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On Milan's offbeat via Tortona, around the corner from Teatro Armani and the Fondazione Pomodoro, contemporary NHOW sits in the shell of the city's former General Electrics factory. From the polished concrete lobby up to the fourth floor, the hotel is dotted with a rotating selection of artworks and limited edition furniture, all for sale (check www.artnhow.com for an up-to-date, comprehensive guide). Rooms are decked out with Artemide lights and funky printed wallpaper, and showers are colourful. Exhibitionists should book the penthouse apartment, complete with glass-bottomed bathtub that acts as the living room's ceiling.
Area Milan
Transport Metro Porta Genova/bus 68.
Telephone 02 489 8861
Rates €152-€282 double.
Facilities Business centre. Bar/café. Concierge. Internet: Wireless (paid). Parking: Parking (paid). Restaurant. Room service. Smoking rooms. TV.


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Faces and Places Shiffrin heats up sponsor market First Look podcast: Opening Day and more Raveling 'an information reservoir' F1 players accelerate growth in U.S. Instagram expands its student program Plugged In: Amy Trask Venue lockers deliver merch, food SunTrust Park brew steeped in the game Teams to get millions in relocation fees
SBJ/20081117/Coast to Coast
Print All-
Coast to Coast
UMass students help market Dew Tour
Mount Snow and the AST Winter Dew Tour are partnering with a group of 14 undergraduate students from the University of Massachusetts Sport Management Program. The students in the "DewMass Marketing" course will help market the Mount Snow stop of the tour to a college student demographic. The Mount Snow event in Vermont is slated for Jan. 8-11.BOSTON
Celtics will have student input
Suffolk University business students will get a chance to create and propose sports marketing programs for the Boston Celtics. Students from the university's Sawyer Business School will study and evaluate the NBA team's business, marketing and community programs as part of their course of study. Students will develop marketing programs to be evaluated and potentially implemented by the team.After dismantling teams down the stretch last
season, Davidson saw ticket sales soar.CHARLOTTE
PGA Tour event keeping name in 2009
The Wachovia Championship will keep its name in 2009 despite the Charlotte-based bank being purchased by Wells Fargo. Today is the PGA Tour event's self-imposed deadline to get branded materials ordered in time for the May tournament, and the bank acquisition is not expected to close until the end of the year.Wildcats double season-ticket base
Davidson College doubled its men's basketball season-ticket base from 2,000 to 4,000 after last year's appearance in the Elite Eight round of the NCAA tournament, according to a report in The Charlotte Observer. The school actually decreased capacity this season at Belk Arena, from 5,800 to 5,219, by adding 1,200 chair-back seats where bleachers used to be, according to the report.CHICAGO
Updated bids requested for Cubs sale
The Tribune Co. asked bidders for the Chicago Cubs to submit new offers before the Nov. 27 Thanksgiving holiday, according to a report in the Chicago Tribune. The updated bids have to include details on how the prospective buyers will finance the purchase of the team, according to the report.CINCINNATI
Reds upgrading boards, club space
The Cincinnati Reds will make a multimillion-dollar investment this offseason in two major improvements to Great American Ball Park. Daktronics is aiming to win the contract for a high-definition scoreboard, and the team plans to gut and renovate the inside of the FSN Ohio Club 4192 to make the space more open than the current layout.DENVER
Pepsi Center picks Qube for signs
Qube Visual of Denver landed a three-year agreement with Kroenke Sports Enterprises to become the exclusive and official sign and graphics company for the Pepsi Center. The deal also covers Kroenke's sports franchises: the Denver Nuggets, the Colorado Avalanche, the Colorado Mammoth and the Colorado Crush. Terms of the deal weren't disclosed.EAST RUTHERFORD, N.J.
Nets offer free tickets to job-seekers
The New Jersey Nets are giving unemployed fans free tickets for five home games. Job-seeking fans can sign up at www.njnets.com and can e-mail résumés to the team. The Nets will release 300 tickets per game for fans that enroll in the Nets Employment Program. The team will send résumés to Nets sponsors and season-ticket holders with businesses that are involved in the program.HONOLULU
Sugar Bowl boosts UH revenue
Licensing revenue for University of Hawaii products nearly doubled last year, largely due to sales of Sugar Bowl merchandise, according to a report in the Honolulu Star-Bulletin. Carolyn Tanaka, the university's associate vice president for external affairs, said that UH received $631,910 in the fiscal year ending June 30, compared with $317,009 in the previous year, according to the report.HOUSTON
Dynamo near deal to extend stadium lease
The Houston Dynamo is close to finalizing a two-year lease extension — with a rent increase — through 2010 at the University of Houston's Robertson Stadium. The MLS team will have to wait until 2011 at the earliest before the team's proposed downtown stadium can be completed.State's first Adidas store opening
Adidas hits the Lone Star State when its new Adidas Sport Performance Store opens Nov. 22 at the Houston Galleria mall. The 8,000-square-foot location will be the first Adidas store in Texas. On the schedule of events at the opening is a ribbon-cutting ceremony and autograph sessions with athletes Jeremy Wariner (track), Doc Patton (track) and Adam Dunn (baseball).LUBBOCK, TEXAS
Tech athletes to wear Under Armour
Under Armour agreed to a five-year, $11 million deal with Texas Tech University to become the exclusive performance footwear and apparel outfitter for all of the school's 17 athletic teams. The deal will go into effect in July 2009.MILWAUKEE
Bucks sign cognac sponsorship
The Milwaukee Bucks signed a sponsorship agreement with J&M Heritage Imports, which distributes Bache-Gabrielsen cognac, according to a report in the Milwaukee Journal-Sentinel. The cognac is available in the bars, clubs and suites at the Bradley Center, and the deal also names Bache-Gabrielsen as the exclusive sponsor of the Atrium Bar inside the Bradley Center lobby, according to the report.MINNEAPOLIS-ST. PAUL
TCF Bank Stadium boxes sold out
The University of Minnesota sold all of its 58 stadium boxes at TCF Bank Stadium, and it has eight private suites left to sell at $45,000 each, according to a report in the St. Paul Pioneer Press. Nearly half of the 1,200 outdoor club seats have been sold, and the school has a waiting list of 400 for regular-season tickets, according to the report.Timberwolves employees get connected
The Minnesota Timberwolves replaced the company's intranet with an interactive, companywide social-networking site called "Team Connect." The program consolidates job requests and orders, company announcements, human resources forms, project trackers, game-day schedules and even birthday announcements. Employees can edit personal information, upload pictures and send messages to other employees. It was developed by Marzan Interactive.PHILADELPHIA
JCPenney in step with Elton Brand
Converse and Philadelphia 76ers forward Elton Brand created a signature shoe that is available exclusively at JCPenney locations and online at jcp.com. The EB1 shoe, which was released Nov. 1, retails for $65. The EB1 will be supported through a national radio campaign, in-store signage, the retailer's circular advertising and on both converse.com and jcp.com.PHOENIX
Cox Business wired for Coyotes, arena
The Phoenix Coyotes and Jobing.com Arena selected Cox Business as their exclusive provider for video cable, phone, Internet and data services. Cox is now the official local, long distance and Internet service provider of the Phoenix Coyotes and Jobing.com Arena. As part of the three-year agreement, Cox will add a Phoenix Coyotes/Jobing.com Arena channel to its video-on-demand free service for Cox digital cable customers.ST. LOUIS
Blues push Saturday mortgage promotion
The St. Louis Blues are rolling out a unique "bailout" promotion that will see the team select one fan at Saturday home games and pay $1,000 toward the fan's mortgage or rent payments. The team will host 11 "Fannie and Freddie Mortgage Saturdays" over the course of the season and pay $1,000 per month for four months for all 11 selected fans.Send your Coast to Coast news to: firstname.lastname@example.com
or phone (704) 973-1436.

subset: commoncrawl


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Michelle M
Michelle loves her work as a temp secretary but also loves to work from home on her web-cam. The attraction to this for her boss is that Michelle is an asset in all departments bur especially when you need the extra glamour and brains to clinch a deal. However, she also loves to slip out of her chic business suit when working from home and loves to work 9-5 in her lingerie which makes her more comfortable and so far we have had no complaints from any of her employers!
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Cask Ale Week (Easter week) is about celebrating Britain's national drink – cask beer. These linked articles talk about success – people, pubs, breweries and, of course, cask beer. It's great to have something to cheer about.
The history of Cask Marque says much about the ups and downs of the cask beer sector. In the early Nineties when the Government broke up the vertical integration in the brewery industry, whereby all the brewers owned all the pubs, with the now infamous 1989 "Beer Orders", there was a surge in cask beer sales as the market opened up to new brewers.
However, this was shortlived as many pubs rushed to stock cask beer, and beer quality declined rapidly as landlords lacked the skill set to undertake the last part of the brewery process in the cellar – the second fermentation. Disappointed customers left to find alternative drinks.
In the late Nineties, Adnams, Greene King, Marston's and Morland breweries, which were growing their sales but in a declining market, met and identified the need to tackle quality issues. At the time, I was the sales and marketing director at Adnams. Each brewer contributed to a £40,000 fund which paid for research showing that two out of every five pints sold were outside brewery specification: hence the birth of Cask Marque. This non-profit organisation was set up to accredit landlords who served great beer, with the aim of inspiring others to follow suit.
This award is to the licensee and not the pub, because it is they rather than the pub who look after the beer. Subsequently, the industry has heavily invested in equipment and cellar management training, and today there are more than 6,300 pubs which display the distinctive Cask Marque plaque.
Cask Marque has 45 trained assessors, said by some to enjoy "the best job in the world". They visit pubs nationwide, checking on beer quality and offering licensees advice on beer range, throughput and cellar management. Before you ask, you need to be a brewer to be able to join the team!
Surprise, surprise, customers are rediscovering cask beer, and last year it outperformed almost every drink on the bar, including lager and wines and spirits. A total of 400,000 new drinkers enjoyed cask beer, and the number of female drinkers doubled in 12 months.
There are more brewers now than at any time since the early Forties. Camra membership has reached record levels – now exceeding 100,000 – and beer festivals have enjoyed record attendances.
Now we have this momentum, it is important that we continue to maintain quality standards and to learn from the mistakes of the early Nineties. That is where you as the consumer can play an important role. When you see the Cask Marque plaque if great beer is on sale, do tell the licensee. If, however, it has not reached your high level of expectation, do let Cask Marque know. We will follow up the complaint and it may trigger a further assessor's visit.
To help you to identify the Cask Marque award-winning licensees, you can either download a satnav programme from our website or use our new iPhone app, both of which are free from our website.
You can, however, just text to 60300 the word "cask.", and add your postcode. For example, CASK.CO49HT. Within 30 seconds, you will have details of your two nearest outlets.
I always remind people that cask beer is unique to the British pub. You can't buy it in the supermarket or drink it at home – you have to go to the pub and socialise. This is why Cask Ale Week focuses around the pub.
This year, more than 10,000 pubs will be celebrating Cask Ale Week by running events and promotions. Do visit the Cask Ale Week website www.caskaleweek.co.uk and see which pubs in your area are supporting the event.
We have lots of reasons to be cheerful during Easter week, so let's celebrate cask beer – Britain's national drink linked to the success of the British pub.


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Still shambling the streets of the city Nelson Algren defined, I am the Monster in a madhouse refined. Burma Shave.
Saturday, January 15, 2011
Ghost Hood on The Red Line
Photos from a few Mondays back. Nothing cool, just bus and subway shots. I do like the way the hooded guy is ghosted through the opposite window of the Red Line. And even though I'm standing in a well-lit room as I wait for the bus on the ride home, I still have to contend with an open stairwell that leads to the el tracks and the Dan Ryan Expressway, gusts of frigid air are continually thrust upwards and after awhile, I grudgingly accept that I will have to put up with this for forty minutes.
87th Street
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350 SBC Build
Here is a link that shows the parts i am thinking about getting. I would like some input on what else would go good with these parts. I am leaving the stock cam in it for now, but i will be getting another one in a couple months. Im not looking for crazy HP but i do want to be in the neiborhood of about 375 BHP. right now i have a 350 SBC, casting # 10066036 Hencho Motor. Any input is greatly appreaciated.
Chris http://www.summitracing.com/checkout/cart.aspx
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X2 and 375 brake hp is about 470hp to the flywheel, although that may not be "crazy" horsepower, that is still quite a bit out of 350. list your parts and specs (so we dont have to search for them) and we can give you an idea if you are on the right track |
I agree with waiting and doing all of it at one time. List the individual parts you were thinking about using, along with what you will be asking the motor to do for future duty and some of us will try to help you. |
Yes, i do mean at the flywheel, sorry. Here is a list of the part numbers i am going for and summitracing.com CMB-08-0034 i found a fet sets of rocker arms, but im not sure wich would be best CMB-08-0039 come with a cam and roller timing set but for some reason i keep second guessing the cam???? i know you are going to tell me to get the cam and i most likley will, but i would like some input as to what rocker arms and lifters to go with. if i stay with the Hyd flat tappet i have now, and flat tappet lifters, would they be compatible with the head/rocker set up?here is the information for my engines current set up -(4) Bolt main block with a (2) piece rear main seal. -Cast Iron Crank. -Forged steel connecting rods. -Cast Pistons, (dished). -Hydraulic flat tappet cam, (.383� intake / .401� exhaust) and a 112-degree lobe separation. -Cast Iron Cylinder heads with a 76cc combustion chamber. (Non vortec design) -8.5:1 compression ratio. thanks again and sorry for the first post, i was in a litle bit of a hurry when i posted it. Chris |
personally i like the first combo better, although the edelbrock heads probably perform better than the summit vortec heads. i dont like the cam in the edelbrock kit at all you have a 278-288 advertised duration with a 204-214 advanced duration, and then with a 112 LSA, and also only having .420" lift on the intake, this is a very mild mannered cam. i hav a rule of thumb that i stick to when looking at cams i always want my advanced duration to be no more than 50ish degrees from my advertised duration. so for the advertised spec on this cam i would want an advanced duration around 222-226int and 232-236exh. this cam has over 70 degrees from advertised to advanced.
the vortec kit doesn't mention what the max lift is so i would call summit to see if they could tell you. but for now i will just stick to what a standard vortec's range is. i would say that a decent cam somewhere around 272-278int/ 276-282exh (i would look at dual pattern beacause of the 1.50" exh valve) 220-226 @ 050, with around a .460" lift. the motor you have has actually shown to be closer to 8.0:1 although i know it says 8.5:1 so the 64cc heads will get you to 9.0:1, with the cams i mentioned you will end up needting to change your stall and rear gears if they aren't already upgraded, but these thing should put you right at you're goal of about 375hp |
Keep in ind adv. duration varies from manufacturer to manufacturer, so its relatively insignificant. The second build won't hit 375hp. |
I believe he's referring to duration @ 0.050" as "advanced" duration, although I've not heard it called that before.
You have advertised duration and you have duration @ 0.050" tappet lift. As ap72 said, the advertised can vary not only from grinder to grinder, but cam grind style to style. Flat tappet solids are usually rated from 0.020" tappet lift for the advertised figures, while flat tappet hydraulics are rated from 0.006" (usually )
When you subtract the 0.050 figure from the advertised figure, you are left with the combined (opening and closing) ramp durations. Dividing that in half will give you the number of degrees of ramp for either the opening or the closing side, assuming a symetrical grind. In other words, if you have 230 and 280, one side of the lobe is 25 degrees duration. If you have a 230 and 300, one side of the lobe is 35 degrees duration. Now, it's easy to see that if it takes 35 degrees to list the valve from 0.006" to 0.050", it's gonna be easier on the lifter/lobe interface than if you lifted the valve the same distance in only 25 degrees of rotation. I think you will see more cam failures with the "extreme" grinds than you will with the old school "lazy" grinds. The lazy grinds may not make as much hp, but hp doesn't mean much when you have to pull the motor down to clean out the shrapnel from a pooched lobe/lifter. |
I like the first package better too. The first kit has GM vortec heads #12558060.
Might as well spend the $200 while you're at it and get a cam & lifters to match you combo. Get you a new timing gear while you're at it. They're cheap. Also, is you block zero decked? You might want to find out how far down in the hole your pistons are before you get that kit. Otherwise, you squish will probably be too much. The gasket in the kit is a .041. |
And yea, the advertised numbers are measured at .003, .004, .005, and .006 as far as I know, depending on the manufacturer. the solid cams are sometime measured at .020, and sometimes at their recommended lash value (can vary from .012 to .030), and sometimes something else all together. Which is why we use .050" values- it standardizes it. BTW .050" on a hyd. and a solid cam are NOT the same; as the hyd. cam essentially follows the lobe exactly (not true but close enough for this discussion), and solids have the play from the lash at the valve (which can vary but is more than the slop felt in a hyd. cam). |
yes duration @ .050" is what advanced duration means, not sure exactly where i heard it from but it stuck so i tend to use both saying |
would anybody know a good setup to get 440-470hp from a 350
11.0-11.5:1 compression, a roller cam with 240-250 degrees @.050 w/ .550+", a decent set of heads such as Brodix IK200, Dart pro1 200cc, or AFR 195cc, with either pair of heads I would have some mild runner and bowl machine work done, 750CFM DP, decent single plane intake such as a victor Jr.
When tuned right it should have you right in the 475hp range |
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"The candidates also know we have experience of democracy, those of us who live here. We know what to listen for. We know if anything they're saying makes sense. So they come here and they try to convince us, so we'll call our families back home and tell them how to vote."
Quetel Osterval
"Republics decline into democracies and democracies degenerate into despotisms."
"Let us in education dream of an aristocracy of achievement arising out of a democracy of opportunity"
Thomas Jefferson
"Democracy is being allowed to vote for the candidate you dislike least."
Robert Byrne
"Every government is a parliament of whores. The trouble is, in a democracy, the whores are us."
P. J. O'Rourke
"Democracy forever teases us with the contrast between its ideals and its realities, between its heroic possibilities and its sorry achievements."
Agnes Repplier
"Democracy is when the indigent, and not the men of property, are the rulers."


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Music is ending for MP3tunes.com, the service created by Michael Robertson in 2005 as a "cyber locker" ahead of its times and inevitably sued by the record industry for copyright infringement. The company filed for bankruptcy in the Southern District of California, and its founder isn't wary of directly accusing the music majors for this unfortunate outcome.
Already well known for MP3.com and his Lindows/Linspire project, Robertson funded MP3tunes to let people share their music with others and access it on-line from any device – in DRM-less digital format and with no need to pay a single cent to the copyright-owning labels.
MP3tunes was obviously taken to court by one of these labels (EMI), a case filed in 2007 and that still has to celebrate a proper trial. Robertson now explains that after four years of fruitless legal cost, "MP3tunes has no choice but to file" for bankruptcy.
It's how the "Big Four" of the recording industry operate, the entrepreneur states, "the labels engage in multiyear legal battles and put small companies through hell for years" so that they don't have the opportunity to flourish and develop their business.
MP3tunes is going bankrupt with debts valued between 1 million and 10 million dollars, while Robertson previously managed to get a now–Pyrrhic victory when a court in Manhattan judged that his company was not liable of violating the Digital Millennium Copyright Act (DMCA) for letting its users download audio tracks with no known legal status.


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Yoga and Wine Weekend Spring Schedule
at the beautiful Savannah House in Himrod, NY close to Watkins Glen
Please check the Savannah House website for details!
Weekends include two nights accommodation, welcome wine reception, daily yoga and meditation instruction, a visit to the Farm Sanctuary, opportunities to visit local wineries, and Saturday night cook-out and movie (in season)
Please contact the Savannah House for reservations!
Copyright 2010 ecoyogaretreats. All rights reserved.


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Salvia provides a ton of color and interest in the landscape. Here are four beautiful new varieties that you can produce for your 2014 sales seasons.
September 15, 2014
Harvest Automation Has Moved More Than 5 Million Plants Following Free Robot Work Offer
Harvest Automation recently released a report on the progress of its HV-100 Robots this summer. The HV-100 Robots have been busy since the company started offering free robot work earlier this year to greenhouses and nurseries.
July 30, 2014
Ball Seed's 2014 Field And Landscape Day Geared Toward The Customer Experience
The Ball Seed Field and Landscape Day, held on July 25, 2014 in West Chicago, Ill., featured more than 150,000 plants for growers, landscapers and retailers to enjoy.
July 22, 2014
Six New Edibles Make The All-America Selection List
All-America Selections announces six new edibles as its first six winners for the 2015 gardening season.
June 20, 2014
New Genus Sneak Peek From Terra Nova Nurseries, Mukgenia Nova 'Flame'
Terra Nova Nurseries introduces a brand-new genus, Mukgenia Nova 'Flame,' as part of its Sneak Peek variety introductions.
Salvia provides a ton of color and interest in the landscape. Here are four beautiful new varieties that you can produce for your 2014 sales seasons.
When and where will Saucy Red Salvia be available?
July 20, 2016
How To Prevent Greenhouse Heating Leaks
Ethylene from malfunctioning greenhouse heaters can lead to crop injury, while carbon monoxide can lead to worker illness. Know the symptoms and how to check greenhouse heaters to avoid these concerns.
April 5, 2016
Portland Garden Stores: Check Out Where The GCA Tour Will Be Stopping
Garden Centers of America [GCA] has announced this year's Summer Tour itinerary. There will be 17 stops at various locally owned garden stores, growers and inspirational throughout the greater Portland area. All 17 stops will fit into a 3-day tour, taking place from June 26 to 29. Retailers on the tour will travel on June 26 and meet for an evening reception before leaving for the tour on Monday morning, June 27. "Network with your fellow garden center professionals and energize your business with fresh retail strategies driven by the best practices proven to power profits. Bring your toughest questions to each tour stop for answers," a GCA press release says. Here's the list of stops: Al's Garden Center, Gresham Al's Garden Center, Sherwood Al's Garden Center, Woodburn Bauman's Farm & Garden, Gervais Cornell Farm, Portland Farmington Garden, Beaverton The Garden Corner, Tualatin Garden Fever, Portland Gardener's Choice, Tigard Good News Gardening, […]
March 29, 2016
Registration Is Now Open For Both IGC Shows
Registration is now open for The Eastern Show for IGCs and IGC Show Chicago, event organizers just announced. Quick-click registration takes only minutes at the event websites, www.EIGCshow.com and www.IGCshow.com, which detail everything planned for the summer industry gatherings. At both events, the trade show, three keynotes and Tuesday evening's party and concert are all free. For a limited time, 'All-Access Pass' Packages, providing entry privileges to the interactive retail education conference and other key benefits, are available at a discounted rate. EIGC – The Eastern Show for IGCs will be held August 2-4 at the Valley Forge Casino Resort just outside Philadelphia. In addition to offering slots and table games for gaming enthusiasts, the venue offers seven diverse on-site dining options, including celebrity chef Luke Palladino's LP Steak, a newly renovated spa and fitness center, easy access from all major roads and free valet parking daily – all in an […]


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The exact location of the various Courts and the function of each building is shown in this aerial photograph. Place the pointer on each building marked with a green dot to see a description. Click to go to the page of the relevant court.
A new District Court building will be erected in the same location in the near future.
Contact information Postal address: Nicosia District Court Charalambos Mouskos Street 1405 - Nicosia Cyprus Telephone: (+357) 22865518 Fax:(+357) 22304212 / 22805330 e-mail: firstname.lastname@example.com
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From | Jake Mannix <jake.man...@gmail.com> |
Subject | Re: lucene and solr trunk |
Date | Tue, 16 Mar 2010 21:42:02 GMT |
On Tue, Mar 16, 2010 at 2:31 PM, Michael McCandless < firstname.lastname@example.com> wrote: > > If we move lucene under Solr's existing svn path, ie: > > /solr/trunk/lucene Chiming in just a bit here - isn't there any concern that independent of whether or not people "can" build lucene without checking out solr, the mere fact that Lucene will be effectively a "subdirectory" of solr... is there no concern that there will then be a perception that Lucene is a subproject of Solr, instead of vice-versa? The way mavenified projects work is that there would instead be a top level in which both solr and lucene would be submodules (and thus also subdirectories in svn), with a dependency from solr to lucene (in the pom.xml for maven, but easy enough to do with the build.xml with ant). Checking out solr without lucene should be doable (using snapshot jars from lucene trunk nightly, maybe?), and the reverse should be easy, as could be checking out the top-level and getting everything (including a top-level build.xml which <include>'s or antcall's into the subdirectory build.xmls). It seems really weird to have Lucene appear as a subdirectory of Solr, especially for people out there who aren't using Solr. -jake | |
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Recent Articles and Reviews
OCZ Vertex 4 256GB Solid State Drive
Samsung 830 256GB Solid State Drive
RAIDMAX Raptor Mid-Tower Gaming Case
DIAMOND Radeon HD 7970 3GB Double Black Diamond Video Card
120-128GB Solid State Drive Roundup (Mac + PC)
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Thermaltake and MSI World First LGA 2011 Collaboration
November 15, 2011 - 8:30am — brandon
Thermaltake and MSI World First LGA 2011 Collaboration Tendering Fanatics with Thermaltake Frio Advanced and MSI X79A-GD65 (8D) Mainboard Simultaneously
Taipei, Taiwan -November 15, 2011-Thermaltake, being the industry pioneer
brand in thermal solutions, carrying the corporate vision of "building Thermaltake
Technology into a cultural brand for the enjoyment of entertainment, e-Sports,
technology, and lifestyle" and continues to drive toward the corporate mission
of "delivering the perfect user experience" on all segment of the market. Today, is
thrilled to announce the global partnership with MSI, the leading international
mainboard and graphics card maker, on the joint of a limited sale promotion hosted by
MSI. The limited sale promotion offers fanatics Thermaltake Frio Advanced CPU
cooler and MSI X79A-GD65 (8D) mainboard as a package. Both items will prepare
fanatics for LGA 2011 socket which support the latest Intel's 2nd generation Core i7
"We are very happy to form this new global sales partnership with MSI to provide
consumers with the best platform performance. Both brands will benefit from this
development," said Louis Huang, Thermaltake Executive Vice President of Business
Operation. "Thermaltake is a leading provider of computer cooling solutions and we
began offering the Frio CPU cooler series 2010. The Frio is designed to effectively
reduce the temperature of CPUs, even when overclocked. Thermaltake has now
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Document Type: | Book |
All Authors / Contributors: |
Myron F Weiner; Anne M Lipton; American Psychiatric Association. |
OCLC Number: | 744289016 |
Description: | xxxiv, 428 pages, [8] pages of plates : illustrations (some color) ; 21 cm |
Contents: | pt. I. Assessment and diagnosis -- Neuropsychiatric assessment and diagnosis / Myron F. Weiner, Robert Garrett, Mary E. Bret -- Medical and neurological evaluation and diagnosis / Anne M. Lipton, Craig D. Rubin -- Neuropsychological assessment / C. Munro Cullum, Laura H. Lacritz -- Neuroimaging / Norman L. Foster -- Alzheimer disease / David S. Geldmacher -- Mild cognitive impairment / Yonas E. Geda, Selamawit Negash, Ronald C. Petersen -- Vascular cognitive disorder / Cassandra E.I. Szoeke [and others] -- Dementia with lewy bodies and other synucleinopathies / Rawan Tarawneh, James E. Galvin -- Frontotemporal dementia and other tauopathies / Anne. M. Lipton, Adam Boxer -- Traumatic brain injury / Erin D. Bigler -- Other causes of dementia / Edward Y. Zamrini, Mary Quiceno -- pt. II. Treatment -- Treatment of psychiatric disorders in people with dementia / Martin Steinberg, Constantine G. Lyketsos -- Pharmacological treatment of neuropsychiatric symptoms / Roy Yaari, Pierre N. Tariot, Danielle Richards -- Pharmacologic treatment of alzheimer disease and mild cognitive impairment / Martin R. Farlow, Malaz Boustani -- Supporting family caregivers / Kristin Martin-Cook, Myron F. Weiner. |
Responsibility: | edited by Myron F. Weiner, Anne M. Lipton. |
More information: |
In Clinical Manual of Alzheimer Disease and Other Dementias, practicing psychiatrists and neurologists address neuropsychiatric assessment, diagnosis, and treatment of various clinical neuropsychiatric conditions, including Alzheimer disease and traumatic brain injury.
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"The "Clinical Manual of Alzheimer Disease and Other Dementias" edited by Drs. Weiner and Lipton offers the busy professional a concise orientation to the care of patients and families facing the challenge of dementia. This is a multi-authored text with an impressive array of expert contributors. The emphasis is pragmatic as one would expect of a clinical manual but recommendations both pharmacologic and behavioral are based on science."-- "Gary Kennedy, Professor and Director, Division of Geriatric Psychiatry, Montefiore Medical Center, Albert Einstein College of Medicine" Read more...
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Genetic analysis of an allergic rhinitis cohort reveals an intercellular epistasis between FAM134B and CD39
- Rossella Melchiotti†1, 2,
- Kia Joo Puan†1,
- Anand Kumar Andiappan†1,
- Tuang Yeow Poh1,
- Mireille Starke1,
- Li Zhuang1,
- Kerstin Petsch1,
- Tuck Siong Lai1,
- Fook Tim Chew3,
- Anis Larbi1,
- De Yun Wang4Email author,
- Michael Poidinger1Email author and
- Olaf Rotzschke1Email author
© Melchiotti et al.; licensee BioMed Central Ltd. 2014
Received: 5 March 2014
Accepted: 23 June 2014
Published: 27 June 2014
Extracellular ATP is a pro-inflammatory molecule released by damaged cells. Regulatory T cells (Treg) can suppress inflammation by hydrolysing this molecule via ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), also termed as CD39. Multiple studies have reported differences in CD39+ Treg percentages in diseases such as multiple sclerosis, Hepatitis B and HIV-1. In addition, CD39 polymorphisms have been implicated in immune-phenotypes such as susceptibility to inflammatory bowel disease and AIDS progression. However none of the studies published so far has linked disease-associated variants with differences in CD39 Treg surface expression. This study aims at identifying variants affecting CD39 expression on Treg and at evaluating their association with allergic rhinitis, a disease characterized by a strong Treg involvement.
Cohorts consisting of individuals of different ethnicities were employed to identify any association of CD39 variants to surface expression. Significant variant(s) were tested for disease association in a published GWAS cohort by one-locus and two-locus genetic analyses based on logistic models. Further functional characterization was performed using existing microarray data and quantitative RT-PCR on sorted cells.
Our study shows that rs7071836, a promoter SNP in the CD39 gene region, affects the cell surface expression on Treg cells but not on other CD39+ leukocyte subsets. Epistasis analysis revealed that, in conjunction with a SNP upstream of the FAM134B gene (rs257174), it increased the risk of allergic rhinitis (P = 1.98 × 10-6). As a promoter SNP, rs257174 controlled the expression of the gene in monocytes but, notably, not in Treg cells. Whole blood transcriptome data of three large cohorts indicated an inverse relation in the expression of the two proteins. While this observation was in line with the epistasis data, it also implied that a functional link must exist. Exposure of monocytes to extracellular ATP resulted in an up-regulation of FAM134B gene expression, suggesting that extracellular ATP released from damaged cells represents the connection for the biological interaction of CD39 on Treg cells with FAM134B on monocytes.
The interplay between promoter SNPs of CD39 and FAM134B results in an intercellular epistasis which influences the risk of a complex inflammatory disease.
Epistasis Treg Monocyte eQTLs Allergic rhinitisBackground
Allergic Rhinitis (AR) is a common airway disease where allergen exposure triggers an IgE-mediated immune response. The typical symptoms include nasal itchiness, rhinorrhea, sneezing and progressive blockage of the inflamed nasal passages [1]. The disease is driven by a complex interplay of various leukocytes, including mast cells, eosinophils and basophils but also CD4+ T cells, IgE-producing B cells and dendritic cells. Th2 cytokines such as IL-4, IL-5 and IL-13 drive IgE production, promote eosinophil infiltration to the nasal mucosa, and stimulate mast cell release of key vasoactive mediators such as histamine [2–4]. In this context also monocytes are important effectors and regulators of inflammation [5]. While pro-inflammatory monocytes can fuel the allergic reaction by releasing cytokines such as TNF-α and IL-6, they can be converted into anti-inflammatory monocytes to dampen the reaction [6].
Central to the prevention or attenuation of pro-inflammatory immune responses are CD4+ Foxp3+ T regulatory cells (Treg). They can inhibit the proliferation of CD4+ effector T cells and impair the production of various Th2 cytokines [7–10]. A key mechanism by which Treg exert their regulatory function is the expression of the ectoenzyme CD39 [11, 12]. CD39 is involved in the hydrolysis of extracellular ATP, which is typically released from cells following tissue damage. ATP-sensors such as P2X- and P2Y-receptors are important mediators of allergic airway inflammation and their blockade has been shown to strongly suppress allergic reactions in experimental asthma models [13, 14]. Treg-expressed CD39 thus contributes to the control of inflammation via the removal of ATP [11, 12]. Genetic and phenotypic correlations of CD39 variants have already revealed strong associations with inflammatory bowel disease [15] and multiple sclerosis [11, 16], as well as with viral infections including HIV [17] and Hepatitis B [18]. However, a link between CD39 and allergic diseases has not previously been identified.
In the current report we demonstrate that variation in cell surface expression in Treg cells is associated with a genetic polymorphism (rs7071836) located in the promoter region of CD39. On its own this polymorphism had no direct impact on risk of AR but associated with disease risk through an epistatic interaction with rs257174, a promoter SNP of the cis-Golgi protein FAM134B. As rs257174 alters the gene expression in monocytes but not in Treg cells this represents the first example of an intercellular epistasis.
Ethics statement
This study has been approved by the Institutional Review Board of the National University of Singapore (IRB ref. NUS 07–023, NUS 10–343 and NUS 09–256) and complies with the Helsinki declaration. Written informed consent was obtained from all donors prior to sample collection.
Study populations
Case–control cohorts
We used two age-matched cohorts of Singapore Chinese individuals [19], including 456 AR cases and 486 non-atopic controls for investigative discovery and a separate cohort of 676 AR cases, 511 non-atopic controls and 1647 atopic individuals without AR symptoms for validating our statistical interaction and estimating the role played by atopy in the epistasis. These two cohorts were used to evaluate the role played by the variant rs7071836 in AR risk both in the context of disease association and epistatic phenomena. Details of sample collection for each cohort and the genotyping and quality control filters applied for the discovery cohort, are described in [19]. Cases were defined as individuals displaying a positive skin prick test for at least one of the two house dust mite allergens tested (Dermatophagoides pteronyssinus, Blomia tropicalis) and exhibiting two or more symptoms of nasal blockage, sneezing, nasal itching, and rhinorrhea. Controls were defined as skin-prick test negative individuals with no history of allergic disease or AR symptoms. All individuals were genotyped using the Illumina HumanHap 550 k BeadChip version 3 (Illumina, San Diego, California). Due to constraints in the number of available Sequenom slots 20 SNPs were selected for replication. Genotyping of the 20 SNPs chosen for replication in the validation cohort was performed using Sequenom's MassARRAY system and iPLEX technology (Sequenom Inc, San Diego) on 2834 samples. The experiment was carried out according to the manufacturer's guidelines. SNPs were called using the Sequenom TYPER software and were checked for deviation from Hardy-Weinberg equilibrium (variants with an adjusted P-value <0.05 in controls only or across all samples were excluded from the analysis; rs2900474, P unaffected = 6.01 × 10-10; rs4862396, P unaffected = 8.53 × 10-4).
Functional cohorts
An independent cohort of 165 ethnic Chinese volunteers was recruited to validate the genotype-phenotype association between rs7071836 and CD39 protein expression. Samples were collected in a similar manner and were age- and gender-matched to the case–control cohorts. Genotyping was performed on a genome-wide scale using the Illumina HumanOmni5-Quad chip (Illumina, San Diego, California) on DNA extracted from blood following standard protocols. SNP calling was carried out using the Genome Studio genotyping module (Illumina, San Diego, California). The same quality control filters were applied as those described for the case–control cohorts.
A small cohort of 41 self-reported Chinese individuals and 22 self-reported Caucasian subjects was recruited internally and then phenotyped for CD39 protein expression by T regulatory cells to evaluate the relative frequency of the 'CD39lo' phenotype in each ethnic group.
Published whole blood cohorts
Three published cohorts (Kora F4 [20], DILGOM [21], SHIP-TREND [22]) for which whole blood gene expression measurements were available were used to correlate CD39/FAM134B expression levels. The three cohorts are composed respectively of 993, 518 and 991 healthy individuals of Caucasian ethnicity. A detailed description of how each cohort was collected and samples were processed can be found in the respective publications. Gene expression processed values were downloaded from the corresponding public online repositories Array Express (E-MTAB-1708, E-TABM-1036) and Gene Expression Omnibus (GEO) (GSE36382).
FACS analysis
In both functional cohorts, CD39 expression was determined by FACS staining of PBMCs pre-incubated with LIVE/DEAD Fixable Blue Dead Cell Stain kit (Invitrogen) to identify viable cells. The cells were then incubated with anti-CD39 APC (clone TÜ66), anti-CTLA-4 PE (clone BNI3), anti-CCR6 PerCP-Cy5.5 (clone 11A9), anti-CD4 APC-Cy7 (clone RPA-T4), anti-CD25 PE-Cy7 (clone M-A251), anti-CD45RA eFluor605 (clone H100) mAbs. Intracellular staining of Treg was conducted using the anti-FoxP3 eFluor450 (clone PCH101) Staining kit (eBioscience). Adult peripheral blood T cells either express CD45RA or CD45RO and few cells are double positive or double negative [23]. In our cohort, CD45RA- FoxP3+ CD25+ CD4+ T cells are termed as CD45RA- T regulatory (Treg) cells (CD45RO+) whereas CD45RA- FoxP3- CD25- CD4+ are CD4+ effector T (Teff) cells (CD45RO+). The level of CD39 expression was measured using a BD LSR II flow cytometer (BD Biosciences). The gating strategy for Treg, T effector cells, B cells and monocytes is outlined in Additional file 1: Figure S1. The variability of CD39 expression among human Treg from different donors was established by calculating the ratio of CD39 geometric mean fluorescence intensity relative to the CD39 geometric mean fluorescence of donor-matched B cells (which constitutively express high levels of CD39). Samples were classified as CD39 high expressing Treg ('CD39hi') or CD39 low expressing Treg ('CD39lo') using the unsupervised clustering method k-means on the log2-transformed ratios. The analysis was performed using the function k-means in R 2.15.1 [24], with the number of clusters set to two. Each population was considered and classified separately. CD39 expression values for the two groups as clustered by the k-means method are depicted in Additional file 2: Figure S2.
Cell sorting
Human blood was collected into BD K2 EDTA vacutainers (Becton, Dickinson and Company) and the PBMCs were isolated by centrifugation over Ficoll-Paque density gradients (GE Healthcare) for 30 min at 400 × g. PBMCs were then re-suspended in FACS buffer (0.5% bovine serum albumin, 2 mM EDTA in PBS) and incubated at 4°C for 15 min with anti-CD49d FITC (clone MZ18-24A9, Miltenyi Biotec), CD127 PE (clone HIL-7R-M21), CCR6 PerCP-Cy5.5 (clone 11A9), CD4 APC-Cy7 (clone RPA-T4) CD25 PE-CY7 (clone M-A251), and CD19 Alexa700 (clone HIB19). All mAbs were purchased from BD Biosciences unless otherwise stated. After incubation, the cells were washed and re-suspended in FACS buffer at 1–1.5 × 107 cells/ml for cell sorting of Treg, T effector cells, B cells and monocytes using a BD FACS Aria II cell sorter (BD Biosciences). See Additional file 3: Figure S3 for cell sorting strategy.
Expression analysis
FACS-sorted Treg, T effector cells, B cells and monocytes were obtained from 15 healthy donor blood samples selected from the discovery cohort. Target ssDNA was prepared starting with 50 ng total RNA (RIN ≥ 7.1) using the Ambion WT Expression Kit and the Affymetrix WT Terminal Labelling kit. Fragmented ssDNA was hybridized to the Affymetrix Human Exon 1.0ST Arrays. The GeneChip arrays were washed and stained using the GeneChip Fluidics Station 450. After staining, the GeneChip arrays were scanned using a GeneChip Scanner 3000 at the BSF Microarray Facility. Array QC was conducted using the Affymetrix Expression Console Software. Raw data were normalized using the Robust Multi-Array Average (RMA) at the gene level [25].
Monocyte ATP treatment
Monocytes from individuals heterozygous for rs257174 were purified from PBMCs by positive selection using MACS human CD14 MicroBeads (Miltenyi Biotec) according to manufacturer's instructions. Monocytes were plated at 0.5 × 106 cells/well in 24-well tissue culture plates and then incubated with or without cell culture-grade ATP disodium salt hydrate (Sigma-Aldrich) in RPMI-1640 supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 1 mM sodium pyruvate, 100 units/ml of penicillin and 100 μg/ml of streptomycin. For the inhibition of ATP the incubation was carried out in the presence of 10 μM of the purinergic receptor inhibitor A-438079 hydrochloride (Tocris Bioscience). Monocytes were incubated for 2 h before harvesting using cell scrapers. The treated monocytes were stored in TRIzol (Invitrogen Life Technologies) at -80°C until further analysis.
Genotyping was performed by PCR using SsoFast EvaGreen Supermix (Bio-Rad) on a CFX96 Real-Time System (Bio-Rad). DNA was isolated using DNeasy Blood & Tissue Kits (Qiagen) according to the manufacturer's instructions. The following primers were used for the analysis: FAM134B rs257174 forward primer: GCACGCTTTTGCCTTTGTAAT; FAM134B rs257174 reverse primer: CACCCACTGGGAGAAAAGAC. Amplification was carried out using the following protocol: 3 min at 95°C, 40 cycles of 5 s at 95°C, 5 s at 58°C, and final extension for 10 s at 95°C. A melt curve was generated from 65 to 95°C (in 0.2°C increments) with 10 s/step. Genotype analysis was performed using Bio-Rad Precision Melt Analysis software.
Quantitative RT-PCR
Total RNA was isolated using TRIzol and RNeasy RNA isolation Kits (Qiagen) according to the manufacturer's instructions. Reverse transcription was performed using QuantiTect Reverse Transcription Kits (Qiagen). Expression analysis was performed by real-time PCR on a CFX96 Real-Time System (Bio-Rad). The analysis was carried out using the following protocol: 30 s at 95°C, 40 cycles of 5 s at 95°C, and ending with 5 s at 62°C. HPRT was used as the housekeeping reference gene for normalization. qRT-PCR was run using the following primers: FAM134B forward primer for the long isoform (Exon1,2): CTGCTGTTCTGGTTCCTTGC; FAM134B reverse primer for the long isoform (Exon1,2): CGCCCAAGTATCATGACGGA; FAM134B forward primer for the short isoform (Exon4,5): GCAGCCTTTGCCACTGTTATTAT; FAM134B reverse primer for the short isoform (Exon4,5): ATAACTTCCCAGCTTTTGCCTG; HPRT forward primer: CTCAACTTTAACTGGAAAGAATGTC; HPRT reverse primer: TCCTTTTCACCAGCAAGCT.
Statistical analysis
Association analysis was performed using the command --logistic in PLINK v.1.07 [26] software including sex as a covariate (--sex). Due to the homogeneity of the cohort (which consisted of Singapore Chinese university students only), age and population were not included as factors in the model. Gene-gene interactions were evaluated in PLINK v.1.07 [26] conditioning on rs7071836 using the command --condition, fitting a logistic model (--logistic --interaction) and including sex as a covariate (--sex).
where A represents the allele dosage for the first SNP, B represents the allele dosage for the second SNP, AB is the interaction term, and S is the sex covariate.
Association between rs7071836 and CD39 cell surface expression was evaluated using Kruskal-Wallis testing on geometric mean intensity values. Association between genotypes and gene expression was evaluated using one-way ANOVA on log2-transformed expression values considering each genotype class as a distinct group (Graphpad Prism 6).
Differences in gene expression between control samples and samples treated with ATP were evaluated using repeated-measures ANOVA on ∆c(t) values with the assumption of sphericity. The mean of each group was compared to the mean of the control samples using Tukey's multiple comparisons test. Concentration specific effects were evaluated using the post test for linear trends in Graphpad Prism 6. Normality was assessed using the Shapiro-Wilk normality test as implemented by the function shapiro.test in R 2.15.1 [24]. Homoscedasticity was tested using the Bartlett test of homogeneity of variances as implemented by the function bartlett.test in R 2.15.1 [24]. Clustering of whole blood CD39 gene expression into three groups (CD39lo, CD39int, CD39hi) was performed using the unsupervised clustering method k-means as implemented by the function kmeans in R 2.15.1 [24] with the number of clusters set to three. Differences in FAM134B expression across the three groups (CD39lo, CD39int, CD39hi) were estimated using Kruskal-Wallis. Pairwise differences between CD39lo and CD39hi groups were tested using Dunn's multiple comparison test (Graphpad Prism 6). Correlation coefficients and significance were computed using Spearman correlation and the fitting line was evaluated using linear regression (Graphpad Prism 6). Each cohort was analyzed independently.
Linkage disequilibrium plots were built using the software ArchiLD [27] on LD values estimated from the 1000 Genomes Pilot Project for CHB + JPT [28].
Power estimation
Power estimation for epistatic interactions was performed using QUANTO software [29] with a significance threshold of 5 × 10-8 for the discovery study and 0.0025 for the validation study (Bonferroni correction for 20 tests). For both genes, the mode of inheritance was hypothesized to be log-addictive. Prevalence was set to 13% in both the discovery and validation cohorts. For each epistatic pair the allele frequency for the first SNP participating in the interaction was set to 0.25 (i.e. the allele frequency of rs7071836 in the discovery cohort) and the allele frequency of the second SNP was set to the allele frequency, in the discovery cohort, of the epistatic partner under consideration. RGH, the interaction effect, was set to the OR of the interaction in the discovery cohort.
CD39 expression on Treg is influenced by promoter SNP rs7071836
Accordingly, FACS analysis of a larger cohort of 165 ethnic Chinese blood donors confirmed that rs7071836 SNP variants are indeed strongly associated with the phenotype of Treg cells (Figure 1C). Notably, the correlation was restricted to Treg, since CD39 expression on monocytes, B cells and T effector cells appeared unaffected by the allelic state of the SNP. In line with our finding a variant in strong linkage disequilibrium (LD) with rs7071836 was recently reported as being associated with the percentage of CD39+ activated CD4+ Treg in a Caucasian population [34].
SNP rs7071836 tags a cluster of perfectly-linked SNPs
SNP rs7071836 affects AR risk via epistatic interaction with rs257174
Association results for rs7071836 and AR in a Singapore Chinese population
Gene | SNP | Test | Frequency cases | Frequency controls | Allelesa | MAFb | ORc[CId95%] | P-value |
CD39 | rs7071836 | LOGISTIC | 0.25 | 0.25 | G/A | 0.25 | 1.03 [0.83-1.27] | 0.82 |
To identify the 'true' epistatic partners of rs7071836 an independent Singapore Chinese replication cohort consisting of 676 atopic AR cases and 511 non-atopic asymptomatic controls was employed [19]. Twenty SNPs were selected for replication and genotyped by Sequenom (Sequenom Inc, San Diego). After Bonferroni correction, the power to detect a significant interaction was estimated to be 0.88 - 0.99 (Additional file 5: Table S2). This finally allowed us to confirm an interaction of rs7071836 with a second SNP located ~12 kbp upstream of gene FAM134B (rs257174).
Summary of the statistical interaction between rs7071836 and rs257174 across all cohorts
Discovery | Validation | Combined | |||||
SNP1 | SNP2 | ORa interaction [CIb95%] | P interaction | ORa interaction [CIb95%] | P interaction | ORa interaction [CIb95%] | P interaction |
rs7071836 | rs257174 | 0.45 [0.31- 0.66] | 3.64 × 10 -5 | 0.59 [0.41-0.84] | 4.02 × 10 -3 | 0.53 [0.41- 0.69] | 1.98 × 10 -6 |
Epistatic interaction between rs7071836 and rs257174 is associated with AR risk but not atopy
Atopy contribution to the statistical interaction between rs7071836 and rs257174 in the validation cohort
SNP1 | SNP2 | AR cases | Samples with atopy but no AR | ORa[CIb95%] | P-value |
rs7071836 | rs257174 | 676 | 1647 | 0.69 [0.52-0.91] | 9.60 × 10 -3 |
SNP1 | SNP2 | Samples with atopy but no AR | Non atopic samples | OR a [CI b 95%] | P-value |
rs7071836 | rs257174 | 1647 | 511 | 0.87 [0.66-1.15] | 0.34 |
SNP rs257174 influences FAM134B expression levels in monocytes
In-line with our findings, the influence of rs257174 on FAM134B expression has also been detected by other investigators conducting transcriptome studies of human monocytes [36, 37]. For this cell type, 3 of the SNPs in the rs257174-cluster are located in close proximity to an open chromatin region (DNase I Hypersensitivity peak), which, by ENCODE criteria, suggests a functional role in the regulation of gene expression [38] (Figure 3A).
CD39 expression is negatively correlated with FAM134B expression in whole blood
Extracellular ATP enhances FAM134B expression
In this study we provide the first evidence that intercellular epistatic interactions can influence risk of complex human diseases. In this case, rs7071836, which modulated CD39 expression by human Treg, interacted with rs257174, which altered FAM134B gene expression in blood monocytes to affect the risk of AR. Both are functionally connected via extracellular ATP, a damage-associated molecule involved in eliciting a range of host inflammatory responses.
In a cohort of Singapore Chinese volunteers this novel epistatic interaction is associated to risk of allergic rhinitis. With an estimated disease prevalence of 13% [39] and an OR of 0.45, our study exhibited only 5% power to detect our CD39/FAM134B interaction in the discovery cohort at a significance threshold α = 5 × 10-8. We therefore elected for a replication approach to improve the power of the study. By this approach, our power for detection was increased to 89% (α = 0.0025 after Bonferroni correction for 20 tests) with a combined P-value of 1.98 × 10-6. While the epistasis was anchored on rs7071836, an eQTL known to regulate the surface expression of CD39, the epistasis-partner revealed by the statistical analysis also turned out to be functional. Polymorphism rs257174 was part of a SNP-cluster associated with the expression of the cis-Golgi protein FAM134B. Moreover, while the allelic combination of the epistasis suggested that the expression of CD39 and of FAM134B were inversely linked, this correlation could actually be validated from the expression data of a full blood transcriptome analysis.
CD39 is an ecto-ATPase that depletes extracellular ATP from the local microenvironment. Since extracellular ATP is a key indicator of host tissue damage, the efficacy of ATP removal by CD39 has been associated with various inflammatory conditions including autoimmune diseases, viral infections and cancer progression. The CD39 promoter SNP rs7071836 responsible for the effect is part of a large cluster of perfectly linked SNPs containing polymorphisms already implicated in Crohn's disease [15] and in progression of AIDS [17]. Our study indicates that in conjunction with a cluster controlling FAM134B it is also an important component of AR risk. While the biological function of CD39 is well-established, the exact role played by the epistatic partner remains enigmatic. As a newly identified cis-Golgi protein, it has only been shown to be expressed on few cell types mostly associated with the neural system [40–42]. While the protein was detected in autonomic and sensory ganglia, deleterious mutations in this gene have been shown to cause hereditary sensory and autonomic neuropathy type II (HSAN II), a severe genetic disease characterized by a dysfunction of the autonomic system and impaired nociception [40]. FAM134B knock-down in a mouse N2a neuroblastoma cell line resulted in a smaller cis-Golgi compartment and impaired cell proliferation, and FAM134B knock-down in cultured dorsal root ganglion mouse neurons resulted in apoptosis of nociceptive neurons [40]. FAM134B may therefore be involved in mediating multiple cellular pathways that affect the maturation and export of protein precursors and cell surface receptors.
Although FAM134B has been primarily associated with the nervous system, the expression of this gene is in fact far more widespread. Overexpression of FAM134B has been reported before in human esophageal squamous cell carcinoma [43] and this study provides evidence for a constitutive expression in multiple different populations of human leukocytes. The FAM134B molecule thus seems likely to play a significant role in host immune protection and inflammatory responses. Further work will now be required to fully dissect the role played by FAM134B in the numerous different leukocyte subsets that comprise the human immune system. Considering that FAM134B is located in the cis-Golgi compartment, this protein could potentially be involved in vesicle trafficking and may influence cytokine secretion by monocytes in response to external stimuli including ATP.
- Treg:
regulatory T cells
Allergic Rhinitis
Single Nucleotide Polymorphism
Linkage Disequilibrium
Adenosine Triphosphate
House Dust Mite
Hypoxanthine Guanine Phosphoribosyltransferase
- IgE:
Immunoglobulin E
Peripheral Blood Mononuclear Cell.
The authors would like to thank Bernett Lee and Pavandip Singh Wasan for their statistical advice, Josephine Lum and Francesca Zolezzi for performing the microarray experiments, Raffaele Calogero for normalizing the expression arrays, Neil McCarthy of Insight Editing London for critical review of the manuscript, and all the volunteers and their family members who participated in this study. All the Singapore Immunology Network authors are supported by the A*STAR/Singapore Immunology Network core grant. This study was supported by grants from the Singapore Immunology Network (SIgN-06-006, SIgN-08-020 and SIgN-10-029), Singapore; the National Medical Research Council (NMRC/1150/2008), Singapore; the Biomedical Research Council, Singapore; Agency for Science, Technology and Research (A*STAR), Singapore, the National University of Singapore (NUS) for the Graduate Research Scholarship and the A*STAR Research Attachment Program (ARAP) for the students involved in the study. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Authors' Affiliations
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Pre-publication history
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.


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You might recall Stan Sperlak from the June 2012 issue of Pastel Journal. His exquisite pastel paintings were featured in an article on rendering the sky at sunrise or sunset. If you were as enchanted by his pastel landscapes as we were, you'll want to jump at the chance to learn the artist's innovative and direct pastel techniques.
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October 23, 2009
How do you really feel about the black person who is standing next to you on the elevator? What really goes through your mind when you pass an Asian person in the grocery store? Dr. Phil tackles hidden racial biases, and he has help from a panel of experts: comedians Paul Mooney, Kate Rigg and Manny Maldonado, civil and family attorney Areva Martin, USC professor of sociology Amon Emeka and radio host Michael Graham.
Myths about the President
Dr. Phil and his panel examine the subtle attacks many feel have been launched against President Obama.
Don't miss this no-holds barred discussion!
Breaking Down Stereotypes
From crime rates to eating habits, there are prejudiced attitudes that people hold about other races. Dr. Phil has members of his panel bust each stereotype.
"White people, my white brothers, you cannot wear cornrows!"
Painful Perception
Howard says that when he's out in public, white people shun him. He says they don't want to walk near him, and when they see him approaching, they move away.
Dr. Phil conducts an experiment with Howard and an audience member!
Culture Clash
Vicki complains that her children have to learn Spanish in school because of Hispanics, and she admits that she has a bias against Asians.


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Comments (5) - by Edwarus07/07/12by MizT07/07/12
Build Up
what build up? You jumped into this one right where your first story ended. Only this started on a much darker side. W/the deaths of many Neko and thru no fault of their own but rather the fault of a human. Well is sounds like maybe you are going to introduce us to another group of Neko, just don't let the humans get these guys killed too. I look forward to chapter 2 and your next big surprise.....
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Tim Tebow made his analyst debut for ESPN at the BCS National Championship Game on Monday. With the nation watching as the crew made their picks, Tebow laid his out there. The former Heisman Trophy winner predicted a 35-31 win for Florida State.
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There was no way he was going to predict the exact score in his first go of things, right? Well, he didn't actually nail the score on the head, but it was as close as one could come. The Seminoles knocked off the Auburn Tigers, 34-31, just a few short hours after the oracle made his prediction.
[Video via SportsToday]


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- //Home
- //Books
- //Joanna Demers
Free Samples
Bad artists copy. Great artists steal.
—Pablo Picasso
The broad acceptance of the iPod and proliferation of websites from which to legally download music would seem to have solved, for the time being at least, the absurdity of record companies suing 14-year olds for copyright infringement. (Although on the corner of Broadway and 28th Street in New York City, the location of the original Tin Pan Alley, the bootleg-CD/DVD trade remains brisk, helping keep local constabularies occupied.) But according to musicologist Joanna Demers, something more crucial is at stake in today's overreaching intellectual property regime, namely the future of musical creativity itself. It's the subject of Steal This Music: How Intellectual Property Law Affects Musical Creativity, a concise, clearly written book that deserves to be read well beyond the academic community to which its university-press imprint might tend to restrict it.
Steal This Music: How Intellectual Property Law Affects Musical Creativity
Joanna Demers
(University of Georgia Press)
To begin, Demers draws important distinctions between plagiarism, piracy and what she calls "transformative appropriation." The first is copying someone else's work and trying to pass it off as one's own; the second is outright stealing of someone else's product. The third entails using a preexisting work in the process of creating something new. The distinctions between these three concepts are now being blurred as intellectual property owners (who for the most part aren't the creators) of compositions and recordings try to muscle their way to higher profits. The first two are generally agreed to be forms of theft, Demers notes, but the third is the way music (not to mention a lot of other art) has been created since the dawn of human culture. It's also the area where creativity is becoming increasingly stifled by often exorbitant licensing fees and intimidating cease-and-desist orders. The intellectual property rights jihad has gotten more virulent as technology has made it easier for preexisting works to sampled, remixed, and otherwise used outside of "approved" (read: revenue-generating) channels.
The notion of copyright originates with the invention of moveable-type printing in the 15th century. Before that, all manuscripts were handmade and in essence originals; there were no mass-produced copies over which to exert reproduction rights. The first copyrights weren't granted until the mid-1600s. Called "letters patent," they were initially given to publishers not authors and amounted to the right to print documents the government had authorized for public distribution, such as official decrees and statutes, certain religious and scientific texts, and various transaction records like property deeds. A pirate press also operated during this period, presenting views opposed to the ruling order and publishing a variety of other material. With the rise of bourgeois society, controlling public opinion gave way to the pursuit of financial gain. In order to encourage competition, the British Parliament established the Statute of Anne in 1710 that for the first time granted copyright to authors, but only for 14 years after which the work entered the public domain. As few authors and composers could afford to print and distribute their own work, they usually transferred their copyright to publishers, a practice that continues today.
Music has presented copyright challenges nearly from the start, according to Demers, in part because the law has generally lagged behind technology. The first English, French and American copyright laws classified sheet music under books, protecting notes on the printed page but not live performance. In the mid-1800s, US copyright law was changed to restrict the performance of music that was part of a dramatic work such as a stage play or review. Later amendments gave copyright holders exclusive rights to all public performances of their work but proved nearly impossible to enforce due to the wide range of venues where music was played. The American Society of Composers, Authors and Publishers (ASCAP) was created in 1914 to administer performance rights and pay royalties to holders of copyrights on protected compositions. Still, innovations of the day like player pianos and wax-cylinder recordings eluded then-existing copyright law, which only covered human performance not mechanical replay. It wasn't until the Sound Recording Act of 1971 that recorded media were included in copyright statutes.
In recent years, claims to intellectual property rights protection have expanded in an attempt to cover every contingency and thereby lock up every possible source of income. This has been achieved in part through the promotion of what are known as "neighboring rights," i.e., rights that aren't part of the original copyright but held to issue from it, such as trademarked performance style and so-called publicity rights over how a protected work can experienced or used. The rationale for this expanded definition (some might say power play) of intellectual property is the supposed moral right of authors and composers to profit from their creativity. As Demers notes, this is at best misleading if not blatantly dishonest as the primary beneficiaries aren't the artists but the corporate conglomerates that control access to their work. And it might not benefit society either, Demers more importantly argues, as it can prevent new work from being made. This is especially true in recent times when preexisting recordings have served as source material for entirely new musical forms such as concrete and minimal music, hip-hop, and electronica, which question the model of authorship that has prevailed in Western society since at least the Romantic Age.
Indeed, Demers' book serves one of its most useful functions by reminding readers that the Romantic conception of authorship, which includes composers, artists and other creative types, is exactly that: romantic. "The ideal of the author as a lone genius contradicts the fact that transformative appropriation has informed most musical traditions," she observes. Folk music has always relied on shared and repurposed source material as has jazz improvisation. (For years, alto saxophonist Paul Desmond, to cite one example, tested listeners' ability to pick out quotations from Prokofiev's Peter and the Wolf in his solos; many of the bebop classics of Charlie Parker are based on the chord changes of standards like "How High the Moon" and "I've Got Rhythm.") Mozart wrote variations on themes by Haydn, and Bela Bartok incorporated traditional Hungarian melodies into his compositions. John Cage wrote pieces where the "instruments" were radios and the "music" instructions to turn knobs this way or that, mashing up whatever was being broadcast over the airwaves at the time and place of performance. The scratchers, samplers, and loopers of today are carrying on with business as usual if by other technological means.
Besides the technology gap, copyright law, especially as it pertains to music, is marked by another serious disconnect: the tension between private property and culture. Private property as defined under classical economics is the exclusive domain of the individual laying claim to it whereas culture is the bond of shared knowledge, beliefs and practices, including art, music, and other creative productions, which holds society together. Early copyright law sought to resolve this discrepancy by extending exclusive rights only for a brief period. More recent copyright provisions allow exclusive control for upwards of a century and even more, dramatically tilting the scales in favor of long-term property interests. While Demers doesn't add much to the arguments made by "creative commons" proponents like James Boyle, Rosemary Coombe (who writes the book's introduction), and Lawrence Lessig, she does provide several case studies drawn specifically from music that illustrate the some of the unique dilemmas contemporary composers and performers face in negotiating the treacherous terrain of the current intellectual property environment.
There are some bright spots, however. Licensing restrictions over more well-known and thus higher-priced preexisting works have prompted samplers to seek out obscure artists and styles, bringing previously marginalized sounds into the musical mainstream. Some successful artists who have retained control over their catalogs, like George Clinton and David Byrne, have issued pre-cleared versions of their work to encourage transformative appropriation. Others like John Oswald and Negativland have simply defied the powers that be and sometimes faced the consequences. In their wake, anticopyright organizations such as MACOS (Musicians Against the Copyrighting of Samples) and VirComm (Viral Communications) have emerged that enable independent musicians to put their work directly into the public domain. These examples are proof positive that you just can't keep human creativity down, yet Demers cautions that the debate on cultural expression is too important to be left to the self-interest of intellectual property rights holders, whether individual or corporate. It concerns us all. Steal This Music is an excellent introduction as to how and why.
The Romantic Nightmare in Alfred Döblin's 'Bright Magic'
// Re:Print
"The stories in this collection are circular, puzzling; they often end as cruelly as they do quietly, the characters and their journeys extinguished with poisonous calm.
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