text:
|Home | About | Journals | Submit | Contact Us | Français
Most newborn screening (NBS) laboratories use second-tier molecular tests for cystic fibrosis (CF) using dried blood spots (DBS). The Centers for Disease Control and Prevention's NBS Quality Assurance Program offers proficiency testing (PT) in DBS for CF transmembrane conductance regulator (CFTR) gene mutation detection. Extensive molecular characterization on 76 CF patients, family members or screen positive newborns was performed for quality assurance. The coding, regulatory regions and portions of all introns were sequenced and large insertions/deletions were characterized as well as two intronic di-nucleotide microsatellites. For CF patient samples, at least two mutations were identified/verified and four specimens contained three likely CF-associated mutations. Thirty-four sequence variations in 152 chromosomes were identified, five of which were not previously reported. Twenty-seven of these variants were used to predict haplotypes from the major haplotype block defined by HapMap data that spans the promoter through intron 19. Chromosomes containing the F508del (p.Phe508del), G542X (p.Gly542X) and N1303K (p.Asn1303Lys) mutations shared a common haplotype subgroup, consistent with a common ancient European founder. Understanding the haplotype background of CF-associated mutations in the U.S. population provides a framework for future phenotype/genotype studies and will assist in determining a likely cis/trans phase of the mutations without need for parent studies.
Cystic fibrosis (CF) is a childhood-onset inherited disorder that significantly shortens the life span of affected individuals. The CF transmembrane conductance regulator (CFTR, OMIM ID: 602421) gene is located on chromosome 7 and codes for a protein that is expressed in the respiratory epithelial cells, gastrointestinal system (pancreatic and liver ductals), the vas deferens in males, mucous-secreting cervical cells in women and sweat gland ductals [1]. Defects in the CFTR gene that alter structure, function or expression of this protein can lead to malfunctions or disease processes in the lungs and upper respiratory tract, gastrointestinal tract, pancreas, liver, sweat glands and genitourinary tract [2]. CF is an autosomal recessive disorder that affects approximately 1:4000 people of Western European, North American and Australasian descent. There are over 1850 mutations in the CFTR gene, of which many have been linked to CF while others have unknown or no known consequences [3,4]. Newborn screening (NBS) for CF first became feasible in 1979 when the dried blood spot (DBS) specimens from newborn infants diagnosed with CF were shown to have elevated levels of immunoreactive trypsinogen (IRT) [5], leading to an IRT/IRT screening method [6]. After the discovery of the CFTR gene in 1989, screening expanded to include an IRT/DNA method [7,8]. Data from early screening programs prompted the Centers for Disease Control and Prevention (CDC) to recommend the inclusion CF in NBS panels [9].
CDC's Newborn Screening and Molecular Biology Branch houses the NBS Quality Assurance Program (NSQAP), co-sponsored by the Association of Public Health Laboratories (APHL), which offers proficiency testing (PT) programs for both IRT and CFTR mutation detection [10,11]. At the end of 2010, ~84% of newborns were screened for CF using the IRT/DNA screening algorithm, which was the first widespread DNA based screening assay [12]. NSQAP's CFTR mutation collection contains a wide variety of CF-causing mutations including the 23 recommended by the American College of Medical Genetics (ACMG) [13,14] providing quarterly PT challenges to 60 participating laboratories. The aims of this analysis were to verify and identify all CFTR mutations in a diverse group of CF cases and some carriers using comprehensive molecular detection methods. The results from the molecular analysis allowed the prediction of haplotypes for the identified CFTR mutations, providing a detailed molecular framework for the CFTR gene. This framework may assist in understanding why certain genotype combinations may be expressed phenotypically more than others.
NSQAP's CF Mutation Detection PT program received samples from 72 adult or adolescent CF patients or family members [11]. Four N1303K DBS specimens were provided by the California Department of Public Health NBS Program; two from patients diagnosed with CF and two from patients diagnosed with CF-related metabolic syndrome [15]. CDC's Human Research Protection Office did not consider this study to be human research as all specimens are de-identified and cannot be traced back to the donor. DNA was extracted either from three 3 mm DBS punches (Whatman Grade filter 903 paper, Kent, United Kingdom) using Qiagen's QIAamp DNA Micro kit or from 250 μl of blood using QIAamp DNA Mini kit (Valencia, California). DNA concentrations were determined by quantitative PCR of the RNase P gene (Applied Biosystems, Foster City, California) using a standard curve made from pooled human genomic DNA (Roche Applied Science, Indianapolis, Indiana).
The CFTR gene was amplified and sequenced using VariantSEQr CFTR (set RSS000010013, Applied Biosystems) with the following modifications: amplification using HotStarTaq Master Mix (Qiagen), unused primer and nucleotide removal using ExoSAP-IT (USB Corporation, Cleveland, Ohio), sequencing using BigDye Terminator (BDT) Ready Reaction kit ver 1.1 and sequencing reaction purification using Applied Biosystem's BigDye XTerminator. Since Variant SEQr kit provided incomplete coverage for exons 10, 14, 15, intronic mutation c.3717+12191C>T (3849+10kbC→T) and the 3′ UTR, and exon 1 failed to amplify, published primer sequences were used to detect exon 14 [16,17], exon 15 and the intron 22 mutation [16,17]. Primer sequences for exons 1, 10, 14 and the 3′ UTR were custom designed (Table 1). Amplification for custom designed regions used Qiagen's HotStarTaq Master Mix with 1 μM of forward and reverse primer. Cycling parameters included a 10 min denaturing step at 95 °C followed by 34–38 cycles at 95 °C for 30 s, specific primer annealing temperature for 30 s, and 72 °C for 1 min; followed by an extension at 72 °C for 8 min and an indefinite hold at 4 °C (Table 1). Unused primer and nucleotides were removed using ExoSAP-IT. Cycle sequencing reactions consisted of 1 μl of PCR product, 0.5 μl of BDT ver1.1, 1.75 μl of 5× sequencing buffer, and 3.2 pmol of primer. Sequencing reactions were purified and electrophoresed with run module BDx_Rapid-Seq36_POP7 and data was analyzed using SeqScape software from Applied Biosystems. DNA sequence was aligned with Genbank CFTR genomic reference sequence NG_016465.
The SALSA MLPA kit P091 CFTR (MRC Holland, Amsterdam, Netherlands) was performed with modifications: 5% glycerol was added to the denaturation step, which was extended from 5 to 10 min. Peak sizes were determined using the internal lane standard, LIZ500, with Applied Biosystems's GeneMapper software and imported into MRC-Holland's Coffalyser software to determine deletions and/or insertions.
Microsatellites IVS8CA and IVS17bCA were amplified in a multiplex PCR using primer sequences described previously [18] modified for capillary electrophoresis fluorescent detection on the ABI 3730 DNA Analyzer. Microsatellites were amplified with Phusion High-Fidelity Master Mix (Finnzymes, Espoo, Finland). An allelic ladder, constructed with in-house samples, was characterized by fragment analysis and sequencing. Peak sizes were determined using the internal lane standard, LIZ500, and the number of repeats was determined using the GeneMapper software (Applied Biosystems).
Analysis of microsatellite IVS17bTA was performed using previously defined primers [18] with several different polymerase enzymes (AmpliTaqGold DNA Polymerase with Gold Buffer and Buffer II (Applied Biosystems), Phusion HF and Phusion GC Master Mix (Finnzymes), Herculease II Fusion DNA Polymerase (Stratagene), EmeraldAmp Max HS PCR Master Mix (Takara) and HotStarTaq Master Mix (Qiagen)) and PCR additives (3–5% DMSO, 8% glycerol, and 1 M Betaine), however, all conditions gave a cluster of 2–5 fragments for each allele.
Linkage disequilibrium (LD) data from the International HapMap Project was examined using the HapMap Genome Browser (Phase 1, 2 and 3—merged genotypes and frequencies). An LD plot of the logarithm of the odds (LOD score) of the Human Genome Diversity Cell Line Panel (HGDP) CEPH population with HAPMAP preset defaults was used to characterize the LD between a given marker pair in this population (Fig. 1). The diamond color where two SNPs intersect indicates the level of LD; darker shades indicate a higher LD while lighter shades indicate lower LD. Gray regions represent missing data points. Haplotypes were predicted from the 34 sequence variants and two intronic microsatellites with an expectation maximization (EM) algorithm in JMP Genomics (SAS, Cary, North Carolina) using the PROC HAPLOTYPE procedure. The CFTR polymorphisms segregated into two haplotype blocks and compared to the HAPMAP LD plot. The two haplotype blocks assort independently, determined by contingency χ2, and CFTR mutations were assigned to specific predicted haplotypes through association frequency.
DNA sequence data and large deletion analysis of the CFTR gene was performed on 152 unique chromosomes from CF patient or carrier specimens to identify and verify CF-causing mutations and likely benign polymorphisms. In addition to the ACMG 23 recommended mutations, 19 other mutations are represented [11]. Supplemental Table S1 contains a complete list of mutations with HGVS standardized nomenclature. Four specimens contained three mutations (Table 2); however, in all cases, the third mutation was not common, was associated with limited clinical information in the CF mutation database, and was not part of the ACMG recommended 23 mutations. The I1027T mutation, the third mutation in two specimens, has been found in cis with the F508del mutation greater than 5% in the Brittany population (western France) [19]. A number of sequence variants (N=34) with no known consequences also were identified, and were present most often in the non-coding regions of the CFTR gene. Five of these sequence variants have not been described previously in either of the CF Mutation database or NCBI's dbSNP [4,20]. These new sequence variants are located in non-coding regions: c.1209+ 43T>G (Intron 9, ss432791813), c.1767-231T>C (Intron 13, ss432791824), c.1767-132A>G, (Intron 13, ss432791829), c.*94C>T (3′ UTR, ss432791834) and c.*1823C>T (3′ UTR, ss432791840).
The analysis of the CFTR sequence variants and mutations identified in this study was based on predicted haplotype blocks from the HGDP-CEPH population from the International HapMap project. The HapMap predicts one major haplotype block that spans the promoter through exon 22 (Fig. 1) [21]. Twenty-five sequence variants and 2 microsatellites were characterized in this major block and were used to predict haplotypes with greater than 95% probability. In four samples, 2184delA/394delTT, 3905insT/1248+1G→A, 3120+ 1G→A/−102T→A and 3120+1G→A/L467P, the predicted haplotype could not be unambiguously assigned to one of the two CF-causing mutations. The minor HapMap block spanning intron 23 through the 3′ UTR was randomly associated with the block 1 haplotypes (p=0.850) and was not informative (data not shown).
Among the 144 haplotypes assigned to a CF-causing mutation, there were 34 classes of which four contained the F508del mutation (N=63 chromosomes) (Table 3). Three F508del containing haplotypes were identical except for the number of repeats found at the IVS8CA microsatellite and the fourth was a probable product of a recombination event. The two most common F508del containing haplotypes differed only by the number of repeats of the IVS8CA microsatellite; 32 chromosomes contained 17 repeats and 29 chromosomes contained 23 repeats. The F508del haplotype that contained 23 repeats of the IVS8CA microsatellite was identical to the predicted haplotypes associated with G542X (N=6 of 6), N1303K (N=6 of 6), del Ex17a, b and 18 (N=1 of 1), and 3849+10 kb C→T (N=1 of 2).
The R117H mutation, known to be variable in its disease expression, was found in three specimens. Two had an almost identical predicted haplotype including the 5T variant, with the exception of 15 versus 16 IVS8CA repeats. The third R117H predicted haplotype contained a 7T variant and multiple differences from the other two R117H haplotypes. The haplotype containing the R117H mutation with the 7T variant was identical to the 1717-1G→A containing haplotype; however the significance is unknown since each is only found in one chromosome (Table 3). A single CF-related metabolic syndrome chromosome containing the 5T variant in the absence of R117H had a unique haplotype quite different from all other R117H containing haplotypes.
The goal of this analysis was to characterize the 72 PT specimens in NSQAP's CFTR Mutation Detection repository, which are used to assist NBS laboratories in ensuring accuracy when they utilize a molecular second tier test for CF. This comprehensive analysis resulted in the identification of 34 classes of predicted haplotypes that span the CFTR gene promoter through intron 18. These haplotypes are consistent with the LD defined by the International HapMap project. Half (N=77) of the 152 chromosomes examined shared a common haplotype subgroup which was associated with three of the most prevalent CF-causing mutations, F508del, G542X, and N1303K.
To understand CFTR mutations, a previous study assessing the origin of 27,177 CF chromosomes from 29 European countries and three North African countries described the five most common CF-causing mutations: F508del (66.8%), G542X (2.6%), N1303K (1.6%), G551D (1.5%) and W1282X (1.0%) [22]. Similarly, Bobadilla et al. described the five most common CF-causing mutations in the U.S., which included F508del (68.6%), G542X (2.4%), G551D (2.1%), W1282X (1.4%) and N1303K (1.3%) [23]. Hence, F508del, G542X, and N1303K are the more common mutations in Caucasians from Europe and the United States. A study on Spanish CF patients suggested an ancient common origin of these three mutations by showing that they all carried a common haplotype subgroup as defined by the IVS8CA, IVS17bCA and IVS17bTA microsatellites [24]. The haplotypes identified in the present study were consistent with the Spanish patient findings, showing that F508del, G542X, and N1303K again share a common haplotype subgroup [24]. Of our 62 F508del containing chromosomes (excluding the one probable recombinant), 29 predicted haplotypes are identical across 27 polymorphisms from the promoter to intron 21 to the G542X containing haplotypes (N=6) and the N1303K containing haplotypes (N=6). The remaining 33 F508del containing haplotypes are identical to this common haplotype except that they contain either 17 or 21 di-nucleotide repeats of the intron 9 IVS8CA microsatellite versus 23. Taken together, these data from a heterogeneous group of CF patients living in the United States support the existence of a common ancient European ancestral haplotype that independently gave rise to these three CF mutations.
A recent study examined the association of common CFTR gene variants and their potential influence on body composition and survival in a non-CF population in rural Ghana [25]. As expected, the LD across the CFTR gene in this Ghana population was not as strong as that seen in a population of European descent; however, they reported specific intron 11 haplotype (comprised of 4 SNPs) associations with young versus old study participants as well as with lower or higher weight in children less than 5 years old. While further studies are necessary to understand if these associations are by chance or if they have any direct influence on health, it provides further motivation to understand the molecular framework of the CFTR gene.
Molecular analysis of CF, as with many autosomal recessive disorders, is complicated by the imperfect correlation between mutations in the CFTR gene and CF phenotype [26,27]. In order to better understand the consequences of the greater than 1850 CFTR mutations, Rowntree and Harris have classified CFTR mutations into five groups, where each classification describes the mechanism by which a group of mutations disrupt CFTR function [27]. To further explain the inability to correlate phenotype and genotype in a supposedly simple "single-gene" disorder, Dipple and McCabe have proposed that there are two functional thresholds relating mutant protein function to phenotype. When protein function is below the first threshold, a severe phenotype will always be observed, whereas if protein function is above the second threshold, the phenotype will be consistently mild. Between these two thresholds, mutations will not necessarily correlate with phenotype and thus should be viewed as "complex traits" [28]. Complex traits are influenced by functional activity thresholds, modifier gene and system dynamics, thereby blurring the lines between genotype phenotype correlations [29–31]. For CF, there are numerous studies that also describe modulatory effects of different genes on the severity of phenotype in CF patients (e.g. mannose-binding lectin 2 and transforming growth factor beta 1) [27,32].
To further define the phenotypic heterogeneity in patients who have the same CF causing mutations, several molecular studies have analyzed the context of disease causing mutations. Researchers found that the phenotypic severity of a CF-causing mutation could be impacted by the genomic context of the CFTR gene as seen when R117H is in cis with the 5T variant and when S1251N is in cis with F508C [33,34]. Thus, the haplotypes defined in this study may assist newborn screeners and clinicians in predicting the cis/trans phase for mutations and poly T variants with variable expression without requiring parent studies. For example, when a newborn specimen is positive for R117H and either F508del, G542X or N1303K, and also carries both an 5T and a 9T variant, a clinician could use haplotype information to proceed with a strong probability that the 9T variant is in cis with F508del, G542X or N1310K and not R117H (Table 3). This study also shows that R117H may reside on the opposite chromosome from nearly all of the listed mutations in Table 3 because it has a different polymorphism background. Additionally, more extensive haplotype studies may allow researchers to determine what if any phenotypic effects results when a particular variant such as 5T are in cis or trans with an identified CF-causing mutation.
This study has defined 144 CFTR haplotypes associated with many CF-causing mutations, laying the groundwork for future research on the molecular structure of the CFTR gene and its potential influence on phenotypic heterogeneity in CF patients. In addition, these extensively characterized specimens will enhance the quality of the PT challenges offered by NSQAP to participating NBS laboratories.
The authors wish to thank Dr Cédric Le Marechal from Laboratoire de génétique moléculaire et d'histocompatibilité, Génétique moléculaire et génétique épidémiologique, CHU Hôpital Morvan in Brest, France for helpful comments and review. Sean Mochal was funded by the Research Participation Program at the Centers for Disease Control and Prevention (CDC), National Center for Environmental Health's Division of Laboratory Sciences, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and CDC. Dr. Philip Farrell was supported by NIH grant DK 34108. All work performed was supported by CDC.
Author disclosure: Dr. Hannon, Emeritus Chief (retired) from the Newborn Screening and Molecular Biology Branch of CDC serves on the NBS Scientific Advisory Council for Advanced Liquid Logic, Inc., Research Triangle Park, North Carolina, and the Georgia Governor's Public Health Advisory Council. Dr. Hannon also provides consulting services to National Newborn Screening and Genetic Resource Center in Austin, Texas and PerkinElmer, Inc. in Waltham, Massachusetts.
Supplementary materials related to this article can be found online at doi:10.1016/j.ymgme.2011.10.013.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


text:
I was a slave to my low self-esteem, but the gospel of freedom from sin gave me the power to ...
How am I using these opportunities?
The word "cancer" can have a very powerful effect.
The surprising truth about how difficult it is to be nice.
Doubt makes you powerless.
How God led a Group of seeking Christians to find true, living Christianity.
A man from South Africa talks about the gospel that changes his life.
Every day news headlines report the ups and downs of Wall Street and the weak job market. ...
Sometimes it can feel like there is pressure coming from all directions.
By God's help we can keep ourselves pure. I wish I knew this when I was a teenager.
I had forgotten something essential – my incredible reward.
Marina was strongly bound by fear. Read her own words about how she fought herself free.
Reproduction of material from the Brunstad Christian Church website for use elsewhere is prohibited without prior agreement. © Stiftelsen Skjulte Skatters Forlag.

subset: commoncrawl


text:
Party, Craft & School Supplies
Brainy Toys for Kids of All Ages
Get Free Shipping + $10 Off Orders $49 or more Refer Now
Your cart is currently empty.
Items remain in your shopping cart for 30 days.
Save up to 60% off Shop
Up to 60% Off Wedding Supplies Shop
Save Up to 50% Off! Ends April 6 Shop
Hersheys as low as 9¢ per piece! Shop
I Love To Read Bookmark Kit. Perfect for every little bookworm! These green bookmark kits are simple to make and feature two metal charms, an adorable bookworm with glasses and a book titled "Love To Read." These yarn bookmarks are ideal for any classroom, library craft time or as a gift to go along with book orders. 3/4" - 1 1/4" All craft kit pieces are pre-packaged for individual use. Kits include instructions and extra pieces. © OTC
Age Recommendation:
Makes 12


text:
Senlis and Troyes are about the last two towns on my list of day trips from Paris that I have wanted to do - having done practically every other possible one.
Q is - on my next trip I will have to chose one over the other and I would like input from anyone who has been to either one as to how you liked it or if you have been to both a comparison.
My impression the Troyes is a much bigger city and Senlis more like Provins, which I loved - a smaller thoroughly old-looking town. But I really have no real impression.
So Troyes or Senlis is my conundrum - guidance S V P!
Merci in advance.
Recent ActivityView all Europe activity »
- 1 30 Days in France with Family (6 y/o, 23 mo), what city to stay?
- 2 Current Paris vacation rental news...
- 3 Plitvice Lakes - is it worth it for a short visit?
- 4 December in Deutschland
- 5 If your question is "Is This Trip Crazy?"
- 6 Relaxing destinations?
- 7 Best places for 21 day family vacay w/ 5 year old?
- 8 Rome, Florence, Venice and back to Rome in 5 days...doable?
- 9 8 day outdoorsy Itinerary Help (Lake Geneva, Bernese Oberland)
- 10 Just beginning to plan trip to Croatia
- 11 Have You Ever Been Robbed in Europe?
- 12 Driving Tour - Bari to Bologna
- 13 3 Night Stopover mid September - What to see/do?
- 14 The unrequested appetizers in Portugal
- 15 Can you recommend a hotel in Paris? What about Hotel Spendide Etoile?
- 16 Rome & Florence, 10-12 days or so
- 17 Please Help! Europe in 5 days!
- 18 Suggestions for our Itinerary for June in Italy
- 19 Norway night train questions for Norway in a nutshell
- 20 First trip to London and Paris, need your comments
- 21 Scotland Highlands
- 22 Four people, three countries, two weeks
- 23 Please help with Itinerary draft for 29 days in France
- 24 Lazing it in Lisbon; Notes and Rambling Thoughts from and Extended Stay
- 25 Novice needs help with Italy itinerary
Paris Day Trip - Senlis or Troyes?
Senlis and Troyes are about the last two towns on my list of day trips from Paris that I have wanted to do - having done practically every other possible one.
Report Abuse
We've visited both - Senlis last year and Troyes about 5 years ago. Both my wife & I prefer Troyes. Beautiful architecture, interesting & unusual museums, a few streets only 3 meters wide, and a nice "square". We stayed overnight. We walked around Senlis & thought it was OK. But in Michelin terms - it is not "worth a journey" - Troyes is. We preferred Provins over Senlis.
Stu Dudley
Report Abuse
I preferred Senlis. Troyes was one of the few towns in France that I did not particularly like. Difficult to remember exactly why- but I found it lacking the charm of most Fench towns. However, rather than a day trip, we stayed in Senlis the night before we flew out of France, as it is convenient to CDG.
Report Abuse
One nice thing about Senlis is that you can also visit Chantilly on the same trip and both are easy to get to using public transportation from Paris.
I have really enjoyed my multiple trips to Provins and Senlis. I've never been to Troyes but I get the impression it is a larger town than Senlis with more to explore.
Seems like you can't go wrong with your choice!
Report Abuse
zoecat - the Chantilly angle would be great - if going by train as I do you I believe have to get off at Chantilly, have some creme Chantilly and take a bus to Senlis - an SNCF bus I believe replacing rail travel on a line on which passenger service has been withdrawn - hop my railpass works on the bus if I chose Senlis and I may try for both this time.
But I have already seen the splendid Chantilly castle and loved it - but otherwise that may have tipped it to me.
Thanks for the comments. I'm leaning to Troyes right now. I like bigger towns in general.
Report Abuse
topping for other opinions?
thanks in advance!
Report Abuse
I haven't been to Troyes yet but I recently did a couple of visits to Senlis and Chantilly. I took a lot of photos of Senlis if you want to have a look at my report:
I really liked Senlis. I found it much different than Provins even though both are medieval towns. Troyes would definitely have a lot more to do in terms of museums and such but Senlis is really nice to wander around.
Report Abuse
I haven't been to Senlis, but I liked Troyes well enough. It has a few interesting things to see and is generally a pleasant town, I don't ask for much else.
Report Abuse
If you like tools, you might choose Troyes. It has a museum of 19th century tools of the trades that preceded the industrial revolution.
Report Abuse
again thanks all for your inputs - it helped me decide to try to do both towns next trip - not on the same day to be sure!
Sign in to comment.


text:
Sign in
Switch Lights
The lights are on
PlayStation 4
Xbox One
Wii U
PlayStation 3
Xbox 360
Editor Blogs
Review Archive
The Vault
Site Help
Take Part
Newsletter Sign-up
Read Current Issue
iPad App
Contact Us
Review Archive
Cover Gallery
Final Fantasy XV
Gears of War 4
Lego Star Wars
The GI Show
Test Chamber
The Essentials
Gamer Culture
2016 Video Game Release Schedule
Apr 29 2016 03:11 PM
Sega's Shinobi Becoming A Feature Film
Apr 29 2016 03:06 PM
Did Teases For The Next Call Of Duty Just Appear In Black Ops III?
Apr 29 2016 12:50 PM
Ubisoft Addresses Cheating In The Division With A Huge Wave Of Bans And Suspensions
Apr 29 2016 12:22 PM
Firaxis Partners With Long War Studios For New XCOM 2 Mods
Apr 29 2016 12:00 PM
Vivendi Tightens Hold On Ubisoft With Additional Stock Purchase
Apr 29 2016 11:03 AM
Battlefield Reveal Will Happen On May 6
Apr 29 2016 10:35 AM
John Romero's Night Work Games Cancels Kickstarter For First-Person Shooter Blackroom
Apr 29 2016 10:02 AM
Xbox One Players Can Check Out Madden 16 At No Cost This Weekend
Apr 29 2016 09:37 AM
Rumor: Call Of Duty: Modern Warfare Remastered Comes With Campaign And Multiplayer
Apr 29 2016 09:34 AM
Blog Post:
Stan Bush Remixes The Touch With Transformers: Fall Of Cybertron Footage
Mike Futter
on December 16, 2013 at 08:30 AM
Ever since, 1986's Transformers movie, Stan Bush's The Touch has been synonymous with the conflicting feelings of Optimus Prime's death and Hot Rod's ascension to leadership. The song was featured at the end of High Moon Studios' Transformers: Fall of Cybertron, but now...
Blog Post:
Sony Rolls Out PlayStation Store Ultimate Edition Sale
Mike Futter
on May 20, 2013 at 04:28 PM
If you've made the leap to digital and are looking to expand your PlayStation 3 collection, Sony has a deal for you. Now through May 27th, you can choose from 10 games, each up to 65 percent off (75 percent for PlayStation Plus Members). Each title comes with all available DLC at a low price. The...
Blog Post:
Dinobot Destructor DLC For Transformers: Fall of Cybertron
Matthew Kato
on September 11, 2012 at 10:00 AM
Today Activision and developer High Moon Studio released new Transformers: Fall of Cybertron's DLC, which brings the Dinobots into multiplayer as well as their parts into the character creator. The Multiplayer Havoc Pack and the Dinobot Destructor Pack are now available (for $10 or 800 MS points...
Blog Post:
Dinobots Come To Fall of Cybertron's Multiplayer
Jim Reilly
on September 05, 2012 at 11:44 AM
Starting next week, Transformers: Fall of Cybertron players can access four of the Dinobots in the game's multiplayer. The Dinobot Destructor Pack download content launches on September 11 and includes Grimlock, Slug, Snarl, and Swoop. Players can select their full body and individual parts for the...
Blog Post:
Transformers: Fall of Cybertron Demo Available Now
Josh Straub
on July 31, 2012 at 12:50 PM
High Moon Studios is giving you a chance to get an early taste of their upcoming blockbuster game. Players can experience Transformers: Fall of Cybertron today when they download the free demo on XBLA and PSN. The demo includes the entire first mission, in which the player plays as Bumblebee, defending...
Blog Post:
Transformers: Fall Of Cybertron Prequel Coming To Comics
Andrew Reiner
on July 12, 2012 at 03:05 PM
San Diego Comic Con is in full swing, and High Moon Studios' Transformers: Fall of Cybertron is the talk of the show. Earlier today, we learned that the Dinobots are a part of the game's multiplayer character creation system , and the show game Hasbro the opportunity to unveil a new series of...
Blog Post:
New Transformers: Fall Of Cybertron Figures Revealed
Matt Miller
on July 12, 2012 at 03:00 PM
Comic-Con brings us a wealth of new toys that tie into the upcoming Transformers video game from High Moon Studios. We've known for some time that Hasbro was investing big in toys related to the Fall of Cybertron video game, but the San Diego Comic-Con is helping to show off just how big an investment...
Blog Post:
Week in Review: 7/6/12
Matt Helgeson
on July 06, 2012 at 06:45 PM
Life moves pretty fast. If you don't stop and look around once in a while, you could miss it. But if you do, you can always read this Week in Review column and catch up on all the big video game news you slept on. Sony Surprises Sony dominated the industry news this week. The most notable announcement...
Blog Post:
Transformers: Fall of Cybertron Gets New Release Date, Box Art & Trailer
Matthew Kato
on July 05, 2012 at 09:15 AM
So often we hear about delays in release dates, so it's great that Activision and developer High Moon Studios are bumping up the release date of Transformers: Fall of Cybertron. The game is now coming out a week earlier on August 21 for Xbox 360, PC, and PlayStation 3. To celebrate, take a look at...
Blog Post:
Transformers: Fall of Cybertron Voice Cast Revealed
Jim Reilly
on June 13, 2012 at 05:25 PM
Peter Cullen, Greg Berger, and Nolan North round out the voice cast list for Transformers: Fall of Cybertron. Peter Cullen is best known for voicing Optimus Prime in both the original animated series and recent movies. Greg Berger also voiced Grimlock in the animated series. "This is the definitive...
Blog Post:
Transformers: Fall of Cybertron Coming To PC
Jim Reilly
on June 01, 2012 at 12:18 PM
Activision announced a PC version of Transformers: Fall of Cybertron. The game is being ported by developer Mercenary Games. This version is available the same day as the console ones, August 28, 2012. It'll be available for download purchase at digital retailers soon.
Blog Post:
G1 Optimus Prime Returns As Preorder Bonus
Jim Reilly
on May 30, 2012 at 02:44 PM
Transformers: Fall of Cybertron is getting a dose of retailer-exclusive preorder content. One of the offers includes a G1 skin of Optimus Prime. The skin is available only through GameStop as part of a Retro Pack and is available in both the single-player and multiplayer. The pack also includes a G1...
Blog Post:
Transformers: Fall Of Cybertron Release Date
Jim Reilly
on March 28, 2012 at 01:34 PM
Activision has confirmed the release date for Transformers: Fall of Cybertron for this August. The game hits stores on August 28, 2012 for Xbox 360 and PlayStation 3. The release date comes in a new trailer posted on GameSpot, which you can see by clicking here . Also, if you haven't done so already...
Blog Post:
Transformers: Fall Of Cybertron: Ask The Developer
Matt Miller
on October 28, 2011 at 04:30 PM
After a full month of blowout Transformers coverage, we're set to wind down our initial batch of online stories on Transformers: Fall of Cybertron. While we'll have lots more to share about the game in the coming months leading up to launch, now's a great time to take a look at all the info...
Blog Post:
November Cover Revealed: Transformers: Fall Of Cybertron
Matt Miller
on October 06, 2011 at 11:00 AM
In 2010, High Moon Studios released War For Cybertron, finally giving Transformers fans a game worth getting excited about. Afterwards, the developer settled back and listened to what the fans wanted, going back to the drawing board to craft a new and improved follow-up. Transformers: Fall of Cybertron...
Page 1 of 1 (15 items)


text:
Finance your future with Future Finance
Many people regard getting a postgraduate degree as an investment in their future and they borrow money to achieve this goal. If you're looking for a postgraduate loan tailor-made just for you, look no further then our new funding partner Future Finance – a fantastic new alternative to a bank loan.
Tailor-made postgraduate loans from £2,500-£40,000
Affordable repayment plans
Plenty of time for repayment
No penalty early repayment options
Simple online application
Representative 10.1% APR (variable)
Future Finance is Europe's first education specialist money lender, creating finance options for both postgraduate and undergraduate students from £2,500–£40,000 with a representative 10.1% APR (variable) to bridge the gap between government loans and the actual cost of studying a university program. Launched in Ireland in May 2014, to date Future Finance has lent money to students from over 130 UK universities and is expanding on a daily basis – currently lending students over £1 million per week.
Future Finance CEO Brian Norton explains, "Future Finance was established to give students across Europe access to a tailored, affordable and transparent financing option to help bridge this funding gap."
Representative example:
A Great Alternative To A Bank Loan
With an APR of 10.1% variable – although depending on circumstances and credit ratings rates can be as low as 6% – Future Finance is much cheaper than the payday loans on the market. Plus it is also competitive with bank loans, whilst offering some unique features for students that the bank loans just don't offer. This is because the repayment terms offered by Future Finance have been uniquely created to help students. Although successful applicants are required to start making their repayments as soon as their funds are received – these monthly repayments are capped at £75 per month maximum until three months after graduation. Then, once they have graduated the students have up to ten years to repay their loan, and during this time they can take up to four payment holidays lasting up to three months each. Having such a long repayment period means that monthly instalments can be kept low, however you need to take into consideration that having longer payment terms will result in the total cost of your loan increasing. Look at the Representative example above to see what your total payment figures could be.
Work Out Your Budget
For many postgraduate students it is necessary to get additional funding to help with tuition fees and living costs while completing their postgrad programs, and Future Finance is a great option. However, before you do anything (even start your course) it's a good idea to work out your budget and expenses so you have some idea of how much money you will need for the duration of your course. In fact Julie Monaghan, a loan manager from Future Finance, thinks this is essential so you don't apply for too much or too little. She advises, "Before you apply for a loan, you should make out a budget plan for the year, to figure out how much you will be spending and what-if anything-you will need to borrow. Even if you are not taking a student loan, this is still something every student should do, just to make it easier to stay on top of your finances".
Don't Let Finance Stand In The Way Of Your Future
Future Finance is passionate about helping students fulfil their education potential and adamant that financing issues shouldn't get in the way of this. CEO Brian Norton explains, "The growing gap between the costs of education and available financing sources is still leading students to make bad choices, or in some cases, could simply exclude them from furthering their education altogether." Future Finance has developed some unique software, which is used to assess each applicant and work out his or her finance solution. By looking at what and where the applicant is studying – the focus of their loan proposal is based on affordability, to ensure that students don't get into unmanageable debt and find themselves in a situation they can't deal with. "We are really focused on affordability," says Brian Norton.
Simple Online Application
It's really easy to apply for a loan – it can be done online as long as you make sure you have the correct supporting documentation to hand: ID, proof of your postgraduate course, summary of income and passport selfie! You may find you need a guarantor's support – particularly as students often don't have a great credit score – and by having a decent guarantor in place this could actually lower your APR. Once you have applied for a Future Finance loan you will hopefully receive a no-obligation loan quote, which won't affect your credit score. So if you are concerned about financing your postgraduate education explore your options with Future Finance.
Postgrad.com is proud to have Future Finance as its finance partner. Other student funding options are available and we advise you to research all your options thoroughly before making such a commitment. Postgrad.com accepts no responsibility for your choice of loan and does not endorse or support Future Finance.
Bank Loans and Professional and Career Development Loans
Other funding options include bank loans and professional and career development loans. Bank loans for postgraduates are 'proper adult loans' so there are serious consequences if you do not keep up with repayments. You may think that a masters looks good on your CV, but it's not worth having bankruptcy on your records for it! There is no guarantee that will be able to get bank loans for postgraduate study. First you must apply for one and attempt to demonstrate to a bank that there will be a return on investment, plus your credit rating needs to make you a trustworthy borrower for them to agree to lend you the cash. However, despite all the doom and gloom, bank loans are generally a safe and good option if you are responsible about lending. You need to be able to manage your money and make sure that you can always make repayments, and if you feel confident in that, then there is no reason why you shouldn't get yourself a bank loans.
If you are over 18 and are a UK resident or have been settled in the UK for at least three years and intend to work in the UK or EU after completing your degree then a Professional and Career Development Loan might be an option for you if you need a loan for postgraduate study. Career Development Loans (CDLs) are a new type of loan being sponsored by the government and organised by Barclays Bank, The Royal Bank of Scotland and The Co-Operative Bank. The aim is to give loans that will help people advance their careers. Postgraduate degrees fall into this category, and therefore CDLs can be a perfect way to fund your study.
Pros and Cons of Career Development Loans
There are certain conditions that come with CDLs, both good and bad. On the plus side you do not need to start paying back the loan until after you complete your course, which means you will not be laden with debt while studying as the government pays for your interest as you study. The interest is also fixed so you don't have to worry about a massive jump in the cost of the loan – you always know where you stand with what you need to pay. However there is some rigidness to contend with. There are fixed percentages on what you can spend your loan on – for example, no more than 30% can be spent on your living costs. Also, the issuing of the career development loan is still subject to the bank's agreement, so if you suffer from a poor credit rating you may not qualify for the loan.
Related Editorial Links
Postgrad Solutions Study Bursaries
Related Blog Links
Government Postgraduate Student Loans Announced


text:
Ralph E. Delp, 85, Cloverdale, died on Thursday, Nov. 5, 2009 at the Richard L. Roudebush Medical Center in Indianapolis.
He was born on Oct. 12, 1924 in Vermillion County, Ill., and was the son of the late William Vernon and Ida Crisp Delp. He married Gracie Juanita Jaynes on Dec. 1, 1952, and she preceded him in death on Sept. 8, 1998.
Mr. Delp was a farmer, excavator and had been employed by the Putnam County Highway Department.
He is survived by his children, Anna Marie Delp of Brazil, Christine Ann Delp of Cloverdale, Jeanette Tiedemann and husband Dennis of Cloverdale, Janie Evelyn Kolesar and husband Joe of Brazil, David Lee Delp of Spencer, Chancey Edward Delp of Cloverdale, Mark Criss Delp of Cloverdale and Paul Robert Delp of Cloverdale; his brother, William Howard Delp of Wenatchee, Wash.; 14 grandchildren; and six great-grandchildren.
Graveside Services will be at 3 p.m. Monday at the Cloverdale Cemetery. Calling will be from 2 to 3 p.m. Monday at the Whitaker Funeral Home, Cloverdale.
Condolences may be sent to the family at firstname.lastname@example.com.


text:
US bank regulation05 Dec 2012
Take a Financial News trial today:
- Breaking industry news & commentary
- 10 year searchable archive
- FN Powerlists & Special Reports
- FN on mobile and iPad
Does your company already have an FN licence? Email us now
Senior Fed policymaker urges curbs on megabanks
US regulators should consider enacting "a set of policy measures complimentary" to the Dodd-Frank financial reform law, in order to "confine" the problem posed by so-called "too-big-to-fail" domestic banks in a "more substantial" manner than was the case in the pre-financial crisis era, Daniel Tarullo, head of bank supervision at the Federal Reserve, said on Tuesday.
In a speech at the Brookings Institution, Tarullo suggested additional capital requirements for megabanks, arguing that such a move would boost market confidence that shareholders and creditors, not taxpayers, would shoulder all losses at a failed bank.
The influential Fed policymaker also reiterated his earlier calls for capping the non-deposit liabilities of giant financial institutions, saying that banks' reliance on funding sources other than consumer deposits makes them more vulnerable in crises.
Article Tags
Other press digests in this section
Most Read
Most Emailed
How Barclays is making progress – even if the numbers aren't
Heard on the Street: The bank's restructuring is moving ahead, but investors will have to wait to see real results
From The Wall Street Journal


text:
In âFirst Moose on the Moon,â The Pottsylvania Space Program, which was started in 1961, has finally managed to launch their first rocketâ¦with Boris and Natasha inside! What are they building on the moon?! And Dudleyâs up against Snidleyâs new scheme: The Snidely Shopping Network, a TV channel that sells worthless junk. Why canât Dudley turn it off?
"Tomb Raider" Finds Its Lara Croft in "Ex Machina's" Alicia Vikander
Video Games, Film


text:
ALMS looks at the Viper's top 5 wins
The folks at the American LeMans Series are as excited as we are about the return of the Viper to the racing world and leading up to the ALMS debut of the 2013 SRT Viper GTS-R later this season; the racing league has put together a video review of the top 5 wins for the […] More »
Ram sponsors tomorrow's 2012 Kentucky Derby
Tomorrow at 6:24pm Eastern Standard Time, the 138th running of the Run for the Roses will take place as the horses take the post for the 2012 Kentucky Derby and the Chrysler Ram Truck brand is once again one of the key sponsors for horse racing's crown jewel. In addition to having the Ram Truck […] More »
Strong sales to keep Chrysler plants open this summer
Each summer, Chrysler Group plants around North American take a couple weeks off so that they can re-tool the facilities for the upcoming model year while also allowing the dealerships to sell off existing models sitting on lots but due to strong sales through the first four months of 2012 – several Chrysler Group plants […] More »
What's New This Week: Press Release Roundup
My Jaguar XJ6 had an automatic, and so did my old pickup. But all my other cars have been sticks, it fit those vehicles, but I've always preferred rowing my own gears. So it's been depressing to see standards disappearing, and even more depressing to see what a dismal percentage of populace can drive one. […] More »
Chrysler establishes new Detroit offices for CEO Marchionne
This morning the Chrysler Group announced a new move to show their support for the city of Detroit with the renaming of the old Dime Building as the new Chrysler House. The Chrysler House will soon serve as the new home of the Great Lakes Business Center and with the 70 employees who will work […] More »


text:
I have had an issue with cyrus. It stopped delivering mail to the user. After restarting mail service all started working again nicely.
Problem is all the e-mail that have not been delivered have been left in the defer and deferred queues.
Running postsuper -r ALL does not requeue them. The rest of the mail server is running fine. Just cannot get these e-mails out.
Any help would be really appreciated.
Retrieving data ...


text:
Shopify draws 100,000-plus e-retailer clients in a year
E-commerce software provider Shopify had 275,000 clients at the end of the first quarter, up from just over 162,000 a year earlier.
Shopify draws 100,000-plus e-retailer clients in a year
E-commerce software provider Shopify had 275,000 clients at the end of the first quarter, up from just over 162,000 a year earlier.
Amazon aims for more air cargo capacity with Atlas Air deal
Amazon's stake in Atlas could be as high as 30% and involve 20 Boeing Co. 767-300 cargo planes.
Sign up for IRNewsLink and get daily reports delivery to your inbox. Sign Up Now
Sponsored by 2013 Social Media 300
1 - 10 of 23 Results
In advance of Mother's Day, moms who want tangible gifts put jewelry high on their wish lists. And e-retailer Overstock.com is seeing double-digit increases this week in sales of jewelry and of home products.
Posted 05/09/2014Thad RueterPost a comment
Price-matching, special discounts and free shipping decorate Top 1000 home pages.
Posted 11/15/2013Amy DustoPost a comment
Related Content:Minimum Advertised Price Policy | Top 1000
The deal brings together two sellers of party favors.
Posted 09/17/2013Thad RueterPost a comment
Printed catalogs are not as profitable as they once were, but they can complement online marketing.
Posted 06/03/2013Kevin WoodwardPost a comment
Top 500 data show a 4.7% decrease in average monthly spend from 2011.
Posted 05/07/2013Kevin WoodwardPost a comment
E-mail and online ads fill in when a catalog is not warranted.
Posted 04/16/2013Kevin WoodwardPost a comment
New Low Price Guarantee will match prices at local stores and 19 e-retailers.
Posted 02/19/2013Bill BriggsPost a comment
E-marketers anticipate a big increase in holiday web sales, a new study says.
Posted 11/29/2012Paul DemeryPost a comment
Sears and QVC are highlighting seasonal offers.
Posted 11/09/2012Zak StamborPost a comment
It's the month before the holiday season. Do you know where your e-mail is headed?
Posted 10/01/2012Paul DemeryPost a comment


text:
This building in Sleepy Hollow NY was done up as a tire store and used as an exterior and interior prop for the Movie THE FAMILY MAN released in 2000. The snow seen in the photo is fake. Photo taken 12/1999.
Sign up to comment.
Sign in if you already did it.
Photo taken in Sleepy Hollow, NY, USA
Misplaced? Suggest new location


text:
I have found a light&dark pink capsule - apo 020 . What is it?
- Posted:
- 30 Oct 2009 by operafella
- Topics:
- heartburn relief
Answers (1)
Further Information
Search for questions
Still looking for answers? Try searching for what you seek or ask your own question.
Similar Questions
What is this pill - with 'none' imprint?
I found a dark green capsule packed with yeast-scented very fine light tan powder inside. No marks were on the capsule.
1 answer • 15 Feb 2010
What is this pill - with '' Dark red capsule with NO imprint?
I found a dark red capsule amongst my teenagers belongings. It has no markings or imprints. Is Dark red in color nad is alittle bigger than a typical ...
1 answer • 26 Aug 2010
I found a light pink pill, never seen it before, what could it be?
The pill is light pink, solid but is in capsule shape, and has no letters or number on it. It is a big pill.
1 answer • 25 Feb 2011
Pink pill with no markings/imprint?
I found a pink pill on my floor and don't know what it is. I'm concerned because my teenage niece was here recently and these are ...
1 answer • 4 Nov 2011
What is this pill - with 'OMEPRAZOLE 20mg APO' imprint?
Apo/020 marron/pink capcle united states
1 answer • 1 Mar 2013


text:
Artichoke Seeds
|Organic Chives, Garlic Herb Seed
Garlic chives are also hardy perennials. The foliage is flat rather than hollow, and grows to about twelve inches high. The flower stalks grow up to 30 inches high, topped with greenish-white flower heads which are quite showy. The mild garlic flavor of the foliage is useful in many foods.
|Siletz Tomato Seeds
Determinate. Siletz is an early red slicing tomato that is ready just before Oregon Spring. It produces 4-5" fruits that weigh about 9 ounces. These flavor packed tomatoes are perfect for slicing and are nearly seedless. Very hearty flavor. Outstanding producer in cooler weather.