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The purpose of this study was to identify associations between maternal and fetal genetic variants in candidate genes and spontaneous preterm birth (PTB) in a Norwegian population and to determine the effect size of those associations that corroborate a previous study of PTB.
DNA from 434 mother-baby dyads (214 cases and 220 controls) collected from the Norwegian Mother and Child Cohort (MoBa) was examined for association between 1,430 single nucleotide polymorphisms in 143 genes and PTB. These results were compared to a previous study on European Americans (EA) from Centennial Women's Hospital in Nashville, TN, USA. Odds ratios for SNPs that corroborated the Cenntennial study were determined on the combined MoBa and Centennial studies.
In maternal samples the strongest results that corroborated the Centennial study were in the prostaglandin E receptor 3 gene (PTGER3; rs977214) (combined genotype p = 3×10−4). The best model for rs977214 was the AG/GG genotypes relative to the AA genotype and resulted in an OR of 0.55 (95% CI = 0.37–0.82, p = 0.003), indicating a protective effect. In fetal samples the most significant association in the combined data was rs854552 in the paraoxonase 1 gene (PON1) (combined allele p = 8×10−4). The best model was the TT genotype relative to the CC/CT genotypes, and resulted in an OR of 1.32 (95% CI = 1.13–1.53, p = 4×10−4).
Citation: Ryckman KK, Morken N-H, White MJ, Velez DR, Menon R, Fortunato SJ, et al. (2010) Maternal and Fetal Genetic Associations of PTGER3 and PON1 with Preterm Birth. PLoS ONE 5(2): e9040. doi:10.1371/journal.pone.0009040
Editor: Carlos Penha-Goncalves, Instituto Gulbenkian de Ciência, Portugal
Received: September 8, 2009; Accepted: January 8, 2010; Published: February 3, 2010
Copyright: © 2010 Ryckman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by grants from the Norwegian Research Council (FRIMEDKLI-05 ES236011), Norwegian Research Council FUGE - Functional Genomics at Norwegian Research Counsile (183220/S10), Telemark Hospital Research Foundation, The Southern Health Region in Norway, Swedish government grants to researchers in public health service (ALFGBG-5173 and ALFGBG-11522). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health, NIH/NIEHS (grant no N01-ES-85433), NIH/NINDS (grant no.1 UO1 NS 047537-01), and the Norwegian Research Council/FUGE (grant no. 151918/S10). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Preterm birth (PTB) (<37 weeks of gestation) is a major obstetrical problem, contributing to a substantial proportion of infant morbidity and mortality worldwide. Preterm birth accounts for as much as 75% of perinatal mortality and a disproportionately large percentage of infant morbidities [1]–[4]. In the US alone, of the approximately five million births each year almost 13% are born preterm, accounting for greater than $26 billion per year in excess health care costs [5], [6]. The majority of PTB (∼75%) results from spontaneous contractions often associated with infection, prelabor preterm rupture of the membranes and unknown causes [7]. Based on human and animal studies, four main pathways have been hypothesized to lead to PTB: 1) activation of maternal or fetal hypothalamic pituitary-adrenal axis, 2) inflammation and infection, 3) decidual hemorrhage, and 4) uterine distension [8]. These pathways converge on a final terminal pathway where uterotonins, such as prostaglandins and extra cellular matrix (ECM) degrading proteases, are released leading to early contractions, cervical ripening and rupture of the membranes eventually resulting in PTB. The specific factors involved in these putative PTB pathways and how each contributes to the etiology of PTB are poorly understood.
There is growing evidence that among the risk factors that have been hypothesized to be associated with PTB genetic predisposition plays a significant role. First, personal and family history of PTB are among the strongest known risk factors for PTB [9]–[11]. Second, twin studies estimate the heritability of PTB at 20–40% [12], [13]. In addition, there is substantial evidence suggesting geographic ancestry is associated with risk for PTB; therefore, it is reasonable to conclude that genetic variations can affect risk [14]–[16]. Finally, in the last ten years many studies have found significant genetic associations with PTB, particularly with genes in the inflammation and infection pathway [17]–[19]. However, often these findings fail to replicate [20].
Recently, a candidate gene association study of PTB was performed examining 1,536 single nucleotide polymorphisms (SNPs) in approximately 130 candidate genes [21]. The strongest maternal associations with PTB were in factor V (FV), factor VII (FVII) and tissue plasminogen activator (tPA) in European Americans (EA). These genes are involved in the complement-coagulation pathway, related to decidual hemorrhage. The most significant fetal associations were in interleukin 10 receptor antagonist (IL-10RA) and other genes related to the infection and inflammation pathway.
In the present study we sought to identify genetic risk factors for PTB in a Norwegian cohort, and corroborate these results with data from the study described above[21]. In addition to the SNPs that were previously studied we included 132 SNPs from 14 genes emphasizing genes from the complement coagulation pathway that were not previously represented because of strong associations between SNPs in this pathway and PTB previously identified in EA. The results of the two studies were compared to identify genes involved in PTB pathways.
Demographic and Clinical Characteristics
Clinical differences between cases and controls for the Norwegian Mother and Child Cohort (MoBa) are presented in Table 1. There were no statistically significant differences between cases and controls for APGAR score at either 1 minute or 5 minutes, maternal age or smoking; however, as expected, cases had babies with lower birth weight and gestational age (p<0.001 for both). Additionally, cases and controls significantly differed in parity (p<0.001), where having one or more children was protective against PTB (OR = 0.45, CI = 0.30–0.67, p-value<0.001).
The MoBa and the Centennial Medical Center study (Cenn) used slightly different but substantially overlapping gestational age definition; in MoBa <366/7 weeks was used and in the Cenn study cases were defined by a gestational age of <360/7 weeks (Table 2). The controls were defined by a gestational age of ≥390/7 weeks in the Moba study and ≥370/7 weeks in the Cenn study. Gravidity, gestational age and birth weight differed between the two study populations in cases and controls. When data from the two studies are combined, the median gestational age was 248 days (range = 166–258) in cases and 278 days in controls (range = 257–296).
Single Locus Association
Of the 1430 SNPs analyzed in MoBa, there were 125 suggestive (p<0.05) allelic and/or genotypic single locus results in maternal samples and 142 suggestive allelic and/or genotypic results in fetal samples (Figure 1A-D, Table S3). The most significant maternal single locus result was in collagen, type 1, alpha 2 (COL1A2) at rs2472 (allelic p = 2×10−3, genotypic p = 1×10−3) (Table 3). This SNP was also associated in fetal samples (allelic p = 8×10−3, genotypic p = 8×10−3) (Table 3). In maternal samples this SNP had an OR of 0.32 (95% CI = 0.16–0.66, p = 2×10−3) when comparing the AG genotype to the AA genotype. This result remained significant after adjusting for parity (p = 2×10−3), and was also identified using the method PRAT (Table 3). In addition to rs2472, nine SNPs of the thirty-four examined in COL1A2 associated with PTB (p<0.05); seven SNPs associated in fetal samples only, one in maternal samples only and one in both maternal and fetal samples (Table 3). None of these results were significant after correction for multiple testing with FDR (q = 0.20).
Each point on the graph represents an association test either allelic (a, c) or genotypic (b, d). The x axis is SNP position in chromosomal order and the y axis is the inverse negative log of the p-value. Suggestive associations are highlighted in genes with at least one association at p<0.005. TFPI (rs6434222) is significant after correction for multiple testing with FDR. Maternal samples are represented in panels a and b, and fetal samples are represented in panels c and d.
The most significant fetal single locus result was in tissue factor pathway inhibitor (TFPI) at rs6434222 (allelic p = 6×10−5, genotypic p = 1×10−4, both of which were significant after FDR correction) (Table 3). This SNP was not significantly associated with PTB in maternal samples. In fetal samples this SNP had an OR of 2.49 (95% CI = 1.59–3.91, p = 7×10−5) for the additive model, that remained significant after adjusting for parity (p = 8×10−5). In addition to rs6434222 eight SNPs out of the seventeen examined in TFPI associated in both maternal and fetal samples. All of the associating SNPs in TFPI were also significant, using PRAT (Table 3). Only rs6434222 was significant after FDR correction.
Several significant haplotype associations, mostly spanning two areas of the TFPI gene, were identified (Figure 2). One area includes five SNPs denoted by Block 1 (rs12693471, rs8176541, rs7586970, rs3213739 and rs8176508). All of these SNPs had suggestive associations in the single SNP analyses, and showed evidence of both maternal and fetal haplotype association. The other significant haplotype effects were in fetal samples and appear to be driven by rs6434222. Maternal single locus and haplotype associations were not observed for this SNP. In maternal and fetal controls there was weak linkage disequilibrium (LD) between the two regions of the genes defined by Block 1 and rs6434222, indicating two potentially independent effects within this gene (Figure S1).
Asterisks to the right of a SNP indicates significant single locus allelic associations with PTB, red indicates significance in maternal samples and black indicates significance in fetal samples. The number of asterisks denotes the strength of significance. Lines denote a significant haplotype, red is for maternal samples and black is in fetal samples. The thickness of the line denotes the strength of significance. Only SNPs with MAF > 0.05 in maternal or fetal samples are presented in graph. Linkage disequilibrium plots (r2) are shown for fetal controls.
Corroboration of Results
SNPs were included for combined analysis if the allele or genotype p-values were less than 0.05 in one study (MoBa or Cenn) and less than 0.20 in the other study. In maternal samples, 60 SNPs met the criterion for the combined analysis, 30 of which had significant allelic and/or genotypic p-values in the combined dataset after correction for multiple testing with FDR (Table S4). The most significant single locus result in maternal combined samples was in prostaglandin E receptor 3 (PTGER3) (Table 4). There were six SNPs in this gene that met the criteria for combined analysis and three of these (rs2072947, rs977214 and rs6665776) had significant allelic and/or genotypic results in the combined data, all of which were significant after correction with FDR; rs977214 also remained significant after Bonferroni correction. Two of these SNPs (rs977214 and rs6665776) strongly associated with PTB in the combined data (rs977214: genotypic p = 3×10−4; rs6665776: genotypic p = 5×10−4) (Table 4). The best model for rs977214 after correcting for study site and gravidity was the AG/GG genotypes relative to the AA genotype and resulted in an OR of 0.55 (95% CI = 0.37–0.82, p = 3×10−3), indicating a protective effect (Table 5). This SNP deviated from HWE in both cases and controls in the combined data set; however, the sign of the inbreeding coefficients (f) was negative in controls (−0.097) and positive in cases (0.130), indicating that the deviations from HWE were not due to genotyping error as cases and controls were randomly placed on each plate for genotyping, nor are these results due to mixing of population samples (Wahlund Effect). The best model for rs6665776 after correcting for study site and gravidity was CC genotype relative to the AA/AC genotypes and had an OR of 1.75 (95% CI = 1.18–2.60, p = 5×10−3) (Table 5). There was strong LD (r2≥0.95) between these two SNPs in both Cenn and MoBa maternal controls (Figures S2A and B). Haplotype associations spanned three general regions of the PTGER3 gene; two of these regions were significant only in the Cenn study and one of these regions was significant only in the Moba study (Figure 3A, Table S5); however, taken together they both support the association of this gene with PTB.
a) PTGER3 for maternal samples and b) PON1 for fetal samples. Asterisks to the right of a single nucleotide polymorphism indicates significant single locus allelic associations with preterm birth, blue denotes significance in pooled samples, red indicates significance in the MoBa study only and black indicates significance in the Cenn study only. All pooled results are significant after correction for multiple testing with FDR. The number of asterisks denotes the strength of significance. Lines denote a significant haplotype, red is for the MoBa study and black is for the Cenntennial study. The thickness of the line denotes the strength of significance. Linkage disequilibrium plots (r2) are shown for MoBa maternal controls for PTGER3 (a) and MoBa fetal controls for PON1 (b).
In fetal samples, 44 SNPs met the criteria for the combined analysis, 28 of these SNPs had significant allelic and/or genotypic associations in the combined data after correction for multiple testing with FDR (Table S4). The most significant single locus association in pooled samples was in PON1 at rs854552 (allelic p = 8×10−4, genotypic p = 2×10−3). This SNP remained significant after correction for multiple testing with FDR. The best model after correcting for study site and gravidity compared the rs854552 TT genotype to the CC/CT genotypes and resulted in an OR of 1.32 (95% CI = 1.13–1.53, p = 4×10−4) (Table 5). The LD patterns were similar in Cenn and MoBa fetal controls (Figure S2C and D). There were very few haplotype or single locus associations in the Cenn study for PON1; however, there were strong haplotype associations in the MoBa data that is being driven by the single locus association at rs854552 (Figure 3B, Table S5).
Our study explored candidate genes in the four hypothesized preterm labor pathways [8] for associations with PTB and determined the effect size of associations that corroborated a second PTB cohort. In MoBa the only association significant after correction for multiple testing was in fetal samples at rs6434222 in TFPI. This SNP was not significantly associated with PTB in maternal samples and there was only weak LD in maternal controls with this SNP, whereas in fetal controls there was stronger LD between this SNP and other SNPs with significant associations (Figure S1). This indicates that this SNP may exhibit an independent fetal single locus association with PTB. This conclusion is supported by the strong fetal haplotype associations involving this SNP in fetal but not maternal samples. TFPI is involved in the complement coagulation pathway and inhibits Coagulation Factor 3 and Coagulation Factor 10, both of which are important for the production of Coagulation Factor 2 (F2), a critical component in clot formation. Overproduction of F2 can cause contractions and activate matrix metalloproteinases (MMPs) [22]–[24], possibly leading to degradation of the extracellular matrix (ECM). ECM degradation causes changes in the cervix and rupture of the membranes that may result in PTB. The single SNP associations may indicate TFPI as a novel candidate gene for PTB risk. While these associations did not corroborate in the Cenn population other genes in the complement coagulation pathway, particularly tPA were associated with PTB in previous reports, indicating that this pathway may be important in PTB [21].
Among the genes examined for association with PTB ∼19% (26 genes) had suggestive associations (p<0.05) in fetal but not in maternal samples. This may indicate a potential paternal genetic effect, at least in part, for some pathways involved in PTB. This is in contrast to recent studies, based on epidemiological data, indicating that paternal factors contribute little to the risk of PTB [25], [26]. However, to adequately understand the involvement of the maternal and paternal genome in PTB additional methods to examine either maternal and fetal samples simultaneously or trios consisting of paternal, maternal and fetal samples are needed. As better methods are developed to handle such analyses, particularly with respect to perinatal medicine, where both maternal and fetal genomes are involved in the disease outcome, this question can be explored in greater detail. While in general, the genetic contribution of paternal genes may be marginal, it is possible that particular pathways are influenced more by paternal genetic contributions.
The genes that were suggestive for association with PTB in fetal (IL1A, IL4 and MMP8) and maternal samples (IL-1R2 and IL-6R) in both the MoBa and Cenn studies were mainly infection and inflammation genes (Figure 4, sector D). It is interesting to note that most associating fetal variants were in the cytokines genes themselves whereas maternal associations were generally in cytokine receptor genes (Figure 4, sector H). This suggests maternal polymorphisms may influence or modulate functional contributions of fetal SNPs in the inflammatory pathways. We speculate that fetal immunological response to the maternal environment may be affected by maternal variants, thereby regulating the impact of fetal encoded risks through complex interactions. Further studies, particularly genome-wide association studies and inclusion of paternal samples will be essential for elucidating the relative contributions of paternal and fetal genotypes to the risk of PTB.
Genetic associations are defined as any suggestive allelic or genotypic association (p<0.05) occurring in a given gene. These associations are uncorrected for multiple testing and are before correction for covariates such as parity. A: ADRB2, CARD15, CBS, CCL8, EPHX1, FAS, GSTP1, IL1B, IL1RN, IL2RB, IL8RA, MMP2, NFKBIE, PAFAH1B1, PGRMC2, PTGES B: ADH1B, MTHFR, NFKB1, PTGFR, SLC6A4, TLR4 C: CRH, F5, HSD11B1, HSD17B7, HSPA1A, IGFBP3, IL10RB, IL13, IL15, PGEA1, PGRMC1, PTGER2, SERPINE1, TCN2, TIMP4 D: HSPA6, IL1A, IL4, MMP8 E: CBS, GSTP1, HSPA14, IGF1, IL1B, IL1RN, IL2RB, NFKBIA, NFKBIE, NOS3, PAFAH1B1, PTGS2, SLC23A1 F: IL10RA, IL5, MMP1, MMP3 G: CCL2, CTLA4, DHFR, F5, IL10, PGRMC1, PTGS1, TLR2, TLR7, TNFRI, TNFRII, VEGF H: COL1A1, F7, IL18, IL1R2, IL6R, MTHFD1, NAT1, PLA2G4A I: COL5A1, IL1R1, IL4R J: KL, PLAT K: COL1A2, COL3A1, CYP19A1, IL1RAP, IL2RA, NFKBIB, PON2, PTGER3, TIMP3, TSHR, UGT1A1 L: CRHR2, EDN2, NR3C1, PGR, PON1, TREM1 M: COL5A2, CRHBP, EPHX2.
In our study several genes from multiple biological pathways had modest to strong associations with PTB, and many of these corroborated an independent data set on PTB. While this study did not directly test replication, results from the combined analyses indicate genes with universal or generalized associations. The most significant associations in the combined samples were from two major PTB pathways: 1) prostaglandin (PG) effectors (PTGER3) in maternal samples that influence PG mediated uterotonic activity and 2) decidual hemorrhage (PON1) in fetal samples. PTGER3 is a receptor required for prostaglandin response that plays a role in initiation of contraction (labor). Activation of the inflammatory process has been documented to increase prostaglandins[27], [28]. Several SNPs in PTGER3 were significant in the combined MoBa and Cenn maternal samples, supporting the role of variation in this contractile agent in the final effecter pathway and PTB. However, we note that the patterns of haplotype association in MoBa and Cenn differed. Although there is some evidence for differences in LD pattern between these two cohorts, we do not think that the differences are enough to motivate such strong differences in haplotype associations, especially since there is some evidence for SNPs associating in both studies in the middle portion of the gene. Rather it is possible that our data support allelic heterogeneity across the two studies.
The second pathway that associated with PTB in the two cohorts is the decidual hemorrhage pathway that can potentially activate biochemical mediators such as matrix metalloproteinases and cause ECM degradation. PON1 is a member of the paraoxonase gene family and it can impact preterm labor in multiple ways. Primarily, mutations in this gene are associated with changes in lipid profiles (high-density lipoprotein (HDL) low-density lipoprotein (LDL)) [29], [30]. HDL increases the production of prostaglandin E2, leading to contractions [31]. Additionally, hypothesized mutations in this gene could indirectly disrupt thrombotic pathways and activation of thrombin and plasminogen cascade can activate MMPs and MMP mediated ECM degradation [31]–[33]. A previous study examining one mutation in PON1 (rs662) found an association in fetal but not maternal Chinese samples [31]. While this SNP was not associated in the Cenn, MoBa or pooled samples we did identify a different SNP (rs854552) located in the 3'UTR of the gene that was strongly associated with PTB in the pooled fetal samples. It is difficult to conclude that this SNP replicates the association found in the Chinese samples; however, this gene does replicate in two populations of European descent and the Chinese population, indicating perhaps allelic heterogeneity for PON1, but more importantly a consistent role for PON1 in PTB.
Our studies were limited in that they are candidate gene studies; therefore many associations may be missed, including genes representing novel biology with respect to PTB. In addition, the case-control criteria for the MoBa and Cenn studies were slightly different and while there were still many associations discovered, studies with more carefully defined phenotypic criteria are needed to validate these results. Finally, we emphasize that although some results were found to be consistent across MoBa and Cenn, there was evidence for different patterns of association. This was especially pronounced for TFPI, which did not corroborate, and PTGER3 haplotype analyses that showed differences in genic region that associated with PTB. This may be due to underlying population differences between our samples, possibly allele frequency differences that impact power. Alternatively, there could be population specific risk alleles that were indirectly detected through our analyses. Lastly, it is possible that the underlying genetic models for PTB are multi-factorial and that the ability to detect single locus association is impacted by changes in a second or third factor that were not corrected measured or corrected for in our analyses [34].
Despite its potential limitations this study identified multiple genes with significant or marginally significant associations with PTB in two separate samples. When samples were combined, multiple SNPs with strong allelic or genotypic p-values were identified, including SNPs involved in inflammation and infection, ECM degradation and decidual hemorrhage pathways. This study validated a previously identified genetic association with PTB and further studies can address the biological role these genes play.
Materials and Methods
The Norwegian Mother and Child Cohort (MoBa) is a national pregnancy cohort designed to explore the causes of complex pregnancy related phenotypes. The main objective of this cohort is to develop a long term resource to test hypotheses relating to pregnancy outcomes and childhood health. More than 100,000 pregnancies have been included during the study period of 1999–2008 by the Norwegian Institute of Public Health. The target population consisted of all pregnant women in Norway. Women were invited to participate during their routine ultrasound scan at gestational week 17–18. All hospitals and maternity units with more than 100 deliveries annually were invited to participate, and 50 of 52 such units participated. The total participation rate was 42.7% [35]. Epidemiological data and biological material have been and will continue to be collected from both the mothers and the children. The MoBa study collected data on nutrition, overall health status, and child outcome. In addition to these variables additional data were added from the Medical Birth Registry of Norway. The MoBa study has been described in detail elsewhere [35]. The present study used samples derived from a subset of the MoBa cohort (version 2) available at its outset (53,711 pregnancies) [36].
Data from the Medical Birth Registry on gestational age, type of delivery, intrauterine fetal death, congenital malformations and plurality were used. Gestational age was based on ultrasound in early second trimester (week 16–19) and/or the date of last menstrual period. However, ultrasound was the main method of determining gestational age as most pregnancies in Norway are dated by ultrasound.
The cases in this study were defined as singletons with spontaneous onset of PTB between 22 gestational weeks and 0 out of 7 days (220/7) and 366/7 gestational weeks in women aged 20–35 years. This age range was chosen to ensure that women at high risk for PTB because of age (young women less than 20 years of age and older women greater than 35 years of age) were not included in the study. Type of delivery was recorded as spontaneous labor, induced labor, or pre-labor caesarean section. Women with induced labor and pre-labor caesarean section groups, intrauterine fetal death, plurality and if the fetus had congenital malformations were all excluded. The definitions of these conditions have been previously described [7]. Other exclusion criteria were pre-existing medical conditions such as diabetes, hypertension, autoimmune diseases, inflammatory bowel diseases, systemic lupus erythematosus, rheumatoid arthritis, scleroderma or any immune-compromised condition. Women were also excluded if they had pregnancy complications such as preeclampsia, hypertension, diabetes, small for gestational age (according to intrauterine growth curves), abruption of the placenta, placenta previa, cervical cerclage or fetal malformations [37]. The controls were selected according to the same criteria as above except for spontaneous onset of term birth with gestational age between 390/7 and 406/7 weeks. The Regional Committee for Medical Research and Ethics (S-06075) approved the MoBa study and approval was also achieved from the Norwegian Data Inspectorate.
For this study 434 mother-baby pairs (214 cases and 220 controls) were selected for analysis from MoBa. A previously published study on PTB was used to corroborate results from our study. This study utilized samples from the Centennial study (Cenn) collected in Nashville, TN and is described in detail elsewhere [21]. This sample consisted of maternal and fetal individuals of both European (European American – EA) and African (African-American) descent, but only the EA samples were used for corroboration. The combined datasets contained 764 maternal samples (353 cases and 411 controls) and 738 fetal samples (343 cases and 395 controls).
DNA Genotyping and Quality Control
A total of 1,536 tag SNPs were selected from 143 PTB candidate genes. Of these 1,404 SNPs from 129 genes were chosen because they had been included in a previous study of PTB [21]. In addition, 132 SNPs from 14 genes in the complement-coagulation pathway were added to the present study because this pathway was associated with PTB previously. SNPs in Velez et al[21] were selected based on their ability to tag surrounding variants in the Caucasian and Yoruban populations of the HapMap database (http://www.hapmap.org). A minor allele frequency of 0.07 in CEPH and 0.20 in YRI and an r2 of 0.80 was used to determine tagSNPs. The additional SNPs were selected as tagSNPs in the CEPH, based on similar criteria. Genotyping was performed on the Illumina GoldenGate Assay system. 1,430 SNPs encompassing 140 candidate genes were successfully genotyped with genotyping efficiency greater than 95% (Table S1).
Both maternal and fetal samples were excluded if the last menstrual period and birth weight were not consistent with case-control status, suggestive of sample misidentification or if extracted DNA was not available in the Biobank. Additionally, samples were excluded if greater than 1% of the SNPs had Mendelian errors. This was done to ensure high quality genotyping accuracy. Additionally, individuals were excluded for low genotyping efficiency (<95%). The final sample size included 419 fetal samples (203 cases, 216 controls) and 424 maternal samples (207 cases, 217 controls).
DNA Genotyping: Corroboration of Results
A total of 1,316 SNPs in the present study overlapped with the previous study on PTB in EA maternal and fetal samples (Table S1). Additionally, 38 SNPs from three genes (plasminogen [PLG], methionine synthase reductase [MTRR] and tissue factor pathway inhibitor [TFPI]) were successfully genotyped (genotyping efficiency >95%) in the Cenn samples, using the Sequenom platform. A total of 304 maternal and 272 fetal samples were successfully genotyped on this platform with >85% genotyping efficiency. These genes were not originally included in the Cenn analysis; however, significant associations were identified in the MoBa samples and the Cenn samples were reanalyzed for association with these SNPs to determine if these associations could be replicated (Table S2). Institutional Review Boards at TriStar Nashville, TN and Vanderbilt University, Nashville, TN approved this study.
Statistical Analysis: MoBa
Chi-square tests were used to examine differences between cases and controls for APGAR at 1 minute (<7 versus ≥7), APGAR score at 5 minutes (<7 versus ≥7) and smoking (non-smokers versus smokers). Parity (number of times a woman has given birth defined by birth registry), gestational age (days), birth weight (grams) and maternal age were tested for normality using Shapiro-Wilks tests. None of these variables were normally distributed; therefore, these variables were analyzed with nonparametric Mann-Whitney two-sample ranksum tests. Stata version 10 statistical software was used for all analyses (StataCorp, College Station, TX).
Gene names, marker positions (base pair – bp) and marker function were identified using the SNPper database (http://snpper.chip.org). Allele and genotype differences between cases and controls, deviations in Hardy-Weinberg equilibrium (HWE) and inbreeding coefficients (f) were calculated with PLINK (http://pngu.mgh.harvard.edu/purcell/plink/)[38], the Whole-genome Association Study Pipeline (WASP) developed at the Center for Human Genetics Research of Vanderbilt University (http://chgr.mc.vanderbilt.edu/wasp/) and Powermarker software programs [39]. Statistical significance for these analyses was determined using chi-square tests or Fisher's exact tests (if there were less than five individuals for any allele or genotype). These results were corroborated using a prevalence based association test (PRAT) [40]. This test calculates a global allele frequency based on the prevalence of the disease in order to calculate expected frequencies of each genotype in cases and controls separately, and a permutation test is used to determine the significance. The global allele frequency was determined using a PTB prevalence of 5% in the Norwegian cohort. False discovery rate (q = 0.2) was used to correct for multiple testing in maternal and fetal samples, separately [41].
The most significant allelic and/or genotypic associations were followed up with additive, dominant and recessive genotype models, using the minor allele as the risk allele, using logistic regression. Significant (p<0.05) logistic regression models were adjusted for parity because this was the only risk factor that was significantly different between cases and controls in MoBa. These analyses were performed with Stata version 10. Graphical representation of significant results and haplotypes was performed with Haploview [42].
Statistical Analysis: Corroboration of Results
The MoBa and Cenn samples were combined for SNPs that met the criteria described below, and analyzed for allelic and genotypic association. SNPs were included for combined analysis if the allele or genotype p-values were less than 0.05 in one study (MoBa or Cenn) and less than 0.20 in the other study. This criterion, while arbitrary, was designed to capture associations that may have been missed due to inadequate power in an individual study. However, this criterion was also designed to exclude associations that were primarily driven by only one of the two studies. Genotype and allele associations were corrected for multiple testing in maternal and fetal sample separately with FDR (q = 0.2). An effect size was determined with logistic regression for additive, recessive and dominant models again, using the minor allele as the risk allele and correcting for site of collection and gravidity.
The genes with the most significant single SNP associations in maternal and fetal samples were followed-up with 2, 3 and 4 marker sliding window haplotype analysis using Unphased [43]. This software uses a quasi-Newton algorithm to maximize the likelihood of each haplotype when an individual's phase is unknown. The overall test of association is a likelihood ratio test based on the null hypothesis that all of the haplotypes have equal odds ratios. Haplotype analysis was performed in the MoBa and Cenn samples separately.
Supporting Information
Figure S1.
Linkage disequilibrium plots (r2) are shown for maternal (a) and fetal (b) controls for TFPI.
Figure S2.
Linkage disequilibrium plots (r2) are shown for a) Cenn maternal PTGER3 b) Moba maternal PTGER3 c) Cenn fetal PON1 d) Moba fetal PON1.
Author Contributions
Conceived and designed the experiments: KKR NHM PM SMW BJ. Performed the experiments: KKR NHM SMW. Analyzed the data: KKR MJW SMW. Contributed reagents/materials/analysis tools: NHM MJW DRV RM SJF PM BJ. Wrote the paper: KKR SMW BJ.
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With the next gen release of TPP its often easy to forget that this game is also releasing on PS3 - a comparison to MGS4 of the mechanics isn't something we've discussed in great depth. Sticking a pin in the open world which is obviously a huge difference. Quick overview: Reticle is smaller and more accurate Climbing! Jumping! (Kinda) Cover is once again automatic, not as smooth Cover shooting is about a million times smoother Rolling has been replaced with quick dive Prone-rolling controls simplified Multi-person CQC brought back from Peace Walker Guard search removed Permanent held-up guards Interrogation return! Disarm control change, more useful Ground choke simplified Wall knock eliminated Prone-flip control simplified, have to be aiming gun Playing dead removed Prone side-to-side movement added Standing flip removed Dynamic CQC added (corners, cover) Probably missed some stuff out there, majority of changes seem to be positive. Crazy though it seems in 2014 but MGS4 was KP's first attempt at making the standardised TPS "western" approach. It was very rough in places, while stuff like hold-ups were easier than ever, the giant reticle meant that you often had to rely on FPS mode to do precise shots. You still do in GZ's but it's when you're making real marksman type shit. Lot of positive changes which make MGS feel like a modern stealth game like dynamic cqc as a guard approaches you from cover, smoother cover shooting and climbing. Much of the CQC and ground controls have been simplified by removing superfluous extra buttons, like how prone roll used to be R1, the analogue stick and X, where as now its just the analogue stick and L2 Interrogation is back which was sorely missed in MGS4, but we've lost searching guards which seems strange given the asset collection meta-game. On the negative side we're missing a couple of moves like playing dead (although I get that made more sense on MGS4's battlefields), standing flip which was always a bit of a crazy animation, wall-knocking which is kind of returning. Most interestingly entering cover has once again changed. They specifically changed this in MGS4 so you entered cover with the triangle button to stop you slipping out of place like in the old games when you pressed yourself up against it, GZ's system is similar to this but you're permanently locked in. It doesn't feel very smooth and has the old MGS4 janky feel, its clunky getting it to work and its clunky leaving cover, Snake doesn't always seem to do what you want.
The cover system always works for me, I like it. It felt a little janky at first, but I got used to it. As for guard search being removed, that's not really true. Guards still search for you, and rather effectively at that..
Oh yeah. I just realized that, wow. You have to pick everything up from the environment now. I wonder if searching a guard a la Peace Walker will return?
I always used it in that one area right before you meet Otacon in Mk. 2 when that squad rounds the corner sweeping the area and there's no real place to hide.
In GZ, you can't lean while aiming in first person. IMO standing on tiptoes should also be brought back.
Loads of times, the corpse section after you first see the B&B Unit, during all of the major militia battles, really in any section where it made sense and you weren't in the direct path of a guard
The attack combo in MGS4 could be used against multiple enemies, you hit one soldier but finish with a knee hit/calf hit to another. In GZ you start the combo and it will only finish with one soldier at a time. I haven't dwell too much into the cqc controls but they're much more refined and leave very little room for error. You want to throw, interrogate or throw down, the commands don't cross into one another.
Why would you want guard searching back? Ground Zeroes is the first game in a long time to feature some semblance of resource management. Peace Walker and MGS4 showered you with enough ammo and supplies to last four lifetimes, the only reason you even bothered to pick this stuff up is because you'd been conditioned like a dog.
running out of ammo in a video game makes everything more exciting and tense, but it hardly ever happens anymore besides, the only ammo that matters is tranq ammo, and why would guards be carrying that around?
Well I agree that resource management goes well with stealth, but sneaking into what should be heavily guarded supply rooms and capturing guards should net you something for your effort. I'm a big fan of POS and guard searching fits into that - I wasn't a fan of Drebin's shop and I'm not going to be a fan of TPP's ammo drops either.

subset: commoncrawl


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Country Living
Illustration & Design
Wednesday, August 26, 2015
A Cotswold Dream - Part two
From Burford to Chipping Campden I was lost in the beauty of the golden Cotswolds and all the Hollyhocks welcoming guests at front doors!
I'm busily creating new paintings and patterns behind the scenes.
Thanks for visiting,
Saturday, August 15, 2015
A Cotswolds Dream - Part One
I had a long held dream of visiting The Cotswolds and I am excited to say this came true a few weeks ago. It is such a beautiful part of the UK, with golden cottages and gardens overflowing with Hollyhocks and roses, looking out over rolling hills stretched as far as the eye can see. I felt like painting every little scene I saw, and I'm sure there will be future Cotswold inspired designs at Bumpkin Hill!
I will start our journey together in
Hidcote Gardens
. Lawrence Johnson, the American creator of Hidcote Manor Gardens arrived with his Mother in 1907. She bought the house and 287 acre for £7,200, with a deposit of £10!
The garden is famously divided into rooms divided by high hedges, giving many wonderful surprises around each corner.
Just before my trip I finished this commissioned painting of my Garden. I grow flowers that I love, that bring happy memories and inspired by all the wonderful English Gardens I visit.
Do join me back here soon for the rest of my journey, I will share the welcoming little Towns next,
Hugs and flowers,
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In the Stars
Your Horoscope: Friday, November 27, 2009
-Margaret Santangelo
Sagittarius: Today you are more creatively inspired than you have been in months. If you are collaborating with a friend or colleague on a daring project, discuss your concepts with him or her to help you put your ideas into perspective. This evening, toss some ideas around with your colleagues; you'll come away completely inspired.
Capricorn: Today everyone is expressive, outgoing, and energetic, and you'll be in a great mood. Take some alone time if you need it this afternoon. Definitely get out of the house this weekend; you may meet someone attractive and interesting while out socializing with friends.
Aquarius: A difference of opinion between you and your significant other may escalate into a massive argument this morning due to underlying problems you have both been ignoring. This weekend, sit down and talk things over. You'll be able to work things out – as long as you are both willing to listen.
Pisces: Today you'll focus on your ideals, dreams, and hopes for the future. You'll need to function in a somewhat restrictive or rigid structure today. If you simply get down to business and complete necessary tasks this afternoon, you'll be relieved of most of your stress by nightfall.
Aries: Get your work done early this afternoon so you can enjoy a guilt-free evening of entertainment. This weekend is especially propitious for romantic encounters; a friend may introduce you to someone you are immediately drawn to this evening, so don't blow off your evening plans.
Taurus: This morning you'll focus on practical details. You'll be especially cheerful and affectionate all day, and your romantic partner is the focus of your warmth and love. Don't fall victim to wishful thinking or delusions about your relationship; though, take a hard look at it and come to terms with what it is this evening.
Gemini: You'll feel self-indulgent and generous this morning, so do something you enjoy. Someone may try to force you to give in to his or her demands about what to do, so you may just be the best company for yourself tonight. Or you could compromise – do his or her activity tonight and yours later this weekend.
Cancer: This morning you may discover a new approach to solve some problem. However, you may still be preoccupied tonight. A heart-to-heart talk with a close friend could help you sort through some difficult emotions, but a short trip or longer vacation could be a great way to take some time for your deepest thoughts.
Leo: You feel balanced and confident today, and you'll be especially productive with work this afternoon. You'll be exhausted tonight, though so you may need to cancel your evening plans. Recharge your batteries tonight; you'll have plenty of time for fun this weekend.
Virgo: Don't be overly critical of others, especially anyone you are involved with financially, this evening. Money is likely to be the cause of tension this afternoon. This weekend, go out and socialize with friends– you'll get your mind off more serious issues and lighten your mood.
Libra: Your significant other may surprise you with some token of affection this morning. The late afternoon could find you engaged in a heated discussion, but you'll enjoy the argumentative mood. Spend some alone time with your special someone this weekend.
Scorpio: Today is an active and busy day, especially around the house. If there's something you've wanted to say to a lover or friend but haven't had the nerve, get it off your chest today. You'll feel much better once you vent your feelings.


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You Pay: $37.99
The Atlas QR-2 Microphone Stand Base Quick Release System installs between the 7/8" threaded microphone stand tube and round base. The system is intended to provide quick installation and breakdown of microphone stands, by allowing the technician to simply insert the tube into the base.
The ball bearing interconnect system provides a sturdy, secure fit. Technicians must step on the outer ring of the quick release in order to detach the tube from the base; this will also avoid inadvertent detachment during performances. The QR-2 is an ideal solution for touring situations, stage performances, theaters, and is completely compatible with the Atlas MS-10C, MS-10CE, MS-12C and MS microphone stands.
Diameter | 7/8" (2.2225cm) |
Shipping Weight | 1.50 lb (0.68kg) |
Packaging Info | |
Package Weight | 0.45 lb |
Box Dimensions (LxWxH) | 4.409 x 3.543 x 1.496" |


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The new ERK-525 Emergency Response Kit includes the DSM-525 digital survey meter (dual probes), MRSP-1 Plastic Scintillation Probe, HP-265 pancake G-M probe with check source and holder. This emergency response kit is ideal for police, fire and rescue as well as scientific applications.
ERK-525 Response Kit................
The DSM-525 is a microprocessor Scaler/Ratemeter with a large digital display and separate inputs for 2 detectors. The 525 has separate adjustable HV supplies for each detector and each detector can have different DOSE & CPM calibrations. Inputs can have different functions i.e. Ratemeter on one input and Scaler on the other input. A threshold that is variable from 0– 100 % on the input signal eliminates unwanted signals below preset amplitudes. Alarms are provided from 5 - 95% of full scale. Both probes can be connected and only require adjusting selector switch to the probe for completely automatic operation.
Input Sensitivity: 0.050 v p-p
Threshold Variable: from 0-100% of input signal
Display: 4 DIGIT X .75" Tall 19 mm) LCD W/Led BACKLIGHT
Display: Back light Push Button ON for 30 seconds Auto Off
Dose Ranges # 1: Probe 0.0 μR/hr to 9999 R/hr & 0.0 μSv/hr to 999.9 Sv/hr
Dose Ranges # 2: Probe 0.0 μR/hr to 9999 R/hr & 0.0 μSv/hr to 999.9 Sv/hr
Scaler Ranges: 0-9,999 cps, 0-9999 cpm and 0-9999 Kcpm
Scaler Count Time Ranges :10 second increments to 2500 seconds
Calibration Controls: Standard 12 turn Potentiometer for each range
Range: Adjustment Auto-ranging
Electrical Linearity: ±5%
Response Time: Slow-20 seconds FS, Fast-4 Seconds FS
Drift: <5%
Environmental: -20 deg F (-28 deg C)-140 deg F (60 deg ?C) | 5-95% RH IPX4 Housing
HV 1 & 2: ( Separate Adjustment) Adjustable 300-1500 VDC | Regulation ±1%
Audio Front panel switch: water & solvent resistant
Battery: 6 AA, Nominal 200 hrs operation
Dimensions: 5.5" (14cm) H X 4" (10cm) W X 7" (18cm) L
Weight: 2.5 lbs (1.1kilo) W/ Batteries
Construction: Heavy Duty Cast Aluminum & Stainless Steel
Alarm: 5-95% of full scale
The MRSP-1 plastic scintillation probe our newest microR Detector. The probe is tissue equivalent, and has greater accuracy and sensitivity than a sodium iodide chamber. It is sensitive to gamma radiation at the microR level between 15 keV and 2 MeV. The range is 0-10,000 micro R.
SpecificationsGeneral: Micro R Detector
Range: 0 -
5,000 Micro R
Energy Response: Gamma: 40 keV-2MeV
Operating Voltage: 900 vdc
Window Density: 7 mg/cm2
Dead Time: <5 μSec
Sensitive to Cs-137: 60 CPM/μR/hr
Sensitive Area: 1" (2.54cm) X 1" (2.54cm)
Environmental: -20°F (-28° C)— 140°F (60° C) — 5 - 95% RH, IPX4 Housing
Dimensions: 1.875" (4.76cm) Diameter X 6" (15.2cm) Long
Weight: 0.5 Pounds (.23 kilos)
The 2.5 inch pancake G-M probe is ideal for general purpose survey. This G-M probe detects alpha, beta, and gamma radiation. The HP-265 measures 14C, 32P, 35S and 137Cs with notable efficiency.
SpecificationsDescription: Long life halogen pancake G-M detector with 1.6 mg/cm2 End Window
Efficiency (4pi geometry): Typically 5%-C-14; 22%-Sr-90/Y-90; 19%-Tc-99; 32%-P-32; 15%-Pu-239, Gamma dose to 200 mR/hr (Based on 137Cs calibration)
Operating Voltage: 900 vdc
Window Thickness: 1.6mg/cm2
CPM/mR/hr: (137CS): 2,500
Energy Response: Alpha - 3.5 meV min, Beta - 1 keV min, Gamma - 20 keV-2 meV
Sensitive Area: 15 cm2
Finish: Polyurethane Coated Aluminum
Dimensions: 2.75" diameter. X 11" long
Weight: 16 ounces
Environmental: 20º - 60ºC, 5% - 95% RH non-condensing---IPX4
Construction: Polyurethane coated aluminum probe housing, nylon coated stainless steel probe clip
Cs-137 1 uCi, 1 inch check source with holder
Direct Scientific / tel (310) 589 0601 / Email |
Open 8:00 AM - 5:00 PM Pacific Standard Time |


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From the Editors
The Spring issue of the Arab Studies Journal is out! Click here.
Don't miss Tadween Publishing's latest blog entries at Al-Diwan. Click here.
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New Texts Out Now: Henri Lauzière, The Making of Salafism: Islamic Reform in the Twentieth Century
Henri Lauzière, The Making of Salafism: Islamic Reform in the Twentieth Century. New York: Columbia University Press, 2016. Jadaliyya (J): What made you write this book? Henri Lauzière (HL): I wrote the book in an attempt to solve a nagging problem in Islamic intellectual history. For the last three decades or so, ... Read More »
New Texts Out Now: Karine Walther, Sacred Interests: The United States and the Islamic World, 1821-1921
Karine Walther, Sacred Interests: The United States and the Islamic World, 1821-1921. Chapel Hill: University of North Carolina Press, 2015. Jadliyya (J): What made you write this book? Karine Walther (KW): As my parents were both French immigrants to the United States, I have always been interested ... Read More »
أسئلة الاستشراق الجديد ودوره في صناعة كراهية الإسلام في كتاب جديد لفخري صالح
أسئلة «الاستشراق الجديد» ودوره في صناعة «كراهية الإسلام» في كتاب جديد لفخري صالح صدر حديثًا عن "الدار العربية للعلوم" في بيروت، كتاب «كراهية الإسلام: كيف يصور الاستشراق الجديد العرب والمسلمين» للناقد والمترجم الفلسطيني/ الأردني فخري صالح، والذي يتناول في محتواه (المقدّمة، وفصوله الثلاثة الأساسية، ... Read More »
Interview with Taraneh Hemami
Taraneh Hemami is a San Francisco-based artist and arts educator whose work is known internationally. Born in Tehran, Hemami emigrated to the the United States to attend college in 1978. Roula Seikaly spoke with the artist about the publication entitled Bulletin, its relationship to Hemami's ongoing collaborative ... Read More »
Caliphate, An Idea Throughout History: An Interview with Hugh Kennedy
What is a caliphate? Who can be caliph? What is the history of the idea? How can we interpret and use it today? These are the themes discussed in Hugh Kennedy's new book, The Caliphate (Pelican Books), which aims to find the long-term historical context for the idea of caliphate. Tracing the history from the choosing ... Read More »
Neo-Ottoman Architecture and the Transnational Mosque: An Interview with Kishwar Rizvi
Mosques are enduring architectural and institutional features of Muslim communities throughout the world, and thus it is natural to encounter large mosque complexes that occupy prominent positions within the cityscapes of the Middle East and beyond. Yet among the many historical mosques and buildings in the region's ... Read More »
Turkey Media Roundup (June 22)
[This is a roundup of news articles and other materials circulating on Turkey and reflects a wide variety of opinions. It does not reflect the views of the Turkey Page Editors or of Jadaliyya. You may send your own recommendations for inclusion in each week's roundup to firstname.lastname@example.com by Sunday night of ... Read More »
Critical Currents in Islam Media Roundup (March–April 2016)
[This is a roundup of news articles and other materials circulating about Islam and reflects a wide variety of opinions and approaches. It does not reflect the views of the Critical Currents in Islam page or of Jadaliyya. You may send your own recommendations for inclusion in each week's roundup to firstname.lastname@example.com ... Read More »
Islamic Reformation?
We keep hearing calls for an "Islamic Reformation," assumed to be the remedy for a fundamentalist Islam behind the conservative Salafi brand as well as the Jihadist. Islam, under these assumptions, generates problems because it had not been "reformed." The assumed model is the Christian Reformation of the sixteenth ... Read More »
Hasan al-Turabi and Contemporary Islam
The passing of Dr. Hasan al-Turabi on 5 March 2016 marks the ending of important eras in Muslim political and ideological history. He is hailed by some as a significant articulator of necessary Muslim intellectual renewal and vigorously opposed by others who see him as important in shaping authoritarian dimensions of ... Read More »
New York Event--The Fall of the Turkish Model: How the Arab Uprisings Brought Down Islamic Liberalism (March 1 @ 12.30pm)
The Fall of the Turkish Model: How the Arab Uprisings Brought Down Islamic Liberalism New Book by Cihan Tuğal (Verso, 2016) Date and Time: Tuesday, March 1, 12:30 pm - 1:30pm Location: The Hagop Kevorkian Center, 255 Sullivan Street, New York University Tuğal's masterful explication of the demise of Islamic ... Read More »
New Texts Out Now: Ward Vloeberghs, Architecture, Power, and Religion in Lebanon
Ward Vloeberghs, Architecture, Power, and Religion in Lebanon: Rafiq Hariri and the Politics of Sacred Space in Beirut. Leiden and Boston: Brill, 2015. Jadaliyya (J): What made you write this book? Ward Vloeberghs (WV): While studying in Beirut in the early 2000s, I witnessed a construction site on the ... Read More »
Islamophobia Is An American Tradition
When Republican presidential candidate Ben Carson made news recently by questioning whether a Muslim American could (or should) ever become president of the United States, his assertions recalled similar concerns raised by a political supporter of John McCain's presidency at a rally seven years earlier. "I can't trust ... Read More »
A Muslim Future to Come?
[This article was first published on Public Books.] Michel Houellebecq, Submission. Translated from the French by Lorin Stein. New York: Farrar, Straus, & Giroux, 2015. The devastating attacks of 13 November on Paris's tenth and eleventh arrondissements viciously targeted the "progressive" heart ... Read More »
New Texts Out Now: Jeanette S. Jouili, Pious Practice and Secular Constraints: Women in the Islamic Revival in Europe
Jeanette S. Jouili, Pious Practice and Secular Constraints: Women in the Islamic Revival in Europe. Palo Alto: Stanford University Press 2015. Jadaliyya (J): What made you write this book? Jeanette Jouili (JJ): I began research for this book in 2002, the year after 9/11. The global impact of that event was made ... Read More »
كُلفة العنف: المُكوّن الاجتماعيّ للحركات الإسلامية في مصر
شهدت مصر في الآونة الأخيرة تصاعداً غير مسبوق في أحداث العنف المادي المتبادل، فمجازر الدولة تجاه الإسلاميين بشكل خاص والاعتقالات العشوائية لما يزيد عن أربعين ألف شخص حسب التقارير، والممارسات السلطوية ضد كافة خصوم النظام المصري الحالي، والحملات الأمنية الشرسة التي بلغت ذروتها بتهجير مئات الأسر وتدمير آلاف ... Read More »
New Texts Out Now: Moustafa Bayoumi, This Muslim American Life: Dispatches from the War on Terror
Moustafa Bayoumi, This Muslim American Life: Dispatches from the War on Terror. New York: New York University Press, 2015. Jadaliyya (J): What made you write this book? Moustafa Bayoumi (MB): The War on Terror made me write This Muslim American Life. I believe that the people of the United States aren't taking ... Read More »
Can Total War in the Middle East Be Prevented?
Three weeks ago, Russia started to directly intervene in Syria. The proxy war between Russia and Iran on the one hand, and the United States and Saudi Arabia on the other, threatens to turn into an actual war. Having lost control over its "victories" in the last fourteen years, the United States would rather keep this ... Read More »
حزن مستيقظ إلى الأبد
[تنشر هذه المادة ضمن ملف " الموجة الجديدة في الشعر السوري ( أثر الحرب )" انقر/يهنا لمواد الملف الكاملة] -1- سنعتادُ الأمر؛ /اعذر وقاحتي / المصافحة حركةٌ تافهة؛ ودمي مازال قلقاً مذ ذهب آخر جنديّ الى ... Read More »
Syria Media Roundup (August 5)
[This is a roundup of news articles and other materials circulating on Syria and reflects a wide variety of opinions. It does not reflect the views of the Syria Page Editors or of Jadaliyya. You may send your own recommendations for inclusion in each week's roundup to email@example.com by Monday night of every ... Read More »
Three Theses on ISIS: The Universal, the Millenarian, and the Philistine
The ruthless brutality of the Islamic State in Iraq and Syria (ISIS or ISIL) unfolds before our eyes on the screens. As commentators struggle to explain and understand it, it becomes convenient to revive old Orientalist tropes. Beyond the spectacular brutality, the reason that ISIS invites attention (both fascination ... Read More »
Daoud's Camus Fanfiction Is More of the Same
Kamel Daoud, The Meursault Investigation. Translated by John Cullen. New York: Other Press 2015. Algerian journalist Kamel Daoud's debut novel The Meursault Investigation, recently translated into English, retells the story of Albert Camus's The Stranger from the point of view of Harun, the brother of the unnamed ... Read More »
تدمر، واحة للظلام
تعرضت تدمر منذ مدة لغزوة بربرية في وقت قياسي، وتردد صدى الخبر في أنحاء سوريا والعالم لأن تدمر تتمتع بشهرة خاصة كونها رمزاً ثقافياً وحضارياً، ونظراً لموقعها الجغرافي الذي جعل منها في الأزمنة القديمة محطة لطرق القوافل بين سوريا وبلاد ما بين النهرين، ولتاريخها العريق المتداخل مع تواريخ متجاوزة للحدود المحلية، ونظراً ... Read More »
The Rise and Fall of Abu 'Iyadh: Reported Death Leaves Questions Unanswered
On 2 July 2015, Mosaïque FM, the largest radio station in Tunisia, reported that Sayfallah 'Omer bin Hussayn al-Tunisi (al-Tunisi), also known as Abu 'Iyadh, had been killed in a US led airstrike targeting former Al Qaeda in the Islamic Maghreb (AQIM) commander Mokhtar al-Mokhtar. No sources were attributed to this ... Read More »
Ramadan 2015 for Uyghurs: Another Crackdown on Islam in China's Xinjiang
In the Xinjiang Uyghur Autonomous Region (XUAR), another Ramadan inevitably ushers in an intensified campaign to crack down on the Uyghurs' religious beliefs, practices, and identity, alongside year-round social, political, and religious restrictions. As in previous years, local Xinjiang authorities have instituted a ... Read More »
Beyond Blame: Troubling the Semiotic Ideology of Muslim Passion
In the months following the tragic murders at the offices of the satirical magazine Charlie Hebdo and a kosher grocery in Paris, reactions to the attacks predictably gravitated toward two polar positions. Pundits and politicians in Western Europe and North America—almost entirely non-Muslim—deplored not only the ... Read More »
ISIS in the News: Extensive Media Roundup (March-April 2015)
[Editorial Note: This is not a "Best of," only a roundup of significant pieces. See here for an introduction to this roundup series] English Articles ISIS Threatens Twitter Founder And Employees Over Blocked Accounts (1 March 2015) David Mack reports ... Read More »
Answering the Call: Popular Islamic Activism in Sadat's Egypt: A STATUS/الوضع Conversation between Abdullah Al-Arian and Anthony Alessandrini
Abdullah Al-Arian, a founding editor of Jadaliyya's Critical Currents in Islam page, discusses his new book, Answering the Call: Popular Islamic Activism in Sadat's Egypt, and how it speaks to popular Islamic activism in Egypt today. The interview below includes three parts that you can click on separately. Abdullah ... Read More »
ISIS in the News: Extensive Media Roundup (January-February 2015)
[Editorial Note: This is not a "Best of," only a roundup of significant pieces. See here for an introduction to this roundup series] English Articles 2014: The Year ISIS Won the Propaganda Battle (31 December 2014) Markham Nolan writes about the ... Read More »
New Texts Out Now: Joseph A. Massad, Islam in Liberalism
Joseph A. Massad, Islam in Liberalism. Chicago: University of Chicago Press, 2015. Jadaliyya (J): What made you write this book? Joseph Massad (JM): I had been thinking for a while about a different book, namely one that traces genealogically the transformation in the semantic uses of the term "Islam" since the ... Read More »
About Turkey Page
Jadaliyya's Turkey Page features exclusive and in-depth coverage by contributors on the ground in Turkey as well as outside observers, from a wide range of perspectives. We aim to enrich the coverage of Turkey throughout the English-language media, to generate new critical conversations, and to translate work being published in Turkish for an English-language audience. We welcome submissions in both English and Turkish. If you wish to contribute to this page, send your material to firstname.lastname@example.com or click below:
Turkey Map and Stats
Population: 75,627,384
Government: Republican parliamentary democracy
Year of independence: 1923
GDP: $795 billion (nominal); $1.306 trillion (purchasing power parity)
Unemployment: 9.2%; Youth Unemployment (ages 15-24): 25.3%
Internet Users: 45.7% (37.455) million
Exchange Rate: ~ 1.8 Turkish lira per US dollar
GDP Growth Rate: 5.2%
Military Expenditures: 2.4% of GDP (World Rank: 15)
Health Expenditures: 6.74% of GDP (World Rank: 88)
Population Growth Rate: 1.2%
Age Structure: 0-14 years: 24.5%; 15-64 years: 67.8%; 65 years and over: 7.7%
Literacy: 87% (Male: 95%; Female: 80%)
Religious Demographics: Sunni Muslim 80-85%; Alevi Muslim 15-20%; Christian (various denominations) 0.13%; Jewish 0.03%
Ethnic Demographics: Turks 80%, Kurds 18%, Arabs 1.4%, Armenians 0.1%, and other (Assyrian, Greek Orthodox, Georgian, Circassian) 0.5%
Languages: Turkish, Kurdish, Zaza, Arabic, Armenian, Greek, Albanian, Neo-Aramaic Laz, Ladino
Area: 301,159 square miles
لأكثر من أربعين عاما ً، عاش زهاء العشرة ملايين شخص بين نهر الأردن والبحر الأبيض المتوسط في ظل نظام ينتهج سياسة الفصل العنصريclick | email | tweet
Latest Entries
View All Entries »- Cities Media Roundup (March 2017)
- Media on Media Roundup (March 30)
- The Naksa Fifty Years Later: New Sources, Questions, and Approaches to the '67 War (Conference at Harvard)
- Political Economy Project Book Prize Competition: Call For Books Published in 2016
- The World in the City and the City in the World: Reading the Janet Abu-Lughod Library
- New Texts Out Now: Henri Lauzière, The Making of Salafism: Islamic Reform in the Twentieth Century
- الوضع العارض والمؤقت للشباب: ريادة الأعمال ليست حلاً
- Arabian Peninsula Media Roundup (March 28)
- Violence: Theirs and Ours
- Syria Media Roundup (March 27)
- إسطنبول.. لجوء في انتظار اللجوء
- الأغنية الوطنية الفلسطينية: مقابلة لمجلة الوضع مع ايليني مستكلم وفارس شوملي
- Yemen's War [Ongoing Post]
- Last Week on Jadaliyya (March 20-26)
- Egypt Media Roundup (March 27)
- Dark Beirut: The (In)Visibility of Electricity
- Palestine Media Roundup (March 26)
- قصائد للشاعر أمبرتو سابا، المجلد الاول
- Critical Currents in Islam Media Roundup (March 6 - March 19)
- Maghreb Media Roundup (March 23)


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Welcome to Asar
OS X and iOS application development.
Hogwasher is a full-featured newsreader for OS X. File downloads in multiple connections across multiple servers, thread trees and extensive filtering for keeping your discussions accessible, with a beautiful interface built for OS X Yosemite.
NZB Drop
NZB Drop frees you from crawling through millions of headers to get at the content you want. Use the built-in search to locate files of interest, then experience the simplest, fastest Usenet downloads available anywhere, complete with full post processing.
Our first lil' app, the best bpm tapper for OS X. Tap your way through entire playlists quickly and efficently, or tap out songs as they come up with minimal disruption to your workflow.


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My Flickr
More Photos-
Recent Posts
My Tweets
Error: Twitter did not respond. Please wait a few minutes and refresh this page.
Tag Archives: clapotis
Goodies from Michigan
I went to see Kie and Eric in Lansing recently, and visited my favorite little yarn shop in the universe, Woven Art. Maybe I should have strongly considered, MSU, just to be close to this shop. It has an amazing … Continue reading


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My address book keeps displaying my old cell phone when i hover over the bluetooth icon. I am able to connect to the phone from the bluetooth preferences panel in OSX but address book just keeps looking for my old phone. Solution? Thanks, Danny
Don't actually know, but one thing you can look into: Is iSync set up to synchronize your old phone or your new one (or both)?
The thing is i dont necessarily want to sync the phone. I want to be able to have the phone connected to Address Book so i can see who's calling when im in a meeting and send text messages so on and so forth. Danny
That's up to you, but I'm not suggesting that you actually sync it... just look if one or both is added and active. This is because when I recently got a new phone I added that to iSync and at the same time turned off syncing for my old phone (it still appears in iSync but inactive) and the tool tips on the Bluetooth button in my Address Book now refers to my new phone (and I cannot remember doing anything in Address Book to make it so).


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Educate Your Body
In addition to being open to the public, all current RRU students receive free membership to the RRU Recreation Centre. Come nurture your body, mind and spirit in this beautiful heritage facility located on the Royal Roads University campus in Colwood on the Westshore. Please bring your student ID card as proof of membership.
To register or find out more, please call RRU Recreation Centre at 250-391-2700 or send us an email.
Visit us on Facebook for pictures of the Recreation Centre, updates, and promotions or download our schedule for a full list of current classes.
Free 10 Day Trial
Enter your details below to sign up for a free 10 day trial with us. You will receive an email with trial details afterwards.
*This offer is available to new members or those who have not had a membership at the RRU Recreation Centre in the past year.*
Hours of Operation
Monday to Friday: 5:30 am - 10:00 pm
Saturday & Sunday: 8:00 am - 6:00 pm
Statutory Holidays: 8:00 am - 4:00 pm
Amenities and Services
- Free weight room (Atlantis equipment)
- Over 30 cardio machines (treadmills, stairclimbers, jacobs ladder, ellipticals, upright & recumbent bikes, rowing ergs)
- Keiser (air) machines
- Gym Court
- Aerobics/Yoga studio
- Bike rentals
- Personal Trainers & Exercise Physiologists available
Drop-in Activities
- Two Squash courts
- Basketball court
- Volleyball
- Badminton
- Pickleball
- Table tennis
- Numerous fitness classes (included with membership)
Open Gym Time
- Anytime the gym court or aerobics studio are not booked members are welcome to use the space for activities.
- Scheduled activities have priority booking, so patrons may be asked to vacate the area when the booked time is reached.
- Please check the schedule board, facebook, or ask staff to confirm when these activities may occur.
- Organizations/individuals may arrange to book the aerobics studio or gym for one time or ongoing activities. Please check with the Recreation Centre staff regarding guidelines, availability and applicable rental fees.


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Committed an enormous technical debt today. If I wrote the two template pages instead of relying on a completely foreign base theme to make TWO pages. It would have been done in a week.
Oh my! Mabuhay ka Twig. Lumabas ka na sana.
Ayoko nang magtiis sa themes na nag complex na nauubos ang 2 days ko kaka-reverse engineer ng ma-gets ito. Eh kung isulat na lang natin ang theme ng site na ito. 3 template pages lang naman sa maximum. Aaaaargh.
Kaya paglabas ng Twig sa 8. Pramis. Bahala kayo sa sub-theming! Magsusulat na lang ako.
Don't do it
If you won't bother to make it presentable, consumable, don't bother. The last thing we need is a pile of gunk wasting electricity in the interwebs.
This is nice
This is nice. But doing this everday… is not nice anymore.
My machine is dead
There was a time a few years back when weekends meant shuffling across Guimaras Strait, boat rides and one night at our Bacolod home. It was also at this point of my life that I started to enjoy one of the best things in the universe – physics.
Now that I am a little older and I make websites and organize things and people I can only sneak away from work once a week and study physics. Now that my machine is dead there is no sneaking around required. I can just sit back and enjoy the most beautiful, elegant and constant thing in my life.
I will never be not interested in you physics.
Weekend summed-up
Quite a few vagrant ups and downs
Loom band lessons in exchange for HTML/CSS wizardry
A free mocha frappe
Theming colour horror
Making fancy banners
Wishing I could be looking at the moon and making fun science
Reading tagalog…
Reading tagalog makes me sleepy. I cannot process anything. We should have more subjects in Hiligaynon and FIlipino!


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Two suspense-filled novels in one by author Shirlee McCoy
Running Blind
Jenna Dougherty's mission trip to Mexico turns sour when she and her roommate Magdalena are kidnapped. When Jenna's finally rescued by ex-marine Nick Jansen, she learns it's too late to save her friend. Can Nick help her find Magdalena's killer? Or will chasing this trail have Jenna running blindly into danger?
Lone Defender
Abandoned in the desert, private investigator Skylar Grady realizes that someone will kill to keep her from finding the deadbeat dad she's been tracking. Yet she won't be scared off. So if former patrol agent Jonas Sampson wants to keep her safe, he'll have to stick by her side. But her new partner is a mystery, tooone Skylar will risk her heart to solve.
Format | ISBN |
Paperback | 9780373602902 |


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- Height: 25m
- Ascents: 1
Route History:
- There is no known route history.
Located in The Northern Group approx:
Lat/Long: -37.182189,144.492112
Route Grade Citations
24 | Community registered grade |
24 | Pocket RockGUIDE: Melbourne's Best |
Route quality
Overall quality score: 50%
Lead Styles
Comments keywords
Learn about creating circuits.
Activity Configure
Check out what is happening on The Cult Master (note there is an unresolved system issue where ascents logged before 2010 are not displayed in the stream below). If you just want to see beta then click on view ascents with beta.


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Products in the Alessi Bird Kettle category have been rated stars based on 1 reviews |
An iconic Alessi design, the 9093 Whistling Bird Stovetop Kettle was designed by Michael Graves. Regarded as a design classic, the 9093 remains one of the best selling Alessi products and would look fantastic on any hob.
The original colourway for the Alessi Bird Kettle was the blue handled version, with black and white varieties later becoming available. Featuring a charming bird shaped whistle, the Alessi Bird Kettle would be ideal for modern and minimalist kitchens.
Made from 18/10 mirror polished stainless steel with a magnetic stainless steel heat diffusing bottom, this beautiful Alessi kettle is suitable for induction hobs.
An Alessi Bird Kettle would be a stylish addition to a home and a great designer gift idea.
At Hurn and Hurn we stock the original Alessi 9093 Bird Kettles, alongside the 30th Anniversary celebration editions which feature dragon whistles instead of bird whistles.
Discover the 9093 Alessi Bird Kettle today.


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'Gay cure' therapies could be banned under Tory government, says David Cameron
So-called 'gay cure' therapies could be banned under a Conservative government, the Prime Minister has said.
David Cameron said such practices were "profoundly wrong" and pledged that if a Government led by him needed to legislate to "protect people from harm", it would.
Conversion therapies, which seek to change a person's sexuality, are not endorsed or supported by health authorities in the UK, but are offered by some Christian groups.
Mr Cameron told PinkNews that he strongly disagreed with anyone who thought that homosexuality was an illness to be 'cured'.
"We are creating a country where people can be free to be themselves, and no-one should be pressured into being someone that they're not," he said.
He said the NHS in England had signed up to a "memorandum of understanding" that conversion therapies were unethical and potentially harmful.
"I think that's a pretty firm approach to stop the use of these practices, but if we need to go further to protect people from harm, we will," he said.
The Liberal Democrat leader Nick Clegg has also spoken out over gay cure therapies, calling them "dangerous nonsense", and Labour leader Ed Miliband has said his party is opposed to them.
Some US states have banned the practice for use on minors, and President Obama has said he supports a ban.
Further reading
David Cameron: I will never validate the DUP's stance on gay rights and LGBT issues
Gay marriage rejected by Northern Ireland Stormont Assembly
DUP minister Jim Wells quits after gay abuse comments controversy
Iris Robinson 'gay cure' psychiatrist cleared over claims of malpractice with a patient
'Gay cure' doc hailed by Iris Robinson faces disciplinary charges at hearing
Editor's viewpoint: Gay 'cure' meeting fuels intolerance
Online Editors


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Kassandra "Kassy" Juarez is slated to open for Steeven Sandoval at a special Seranata para Las Madres. The 18-year-old singer and violinist began practicing mariachi music in the 6th grade... read more →
This Mother's Day weekend, Steeven Sandoval will perform his first headliner concert in San Antonio for Serenata para las Madres at the Charline McCombs Empire Theatre. Steeven will be accompanied by Mariachi Azteca de... read more →
This Friday, February 10th, San Antonio will host Noche de Romance, a very special Valentine's Day concert featuring some of Texas' greatest Latin music performing and recording artists. Noche de... read more →
Fifty mariachi groups will gather for the 22nd annual Mariachi Vargas Extravaganza in San Antonio on December 1-3. Several of these ensembles will perform at the Serenata en el Río on... read more →
The Mariachi Vargas Extravaganza is less than a month away, and lots of excitement is building up for this year's event. Vocal finalists have been posted on mariachimusic.com, and the... read more →
A huge thanks to everyone involved in submitting entries for the 22nd Annual Mariachi Vargas Extravaganza National Vocal Competition. We sincerely appreciate all the time and effort that went into preparing... read more →
Two legendary names in Mexican music unite for a concert extravaganza! Aida Cuevas, Latin Grammy Award® Winner, and Mariachi Reyna de Los Angeles, the first all-female mariachi ensemble, are joining... read more →
There are 13 days left to submit an entry for the 22nd Annual Mariachi Vargas Extravaganza National Mariachi Vocal Competition. The deadline to register at mariachimusic.com is October 1. Entries... read more →
https://www.youtube.com/watch?v=PBcBRPIf4ew By Astrid Téllez The Mariachi Vargas Extravaganza is so much more than just a concert! My first time attending the event was in 2011, and I've attended almost... read more →
https://youtu.be/V9lPVdOYKN4 On July 23rd, the University of Northern Colorado (UNC) in Greely will host a Mariachi Extravaganza concert featuring participants and winners of San Antonio's well-known Mariachi Vargas Extravaganza... read more →


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For the past year, Dave has had issues with his right shoulder. It's not the chronic masturbation, but he still decided to live with the pain. (Also, a rant on how Dave is going to break Tony Robbins.) While paying ball with his son, he TORE something. Dave rants on insurance, x-rays, co-pays, and MRI […] Read More »
Worst. Show. Ever.
You'll probably want to avoid this podcast. It sucks. It's filled with neurotic tales of thieving bears, decoy wallets, and epic Olive Garden rants. It's irreverent and stupid and terrible, and the hosts should really be ashamed of themselves. You can also find archives of this travesty in the "Better Off Undead" podcast, which was just as bad but also had an even stupider name.
Latest Episode
WSE55 Dave Gets an MRI
Released On: March 24, 2017
Podcast: Play in new window | Download


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Monday night's "Late Night With Seth Meyers" did not feature a musical performance. Tuesday night's "Late Night With Seth Meyers" did not feature a musical performance.
Wednesday night's episode does.
Update: Tatiana Maslany appeared on Wednesday's "Late Show With Stephen Colbert."
The Emmy winner's appearance came in support of "The Other Half," which opens in the US next month. Her …
Read More
Update: Marking her late-night television debut, Maggie Rogers took the stage on Wednesday's "Tonight Show Starring Jimmy Fallon."
She performed "Alaska" on the broadcast.
When introducing Rogers, host Jimmy Fallon …
Read More
Update: Season twelve "The Voice" coach Gwen Stefani appeared on Wednesday's "Tonight Show Starring Jimmy Fallon."
NBC has released a clip from the interview, which included a discussion about Stefani's …
Read More
The reign of Joy Villa's "I Make The Static" is over.
Villa's EP, which held the #1 spot on the US iTunes album sales chart since early Monday morning, is …
Read More
As the group's international smash "Rockabye" climbs the charts in the US, news comes that Clean Bandit will play an upcoming "Good Morning America."
The 1iota ticketing website says Clean …
Read More
The second installment of Bravo's "Imposters" narrowly outdrew the first.
According to live+same-day data posted by Showbuzz, Tuesday's episode drew a 0.22 adults 18-49 rating and averaged 661,000 viewers.
The …
Read More
Linkin Park scored some hits at its core rock radio formats in 2013 and 2014, but its last chart entry at the pop format was 2012's "Burn It Down."
Will …
Read More
"Tangled: The Series" does not begin its first season until next March, but Disney Channel is demonstrating a big commitment to the show.
The family-oriented cable network just ordered a …
Read More
The annual Red Nose Day charity event is right around the corner, and "Love Actually" fans have a special reason to be excited.
Writer-director Richard Curtis and cast members Hugh …
Read More


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BRB Burger Out at The Yards Near Nats Park
Don't go looking for a burg when the Boilermaker Shops open up at The Yards later this year– brb burger is no longer coming to the new development near Nats Park.
JDLand has the word that brb and Austin Grill Express, both Thompson Hospitality restaurants, no longer have leases at the development. We originally reported the Reston Town Center burger joint was doubling up its locations –from 1 to 2– by expanding to the new mixed-use space last June.
As for how the year-old brb burger joint is doing at the moment, well, we're not really sure. We're still waiting on word of a menu overhaul after the brb team invited us in for a taste test all the way back in January. They originally said they were looking to debut the new burgers in "the next month" but now, over five months later, we're still waiting on them to pop up on the menu.
That, combined with this latest development, leaves us thinking the state of brb is not in the tip-toppest of forms.
We have an email in to Thompson Hospitality and we'll let you know what we hear back.
Be Right Burger | Reston Town Center | 1820 Discovery Street | Reston | eatbrb.com | @eatbrb


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DOCUMENTSEXAMPLES HELP How to Navigate the web site
HELP How to Navigate the web site
Job Task Analysis is a systemic approach that identifies all the steps required to perform a task and sets standards for successful job performance. The following JTAs were developed by mine operators in partnership with MSHA. Please feel free to tailor these JTAs to your operation's specific needs, making sure to add required components, such as HAZCOM training. We would like to take this opportunity to thank the operators who helped to develop these materials.