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Also, in the past 25 years, hayman has been advising women How to look their best from the movie stars who frequented giorgio, the highpowered boutique she and exhusband fred hayman owned in beverly hills, to the latenight tv habitues who buy her cosmetics line in its signature leopardprint cases on qvc.Now, she has put the wisdom of her whole professional life in a new book for called"How?Guide to inner and outer beauty:From cosmetics to confidence. " Hayman, who is now married to geneticist and exharvard professor, was recently in san francisco, feted by her old pal from hollywood days, at a luncheon at stars.She is two years shy of 50 and still has that delicate, deerlike quality to her face and body that most dancers retain big eyes, long hair and legs to die for. Clad in a khaki chanel military suit, ralph lauren polo sale she dispensed some wellchosen tips to the assembled types: Get rid of puffy eyes with two cooled lipton tea bags. Learn to collect the classics like a great polo shirt, cotton turtlenecks, a classic navy crewneck sweater, a big wool or cashmere shawl, oversized men's cardigans or jackets with the sleeves rolled home page up. Use a gutted grapefruit as an organic(And cheap)Facial exfoliant. Spend money on:Handbags, blazers, shoes, suits, coats and jewelry. Skimp on:Summer clothes, weekend casual clothes(You don't need to make a"Designer fuss,"She says);Scarves;Stockings(She likes l'eggs);Socks, underwear and watches(Look for great copies). "Women all over the world have the same questions,"She tells me a few weeks later over the phone from new york.Women of leisure and working women?Really? "Absolutely really,"She says. "That's why i did this book.It is quite basic and answers the questions everybody asks:What should i wear?What goes with what?What colors look good on me?I bought this lipstick and it's the wrong color.Now what? " In very simple prose with helpful illustrations, hayman confirms the axioms that classic and practical rule and the stuff that you see flouncing its way down the couture runways is pure pr and fluff. "Most of that stuff doesn't get made at all,"She says. "It's for the press and tv.Nobody wears it. " One of the more practical things about hayman is that, even though she has sold thousands of dollars' worth of highfashion clothing to hollywood's most stunning women, she likes nothing more than a bargain or recycling her own clothing.She calls the latter:Shopping your closet.Her cardinal rules:Be ruthless, discerning and honest. "You have to be practical.You owe it to yourself to look your best and you deserve it.Let your fulllength mirror be your best critic,"She goes on. "Decide what will work and what will not work.You may have things that don't work now like a tweed suit that never looked good on you because the skirt made you feel too fat.But the jacket is great.So, put that in the"Salvage' pile and find something new that will go with it like a great black gab skirt. " Shopping your closet involves three separate piles, hayman says:The alterations box;The"I can wear this if only I hadTheright thing to go with it" andThehopeless box, she laughs. "That'sTheone that goes byebye. " When hayman divorced fred hayman and left the giorgio empire(She is the fragrance"Nose,"Who invented the effusive giorgio fragrance), she took her Hollywood wife clothes with her.Most of them she gave away to museums(They were, after all, couture);The classic halstons are in her attic and the others she recycled for her current life as the working wife of a famous scientist.Shuttle, going back and forth from the haseltine home in georgetown to their apartment in manhattan.But they are never apart more than two nights.A vow, she says, they made when they married nearly 9 years ago. Hayman's own style must conform to three separate lives.The first is the new york cosmetics magnate(She sells on qvc, sears and through her tollfree number, 1800forgale)Where her uniforms are usually chic suits or khaki pants, white shirts, a ralph lauren navy crew neck and jp todd loafers.The second, washington wife and hostess. 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The shoes of sex and the city (At least until season 5 when she is given a book offer. )Indeed, many of the people around her comment that she cannot afford her shopping addiction.Carrie occasionally maxes out credit cards, could not secure a loan on her own due to poor savings and a bad credit rating as a result of extensive shopping, and has admitted her"Shoe needs"Have accounted for most of her spending;Amounting in one episode to her humorous concern that she might"Literally be the woman who lived in her shoe". Carrie is particularly known for her addiction to shoes, calling it her"Substance abuse problem"In the episode"Power of female sex"In season one.Notable moments include an incident when she is mugged near west broadway and the bandit makes off with her fendi baguette clutch and manolo blahnik pink suede strappy sandals, which she purchased"Half off at a sample sale! ", adding that they are her favorite shoes.In season 3 she chases after the staten island ferry and ends up missing it after slipping out of her shoe yelling,"Wait, i lost my choo! " In 'a woman's right to shoes' she unashamedly asks for reimbursement after a pair of manolo's are stolen when she is forced to remove them at a friend's party.Carrie notes the hypocrisy in the fact that the friend, who 'shoe shames' her("It was your choice to buy shoes that expensive")Is rewarded over the years with thousands of dollars worth of gifts for her life choices(Baby showers, engagement presents, wedding gifts etc. )Whereas single women do not have their life choices celebrated("Hallmark don't make a 'congratulationsyoudidn'tmarrythewrongguy card'! ")And so comes to the conclusion that it is okay to spend that much on oneself, specifically one's shoes, to make the single girl's walk through life a little more fun.Her weekly column,"Sex and the city,"Provides the title, story lines, and narration for each episode. Carrie has been described as someone who lives for fashion, and has confessed to buying vogue instead of dinner.A known shoe lover with penchant for expensive designer shoes(Notably manolo blahniks, but also christian louboutin and jimmy choo), Carrie claims she has spent over $40, 000 on shoes.Her pairs seem to average at least $400 a pair(According to miranda), and it is implied that she has at least, if not more than, 100 unique pairs. (At least until season 5 when she is given a book offer. )Indeed, many of the people around her comment that she cannot afford her shopping addiction.Carrie occasionally maxes out credit cards, could not secure a loan on her own due to poor savings and a bad credit rating as a result of extensive shopping, and has admitted her"Shoe needs"Have accounted for most of her spending;Amounting in one episode to her humorous concern that she might"Literally be the woman who lived in her shoe". Carrie is particularly known for her addiction to shoes, calling it her"Substance abuse problem"In the episode"Power of female sex"In season one.Notable moments include an incident when she is mugged near west broadway and the bandit makes off with her fendi baguette clutch and manolo blahnik pink suede strappy sandals, which she purchased"Half off at a sample sale! ", adding that they are her favorite shoes.In season 3 she chases after the staten island ferry and ends up missing it after slipping out of her shoe yelling,"Wait, i lost my choo! ".In 'a woman's right to shoes' she unashamedly asks for reimbursement after a pair of manolo's are stolen when she is forced to remove them at a friend's party.Carrie notes the hypocrisy in the fact that the friend, who 'shoe shames' her("It was your choice to buy shoes that expensive")Is rewarded over the years with thousands of dollars worth of gifts for her life choices(Baby showers, engagement presents, wedding gifts etc. )Whereas single women do not have their life choices celebrated("Hallmark don't make a 'congratulationsyoudidn'tmarrythewrongguy card'! ")And so comes to the conclusion that it is okay to spend that much on oneself, specifically one's shoes, to make the single girl's walk through life a little more fun. Samantha is one of four single friends portrayed in the series.She is the most promiscuous and egoistic of the four since most of her storylines revolve around the frequent sex she has.She is outspoken and a selfproclaimed"Trysexual" (Meaning she'll try anything at least once).In the book's prequel series, it is revealed that carrie met samantha first. Samantha is the eldest of the four friends(In the final scene of sex and the city:The movie, her 50th birthday is celebrated), and she has her own publicrelations company.Not much is known about samantha's younger years, except that she came from more of a working class background, and she spent most of her teenage years selling dilly bars at dairy queen to earn pocket money.Season 3 implies that she has at least two siblings, when she mentions that at her age, her mother"Was saddled with three kids and a drunk husband. "She later mentions partying at studio 54 during its heyday, implying she moved sometime in the mid to late1970s from wherever she grew up to new york city. She has mentioned having had at least two abortions, one of which occurred while she was in college. Charlotte york is the daughter of dr.Stephen foster york and sandra whitehead york.She is an art dealer and smith college graduate(Where she was a member of kappa kappa gamma)With a connecticut blueblooded upbringing.She is the most conservative and traditional of the group, placing more emphasis on emotional love than lust, and is always searching for her"Knight in shining armor. "Presenting a more straightforward attitude about relationships, usually based upon"The rules"Of love and dating, she often scoffs at the lewder, more libertine antics that the show presents(Primarily from samantha). Despite her conservative outlook, she has been known to make concessions that surprise even her sexually freer girlfriends(Such as her level of dirty talk and oral sex).It has been hinted at throughout the series, particularly in the first and second seasons, that she is the newest close friend of the group(For example being unaware of miranda's longterm relationship two years prior to the start date of the series). She gives up her career shortly http://www.listmint.com/ after marrying her first husband, trey macdougal, but divorces him upon irreconcilable differences concerning invitro fertilization, and receives a park avenue apartment as her divorce settlement.She eventually remarries her seemingly lessthanperfect, but goodhearted divorce lawyer, harry goldenblatt, after converting to judaism.In the series finale, charlotte and harry adopt a baby girl from china. Charlotte is viewed by some to be the most naive of the four characters, often showing signs of belief in the oldfashioned,"Love conquers all"Notion.This type of outlook has even earned her the nickname"Park avenue pollyanna,"Coined michael kors taschen online by carrie bradshaw in narrations. Yet, her friends are sometimes envious and even in awe of her overall optimism on love and life, leading carrie to dedicate her book to charlotte.Charlotte also possesses a soft personality towards her friends, always"Being there"For them.Due to her conservative outlook however she sometimes clashes with the sexually liberal samantha once asking"Is your vagina in the new york city guide books?Because it should be;It's the hottest spot in town, it's always open! "Yet in this instance she resolves the situation by baking samantha a basket of muffins, demonstrating charlotte's classic graceful and sweetnatured style.She is also fiercely loyal to her friends('cursing' Mr.Big after he abandons carrie at the altar in the first film)And to her beliefs in the sanctity of marriage(She is the only friend to chastise and shame carrie regarding her adulterous affair with mr.Big).It is revealed throughout the series that charlotte enjoyed various degrees of status in her younger life, such as being prom queen, a varsity cheerleader, track and field captain, teen model, and equestrienne.She is occasionally described as a wasp, an identity she seems to happily accept.However, charlotte later converted to judaism.Charlotte is a sorority member of kappa kappa gamma. A 1990 harvard university law graduate from the philadelphia area, she is carrie's best friend, confidante, and voice of reason.In the early seasons she is portrayed as masculine and pathologically misandric but this image softens over the years, particularly after she becomes pregnant by her onagain, offagain boyfriend, steve brady, whom she eventually marries. The birth of her son, brady hobbes, brings up new issues for her type a, workaholic personality, but she eventually finds a way to balance career, being single, and motherhood.Of the four women, she is the first to purchase an apartment(An indicator of her success), which she gives up when she moves into a Brooklyn townhouse in the final season to make room for her growing family. More labels.More love.In this muCh antiCipated movie event, Carrie, samantha(Kim Cattrall), Charlotte(Kristin davis)And miranda(Cynthia nixon)Are baCk, four years after the hit tv series ended.As they Continue to juggle Career, relationships, motherhood and life in manhattan, the girls realize that more than ever, true friendship never goes out of style.Mpaa rating:R(C)Mmviii new line productions, inc.Sex and the city tm and all related characters, places, names and other indicia are trademarks of home box office, inc.Under license to new line productions, inc.


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Anaemia may add information to standardised disease activity assessment to predict radiographic damage in rheumatoid arthritis Anaemia beats by dre uk wireless in rheumatoid arthritis(Ra)Is prototypical of anaemia of chronic disease(Acd), characterised by low serum iron Concentrations in conjunction with normal or increased storage iron.1 ACD without functional iron deficiency is normochromic, normocytic, and usually mild.2 Haemoglobin concentrations were a component of earlier RA disease activity measures until they were omitted during validation Of the original ra disease activity score(Das)Due to low correlation with other disease activity measures, despite moderateantirheumatic drugs(Dmards).4 Inhibition of human erythroid colonyforming units in the bone marrow downstream of tumour necrosis factor(Tnf)5 and anemia6 is reversible upon TNF blockade, even in otherwise refractory RA patients.Here, we question whether anaemia in ra is still Relevant in terms of prevalence and clinical consequences in the era of tnf blockade, one of the most efficacious and commonthis longitudinal populationbased cohort study is nested within the swiss clinical quality management(Scqm)Database, which Is described elsewhere.7 Patient registration in SCQM is restricted to boardcertified rheumatologists to follow the effectiveness and safety of antirheumatic Therapies.More than twothirds of all practicing rheumatologists in switzerland contributed patients, representing 10% of All hypothetical swiss ra patients.8, 9 Approximately 60% of patients come from private practices, 20% from university hospitals, and 20% from nonacademic centres. Ethical approval for patient enrolment into the scqm programme and related studies was obtained from the swiss academy of Medical sciences review board.Written informed consent was provided by all 4377 participants with classification criteriaguided Ra diagnosis, 10 and at least one haemoglobin assessment between the start of the registry in 1996 and a major system revision in 2007. We used the who definition of anaemia with lower normal haemoglobin limits of 12g/dl in women and 13g/dl in men.11 To explore the effect of anaemia severity, we used the less stringent anaemia definition proposed by Beutler et al, 12 using thresholds of 12.2g/dl in white women and of 13.7g/dl or 13.2g/dl in white men aged 2059 years, or 60+years, respectively, In sensitivity analyses.'More severe anaemia' was arbitrarily defined(In the absence of official definitions)By haemoglobin Levels lower than 11g/dl drdrestudio in women and 12g/dl in men.Haemoglobin concentrations, white blood cell counts, and platelet counts Were derived from certified local laboratories. Registry documentation provided the american college of rheumatology core set of disease activity measures, 13 which allowed to calculate the das including the 28joint count for tender and swollen joints and erythrocyte sedimentation Rate(Das28esr)14 and the clinical disease activity index(Cdai).15 Other covariates were age and gender, rheumatoid factor(Rf)Status, and ra disease duration.Ra therapies, including tnf Blockers, methotrexate with or without folic acid supplementation, and other synthetic dmards, corticosteroids, cyclooxygenaseii Selective(Coxib type) NSAIDs, nonSelectiveNSAIDs and protonpump inhibitors (Ppi).Generic information on the presence Of haematological, renal, or gastrointestinal comorbidities was also available, without detailed information. Descriptive statistics included the mean and sd for normally distributed variables, and the median and iqr for nonparametric Continuous variables.Sporadic missing covariates were replaced by the population mean(2 test for beats by dre sale dichotomous variables.We examined potential time trends in the prevalence and incidence of anaemia and the haemoglobin Normalisation rates with cox regression analyses.Patients were defined as 'anaemic' according to the chosen definition between Two radiographs by subnormal haemoglobin concentrations in more than 50% of determinations.We used mixedmodel randomslope


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Although they are designed to be used just once, plastic bags can last for up to 1, 000 years when they're thrown in the trash and buried in a landfill.Others can wreak havoc on recycling centers escarpins noirs louboutin pas cher not equipped to handle thin polyethylene bags, clog storm drains or end up in the ocean where they pose a serious threat to marine life as they slowly photodegrade into microscopic bits of plastic. When you consider the longterm implications of a product designed to be used for just a few minutes, reducing the number of plastic bags seems like a nobrainer.So why wouldn't new york city try to get rid of them altogether with a ban or at least some kind of fee? Think about it:No more discarded plastic bags dancing in the wind along our streets, tangled in tree branches or floating around our ankles at the beach. (Perhaps sadly, no more bag monster costumes. )But there are a couple of reasons why bag restrictions are a tough sell in new york city. First, let's face it:We've gotten really used to having these bags around.I rarely see anyone picking up their dog's poop with anything other than a plastic shopping bag.The bags also happen to be the perfect size for lining small trashcans.And what better way to store food waste for composting than in a plastic bag in the freezer, safe from the relentless pursuit of pests? The fact is none of these are deal breakers.Reusable bags or containers will work just fine in the freezer, trashcans don't always need liners if you wash them regularly and your canine companion has a lot of pooperscooper options at its disposal.Human behavior being what it is, there would have to be some christian louboutin chaussures soldes sort of negative financial consequence to inspire us to give up our plastic fetish.In other words, bans or fees. Enter problem number two:The progressive bag affiliates(Pba, previously"Progressive bag alliance").The pba comprised of the american chemistry council and a lot of plastic bag manufacturers would really rather we recycle our plastic bags.So new yorkers do.Maybe. Let's review.Plastic bags make up the largest source of plastic in the city's waste, so back in 2008 city council speaker christine quinn, with the pba's blessing, successfully pushed for new york city's plastic bag recycling program.The problem was that plastic bag recycling nationwide was a meager 6 percent, and since the city's program relied on customers bringing their plastic bags to large stores or retail chains to recycle them, it's nowhere near as easy as leaving them in bins outside your house.Still, this was progress. Then, mayor bloomberg got another idea:Why not up the ante and charge a sixcentsperbag fee to cut the plastic waste stream even more?After all, it worked for the brooklyn ikea, which started charging five cents per bag with nary a customer revolt, and in turn cut plastic bag use in half.Why not take that successful concept and run with it? Because while the pba loves recycling, it hates bans and taxes.When the pba testified in favor of speaker quinn's bag recycling program, the association's pr consultant made his feelings on any stricter measures abundantly clear: "Bans are all feel good and do no good. "The mayor backed off when speaker quinn took the bag fee off the table amid rumblings from some council members that the fee constituted a tax on food. But how lbtinpaser are bag restrictions in other cities, states and countries working out? Let's take a quick world tour.In 2002, ireland began taxing plastic bags to the tune of 21 cents per bag, leading to a 90 percent reduction in retailer purchases of the bags(And that fee was increased in 2006).In china, the government banned singleuse plastic bags in 2008, reducing plastic bag use by 66 percent and saving the country 1.6 million tons of petroleum.Back in the united states, san francisco banned plastic bags outright in 2007 and since then 13 other cities or counties in california have imposed some sort of restriction on the bags.The first plastic bag restriction east of the mississippi was enacted in 2009 in westport, ct, while easthampton and southampton, ny enacted bans earlier this year. In 2010, the nation's capitol imposed a five cent fee for both plastic and paper singleuse bags, the proceeds of which go towards cleaning up the anacostia river, which was being choked by plastic litter.The result was an immediate decline in the number of disposable bags given out by food and grocery establishments, from 22.5 million per month in 2009, to about 3 million in January 2010, the first month with the new fee.First, the city diffused the"Food tax"Argument because retailers gave out hundreds of thousands of free reusable bags when the fee was enacted.Second, the city didn't focus on plastic bags exclusively, instead the focus was on singleuse, disposable bags, whether paper or plastic. This is a key point because, surprisingly, the plastic and paper bag industries are in no way aligned against efforts to ban or tax single use bags.In fact, they often pit themselves against each other.Case in point is a pba fact sheet that claims to be about the benefits of plastic bag recycling, but instead just hammers away on the negative impacts of paper bags(Which, to be fair, are many). So if a new york city council member, or perhaps the next mayor, were brave enough to push for drastic reductions in single use bag waste beyond the current recycling program, the effort would have to expand beyond plastic bags.Reducing the amount of singleuse bags, whether paper or plastic, and the impact they have throughout their whole lifecycle, from the energy and water needed for manufacturing to the economic and environmental costs of disposal, should be the goal. As other cities and countries have shown, the most effective way to significantly cut down on singleuse bags is by revealing their hidden costs and making the convenience they provide a little less attractive. Recycling is a nice start, but for each of us to kick our 330disposablebagperyear habit, we're going to need a little push.Paper or plastic?Time to think ahead and byob.


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Stars put punk edge on gala outfits the argus Miley cyrus, anne hathaway and cameron diaz were among the celebrities to embrace miaelkorssaleonline the punk theme at the annual met gala in new york. The stars were out in force for the fundraiser at the metropolitan museum of art. And while many embraced the 2013 theme punk:From chaos to couture, home the event's honorary chairwoman beyonce, went for a more fiery theme, with a flamemotif gown with long gloves and a long train by givenchy's riccardo tisci. Stars who went all out punk included actress rooney mara, who wore a white lace gown with exaggerated shoulders and a heavyhardware zip front. Rooney said she never went through a punk fashion phase but added: "I was definitely a punk. " Sarah jessica parker donned an oversized feather mohawk by philip treacy that complemented her graffitisplashed and slashed gown by giles deacon, which she also paired with custommade, thighhigh, tartanplaid christian louboutin boots.She paid careful attention to the theme, saying: "I just want to be asked back next year!That's all that matters! " Cameron diaz and anne hathaway both said they were influenced by the punk scene especially the music when they were growing up. Cameron arrived with kristen stewart and stella mccartney, who designed both of their outfits.Her cobaltcoloured cape dress had a severe studded belt. "I feel so chic,"Diaz said.


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March 21, 2014

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Alpha chpbts promoter single nucleotide polymorphisms are markers cheap beats by dre studio of human ancestry Top of pageabstractwe present a map of single nucleotide polymorphisms(Snps)In the human tumor necrosis factor(Tnf)Promoter based upon exploratory sequencing of 333 human tnf gene promoters from individuals of distinct ancestral backgrounds.We detect 10 tnf promoter snps that occur with distinct frequencies in populations of different ancestry.Consistent with these findings, we show that two tnf snps, the snp and the snp, are the first snp markers of a subsaharan africanderived extended haplotype and an amerindian hla haplotype, respectively.Comparisons of tnf promoter snp allele frequencies can thus help elucidate variation of hla haplotypes and their distribution among existing ethnic groups and shed light into the history of human populations.Additionally, the and snps have been associated with hla haplotypes that do not contain complotype information in individuals of japanese ancestry.8A critical question in the genetic origin of humans is what types of nuclear DNA sequence variation have accumulated.Previously taking a phylogenetic approach, we identified phylogenetic footprints or conserved regions in primate tnf promoters and presented evidence for a mechanism by which the human tnf regulatory region evolved.6 That is, sequences containing functional activator binding sites have been conserved in the primate lineage, whereas regions that are not essential for regulation display a high density of variable sites.To determine the degree of variability of human tnf promoters, we undertook largescale sequencing of 333 fulllength tnf promoters from ethnically distinct human populations. (Iii)Tnf snps are markers of ethnicspecific hla haplotypes.Taken together, these data are consistent with the hypothesis6 that accumulation of snps in the tnf promoter has been nonrandom and driven by the conservation of tnf activator binding sites.Tnf snps appear to have been maintained as silent substitutions in different ancestral human genetic backgrounds where they were incorporated into conserved or extended haplotypes, which became haplospecific in populations of different ethnic groups.Top of pageresults and discussionexploratory sequencing of the tnf promoter region of individuals of caucasian(North american), Asian(Cambodian), African(Malawian, southern nigerian, africanamerican and africancaribbean), and Amerindian(Quechua and paez)Descent revealed nine previously reported snps located at and nt and one novel snp a c to g transversion, at nt relative to the tnf transcription start site.The snp was found in two individuals from malawi and in one individual from nigeria;All three were heterozygous for the variant g nucleotide(Table 1).Inspection of the distribution of snps reveals that the three african populations studied have the highest relative diversity of tnf snps(Table 1).This finding is consistent with the africa hypothesis based upon human mitochondrial dna analyses, 18 which contends that the genetic variation occurring in subsaharan africa gave rise to the variation in populations outside of africa.Our analysis here of the nuclear dna diversity of the human tnf promoter supports this hypothesis and is consistent with other recent nuclear dna snp surveys.1, 19 We note that using the principles of probability, there is a 95 probability that an analysis of direct sequencing of 333 kb of DNA could detect any existent SNP in the TNF promoter in the human population with a heterozygosity rate of 0.0090 or greater(See legend to Table 1).Thus, the 10 snps detected in this study likely represent the majority of human tnf promoter snps that exist.The and tnf snps are the most frequently observed snps among the 43 caucasian(35 and 26 respectively)And 40 cambodian(30 and 25 respectively)Tnf promoters evaluated(Table 1).The and snps are also frequently observed in the 66 malawian(17 and 11 respectively), 54 Nigerian(7 and 7 and 34 AfricanAmerican samples(29 and 8 respectively)Relative to the frequencies of the other tnf snps in these populations.However, their relative frequencies are lower when compared to the caucasian and cambodian samples(Table 1).The and snps were also detected in the 54 quechua(9 and 7 respectively)And 42 paez(7 and 2 respectively)Promoters examined;However, their relative frequencies were also significantly less as compared to caucasian and cambodian samples examined(Table 1).Furthermore, the snp always occurred in association with the snp in all the ethnic groups studied.Of the 333 promoters studied, 273 were wild type at both positions, and 40 carried both the and and 20 carried the snp alone(Table 1).Thus, these snps likely became linked before human migration out of africa(Table 1).Unexpectedly, the tnf snp, a relatively highfrequency snp in caucasian(14 and Cambodian(13 samples, was absent in the Malawian promoters and found in only one of the Nigerian promoters analyzed and was absent in the AfricanAmerican promoters(Table 1).Strikingly, by contrast, the tnf snp was found in 30 of the quechua promoters and 45 of the paez promoters studied(Table 1).Furthermore, the snp, which occurs with relative high frequency in caucasian(21 Malawian(12 Nigerian(13 AfricanAmerican(12 and Cambodian(8 promoters, was not detected in any of the 96 TNF promoters derived from the two distinct indigenous Amerindian populations analyzed(Table 1).Consistent with our results, the snp was not detected in examples of other amerindian(Chachi indians from ecuador and pima indians of arizona)Samples previously analyzed.10, 13 Thus, these data establish that TNF SNPs occur with distinct patterns in ethnically distinct populations.The dramatic increase of the and absence of the tnf snp in the amerindian samples examined led us to speculate that this snp pattern was not random and was likely to be associated with neighboring hla genes in amerindians where it may be a haplospecific marker.We thus next performed highresolution hla typing of the hlac, b, and drb1 loci of the paez samples where 45 of the 42 samples examined contained the tnf snp.Of the 19 examples of the snp in the paez samples, only six were random and not associated with a known amerindian haplotype(Table 2).We note that where it was detected, the snp occurred as the sole tnf snp in each of the haplotypes evaluated(Table 2).Since the hlacw and b hla fragment has been observed in indigenous populations from taiwan, new zealand(Maori), Northeast China(Orochon), Inuit, and Tlingit, 24 our results are consistent with the hypothesis that Amerindians may have originated from a postneolithic migration from Asia to South America.25In addition to the Amerindian samples, we also detected the SNP in promoters of all three Africanderived populations.Although the variant has previously been reported in caucasians9 and asians, 8 we did not detect it in the caucasian or cambodian samples evaluated(Table 1), consistent with its very low frequency in these groups.By contrast, the snp was not detected in any of the nonafrican samples examined(Table 1).Furthermore, the four malawians carrying the snp also carried the snp on the same chromosome, which we determined by cloning promoter fragments of the snppositive individuals and sequencing individual alleles(Table 1 and Data not shown).Since we previously detected the snp in two old world monkeys(Baboon and macaque)And in a new world monkey(Aotus trivirgatus), 6 our data are consistent with the hypothesis that the SNP entered the primate lineage before the split of the old and new world monkeys and sometime after the migration out of Africa became associated with the SNP in African populations that remained behind.Intriguingly, we also detected the snp on the same chromosome as the snp in three cases(In a paece, table 2)And in two individuals of the africanamerican group(Data not shown).We imagine that those tnf snps, which are found randomly and in no apparent association with other tnf variants or mhc genes in individuals of all continents, may have occurred in the human population before the migration out of africa and then in certain cases were integrated into a conserved mhc haplotype or linked with another tnf variant.The snp that was previously detected in south american black people10 was enriched in malawians(9 and in 17 individuals of AfricanAmerican or AfricanCaribbean background(26 where highresolution MHC typing was available and previous family studies allowed us to determine the haplotypes of particular individuals17(Table 1).Remarkably, among six examples of the subsaharan africanderived extended haplotype of hlacw b fc(1, 90)0, DRB1 contained in this sample set, five carried the SNP.One individual was homozygous for both the extended haplotype and the snp(Haplotypes 1 and 2, table 3).We also found the snp in an individual who carried a fragment of the extended haplotype and had a distinct complotype(Haplotype7).In two other individuals, the variant appeared to be in nonrandom association with their mhc(Haplotypes 8 and 9).To test the hypothesis that the snp was indeed a part of the extended subsaharan haplotype, we sequenced the tnf promoter in a cell line(Rsh, homozygous for the haplotype26 and, strikingly, we found that it was also homozygous for the variant(Data not shown).This analysis thus establishes the variant as the first tnf snp linked to an africanderived extended hla haplotype.We have also shown that these patterns are at least in part secondary to beats by dre pro cheap the nonrandom association of tnf snps with neighboring hla genes that differ in distinct ancestral backgrounds.Genes that are in linkage disequilibrium with neighboring genes are thought to reflect a more ancient evolutionary history since it requires a long time for genetic segments to be united by recombination events.1 The enrichment of the SNP in African populations and the SNP in Amerindian populations thus appears to be ancient since they were incorporated into African and Amerindian HLA haplotypes, respectively.The fact that examples of the snp in nonafricanderived populations are rare suggests that it was adaptive to natural selection within the african context where it became a marker for neighboring genes including hla class i, class ii, and complement genes that may have functional importance in infectious diseases.Despite this high level of variation, here we have shown that the sequences involved in enhanceosome formation involved in the regulation of the gene3, 4, 5 are highly conserved in humans of distinct ancestral backgrounds since we did not detect a single snp in this region.By contrast, human tnf snps including the novel variant described here occur within or immediately adjacent to regions of the promoter with high variability in the primate lineage.6 Furthermore, statistical analyses of sample configurations of TNF promoter SNPs suggest that they are effectively neutral and act as silent substitutions.27 Taken together, we conclude that similar to coding regions, promoter region variation is evolutionarily constrained, and substitutions in sequences critical for TNF regulation are not tolerated.One explanation for the high number of snps in the tnf promoter that is consistent with our data is that they have accumulated in regions of the promoter not essential for gene regulation and that they have been incorporated into hla haplotypes where they are in nonrandom association with neighboring genes that in the course of human history have been stratified and maintained in specific ethnic groups.Finally, this compilation of a tnf promoter snp map not only provides insight into the evolution of noncoding sequences in the promoter region of a gene of critical importance in the human immune response, but also demonstrates that comparisons of snp allele frequencies in different populations can help elucidate the history of human populations.Top of pagereferencestop of pageacknowledgementswe are grateful to dan hartl for helpful discussions and to terrie taylor for support of the study in malawi, and we thank adele uglialoro for technical assistance and pedro floresvillanueva for helpful discussions.This work was supported by grants from the american heart association and the nih(Gm56492)To aeg and from the nih(Hl5983 To aeg and ejy


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