lysates from human hepatoma HepG2 cells, HCC (hepatocellular carcinoma) and normal liver tissue (Figure 2B). No FXR protein was detectable in AGS, SNU1, N87, MKN7 or KATOIII cell lysates (results not shown), indicating that the ΔFXRα1/2 transcript is not translated into a detectable protein. Real-time RT–qPCR using primers against the common DNA-binding domain of FXR (GenBank® accession number NM_0012069) confirmed that SNU5 expressed the highest levels of total FXRα mRNA of all the tested human GC cell lines (Figure 2C).
FXR protects against cell damage
To explore the function of gastric FXR in cells, AGS cells were stably transfected with an expression plasmid harbouring the full-length human FXRα1 cDNA (AGS/FXR; GenBank® accession number NM_001206977.1) or with EV (AGS/EV). Chronic inflammation is a risk factor associated with human GC [26]. The present study tested whether FXR modulates the sensitivity of AGS cells towards inflammation-induced stress in the presence of TNFα and CHX, which specifically induce apoptotic cell death [27]. AGS/FXR and AGS/EV cells were treated for 24 h with a mixture of TNFα (100 ng/ml) and CHX (20 μg/ml). The results from MTT assays demonstrated that AGS/FXR cells retained higher viability (3-fold, P<0.05) than AGS/EV cells (Figure 3A). CDCA (at 50 μM) increased further the protective effect of FXR (4-fold, P<0.05) compared with both the vehicle and CDCA-treated AGS/EV cells. SNU5 cells, which expressed the highest level of endogenous FXR, were the most resistant to the apoptotic effect of TNFα and CHX of all parental GC lines and comparable with HepG2 cells (results not shown), suggesting endogenous FXR is also protective.
Increased apoptosis was confirmed by WB that showed cleaved caspase 8 appearing after 6–8 h of TNFα and CHX treatment, followed by appearance of cleaved caspase 3 and PARP after 10 h (Figure 3B). The abundance of the cleavage products was decreased and the time of their appearance was delayed in AGS/FXR compared with AGS/EV cells. These results suggest that FXR delays and limits the activation of TNFα-triggered apoptosis. To quantitatively assess apoptotic cell numbers, annexin/PI dye-exclusion flow cytometry was performed. Statistical analysis of the FACS results revealed that approximately 5-fold more annexin-positive apoptotic cells were present following 6 h of treatment with TNFα and CHX in AGS/EV (25±5%, P<0.05) than in AGS/FXR (5±10%) cells (Figure 3C). These results corroborate the protective effect of FXR against inflammation-mediated cell death.
Human K13 is a novel FXR-target gene
To identify potential mechanisms underlying cell protection by FXR, AGS/FXR and AGS/EV clones were treated with 100 μM CDCA for 16 h, and total RNAs were subjected to DNA microarray analysis (see Supplementary Table S5 at http://www.BiochemJ.org/bj/438/bj4380315add.htm). Comparative analysis identified K13 mRNA (GenBank® accession number NM_002274.3, variant b) as the most highly up-regulated transcript in AGS/FXR compared with AGS/EV cells. Other keratin types, including K6, keratin-associated protein 2-1 and plakophilin 4, a structural component of desmosomes, were also increased (Supplementary Table S2). The mRNAs for TNFAIP8 (TNFα-induced protein 8), an inhibitor of caspases and anti-apoptotic factor, and the gastroprotective protein SERPINB2 (plasminogen activator inhibitor 2) were also specifically increased in AGS/FXR cells [28]. Induction of the human organic solute transporter OSTα, a well-characterized FXR-target gene, confirmed that FXR activity was increased by CDCA in AGS/FXR cells.
RT–qPCR expression analysis was performed to confirm the microarray results. Treatment for 24 h with 75 μM CDCA up-regulated K13 mRNA (4-fold) and the FXR-target genes OSTα (2-fold) and IBABP (ileal bile-acid-binding protein) (36-fold) in AGS/FXR cells (P<0.05), but not in AGS/EV cells (Figure 4A). Using WB it was demonstrated that the ~54 kDa K13 protein (K1C13/UniProtKB/Swiss-Prot number P13646) was also increased in parallel with its mRNA (Figure 4B). CDCA also increased K13 and OSTα mRNA (~2-fold, P<0.05) in the parental SNU5 and MKN45 cells (results not shown), indicating that K13 is also regulated by endogenous FXR. To further test their role in apoptosis protection, both FXR and K13 expression were knocked-down by transient transfection of siRNA oligonucleotides into AGS/FXR cells, followed by a 24 h challenge with TNFα and CHX (100 ng/ml and 20 μg/ml respectively) in absence and presence of 50 μM CDCA (Figure 4C). The survival rate of RNAi (RNA interference)treated cells was lower (~25–60%, P<0.05) than for mocktransfected cells, both in vehicle- and CDCA-treated cultures. Similar results were obtained after FXR silencing in MKN45 and HepG2 cells (results not shown), suggesting an anti-apoptotic role also for endogenous FXR.
FXR directly binds to and transactivates the human K13 gene promoter
In the human K13 proximal promoter (GenBank® accession number AF049259) binding sites for retinoic acid [21] and vitamin D3 receptors have been predicted (M. Ebeling, unpublished work), and its regulation by retinoids has been shown experimentally in vitro [29,30] and in vivo [31,32]. To determine whether FXR binds to these elements, we designed ChIP primers flanking the first 500 bp upstream to the predicted transcriptional start site (Figure 5A). AGS/EV and AGS/FXR cells were incubated for 16 h with either vehicle or 75 μM CDCA, and cell lysates were subjected to ChIP. Genomic qPCRs were visualized by gel electrophoresis and quantified (Figure 5B). No pull-down of genomic DNA was observed with agarose beads coupled to control IgG (Figure 5B, lane 3). ChIP against FXR revealed an increased FXR binding (2-fold, P<0.05) to the K13 promoter amplicon in the presence of CDCA (Figure 5B, lane 2) compared with the vehicle (Figure 5B, lane 1) in AGS/FXR cells, but not in AGS/EV cells. These results indicate that CDCA increases FXR binding within the proximal K13 promoter.
To determine whether this genomic region mediates CDCA- and FXR-dependent transactivation of a heterologous gene [20], we cloned the proximal human K13 (−500/+1) promoter (GenBank® accession number AF049259) into pGL3-basic luciferase vector (Figure 5C). HEK-293 cells [20] were transiently transfected with either EV or FXR expression plasmids, together with the reporter plasmid driven under the control of the K13 promoter (RARE2-WT-K13p-luc) or a control reporter plasmid containing a cognate FXR-RE from the BSEP promoter (FXR-RE-luc). The cells were treated for 24 h with 30 and 100 μM CDCA and luciferase activity was determined in cell lysates. CDCA strongly stimulated the activity of the K13 promoter (7–9-fold, P<0.05) only in cells co-transfected with the FXR expression plasmid (Figure 5C).
Despite these findings, a classical IR1 (inverted repeat 1) element was not identified in the proximal 500 bp of the K13 promoter (GenBank® accession number AF049259). Nevertheless, FXR also recognizes hexameric direct repeat elements with a variable number of intervening nucleotides between the half sites [33]. Within the region amplified in our ChIP experiments, we localized three half site AGGTCA-like elements that had previously been described as RAREs (retinoic acid receptor-responsive elements) [21]. One of these half sites (RARE2) was well-conserved between human and rodents and overlapped with an experimentally proven RARE [34] and a predicted SP1 [21] site (Supplementary Table S3 at http://www.BiochemJ.org/bj/438/bj4380315add.htm). The RARE2 element was specifically deleted in the K13 promoter-luciferase expression construct (RARE2-MUT-K13p-luc), and we repeated the reporter gene assay in HEK-293 cells. Deletion of RARE2 abrogated the CDCA- and FXR-dependent transcriptional activation of the K13 promoter (Figure 5C), demonstrating that RARE2 is necessary for the transcriptional activity of FXR.
To explore the direct interaction of FXR with the K13 promoter, EMSAs were performed [20] using a biotin-labelled oligonucleotide, which contained a consensus IR1 element. Nuclear extracts were prepared from HEK-293 cells that had been transiently co-transfected with FXR or EV plasmids. Increased protein binding to the IR1 element was visible in the nuclear extracts from CDCA-treated FXR-transfected cells compared with untransfected cells (Figure 5D, lanes 2 and 4 respectively). Both the basal and CDCA-dependent (Figure 5D, lanes 3 and 4 respectively) complexes were effectively reduced by competition with an unlabelled RARE2 oligonucleotide (Figure 5D, lanes 5 and 6), but not by a mutated RARE2 sequence (Figure 5D, lanes 7 and 8). Direct binding of FXR to a biotin-labelled RARE2 oligonucleotide was then tested (Figure 5E). Nuclear extracts of FXR-transfected and CDCA-treated cells produced an enhanced mobility shift compared with vehicle-treated samples (Figure 5E, lanes 2 and 1 respectively), which was efficiently competed by an excess of unlabelled RARE2 oligonucleotide (Figure 5E, lanes 3 and 4), but not by the mutated RARE2 oligonucleotide (results not shown). Addition of polyclonal FXR antiserum (1 μg), which recognizes the DNA-binding domain of FXR, interfered with the band shift (Figure 5E, lane 5), corroborating that the DNA–protein complex observed (Figure 5E, lane 2) contains FXR bound to the RARE2 element. These results indicate that FXR binds RARE2 driving the bile-acid responsiveness of the K13 promoter.
K13 is also regulated by FXR in vivo
To examine K13 regulation by FXR in vivo, WT and FXR-KO mice were fed on a chow diet enriched in 1% (w/w) CDCA for 7 days (n=5 per group and genotype). This diet was well tolerated and elicited a general FXR response in the GI tract [20]. Nuclear FXR (Nr1h4/UniProtKB/Swiss-Prot number Q60641) was visualized by IHC in the corpus and antral glands of the mouse stomach using the rabbit polyclonal antibody (Supplementary Figure S1 at http://www.BiochemJ.org/bj/438/bj4380315add.htm). Murine K13 protein (K1c13/UniProtKB/Swiss-Prot number P08730) was mainly expressed in the non-epithelial compartment facing the basolateral side of the gastric epithelial cells and in the squamous epithelium of the forestomach. The gastric mRNAs of K13 (5–6-fold, P<0.05) (GenBank® accession number NM_010662.1) and the cognate FXR-target gene Ibabp (30-fold, P<0.05) were robustly increased by CDCA in WT but not in FXR-KO mice. These data indicated that K13 is also regulated by FXR in murine gastric epithelial cells.
To determine whether K13 (K1C13/UniProtKB/Swiss-Prot number P13646) is co-expressed with FXR in the human stomach, IHC was performed. In normal gastric tissue, K13 staining revealed a net-like pattern within the foveolar epithelium which was absent in GC (Supplementary Figure S1). The ~54 kDa K13 protein was present in whole-tissue lysates of the normal gastric mucosa and in GC biopsies. Total FXRα mRNA levels were determined in a larger series of GC specimens using RT–qPCR primers directed against its common zinc-finger DNA-binding domain. Total FXRα mRNA (GenBank® accession number NM_0012069) was reduced in 25 out of 30 biopsies (Figure 5D, P<0.05) of GC patients as compared with matched tumour-free tissue. K13 mRNA (GenBank® accession number NM_002274) was also decreased in 24 out of 30 GC biopsies (P<0.05). These results indicate that K13 expression may be dependent on FXR also in vivo.
FXR deficiency promotes susceptibility to gastric injury in vivo
To examine the role of gastric FXR in vivo, stomach ulcers were induced in C57BL/6 WT (n=9) and FXR-KO (n=8) mice by intraperitoneal administration of Indo (35 mg/kg of body weight) for 24 h [18]. The control WT (n=6) and FXR-KO (n=6) animals received a mock injection of 0.9% NaCl. Gastric tissue sections were stained for H&E (haematoxylin and eosin) and injury scores were determined for each mouse stomach (Figure 6A). The control mice did not show any lesions in either genotype. WT mice administered Indo displayed no (score 0, n=2) or superficial (score 1+, n=4) erosive gastritis or had moderate discrete erosive gastritis (score 2+, n=2). In contrast, almost all of the Indo-treated FXR-KO mice exhibited moderate discrete erosive gastritis (score 2+, n=3) or suffered from severe gastritis with elongated erosions and ulcerations of the gastric mucosa (score 3+, n=3) (Supplementary Table S4 at http://www.BiochemJ.org/bj/438/bj4380315add.htm). The mean injury score and the area of the lesions (mm2) were significantly increased in the FXR-KO compared with WT animals (P<0.05; Figure 6B). The percentage of mice having ulcers was 50% (four out of eight) in FXR-KO and 22% (two out of nine) in WT (Figure 6B). All mice on Indo expressed elevated gastric mRNAs for Tnfα, IL (interleukin)-1β and IL-6 (results not shown) as compared with NaCl-treated mice. Interestingly, only the Indo-treated WT mice showed an increase in gastric Fxr (GenBank® accession number NM_001163700.1) and K13 ( GenBank® accession number NM_010662.1) mRNA (2-fold, P<0.05) as compared with NaCl-treated littermates. The mRNAs did not change in FXR-KO mice whether treated with Indo or NaCl (Figure 6C). Thus FXR-KO mice showed an enhanced susceptibility to gastric ulceration compared with WT mice. Collectively, these findings in vivo confirmed our in vitro data that gastric FXR prevents apoptosis and cell damage.
In the present study, we described a novel role for bile-acid-activated FXR in the protection of human and murine gastric epithelial cells against inflammation-induced damage and identified K13 as a novel FXR-target gene.
FXR mRNA variants have been described in the stomach tissue of humans, rodents and other species [15,16]. FXRα1/2 and FXRα3/4 mRNA, as defined by Huber et al. [15], and the ~56 kDa FXR protein were detected in the non-neoplastic human stomach and in human GC cell lines. In human GC specimens, FXR protein expression was most abundant in I-T GC tissue with IM. IM is considered a potential pre-neoplastic lesion of cancer of the upper-GI tract that is known to be associated with bile acid reflux [2,26,35]. IM is characterized by aberrant transcription factor regulation and altered gene expression [26,36]. Previously, bile acids were shown to up-regulate intestinal differentiation markers (CDX2) and the FXR-target gene SHP in human and rat gastric epithelial cell lines [37,38]. Thus our findings are consistent with the previously described elevation of FXR expression in oesophagitis and in Barrett's IM of the oesophagus [14,25]. Gastrooesophageal reflux disease promotes IM in the gastric cardia [2] and contributes to Barrett's metaplasia and oesophageal carcinogenesis. Duodenogastric reflux that occurs for example as a complication of surgical resection, increases the risk for GC [3]. Thus bile-acid-activated FXR may be part of a protective defence reaction against the chronic irritation and inflammation of the gastric mucosa, which is thought to facilitate the formation of intestinal type GC.
In support of this concept, the present study has shown that ectopic FXR confers resistance to inflammation-induced apoptosis in the human GC cell line AGS, which is naturally devoid of FXR. We identified K13 that, together with other desmosomal components (K6, keratin-associated protein 2-1 and plakophilin 4), is up-regulated in response to FXR and its ligand CDCA, and showed that K13 appears to mediate at least some of the anti-apoptotic effects of FXR. This particular cluster of structural proteins suggests a possible role of FXR in maintaining the epithelial barrier by preserving cell junctions. K13 is a differentiation marker of stratified mucosal epithelia and is also expressed in human GC [39–42]. Consistent with the well-characterized regulation of K13 by retinoids in the squamous epithelium [29–32], we discovered that K13 is up-regulated by CDCA-activated FXR via a conserved RARE in vitro and by a CDCA-enriched diet in vivo. In addition to their structural functions, keratins such as K8/18 in columnar epithelia directly interfere with apoptotic signalling. Keratins interact with and inhibit the death pathway components TNFR (TNF receptor)/Fas and TRADD (TNF-associated death domain)/FADD (Fas-associated death domain) [27,43–47], suggesting a direct mechanistic link between FXR and K13 to these proteins.
In further support of a protective role of gastric FXR, the present study found that tissue injury evoked by Indo-mediated ulceration [18] of the gastric mucosa was more severe in FXR-deficient mice compared with WT animals. This in vivo observation is consistent with previous studies in mouse models of colitis and colon cancer, in which FXR deficiency exacerbated both inflammation [23] and tumorigenesis [10]. In those previous studies, it was suggested that one important mechanism was FXR-mediated transrepression of pro-inflammatory NF-κB (nuclear factor κB)-regulated genes in myeloid cells [10]. In the present studies, both Fxr and K13 mRNA were up-regulated upon Indo-induced gastric ulceration, suggesting a similar protective role in the non-neoplastic stomach.
In conclusion, the results of the present study suggest that FXR protects against inflammation-induced cell damage in the normal stomach under stress conditions. As a consequence of chronic inflammation, FXR may contribute to the development of I-T GC by promoting resistance to apoptosis in transformed cells. Down-regulation of FXR in GC, similar to what has been described in the human colon [10] and Barrett oesophageal [14] cancers, may be a secondary event that leads to a loss of the protective functions exerted by FXR in non-malignant tissue.
Fan Lian, Xiangbin Xing and Gang Yuan performed the experiments, and collected and analysed the data. Claus Schäfer contributed to the animal work. Sandra Rauser, Axel Walch and Christoph Röcken did the histological staining and the quantitative evaluation. Martin Ebeling worked on the promoter sequence analysis, and Matthew Wright edited and proofread the paper prior to submission. Roland Schmid and Matthias Ebert supervised the project and gave conceptual advice. Elke Burgermeister designed the study, performed the experiments, analysed the data and wrote the paper.
This work was supported by the Deutsche Forschungsgemeinschaft (DFG) [grant number SFB 824], the Deutsche Krebshilfe [grant number 107885], Else Kröner Stiftung [grant number P14/07//A104/06] and the Bundesministerium für Bildung und Forschung (BMBF) [grant number 01EZ0802].
We thank Minhu Chen (Department of Gastroenterology, First Affiliated Hospital, Sunyat-Sen University, Guangzhou, China) for support on collaborations and Elke Prade (Department of Chemistry, Technische Universität München, Garching, Germany) for technical help. We thank Hans-Peter Märki (Medicinal Chemistry, F. Hoffmann-Laroche, Basel, Switzerland) for the supply of ligands.
Abbreviations: BSEP, bile salt export pump; CDCA, chenodeoxycholic acid; ChIP, chromatin immunoprecipitation; CHX, cycloheximide; D-T, diffuse-type; EMSA, electrophoretic mobility-shift assay; EV, empty vector; FXR, farnesoid X receptor; GC, gastric cancer; GI, gastrointestinal; HCC, hepatocellular carcinoma; H&E, haematoxylin and eosin; HEK, human embryonic kidney; IBABP, ileal bile-acid-binding protein; IHC, immunohistochemistry; IL, interleukin; IM, intestinal metaplasia; IM-T, IM-type; Indo, indomethacin; IR1, inverted repeat 1; I-T, intestinal-type; K13, etc., keratin 13 etc.; KO, knockout; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; OSTα, organic solute transporter α; PARP, poly(ADP-ribose) polymerase; PI, propidium iodide; qPCR, quantitative PCR; RARE, retinoic acid receptor-responsive element; RNAi, RNA interference; RT, reverse transcription; SHP, small heterodimer partner; siRNA, short interfering RNA; TMA, tissue microarray; TNF, tumour necrosis factor; WB, Western blotting; WT, wild-type
- © The Authors Journal compilation © 2011 Biochemical Society


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Phil Byrd Elected 69th Chairman of American Trucking Associations
Oct 23, 2013
Orlando, Fla. – Today, the Board of Directors of American Trucking Associations elected Phil Byrd, president of Bulldog Hiway Express, Charleston, S.C., as the federation's 69th chairman.
"I am deeply humbled that my fellow ATA members would grant me the tremendous honor of representing them, and our industry, as chairman," Byrd said.
"I believe our industry and our association on the precipice of momentous change," Byrd said. "And I hope that as chairman I can help not just ATA but our entire industry position themselves for these changes."
"I have great confidence that Phil will be a tremendous chairman," said ATA President and CEO Bill Graves. "He is as humble and dedicated an individual as I have had the privilege of working with while at ATA and I look forward to his leadership this year."
Byrd replaces Mike Card, president of Combined Transport, Central Point, Ore., as chairman.
"This past year has been a remarkable experience," Card said. "I'd like to thank my fellow members and the staff of ATA for all they've done for me these past 12 months and wish Phil the best of luck. I believe he'll be an excellent representative of our industry."
In addition, the Board elected Pat Thomas, vice president of public affairs at UPS Inc., ATA second vice chairman. The current first vice chairman is Duane Long, chairman of Longistics, Raleigh, N.C.
For Byrd's biography, please click here.
American Trucking Associations is the largest national trade association for the trucking industry. Through a federation of 50 affiliated state trucking associations and industry-related conferences and councils, ATA is the voice of the industry America depends on most to move our nation's freight. Follow ATA on Twitter or on Facebook.Good stuff. Trucks Bring It!

subset: commoncrawl


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The second day of hearing in Los Angeles brought another witness who claimed that Paris and Prince were in the room when their dad was resuscitated.
A devastating headline is circulating around following a second-day hearing on Michael Jackson's death. People reports a former employee testified on Wednesday, January 5 that two of Michael's children, Paris and Prince, stormed into his bedroom when Dr. Conrad Murray made an attempt to revive him.
"Paris screamed, 'Daddy,' and she started crying," Alberto Alvarez, a logistics director for Jackson said. As Alberto told this, Janet Jackson shook her head while mom Katherine Jackson dabbed away tears. Michael, according to Alberto, was on his back with eyes and mouth open while Dr. Conrad performed a mouth-to-mouth resuscitation. Alberto said the personal physician shouted, "Get them out! Get them out! Don't let them see their father like this."
Alberto also revealed that he was instructed to remove bottles of a milky-white substance from the singer's room before calling emergency services. He said, "He instructed me to remove the IV bag from the IV stand." However, Conrad reportedly told Alberto to leave a second IV bag containing saline where it was.
The milky-white substance is believed to be Propofol, a powerful anaesthetic which killed Michael. Conrad told Alberto that the King of Pop had an "allergic reaction" and ordered him to collect the bottles around the room in a bag.
The preliminary hearings in Los Angeles are held to find whether there's enough evidence for an involuntary manslaughter charge against Conrad.


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#TOC2014 Preview: Jake Owen Takes Us Through Building His Show As 'The Headliner' [VIDEO]
Here's a cool look at what really goes into a concert.
We just show up, drink beer and sing at the top of our lungs, and the performer makes it look so easy. Here's a closer look of what actually goes on before a show, from practicing, building a stage and, ultimately, being the boss to tons of people.
In this video, Jake Owen opens up about what it's like to build and headline the Days Of Gold Tour. We'll see you at the Taste Of Country!
Subscribe to 106.5 WYRK on


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Saint Paul Regional Water Services is implementing a new, radio-read, water metering system throughout its service area.
The new radio-read, water metering system will bring efficiency to meter reading and billing operation and eliminate estimated bills due to inaccessibility.
Driving by homes and businesses to get meter readings will be more convenient for our customers, who no longer need to allow meter readers onto their private property, and less labor intensive for the utility, providing cost savings.
How Does it Work?
The new water metering system incorporates an off-the-shelf, battery-operated radio transmitter onto the water meter.
The water meter, with its integrated radio, transmits a relatively weak radio frequency signal, producing radio frequency waves many times lower than many other everyday items found in homes, such as cell phones, baby monitors, and wireless routers.
When it is time to get your water meter reading, we drive by the property with a special receiver. Data consisting of your unique meter number and the digits of your meter reading are transmitted to our receiver. We use those meter readings in our billing software to generate your water bill.
If we can not get that data, an error code transmits. No personal information is transmitted.Watch a video of the meter replacement process
View a map of the replacement schedule. Find out when installations will take place in your area.
Quick Facts
- All 94,000 water meters in the areas served by Saint Paul Regional Water Services will be replaced between now and 2013.
- New water meters ensure everyone who uses SPRWS water is paying for actual water used, no more, no less.
- Meter replacement is required of all SPRWS customers.
- There is no upfront cost for the meter replacement. You will not be asked for payment.
- The more modern and reliable meters have an integrated radio transmission device and allow SPRWS to obtain meter readings using drive-by reading technology.
- New meter radio reads will be less disruptive for customers with less chance of estimated readings due to access limitations.
- Meter readers will no longer need to enter private property to plug in a hand-held reading device.
- New meters will be more efficient to read and allow easier access for staff and less staff time resulting in savings to customers over time.


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Buy Towner Term Life insurance Rates
Meticulously choose your protection as the plan you will certainly choose for will impact your daily life. Entire life is a type of long-term life insurance policy that is meant to provide lifetime coverage.
See just how a Towner ND term life insurance plan secures you and also your loved ones.
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Get free instantaneous North Dakota life insurance policy quotes online.
With Whole Life, you have to ask what the interest rate gets on the cash value account. Also you should think of contrasting various rates from other business in order to choose your right option. Though life insurance rates are incredibly budget-friendly today, roughly 30 percent of men and women in the united states do not have any insurance coverage.
Lifestyle insurance policy plays a crucial part in our way of living and also therefore it should not be forgotten by any kind of possibility. It is among the most crucial life choices you may make. It is evident that whole life insurance offers a variety of benefits to the policyholder, in addition to helping the beneficiary.
Constantly produce a budget plan which you will create your life insurance coverage around if you choose to get a life insurance which you do not be sorry for. Getting life insurance provides a peace of mind which various other insurance products merely do not offer. Term life insurance gives you protection over a recognized period, despite the fact that there is long-term insurance, likewise referred to as global life, that supplies lifetime coverage.
You must request 3 or even more or great deals of quotes consequently you'll compare different rates. There's an extremely easy reason behind that-when you ask for a quote, your healthcare assessment hasn't already yet been done. When you have the quotes in hand, developing a table for contrast allows you to select one of the most really efficient plan for your needs. To start with, you're able to merely examine the quotes using the online calculator. Really, if you discover an incredibly economical quote, you should certainly be two times as careful and confirm there are no hidden charges or conditions. Life insurance quote is the total policy expense that hinges on numerous elements like Age, Health Problem, Lifestyle, and also Protection Requested. It is feasible to get economical life insurance policy prices quote that also cover much less.
You need to make sure that the policy will certainly offer enough financial assistance to your relative in instance of your death. In situation you are searching for personalized term policies, then on-line segment could be the most ideal for you. If you choose to go term plan then it's the range of years that you choose to pick the insurance coverage for that will certainly leave an impact on your quote. You can obtain term way of living insurance coverage plan online at the most affordable asking price feasible.
Besides the two significant kinds pointed out formerly, another kind of insurance plan you'll have the ability to get is ensured issue private plan. Not everyone understands that universal insurance plan typically aren't the only choice. Generally talking, a life insurance strategy is a kind of contract which you have with an insurance policy carrier. It is an adaptable and also effective device that will certainly safeguard you and your liked ones as well as will certainly verify to be an absolute worth for money. Normally, it will be chosen based upon the goals and needs of the policy owner. A great deal of the life insurance plans belong to medical examination and also questionnaire worrying the health and wellness problem of the candidate.


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Lt. Thomas Gillham
b.Abt. 1709 prob. Ireland
d.Bet. 1789 - 1790 York County, South Carolina
Family tree▼
m. Abt. 1729
m. 1742
Facts and Events
Thomas Gilham was one of the Early Settlers of Augusta County, Virginia
Early Land Acquisition in Augusta County, VA
Acquisition of Land from Orange County, Virginia Records
Acquisition of Land in Augusta County, VA:
Disposition of Land from Chalkley's:
Advisory on Thomas Gilham
This Thomas Gilham should not be confused with Thomas Gilliam, son of William Gilliam and Mary Jarrett from neighboring Culpeper County, Virginia. That family was probably not related, and generally spelled their name "Gilliam" and not "Gilham or Gillham" as did this family. (Source: Gilliam's of Orange County, Virginia, http://home.roadrunner.com/~gilliamsofva/Orange/Orange.html)
Records of Thomas Gilham in Augusta County, VA
Information on Thomas Gillham
From "Ancestors of John Patrick Kirkpatrick": http://www.jpkirkpatrick.com/jpkirkancs.htm
The Kirkpatrick family described in this book formed an early and close association with the Gillham family of South Carolina. The Gillham family was established in this country by Thomas Gillham, who was born probably in Ulster, Ireland about 1700. He emigrated to America in the 1730's with his wife, Mary Meade, and at least one child. By 1738 Thomas and his family were well established in the New World, as is evidenced by the grant by the governor of Virginia to Thomas Gillham, of "1000 acres of land in Brunswick County, Virginia, on both sides of the Meherrin River, joined the land of Henry Briggs, 19 December 1738."
Tradition, which can not probably be substantiated at this late date, tells of a tragedy which struck the Gillham family at about this time. According to the tradition, Mary Meade Gillham was murdered by a Negro slave who had been admitted to the house by a maid servant. While the incident cannot be verified, it is a fact that Thomas Gillham sold all his slaves a few years later before moving to South Carolina, and that his sons held few, if any slaves when they made the long move to Illinois in the first few years of the nineteenth century. Moreover, Gillhams and their relatives (including the Kirkpatrick's) were quite active in efforts to prevent the spread of slavery to the Illinois country, both before and after Illinois was admitted as a state.
Sometime before 1743, Thomas moved his family to the Virginia frontier in Augusta County, where it is recorded that Thomas was made a "Captain of Foot" in the Augusta County Militia in that year. In 1744 he is recorded as an "original settler" of the Calfpasture area in Augusta County. About this time or a little later he married his second wife, Margaret Campbell, daughter of his neighbors in Calfpasture, William and Sarah (Gay) Campbell. Thomas' oldest daughter, Mary, married Alexander Campbell in 1744. Alexander was the brother of Margaret Campbell, Thomas' second wife, and it is said that he met her at his daughter's wedding.
In 1765 Thomas received a land grant near Bullock's Creek in what is now South Carolina, but was then considered to be in North Carolina. It is probable that it was about this time that the Gillhams moved to York County, and became neighbors of the Kirkpatrick's. Thomas had four children by his first wife, Charles, Ezekiel, Mary, and Nancy; and had seven more children by his second wife, Thomas, James C., William, John, Isaac, Sarah, and Susannah. Susannah, the youngest daughter of Thomas Gillham, married James Kirkpatrick, the son of the Kirkpatrick Immigrant. It was he who was assassinated in front of his wife by Tories during the Revolution. James and Susannah's son Francis also married a Gillham, Mary, daughter of Susannah's brother William Gillham. Isaac Gillham, another of Susannah's brothers, married Jane Kirkpatrick, daughter of James' brother Thomas Kirkpatrick. Jane Kirkpatrick's niece, Elizabeth (Eliza), daughter of her brother James, married in Bond County, Illinois, Thomas Cunningham Gillham. With the number of intermarriages between the two families, it is not surprising that many Kirkpatrick's bore the middle name of Gillham.
Many Gillhams and Gillham relatives moved to Illinois in the first years of the nineteenth century, the first arriving in 1797. Some accounts state that as many as 140 Gillhams and other relatives took part in the migration before it finally ended. The first Gillham to visit the Illinois country was James, the son of Immigrant Thomas. He had settled in Kentucky with his family and had developed a farm there. One day in 1794, while he was working in a field far from his cabin with his son Isaac, the cabin was visited by Kickapoo Indians who kidnapped James' wife and other children, carrying them back across the Ohio to the Indian's home territory. Some accounts state that they were kept prisoner for five years, but is more likely that it was only a few months. At any rate, while searching for his family, James visited the Illinois country and was highly impressed by it. After he recovered his family from the Indians, he moved to Illinois in 1797, and eventually settled in American Bottom, across the Mississippi from St. Louis.
James' letters to his brothers and other members of the family back in South Carolina, Georgia, and Kentucky, were instrumental in persuading so many of them to migrate to Illinois during the opening years of the nineteenth century. Among these immigrants were Thomas Newton, James Gillham, and John Kirkpatrick, brothers, and sons of Susannah (Gillham) Kirkpatrick, as well as Jane (Kirkpatrick) Gillham and her husband Isaac, and Janes' two brothers, James and John Kirkpatrick.
Most of the Gillhams and Kirkpatricks settled initially what is now Madison County, Illinois, in or near the American Bottom, rich bottom land along the Mississippi river, across and a little north of St. Louis. The Gillhams, Kirkpatricks, and others of this very large clan played an important role in the early history of the area and Illinois in general.
Information from "Family Bible Records, Wayne County, Tennessee" By Wayne Co. Historical Society, Wayne, pg. 72-74From Genforum.com post:
Re: James Lockridge, 1723-1790 SC, REV. WAR SOLDIER? Posted by: Donna Crosby (ID *****1813) Date: September 23, 2006 at 12:30:33 In Reply to: Re: James Lockridge, 1723-1790 SC, REV. WAR SOLDIER? by Joan Cole of 178
Does this book mention anything about Thomas Gillham? As it appears that these folks knew one another before coming to America, where did the folks Gay, Lockridge, Campbell, and Kincaid come from? It is said that my Thomas Gillham was born in Ulster IR in abt 1720..maybe I can find my Gillham ancestors through his other family members mentioned here. I have never found parents or siblings for Thomas Gillham in America.
Thank you so very MUCH for your wonderful help! Donna


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movies: I'm a movie nerd. My favorite genres are comedy and suspense. I dnt like crude humor though I love sarcastic dry humor (Tim burton's stuff) and I love movies with twists I love trying to figure out what's happening 99% of the time I'm right cuz I'm kinda a genius lol
tv: I'm a reality competition nerd too my all time favorite is so you think you can dance. When that show is on no1 is allowed to speak and do not dare ask me to fast forward through any of it I might cut you


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Penguins lose Lovejoy with broken wrist
SAN JOSE, Calif. — Penguins defenseman Ben Lovejoy is out indefinitely with a broken wrist.
Lovejoy was involved in a collision with San Jose centers Joe Pavelski and Logan Couture along the boards when the injury took place. The Penguins were forced to play most of the game with only five defensemen.
Defenseman Alexandre Picard is on the trip and will play Saturday in Los Angeles.
The Penguins are already playing without injured defensemen Zbynek Michalek (broken finger) and Brian Strait (wrist injury). They have played portions of the season without defensemen Brooks Orpik (abdominal surgery) and Kris Letang (suspension).


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Charlie Crist sheds environmentalist image
"(Charlie Crist) was more green than any governor had ever been before," said David Guest of Earthjustice, an environmental law firm.
But since he launched his bid for a U.S. Senate seat this year, Crist has left environmentalists feeling jilted. He canceled his climate summit. He didn't fight the Legislature's move to end funding for the popular Florida Forever environmental land-buying program. He signed a controversial bill changing the state's growth management law. And he has all but endorsed a proposal to allow drilling for oil near Florida's gulf beaches.
What happened to the man they once called "Governor Green"? A tough primary challenge from Marco Rubio.


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A Walmart shooting has left a woman in critical condition after a fellow employee opened fire on her inside a Neenah, Wisconsin, store.
The incident took place on Wednesday, and though police have few details about what caused the incident the facts appear to point to a targeted shooting. The suspect, 46-year-old Justine Boyd from Greenville, was working in the store at the time she is suspected of shooting the 56-year-old victim, who was working as a liquor store cashier.
The victim was left in critical condition after the Walmart shooting, police said.
"We're still very concerned for the victim," Police Chief Kevin Wilkinson told reporters. "We're obviously all hoping and praying for the best for her."
Since the shooting police have been in contact with the victim's family to sort out why the incident may have taken place, but admit that "the whole thing is really weird."
No other people were hurt in the shooting, police said, and some customers didn't even know what had happened.
"We have no reason to believe that there is anyone else involved, nor do we have any reason to believe that there's any other threat to our community," Lieutenant John Karner of the Neenah Police Department said.
The incident was reminiscent of another strange Walmart shooting earlier this summer. In late June, a man grabbed a 2-year-old girl inside an Oklahoma Walmart and held a knife to her neck. As the man ranted about how President Bush was watching him and talked about a connection to the secret society known as Illuminati, he grew closer to stabbing the toddler.
Police tried to negotiate, but when it became clear the man wasn't competent an officer fired a shot, killing the man.
After Wednesday's Walmart shooting, police arrested Boyd on a charge of attempted first-degree intentional homicide.


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Fodor's To Europe!
Ring of Kerry Drive/Skellig RocksBack to Ireland: Dingle and the Ring of Kerry »
The Ring of Kerry is arguably Ireland's most popular scenic drive, which means you have to plan your visit accordingly so that your main view isn't of other tourists. Buck the trend and do the ring on foot or by horseback, and make sure to explore beyond it. Take a fishing trip or a cruise for a different perspective, or head out to the Skellig Rocks for some solitude.
Learn more about The Ring of Kerry »
- Natural Beauty
- Great Drive
- The Ring of Kerry is one of Ireland's most scenic drives, but to beat the rest of the tour buses, start your journey in Kenmare and head clockwise.
- The dramatic Skellig Rocks, 8 miles (12.9 km) off the west of Kerry coast, house the remains of a 7th-century monastery occupied by hermit monks.
- To enjoy the unspoiled views along the Ring of Kerry, skip the car (or tour bus) and admire the view on horseback, from a fishing boat, or by hiking.
Side Trips
- The Kerry Bog Village Museum in Glenbeigh (17 mi/27.4 km northeast of Cahirciveen) showcases the daily life of the region's working class in the early 1880s.


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Browsing Josephine Bay Paul Center in Comparative Molecular Biology and Evolution by Keyword "SAGE"
Now showing items 1-1 of 1
Transcriptome analyses of the Giardia lamblia life cycle (2010-06-04)We quantified mRNA abundance from 10 stages in the Giardia lamblia life cycle in vitro using Serial Analysis of Gene Expression (SAGE). 163 abundant transcripts were expressed constitutively. 71 transcripts were upregulated ...


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Determined to do a lot of hiking this year, one of my mates seems to think we can climb 3 mountains in 24 hours so i'm sure that will be an entertaining ordeal.
Always enjoy a night out camping with a few friends, a few drinks, and a few accidents involving the fire.
As you can probably take from all this I like to keep myself active any way I can, I've an active outdoors job and pretty much all of my hobbies involve being outside, doesn't always work out with our bipolar weather but you make the best of things.
I'm honest and can be pretty straight to the point at times, not everybodies favourite attribute but I personally find it to be an admirable trait in others, lifes too short for bullshit.
I'm looking for somebody honest, loyal and healthy enough to hopefully be able to join in with some of the things I do in my spare time.
So don't be afraid to send me a message, i'm always up for a chat.


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- Released: Jan 1, 2008
- Sound: 8
- Lyrics: 8
- Overall Impression: 9
Users' score:
(5 votes)
Sound — 8
Only Way To Be Alone enters the music scene as a truly organic indie-folk album. Evolving from the geniuses of Keith (Good)win, Tim Arn>(old), and Dan Sch(war)tz (Get it?) is a piece of beauty worthy for the ears of any fan of the genre. Try picturing a Bright Eyes vibe mixed together with a touch of the oohhs and aahhs commonly found in 60s-era pop. The simple compilation of instruments by the Good Old War trio (acoustic guitars, vocal harmonization, and light drums) work magnificently to accentuate the rawness of the album. Stick-in-your-head tracks like Coney Island and Weak Man, which feature the vocal talents of Circa Survive's Anthony Green , fortunately, aren't few, though there are a couple of songs that can be questionable to taste as well as those that take two or three listens to totally appreciate. Many albums today are too overly tricked out by annoying studio funk and eccentric doodads that completely take away from the record's natural beauty. In the case of Only Way To Be Alone, an appropriate balance of simplicity and studio production is achieved. You can literally pick up an acoustic guitar and start jamming to many of the songs. With Good Old War's album, it being under-produced adds to the appeal of the tracks. For the most part, Only Way To Be Alone does a more than decent job in making listeners hit the repeat option on their iPods.
Lyrics — 8
The lyrics complement the music nicely, retaining the down to earth feel. A plus for Only Way To Be Alone is that the simplicity of the lyrics don't take away from the album, if anything they make it better! A bit from the single Coney Island (I found a letter in the mail box today And I said thank you for your thoughts but I'm done I said that I would never build this up right here He said that's why I can't work with you son But I can't let this go I'm on my way And you can only hold my diamond ring I'll go crawling back to the city I love 'cause it's already taken everything) is the style throughout the album. The lyrics and music form a symbiotic relationship with each other, both only being effective and powerful if the light and airy format of the songs carry through from the words to the instruments. Lyrics are not overemphasized in Only Way To Be Alone. In general, you will probably find that the lyrics are quite literal, yet stay open for interpretation. The result of Good Old War's lyrics and music combo is an album with sing-along worthy tracks that tend to be very memorable.
Overall Impression — 9
Only Way To Be Alone launches off with the single Coney Island", setting the bar for the whole album. The album can be a little monotonous at times, but leaves a positive impression more times than not. There isn't an Aretha Franklin or a Frank Sinatra locked up in the pipes of the Good Old War fellas, but there's no doubt that they deserve a round of applause for the production of a magnificent record. Some favorable tracks that may appeal to new listeners include Coney Island, Looking For Shelter and Weak Man. Words won't do this album justice. I highly recommend Only Way To Be Alone to any follower of the indie-folk genre. Overall, Good Old War has produced a very listenable album as well as a good reason for fans to want more.


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Hey there, time traveller!
This article was published 26/10/2012 (1761 days ago), so information in it may no longer be current.
Oliver's Twist
By Craig Oliver (Penguin, $20)
THE veteran Canadian journalist recalls his life and times.
Team of Rivals
By Doris Kearns Goodwin (Simon & Schuster, $24)
THIS respected American historian's 2005 Pulitzer Prize-winning tome about Abraham Lincoln and his cabinet has been given a new cover to tie in with the Steven Spielberg movie Lincoln.
By Cheryl Strayed (Vintage, $18)
THE author's 2005 novel has been re-released to capitalize on the success of her recent memoir, Wild.


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The iPhone 7 is already off to a booming start. Shortly after pre-orders began, Apple's carrier partners were blown away by unprecedented demand.
Most notably, T-Mobile said pre-orders were up 400 percent relative to the iPhone 6. Just yesterday, T-Mobile CEO John Legere added that the iPhone 7 is now the most pre-ordered device in T-Mobile history. On top of that, Sprint relayed that iPhone 7 pre-orders this year are up an astonishing 375 percent compared to last year.
Suffice it to say, the iPhone 7 may very well set a new weekend sales record, though as we covered earlier, Apple won't be releasing specific sales figures this year.
Speaking to the popularity of the iPhone 7, most prospective buyers hoping to walk into an Apple retail store and pick up the iPhone 7 model of their choice may be in for a rude awakening. According to a statement from Apple, all in-store stock of the iPhone 7 Plus and the Jet Black iPhone 7 are already sold out.
In a statement provided to Recode, Apple said:
We couldn't be happier with the initial response to iPhone 7 and iPhone 7 Plus, and we are looking forward to beginning sales through our retail stores and partners around the world.
Beginning Friday, limited quantities of iPhone 7 in silver, gold, rose gold and black will be available for walk-in customers at Apple retail stores. During the online pre-order period, initial quantities of iPhone 7 Plus in all finishes and iPhone 7 in jet black sold out and will not be available for walk-in customers. Availability at partner locations for all finishes may vary, and we recommend checking directly with them.
Customers can continue to order all models in all colors on apple.com. We sincerely appreciate our customers' patience as we work hard to get the new iPhone into the hands of everyone who wants one as quickly as possible.
Talk about a good problem to have.


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Hey there, time traveller!
This article was published 1/8/2011 (2207 days ago), so information in it may no longer be current.
DEAR MISS LONELYHEARTS: Approximately eight months ago I left my abusive husband, and I still need to tell him off. He never hit, but he yelled at me constantly. I was practically kept a prisoner in my own home. I was expected to come straight home from work, make his dinner and look after the three dogs, while he'd go to the gym and out with friends. Also, I suspected he was having an affair. When I called him on it, he blamed my moods on menopause. I felt my husband was a coward and was trying to make my life miserable so I would leave. His plan worked. I'm mad at myself for letting him get away with what he did without telling him what I think! Someone told me to write down what I would like to tell him and then burn the letter, but I don't see what good that would do, as I'd like to say a few things to his face, but he has moved. I wouldn't know where to send the letter. This marriage needs closure so I can move on. Any suggestions? -- Want To Tell Him Off
Dear Want To Tell Him Off: Are you through all the legal wrangling? If not, write the letter and throw it deep in the freezer until things are finished legally. But get it written and finished now -- out of the "whirling in your head" phase. He deserves a final expression of your feelings, at the very least, but you don't need a letter that could be sent to his lawyer as evidence that you are a wingnut. Maybe things will settle so much in your favour, you won't care. But if you still need to say something, see a counsellor to talk about what you should say and in what form. Pull the old letter out of the freezer and re-read it once. Tear it up. You'll want to send a totally new letter -- about the abuse you took from him and never would again -- or nothing at all. Why? The catch with an angry letter is he may show it to people, like your kids, saying, "See how crazy your mother is?" or his new woman, saying, "Look at what a psycho my ex-wife was." Fury always looks worse on paper.
Dear Miss Lonelyhearts: Can you please let the girl worried about her boyfriend's chronic pot use know anyone who is using drugs to cope with day to day life may have an undiagnosed mental illness? Marijuana is a great anti-anxiety drug; he may have issues with anxiety, depression, even undiagnosed ADHD. I have seen many a drug user find out the reason they started using (and were unable to stop) is they were self-medicating undiagnosed mental illnesses, anything from depression to bipolar affective disorder. Although a lot of illegal drugs aren't physically addictive, they provide the user with a way to cope with life. Unless it is replaced by another effective way to deal with the stress and anxiety, they are doomed to failure. -- One Who Knows, Winnipeg
Dear Knows: Thanks for taking the time to write in to add your information to the conversation. Consider it passed on.
Questions or comments? Write Miss Lonelyhearts c/o Winnipeg Free Press 1355 Mountain Ave. Wpg R2X 3B6 or email email@example.com


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NYC Parks Events Calendar
Get up, get out, and do something! Just about any day of the year, you can find something fun, informative, and healthy to enjoy at an area park. Feel free to browse the listings below, or use the search tools to find an event that matches your interests and location.
Viewing 3,421–3,430 out of 15,379 events
from September 7, 2013 (x) to January 20, 2018
Saturday, September 17, 2016
Central Park Tour: Mid-Park Welcome Tour
at Alexander von Humboldt statue (in Central Park), Manhattan
11:00 a.m.–12:00 p.m.
Explore some of the park's best-known features, including the Lake and the Ramble, and then marvel at the view from Belvedere Castle, on this tour led by Central Park Conservancy guides.
Category: Education, Nature, History, Tours
CANCELLED: Summer Sports Experience at Chelsea Park
at Chelsea Park, Manhattan
11:00 a.m.–2:00 p.m.
The Summer Sports Experience provides a friendly introduction to sports for kids!
Category: Best for Kids, Sports, Summer Sports Experience
Garden Centennial Exhibition
at Bartow-Pell Mansion Museum (in Pelham Bay Park), Bronx
12:00 p.m.–4:00 p.m.
Bartow-Pell Mansion Museum is pleased to present an exhibition of outdoor sculpture celebrating one hundred years of its formal garden designed by Delano & Aldrich in 1916.
Category: Nature, Seniors
Plein Air Paintings of the Bartow-Pell Gardens
at Bartow-Pell Mansion Museum (in Pelham Bay Park), Bronx
12:00 p.m.–4:00 p.m.
Paintings created outdoors capture the changing light and atmospheric mood of the historical landmarks and hidden treasures of the Bartow-Pell gardens and grounds.
Category: Art
Saturday Sculpture Workshops
at Socrates Sculpture Park, Queens
12:00 p.m.–3:00 p.m.
Participants will work with a different artist each week, exploring innovative art mediums and a variety of subject matter.
Category: Arts & Crafts, Education, Art, Best for Kids, Waterfront
Poseidon's Parade
at Beach 106th Street and Shorefront Parkway (in Rockaway Beach), Queens
12:00 p.m.–3:00 p.m.
Poseidon's Parade is a family-friendly celebration of participants wearing sea-themed costumes with floats and artwork while celebrating the opening of Rockaway Boardwalk.
Category: Dance, Festivals
Capoeira for Beginners
at Socrates Sculpture Park, Queens
12:00 p.m.–1:00 p.m.
Led by certified instructors from Capoeira Nago Queen, this six-part series will introduce participants to the basic fundamentals of the Brazilian martial art of capoeira.
Category: Fitness, Waterfront
GreenThumb Harvest Fair
at Diamante Garden (in ), Manhattan
12:00 p.m.–4:00 p.m.
Join GreenThumb for our annual celebration that honors thousands of community gardeners and greening professionals across New York City.
Category: Accessible, Arts & Crafts, Education, Concerts, Dance, Nature, Festivals, Fitness, Games, Best for Kids, Volunteer, Food, Talks, Seniors
Bryant Park College Essay Writing with Writopia Lab
at Reading Room (in Bryant Park), Manhattan
12:30 p.m.–1:45 p.m.
Writopia Lab will be on-hand to help students find their voices, give students the confidence they need, and ultimately provide guidance on the structure and editing.
Category: Education
Wave Hill History Walk
at Perkins Visitors Center (in Wave Hill), Bronx
1:00 p.m.–2:00 p.m.
Discover the fascinating history of Wave Hill's architecture and landscape on a walk with a Wave Hill Garden Guide.
Category: History, Tours
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New Year's Eve Dinner
at the Mason Street Grill
Dec. 31, 2010
With old acquaintances or new, Mason Street Grill is the place to be on December 31. Reservations for their American, wood-grilled classics or the Chef's Five Course Tasting Menu are available from 5pm-11pm. Swing in the new year with live music in the bar. Private dining rooms are also available for your gathering whether its six of 60. For reservations call (414) 298-3131 or visitwww.opentable.com


text:
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- Commissarial
- Commissarial Com`mis*sa"ri*al, a. Of or pertaining to a commissary. [1913 Webster]
The Collaborative International Dictionary of English. 2000.
The Collaborative International Dictionary of English. 2000.
commissarial — adjective see commissar … New Collegiate Dictionary
commissarial — adjective Of or pertaining to a commissary … Wiktionary
commissarial — commissāˈrial adjective Relating to a commissary • • • Main Entry: ↑commissary … Useful english dictionary
commissary — commissarial /kom i sair ee euhl/, adj. /kom euh ser ee/, n., pl. commissaries. 1. a store that sells food and supplies to the personnel or workers in a military post, mining camp, lumber camp, or the like. 2. a dining room or cafeteria, esp. one … Universalium
Flag of the Department of Amazonas — The Flag of the Department of Amazonas was officially adopted on August 21, 1974, by means of the Commissarial Decree Nº 090. The flag design is a defaced fimbriated horizontal tricolour triband of unequal sizes.DimensionsIts dimensions, colors… … Wikipedia
commissar — noun Etymology: Russian komissar, from German Kommissar, from Medieval Latin commissarius Date: 1918 1. a. a Communist party official assigned to a military unit to teach party principles and policies and to ensure party loyalty b. one that… … New Collegiate Dictionary
Norway — /nawr way/, n. Norwegian, Norge. a kingdom in N Europe, in the W part of the Scandinavian Peninsula. 4,404,456; 124,555 sq. mi. (322,597 sq. km). Cap.: Oslo. * * * Norway Introduction Norway Background: Despite its neutrality, Norway was not able … Universalium
Magnus von Braun (senior) — Magnus Freiherr von Braun Born February 8, 1878(1878 02 08) Neucken/Pr. Eylau, East Prussia, German Empire Died August 30, 1972(1972 08 30) (aged 94) Oberaudorf, Germany … Wikipedia
Drapeau du département d'Amazonas (Colombie) — Drapeau du département d Amazonas Utilisation … Wikipédia en Français
commissary — [ kɒmɪs(ə)ri] noun (plural commissaries) 1》 a deputy or delegate. ↘a representative or deputy of a bishop. 2》 N. Amer. a restaurant or food store in a military base or other institution. Derivatives commissarial sɛ:rɪəl adjective Origin ME:… … English new terms dictionary


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A mayor had a gambling habit when he pocketed £220 of takings from an ice cream van during his community's celebrations of the Queen's Diamond Jubilee, it was claimed yesterday.
Senior councillor Andrew Williams allegedly depended on loans from pay day lenders to tide him over while serving as Ripon's First Citizen in 2012.
A jury was told Williams had put on a suit and his gold chain of office to hand out prizes on the evening of Ripon's Jubilee festivities that June.
York Crown Court was told that in return for selling ice creams at the event John Taylor, of Harrogate-based C & M Ices, had agreed with council bosses by email to hand over 20 to 25 per cent of the day's takings.
When he cashed up, he reckoned he owed the authority about £220, said Prosecutor David McGonigal.
He put the cash in a clear money bag with a couple of his business cards and went wandering around the market square looking for someone from the council to give it to, the jury was told.
Mr Taylor spotted a local councillor Stuart Martin and tried to give it to him. But he refused to take it and pointed out Williams, 43, who was standing nearby, Mr McGonigal continued.
He added: "The defendant was wearing his gold chain of office around his neck and was therefore easily identifiable.
"Mr Martin pointed to Mr Williams and suggested Mr Taylor give him the money.
"Mr Taylor walked across to Mr Williams and gave him the money. That's the prosecution case. Mr Williams's case is he never received the money - that he never received it at all."
The court heard that if Williams did receive the money he had a duty to pass it to Ruth Terry who was responsible for banking it for the council.
But no money was received. "The prosecution's case is Mr Williams kept the money for his own purposes," added Mr McGonigal.
He added that when interviewed by police Williams said he was under financial pressure partly because his partner was pregnant and had stopped working.
"It was partly caused by a gambling habit," the prosecutor continued.
The court heard when the missing money was noted by the council's Jubilee accounting committee in September, Williams offered to chase it up.
The jury heard that towards the end of 2012 the matter was reported to police who began making inquiries.
In April 2013, Ruth Terry was opening the post when she came across an envelope containing £220 in £10 notes. She handed it to police, who arrested Williams on June 23.
Mr Taylor said while he was looking for someone to pay he was told "Give it to the Mayor" so he did so.
Williams, of Pine View, Locker Lane, Ripon, denies one offence of fraud. The trial continues.


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Assessing The Performance Of Non-Banking Financial Institutions – A Knowledge Discovery Approach
This paper proposes a framework for assessing the performance of non-banking financial institutions (NFIs). Firstly, we present an overview of the non-banking financial institutions' sector in Romania and, then, the CAAMPL system which is used to evaluate the performance of banks. We argue that this system is suboptimal when applied to assessing NFIs' performance and that the Knowledge Discovery in Databases (KDD) process could offer specific methods that may be used to developing better systems. Next, we discuss different concepts that are closely related with the KDD process: data, information and knowledge. Finally, we present the KDD process and we show how our research problem can be formalized as a KDD process.
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Volume (Year): 3 (2011)
Issue (Month): 39 ()
Pages: 174-185
|Contact details of provider:
| Postal: Str. A.I. Cuza nr. 13, Craiova
Phone: 004 0251 411317
Fax: 004 0251 411317
Web page: http://feaa.ucv.ro/
More information through EDIRC
References listed on IDEAS
Please report citation or reference errors to , or , if you are the registered author of the cited work, log in to your RePEc Author Service profile, click on "citations" and make appropriate adjustments.:
- David J. Hand & Heikki Mannila & Padhraic Smyth, 2001. "Principles of Data Mining," MIT Press Books, The MIT Press, edition 1, volume 1, number 026208290x, July.
- Liliana Eva Donath & Laura Mariana Cismas, 2008. "Determinants of Financial Stability," Romanian Economic Journal, Department of International Business and Economics from the Academy of Economic Studies Bucharest, vol. 11(29), pages 27-44, (3).
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text:
Flames NewsFlames Home > News
Today's Flames Minute: Tuesday
Flames Audio:
Today's Flames Minute begins to preview Saturday's football matchup with Richmond, including a look at the athletics department's "Rollin' to Richmond" caravan campaign for the road game, plus recaps men's tennis' successful weekend at the Southern Intercollegiate Championships in Athens, Ga., and looks at this week's cross country regional rankings where the men's cross country team is ranked No. 10 in the Southeast rankings.
Be sure to log onto LibertyFlames.com, each Monday through Friday, to hear the latest around Liberty Athletics on the Flames Minute.


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Our qualified high deductible health plans with an HSA offers your clients great basic coverage and a chance to save money and invest it for future healthcare expenses. Helping people choose an HSA health plan also allows your clients to reduce their taxable income. We make it easy to enroll in and to manage both the health plan and the savings account.
HSAs offers a triple tax advantage:
You also enjoy:
Member resources available:


text:
There Is Something You Must Know About Dr. Phil's Genitalia
"[Dr. Phil's wife got pregnant unexpectedly at a time in his life when he was not ready to have children.] I was doing work in another city with a good friend of mine. He said, 'The office closes at five – why don't you come in and we'll do your vasectomy?" He didn't have a nurse there, so I actually assisted him by handing him the instruments. It's painful when they kind of pull on it. He put me in the car with an ice pack, and I drove myself to the airport and flew home."
Whoa. Just whoa. TMI alert! Dr. Phil gave himself a vasectomy! But don't worry, ladies. He had it reversed. [Daily Mail UK]


text:
Campbell's Soup ThermosFood & Wine, Novelty, Unusual August 17, 2008, 0 Comment 32
Looking for a gift idea for someone that loves to bring soup to work?
This Campbell's soup thermos is fun, functional and pretty darn cool.
The screw top serves as a cup for easy eating and makes it easy to sip your soup in style.
Update: Looks like the Campbell's thermos is out of stock at Urban Outfitters…sadness. Check out this funky Stanley thermos instead.


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A General Equilibrium Analysis of the Demand for Money
A model of capital service is constructed on stylized consumer behaviour and the total quantity of financial resources. The demand for money becomes a function of the wage rate under agreement as well as interests rates and overall economic activity.
If you experience problems downloading a file, check if you have the proper application to view it first. In case of further problems read the IDEAS help page. Note that these files are not on the IDEAS site. Please be patient as the files may be large.
|11 pages
|Date of creation:
|16 Oct 2004
|Type of Document - doc; pages: 11. Word for Windows document submitted via ftp
|Contact details of provider:
| Web page: http://econwpa.repec.org
References listed on IDEAS
Please report citation or reference errors to , or , if you are the registered author of the cited work, log in to your RePEc Author Service profile, click on "citations" and make appropriate adjustments.:
- Tobin, James, 1969. "A General Equilibrium Approach to Monetary Theory," Journal of Money, Credit and Banking, Blackwell Publishing, vol. 1(1), pages 15-29, February.
- Stiglitz, Joseph E & Weiss, Andrew, 1981. "Credit Rationing in Markets with Imperfect Information," American Economic Review, American Economic Association, vol. 71(3), pages 393-410, June.
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The baseball season is more than a month old and daily fantasy players have a pretty good idea of which pitchers are for real and which ones aren't living up to their DFS price tags. Here are the top pitching options on FanDuel for the coming week:
Tuesday - LHP Robbie Ray, Diamondbacks (vs. Tigers)
Ray was one of the most frustrating players in daily fantasy last season, capable of racking up double-digit strikeouts in a given start but rarely able to last long enough to do so. The strikeouts are still there in abundance this season, but he's rocking a modest 3.49 ERA while doing a good job of keeping the ball in the park (four homers allowed over 36 1-3 innings). He has struggled at home, but the Tigers come into the week with a 21.3 percent strikeout rate and can be exploited. Lean on Ray as a tournament option.
Wednesday - RHP Yu Darvish, Rangers (vs. Padres)
Darvish was slightly less irritating than Ray last season, though control issues often capped his daily fantasy upside despite being one of the top strikeout pitchers in the majors. Darvish has looked much better so far in 2017, throwing seven or more innings in three of his first seven starts. The walks are still a niggling issue, but he should have no trouble corralling an overmatched Padres team. Darvish will cost a mint, but he's playable in all formats as one of the top options on the slate.
Thursday - LHP Jason Vargas, Royals (at Rays)
On a night when Clayton Kershaw toes the rubber, did you ever think six weeks ago we'd be recommending fellow left-hander Vargas instead? Kershaw is a hard fade Thursday as he tangles with the Colorado Rockies at hitter-happy Coors Field, while Vargas looks to continue his incredible early season run against a Tampa Bay team that enters the week with the third-highest K rate in the league. Vargas might not have tournament-level upside, but he's the safest cash-game play of the day.
Friday - LHP Danny Duffy, Royals (vs. Orioles)
Sometimes, your best bet is to ride a starter who has been pitching well - and other times, you might be inclined to take a hurler whose struggles have resulted in a lower price point. Duffy fits the latter category, having dropped three straight decisions while compiling just 12 strikeouts over his previous four starts. The Orioles have the league's fourth-lowest wOBA against left-handed pitching, so Duffy should at least be in good shape for a win. Trust him in cash games, but not in tournaments.
Saturday - LHP Chris Sale, Red Sox (vs. Rays)
This is the easiest choice you'll have to make all week - at least, with regard to your daily fantasy starting pitcher. Sale is off to an incredible start to the season, racking up double-digit strikeouts in six consecutive games while giving up just a pair of home runs over his first 51 2-3 innings. The Rays are only league-average versus lefties so far this season, but were held to a run on three hits over seven dominant innings the last time they faced Sale. Spend up for him in all formats.
Sunday - RHP Max Scherzer, Nationals (vs. Phillies)
This is a dream matchup for Scherzer, who is coming off a terrific seven-inning performance against Arizona (7 IP, 2 H, 1 ER, 12 K) last time out. Scherzer cruised past the Phillies in their first meeting of the season, striking out seven over 6 2-3 innings. And, while he has surrendered five home runs over his previous three starts, he shouldn't be threatened against a Philadelphia lineup boasting the league's second-lowest wOBA versus right-handers. He is suitable for rostering in both cash games and tournaments.


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West Point, NY (SportsNetwork.com) - Terry Baggett broke Army's single-game rushing record as he ran for 304 yards and four touchdowns, leading the Black Knights to a 50-25 win over the Eastern Michigan Eagles at Michie Stadium.
Baggett easily topped the previous school record held by Michael Wallace, who ran for 269 yards against Louisville on Oct. 7, 1999. Baggett's four rushing touchdowns tied the second-best mark in school history. As a team, the Black Knights (3-4) ran for 513 yards and averaged nearly a first down per rush (9.5 ypc).
The Eagles (1-5) suffered their fifth consecutive loss despite a big day from Bronson Hill, who ran for 143 yards and a touchdown to go along with 91 yards receiving and another score through the air.
Benz got the Eagles on the scoreboard first with a 17-yard touchdown pass to Hill at the 9:24 mark of the opening quarter. EMU went for two after botching the hold on the PAT, and Mark Iannotti completed a pass to Cole Gardner in the end zone for an 8-0 lead.
Army answered with an eight-play, 70-yard drive, capped by Baggett's four-yard TD scamper.
EMU struck back just one minute later, as Hill scored on a 12-yard run to put the Eagles on top, 15-7.
However, Army responded once again, this time on the very next play from scrimmage as Baggett shook loose for a 67-yard touchdown run. Angel Santiago converted the two-point attempt on a run to tie the score at 15-15 with 3:35 remaining in the first quarter.
Army took its first lead at the 9:46 mark of the second quarter, as Trenton Turrentine punctuated a 17-play drive with a one-yard touchdown run.
Later in the second quarter, EMU went on a 17-play, 73-yard drive that lasted more than six minutes. However, the Eagles had to settle for a 31-yard Dylan Mulder field goal just before halftime as they went into the locker room trailing, 22-18.
The third quarter belonged to the Black Knights. Baggett scored on a 34-yard run at the 11:08 mark, then he added another long touchdown run from 96 yards out with 9:05 to play in the frame.
Larry Dixon tacked on a 30-yard TD scamper with 1:40 to play in the third to put Army on top, 43-18.
EMU hung around for a bit in the fourth quarter, thanks to a 28-yard touchdown pass from Benz to Dustin Creel that made it a 43-25 game with just under 12 minutes to play in regulation.
However, Army put the game away on Matt Giachinta's four-yard TD run with 6:18 remaining.
Whereas Army gained 513 yards on the ground, EMU finished with 417 yards of total offense on the day. The Eagles converted only 3-of-11 third downs, compared to a 7-of-9 success rate for Army.


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Director: Dave Grohl
Language: English
What do Neil Young, Metallica, Fleetwood Mac and Nirvana all have in common? They all recorded at legendary Los Angeles studio Sound City. This doc by first-time director Dave Grohl (of Nirvana, Foo Fighters) is a star-studded inside look at the late, lamented studio and its legendary Neve mixing desk; when boffins talk about the "presence" on Fleetwood Mac's "Rumours", this is where it came from. Grohl digresses into how digital recording, piracy etc. are killing off these temples of sound.


text:
Credits & Info
- Uploaded
- Dec 24, 2010 | 11:12 AM EST
- File Info
- Song
- 5 min 57 sec
- Score
- 4.44 / 5.00
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Licensing Terms
Please contact me if you would like to use this in a project. We can discuss the details.
- Score:
- Rated 4.44 / 5 stars
- Plays & Downloads:
- 15,415 Plays | 2,158 Downloads
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- Genres:
- Electronic - Trance
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Author Comments
Rated 5 / 5 stars
It certainly retains the cold, arctic feel. Orchestrated very well. Certainly a song I would and could rave too. Just need to find that strobe light and a few glow sticks.
heck yeah
Rated 5 / 5 stars
Not bad...
I like the constant change in the flow of the song, it still keeps the same arctic feel it has to it. While most songs that are in that theme are usually sad and slow, but this is one of the few that is upbeat and sounds nice. I hope to hear more from you
Good job
Well thank you :D
Rated 5 / 5 stars
fuckin awsome
i dont know why but it sooths me, i really like this song, makes me think back of the old times. sorry im not very good at this kind of stuff, but keep up the good work i really like it :)
Thanks for the review!
Rated 5 / 5 stars
Good production
The track had a nice tone, and was compressed well.
A nice tone is always nice
Rated 5 / 5 stars
How does one make a song feel like winter?
you compose this
i compose this


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Member Discount Program
Member Discounts
As a member benefit, MHI is pleased to offer a discount program with substantial savings on your shipping and business needs. When contacting these providers, please identify your company as a member of the Manufactured Housing Institute. All programs, rates and prices are subject to change without notice. Please check back often as new programs will be added. For more information on this program, please contact Cheryl Berard at (703) 558-0668 or firstname.lastname@example.com.


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- Very nice hotel with great sea views. Good supermarket onsite which is helpful. Plenty of sunbeams and excellent beach next to hotel.
Published on: 20 June 2017
3 nights' bed & breakfast at Sunset Beach Club and 3 rounds of golf (La Cala Asia, La Cala America, Los Olivos, Los Lagos or La Cala Europa)
7 nights' bed & breakfast at Sunset Beach Club and 4 rounds of golf (La Cala Asia, La Cala America, Santana Golf , Torrequebrada or La Cala Europa)
4* Aparthotel, situated on the Benalmadena beachfront. It features 553 1-bedroom apartments and is perfect for golfing groups looking to mix golf with nightlife.
Parador Golf is within a 15 minute drive. Other golf courses closeby include Lauro, Alhaurin and Mijas Golf.
Sunset Beach Club is situated in Benalmadena, Costa del Sol (15 mins from Malaga Airport).
Sunset Beach has 553 hotel apartments, well equipped to cater for the needs of the travelling golfers. Each apartment is decorated in elegant, modern style, most apartments have now been completely refurbished, and include a twin bedroom,a lounge with double bed settee, dining area with table and 4 chairs, separate bathroom accessed via sliding doors, fully equipped kitchenette, bathroom and a large balcony with table and chairs. Exterior apartments have sea or mountain views. Interior apartments have no views. All have individual climate control, safe (payable locally), direct-dial telephone, satellite TV and golf club storage in each apartment.
A very popular hotel, this one is in a great location, close to all the golf and nightlife.
Check in:5pm - Check out:12pmAre the facilities free of charge?
An extra fee applies for use of the indoor pool, aerobics, pilates, gym & fitness room, massage, sauna and jacuzzi.Is there parking onsite?
On-site parking, €12.50 per day


text:
After long pondering and some testing, the Asakran army has finally allowed the use of advanced magic on the battlefield. This is the prototype of intense research.
Don't just lug your loot around put it to work
One of many small artifacts created eons ago, The Sands of Fury is capable of creating massive turmoil and destruction from above.
"Wolf, have you not heard, Red Riding left to college years ago and is married with 2 kids of her own, she has not come to Grandmother's house for 5 years now. What have you done with Grandma, for if it is murder, the axe you will have."
Manifold collections of wheels, and gears, springs and coils, all bound by the inexoriable tread of time.
This card when used in a strange ritual lets you talk to one dead person, but there is a catch
flying machine
This large blue fruit's pit holds a polarized electrical charge
It is an long simple key, with a crystal in the turning loop. It seems insignificant, but it is a thing of legend. Every thief in the four realms has heard of it. Scholars and madmen, and those opposing the madmen all quest for it. It is a simple key to lock or unlock anything.
Another scary child's toy…
A fluffy, pink stuffed bear which always seems to end up in unlikely places, and which people tend to get quite attatched to…
Small bits of precious metal, and flawless jewels woven into the mane of a noble steed
Small wooden discs about 2 1/4 inches in diameter and between 5 and 10mm thick (see below). They are rumoured to be made from the roots of the great tree Unity that supports the centre of the world.
Firey food for your favorite feathered friend.
A prison ... a sanctuary ... a gateway ... a murderous tool. Grasp the power of a circle of midnight.
Feu'mer the inspector was quite adept at his work of solving and preventing crimes. He was known for a very sharp eye - and not the one remaining eye that was in his head.
Made of dark steel by those of an age gone by, this is the last of the giant war golems. Taller than elder dragon is long, this clanking behemoth plods across the land, obliveous to all works of men, elves, or dwarves.
It sees you, can you see it? Even when the room is lit?
Funny how those shadows twist, as though the room were filled with mist.
But theres no mist, the room is clear! About now, you should start to fear.
clear your mind, take a last breath. For in a second, you'll meet with death.
Pembridge Maccadia, the Mindless Ruler, the Crafter of Graf Malin, sacrificed his very life to destroy a nation. A breathing, living machine with the heart of blades, a testament to his loathing of Man. His hatred for his own people…
A legendary relic, suited to base a campaign around, with the power of Creation crystallized in a single milky seed…
A simple flag, faded by time and sun, tattered and worn by untold years flying from the pole of a bannerman, passing hands from officer to officer, from one generation to another. It is a humble symbol of great importance, and greater inspiration to those who see it. Soldiers become heros filled with espirit de corps, enemies loose their nerve and fire. It is not an enchanted item, but a powerful item still...