Gratitude for Traditional Home, Feeling Like a Movie Star and Family ...

I am so happy to be back on my home turf after an AMAZING few days in New York City. I had so much fun with my mom and daughter in tow that it didn?t even seem like I was working.

First, I had to get my photo taken by Traditional Home in my Holiday House NYC showhouse room before it was disassembled. You may not know that the room I designed was the ?Traditional Home Room?. Traditional Home asked me to design their sponsored space which was such an honor. I?m not sure where or when these photos might show up, but I am sure they will do something great with them soon.

I also did another photo shoot with Traditional Home for something else they are working on. As soon as I know more about it, I will be sure to let you know where to look for me. It was a VERY exciting experience. I even got professional ?hair and makeup? which made me feel like a movie star, and I have to say that I LOVED what Kanesha did with both my hair and my makeup. And believe me when I say I?m not so easy to please in that department.

I have to find out what products she used on my hair and how she made my eyes look SO BIG!! Part of it was the false eyelashes. The white pencil inside the lower lid made a big difference too. But it was even more than that?maybe just the fact that she?s awesome at her job!!!

It felt really good to REALLY like the way I looked for a photoshoot for the first time in a long time, maybe ever! Being healthy and fit makes me feel much more comfortable in my skin than before.

So a BIG thanks to Beth, Maureen, Kanesha and everyone at Meredith including the photographer Brian that made me look SO great!! And thanks for taking a moment to let my little one join in the fun!!

Other than these 2 glamorous photo ops, I got to rest and relax with my mom and cutie along for the ride. We had great meals at Sant Ambrose, the Eatery on 9th Avenue, Catch, BG, Park Avenue Winter, Balthazar and Nobu 57.

This trip was honestly some of the best food I have ever eaten in New York. And so much of it fresh and healthy. Lots of beet salad, kale salad, sweet potato soup, brussels sprouts, fresh seabass and cod rounded out my menus. YUM!

And there was the gorgeous restaurant design that was quite inspiring including the cool local vibe at Eatery, the hip atmosphere at Catch, and the chic Park Avenue Winter with their newly transformed dining room from their Autumn look the day before.

Of course even when dining in fancy places, with a 7-year-old in tow you have to have some fun while waiting for your table!

And for those of you who have been following my ?get healthy? process and wondering how I can stay fit while eating all this delicious food?I am thrilled to say that I made it to the gym for a run EVERY morning while away. ?This new healthy lifestyle seems like it?s becoming a habit. ?And for a ?Type A? like me, it relieves lots of stress and adds to my patience level when traveling for days with a second grader. LOL.

What wasn?t so healthy was our trip to Dylan?s Candy Bar. But it sure was fun!! :)

Also making my trip great was some Christmas Shopping (I got 4 people crossed off my list) and seeing a few snowflakes?our first of the season. And if snow didn?t get us in the holiday spirit, ?there was the Rockettes Christmas Spectacular which put us in a festive mood.

And our trip highlight?Annie the musical, which was REALLY great! We even had a chance to meet the cast and get autographs which my daughter thought was ?way cool?.

Plus there was still time for some fun and carefree moments in Central Park in the brisk, cool, November air and Sunshine!

So, today it?s back to the grindstone (gladly) as I?ve been missing work. Yes, I love what I do, but I?ll be smiling all day thinking of the fun we had in my favorite city this week. And even though I may be counting my calories a bit more strictly through the weekend, I?ll be remembering our glorious food, wine and fun we had for weeks to come.

So our trip to New York put us perfectly in the holiday spirit just before our local Holiday Season kicked into high gear.?Thank goodness, because we got home just in time for my cutie to go on a Daddy-Daughter date last night to the Sugar Plum Ball.

Now?Tell me what?s happening in your world to kick off this holiday season and get you in the spirit. Any fun trips or events you?re willing to share? I?d love to hear about them so leave me a comment and fill me in.

Happy Travels and Happy Holidays!

P.S. Are you a Designer or MEGA Design Enthusiast? Do you want your holiday to be SPECTACULAR? Then how about winning one of 4 FREE tickets to my upcoming design camps to learn how to make your business REALLY profitable or Learn all you can about the latest in Interior Design? Enter my contest with Olioboard and Benjamin Moore and show me what you think the HOT Color Trends will be in 2013, and you could get your best Christmas present ever?tickets to Camp Tobi Fairley!! Here?s the link to enter today!

Source: http://tobifairley.com/blog/2012/gratitude-for-traditional-home-feeling-like-a-movie-star-and-family-time/

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UK blocks aid to Rwanda over Congo rebel claims

LONDON/KIGALI (Reuters) - Britain said on Friday it was withholding 21 million pounds of aid which was about to be paid to Rwanda because of "credible" reports the government in Kigali is supporting rebels in neighbouring Democratic Republic of Congo (DRC).

Britain, one of Rwanda's largest donors, is the latest Western ally to freeze aid after a United Nations report said Rwanda was behind an eight-month-old rebellion responsible for the worst fighting in eastern Congo for years.

The Kigali government said it was disappointed with the move and that blaming Rwanda for the latest bout of violence in the region might suit short-term political gains but would not end the conflict.

"This action harms Rwanda and does nothing to help the DRC," Rwanda's foreign minister Louise Mushikiwabo said.

The U.N. report accused Rwanda of coordinating the creation of the rebel movement as well as military operations - charges Rwanda has denied.

However, British International Development Secretary Justine Greening said Rwanda had breached the principles underpinning their bilateral aid relationship. She said the 21 million pounds of support due in December for the government's general budget would not be paid.

"The government has already set out its concerns over credible and compelling reports of Rwandan involvement with M23 in DRC," Greening said.

The M23 rebellion poses the biggest threat to Congolese President Joseph Kabila's leadership in years and threatens to develop into all-out war after the rebels seized the eastern city of Goma 10 days ago.

M23 commanders said this week they would vacate North Kivu's provincial capital. On Friday, however, the reluctance of some rank and file fighters to withdraw from the border city was complicating a deal brokered with regional governments.

BUDGET SUPPORT

Britain had already frozen budget support to Rwanda in July, after a U.N. interim report accused officials in Rwanda of backing M23.

The findings prompted other Western partners, including the European Union and the United States, to suspend aid to Rwanda, which relies on such support for about 40 percent of its budget.

However, Britain's former international development secretary Andrew Mitchell unblocked part of the cash in September, praising the Rwandan state for what he said were its constructive efforts to solve the conflict.

Britain is the biggest bilateral donor to Rwanda's general budget, and is the country's second largest bilateral donor of aid overall after the United States.

Britain's Department for International Development (DFID) planned to spend 75 million pounds this financial year on total bilateral aid to Rwanda and is now looking at alternatives to general budget support, for instance aid provided through sector-specific programmes or NGOs.

"Justine Greening will look at the issue of general budget support in the light of progress made by the Government of Rwanda on the partnership principles. She will consider options on how the UK can continue to help protect the poorest in Rwanda," a DFID spokesman said.

(Editing by Angus MacSwan and Greg Mahlich)

Source: http://news.yahoo.com/uk-blocks-aid-rwanda-over-congo-rebel-claims-155615232.html

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Tristan Foerster Presents ClimatePartner and Climate Change ...

Ecosummit TV: Tristan Foerster, Managing Director of ClimatePartner, talks about climate change management and explains what companies can do to protect the climate. First, companies have to measure, avoid and reduce greenhouse gas emissions. Then they can offset their residual carbon footprint which cannot be reduced any further by buying CO2 certificates in the market. In fact, we are doing it and cooperate with ClimatePartner as Ecosummit?s carbon offset partner. Together we made both ECO12 Berlin and ECO12 D?sseldorf carbon neutral. Do you know other cleantech conferences that invest in being climate neutral?

ECO12 Berlin Tristan Foerster ClimatePartner

ECO12 Jan Michael Hess Tristan Foerster Climate Neutral Ecosummit Certificate

ECO12 Berlin Tristan Foerster ClimatePartner

Tags: Carbon Offset, Cleantech, Climate Change Management, Climate Neutral, Climate Protection, ClimatePartner, ECO12 Berlin, Ecosummit TV, Smart Green Business Network, Sustainability Management, Tristan Foerster


Source: http://ecosummit.net/articles/tristan-foerster-presents-climatepartner-and-climate-change-management

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French court clears Continental of Concorde crash

9 hrs.

VERSAILLES, France -- A French appeals court on Thursday absolved Continental Airlines of blame for a 2000 Concorde crash that killed 113 people and cleared a mechanic at the U.S. airline of the charge of involuntary manslaughter.

The verdict comes over a decade after the accident helped to spell the end of the supersonic airliner. A previous court ruled that a small metal strip that fell onto the runway from a Continental aircraft just before the Concorde took off from Paris, caused the crash.

Continental was originally fined 200,000 euros and ordered to pay the Concorde's operator, Air France, a million euros in damages. Continental appealed the verdict which it described as unfair and absurd.

Welder John Taylor was cleared of a 15-month suspended prison sentence for having gone against industry norms and used titanium to forge the piece that dropped off the plane.

Continental, now part of United Continental Holdings , had been ordered under the original ruling to pay 70 percent of any damages payable to families of victims. Airbus parent EADS would have to pay the other 30 percent.

The crash sped up the demise of the droop-nosed Concorde - the fastest commercial airliner in history and a symbol of Franco-British co-operation - as safety concerns coupled with an economic downturn after 9/11 drove away its wealthy customers.

The Air France Concorde, carrying mostly German tourists bound for a Caribbean cruise, was taking off from Paris on July 25, 2000 when an engine caught fire. Trailing a plume of flames, it crashed into a hotel near Charles de Gaulle airport. All 109 passengers and four people on the ground died.

After modifications, the plane returned to service but its operators, Air France and British Airways, retired it in 2003, citing high operating costs and a drop in demand.?

Copyright 2012 Thomson Reuters. Click for restrictions.

Source: http://www.nbcnews.com/travel/french-court-clears-continental-concorde-crash-1C7325956

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November Sales Disappoint; What Happened to Black Friday's 13 ...

?Sales at stores open at least a year declined in November at major American store chains, including Macy?s, Nordstrom, Kohl?s and Target, sending a shiver through the retail world Thursday.

The reporting period included Thanksgiving and Black Friday, the official kickoff of the critical holiday shopping season. Early reports regarding those days had been mixed, and the individual retailers? dim results suggest a big challenge in the coming weeks for retailers.?

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Thomson Reuters tracks major retailers actual sales results ? not surveys ? and the most recent data was disappointing. Sales at stores open at least a year gained 1.6% increase in November. This is far below the nonsensical 13% number the?National Retail Federation (NRF) trumpets to gullible journalists. It was even below the 3.3% increase consensus of analysts.

The NYT rounds up some of the sales figures, and they are not pretty:

Kohl?s sales -5.6% (vs expectations of +1.9%)

Target -1% (vs +2.1%)

Nordstrom -1.1% (vs +4.3%)

Macy?s -0.7% (vs + 1.5%)

There were a few winners:

Costco +6%

Limited? +5%

Gap +3%

We won?t get the final holiday sales figures til January, but you can be pretty comfortable with the premise that there will not be an increase of 13% of retail sales this holiday season.

The lesson here is pretty stark. Be very aware of what you accept as a data source. Understand the differences between hard numbers ? i.e., sales receipts ? and squishy emotional guesses produced by surveying consumers.

The bottom line:? The NRF is an industry shill group that produces nonsensical spin that misleads investors, fools the public, and bamboozles incompetent journalists. Any writer who uncritically reprints their nonsense deserves to be fired; any media outlets that publishes their junk should be put quarantined and put on your DO NOT READ list.

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Previously:

Black Friday Skepticism (Finally!) Goes Mainstream (November 23rd, 2012)

Black Friday?s Media Hall of Shame (November 28, 2012)

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Source:
Sales at Nation?s Retailers Fell Short of Expectations in November
STEPHANIE CLIFFORD
NYT, November 29, 2012
http://www.nytimes.com/2012/11/30/business/sales-at-nations-retailers-fall-sh...

Source: http://www.ritholtz.com/blog/2012/11/november-sales-disappoint-what-happened-to-black-fridays-13/

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Exome Analysis Pipeline for Rare Variant Calling, Prioritization and ...

Group-8: Artika Nath, Piyush Ranjan, Angela Pena and Monica Rojas

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Pipeline

Screen Shot 2012-11-29 at 6.04.06 PM

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A: Selecting the Exome Sequence from 1000 Genomes Project

The exome sequence selected, from the 1000 Genomes Project,?for exome analysis and variant calling was HG01112 corresponding to Colombian nationality. Following are the bam and bai files representing the exome:

HG01112.mapped.ILLUMINA.bwa.CLM.exome.20111114.bam

HG01112.mapped.ILLUMINA.bwa.CLM.exome.20111114.bam.bai

The reference genome used for this exome analysis project was 1000 Genomes project phase II reference genome hs37d5.fa.gz which is integrated reference sequence from the GRCh37 primary assembly (chromosomal plus unlocalized and unplaced contigs).

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B: Variant Calling Using different Tools Calling variants?

(i)????? Generating BCF fies

We used SAMtools?mpileup to call the variants which were initially put into BCF files.

Command:?samtools mpileup -ugf hs37d5.fa HG01112.mapped.ILLUMINA.bwa.CLM.exome.20111114.bam | bcftools view -bvcg ? > HG01112.bcf

(ii)??? Generating VCF files

BCF file was converted to VCF file using bcftools in the SAMtools package

Command:?bcftools view HG01112.bcf?| vcfutils.pl varFilter -D 100 > HG01112.vcf

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C: Annotating and Filtering the Variants using Different Tools

(i) VAT: Variant Annotation Tool (Habegger et al. 2012) which is designed as computational framework to functionally annotate variants in the exome using a cloud-computing environment. VAT uses GENCODE which is part of the ENCODE project to annotate the variants.

Filters were placed based on selecting only non synonymous and premature stops.

Command:?cat HG01112.vcf | snpMapper ../VAT/gencode7.interval ../VAT/gencode7.fa > HG01112_annotated.vcf

(ii) ANNOVAR:?Functional annotation of genetic variants from high-throughput sequencing data (Wang et al. 2010).?ANNOVAR tool annotates single nucleotide variants and indels, it also looks for finding variants on conserved regions and identifying variants which have been identified and reported in the 1000 Genomes Project and dbSNP.

Filtering using ANNOVAR was done as shown in the table below:

Annovar filtering

(iii) GATK for variant filtration:?After you run two or more variant annotation/analysis programs, each of which outputs a vcf file, you have to combine them into a single vcf file. This task was done using GATK combine variants utility:

http://www.broadinstitute.org/gatk/gatkdocs/org_broadinstitute_sting_gatk_wal...

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Top 20 Pathogenic Variants:

Untitled

D: Analysis of Pathogenic variants

We analyzed four variants in-depth.

selected_genes

We looked for evidence for or against pathogenicity, including conservation, 3-D structure, experimental data (from GWAS or case-control studies, experiments with mouse models), clinical data (if available), population data (frequency of variant in different populations.? For this purpose, we retrieved information from several GWAS databases described below:

(i) dbGaP:?dbGaP is the database of Genotypes and Phenotypes. It was developed to archive and distribute the results of studies that have investigated the interaction of genotype and phenotype. Such studies include genome-wide association studies (GWAS), medical sequencing, molecular diagnostic assays, as well as association between genotype and non-clinical traits. It is available at: http://www.ncbi.nlm.nih.gov/gap

(ii) A Catalog of Published Genome-Wide Association Studies:?This is an online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs). It is available at http://www.genome.gov/gwastudies/

(iii) GWAS Central:?GWAS Central (previously the Human Genome Variation database of Genotype-to-Phenotype information) is a database of summary level findings from genetic association studies, both large and small. It is available at https://www.gwascentral.org/index

(iv) Gen2Phen (G2P):?G2P is a knowledge Centre that host the results obtained from the GEN2PHEN project. The GEN2PHEN project aims to unify human and model organism genetic variation databases towards increasingly holistic views into Genotype-To-Phenotype (G2P) data, and to link this system into other biomedical knowledge sources via genome browser functionality.?It is available at http://www.gen2phen.org/

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E: Functional Characterization of Variants

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1. CTNND2:

Function: Gene encodes an adhesive junction protein called delta-catenin which is implicated in brain and eye development.

Conservation: The CTNND2 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken,??? zebrafish, fruit fly, and mosquito. The conserved regions are ICP4 whichhas two broad?transcriptional?regulatory domains and armadillo/beta-catenin-like repeats (an approximately 40 amino acid long tandemly repeated sequence)

Pathogenicity: CTNND2 is located on the short arm of chromosome 5 which is the critical regions for autism spectrum disorder (Harvard et al., 2005), mental/neurological disorders (Medina et al. 2000)and Cri du Chat syndrome.

Heterzygous deletion of short arm of chromosome 5 where CTNND2 is located has been found in Cri-du-Chat syndrome (Medina et al., 2000).

GWAS studies in Chinese populations showed that SNPs (rs6885224 and rs12716080) in the non coding region of CTNND2 which is located inside the linkage interval of MYP16 is strongly associated with high myopia (cause of visual impairment) (Li et al., 2011; Lu et al., 2011). However, minor allele C present at rs6885224 was shown to protect against myopia in the Lu et al study but was associated with risk for myopia in Li et al study.

In addition, a rare copy number variant as disrupts the CTNND2 a result of duplication which has been associated with schizophrenia. (Vrijenhoek et al., 2008)

Overexpression of CTNND2 has been seen in prostate tumors (Bertucci et al, 2006) and breast tumors (Lu et al., 209)

References

Medina?M,? Marinescu?RC,? Overhauser?J,? Kosik?KS. (2000) .?Hemizygosity of delta-catenin (CTNND2) is associated with severe mental retardation in Cri-du-Chat syndrome.?Genomics; ?63:157?164.

Bertucci?F,?Finetti?P,?Cervera?N,?et al. (2006).?Gene expression profiling shows medullary breast cancer is a subgroup of basal breast cancers.?Cancer Res; 66:4636?4644.

Lu?Q,? Zhang?J,?Allison?R,? et al. (2009) ?Identification of extracellular delta-catenin accumulation for prostate cancer detection.?Prostate; 69:411?418.

Vrijenhoek T, ?Buizer-Voskamp JE, ?Stelt I et al. (2008) Recurrent CNVs Disrupt Three Candidate Genes in Schizophrenia Patients. Am J Hum Genet; 83(4): 504?510.

Harvard C, Malenfant P, Koochek M, Creighton S, Mickelson EC, Holden JJ, Lewis ME et al. (2005)? A variant Cri du Chat phenotype and autism spectrum disorder in a subject with de novo cryptic microdeletions involving 5p15.2 and 3p24.3-25 detected using whole genomic array CGH.?Clin. Genet.?;67:341?351.

Medina M, Marinescu RC, Overhauser J, Kosik KS. et al. (2000) Hemizygosity of delta-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome.?Genomics; 63:157?164

Lu B,?Jiang D,?Wang P,?Gao Y,?et al.2011. Replication study supports CTNND2 as a susceptibility gene for high myopia. Invest Ophthalmol Vis Sci.;52:8258-8261.

Li YJ, Goh L, Khor CC, et al. (2011) Genome-wide association studies reveal genetic variants in CTNND2 for high myopia in Singapore.?Chinese. Ophthalmology;118:368?375.

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2. GOLGA8B:

Function: Gene encodes for a protein Golgin A8 family, member B that belong to the family of Golgins.?Golgins constitute a family of proteins that are localized to the Golgi apparatus and their?main function is the glycosylation and transport of proteins and lipids in the secretory?pathway.

Conservation: The GOLGA8B gene is conserved in Mouse, Dog, and Elephant.

Pathogenicity: GOLGA8B is located on the complementary strain in large arm of chromosome 15 and it contains 14 exons. Its size is 58.29kb (NC_000015.9) and encodes for a protein of 603 a.a in length (NP_001018861.3). There are more than 50 variations reported for this gene, most of them located in the Exon 14.? Evidence from a GWAS study suggests that variations in the gene GOLGA8B may be related with susceptibility to develop myopia and eye refractive errors in human populations (Solouki et al. 2010).

GWAS Report: Solouki and collaborators published in 2010 a paper entitled ?A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14? In this study a cohort of 5,328 individual from a Dutch population were screened. Researcher found a significant association (p-value: 2.21?10-14) between eye refractive errors and a locus in the chromosome 15q14 (rs634990).? The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16-1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42-2.36) for individuals homozygous for the allele. An interesting observation derived from this study is that this chromosome position is located near to genes that are expressed in the retina (GJD2 and ACTC1) and it appears to harbor regulatory elements that may be involved in the transcription of these genes.? The main conclusion in this study was that common variants at 15q14 might influence susceptibility for refractive errors in the general population. GOLGA8B is precisely located in this locus and it contains more than 50 SNPs described to date. However the variation that we are reporting is a new one in the exon 3 of the gene.

References

1. Solouki et al. A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14. 2010. NATURE GENETICS, 42(10): 897-903.

2. G.A.Thorisson, O.Lancaster, R.C.Free, R.K.Hastings, P.Sarmah, D.Dash, S.K.Brahmachari, A.J.Brookes.?HGVbaseG2P: a central genetic association database.?2009. Nucleic Acids Research, 37:D797-802

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3. PWWP2A:

Function: Gene encodes for a protein 2A containing a PWWP domain. According with the Conserved Domain Database (CDD) for the functional annotation of proteins the PWWP domain, named for a conserved Pro-Trp-Trp-Pro motif, is a small domain consisting of 100-150 amino acids, which is found in numerous proteins that are involved in cell division, growth and differentiation. Most PWWP-domain proteins seem to be nuclear, often DNA-binding, proteins that function as transcription factors regulating a variety of developmental processes.?For example, the PWWP domain is essential in DNA methyltransferase 3 B (Dnmt3b) that is responsible for establishing DNA methylation patterns during embryogenesis and gametogenesis. In tumorigenesis, DNA methylation by Dnmt3b is known to play a role in the inactivation of tumor suppressor genes. In addition, a point mutation in the PWWP domain of Dnmt3b has been identified in patients with ICF syndrome (immunodeficiency, centromeric instability, and facial anomalies), a rare autosomal recessive disorder characterized by hypomethylation of classical satellite DNA.

Conservation: The PWWP2A gene is conserved in chimpanzee, Rhesus monkey, dog, mouse, rat,?chicken, and zebrafish.

Pathogenicity: PWWP2A gene is located on the complementary strain of the ?q? arm in chromosome 5 and it contains 4 exons. It has been identified three transcript variants that produces three isoform of the protein: a, b and c. There is not experimental evidence for direct association between the gene and any diseases.

GWAS Report:? According with the Catalog of Published Genome-Wide Association Studies Available at: www.genome.gov/gwastudies two variations located in the intergenic region between PWWP2A and FABP6 has been (rs2546371 and rs4921110) associated with Waist-Hip ratio trait (the waist circumference measurement divided by the hip circumference measurement), both of them have the same significant p-value: 8.645?10-5. For both men and women, a waist-to-hip ratio (WHR) of 1.0 or higher is considered ?at risk? for undesirable health consequences, such as heart disease and ailments associated with OVERWEIGHT. Variation identified may be part of regulatory sequences that control the expression of PWWP2A and FABP6.

Picture1

Reference

1. Hindorff LA, MacArthur J (European Bioinformatics Institute), Morales J (European Bioinformatics Institute), Junkins HA, Hall PN, Klemm AK, and Manolio TA. A Catalog of Published Genome-Wide Association Studies. Available at: www.genome.gov/gwastudies. Accessed [Nov 25, 2012].

4. AGXT:

Function: Gene encodes for an enzyme alanine-glyoxylate aminotransferase (AGXT), which is a hepatic enzyme that converts glyoxylate to glycine. This gene is located in the large arm of the chromosome 2 (2q37.3) and it is expressed only in the liver.? The encoded protein is functionally active in the peroxisomes, where it is involved in glyoxylate detoxification. Mutations in this gene, some of which alter subcellular targetting, have been associated with type I primary hyperoxaluria.

Conservation: The AGXT gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat,?chicken, zebrafish, fruit fly, mosquito, C.elegans, S.cerevisiae, K.lactis, M.oryzae,?N.crassa, A.thaliana, and rice.

Pathogenicity: Mutations in this gene, some of which alter subcellular targeting, have been associated with type I primary hyperoxaluria (PH1). Absence of AGT activity results in conversion of glyoxylate to oxalate, which is not capable of being degraded. Excess oxalate is excreted in the urine, causing kidney stones (urolithiasis), nephrocalcinosis, and kidney failure. As kidney function declines, blood levels of oxalate increase markedly, and oxalate combines with calcium to form calcium oxalate deposits in the kidney, eyes, heart, bones, and other organs, resulting in systemic disease. Pyridoxine (vitamin B6), a cofactor of AGT, is effective in reducing urine oxalate excretion in some PH1 patients.

GWAS Report:? According with the GWAS Central?available at: http://www.gwascentral.org/study/HGVST634 variations in the gene AGXT has been associated with human body height. A GWAS study performed by Lango et al. i2010 involving 183,727 individuals showed that that hundreds of genetic variants, in at least 180 loci influence adult height, a highly heritable and classic polygenic trait. Variations in the gene AGXT made part of the set of loci that were identified to explain adult height trait. ?Four variations were significantly observed in this study: rs12695032 (-log p= 3.47), rs5013752 (-log p= 3.19), rs4426527 (-log p= 3.25) and rs4344931 (-log p= 4.22).

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References

1. Lango Allen et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. 2010. Nature 14; 467(7317): 832?838. doi:10.1038/nature09410.

2. Hindorffa L.A., Sethupathyb P., Junkinsa H.A., Ramosa E.M., Mehtac J.P., Collins F.S., and Teri A. Manolio. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. 2009. PNAS 106 (23): 9362?9367.

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F. Structural Characterization of Variants

We structurally characterized two of the genes containing variants with high likelihood of being pathogenic. These genes were AGXT and GOLGA8B.

Protein Structure Prediction was done by threading using an online server side program called RaptorX (http://raptorx.uchicago.edu) . The modeled protein was visualized using VMD and the active-site prediction was carried out using DoGSiteScorer (http://dogsite.zbh.uni-hamburg.de)

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1. AGXT

Screen Shot 2012-11-29 at 5.39.44 PM

Figure 1. The predicted protein structure of AGXT (enzyme alanine-glyoxylate aminotransferase) showing the hypothesized catalytic site and the amino acid chain where the substitution occurs as a result of the variant Cytosine to Thymine at position 32 of the nucleotide sequence and Proline to Leucine at position 11 in the amino acid sequence.

Screen Shot 2012-11-29 at 5.35.56 PM

Figure 2.?Comparative analysis of the catalytic domain of the modeled protein AGXT (B), with template (A) demonstrating known active site. The C to T variant in AGXT sequence changes proline (polar) to leucine (aliphatic amino acid) in the vicinity of the catalytic domain, which could affect the enzymatic function of the protein, which is mainly involved in the glyoxylate metabolic pathway in hepatic cells. The template (A) shows experimental ligands bound to a very huge active site (white arrows) suggesting catalytic domain may also function in protein-protein interaction.

2. GOLGA8B

Screen Shot 2012-11-29 at 5.58.16 PM

Figure 3. The predicted threading protein model for GOLGA8B fragment (containing mutation), a Golgin A8 family member. GOLGA8B has the variant C to T at 178 nucleotide position leading to a change from arginine (polar) to threonine (uncharged) (white arrows). The mutation is included in the predicted active site (4th rank cluster) suggesting change in possible catalytic interactions.

Source: http://gtbinf.wordpress.com/2012/11/30/exome-analysis-pipeline-for-rare-variant-calling-prioritization-and-disease-association-in-exome-of-an-individual-from-colombian-descent/

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