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Thursday's game postponed; Doubleheader on Friday
By Springfield Cardinals | May 9, 2013 7:06 PM ET
Springfield, MO - Thursday night's game between the Springfield Cardinals and the Northwest Arkansas Naturals at Hammons Field has been postponed due to continuous rain.
The Naturals were leading, 2-1, in the bottom of the second inning before the umpires sent the game into the rain delay. After a delay of 1:51, the game was postponed.
Thursday's game will be made up as part of a doubleheader on Friday, May 10th, with two 7 inning games beginning at 5:09 pm. Tickets dated for Friday, May 10th, will be valid at the gate for both games of Friday's doubleheader. Gates will open at 4:30pm on Friday, May 10th.
Tickets from the rained out May 9th, 2013 game against the Northwest Arkansas Naturals may be exchanged for any remaining regular season game during the 2013 season. Tickets must be mailed or presented in person to the Cardinals Ticket Office, located at Gate 1 at Hammons Field, at anytime during the remainder of the 2013 season. Complimentary tickets are not exchangeable.
The Cardinals and the Naturals continue the series at Hammons Field this Friday with AM Pyrotechnics Friday Night Fireworks after the second game of Friday's doubleheader. This week's phenomenal fireworks will be set to music from the 80s. First Pitch of Game 1 is 5:09pm, gates open at 4:30pm.
The great Championship giveaways continue this Saturday with the Coca-Cola Texas League Championship Long Sleeve Shirt Giveaway (2,500 fans). Show your Championship pride with these have-to-have shirts! First Pitch is 6:09pm, gates open at 5:09pm.
The homestand wraps up on Sunday with a 2:09pm First Pitch. It's a Hiland Dairy Ice Cream Sunday with a free ice cream party for kids before the game. All kids can then run the bases just like the Cardinals after the game! Gates open at 1:09pm.
For information about becoming a Season Ticket Holder, organizing a Group Outing, booking a Cake Pop Company Birthday Party or ordering Individual Game Tickets right now, call the Front Office at (417) 863-2143 or visit SpringfieldCardinals.com.
Click here for the Cardinals full 2013 Promotional Schedule and to get your tickets right now.
Escape to Cardinals Baseball!
This story was not subject to the approval of the National Association of Professional Baseball Leagues or its clubs.View More


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Best Gastropubs in the U.S.
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18 of 27
Pat's Tap; Minneapolis
Named after the mom of the owner, Wisconsin native Kim Bartmann, this neighborhood hangout is big on Badger State pride (see: Packers memorabilia), vintage gaming (Skee-Ball) and beer: 20 taps and more than 138 cans, featuring craft pours like Minneapolis's Indeed Day Tripper and the seasonal Zombie Monkie porter from the all–can Tallgrass Brewing. Chef Matt Gray's menu is equally lively, from the bacon burger—a 50/50 blend of pork belly and ground beef—to the vegetable curry. patstap.com

subset: commoncrawl


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Video: Star man to watch Andros Townsend
Rory Smith says that Andros Townsend needs to take on as much responsibility for Tottenham Hotspur as he does when he is wearing an England shirt.
The Times football writer believes that the 22-year-old winger is integral to his club side's hopes of overcoming their stuttering form of recent weeks going into Sunday's game against Manchester City.
Watch the video for Rory's full analysis of a player whose impressive displays have won praise for club and country.
Please note: video not available to viewers outside the UK


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2002 Jaguar XJR Reviews and Owner Comments
2002 Jaguar XJR owners review and rate their 2002 Jaguar XJR.
Login to Review This Car
2002 Jaguar XJR (2 Reviews)
Im a proud owner in one with 96000 M she drives like a dream and came with a "nanny" who has taken care of her sonce new! The only problem is sun roof slder plate stuck back and it leaks a bit of rain water... everything else is a Beast! Black on Black...
Best Jaguar i have owned, purchased used, my question relates to the drivers seat and steering wheel. When turning car off shouldnt the seat and steering wheel move back, and up to ease exit. I can hear a motor running for approx 10 seconds and it is not the antenna mast.


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Carmel Firepit/Coffee Table
If you're looking to entertain outdoors this summer, having a firepit and a coffee table outside is nice. However, having them both in one is even better. The Carmel Firepit/Coffee Table ($390) is a simply-designed table that can be used as both an open firepit and a grill, making it more versatile than name suggests. Each one is handcrafted from rustproof cast aluminum, the unique welding adds an antique quality, and the weighted legs help hold it in place.


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If you need advice help is only a click away
We provide a tailored service and offer recommendations using a 'best advice' approach. This means that we'll tell you of the most suitable option for your circumstances – which may also include seeking help from the free sector.
Why use our services?
We're currently helping over 50,000 customers manage their debts
We offer a confidential service
We work using the best advice model. This means you get the most suitable advice for your circumstances – which may include getting help from the free sector.
How it works
Enter your details to request a call back - or simply give us a call
When you talk to us we'll listen and confidentially review your financial situation.
After hearing the facts we'll guide you through all the options available.
Getting free impartial advice
The Money Advice Service is an impartial service set up by the Government.
They provide free debt counselling, debt adjustment and credit information services.
visit Money Advice Service
Useful IVA facts
Unsecured debts are the most typical which can be included. These include
- Unsecured debts from personal borrowing (loans, credit cards and overdrafts).
- Tax arrears
- Catalogue debts
- Utility bills (from a previous address and supplier)
- Disconnected mobile bill
- Rent arrears (from a previous address)
- Selected items purchased through finance
- Car finance (if you don't have the car)
- Council tax arrears
In some instances a service which you're are no longer using, but where money is owed, has the potential for inclusion in an IVA e.g. unpaid medical or nursery bills.
Secured debts cannot be included.
Details of IVAs are made public. A record of when you started your IVA will be retained by credit reference agencies for a minimum of six years. During this period you may find it harder to obtain credit below the market average rate.
Within the proposal your creditors are looking for your ability to repay as much of the debt as reasonably possible. But restrictions may have to be applied to your expenditure as part of your IVA.
Important: There is no guarantee that an IVA proposal will be accepted by creditors. Though we would only propose this when there is a high expectation of success.
With an IVA your mortgage and secured payments are taken in to account before other outgoings – this includes your debts. As a result, unlike bankruptcy, your home is protected.
If you have a large amount of equity in your property you may be required to make a contribution from this. You would do this through re-mortgaging. The re-mortgage clause is subject to affordability – so you're won't be required to pay more than you can afford. During an IVA your credit rating will be adversely affected – and this may affect your ability to get a re-mortgage. In the event you can't re-mortgage the IVA may be extended by an additional year.
Should your financial circumstances get worse it may be possible to reduce payments in one of two ways:
- Through a review and approval of your IVA supervisor
- For bigger changes this would be done through 'variation'. This is where creditors vote to approve or refuse the change.
Should your circumstances improve (e.g. through a windfall or inheritance) you will be expected to contribute some part of this into the IVA.
If your IVA fails and you don't make arrangements with those creditors you could be at risk of being made bankrupt.
Two of the main criteria are
- You must have debts of at least £5,000
- You can afford a monthly minimum of £70 towards them
If you fail to meet or fulfil the obligations of your IVA creditors could contact you regarding these debts or also petition for your bankruptcy.
An IVA is based on individual circumstances so payments will vary on a case by case basis. In the event your circumstances change this may affect your monthly payment. However the overall duration of the IVA won't change.
IVAs normally exclude the following debts:
- Student loans
- Child Maintenance
- Secured debts
- Court fines
Other debt exclusions may apply. IVAs are not available in Scotland.
Every IVA case is considered based on the circumstances. So costs will vary.
For illustrative purposes we'll provide an example scenario to help outline the costs.
This is based on an IVA with £31,000 of unsecured debts, five year duration without equity in a property paying £300 per month.
Nominee's fee (usually equivalent to the first five contributions): £1,500
Supervisor's fee**: £2,475
Supervisor's costs*: £900
Total returned to creditors: £13,625 (44%)
Total paid by borrower: £18,000 (58%)
**15% of further monthly payments once the Nominee's fee has been satisfied
* Bond fee £50, DTI Fee £15, plus other case dependent costs.
For more information we recommend that to speak to us first for a breakdown of costs for any individual scenario.
IVAs are not available in Scotland but alternatives are available.


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The Republican establishment is fed up with the "outside groups" — the conservative lobbying shops and super PACs that have pulled the party Rightward in recent years — and this time, it's the establishment that is uninterested in compromise.
House Speaker John Boehner and Senate Minority Leader Mitch McConnell are playing to win. But here's the problem: Directly fighting the insurgent groups only makes them stronger.
In a span of 48 hours, the party leadership took two direct shots at the conservative insurgents. Boehner attacked the outside groups on camera, singling out Heritage Action. Also, Rep. Steve Scalise, R-La., fired Republican Study Committee Executive Director Paul Teller, the universally liked longtime leader of the conservative wing on Capitol Hill. The occasion was a dispute over the budget, but it sure looks like a broad effort to bring the insurgency to heel.
Heritage Action, the Club for Growth and the Senate Conservatives Fund all came out against the budget resolution that Rep. Paul Ryan, R-Wis., crafted with Democrats. The agreement neuters the automatic spending cuts known as the sequester, and conservatives argued that the budget's "fee increases" are really tax hikes.
Party leadership regularly knocks the outside groups for fighting too nasty. When Sen. Jeff Flake, R-Ariz., rejected the tactic of trying to defund Obamacare by threating a government shutdown, SCF ran an ad saying "Jeff Flake used to be one of us, but now he has become one of them."
Boehner's blowup was spurred by Heritage Action's critique of the Ryan budget plan, which called no one any names and questioned nobody's motives.
These days, you see, it's the establishment wearing brass knuckles.
When a reporter asked Boehner about the groups opposing the budget, the Speaker unloaded. He accused outside groups of "misleading" voters and said the groups had "lost credibility." This echoes the way McConnell has called the conservative groups "bullies" who deserve to be "punch[ed] in the nose."
Brian Walsh, a consultant for the National Republican Senatorial Committee, attacked Heritage Action and SCF as "purity for profit" groups because their attacks on the party establishment helps them raise money.
But the kernel of truth in the "purity for profit" attack shows why this offensive by the establishment may be self-defeating. When McConnell and Boehner attack the Heritage Foundation and the SCF, how do you think that affects these groups' fundraising? Do you think the Boehner blowup and the Teller firing were good or bad for the outside groups?
There's the establishment's first problem: It can't win with a frontal assault. If it strikes SCF, it makes SCF more powerful. And some in the leadership see specific groups, or even individuals, as the problem. One GOP operative referred to SCF president Matt Hoskins as "some guy in a swivel chair in San Diego."
Hoskins sees it differently. If SCF didn't exist, grassroots conservatives would still demand more of their party leadership than they're getting. "They hold the grassroots in contempt," Hoskins says of GOP leaders.
Here's the establishment's second problem: Some in the GOP want to go back to an era in which official party leaders had a monopoly on money and power within the party, and that era is never returning. Changes in campaign finance law has made it possible for small, loosely organized groups to raise money; new technology means news no longer belongs to people who own printing presses or television stations.
Many establishment complaints about Heritage and SCF are justified. The groups are sometimes too quick to call people names or question their motives, and occasionally their demands are obviously unrealistic. But the heart of the establishment complaint is that these groups pressure lawmakers not only through old-fashioned lobbying, but also by directly petitioning constituents. SCF runs ads in GOP Senators' states saying, "Tell your Senator to oppose the amendment." This inside-outside lobbying is unacceptable to the old guard. But it's also here to stay.
That's why, for now, there is no peace. "I don't think Humpty-Dumpty can be put back together again," Hoskins tells me.
"This is just going to play out in the primary elections next year, and there's going to be a battle for control of the party."
On the other side of the schoolyard, the feeling is mutual. Walsh wants peace, he tells me, but the only move for the establishment now is to "beat them in every primary."
Teller's firing and Boehner's blowup show that the GOP establishment has decided that with peace no longer an option, total victory is the only path.Timothy P. Carney, the Washington Examiner's senior political columnist, can be contacted at email@example.com. His column appears Sunday and Wednesday on washingtonexaminer.com.


text: If you've listened to Marissa Nadler recent album, July, it probably won't surprise you that her new video for Drive was directed by Naomi Yang of Galaxie 500. Though G500 tends to sound a lot more washed out than Nadler's dark folk, the sense of cerebral vapor that flows through their music is a defining characteristic for both artists. The visual for Drive is similarly vaporous, layering open road film footage from French artist Bernard Faucon with brief moments of Nadler alone in an ornate home. Watch it below and read our Q&A with Nadler here.


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Awena Abala Wardrobe Stylist
MissTamikajModel Female Toronto, Ontario, Canada
My Website: Boss Magazine WebsiteMy MM URL: http://www.modelmayhem.com/misstamikaj
Mayhem # 2880449
About MeMy name Tamika Johnson, I am a model I also do styling and editing. I have enjoyed modelling with Sutherland models. Now styling and editing shoots for Boss Magazine are my new found love. I love turning ideas into print masterpieces. I specialize in editorials for fashion and beauty shoots. I love to try new and exciting concepts and challenge the everyday boring traditional looks of beauty. I am also currently enrolled at York University studying philosophy & criminology as double major honours student. I have joined MM to gain more experience in modelling and to meet new people. My future plans aside from modelling are to become a Supreme Court Judge, to continue to be an advocate for young black woman all over the world and to restore hope in my native country Jamaica.
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text: Part of the Swatch Group, Swiss watch brand Omega has been synonymous with luxury since 1917, when the British Royal Flying Corps and, soon after, the US Army selected Omega watches as their official timepieces. The watchmaker continues to be one of the most trusted brands in the world, owing to the consistency of its hand-wound mechanical movements, as well as an eminent tastemaker in fashion. In fact, the iconic Speedmaster is still powered by virtually the same movement as the watches that NASA astronauts wore on the moon while the Seamaster has been the exclusive watch of the James Bond movies since 1995.


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Michael Fassbender & McQueen Reteaming Again for '12 Years a Slave'
by Alex Billington
October 11, 2011
Source: Variety
Get ready to hear a lot about these two this awards season. British filmmaker Steve McQueen (seen right above), of Hunger and this year's Shame, and actor Michael Fassbender have been working together since 2007 on both films, and will continue that relationship again. Variety is reporting that Fassbender will play a role in McQueen's next film, titled 12 Years a Slave, that's already set to star Chiwetel Ejiofor in the true story of Solomon Northrup, a New Yorker who was kidnapped in Washington and rescued from a cotton plantation in Louisiana in 1853. Pre-production is already underway to start shooting early next year.
Fassbender and McQueen will be getting a lot of acclaim this year (and next) for their work on Shame, so it's great to see these two already planning to work together yet again. In 12 Years a Slave, the story follows Northup, a married, educated and free black man living in New York who was approached by two men with a job offer in Washington D.C. But upon his arrival, he was kidnapped, put in a slave pen and passed around through various slave owners for twelve years. While Variety doesn't specify Fassbender's role, we assume it will be that of a Canadian carpenter who opposed slavery and smuggled letters to Northup's wife, which help launch a court case to set him free. Plan B's Dede Gardner and Jeremy Kleiner are set to produce the film, from a script by McQueen and John Ridley (Bobby, Three Kings). We'll definitely keep an eye on this.
Follow Alex's main profile on :


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Kleines rechteckiges Deckchen Fig 3 by Herbert Niebling
Welcome! You are browsing as a guestWould you like to see projects made from this pattern and much more? create a free account What am I missing?
Kleines rechteckiges Deckchen Fig 3
Band 760: photo 24, page 14, Fig 3 (Abb. 24, Seite 14)
Small rectangular doily
15 x 22 cm knitted in 15 gm. thin rayon with steel knitting needle Nr. 7/0 (old German needle size)
The middle part is worked flat on 27 stitches (Fig 3 A). Wrong-side rows are purled.
Repeat rows 3 and 5 until a total of 80 rows have been completed. Work row 81 and 82.
Then without casting off the 27 stitches on the needle, pick up 41 stitches on each long side and 27 stitches at the cast-on edge, and knit one row in the round.
Increase by 19 stitches along each long side, adding one at the 3-stitch groups and another 18 out of every 2M 2M knit.
After one more knit round, over now 174 stitches, begin the border part in Fig. 3 B.


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FRESNO, Calif. — One day after knocking off defending national champion Fresno State, the CSUB baseball team put forth a 12-hit effort against the Bulldogs, but stranded 13 on base and gave up nine earned runs in a 9-2 final at Beiden Field.
Fresno State (16-12) scored at least one run in every inning except the third and eighth, collecting 13 total hits, including three home runs. Left fielder Trent Soares was 3-for-5, including two home runs, while right fielder Steve Detwiler had a solo shot for his one hit of the day.
The Roadrunners' first run came in the top of the third on one hit and a pair of Bulldog errors. With one out, Ryan McIntyre doubled down the right field line, then advanced to third when Detwiler fumbled the ball. Martin Medina then reached on a fielder's choice as third baseman Tom Mendonca attempted to get McIntyre out at home, but the throw was long and McIntyre safely crossed home plate.
With two outs in the seventh, Medina and Jeremy Rodriguez drew back-to-back walks from reliever Josh Poytress. Designated hitter Mick Gaston then singled through the left side and a second fielding error by the Bulldogs' outfield allowed Medina to continue to home.
After his 10-game hit streak was broken in Saturday's victory, McIntyre led the Roadrunners by going 3-for-5 with a run and stolen base. Stuart Smith had two hits after going 2-for-23 over the past six games. Freshman Matthew Akiyama, making his first appearance of the season for CSUB, also had a pair of hits in four at bats.
On the mound for CSUB, Erik Draxton (1-4) struck out a season-high seven, but walked five and gave up 10 hits in 5 2/3 innings.
Holden Sprague (3-0) picked up the win for Fresno State, striking out eight and scattering eight hits for one run in six innings. A trio of Bulldog relievers combined for two strikeouts, two walks and four hits allowed.
Bakersfield and Fresno State take Monday off from action, then continue play Tuesday and Wednesday in Bakersfield. Both match-ups are scheduled for 2 p.m. at Hardt Field.


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MMS: Duke Kunshan University
Corporate Visits
Get a front row seat to different industries and employers during the program. On-site visits are an ideal way to get firsthand knowledge of a company or business industry. Tour the workspace, meet employees and managers through panel discussions, and get a sense of the type of work that is done there. You'll learn about the industry, job functions, and current business challenges from company representatives and leaders, some of whom are Duke alumni.
Corporate visits to organizations in cities like Atlanta, New York, and Washington. DC, may be organized by leaders of the MMS student clubs during breaks, while visits in and around Kunshan and Shanghai will take place during your China residency. Suzhou Industrial Park, where 88 of the Fortune 500 companies have invested, is a short trip from Duke Kunshan University, and the world business capital of Shanghai is 20 minutes away.
Some of the organizations you might visit during your US and China residencies include:
- Disney Shanghai — the first Disney resort in mainland China
- BMW China — a major automotive company
- China Resources Group — a State Owned Enterprise (SOE) with holdings in multiple industries
- Ogilvy & Mather — an international advertising, marketing, and public relations agency
- MacQuairie Capital — a diversified financial services provider
- NOMURA Securities International — a global investment banking and securities firm
- Bloomberg — a business and financial news conglomerate
- Accenture — a global management consulting, technology services and outsourcing company
- ABB — a multinational company and leader in power and automation technologies
- Burt's Bees — a US-based producer of environmentally friendly personal care products
- Cisco Systems, Inc. — a global leader in internet networking
- Washington Nationals — a major league US baseball team
- Agricultural Bank of China, Private Wealth — SOE in financial services
- Nielsen China — an international marketing services organization
- P&G China — a multinational consumer products company
Is there a corporation you're interested in visiting? Do you have a personal connection to someone at a leading company and think they might be interested in hosting a student group? Let us know about it and we'll reach out to the corporation.


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The summer issue of Jamie Magazine is here, crammed with barbecue recipes, ice cream ideas and festival favourites
Next week Jamie Oliver's Drinks Tube is setting up shop in Old Street Tube Station in East London for a special week of cocktail making.
If you live in the US or UK, we're offering you the opportunity to be your own boss, as well as join the Jamie Oliver family, as a Jamie at Home consultant.
With every day that passes, the line-up for Jamie's Big Feastival 2014 gets more and more exciting. The last two years have been off the hook, but this time it's going to be a real party, because Jamie's favourite Food Tube stars are going to be cooking up a storm. As well as Jamie's mentor Read the full article…
Well not quite – it's actually only six years old – but today they release their 50th magazine and they are celebrating in style. The bumper issue is a visual feast of party recipes, show-stopping cakes and envy-inducing travel writing.
To celebrate the launch of Drinks Tube, Jamie is presenting a live food and drink extravaganza tonight on the roof of his restaurant in Piccadilly, London.
Father's Day is this Sunday, so if it's crept up on you, we've got lots of hints, tips, ideas, presents and deals to make sure your dad gets the day he deserves
Jamie Oliver's Food Tube stars have published their first cookbooks – including the best barbecue recipes, family meals and utterly amazing cakes.
We're excited to announce that a new series of Jamie's Money Saving Meals starts tonight on Channel 4 at 8.30pm.


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This ministry has a twofold mission:
1. To share and promote news and media, related to assembly ministries around the world.
2. To provide various assistance to the Lord's servants and assembly ministries around the world.
Our initial goal is to collect Christian news, audio, and video of Christian events; share them through available technologies and various media; and involve assembly believers (especially the youth) around the world in the Great Commission. As the Lord enables us, we will definitely look into the opportunity to help missionaries and provide various assistance; native and/or foreign; who may or may not be supported by any existing funds, foundations or agencies.


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Michael Hamelin on the 2014Q1 X-Force Threat Intelligence Quarterly
Visits (28537)
Michael Hamelin introduces the new format for th
Michael Hamelin:
Michael Hamelin on the IBM X-Force 2013 Mid-Year Trend and Risk Report
Visits (5591)
IBM's X-Force research team has released th
You can d
Michael Hamelin:
Python for Streams, Rational IDE in SmartCloud Enterprise, X-Force Report
Visits (3812)
This Week On developerWorks for April 12, 2013
IBM Research senior software application developer Senthil Nathan joins me to talk about opening up the IBM InfoSphere Streams platform to Python code with the goal of performing analytics in InfoSphere. You can dive deeper into this topic by reading Senthil's (and Glenn Hochberg's) article, Calling Python code from IBM InfoSphere Streams.
Also among this week's valuable bits of knowledge:
Learn how to create a Rational development environment in IBM SmartCloud.
Discover how to connect to your enterprise IT environment from IBM SmartCloud using OpenVPN.
Discuss some of the key findings in the latest IBM X-Force Report.
You can download this podcast in audio | listen to it on iTunes | read the transcript.


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On-site counselor
Provide on-site telephone and office crisis counseling to victims
1 four-hour shift per week during weekday or evening hours. Overnight
Provide telephone crisis counseling to victims and survivors of
domestic violence and sexual assault. Requirement: 2 overnight
or weekend shifts per month.
Provide hospital advocacy to survivors of sexual assault at S.A.F.E
Center at Wake Med. or other area hospitals. Requirement: 2-4
overnight or weekend shifts per month.
Group Facilitator
Co-facilitate support/educational group for children affected
by domestic violence following established curriculum. Requirement:
2 eight-week groups per year.
Group Facilitator
Co-facilitate support group for victims and survivors of domestic
violence, sexual assault, and incest following established curriculum.
Six months of direct client experience at InterAct is necessary
before becoming a group facilitator. Requirement: 2 eight-week
groups per year.
Assist shelter staff in providing services to residents of 18-bed
transitional, residential facility. Duties may include providing
shelter coverage and emotional support, transporting residents
to meetings, organizing donations, and helping staff with special
house projects. Requirement: 6-8 hours per month.
Provide support to children of various age groups living at the
shelter by modeling positive behavior and maintaining non-violent
forms of discipline, participate in weekly support group for children,
and assist with other scheduled activities. Requirement: 6-8 hours
per month.
Assist staff with daily administrative tasks including filing,
data entry, answering phones, preparing mailings, etc. Requirement:
Must be available during regular business hours; Hours flexible.
Project Volunteer
Participate in agency special events and projects, such as fundraisers,
and assist staff as needed. Requirement: Hours flexible.
Make presentations to 3-12 school classes about anger, conflict
resolution, sexual harassment, dating violence, and date rape.
Requirements: Must be available during normal school hours.
Speakers' Bureau Adult Presenter
Make presentations to community groups about the agency, domestic
violence, and sexual assault. Also staff agency displays as needed.
Requirement: 12 presentations and/or displays per year.
Victim Advocate
Provide on-site telephone and office crisis counseling to victims and
survivors of domestic violence and sexual assault at Southern Wake Outreach
Center in Fuquay-Varina, NC. Requirement: 12 presentations and/or
displays per year.
Handle all money for sales at InterAct's Pass It On Thrift Store in Fuquay-Varina,
NC and Pass It On, Too in Raleigh, NC. Requirement: 4-hour shifts during weekdays,
evening or Saturday hours.
Sort and place items for sale in the Pass It On Thrift Store in Fuquay-Varina, NC
and Pass It On, Too in Raleigh, NC. Requirement: 1 or 2 4-hour shifts per week
during weekday hours.


text:
Fandango, RAI start shoot for Calm Chaos starring Nanni Moretti
Principal shooting of Calm Chaos (Caos Calmo) has begun in Rome this week. Produced by Fandango and RAI Cinema the picture is directed by Antonello Grimaldi and stars Nanni Moretti who also adapted the screenplay from the award-winning book by Sandro Veronesi.
Restricted Content
Registration is required to read the entire article and to gain access to other restricted areas of the website


text:
An Christmas Theme designed by Theme Project Team.
This Christmas theme is available for Go Sms Pro! Designed in the style that we all know well from christmas, compiling well with interface of the latest GO SMS Pro version! Yours eyes will be Please with it!
Christmas Theme is for you!
1. This is not a standalone app, you need to download the LATEST version of GO SMS Pro app in order to apply this theme. (Search "GO SMS Pro" to download)
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GO SMS Pro theme gosmstheme
Check our developer account often, we will update and ad new themes for GO SMS PRO, Go Locker and Go Launcher Ex.
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text:
Thu Feb 21, 2013, 08:40 PM
alp227 (29,798 posts)
CNBC to Produce 'Nightly Business Report' for Public TV
Source: B&C
CNBC announced Thursday it will purchase the rights to Nightly Business Report from investment firm Atalaya Capital Management.
Terms of the deal were not disclosed.
Beginning March 4, CNBC will produce Nightly Business Report exclusively for public television from its Englewood Cliffs, N.J., headquarters. It will be anchored by CNBC's Tyler Mathisen and Susie Gharib, the show's current coanchor. CNBC will also continue to produce NBR's popular Nightly News Brief. WPBT2 Miami will remain as the presenting station.
Read more: http://www.broadcastingcable.com/article/491969-CNBC_to_Produce_Nightly_Business_Report_for_Public_TV.php
Anyone remember when The Wall Street Journal produced a weekly show on PBS back during when Kenneth Tomlinson chaired the CPB? The current chair of the CPB is former RNC chair Patricia Harrison. Looks like the bad old days are back.
20 replies, 4299 views
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Response to alp227 (Original post)
Thu Feb 21, 2013, 08:43 PM
Cleita (75,480 posts)
1. Considering the Koch Brothers seem to be funding a lot of their
shows, I'm not surprised. I stopped watching their news programs years ago. It seems like there will be even less to watch now.
Response to Cleita (Reply #1)
Thu Feb 21, 2013, 09:20 PM
alp227 (29,798 posts)
3. Not the NewsHour!
Foundation Funders
S. D. Bechtel, Jr. Foundation
Carnegie Corporation of New York
Bill & Melinda Gates Foundation
Gruber Family Foundation
William and Flora Hewlett Foundation
Howard Hughes Medical Institute
Robert Wood Johnson Foundation
Joyce Foundation
John S. and James L. Knight Foundation
John D. and Catherine T. MacArthur Foundation
Gordon and Betty Moore Foundation
National Endowment for the Arts
National Science Foundation
John and Wendy Neu Family Foundation
David and Lucile Packard Foundation
Park Foundation
Poetry Foundation
Rockefeller Foundation
Skoll Foundation
Alfred P. Sloan Foundation
Starr Foundation
Wallace Foundation
However I know that the Koch Foundation has funded the science series Nova (bummer! one of my favorite shows!) According to Wikipedia's article about David H. Koch, "Koch contributed $7 million to the Public Broadcasting Service (PBS) show Nova,[34] and is a contributor to the Smithsonian Institution in Washington, D.C., including a $20 million gift to the American Museum of Natural History, creating the David H. Koch Dinosaur Wing and a contribution of $15 million to the National Museum of Natural History to create the new David H. Koch Hall of Human Origins, which opened on the museum's 100th anniversary of its location on the National Mall on March 17, 2010.[35] In 2012, Koch contributed US $35 million to the Smithsonian to build a new dinosaur exhibition hall at the National Museum of Natural History.[36]"
See this blog by Lawrence Rafferty "PBS: Why I watch but don't contribute"
Response to alp227 (Reply #3)
Thu Feb 21, 2013, 10:21 PM
WHEN CRABS ROAR (3,813 posts)
10. And for every dollar they contribute they probably get two dollars off their taxes.
Response to Cleita (Reply #1)
Thu Feb 21, 2013, 10:03 PM
Cleita (75,480 posts)
9. I didn't say the Koch Brothers are funding the news. I said I stopped watching
them years ago because they weren't reporting unbiased news. Your list shows all those corporations behind the scenes pulling strings.
Response to Cleita (Reply #9)
Thu Feb 21, 2013, 10:37 PM
alp227 (29,798 posts)
11. I still watch pbs news and prefer that over the commercial network news.
PBS does NOT waste time with trivial entertainment items and plays speeches beyond soundbites. PBS and NPR in my opinion are the most reliable broadcast news sources. I also watch Democracy Now and listen to Thom Hartmann, Norman Goldman, and Mike Malloy.
Response to alp227 (Reply #11)
Thu Feb 21, 2013, 10:40 PM
Cleita (75,480 posts)
13. I do Democracy Now!, Thom Hartmann and Rachel Maddow. But mostly I cruise the internet for
news items and some Al Jazeera when I am able to stream. I don't find any of the American TV and radio news sources to be reliable anymore and that includes PBS and NPR.
Response to alp227 (Original post)
Thu Feb 21, 2013, 08:54 PM
OregonBlue (5,347 posts)
2. Not good news. CNBC is very right wing-pro oligarch. Bloomberg is much better.
Bloomberg is conservative but next to CNBC they look like screaming libs.
Response to OregonBlue (Reply #2)
Thu Feb 21, 2013, 09:31 PM
Kolesar (30,970 posts)
5. Yes, CNBC is for unchecked corporate rule
"Prooligarch" is a good term for them.
Response to OregonBlue (Reply #2)
Thu Feb 21, 2013, 09:50 PM
KoKo (84,711 posts)
7. Yep...CNBC is a deathknell. RW to the Core...
Response to alp227 (Original post)
Thu Feb 21, 2013, 09:28 PM
WestSeattle2 (1,722 posts)
4. CNBC is the Fox News of business information - a joke.
Response to alp227 (Original post)
Thu Feb 21, 2013, 09:37 PM
BumRushDaShow (26,345 posts)
6. "The Wall Street Journal produced a weekly show on PBS"
I remember being a regular watcher of "Wall $treet Week with Louis Rukeyser" where Louis would occasionally bring his dad Merryle on.
I don't think there's anyone on the air today from that old school type broadcast business journalism. If anything, a decision was made to report business like a pro sports commentary show - with the wild mind-numbing stats graphics and head-spinning pans and zooms. Probably why my Mom watches Bloomberg for business reporting nowadays.
My have the mighty fallen.
Response to BumRushDaShow (Reply #6)
Thu Feb 21, 2013, 09:59 PM
Honeycombe8 (21,395 posts)
8. I loved Wall Street Week with Louis Rukeyser. I didn't understand it and certainly didn't invest.
I didn't have money to invest. But I still found it interesting, and I grasped some of the things they discussed. They talked in layman's terms and were even witty. And Rukeyser was just an interesting fellow. Then there were new suits to run the show, and they kicked Rukeyser off the show! How short sighted. The show cont'd for a while but I don't think was very successful. I know I didn't watch it. It might still be on...don't know. But if it is, no one talks about it, refers to it, and I never run across it.
Response to Honeycombe8 (Reply #8)
Thu Feb 21, 2013, 10:39 PM
alp227 (29,798 posts)
12. It was canceled in 2005. BUT it has a new life online.
Response to alp227 (Reply #12)
Fri Feb 22, 2013, 12:28 AM
Honeycombe8 (21,395 posts)
18. I wouldn't watch it w/o Rukeyser. He was the only reason I watched. nt
Response to Honeycombe8 (Reply #8)
Thu Feb 21, 2013, 11:48 PM
elleng (78,218 posts)
16. I watched it, learned from it, and enjoyed it.
Seemed to me that it ended/was cancelled when Rukeyser became ill and then died.
I watch Nightly Business Report now, and hope the info it provides continues. I'm more interested in daily 'stats,' and not so much on any recommendations their guests might make. HOPE it doesn't deteriorate.
Response to elleng (Reply #16)
Fri Feb 22, 2013, 12:27 AM
Honeycombe8 (21,395 posts)
17. No...the new young suits fired him, to bring in fresh blood. He may have been sick before...
I don't think so, but he may have been. But he was definitely fired. They thought he was boring and thought it was time to change the program. Then got sick and died.
Sort of like when CNN started fooling with Crossfire, if you remember that show. A precursor to the political talk shows of today. It was very popular. But then the new suits tried to spice it up, etc., until it became not the same show at all, and it failed and was cancelled.
Response to Honeycombe8 (Reply #17)
Fri Feb 22, 2013, 12:48 AM
elleng (78,218 posts)
20. I remember Crossfire,
and as I recall those discussions were civil (compared with the crap drama we see today.) I don't watch CNN now.
Response to alp227 (Original post)
Thu Feb 21, 2013, 11:23 PM
bucolic_frolic (6,653 posts)
14. PBS should simply drop the show
if they can't continue an independent voice, a dispassionate
thinking man's market perspective, they should give it up.
It's no longer a show that belongs on Public TV.
I'd rather see them turn to Bloomberg TV to produce it.
Bloomberg has taken Business Week to quite erudite places.
Nightly Business Report was in its heyday with Linda O'Brien
and Paul Kangas. Never been the same since, although Susie Gharib
is quite good.
Response to alp227 (Original post)
Thu Feb 21, 2013, 11:28 PM
shcrane71 (1,721 posts)
15. Broadcast news has become an oxymoron. nt
Response to alp227 (Original post)
Fri Feb 22, 2013, 12:44 AM
harmonicon (12,008 posts)


text:
That person has been standing by his side for the past month and has unfinished business of his own.
While visiting the artist, the curators candidly asked Johns to allow MoMA to debut his newest, and then unfinished, collection.
In the early 1990s the debate over the future of the unfinished palace, now open to the public, became heated.
A: Taylor Swift, "Haunted" B: Jane Austen, Sanditon (unfinished novel) 12.
The unfinished construction is covered by what appears to be a tarp, she said.
So the stone remains a little while unfinished; till the same hand carves thereon, a few weeks later, "And of Anne, his Wife."
In its unfinished state the play is without the exaltation of great tragedy.
The window was open,—the desk, unfinished letter, everything exactly as he had left it.
She returned to her unfinished letter, but Genius seemed on a vacation.
They belong to the same order as the notes for the unfinished novels, but they are even more informal and confidential.


text:
Failure Are Touring
Tue, 22 Apr 2014 16:13:06
Failure Videos
Failure are touring again! The Tree of Stars Tour will cruise through North America in May and June.
It'll be late spring and early summer -- go see a show!
The tour dates are below.
Tour Dates:
May 10 Los Angeles, CA Cinquanta (The Greek Theatre)
May 11 Los Angeles, CA Cinquanta (The Greek Theatre)
May 14 San Francisco, CA Great American Music Hall
May 15 San Francisco, CA Great American Music Hall
May 17 Vancouver, BC Rickshaw Theatre
May 18 Seattle, WA The Showbox
May 21 Minneapolis, MN The Varsity
May 22 Chicago, IL The Metro
May 24 Milwaukee, WI The Rave II
May 25 Detroit, MI St. Andrew's Hall
May 26 Toronto, ON Mod Club
May 27 Toronto, ON Mod Club
May 29 New York, NY Irving Plaza
May 30 Philadelphia, PA Theatre of Living Arts
May 31 Asbury Park, NJ The Stone Pony
June 1 Boston, MA Paradise Rock Club
June 3 Brooklyn, NY Music Hall of Williamsburg
June 5 Silver Spring, MD The Fillmore
Jun 07 The Masquerade Atlanta, GA
Jun 08 Exit In Nashville, TN
Jun 10 House of Blues Dallas, TX
Jun 11 House of Blues Houston, TX
Jun 13 The Marquee Theatre Phoenix, AZ
Jun 14 The Glasshouse Pomona, CA
Jun 15 House of Blues San Diego, CA
Jun 18 The Mayan Los Angeles, CA
Jun 19 Mayan Theater Los Angeles, CA
For more tour info, visit facebook.com/Failureband.
Failure - Stuck On You
Anyone plan to Fail?
—Maggie Pannacione


text:
Welcome to Amara's documentation!¶
- Running Amara
- Reporting bugs
- API Documentation
- Overview
- Languages
- Videos
- Subtitles
- Users
- Activity
- Messages
- Teams
- Subtitle Request Resource
- Supported languages
- HTTP Callbacks for Teams
- Babelsubs
- Syncing and Importing
- Static Media
- Developer's Guide
- Development Workflow
- Testing
- Caching
- Teams
- The Subtitle Editor
- Subtitle Workflows
- The permission system
- Optional Apps
- Internationalization (i18n)
- Behaviors
The source code to Amara is available on Github. Feel free to fork the project and open a pull request.
Before working on a sizeable feature, please do run it by us in our IRC
channel. We don't want you to waste your time working on something we don't
really want. We are at
#amara on freenode.
Amara is freely available under the terms of the GNU Affero General Public License. You can find the full text of the license here.


text:
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
GPCRs play a critical role in human physiology and are a prime target for drug discovery globally. Novel insights into the functions of GPCRs are providing unique approaches to modulate these proteins to generate unique drug candidates. Next generation ligands include those with novel pharmacologies such as allosteric regulators as well pepducins, that affect the interaction of GPCRs with G proteins, to either block selective receptor signaling pathways or mimic the actions of intracellular domains of receptors, thereby activating GPCRs to signal selectively to intracellular pathways. We will review these new concepts and then discuss how they may be exploited using modern discovery technologies to provide novel drug candidates for the future.
G protein coupled receptors (GPCRs) constitute one of the largest gene families in the human genome. Due to their critical role in cell-cell communication and as causal agents in disease, they are a target for the development of numerous drugs, many of which have received regulatory approval. Emerging knowledge of GPCR physiology has begun to alter our approach to GPCR drug discovery and is providing insight into how to discover new generations of compounds as human therapeutics [
GPCRs are integral cell membrane proteins and their association with membrane lipids is critical for conferring, and maintaining, receptor structures required for function. The phospholipid environment controls the inherent flexibility of the receptor mainly due to the structural disorder of the third intracellular loop, a domain known to undergo major conformational changes following agonist binding and to be critical for G protein coupling [
Unlike most enzymes that are energetically unidirectional (e.g. kinases phosphorylate proteins selectively; proteases hydrolyze selective substrates), GPCR activation can produce a greater diversity of cellular functions as they interact with multiple Guanine nucleotide binding proteins (G proteins) to regulate discrete signaling pathways [
Some drugs of this type are generically referred to as allosteric modulators, whilst others are referred to as 'dualsteric', being molecules that bind both to orthosteric and allosteric sites [
GPCRs are also known to produce constitutive activity, that is activity in the absence of endogenous ligand or agonist [
Constitutive activity of GPCRs is believed to be due to their formation of oligomers in addition to single unit assemblies [
This review will focus on these new avenues of GPCR drug discovery. We also describe briefly the scientific basis of discoveries leading to these new fields of drug discovery. Finally, we provide information on the potential of novel drugs, as well as new technologies used to screen for this new generation of GPCR compounds.
Structure-based, rational drug discovery is widely employed by the pharmaceutical industry to design compounds with optimal specificity and potency to molecular targets, often at soluble enzymes such as protein kinases. The structural information provides information on the physical properties of the ligand binding site(s) and helps to design pharmacophore models of the ligand when docked. This provides the foundation for screening structural families of molecules with predictable chemical characteristics as well as optimal functional properties to modulate the molecular target [
This approach has not been used widely in the GPCR field, because GPCRs are not easily crystalized for structural evaluation. However, within the last decade, six different GPCRs have been crystalized in their inactive form, including the avian β1- adrenoceptor [
Rhodopsin was the first full receptor to be subjected to X-ray analysis [
These authors then conducted structural analysis of the mutant receptor bound to the high affinity inverse agonist, carazolol which further stabilized the receptor. This allowed for analysis of the physical sites and amino acids critical for ligand binding particularly in the hydrophobic pore of the receptor. Similar studies have now been done on other druggable GPCRs. These studies revealed common structural requirements in ligand binding to the orthosteric domain in the transmembrane core. Such information, along with the extensive physical data on these and other GPCRs is now being used to develop computational models of the nature of small molecules binding to GPCRs, thus facilitating medicinal chemistry efforts to discover novel drugs.
To this point, Kolb
In fact, Ivetac and McCammon [
The studies on the crystal structure analysis of the mutant GPCRs provides important information on the static structure of ligand binding to GPCRs. However, the information gained has its limits, in particular with regards to how agonists cause activation. While Rosenbaum
In fact, they noted that extracellular loops may be important sites for discovery of better and more efficient receptor subtype selective drugs. For example, the orthosteric binding domains of the β1- and β2-adrenoceptors are almost identical with 15 or 16 amino acids being the same. In contrast, the extracellular loops of the receptor differ greatly. If the loops are critical in transducing orthosteric agonist induced conformational changes, then small molecules binding to those allosteric sites might be expected to either serve to block or enhance agonism without directly affecting agonist binding and since the loops differ substantially in sequence, then drugs targeting those sites may have greatly enhanced subtype selectivity.
Agonist binding also induced conformational changes in the receptor that differed considerably from inverse agonist binding. The agonist binding causes a shift in the structure of the salt bridge connecting extracellular loops 2 and 3, focused on lysine (Lys) 305, the other end of the bridge from the Phe193. Agonists appear to cause movement of the two extracellular loops. In contrast, inverse agonists appear to stabilize the salt bridge at Phe193 to reduce movement of the extracellular loops. Thus, in the model developed, the unbound GPCR in a basal state exerts flexibility in its third intracellular loop and extracellular loops, and can couple to G protein to produce basal GTPase activity. Inverse agonists stabilize the salt bridge to prevent basal conformational shifting of the receptor to uncouple from G protein to inhibit basal GTPase activity. Agonists cause profound movement of the extracellular loops to orientate the receptor to a most favorable conformation to couple to G protein to increase G protein coupling.
Most importantly, the authors [
The model however does not explain how allosteric activators would work. Consistent with the NMR analysis of Bokoch
The focus of most of the crystal structure and NMR analysis has been on receptors which bind endogenous ligands which are small molecules, such as dopamine, epinephrine, norepinephrine and adenosine. The models and information gained from these studies show how ligands interact with a central hydrophobic core of the GPCRs. However, a large number of GPCRs have large endogenous ligands and those molecules do not easily fit into a hydrophobic binding pocket first described for β-adrenoceptor. In fact, it has been shown that for peptide receptors, such as the opioid receptors, the endogenous ligands, including enkephalins, endorphins and dynorphins appear to primarily bind to orthosteric domains in the extracellular loops of the receptors [
Importantly, the recent crystal structure analysis of the CXCR4 receptor bound to a small molecule antagonist and a cyclic peptide show the ligands bind to pockets more closely associated with the extracellular domains of this GPCR [
In fact, NMR has been employed to study the binding of a number of different endogenous peptides and their agonists to fragments of GPCRs (not the entire receptor) [
Similarly, for Class B1 GPCRs which include the peptide receptors for corticotropin releasing factor (CRF), glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP), pituitary adenylate cyclase activating peptide (PACAP), parathyroid hormone (PTH) and calcitonin gene-related peptide (CGRP), both crystal structure analysis and NMR studies on fragments of the receptors have shown that both endogenous ligands and peptide antagonists bind to the N-termini of the receptors [
This however, does not negate the important nature of the crystal structure and NMR information on the β-adrenoceptor nor its application in understanding how GPCRs work in general. In fact, the studies by Bokoch
Most drugs developed against GPCRs bind to the orthosteric ligand domain. However, as described above, GPCRs have many other extracellular facets besides their orthosteric binding domains that can affect receptor activity and function that can serve as drug binding targets [
Similarly, some GPCR subfamilies have unique properties that make the discovery of orthostatic agonists or antagonists difficult to accomplish. An example is the protease activated receptor (PAR) subfamily which mediates the biological functions of thrombin. Thrombin is a protease and a major physiological factor in blood coagulation and wound healing. Thrombin activates PAR through a unique mechanism in which the protease cleaves the N-terminus of the receptor and the resulting truncated receptor bends back upon the receptor to serve as a tethered ligand to cause continuous activation. Efforts to develop anti-thrombin drugs have primarily focused on inhibiting thrombin activity or in some cases generating PAR receptor orthostatic binding antagonists. Because of the unique manner in which thrombin binds to PAR, development of small molecule antagonists and agonists has proven difficult. However, allosteric enhancers or inhibitors need not bind to PAR in the same manner as thrombin and therefore are not constrained in their receptor interaction as orthostatic agonists or antagonists. As described below, allosteric PAR modulators are beginning to be developed that provide a unique family of drugs targeting this clinically important GPCR family.
Secondly, allosteric ligands do not compete with endogenous transmitters or hormones like orthosteric ligands. As a consequence, allosteric modulators generally can be employed at lower dosing than orthosteric ligands to be effective. Thirdly, allosteric modulators are less likely to desensitize like orthosteric agonists. For allosteric activators, this property means they might be less prone to tolerance development, which plagues many orthosteric agonists, such as in the case of opiate analgesics. Fourthly, allosteric modulators tend to only effect the agonist occupied GPCR without causing actions of their own, reducing toxicity potential. As a consequence, allosteric modulators are usually found to have a ceiling effect, since when the receptor is fully occupied by an orthosteric agonist, the allosteric modulator can produce no further effect, no matter what concentration is employed. This allows allosteric modulators to temper activity of receptors rather than simply turning them off or on, providing a means to fine-tune GPCR activity.
Finally, allosteric modulators have the capacity to affect some functions of an individual GPCR and not others. In fact, as described by Rajagopal
In a similar manner, allosteric modulators can block or enhance GPCR coupling to one G protein and not affect coupling to other G proteins or signaling pathways. Furthermore, allosteric modulators that can prevent β-adrenoceptor kinase (βARK) and β-arrestin interaction with GPCRs may prevent desensitization, thereby providing an approach to prolong the activity of orthosteric agonists.
One of the most obvious examples of allosterism that focuses on G protein coupling domains of GPCRs is found with pepducins. These are ligands corresponding to specific sequences of the intracellular domain of a particular receptor designed to either block receptor coupling or mimic receptor coupling to a particular G protein to produce desired cellular effects. The compounds are synthesized with membrane anchoring segments which allow the compound to enter cells and localize to the cell membrane to be in close proximity to the GPCR target. Because the intracellular sequences of the GPCRs can differ, the pepducins can have high GPCR selectivity as well as target selective functions of a receptor.
Thus, allosteric ligands provide greater diversity in selecting desired functional and potentially clinical outcomes than orthostatic agonists and antagonists. Specially, with respect to orthostatic ligands, allosteric modulators provide greater specificity in targeting individual GPCRs, and can temper receptor activation in a manner not found with agonists. Furthermore, they can direct the activation of individual GPCRs to mediate some but not all of the functions of endogenous ligands and agonists at a given receptor by causing preferred GPCR-G protein interactions. Importantly, structural information now exists for some allosteric sites to allow for rational drug design and high throughput screening (HTS) assays have been developed to identify allosteric modulators. Consequently, the tools needed to begin to develop families of allosteric modulators for targeted GPCRs are at hand to generate new allosteric therapeutics.
Cinacalcet (Sensipar™) was the first allosteric GPCR modulator to gain FDA marketing approval. This was followed by Maraviroc (Celzentry™). These drugs were identified using conventional drug screening technologies and only later on were found to act in an allosteric manner to affect GPCR function.
Cinacalcet is a positive allosteric modulator of the Ca++ sensing receptor (CaR). This receptor is a member of the type C family of GPCRs, characterized by large N-terminal regions. Ca++ binds to the N-terminus and a critical role of this receptor is to regulate circulating Ca++ levels to maintain control of parathyroid hormone (PTH) release and levels. Other endogenous ligands at this receptor are Mg++ and amino acids which also bind to the N-terminus. In contrast to Ca++ and the other orthosteric ligands, cinacalcet is a small molecule that binds to the transmembrane region of the receptor to alter conformation to enhance affinity for Ca++ [
The compound is therapeutically useful because in kidney disease, hypocalcinemia results in excessive PTH which causes bone fractures, pain and cardiovascular disorders. Cinacalcet increases sensitivity of CaR to Ca++ to suppress excess PTH release despite hypocalcemia. The drug does not appear to have intrinsic activity and its actions are dependent on the binding of Ca++ to the receptor. Thus, cinacalcet is an allosteric modulator that binds to the transmembrane regions and hydrophobic pocket of the CaR distal to the orthosteric binding domains in the N-terminus.
Maraviroc has received marketing approval from the FDA for treating HIV disease [
Maraviroc's therapeutic mechanism of action, like a number of other allosteric CCR5 inhibitors, is believed to involve preventing HIV entry into immune cells via the CCR5 receptor. Interestingly, maraviroc is more potent in blocking HIV entry than in affecting chemokine induced internalization of the receptor. This is important, because chemokines are known to be useful in treating HIV disease, in part because they can cause internalization of the CCR5 receptor removing the conduit for HIV entry. Thus, the allosteric inhibitor maraviroc induces conformational changes in CCR5 receptor to block interaction of HIV and also allows native chemokine internalization of the receptor, further preventing HIV infection [
Another allosteric activator with potential clinical utility as an antipsychotic is the muscarinic M4 receptor modulator LY2033298. There are five subtypes of muscarinic receptors and as with the biogenic amine receptors, it has been difficult to identify subtype selective agonists because of similarities of the orthosteric binding pocket. In an effort to identify allosteric activators selective for the individual receptors, the pharmaceutical company Lilly and it's collaborators [
Furthermore, mutagenesis studies indicated that LY2033298 interacts with determinants in the third extracellular loop of the M4 receptor [
LY2033298 acts
A number of potentially therapeutically useful allosteric modulators have been discovered against the metabotrophic glutamate receptors (mGluR). These receptors are members of the type C family of GPCRs, like the CaR described above which have large N-termini. Glutamate binds to these receptors in the N-terminal regions in a structure referred to as the venus fly trap domain [
The mGluRs have prominent role in CNS physiology given that glutamate is one of the major transmitters in brain. Furthermore, abundant information is available that the receptor subtypes may mediate distinct functions of glutamate in brain. However, the mGluRs, like many other receptors have suffered from the lack of subtype selective drugs, which is why developing allosteric modulators is an attractive idea to develop drugs targeting each receptor subtype. Because the orthosteric binding domain of the receptors is in the N-terminus, one approach employed to discover allosteric modulators is to use N-terminal truncated receptors or chimeric receptors to screen for compounds binding to the transmembrane region to affect signaling [
The truncated mGluRs have been employed to identify the binding regions of one of the most well studied allosteric inhibitor of mGluR5, MPEP [
While the classic concept of allosterism focuses on compounds that bind to sites physically distinct from the orthosteric binding domain, ligands are now being designed to bridge the gap to bind to the orthosteric and allosteric sites simultaneously. These so called dualsteric or bitopic molecules can provide several advantages over simple orthosteric or allosteric ligands. First, they can be highly GPCR selective, due to the requirement to bind to both the orthosteric and allosteric sites. Secondly, much like biased agonists, they can be designed to affect some signaling pathways and not others.
They then measured functional responses of the dualsteric ligand using dynamic mass redistribution (DMR). DMR measures movement of the mass within cell in a population as a response to drug action [
A number of studies [
Interestingly, the authors then tested the dualsteric ligands in tissues that differentially express native muscarinic receptor subtypes, including guinea pig left atrium, which predominantly expressed M2 receptors, rabbit vas deferens which mainly expresses M1 receptors and possibly M4 receptors and guinea pig ileum, which expresses M2 and M3 receptors. Because the orthosteric component of the ligand is an oxotremorine analog, the dualsteric ligands maximally stimulated all three tissues compared to non-selective orthosteric agonist. However, the potencies of the dualsteric ligands for stimulating the left atrial tissue where much greater than for the other tissues, indicative of the allosteric component primarily affecting M2 receptor affinity for the ligand. Thus, the dualsteric ligand not only makes for highly selective M2 agonist, but directed the agonism to selectively affect one signaling pathway over another, in contrast to the more promiscuous orthosteric agonists.
The intracellular domains of GPCRs are key sites for allosteric regulation by G proteins and other regulatory proteins such as kinases, including βARK and β-arrestins. While agonist binding to GPCRs induces conformational changes to cause G protein activation, the interaction of G proteins with receptors also induces conformational changes to affect affinity of the receptor for agonists. There are multiple regions in the cytoplasmic domains of GPCRs to which G proteins can make contact, with the polar intracellular loops and the C-terminal tail being the ones most studied. These regions have also been the target for development of allosteric compounds that can affect orthosteric ligand binding but also, most importantly, GPCR signaling. Since GPCRs are capable of coupling to more than one G protein, and able to affect multiple signaling pathways in cells, allosteric modulators targeting these intracellular domains have the ability to select for functions of the receptors.
There are at least two approaches that have been used to develop allosteric modulators of GPCRs targeting intracellular G protein coupling domains. In one, developed by Gilchrist and colleagues [
A second approach to identify drugs targeting the G protein coupling domains of GPCRs has been developed by Anchor Therapeutics and their associates and employs molecules referred to as pepducins as GPCR drugs [
Despite the concerns of using peptides as drugs, pepducins have also been shown to be effective
PAR1 pepducins were also effective in preclinical studies on breast cancer. While PAR1 is not expressed in the epithelia of normal breast tissue, it is highly expressed in carcinomas. Yang
The utility of pepducins targeting PAR1 and PAR4 is particularly important, since despite the clinical importance of these receptors [
In contrast, pepducins would not have to deal with the unusual nature of thrombin activation of the PARs. Instead, they would target the intracellular domains of the PARs involved in G protein coupling and receptor signaling. Thus, pepducins not only may be useful in developing novel PAR1 therapeutics but are likely to be useful in developing probes and drugs against a number of recalcitrant receptors for which orthosteric drug discovery has generally been difficult.
In fact, an important aspect about pepducins is that rational design can be employed in their development. Much information is available on the structure of the intracellular loops of GPCRs including both crystal structure analysis and NMR data [
Classically, GPCRs have been viewed as monomeric proteins. However, evidence has accumulated that GPCRs may physically interact with each other and that oligomeric forms of the same receptor (homodimers) or different receptors (heterodimers) may be functionally active [
Pharmacological approaches have also been employed to establish dimer formation. Studies by Zheng
These authors investigated whether oligomer formation may be a basis of the interaction of the mu opioid and CCK system. They used a BRET assay to measure interaction of the cloned mu opioid and CCK2 receptors. Under basal conditions the receptors did not appear to associate and mu agonist and CCK ligands did not induce oligomerization as measured in the BRET assay. However, bivalent ligands containing a mu agonist and a CCK2 antagonist did cause a BRET response, suggesting that they bound simultaneously to each component of the dimer to promote oligomerization. Similar results were reported by Harikumar
Some studies indicate that dimers may have pharmacological properties that differ from the monomers. Most studies on the pharmacological properties of dimers have shown that the pharmacological profile of ligands binding to monomers and oligomers are similar but that the affinities of the ligands may differ [
In fact, determining whether dimers, especially heterodimers, have pharmacologies that can be distinguished from monomers of each receptor could be more clearly established if compounds, such as the two examples indicated above [
This may be possible in the future since assays exist that can be employed to select for drugs targeting dimers. Most of the luminescent assays to measure dimer formation, in which acceptor and donors are attached to different components of the oligomer, can be employed to identify drugs that block dimer formation, in essence to identify allosteric inhibitors of the receptor complex formation. However, Milligan and associates [
This assay provides an approach to identify compounds selective for activating heterodimers. Compounds effective on the dimer but ineffective on the monomers might be considered dimer selective. Of course, the next problem would be to determine whether such compounds are effective on the native receptors expressed in native tissue.
In fact, while GPCR oligomerization has drawn much interest, a major question remains as to whether GPCR dimers form in native tissue. Studying oligomerization in native tissues has been difficult because of the low expression levels of receptors and dimers. However, recent studies by Albizu
For their studies, they detected dimers using a FRET assay. The assay was dependent on the use of fluorescent ligands binding to the receptors. Specifically, agonists and antagonists were used with tags that contained either FRET donor or acceptors. The tags did not affect ligand binding appreciably. The binding of the ligands to monomeric receptors produced no FRET response. However, if dimers were present and the ligands with acceptor and donors were in close proximity a FRET response could be detected.
The assay system was developed and optimized using tumor cell lines expressing the cloned GPCRs. The authors conducted studies on the cloned vasopressin, oxytocin and dopamine D2 receptors. Interestingly, antagonists could produce strong fluorescent responses while agonists produced much weaker FRET responses. The diminished FRET responses were not due to the agonist causing dimer uncoupling. There may be a number of reasons or interpretations for the weak FRET response to agonist binding. However, the authors suggested that the weak FRET responses following agonist binding were due to negative cooperativity and that essentially one agonist molecule binds to a dimer at a time. In contrast, the strong FRET response found with antagonists is likely to reflect two antagonist molecules binding to a single dimer at a time.
Ultimately, the purpose of these studies was to test whether the FRET based assay could be employed to detect dimers in native tissue. For this, the investigators studied oxytocin receptors in mammary glands from lactating rats. They employed the same ligands as used for the studies on the cloned receptors and showed that antagonist binding yielded FRET responses and in contrast agonist binding yielded much weaker responses. These studies were interpreted as supporting the notion that oxytocin receptor dimers can be detected in native tissues.
However, it should be noted that the studies used tissues that express extremely high levels of oxytocin receptor (1–3 pmol/mg protein), similar to the levels that may be normally expressed in tumor cell lines transfected with recombinant receptors. The investigators could not detect the dimers in tissues with lower receptor expression. In fact, using the same approach, they were not able to detect oxytocin or vasopressin receptor dimers in brain, a tissue with relatively robust receptor expression although at much lower levels than in mammary gland of lactating animals. Thus, the question remains whether dimers are naturally found in tissues in which receptor expression is not abnormally high. This issue is critical in determining the value of dimer selective drugs discovered in immortalized cell lines in which receptor expression is unnaturally high.
Classical approaches to discover drugs targeting GPCRs have either employed radioligand binding assays, assays to measure GTPase activity or second messenger responses including changes in cAMP and Ca++ signaling [
As described above, TR-FRET assays using ligands as acceptors and donors, and GPCR luminescent complementation assays and fluorescent receptor mutants can be employed to study dimer formation and pharmacology [
This approach has been adapted to measure conformational changes in GPCRs in intact cells in a HTS format. This was done by developing FRET based assays in which donor and acceptor moieties were incorporated into the third intracellular loop and the C-terminus of receptors [
This assay was validated in studies with the alpha2-adrenoceptor and muscarinic receptors [
Some of the label free technologies for GPCR drug screening provide complex phenotypic readouts and include DMR, described above, which uses resonant waveguide grating optical biosensors [
These technologies can distinguish different G protein signaling pathways for a specific GPCR, as shown in studies by Schroder
Impedence spectroscopy measures changes in current flow through cells as a phenotypic response to drug action. The idea of this technology for use in cell biology is that when a drug, such as a GPCR agonist stimulates a cell in a selective manner, the resultant signal transduction can induce changes in cell morphology, volume, adherence and interaction with other cells. These alterations in the cell's biology affect current flow through the cell. Therefore, a change in current flow resulting from drug action will induce an alteration in impedance which is detected in the system.
To detect impedance changes, cells can be cultured either onto multielectrode arrays (MEAs) or they can be used in MDS Sciex (now Danaher) CellKey technology which consists of 96 well plates with each well containing gold electrodes at the bottom and fluidics and environmental control systems compatible with automated robotics systems. In these systems, alternating voltages are applied to the cells and the current measured. Calculation of the ratio of the voltage to current reveals the resultant impedance. The response of the cells to drug is detected as changes in the magnitude of the impedance.
The Cellkey technology has been employed to measure impedance responses of GPCRs, both endogenous and recombinant, to drug action. Verdonk
The use of the CellKey technology for GPCR drug discovery was validated by a group at AstraZeneca [
Importantly, in follow up studies, Peters
Like DMR and impedance spectroscopy, surface plasmon resonance (SPR) is a label free, non-destructive optical technology that has been primarily used to measure binding kinetics of different biomolecules, in particular DNA-DNA, protein-protein and DNA-protein binding but is also beginning to find applications in measuring functions of intact cells and has been employed to study GPCRs [
SPR has a number of advantages for use in studying GPCRs. First, the technology is extremely sensitive and is able to study femtomolar levels of receptor in lipid bilayers [
Studies by Alves
More recently SPR has been employed to study cells. One of the first examples of its use to study cells was described by Peterson
In addition to SPR, use of nanoparticles to measure plasmon resonance with optical techniques has been recently employed to detect molecular events in single cells. Thus, Jun
Basic research is driving the development of entirely new fields of GPCR drug discovery and development. It is providing the basis for discovery of compounds with new mechanisms of action, greater GPCR selectivity and unique biological actions. The hope is that these new generations of compounds can be translated into drugs with distinct and desirable therapeutic properties.
First and foremost is the development of allosteric ligands as designer drugs. Physical analysis of GPCRs by crystallography and NMR not only provides insight into the mechanics of drug-receptor interaction but yields critical information on how to rationally design allosteric modulators at specific receptors. We can begin to pick out specific sites on a receptor to affect receptor activation to produce designed responses, such as affecting one signaling pathway over another or to produce activation without desensitization or to facilitate activation only when the endogenous transmitter is present but not when it is absence to produce discrete signaling through the GPCR. The physical and computational analysis allows one to select compounds with particular chemistries to interact with selected sites on the receptor. The new screening technologies provide approaches to select for allosteric modulators using pharmaceutically user friendly HTS assays. Some of these technologies allow for phenotypic responses in native tissues to identify compounds more likely to produce desired therapeutic effects than assay systems dependent on immortalized cell lines over-expressing the receptors. Thus, one would predict a shift in direction of GPCR drug discovery to identification of new allosteric modulators discovered against endogenous GPCRs which may provide more interesting and potentially useful drugs than found with more classical orthosteric ligands.
Drug discovery against dimers also holds promise for the development of unique pharmacological agents and drugs. This may be particularly the case if the dimers have ligand binding properties distinct from the monomers. In this regard, heterodimer drug discovery may provide an approach to develop drugs that are region or tissue selective, which is presently not easily accomplished with classical drug discovery approaches. Furthermore, because dimers are predicted to be in equilibrium with monomers, drugs targeting dimers may shift the equilibrium thereby increasing the biological impact of dimer selective drugs. However, before the full potential of dimer pharmaceutics is realized, much more basic research will be necessary to establish the physiological role of these complexes


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For the Territory's Wildest Wlidlife experience, why not check out Territory Wildlife Park? Open year-round, this unique wildlife experience is for all ages.
Situated in Berry Springs, a 45 minute drive south of Darwin's CBD, and conveniently located next door to Berry Springs Nature Reserve the Territory Wildlife Park truly is the Territory's wildest wildlife experience!
At the Territory Wildlife Park, not only do you see wildlife up-close in their natural habitats, you meet them walking through tree top aviaries, strolling around a natural lagoon and even get to interact with them during daily presentations.
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Uneven tire thread question
I was, or should I say am, having reoccurring uneven tired tread problem with my rear tires. After changing the tires a few times and the problem still occurring relatively quickly, I figured something was wrong. After doing some research and asking around, it seemed that a bad alignment was the most probable cause.
As a result I got an alignment, when getting the alignment, mechanic told me the right rear wheel could not be completely aligned because the lower control arm was bent. So I buy two lower control arms because someone told me (or I read somewhere) to replace suspension parts in pairs. I go back to mechanic he says there's no reason to replace left rear lower control arm. He says, besides it's not as accessible as the right rear one and will take more time, hence more labor costs. He insisted there was no need so I'm like ok then since the right rear control arm is installed just do the alignment. Car has been running fine since.
Except, this morning I wake up and my left rear tire is worn on in the inside .
I'll go back to that mechanic and show them the tire after school and see what they say. If they don't offer to replace the lower control arm and re-do an alignment for free, I'm prob never going back to them again. This is what I plan on doing and the questions I have:
1) What is most likely causing this, should a left rear lower control arm solve this problem?
2) I don't know if this has anything to do with it, but I read somewhere that the DSC sort of tells your car/re-direct your tires so it doesn't swerve and stuff, well mine will will come on while driving. Sometimes the light will start flashing and I'll hear like a clicking noise of something trying to attach, then the light will go on solid after a bit and the noise stops and car still drives fine. Other times the DSC and tire pressure light will come on simultaneously without the noise. And very rarely the car will jerk and the light will come on. Could the dec trying to re-direct force the tires cause that?
Last edited by justanotherone; 10-17-2012 at 02:07 PM.
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Can't help on the cause, but a few thoughts...
Did you check the specs on your last alignment? When I have an alignment done, I always ask for a printout of the before/after, then compare with the last specs. Once, printed at the top of the sheet was 528: the car was a 323 It went right back on the lift.
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Location: such united many state
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Inside rear tire wear is common for our cars due to negative camber. It will noticeably wear faster. When checking tread depth, you should get as close to the inside as you can.
You will also find your passenger-side tire wears slightly faster than your driver's side tire. This is due to a lack of an LSD. When your tire slips from acceleration, it tends to slip the right-side tire. It should not be excessive wear, but it is a little noticeable depending upon the tire brand you have.
Replacing suspension parts will help with this, but the most important thing you can do is keep your car aligned and wheels balanced.
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The print-out on my last alignment was in the car after the alignment. Every tire was green (in the range?) except a bit of the left front tire was red. I know I have that in my room and I do believe it said e46 bmw m3 or something like that. I'll double check. And damn they tried to jipp you, nice catch .
I'll stop by their shop later and see what they have to say. Ordered new tire, should be here tomorrow. Unless they offer to do everything at extremely reduced fee, I'll find a new indy.
Is a replacement lower control arm a hard diy? I still have it from before, just don't know if I'm capable of replacing it.
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I check at least every two weeks, but monthly should be a minimum if you don't have a TPMS.
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Join Date: May 2007
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I thought it was tire "TREAD".
If you have a square set up, just rotate them every 6,000 miles or sooner.
The democracy will cease to exist when you take away from those who are willing to work and give to those who would not.
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Location: Murrieta, CA
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My Ride: '94 325iC & '00 323i
Wear on the inside shoulder of the tire is almost always the result of a heavy foot. If the car has strong negative camber, then this will put more weight, and wear, on the inside shoulder of the tires. But a car with perfect camber will wear the inside shoulder if the gas pedal is operated enthusiastically on frequent occasions. Just because you can go from 0 to 60 in 4 seconds does not mean you should.
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So update: Got home and found the receipt, the right rear trailing arm and alignment was done on the 14th of September. Just a month ago. Also found the reading/specs of the alignment, this was done the day after, the 15th. The top of the paper does read "BMW 2001-06 E46 M3 Cabrio 19" Wheel" the line below that says "Current Measurements." Everything is green and within limits except of a front caster on the left side that's partly to the right of where it needs to be. (That's red) And the rear middle toe is grey. Everything else cambers, toes, total toe, and thrust angle are green.
I had time to go back to the shop and the man (I think he's the head of the shop and he's the one that took care of me before so he remembered me). I explained to him the situation and he said there was no chance that the left rear trailing arm was the cause of the abnormal tire wear because that arm was perfect. It wasn't bent and everything with that arm was a ok and that is why he didn't install for me the first time around. He says he'd love to make the money, but if there's no need to replace it then why do it. The mechanic who did the alignment was also there and said there's no way the alignment was the issue because your alignment is either good or it's bad and it was good.
This is what they're telling me, bring the tire and they'll mount and balance it for 20-ish dollars. Then do a free alignment. And if I want, only if I want to, even though he assures me it won't make a difference, he'll change the other trailing arm for $97. Same price as the previous one, although this one (one on the left) is supposedly harder to get to. So kind of a discount.
I've read you guys' comments and appreciate all the help and input into solving this problem. I admit at times I can get maybe a little reckless and think I'm Vin Diesel in a Fast & Furious movie. I do want to say this, if this is the case wouldn't it happen over time? Ever since this uneven tire wear became an issue, every now and then I kind of check my rear tires for that white metal-ish looking thing that starts to display. Like if I'm walking to my car from the store or something or from getting the mail, I'll randomly just glance down while walking. Not a full on get to my knees inspection every other day or every week, but just a glance. And I do remember, that I checked it and seemed fine (while I was changing my fuel filter which was prob like 1-2week prior) they looked fine. And I might have glanced after that. I saw the wear this morning, and last night I did do some unnecessary taking off. Well, I don't think it was unnecessary, this guy in his truck kind of called me out. I prob hit 90ish that night in a couple secs. Still, I mean it's been one month!! I've never been to a track, I don't drive my car like a mad men everyday, I actually enjoy cruising. I've never been to a track, where you're suppose to speed and all, do those people get new tires every 1-2 weeks?
I did raise my car with some jacks and ramps to change my fuel filter. While I was raising I heard some noise (spring stretching or whatever it could have been), is it possible that not raising the car evenly mess up an alignment?
Edit: He also said that it could have been a defective tire cause he couldn't think of any reason why the tire would wear since the alignment was good.
Update Edit: My right rear tire which I had them mount right before the alignment is also wearing out on the inside. It's not as bad as the one on the left (the white metal-ish isn't showing yet), but it's basically flat on the left side and the right end of that tire has tread. Will take it to them tomorrow morning and see what they say.
Last edited by justanotherone; 10-18-2012 at 07:31 PM.
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I found this interesting thread, http://forums.bimmerforums.com/forum...d.php?t=995556 . Interesting quote from there, "The BMW factory specs care nothing for performance or tire wear, only for safety and a low # of lawsuits. YES I AM SAYING THAT THE BMW FACTORY SPECS WILL NOT ONLY GIVE YOU POOR HANDLING AND PERFORMANCE, IT MAY ALSO WEAR OUT YOUR TIRES PREMATURELY."
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I have check at least every two weeks, but monthly should be a minimum if you don't have a TPMS.
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|Is that you, Mark? Looks fun!
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Taz was his name, the Tasmanian devil of Warner Bros. cartoon fame. A scrappy omnivore who ate anything and everything, he spun in a vortex and bit through everything in his path.
The devil was short-lived, however, making television appearances for a few years in the late 1950s and early 1960s before disappearing from view. In 1991, Taz got a reprieve: his own show, Taz-Mania, which ran for three seasons. Then he was gone for good.
From the screen to the wild
Tasmanian devils in the wild are no less imperiled. Carnivorous marsupials, they're found only on the Australian island of Tasmania. With a stocky build, black fur, keen sense of smell and ferocity when feeding, "real-life" Tasmanian devils and their cartoon namesake have much in common.
The size of small dogs, Tasmanian devils became the largest carnivorous marsupials in the world following the 1936 extinction of thylacines (Thylacinus cynocephalus), known as Tasmanian tigers or Tasmanian wolves. Thylacines lived on continental Australia, Tasmania and New Guinea.
Will the fate of Sarcophilus harrisii, the scientific name for the Tasmanian devil, mimic that of the thylacine?
"If a way isn't found to stop devil facial tumor disease, or DFTD," says disease ecologist Andrew Storfer of Washington State University, "models predict that Tasmanian devils could be extinct in as few as ten years."
And vanishing with them, valuable clues to diseases in other species, including humans.
DTFD is an aggressive, non-viral, transmissible parasitic cancer that is 100 percent lethal, says Storfer. "In short," he says, "it's bad news."
Can we save the Tasmanian devil?
To study DTFD and find ways of understanding its emergence and spread, Storfer has received a grant from the National Science Foundation- (NSF) National Institutes of Health (NIH) Ecology and Evolution of Infectious Diseases (EEID) Program.
Collaborators include Paul Hohenlohe of the University of Idaho, Hamish McCallum of Griffith University, Menna Jones of the University of Tasmania and Elizabeth Murchison of the Wellcome Trust Sanger Institute.
The NSF-NIH EEID Program supports efforts to understand the ecological and biological mechanisms that link environmental changes and the emergence and transmission of infectious diseases.
Projects funded through the program allow scientists to study how large-scale environmental events—such as habitat destruction, invasions of non-native species and pollution—alter the risks of emergence of viral, parasitic and bacterial diseases.
Storfer's research may lead to new insights about the spread of flu in humans. It also may help scientists understand other infectious diseases in animals such as bats, and how certain cancers progress.
"This study provides an excellent test-bed for understanding the spread of infectious diseases," says Sam Scheiner, EEID program director at NSF. "The results may help us control the spread of seasonal flu in people, West Nile virus in birds and white-nose syndrome in bats, among many other diseases."
Tasmanian devils: extinction on the horizon
The first official case of devil tumor facial disease was reported in 1996. Since then, Tasmania's devil population has declined by 70 percent. Findings reported in 2010 show that 80 percent of the remaining devils are affected.
"Tasmanian devils that live in high-density populations may suffer drastic reductions a few years after emergence of the disease," Storfer says.
DTFD has been slowly moving from east to west across Tasmania for the last 17 years; it's now approaching the west coast. "Soon there may be no known uninfected devils," says Storfer.
The disease is spread when Tasmanian devils bite each other's heads while fighting over food, during territorial interactions and when they spar during mating season.
Devils that contract the disease develop lesions around their mouths that become cancerous tumors. The tumors may spread from their faces to their entire bodies. Devils almost always die within six to nine months.
Devil facial tumor disease likely began in what are called Schwann cells. Schwann cells are found in the peripheral nervous system; they produce myelin and other proteins essential for the functions of nerve cells.
In response to DTFD, Tasmanian devils have changed their reproductive habits. Before the outbreak, females started breeding at two years old. Now they breed by the end of their first year—and often die of DTFD soon afterward.
There's a ray of light, however, in this dark day for devils. Some devils have been found with partial immunity to the disease. Breeding in captivity is underway to try to save the species.
"Emerging infectious diseases like DTFD are one of the great scientific challenges of the 21st century," says Storfer. "Infectious diseases are now the sixth leading cause of species extinctions."
Answers in Tasmanian devils' genomes?
Extensive research by Storfer and others, including thousands of samples taken before and after devil die-offs, has given scientists a rare opportunity to study the genomic interactions of an infectious disease and its host—the devils—across an entire species' range.
"The research will tell us about the genetic basis of Tasmanian devils' susceptibility to the tumors," says Storfer, "providing environmental managers with information about which particular devils would be best suited for captive breeding programs."
Knowledge of the rates and direction of past tumor spread will enable scientists to uncover the likely locations of future infections.
Although only a few infectious cancers have been documented, Storfer says, "this disease shares properties with human cancers.
"Our research, especially genetic studies, may reveal the underlying reasons why DTFD is so prevalent and can hold on for so long in a population, perhaps providing information on cancer recurrence in humans."
To test predictions of the course of the epidemic, he and colleagues plan to meld what they call "devil contact network modeling" with genomic studies of Tasmanian devil populations expected to become infected.
"The answers will help in developing responses to this and other disease outbreaks in Tasmanian devils—and potentially in people," says Storfer.
Taz may be gone, but, says Storfer, "Hopefully it's not too late for the real Tasmanian devil."
Explore further: Ancient genes may explain modern threat to Tasmanian devils


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McArthur Towels in Baraboo, Wis., thinks it has an answer to the controversy over female reporters in pro-football locker rooms. The company's recommendation: a cover-up. McArthur, which supplies terry-cloth products to the National Football League, has begun donating some 2,000 wraps and robes for all the players on the league's 28 teams. The robes and the kilt-like wraps, which are held around the waist with a Velcro closure, come in white or the team color. "They are handy, I suppose. They look nice," said Cincinnati Bengals head coach Sam Wyche, who was fined by the N.F.L. last month after he denied...
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HELENE HALDI Ripoff Reports, Complaints, Reviews, Scams, Lawsuits and Frauds Reported
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