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Abberant DNA methylation at CpG dinucleotides represents a common mechanism of transcriptional silencing in cancer. Since CpG methylation is a reversible event, tumor supressor genes that have undergone silencing through this mechanism represent promising targets for epigenetically active anti-cancer therapy. The cytosine analog 5-aza-2'-deoxycytidine (decitabine) induces genomic hypomethylation by inhibiting DNA methyltransferase, and is an example of an epigenetic agent that is thought to act by up-regulating silenced genes.
It is unclear why decitabine causes some silenced loci to re-express, while others remain inactive. By applying data-mining techniques to large-scale datasets, we attempted to elucidate the qualities of promoter regions that define susceptibility to the drug's action. Our experimental data, derived from melanoma cell strains, consist of genome-wide gene expression data before and after treatment with decitabine, as well as genome-wide data on un-treated promoter methylation status, and validation of specific genes by bisulfite sequencing.
We show that the combination of promoter CpG content and methylation level informs the ability of decitabine treatment to up-regulate gene expression. Promoters with high methylation levels and intermediate CpG content appear most susceptible to up-regulation by decitabine, whereas few of those highly methylated promoters with high CpG content are up-regulated. For promoters with low methylation levels, those with high CpG content are more likely to be up-regulated, whereas those with low CpG content are underrepresented among up-regulated genes.
Clinically, elucidating the patterns of action of decitabine could aid in predicting the likelihood of up-regulating epigenetically silenced tumor suppressor genes and others from pathways involved with tumor biology. As a first step toward an eventual translational application, we build a classifier to predict gene up-regulation based on promoter methylation and CpG content, which achieves a performance of 0.77 AUC.
Epigenetic abnormalities, including global losses and local gains in methylation, have been observed in many types of cancer, including melanoma [1-3]. It is thought that, while global hypomethylation may induce genomic instability early in cellular transformation, localized hypermethylation may promote tumorigenesis through silencing of tumor suppressor genes [4,5]. Some genomic loci are more susceptible to such hypermethylation than others, and significant progress has been made in predicting which CpG islands will be subject to methylation on the basis of sequence motifs [6,7].
A well-established relationship exists between promoter methylation and transcriptional repression [8-10]. There are two popular models for this phenomenon, the first positing that the methyl groups directly block the binding of transcription factors [11] and the second citing the role of methyl-binding proteins that recruit transcriptional repressors to the methylated sites [12,13]. Recently, Koga et al. used MeDIP combined with promoter tiling microarrays to evaluate genome-wide methylation levels and transcriptional regulation in a set of melanoma cell strains [14]. Their analysis confirmed that, for promoters containing a minimum number of CpG dinucleotides, increased methylation caused decreased expression.
Recognition of the importance of epigenetic silencing in tumor biology has led to exploration of the therapeutic potential of demethylating agents, such as the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (decitabine). The drug received FDA approval for the treatment of myelodysplastic syndrome in 2004 and is currently the subject of clinical trials exploring its utility in treating a variety of solid tumors. The ability of these agents to up-regulate the expression of aberrantly suppressed genes has been demonstrated in several studies, resulting in lists of individual candidate targets for demethylation-induced up-regulation [15-18]. Similar studies have employed RNAi for DNMT knockdown toward the same end [19]. While these efforts are providing valuable insight into the specific genes and gene pathways that may be targetable through epigenetic manipulation, it is still unclear why decitabine causes some silenced loci to become up-regulated, while others remain inactive. We therefore embarked on systematic, genome-wide studies exploring molecular characteristics of decitabine-responsive genes.
Using microarray analysis of both gene expression and promoter methylation, we sought to identify promoter characteristics that predict the likelihood of response to decitabine treatment. We began by stratifying the promoter regions on the basis of CpG content and pre-decitabine methylation level. We then tested for enrichment of up-regulated genes in each of the resulting promoter categories (i.e., different CpG content and methylation level combinations). Using logistic regression and ten-fold cross-validation, we trained and tested a classifier that predicts the likelihood of decitabine-induced up-regulation on the basis of promoter category.
Decitabine-induced up-regulation varies by promoter methylation level and CpG content
Using the melanoma methylation dataset from Koga et al. [14], combined with gene expression measurements on the same cell strains (Table 1), treated and untreated with decitabine [20], we were able to systematically investigate differential gene expression, as well as the relationship to basal methylation level and CpG content, in response to relatively low doses of the drug.
Table 1. Melanoma cell strains.
Stratifying promoters by methylation level and CpG content, we first assessed the effects of decitabine on absolute expression level as a function of un-treated level. Figure 1A shows the un-treated vs treated expression levels for promoters with low levels of methylation (top row) vs. those that are highly methylated (bottom row) across a range of promoter CpG contents (increasing from left to right). For each promoter category we use the non-parametric Wilcoxon signed-rank test to assess the likelihood that expression levels are lower before treatment than after. Figure 1B shows the -log10 of the p-values resulting from this test, demonstrating that the most significant up-regulation occurs in highly methylated genes with lower CpG content. As methylation level decreases, the likelihood of significant up-regulation occurs at progressively higher CpG content.
Figure 1. Decitabine effect as related to promoter methylation level and CpG content. Panel A. Genes are stratified by promoter CpG content (increasing from left to right) and methylation level (low methylation in top row, high methylation in bottom row). Plotting post-treatment expression level as a function of basal levels demonstrates the distribution of promoters in each bin (orange dots) in the context of all promoters (blue dots). Panel B. Summary of -log p-value from Wilcoxon signed-rank test assessing the likelihood that basal expression < post-treatment expression. The dotted line corresponds to -log10 of 0.05. The promoter category with the most significant trend toward up-regulated genes has highly methylated promoters with intermediate CpG content. As methylation level decreases, up-regulation is apparent in progressively more CpG dense promoters.
Defining decitabine-responsiveness
Defining the effect of decitabine on transcription in terms of the fold-change in expression before and after treatment (as is often done for differential expression) might be misleading, resulting in a biased definition of up-regulated genes. Genes with low basal expression require a lesser absolute increase to meet a 2-fold up-regulation threshold after treatment than do genes with high basal expression. Also, genes with very low basal expression might show a two-fold increase in response to decitabine but still have biologically insignificant amounts of gene expression. Furthermore, it is important to note that the set of genes with low basal expression values are significantly enriched for low CpG-content promoters, whereas genes with high CpG-content promoters generally have greater baseline expression levels [21]. An up-regulation threshold that favors genes with low starting expression would therefore bias the set of decitabine-responsive genes to include a greater proportion of low CpG-content promoters. Given that our initial observation suggests that promoter CpG content is an important factor in decitabine-responsiveness, we were particularly interested in addressing this bias. To do so, in addition to a 2-fold increase in expression, we require a minimum delta expression of 5,000 units in order to consider a gene up-regulated. Additional file 1 contains the list of refseq IDs for each promoter bin, as well as an indication of which are up-regulated.
Additional file 1. Genes identifiers. The file GenesByBin.txt contains refseq ID, name of the cell line, and class assignment (up-regulation by Decitabine) for each gene analyzed in the study. The file is organized by promoter category as defined in the text. The file also contains identifiers for the MCF-7 genes included in the analysis.
Format: TXT Size: 3.4MB Download file
Figure 2A shows delta expression vs. basal expression, again stratified by promoter methylation level and CpG content. Genes to the left of the diagonal and above the horizontal line are those that meet the criteria of up-regulation. In total, 2,265 genes from all genes pooled from 7 cell strains met the criteria for up-regulation. Again, we observe that certain CpG content/methylation bins are enriched for induced genes. On a gross scale, promoters with low levels of methylation (top row), have peak numbers of up-regulated genes in the more CpG-dense promoter bins. Whereas, for highly methylated promoters, more up-regulation is observed in the intermediate CpG content bins. Figure 2B summarizes the percent of up-regulated genes by bin, again demonstrating that the greatest subset of induced genes lies within the highly methylated promoters with intermediate CpG content. As methylation level decreases, the peak amount of up-regulation occurs in progressivley more CpG-dense promoter categories.
Figure 2. Defining decitabine-response by fold-change expression and delta expression. Panel A. Genes are stratified by promoter CpG content (increasing from left to right) and methylation level (low methylation in top row, high methylation in bottom row). Delta expression is plotted as a function of basal expression level. Upregulated genes are defined as those with >= 2-fold expression increase (left of diagonal line) and delta expression >= 5,000 (above horizontal line). Panel B. Percent of upregulated genes per CpG and methylation bin, with maximal up-regulation observed at high methylation and intermediate CpG content. Stars and circles indicate promoter categories with statistically significant enrichment or depletion in the number of up-regulated genes, respectively.
We next employed the hypergeometric distribution to test, for each promoter category, whether the number of up-regulated genes is significantly different than would be expected by chance. Those promoter categories significantly enriched or depleted in up-regulated genes are denoted in figure 2B with a star or a circle, respectively, and the pattern confirms our previously observed trend.
We also investigated whether gene upregulation is explained by factors other than promoter methylation and CpG density. Using the GSEA method over gene expression measurements in the YUMAC strain, we tested for Gene Ontology (GO), KEGG pathway and motif gene set enrichments among the upregulated genes. Our results show that none of the gene sets were enriched at the FDR level of 0.05, indicating that gene upregulation is not dominated by activation of a particular cellular process, or regulation by a transcription factor.
Decitabine-responsive MCF-7 genes
To investigate whether the observed trend was present in an independent cell line, we obtained publicly available data. These included expression data in response to decitabine for the MCF-7 breast cancer cell line from the BROAD connectivity map database [22], and promoter methylation data for the MCF-7 cell line [23]. We analyzed those genes with at least a 2-fold increase in expression following treatment, identifying 18 genes for which we could also obtain methylation data (see Additional file 1). Among these, three of the promoters were highly methylated, five showed intermediate levels of methylation, and ten had low methylation levels. All three of the decitabine-responsive genes with highly methylated promoters had low to intermediate CpG content. For intermediately methylated promoters, the range of CpG content shifted toward greater density. Furthermore, extremely CpG dense promoters were up-regulated only when accompanied by low basal methylation levels. Figure 3 summarizes these findings, all of which are consistent with our observations in melanoma cell strains.
Figure 3. Promoter methylation and CpG content of decitabine-responsive genes in MCF-7 cell line. Of eighteen decitabine-induced genes from the MCF-7 breast cancer cell line, three are highly methylated, five have intermediate methylation levels, and ten have low levels of methylation. Highly methylated, decitabine-responsive genes have lower promoter CpG content. With increasing levels of methylation, CpG content of responsive genes increases. For extremely CpG-dense promoters, only those with low methylation levels are up-regulated. These observations are in accord with the melanoma data.
While this independent dataset is limited in size, the overall trend is consistent with our findings and we found no evidence to contradict our hypothesis. Importantly, the MCF-7 cell lines were treated with a low dose decitabine (100 nM) that is comparable to the 200 nM used in the melanoma experiments. One caveat to the comparison is that the decitabine-response data for the MCF-7 cell line is in the form of fold-change following treatment; we can therefore not account for potential bias introduced by basal expression levels (discussed above).
Predicting decitabine response
To test whether the observed trend in promoter characteristics could be used to build a rudimentary classifier, we trained a logistic regression model to predict individual gene reponse on the basis of promoter methylation and CpG density. As the clinical goal is to induce expression of silenced tumor supressor genes, we began by taking the subset of genes with low basal expression. Using the YUMAC cell strain, which displayed the greatest absolute number of decitabine-responsive genes, we trained and tested the model using methylation and CpG content across the promoter, from 2,200 basepairs upstream to 500 basepairs downstream of the transcription start site. Figure 4 shows the average of the receiver operating curves, including error bars for 2 × standard error, using ten-fold cross-validation.
Figure 4. Predicting decitabine-responsive genes using logistic regression. Receiver operating curve for predicting decitabine response on the basis of promoter CpG content and methylation level. Models were trained and tested on the YUMAC cell line using ten-fold cross-validation. The plot shows the mean across ten runs, with 2*standard error bars. The area under the curve (AUC) is 77%, compared to 72% and 63%, respectively, for models built on promoter methylation status or CpG content alone.
We found that the combination of promoter methylation and CpG content across the entire promoter has an area under the ROC (AUC) of 77%. The predictive power is superior compared to either methylation status or CpG content alone (AUC 72% and 63%, respectively).
To investigate the impact of more localized measures of methylation, we next repeated the above analysis for each of six bins at varying distances from the transcription start site (Table 2). The classifier performance was uniform across the bins, and was lower than using the cumulative methylation and CpG density.
Table 2. Performance of predictive models of up-regulation.
To further strengthen confidence in the model, we performed 500 permutations of the class label, training and testing the model with ten-fold cross-validation each time. The mean AUC for these 500 permutations was 50.4%, as would be expected of a model with no predictive power. This analysis provides further evidence that the trend observed in promoter characteristics of up-regulated genes was not due to chance alone.
Discussion and Conclusion
The ability to re-activate genes that have been epigenetically silenced in cancer could prove a powerful adjunct to existing chemotherapeutics, yet not all methylated genes undergo up-regulation following demethylating treatment. We detect patterns of promoter characteristics that influence susceptibility to decitabine treatment in a group of melanoma cell strains.
Promoters with a high degree of methylation and an intermediate CpG content appear most susceptible to decitabine-induced up-regulation. For these highly methylated promoters, as the CpG content increases, the efficacy of the drug appears to decrease. We conclude that, in CpG-dense promoters with high levels of methylation, the large absolute number of methyl groups overwhelms the ability of the drug to demethylate sufficiently to allow increased expression.
In contrast, for genes with low levels of methylation, the drug's effects become more pronounced as CpG content increases. We theorize that, in promoters that are sufficiently CpG-dense, those with lesser levels of methylation might still contain an absolute number of methyl groups large enough to constitute a viable target for demethylation-induced expression. Silent promoters that are CpG-sparse and have low levels of methylation are likely repressed by regulatory mechanisms that are not responsive to demethylation.
In addition to examining promoter CpG content and methylation level, we have performed initial analyses (data not shown) to suggest that the presence of DNase hypersensitivity sites, reflecting an open chromatin state, also plays a role in determining a promoter's susceptibility to demethylation-induced up-regulation of expression. Further studies using chromatin structure data, as well as more refined analysis of promoter sequence features, will likely improve upon the classifier's predictive power.
In summary, we identified a trend in promoter characteristics that correlates with the likelihood of response to decitabine in a set of melanoma cell strains, and used this trend to build a computational classifier to predict response to treatment. Further study using higher resolution assessment of methylation, as well as integration with genome-wide promoter architecture data (such as DNase hypersensitivity and histone modification) is needed to decipher in more detail the regulatory forces causing gene silencing and the likelihood of up-regulating key tumor supressor genes using drugs that target DNA methylation.
Methods for cell isolation, culture, drug treatment, MeDIP, and methylation and expression-profiling were previously reported [14,20]. Briefly, methylated DNA was enriched using the MeDIP approach followed by hybridization to genomic promoter tiling arrays (NimbleGen C426-00-01) containing 390,000 probes. Standard normalization methods for two-channel arrays were applied, and relative methylation levels were determined using the MEDME bioconductor library [24]. Approximately 20-30 million cells were used for each mRNA extraction. Cells were treated with low-dose (200 nM) decitabine for two days, followed by one day recovery before total RNA extraction. Gene expression data was derived from NimbleGen human whole genome expression microarrays (array 2005_04-20_Human_60 mer_1in2) containing 380,000 probes with an average of 11 probes per refseq, located throughout the gene. Probe measurements were then averaged for each refseq. The same chip was hybridizied with differentially labeled, polyA-selected cDNA from decitabine-treated and untreated cells, experiments were repeated with dye swapping. Data was captured and processed by NimbleGen Systems Iceland LLC. Normalization within arrays was performed with Loess-based methods to correct for biases due to labeling with different dyes on the two microarray channels and to correct for spatial artifacts. As such, M and A values were determined where M describes the amount of differential expression (M = log2(cy5/cy3)) and A associates M with the magnitude of overall expression (A = (log2cy5+log2cy3)/2). Normalization between arrays was performed via quantile-based normalization. mRNA RefSeqs were mapped to the genome and those with < 96% sequence identity, as well as those that mapped to more than two genomic loci, were discarded. Analysis of the data revealed upregulation of 292 common genes across the cell lines after Decitabine treatment, and the treatment effect on demethylation was validated in selected strongly upregulated genes, such as CDKN1A and TGFBI.
For our experiments on decitabine-induced gene upregulation, we pooled information on gene promoter methylation level, CpG density, as well as differential gene expression from 7 cell strains. Data pooling yielded measurements for 22,824 promoters per cell strain, for a total of 159,768 data triplets (methylation, CpG density and differential gene expression).
For each promoter, the sequence from 2,200 basepairs upstream to 500 basepairs downstream of the transcription start site (TSS) was analyzed for CpG content, and five equal categories defined. Methylation levels for these promoters were previously reported for each of six bins spanning the same 2,700 basepairs around the TSS [14]. In order to obtain a single methylation measurement for each promoter, we used the sum of these six values and divided the results into four categories such that each bin contains roughly the same number of promoters (~40,000). Basal and decitabine-induced expression values represent the mean of two replicate experiments for each promoter. Promoters that demonstrate a two-fold increase in expression (post-treatment/pre-treatment expression >= 2) as well as an absolute expression increase of at least 5,000 units are labeled as up-regulated.
For each combination of CpG content and methylation level, the non-parametric wilcoxon signed-rank test was employed to compare post-decitabine to pre-decitabine expression levels. For this analysis we used the R stats module wilcox.test function.
For each combination of CpG content and methylation level, the significance of the difference between the observed number of up-regulated genes and the number expected by chance alone (total number in the bin multiplied by the fraction of all genes that undergo up-regulation) is calculated from the hypergeometric distribution using the R stats module dhyper function with the number up-regulated in the CpG/methylation bin, total number of up-regulated promoters, total number not up-regulated, and number in the CpG/methylation bin.
We used the GSEA program http://www.broadinstitute.org/gsea/ webcite to analyze our expression data for enriched Gene Ontology and motif gene sets. We uploaded the gct and cls files corresponding to our data from the YUMAC cell strain, and set the Metric for ranking genes to Ratio_of_Classes, and the Permutation type to gene_set. All other parameters were set to default.
Expression response data following decitabine treatment on the MCF-7 breast cancer cell line was downloaded from the BROAD Institute Connectivity Map [22]. Methylation data for the MCF-7 cell line was downloaded from the supplementary material from a study by Li et al. that used a modified methylation-specific digital karyotyping for genome-wide methylation profiling of two breast cancer cell lines [23]. Methylation levels were in the form of the number of sequencing reads per fragment. Using the 90th quantiles from the MCF-7 and melanoma datasets, the MCF-7 methylation levels were scaled so that the distribution of values between the two datasets occupied an equivalent range. MCF-7 promoters were then categorized as having either low (0-1), intermediate (1-6), or high (>6) levels of methylation.
A computational model of decitabine-response was built using the generalized linear model for logistic regression. This was implemented using the R stats module glm function with the following arguments: formula = upregulated ~promoter methylation + promoter CpG content; family = gaussian; method = glm.fit (iteratively weighted least squares). Briefly, data from the YUMAC cell line was filtered for genes with pre-treatment expression levels below 700 units (app. 40% of the data). For each promoter bin, and for the region as a whole, the model was then trained and tested using ten-fold cross-validation, receiver operating curves were generated and AUCs calculated using the ROCR package [25]. The class labels were then permuted 500 times, the model trained and tested for each permutation, and the mean AUC calculated.
Gene expression and promoter methylation data have been uploaded to GEO (Accession: GSE13706) and ArrayExpress (Accession: E-MTAB-185).
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
JCR lead the study design, carried out the computational studies, and drafted the manuscript. NT participated in the design of the study. SM provided statistical support. RH provided the experimental results. MOK conceived the study and participated in its design and coordination. All authors read and approved the final manuscript.
This work was supported by the National Library of Medicine (NIH Grant T15 LM07056, BIOMEDICAL INFORMATICS RESEARCH TRAINING AT YALE), the MD-PhD Program at Yale University (NIH MSTP TG 5T32GM07205), and the Yale SPORE in Skin Cancer (5P50CA121974). The authors are grateful to Sebastian Szpakowski for his contributions.
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Pre-publication history
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Pro Beauty provide a professional and friendly service throughout the Leeds area, using top quality products only and having great customer service and aftercare advice.
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Janesville police said a scam targeting businesses has been reported in the area.
Four separate Janesville businesses reported receiving a phone call from 608-721-8076 recently, according to a news alert. The caller identifies themselves as a representative from Alliant Energy, and tells the business that their utility bill is past due.
The caller tells the business that their utilities will be disconnected within the hour if the bill is not paid, police said. The representative suggests the business pay with a debit or prepaid Green Dot card.
Alliant Energy officials told police they are not making the calls, and citizens should never give out any personal information over the phone.
Alliant Energy customers can call 800-255-4268 if they have questions about their account.
City of Beloit crews will be starting their annual fire hydrant flushing program on July 21, according to a release.
The program, which will go through November 26, ensures the fire hydrants are in good working condition in case of emergencies, and helps flush sediment out of the distribution system, officials said.
Residents may experience discolored water, low water pressure or a disruption of service during the flushing, according to the release. Residents are urged to reduce water use and consumption while crews are flushing hydrants in the area, and to wait to do laundry until after 6 p.m.
After hydrants are flushed in the area, residents should run their cold water until the water runs clear before using it, officials said.
City of Beloit officials are reminding residents of some rules and regulations the city has for swimming pools capable of holding more than 2 feet of water.
According to a release, all outdoor swimming pools that can hold more than 2 feet of water must be surrounded by a fence that is at least 4 feet high, and owners must have a valid permit before installing the pool.
Above-ground swimming pools that are available at retailers are also subject to the requirements, officials said.
All swimming pools must also be properly disinfected, and pools deeper than 4 feet must have a throwing buoy and lifeline available, according to the release.
Residents that already have a permit and fence for their swimming pools do not need to take any action, officials said.
Anyone with questions or looking to report an unsafe pool should call 608-364-6700.
Edgerton Hospital's Healing Garden will be dedicated on June 4 from 4:30 p.m. to 6:00 p.m., at the hospital.
Organizers encouraged the community to attend the event, which will include a ribbon cutting, blessing, garden tours, light refreshments, live music by students from the Edgerton school district, fitness demonstrations and the opportunity to visit with key hospital staff.
The Healing Garden, which has been under development since the hospital's opening in 2011, is near completion and now allows access to visitors from the outside.
The Healing Garden is open to the community and aims to reduce stress, offer opportunities for wellness activities and help people feel at ease.
Officials said the garden offers accessible walking paths, water features, quiet areas for contemplation, a pavilion and a myriad of therapeutic plantings. Hiking trails are also open to the community.
The city of Beloit announced Friday that residents will now be able to get their Beloit Utilities statement online.
E-statements are available to all customers whether they currently pay using automatic payment, electronic banking, the online payment service, over the phone, in person, at the city hall drop or by mail, according to the release.
The new e-statements are part of an effort to "protect resources and become more sustainable," officials said.
The program will help the city save paper, it will make keeping customer records more efficient and help the city save money on postage, printing and mailing, according to the release. E-Statements will also eliminate delivery and receipt delays due to mailing paper bills.
City of Beloit officials want to remind residents that trash and recycling will not be collected on Thursday in observance of Thanksgiving.
Collection for the remainder of the week will be delayed by one day, according to a release.
Thursday collection will take place on Friday, and Friday collection will take place on Saturday, officials said.
The recycling center at 2351 Springbrook Ct. will be closed Saturday to accommodate staffing needs for Saturday's garbage and recycling collection, according to the release.
For more information, call the city of Beloit Public Works Operations Division at 608-364-2929.
City of Beloit officials want to remind residents that the final week of free fall curbside yard waste collection started Monday and ends Friday.
Crews will collect leaves and yard clippings on residents' regular trash days, according to a release.
Yard waste must be contained in paper yard waste bags, Back to Nature biodegradable bags or a clean trash container, officials said. Brush and limbs must be bundled or tied, and have a $1.50 sticker affixed to the bundle.
Officials suggest contacting Leaflan Compost Center at 608-364-1909 for additional recycling options.
Harry C. Pohlman Field
WISC-TV/Channel3000.com, 7025 Raymond Road, Madison, WI 53719
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Returning to Genesis » FACQ » Who were the Masoretic Scribes?
Who were the Masoretic Scribes?
Until the printing press was invented, the Bible, and all writings for that matter, had to be hand copied. The Bible was written on different types of materials, and over time they showed signs of wear and needed to be replaced. The Masoretes were a group of Jewish scribes who produced new handmade copies of the Bible. They held the Bible in high regard and understood it to be God's Word; therefore they were compelled to carefully copy the Scriptures.
The Masoretes used an intricate counting system to verify that they correctly copied the text. The Hebrew and Greek languages have letters that also equal numbers. When the scribe copied one line of text, the words actually had a numerical value. The scribe could then add the sums on the older copy and compare it with that of the newer copy to verify that they had correctly written down the text. The different translations of the Bible we have today are from the Masoretic copies.
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text:
Ohio State (12-0)
W, Michigan 42-39
next game: Bowl Game
Just sitting around waiting to see if it's USC, Michigan or Florida.
2. Michigan (11-1)
L, Ohio State 42-39
next game: Bowl Game
The Wolverines aren't going to play for the national title, but they
should be No. 2. If they're really mad about not getting a rematch, they
need to win the Rose Bowl in a blowout.
W, Notre Dame 44-24
next game:
Watch out. You heard it hear first, you'll hear it here all week; Notre
Dame was the easier of the final two games. UCLA, with its pass rush, is
a dangerous team and a tougher matchup for USC.
4. Wisconsin (11-1)
W, Buffalo 35-3
next game: Bowl Game
The Badgers finished the year as a great unknown. The Capital One Bowl
will either expose the team as a fraud or prove they were the real deal
all along.
5. Florida (11-1)
W, at Florida State 21-14
next game: Arkansas (SEC Championship)
Yes, Urban. Style does matter. It might not seem right, but Florida has
to beat Arkansas like a drum to get into the title discussion.
W, at Arkansas 31-26
next game: Bowl Game
LSU is this year's Auburn; everyone's "it" SEC team that couldn't win
its own division. The win at Arkansas might be good enough to mean the
Rose or the Orange Bowl.
7. Arkansas (10-2)
next game: Florida (SEC Championship)
It would've been interesting to have seen Arkansas actually run a
running play on the final drive against LSU instead of letting Casey
Dick throw it. The national title was never going to happen. At the end
of the day, the loss to the Tigers probably means absolutely nothing.
8. Oklahoma (10-2)
W, at Oklahoma State 27-21
next game: Nebraska (Big 12 Championship)
It D'Juan Woods' fingertips were just a big longer, Oklahoma would be
wondering, "what if?" Now it's thinking what the world would be like if
the Oregon game had been called correctly.
W, at Utah 33-31
next game: Bowl Game
Great teams make the great plays needed in rivalry games. Cougar QB John
Beck would be a slam-dunk for the Heisman had he played at a more
visible school (or, at least, he'd have given Troy Smith a big-time
Louisville (10-1)
W, at Pitt 48-24
next game: Connecticut
Somewhat quietly, Louisville bounced back from the Rutgers loss to be
Louisville again. A win against UConn and a West Virginia win over the
Scarlet Knights and Bobby Petrino's group is in the BCS.
11. Nebraska
W, Colorado 37-14
next game: Oklahoma (Big 12 Championship)
O.K. Nebraska, it's time to show that you're back at close to full
strength. Winning the Big 12 title and playing Boise State in the Fiesta
Bowl would finally prove that the Husker powers-that-be might have been
right in canning Frank Solich.
12. Texas A&M (9-3)
W, at Texas 12-7
next game: Bowl Game
Finally, finally, finally, finally, finally, Texas A&M figured out how
to win a close game. The Texas win won't be diminished if the Aggies
clunk in the bowl game, but closing out strong with a ten-win season,
and capitalizing on the current momentum, is now vital.
13. Texas (9-3)
L, Texas A&M 12-9
next game: Bowl Game
Colt McCoy didn't look quite like Colt McCoy against A&M, but that's no
excuse for a lack of a consistent running game.
14. Auburn (10-2)
W, at Alabama 22-15
next game: Bowl Game
Will Auburn prove to be an overrated dud in the bowl game or will it
show that it never played up to its potential in the regular season?
15. West Virginia (9-2)
L, South Florida 24-19
next game: Rutgers
Just when everyone started to have warm, fuzzy feelings about the
Mountaineers, pffffffft. So that's what the West Virginia offense looks
like when Pat White and Steve Slaton aren't running for 63-yard
16. Tennessee (9-3)
W, Kentucky 17-12
next game: Bowl Game
Is there a more maddening team in America? The Vols should be beating
teams like Kentucky without breaking a sweat. Just wait and see how the
athleticism shines through in the bowl game.
17. California (8-3)
L, at USC 23-9
next game: Stanford
With two weeks off after the USC loss, the Bears should be nice and
salty for a rivalry week beating of Stanford. .Anything less than a
30-point win will be a disappointment.
18. Virginia Tech (10-2)
W, Virginia 17-0
next game: Bowl Game
Xavier Adibi and Vince Hall might be the two best linebackers in America
who won't end up on any All-America teams. The defense is destroying
everything in its path.
19. Notre Dame (10-2)
L, at USC 44-24
next game: Bowl Game
Oh lord or all things fair and good, don't force us to sit through a
rematch with Michigan. The Irish vs. the SEC champion, either Arkansas
or Florida, would make for a fascinating matchup.
20. Boise State (12-0)
W, at Nevada 38-7
next game: Bowl Game
You heard it here first: Boise State isn't going to be a pushover of any
sort in the Fiesta Bowl against Oklahoma or Nebraska. The defense is too
Rutgers (10-1)
W, Syracuse 38-7
next game: at West Virginia
Call this an anticipation ranking. Rutgers is about to walk into a West
Virginia buzzsaw. However, a win would put Greg Schiano's club into the
BCS, likely the Orange Bowl in Miami, where he can start shopping for
22. Georgia Tech (9-3)
L, Georgia 15-12
next game: Wake Forest (ACC Championship)
Some day, somehow, Reggie Ball will figure out how to get the ball to
Calvin Johnson on a regular basis.
23. Wake Forest (10-2)
W, at Maryland
next game: Georgia Tech (ACC Championship)
No team in America does a better job of capitalizing on mistakes and
positive momentum. This has already been an amazing season. A win over
Georgia Tech would make it an all-timer.
24. Hawaii (10-2)
W, Purdue 42-35
next game: Oregon State
Fine, so a win over Purdue means Hawaii can basically hang with the
middle-of the-pack Big Ten teams, but it would be a whole bunch of fin
to see what Colt Brennan and the boys could do against a top team.
There's no more fun team to watch.
25.. Boston College (9-3)
L, at Miami 17-14
next game: Bowl Game
It was like Miami was waiting for BC to take the game over, and it never


text:
Vitamin E – R&B Needs Me ( #IAmBuffalo Artist Spotlight )
Every so often in the music world there is the one artist who pops up and shows you what so many others are missing, and Vitamin E is just that.
Every so often in the music world there is the one artist who pops up and shows you what so many others are missing, and Vitamin E is just that.
DJ Bandana Black takes the #IAmBuffalo Challenge after hearing that a small child within Our City may not have had a book bag to start the school year off with he immediately knew that something could be done ASAP
XO links up with 93.7FM WBLK'S @DJBandanaBlack and gives the streets exactly what they have been waiting for. At a time in Hip-Hop when everyone wants the #1 spot but very few are willing to do what it takes to take it, XO & @DJBandanaBlack have no problem with voicing why they are the ones feeding the streets right now.
At A time in Hip-Hop when most artist are so concerned with rapping about popping bottles and Foreign women (Most of which are not foreign but simply light skinned lol) it takes a true artist to be able to put what they are truly thinking into an art form that will reach and be felt by the masses.
DJ Bandana Black has just released the highly anticipated 9th installment in his #IAmBuffalo Mixtape series which is the #1 source for Local / Independent artist to be heard on a larger scale.
Now normally I don't participate in these challenges but after being called out by almost everyone I decided to donate some money and do the Ice Challenge.
After the last Cypher Saturdayz I can honestly I was proud of my City and I was wondering how they would follow up with such a great Cypher. In This Edition Hugo Hurt, PassPort Future & EastSide E show exactly why They are amongst the elite when it comes to this Hip Hop.
At a time in the Industry where very few people know how or what they should be doing to be successful Coach Hilson proves that he does. Years ago the Industry you could safely say was based off of Talent and Talent alone but we are living in a time where money matters so you have to bring more to the table than just your art.
I recently had an interview with Hugo Hurt, and during the interview, he was telling me about a dope idea he was working on to help local/indie artists out. Well, I just seen the first installment of the project, and I had to share it with all of you.
When you hear my slogan, "Life Is What YOU Make It - SO MAKE IT !!!" you can look at Hugo Hurt as a living testimony that the saying is true.
They say all things come full circle, and when it comes to Super Star Buck and DJ Bandana Black, you understand that saying so well.
At a time in the world where new art forms are born every day, Mizz Tree Tree decided to get paid for hers. Most people pay to go out to clubs to have fun and dance, but Mizz Tree Tree turned that into an actual job.


text:
ACS, a global FORTUNE 500 company with 63,000 people supporting client operations reaching more than 100 countries, provides business process outsourcing and information technology solutions to world-class commercial and government clients. The company's Class A common stock trades on the New York Stock Exchange under the symbol "ACS." Learn more about ACS at http://www.acs-inc.com.
Buck's survey report, "Understanding Your Strategies for Coping with the Changing Pharmacy Benefit Landscape," is available to the media by contacting Ed Gadowski at 201-902-2825. It is available to other interested parties for $100 from Buck's Global Survey Resources, 500 Plaza Drive, Secaucus, NJ, 07096-1533. Telephone 1-800-887-0509. It also can be ordered online at www.bucksurveys.com.
Media Relations Contacts:
Ed Gadowski
Media Relations
Buck Consultants
201-902-2825 &n
|Source: PRWeb
Copyright©2008 Vocus, Inc.
All rights reserved


text:
44.1 vs 88.2 ABX report at AES
44.1 vs 88.2 ABX report at AES
Jul 16 2010, 17:07
Post #1
ReplayGain developer
Group: Developer
Posts: 5634
Joined: 5-November 01
From: Yorkshire, UK
Member No.: 409
P18-6 Sampling Rate Discrimination: 44.1 kHz vs. 88.2 kHzAmandine Pras, Catherine Guastavino, McGill University - Montreal, Quebec, Canada
It is currently common practice for sound engineers to record digital music using high-resolution formats, and then down sample the files to 44.1 kHz for commercial release. This study aims at investigating whether listeners can perceive differences between musical files recorded at 44.1 kHz and 88.2 kHz with the same analog chain and type of AD-converter. Sixteen expert listeners were asked to compare 3 versions (44.1 kHz, 88.2 kHz, and the 88.2 kHz version down-sampled to 44.1 kHz) of 5 musical excerpts in a blind ABX task. Overall, participants were able to discriminate between files recorded at 88.2 kHz and their 44.1 kHz down-sampled version. Furthermore, for the orchestral excerpt, they were able to discriminate between files recorded at 88.2 kHz and files recorded at 44.1 kHz.
Convention Paper 8101
Was anyone at the presentation? Has anyone bought the paper?
Jul 17 2010, 23:27
Post #2
Group: Super Moderator
Posts: 10904
Joined: 1-April 04
From: Northern California
Member No.: 13167
I'm taking issue with what I thought was a blanket statement about oversampling and filtering, though in your response to benski, I did see you restated what you said which included qualifiers, which I overlooked.
As it concerns my CD player and your notion that the corner frequency of the lowpass is around 160 kHz, the smoke and fire isn't coming from my profs.
This post has been edited by greynol: Jul 18 2010, 00:50
Unless your eyes can hear, you cannot account for false negatives in sighted evaluations.
|Lo-Fi Version
|Time is now: 30th June 2015 - 00:17


text: Major League Baseball Properties and Victoria's Secret PINK are giving even more fans a chance to display their team pride on the cusp of the 2011 season. After receiving strong demand from the inaugural co-branded line in 2010, MLB and PINK are nearly doubling this exclusive assortment to now include 23 MLB teams. For the 2012 season, all 30 Clubs will be represented.


text:
|Defensive Back
|West Point, Neb.
|High School:
|West Point Central Catholic
Honors & Awards
» Five-Time Nebraska Scholar-Athlete Honor Roll
2014 (Junior)
Anthony Ridder provided depth at defensive back, but did not play in a game this season.
2013 (Sophomore)
Ridder added depth at cornerback, but did not play in a game.
2012 (Redshirt Freshman)
Ridder made the switch to defensive back and added depth, but did not play in a game.
2011 (Redshirt)
Ridder redshirted and worked on the scout team offense at quarterback.
Before Nebraska (West Point Central Catholic HS)
Ridder joined the NU program as a walk-on, following in the footsteps of his father, Dave Ridder. Anthony starred on both sides of the ball for his father at West Point Central Catholic, helping his team to the Class D-1 state title in the school's first year of eight-man competition. As a quarterback, Ridder passed for more than 1,700 yards and 38 touchdowns with just two interceptions. He also rushed for more than 800 yards and 20 touchdowns. Defensively, he led Central Catholic with 106 total tackles.
Ridder was the offensive honorary captain of the Class D-1 all-state team by both the Omaha World-Herald and the Lincoln Journal Star. Anthony had scholarship offers from Augustana and Wayne State.
Ridder was born on Nov. 7, 1992, and is the son of Dave and Terri Ridder. He is a psychology major and has been named to the Nebraska Scholar-Athlete Honor Roll five times. Ridder has volunteered his time with Uplifting Athletes, Husker Hotline, Community Action and Husker Heroes.


text:
Thomas Nelson's Summer Schedule and Holiday Closures Announced
Through Friday, Aug. 7, Thomas Nelson Community College will observe a summer schedule. The College will be closed on Monday, May 25 for Memorial Day and Friday, July 3 in observance of Independence Day. Regular operating hours for both the Hampton and Historic Triangle campuses will resume on Monday, Aug. 10. Summer service hours of operation, unless … Continue Reading ››


text:
Slow 2D performance with Xinerama
1 Attachment(s)
I am running a triple head setup with two 7900GS cards, 3D performance is lovely.
However, 2d is impossibly slow. Anti-aliased fonts take a long time to render, for example reading a 700kb java class in kate, I can hold PageDown for ~3 seconds and Xorg takes ~1 minute before it is finished with the CPU. Dragging windows leaves a long trail, etc etc.
This only happens in Xinerama. If I set up two monitors in twinview, there is no such problem and everything is fast - but I need three so that is no good.
I also get the 2D slowness problem if I have two monitors connected to the same card in Xinerama. If they are on different cards it is faster, but still slow.
Enabling or disabling composite or RenderAccel seem to have no effect.
Attached is an autogenerated nvidia bug report file for the setup with all three screens.
"Your file of 149.6 KB bytes exceeds the forum's limit of 146.9 KB for this filetype" :mad:
gzipped then...
I think this has been touched on before, but only in a dualhead context, so the answer has always been "use twinview", but that doesn't help me.. :(
So.. Any ideas? :/
Re: Slow 2D performance with Xinerama
I have an identical setup and would like to know what options I have besides Xinerama also.
Re: Slow 2D performance with Xinerama
Come on, surely someone must know? :(
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Originally written on Nationals Enquirer | Last updated 3/14/13
In other Washington Nationals spring training news, Ian Desmond revoked "cowboy" Tyler Moore's Man Card for eating corn on the cob with a knife and fork in the Nats clubhouse on Thursday. And yes, this is more important than the cuts earlier this morning that sent Eury Perez, Nathan Karns, Sandy Leon, Anthony Rendon, Pat McCoy, Will Rhymes, and Matt Skole to the minors. (Photo above via @IanDesmond20) Befriend Nats Enquirer on Facebook. Follow on Twitter.
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text:
Stock Photo:
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Morlich Lodge 17 Aviemore
from £250 /night help Price for guests, Nights
from £250 /night help Price for guests, Nights
Estimated nightly price based on a weekly stay. Excludes fees (if applicable). Enter your dates to see the total cost.
Morlich Lodge 17, Spey Valley/Dalfaber Golf & Country Club, Aviemore
Bungalow / 3 bedrooms / sleeps 8
Availability Your dates are available
Bungalow / 3 bedrooms / sleeps 8
|Key Info
Morlich 17 is situated in Aviemore within the Spey Valley/Dalfaber Golf & Country Club complex and has a wide range of activities free to residents of Morlich 17. Facilities for adults and children include childrens' club, golf course, gym, swimming pool and whirl pool, snooker, badminton, children's play area. Cosy lounge bar and steakhouse.
The Lodge sleeps 6-8 people. Detached single storey house with 3 bedrooms - one double, one twin and one king-size bedroom with en-suite bathroom. Separate bathroom with sauna. Utility room with washing machine, fridge/freezer. Open plan lounge with a double sofa bed, glazed conservatory and log burning fire. Large dining area. Well equipped kitchen with dishwasher. Porch with ski store. Up to 2 dogs are permitted at Morlich 17. Interactive tv.
Activities nearby include skiing on the Cairngorm mountains, snow sports, horse riding, mountain biking and climbing.
Local attractions include the Cairngorm mountain railway, landmark forest Heritage Park, Strathspey steam railway, Loch Ness, reindeer herd, sled dog centre, wildlife park and MALT WHISKY TRAIL!!
Aviemore is a bustling Highland town brimming with restaurants, bars, hotels and eateries. A fabulous skiing and winter sports centre. New Year celebrations have to experienced to be believed.
Electricity and logs are extras although starter pack of logs are provided on arrival - available from complex thereafter. A damage deposit of £250.00 is payable and refundable after inspection confirming no damage.
|Sleeps up to 8, 3 bedrooms
|Check in time:
|Check out time:
|Car advised
|Nearest Amenities
|500 m
|Nearest travel links
|Nearest airport: Inverness/Glasgow/Edinburgh, Nearest railway: Aviemore
|Family friendly
|Great for children of all ages
|Pets welcome, No smoking at this property
Features and Facilities
|Jacuzzi or hot tub, Sauna, Log fire, Internet access
|Shared indoor pool, Children's pool
|Central heating, TV, Telephone, Pool or snooker table, Table tennis, Games room, Wi-Fi available
|Kettle, Toaster, Iron
|Clothes dryer, Dishwasher, Cooker, Microwave, Fridge, Freezer, Washing machine
|3 bedrooms, 2 bathrooms of which 1 Family bathrooms and 1 En suites
|1 Sofa beds, Double beds (2), Single beds (2), Dining seats for 8, Lounge seats for 8
|Linen provided, Towels provided, High chair
|Shared indoor pool, Balcony or terrace, Private garden, Shared garden
|Parking, Suitable for people with restricted mobility, Wheelchair users
The Aviemore and the Cairngorms region
Spey Valley/Dalfaber Golf & Country Club is situated a short walk from the centre of Aviemore. Entering the fabulous grounds of the complex you will find the Clubhouse and Reception. There the friendly staff will give you all the help and advice you require to make your holiday perfect. You will receive your membership cards giving entrance to all the on site facilities we have mentioned earlier. There is a shuttle bus throughout the day from Aviemore to and from the ski slopes. The Cairngorm Mountains are amongst the finest in the world for skiing and winter sports and are situated within the Cairngorm National Park. Your holiday in Morlich 17 will give you a real flavour of the wonderful Scottish Highlands. Enjoy fine dining, sampling the local malt whiskies and the wonderful atmosphere that is Aviemore. Celebrate New Year with a stroll into Aviemore to enjoy the wonderful fireworks display and have a few drams!!
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Home / Store / Journals / Electronic Articles / Nuclear Technology / Volume 134 / Number 1
Andrei V. Gribok, Ibrahim K. Attieh, J. Wesley Hines, Robert E. Uhrig
Nuclear Technology
Volume 134 / Number 1 / April 2001 / Pages 3-14
Format:electronic copy (download)
Inferential sensing is a method that can be used to evaluate parameters of a physical system based on a set of measurements related to these parameters. The most common method of inferential sensing uses mathematical models to infer a parameter value from correlated sensor values. However, since inferential sensing is an inverse problem, it can produce inconsistent results due to minor perturbations in the data. This research shows that regularization can be used in inferential sensing to produce consistent results. Data from Florida Power Corporation's Crystal River nuclear power plant (NPP) are used to give an important example of monitoring NPP feedwater flow rate.
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As of 2014, Sandra Bullock primarily lives in a Beverly Hills estate that she bought in 2011 for $22.95 million. She owns another home in the Trousdale Estates area.
Sandra Bullock also owns several other properties throughout the United States. She is rumored to have bought a beach house on Tybee Island, Ga. in 2001. She bought a home in the Garden District of New Orleans in 2009. She also owns a vacation home in Jackson Hole, Wyo. In 2012, she sold her 5,663-square foot home near Austin, Texas for $2.5 million, but she still owns two restaurants in Austin, Bess Bistro and Walton's Fancy & Staple.
she just moved to valley center, ca.
Sandra Bullock lives in Hollywood,
She recently adopted a baby son, named Louis. She also was stepmom to husband Jesse James' children before he had the affairs.
Sandra Annette Bullock was born in Arlington, Virginia on July 26th, 1964. She is 5' 7.5" tall!


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Article ID: 886680 - View products that this article applies to.
This article has been archived. It is offered "as is" and will no longer be updated.
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When you try to debug a stored procedure on a remote computer that is running Microsoft SQL Server 2000, you may receive an error message that is similar to the following:
Note The word "setup" in the first sentence of this error message should be "set up."
Cannot debug stored procedures because the SQL Server database is not setup correctly or user does not have permission to execute master.sp_sdidebug. Run SQL Server setup or contact database administrator.
This problem occurs when the following conditions are true:
Hotfix informationA supported hotfix is now available from Microsoft, but it is only intended to correct the problem that is described in this article. Only apply it to systems that are experiencing this specific problem. This hotfix may receive additional testing. Therefore, if you are not severely affected by this problem, we recommend that you wait for the next Visual Studio .NET 2003 service pack that contains this hotfix.
To resolve this problem immediately, contact Microsoft Product Support Services to obtain the hotfix. For a complete list of Microsoft Product Support Services phone numbers and information about support costs, visit the following Microsoft Web site:
http://support.microsoft.com/default.aspx?scid=fh;[LN];CNTACTMSNote In special cases, charges that are ordinarily incurred for support calls may be canceled if a Microsoft Support Professional determines that a specific update will resolve your problem. The usual support costs will apply to additional support questions and issues that do not qualify for the specific update in question.
Important informationYou must install the following two hotfixes to resolve this problem:
Note Remote Transact-SQL debugging will not work without both client and the SQL Server hotfixes applied.
PrerequisitesMicrosoft Visual Studio .NET 2003
Restart requirementYou do not have to restart your computer after you apply this hotfix.
Hotfix replacement informationThis hotfix does not replace any other hotfixes.
File informationThe English version of this hotfix has the file attributes (or later file attributes) that are listed in the following table. The dates and times for these files are listed in coordinated universal time (UTC). When you view the file information, it is converted to local time. To find the difference between UTC and local time, use the Time Zone tab in the Date and Time tool in Control Panel.
Date Time Version Size File name --------------------------------------------------- 15-Oct-2004 01:27 7.10.4288.0 163,840 Sqlle.dll
Microsoft has confirmed that this is a problem in the Microsoft products that are listed in the "Applies to" section.
Steps to configure Windows FirewallWhen you use Windows Firewall, you must enable TCP port 135 (RPC port) and then add Visual Studio .NET 2003 to the list of exceptions. If you do not do this, you cannot do remote SQL debugging. To enable TCP port 135 and then open Windows Firewall for Visual Studio .NET 2003, follow these steps.
Important These steps may increase your security risk. These steps may also make your computer or your network more vulnerable to attack by malicious users or by malicious software such as viruses. We recommend the process that this article describes to enable programs to operate as they are designed to, or to implement specific program capabilities. Before you make these changes, we recommend that you evaluate the risks that are associated with implementing this process in your particular environment. If you choose to implement this process, take any appropriate additional steps to help protect your system. We recommend that you use this process only if you really require this process.
Steps to reproduce the behavior
(https://support.microsoft.com/kb/824684/ )Description of the standard terminology that is used to describe Microsoft software updates
Article ID: 886680 - Last Review: January 17, 2015 - Revision: 3.3


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- Dustin Rhodes, working as Goldust, was a surprise entrant in the 30-man Royal Rumble match as he entered at number eight.
- Santino Marella returned from a neck injury as entrant number five but was quickly eliminated by Cody Rhodes.
Wrestling news, rumors, spoilers and results. We are a leading resource for WWE, TNA and everything related to pro wrestling.
By Richard Gray
that's like the 5th time he's been a surprise entrant…amazing
I was doing something else while watching RR. I completely missed Santino's involvement altogether.


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President-elect Michelle Bachelet vowed to reduce inequality in Chile by providing free education for all after winning the biggest majority in at least 40 years in yesterday's vote.
Former Chilean President Michelle Bachelet and ruling alliance candidate Evelyn Matthei will face each other in a presidential runoff next month, pitting an advocate of higher taxes to fund education against a supporter of continuity.
One was the daughter of an Air Force official who helped lead the military junta that seized power in Chile 40 years ago today. The other's father was tortured to death by that regime.
Investigators in Chile exhumed Salvador Allende 's remains today as part of an inquiry into the former president's death in a coup d'état 37 years ago.
Former President Michelle Bachelet won a landslide victory in primary elections for Chile's opposition today, lining her up as the favorite for presidential elections in November as the ruling coalition split almost 50-50 between its two candidates.
Sebastian Pinera 's first bill as a Chilean senator 20 years ago aimed to protect the environment. He later created an island nature reserve. Now president, he may oversee approval of a $7 billion project that would flood Patagonian valleys and stretch cables across protected forests.
Chilean President Sebastian Pinera's coalition suffered a defeat in local elections yesterday with the opposition winning key municipalities just one year before presidential elections.
Chilean President Sebastian Pinera 's approval rating rose to the highest since taking office in March after his government rescued 33 miners trapped underground for more than two months, research group Adimark GfK said.
Chilean President Sebastian Pinera 's approval rating slid to 46 percent in July from 52 percent in June, according to a poll published by Adimark GfK.
Chilean President Sebastian Pinera is gaining popularity from his efforts to free 33 trapped copper miners as he asks lawmakers to limit tax increases on companies such as BHP Billiton Ltd . and Xstrata Plc .


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NC man reels in 1,062-pound marlin
Published: Thursday, August 6, 2009 at 10:48 a.m.
Last Modified: Thursday, August 6, 2009 at 10:48 a.m.
OCEAN CITY, Md. (AP) Robert Farris will have an honest big-fish story to tell.
The Charlotte, N.C., resident broke a 20-year-old Maryland record Wednesday at the White Marlin Open in Ocean City. He snagged a blue marlin that weighed 1,062 pounds.
That exceeds the previous record by more than 100 pounds.
It took Farris more than three hours to reel the fish in. The blue marlin is worth about $550,000.
The White Marlin Open is dubbed the largest billfish tournament in the world, with nearly 300 registered boats and cash prizes exceeding $2.1 million.
Farris was aboard the No Problem out of Fenwick Island, Del.
Sean Hanley of Prides Crossing, Mass., has caught the biggest white marlin so far, a 93.5-pounder. It's currently worth $860,000.
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And you're 42 so I assume it would be more difficult to change your mind on any positions you have chosen to hold onto so fiercely. If you don't see it as violence against me then that's it. I strongly disagree, but I'm not going to waste any more time trying to get you to see.May 23 2011 03:15 AM


text: 5 Great Barista Outlet 26 February 2015 Recently visited this Barista outlet. And i had a really nice experience. It was a bit crowded on Sunday but i loved it, the whole atmosphere was so energetic there. Their new sandwiches are super delicious. You MUST try them. We ordered the aromatic chicken and the vegetarian pepperoni. Both tasted amazing.The coffees are well all the same. The service is nice, staffs were friendly.And for deserts, we took the new one on the menu, the chocolate mud pie. One word for it, Heavenly! The chocolate excess cake and the black forest are equally sinful. All in all, this is my favorite barista outlet. Leaves me with happy memories. Reply Like Dislike Flag Deepika ja Reviews (5) Followers (0) Follow +


text: I have to agree with David's comments! I instigated this thread after being asked to pay £39.79 to post what is now a 3.7kg package. As I am the only UK player this is prohibitive if I need to pay this each time the portfolio comes around. I can always drop out and that is an option. Another suggestion might be that we all contribute an amount roughly equal to that which is required to ship the portfolio around the world - I already participate in one such portfolio that is managed in this way. Some people may suggest that why should they subsidise other peoples participation - an equally valid argument!


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A Rotten Deal
January 23, 2002
Steven Malanga
Much of the torrent of criticism of the health-care package just rushed into law by Gov. Pataki and Albany leaders has been procedural, focused on how the governor and Albany leaders rushed the legislation through. Critics see it as a payoff by the governor to keep union leader Dennis Rivera from wielding the power of his union in this fall's elections.
But this legislation is bad not only because of how it was negotiated, or because New York can't afford it right now. As health-care policy, the deal is all wrong for New York.
Rather than restrain New York's spiraling health-care costs, the $2.7 billion spending package will raise them further. And that will make it even more difficult for individuals and businesses in the state to afford private insurance, while simultaneously producing an ever-greater burden on the state's budget.
The deal uses public money to pay raises to private-sector health-care workers. It takes what is already the most heavily subsidized and inefficient health-care system in the country and pumps even more money into itwithout demanding anything in return from health-care workers and institutions.
Little of this is understood because health-care policy can be so complex. That's why it's possible for Rivera to defend his deal with Gov. Pataki by claiming that in doing well for his workers he's also doing good for the state. But nothing could further from the truth.
Here's what's wrong with health care in the state, and why this deal makes it worse:
When Gov. Pataki took office in 1994, the state's health-care system was already in deep trouble: An early-'80s Albany effort to control health-care costs by setting hospital prices had backfired.
The price-control system couldn't account for hospitals that performed inefficiently and were unable to get by on the same rates that other hospitals charged. To keep those lagging hospitals alive, the state let them charge more; gradually, many hospitals in the state grew inefficient because there was no incentive to act otherwise.
Prices increased, doctors kept patients hospitalized far longer in the state than elsewhere and the size of the industry grew even as it was shrinking around most of the country.
Even worse, politicians soon began fiddling with prices. Politically connected hospital executives persuaded the state to tack surcharges onto hospital and insurance bills to pay for the education of medical residents, and to help doctors and hospitals pay for medical malpractice insurance.
The result? By 1995, the bill from a hospital had so many surcharges added onto it that the total cost sometimes amounted to twice the actual charges for a procedure.
Pataki set out to reform this system by proposing to end the state price controls. He also wanted to end or reduce many of the surcharges by cutting back on subsidies to hospitals.
But the governor came under intense political pressure from Rivera and hospital executives, and so he abandoned some of his reform proposals, and kept many of the levies intactexplaining that hospitals needed subsidies for several more years to allow them to make the transition into the era of private competition.
As a result, Pataki's first reform package, which went into effect in 1996, didn't achieve much, and the state's health-care system was ill-prepared for what happened next across the rest of the country.
After a period of low inflation, U.S. health-care prices began rising rapidly in the mid- '90s, driven by the soaring cost of prescription medicine and the failure of HMOs to deliver on their promise to restrain costs. Not surprisingly, the price hikes had a deeper impact on New York's fragile health-care system.
Small businesses increasingly couldn't afford to offer insurance to their workers, and big businesses that asked workers to pay a portion of their soaring health premiums found some workers simply decided not to opt for coverage.
By the close of 1999, New York had more working people without health insurance than any other state.
At that point, Pataki had another chance at real reform, because the 1996 law was expiring. But he succumbed to another intense lobbying effort by Rivera and the hospitals, who spent $13 millionthe most ever on lobbying for a single issue in Albany.
Instead of change, Pataki simply took $9 billion in money from the federal tobacco settlement, including money that many hoped would go to help offset the state's already high health-care costs, and used it instead to further expand the state's health-care spending and to bail out inefficient hospitals that should have been cutting costs.
Meanwhile, individuals and businesses who bought their own insurance got no relief. For instance, the state continued to force anyone who buys private health-care insurance in New York City to pay $350 a year over the cost of the policy to fund medical education and retraining programs for hospital workers.
Continuing this and other surcharges virtually assured that even more working New Yorkers would wind up without health insurance in coming years.
Feeding the hospitals and Rivera's union with big subsidies didn't solve much, because the money gives the industry no incentive to act more efficiently. Soon, the hospitals and Rivera started complaining that the bailout it wasn't enough. By early 2001, Rivera was already asking for another $150 million for workers salaries. Then, after the post-Sept. 11 economic slowdown, the industry's demands escalated.
The result is the current package, in which the governor is taking money from the conversion of Empire Blue Cross and Blue Shield to a public companymoney that was supposed to go to help solve the state's health-care problemsand shoveling it to Rivera.
The deal also adds new costs onto private insurance, this time in the form of a tax on long-term carebut offers no relief to those who are already paying steep surcharges on their insurance premiums.
The ranks of the uninsured are almost certain to continue increasing as a result of the deal. As more people go without insurance, Rivera will demand more money from the state to cover them, portraying himself as their champion and thereby placing ever greater numbers of New Yorkers in ineffective and costly publicly funded health programs.
Meanwhile, the state's hospitals are increasingly becoming wards of the government. In New York City, for instance, more than half of all revenues at private hospitals come from public dollars. Small wonder that the quality of New York's once great health-care system is in decline.
Together, Rivera and Pataki are essentially socializing medicine in New York. As their deals progress, health care is becoming an ever bigger part of the state's budget, crowding out spending on education and other important issues while doing little to solve the true problems of the New York's system.
In short, there is no light at the end of the tunnel that Pataki and Rivera are digging for the Empire State.
Original Source: http://www.manhattan-institute.org/html/_nypost-a_rotten.htm
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