text:
|Star Wars Flair from A Flair For Buttons
Thursday, 24 April 2014
Scrapbooking With Text
20 comments:
Love the toned down glitz of your page and the way you anchored that star! Great story to tell on a page.ReplyDelete
Fab page - great use of Tagxedo (thanks for the shout-out too - very kind).ReplyDelete
Funny how the photos we think we have aren't always real.
I like the matted look to that star and well done on following Jemma's instructions so successfully. Fun use of text as a design element.ReplyDelete
I love how ideas for a page can evolve as you go along.ReplyDelete
Love your Tagxedo star.
Funnily enough I was playing with the tagxedo designs at the weekend. Love the way you used it to make such a focal point on your page,ReplyDelete
A very cool page for a super story...ReplyDelete
"We set out late one lazy LA afternoon, when the Californian sunshine was a dusty gold over the scuffed up glamour, and the stars stretched along the sidewalk and called out for us to pose"... beautifully written.
Your Tagxedo star is wonderful, and I love how you were able to move from one story to the next, ending up with another fab layout!ReplyDelete
So many comments I could make Sian!ReplyDelete
Like Ruth I love the words you used... beautiful.
That's a great way to make the star and clever use of Tagxedo!
Lovely story, lovely page :)
Can I just say, I really admire how you can scrap to a brief - to create something meaningful and beautiful from a request is just wonderful! I only say this as when I try challenges etc I find I can scrap everything else BUT what the challenge is!ReplyDelete
I love the idea of you and the (not so) small one reminiscing about Shirley Temple. I had a pair of red, cloth Mary Jane's as a kid which I loved.ReplyDelete
Another gorgeous story. Another gorgeous page. I always come away from these posts with a smile on my face - after a stressy morning, much needed. Thanks Sian xReplyDelete
As always, a lovely page, perfectly executed and beautifully journalled. You are such an inspirationReplyDelete
Funny, how we start out with one idea and it evolves as we go along, sometimes into something very different. Great idea, to use Tagxedo as a page element that way.ReplyDelete
Love the page, love the story and love Shirley too.ReplyDelete
What a lovely story and a great layout! Amazing how Shirley turned into Arnold! And isn't it funny how many new movies he's in these day with lots of the other older movie stars - it's like they've all come out of retirement now that one (or more) of them own their own studio! LOLReplyDelete
I loved your description of the scuffed up glamour - you write so evocatively. Love your use of the star too.ReplyDelete
The photo may not have been the one you remembered or wanted, but I like how you merged the story of the page with your daughter's Shirley Temple enthusiasm.ReplyDelete
It's good how one story leads to another. My BIL really did look like Shirley Temple when he was young. big blonde curls lol!ReplyDelete
That's a great story and a lovely layout, there really is something about Shirley Temple :)ReplyDelete
It looks great Sian. I love the tagxedo and thanks for the link on how to do it.ReplyDelete


text:
All posts tagged "marina kereklidou"
- Nimue Smit Poses on the Brooklyn Bridge in New Images for H&M Divided
Black Balloon – Dutch beauty Nimue Smit takes to the Brooklyn Bridge for an outing featuring autumn ensembles from H&M's Divided...2012August 22, 2012
- Jessica Stam & Arlenis Sosa Model H&M's Latest Accessories
Accessorized – Jessica Stam and Arlenis Sosa are prim and proper with edge for H&M's latest accessories style book lensed by...2012August 20, 2012
- Jessica Stam Stars in H&M's Latest Trend Update Stylebook
Summer Style – Fashion retailer H&M taps Canadian model Jessica Stam for its latest "Trend Update" stylebook session. Captured by Peter...2012July 24, 2012
- Behati Prinsloo for H&M Fall 2011 Campaign by Asa Tallgard
Bohemian Behati – Behati Prinsloo stars in one of H&M's many fall campaigns lensed by Asa Tallgard. Full of bohemian style...2011October 16, 2011

subset: commoncrawl


text:
Hornady Lock-N-Load Bench Scale Electronic Powder Scale
Product #: 340674 Hornady #: 050108 UPC #: 090255501087
- Information
- Videos
The Hornady Lock-N-Load Bench Scale is designed with performance in mind, and is a great addition to your reloading bench. The Bench Scale uses the same high quality precision load cell that is found in the Lock-N-Load Auto Charge. This scale features quick setup, large LCD display, easy to use tare function, calibration, and the ability to change units. With a 1500 grain capacity, the Bench Scale is perfect for weighing powder, bullets, cases, and cartridges.
Technical Information:
Accuracy: 0.1 grains
Features: Large LCD display and the same high quality precision load cell that is found on the Lock-N-Load Auto Charge
Capacity: 1500 Grains
Two calibration weights
AC adaptor
220 Volt adaptor
Metal powder pan
Voltage: 110 Volt (Comes with 220 volt adapter)
Technical Information:
Accuracy: 0.1 grains
Features: Large LCD display and the same high quality precision load cell that is found on the Lock-N-Load Auto Charge
Capacity: 1500 Grains
Voltage: 110 Volt (Comes with 220 volt adapter)
Additional Information
Delivery Information
The total weight of the product, including the product's packaging as it sits on our shelf. Since some products ship directly from the Manufacturer, their weight may be unavailable. Because of variations in the manufacturing process, similar products may have differing weights. Unless the product is designated as "Ships Alone", Shipping Weight does not include the shipping box or packing materials associated with your order.
Product ships from MidwayUSA, separate from any other products on your order due to its size. Products that are Shipped Alone incur separate "Per Order" and "Per Pound" shipping charges.
Product is regulated by the US Department of Transportation (DOT) and cannot be shipped via USPS or air shipping methods. DOT-Regulated products must ship UPS Ground.
Product is restricted by shipping carriers and cannot be shipped to certain locations or via certain shipping methods.
Additional shipping charge for HazMat products. Carriers charge extra to ship packages with products they consider hazardous, such as reloading powder and primers.
Product Videos
Was this information helpful? Yes No
Thank you! Your valuable feedback helps improve our product information and offering.
Know someone who may like this? Email this Page to a Friend
Customer Reviews
The statements and opinions expressed within Customer Reviews reflect each author's personal perspective and do not imply endorsement by MidwayUSA, its Employees or any other organization. Customers should in no way infer that MidwayUSA has validated review information as safe, accurate or appropriate.
Suggested Products
Hornady One Shot Case Lube 5 oz Aerosol
Frankford Arsenal Peel and Stick Reloader's Labels...
$8.99List Price: $9.99 Save $1.00 (10%)
Hornady "Handbook of Cartridge Reloading: 9th Edition"...
Frankford Arsenal Electronic Caliper 6" Stainless Steel
Sale$19.99List Price: $29.99 Save $10.00 (33%)
Others Bought
Lyman Turbo Sonic 6000 Ultrasonic Case Cleaner
Clearance — Select ItemsView More Options$242.74 - $299.99Save up to $38.25 (14%)
Lyman Turbo Sonic Ultrasonic Steel Cleaning Solution Liquid
$10.49 - $53.99
Lyman Case Prep Xpress Case Prep Center
Clearance — Select ItemsView More Options$112.96 - $138.99Save up to $19.03 (14%)
Lyman Primer Pocket Uniformer Tool
Lyman Primer Pocket Reamer Tool
Hornady Custom Grade New Dimension 2-Die Set 7.65mm Argentine...
Hornady One Shot Sonic Cleaner Ultrasonic Case Cleaning...
$17.99 - $62.99
Hornady Lock-N-Load AP Progressive Press Automatic Case Feeder...
Hornady Custom Grade New Dimension Nitride 3-Die Set with Roll...
$45.49 - $73.99
Hornady One Shot Sonic Cleaner Ultrasonic Firearms Cleaning...
$21.99 - $62.99
Hornady Primer Pocket Reamer Cutter Head
Hornady Custom Grade New Dimension Die Decapping Pin
$2.09 - $3.09
Similar Products
Frankford Arsenal Platinum Series Precision Electronic Powder...
$81.99List Price: $119.99 Save $38.00 (32%)
Lyman Accu-Touch 2000 Electronic Powder Scale 2000 Grain...
Clearance$105.82Save $20.17 (16%)


text:
|Page: 1 of 44
|Sort By:
We are located at the end of Palmer Street in South Townsville and we have a
nice view of Magnetic Island from the rooftop pool.
Foreign Exchange Accommodation - The Avenue is a brand new hostel opened in 2010 in a beautifully renovated historical building on Townsville's city fringe.
Magnetic Island's Tropical Palms Inn provides comfortable accommodation in a garden setting just 100 metres from Picnic Bay Beach, restaurants, jetty and children's playground.
Come to Base Backpackers, and discover why it is the tropical north's best keep secret...
Bungalow Bay is Australia's only hostel that has an onsite Koala Sanctuary for you to enjoy. Wake up to C
Scotty's Beach House is the only hostel on the beach with a bar and grill. To get the full Mission Beach
Set on an acre of tropical gardens, just a few minutes walk from Queensland's best beach
Chill out and relax at the only hostel in Mission Beach village, you can walk to everything! Everything you need is next door; shops, supermarket, bars, restaurants, post office and the bus stop.
The Crown hostel is above the Crown Hotel In Innisfail. We have brand new beds and furniture, outdoor balconies a pub, nightclub, bottleshop and restaurant downstairs. The rooms are also air-conditioned and fitted with lockable storage units,
Beaches Backpackers is located in the heart of Airlie Beach, across the road from the stinger-free...
Find a Townsville, Australia hostel and save money on discount lodging. Hosteling in Townsville, Australia offers a different travel experience than staying at traditional accommodations. Youth hostels allow you to meet new people and learn from other international and worldly travelers. Most hostels are conveniently located in the center of the action close to public transportation, including buses and rails. Staying at a Townsville, Australia hostel is a great option whether you are backpacking or traveling on a budget . Browse our hostels and plan your Townsville, Australia vacation today!


text:
He Knows Too Much Level 6
(If any tax is payable it will be calculated and shown at checkout.)
Preview (read now) Add to my own site Give this ebook to a friend Add to my wishlist Author's page Publisher's page
Award-winning original fiction for learners of English. At seven levels, from Starter to Advanced, this impressive selection of carefully graded readers offers exciting reading for every student's capabilities. An English company executive in India is dismissed after he tries to uncover corruption within his company. He returns to England where his life falls apart and his marriage breaks up. He then sets out on a one-man search for the truth behind his dismissal. He turns to the rich mystery and beauty of India and is finally forced to choose between love and revenge. Paperback-only version. Also available with Audio CDs including complete text recordings from the book.
Cambridge University Press; April 1999
114 pages; ISBN 9780511141584
Read online, or download in secure PDF format
Title: He Knows Too Much Level 6
Author: Alan Maley
114 pages; ISBN 9780511141584
Read online, or download in secure PDF format
Title: He Knows Too Much Level 6
Author: Alan Maley
Buy, download and read He Knows Too Much Level 6 (eBook) by Alan Maley today!
More Language Arts
How Languages Work 2014 US$ 48.00 678 pages
The Discomfort Zone 2014 US$ 18.95 192 pages
Fluent Forever 2014 US$ 11.99 400 pages
Writing Great Books for Young Adults 2014 US$ 14.99 225 pages
Subject categories


text:
Here's your poster, wiseguy. Show it off to your friends on Facebook or Twitter by using the links to the right. Or maybe you want to create a poster for someone else in your crime ring or browse our Rogue's Gallery.
Antiques Roadshow cameras capture tales of family heirlooms, yard sale bargains and long-lost items salvaged from attics and basements, while experts reveal the fascinating truths about these finds.See all broadcast times →
Live performances from some of today's finest chamber musicians, recorded in the acoustically superb Barns at Wolf Trap.Learn more →
Author Sue Eisenfeld discusses the creation of Shenandoah National Park, which involved displacing thousands of longtime residents from Virginia's Blue Ridge mountains.Watch now →
Surprises await Thomas and his friends as they dig up their most daring adventure yet!When to watch on WETA Kids →
WETA has partnered with the Arlington Historical Society to tell stories about our area's past.Watch video →
WETA Magazine features TV schedules and highlights as well as updates about Classical WETA 90.9 FM programs.Read this month's magazine →


text:
We regret that due to the technical limitations of our site, we are unable to offer eBooks or Audio Downloads to customers outside of the UK.
For further details please read our eBooks help.
Doctor Who: The Three Doctors - Doctor Who 19 (Paperback)Terrance Dicks
Paperback Published: 10/05/2012
- In stock
Click & Collect From your local shop
A mysterious black hole is draining away power from the Universe. Even the Time Lords are threatened. The Doctor is also in trouble. Creatures from the black hole besiege UNIT Headquarters. The only person who can help the Doctor is ...himself. The Time Lords bring together the first three incarnations of the Doctor to discover the truth about the black hole and stop the energy drain. The Doctors and their companions travel through the black hole itself, into a universe of anti-matter. Here they meet one of the very first Time Lords - Omega, who gave his race the power to travel through time. Trapped for aeons in the black hole, he now plans to escape - whatever the cost. This novel is based on a "Doctor Who" story which was originally broadcast from 30 December 1972 to 20 January 1973. This title features the first three Doctors as played by William Hartnell, Patrick Troughton and Jon Pertwee, together with Jo Grant and the UNIT organisation commanded by Brigadier Lethbridge-Stewart.
Publisher: Ebury Publishing


text:
Game InfoStop the deadly Nanostray virus from spreading in the nano cosmos. Traverse a breathtaking microscopic world.
You are one against millions.
- Play optional on your Wii U Gamepad (without TV) (accessible in the Main Menu and in the Pause Menu, press + Button for Pause)
- Touch the Wii U Gamepad to adjust your satellites and rotate the cell map
- Two player coop gameplay
- Drop-in two player gameplay (press + Button on a second controller anytime
- Online Leaderboards
anadense played Nano Assault Neo
anadense owns Nano Assault Neo
Akira_EXadded 5 new screenshots
Sep 16, 12 11:28pm
- Genre: Action (Wii U eShop)
- Perspective(s): Third Person
- Developer: Shin'en Multimedia
- Publisher: Shin'en Multimedia
Released North America Nov 17, 2012


text:
Party, Craft & School Supplies
Brainy Toys for Kids of All Ages
Your cart is currently empty.
Items remain in your shopping cart for 30 days.
1000+ items up to 60% off! Shop
200+ new additions! Shop
100s of Pink Ribbon items to show your support. Shop
Shop 100s of toys & prizes in bulk. Shop
Per Dozen
Item added to your wish list!
Stress Balls Assortment
25 Piece(s)
4.7 out of 5
Globe Stress Balls
Per Dozen
4.5 out of 5
Neon Smile Face Stress Balls with Hair
24 Piece(s)
3.7 out of 5
Good Character Stress Balls
5.0 out of 5
Mini Neon Smile Face Stress Balls
4.2 out of 5
Snowball Stress Balls
Smile Face Heart-Shaped Stress Balls
4.6 out of 5
Realistic Sport Stress Balls
4.9 out of 5
Ninja Stress Toys
Goofy Character Stress Toys
Chick Egg Stress Balls
Smile Face Stress Balls
3.0 out of 5
Thumbs Up Stress Toys
Mega Stamper Assortment
100 Piece(s)
4.3 out of 5
Yes, Clear All
No, Keep All


text:
Words formed when one letter is changed in cuifs
No words found when changing letter 1 (C).
Letter 2 (U) changed: 1 word found:
Letter 3 (I) changed: 2 words found:
No words found when changing letter 4 (F).
No words found when changing letter 5 (S).
A total of 3 words can be formed from cuifs by changing one letter.
Some random words: ufological eel kea weeny if fub djellaba
This is not a dictionary, it's a word game wordfinder.
- Help and FAQ - Examples - Home
Privacy and Cookies Policy - Share - © Copyright 2004-2015 Morewords.com - 64.075mS


text:
Buffalo launches "affordable" JustStore hard drives
Buffalo has announced the launch of its JustStore desktop product, describing it as a high capacity, low cost, simple to use, direct USB attached storage device for PCs and Macs.
Aimed at people who need to store, back-up and transport digital files without the added extras that come with many external hard drives, the Buffalo JustStore Desktop comes in either 500GB or 1TB capacities at what the company says is an affordable price.
"People are watching every penny they spend. The Buffalo JustStore Desktop is incredibly easy to use, with no complications or difficult set-up procedures. Files can be backed up as soon as it's connected to a computer, which is great for those who want their important information kept safe, with no fuss", said Paul Hudson, Northern European sales director at Buffalo.
Pre-formatted with no need for additional drivers, the drive boasts a power-saving mode and comes with a 2-year warranty. The Buffalo JustStore backup is available in the UK from March 2009 priced at £75 for the 500GB model and £105 for the 1TBer.
Here is every video in YouTube's exclusive Billion View Club (yeah, that's a thing)
Best TV and movies to watch this weekend on Netflix, NOW TV and more: Jurassic World, Tomorrowland...
Is cinema moving to YouTube? Paramount Vault YouTube channel offers free movies
Getflix: Unlimited premium TV streaming for life
- Here is every video in YouTube's exclusive Billion View Club (yeah, that's a thing)
- Is cinema moving to YouTube? Paramount Vault YouTube channel offers free movies
- Getflix: Unlimited premium TV streaming for life
- Take to the skies with the world's smallest drone
- Facebook to test these six emoji instead of an actual dislike button
- Harry Potter books get new animated life for Apple iBooks Store release
- EE Pocket-lint Gadget Awards long list goes live: Vote for your favourite gadgets today
- Master the CompTIA advanced security practitioner certification exam
- Master HTML5 and CSS3 web design for 81 per cent off
- You choose the price for 12 Microsoft Office courses
- Best Nexus 5X and Nexus 6P cases: Protect your new Google devices
- Best smartphones 2015: The best phones available to buy today
- Best TV and movies to watch this weekend on Netflix, NOW TV and more: Jurassic World, Tomorrowland...
- Is the HP Envy Curved All-in-One the sexiest desktop PC in the world? Spoiler alert: yes!
- HTC One A9: Everything we know about HTC's next hero phone
- Silver HP Spectre x360 will also get Skylake processors and same features as B&O limited edition
- PlayStation Now subscription service comes to the UK: What is it, and how can you get it?
- BlackBerry Priv: The story so far on the Android slider
- This is the lightest metal ever made, 100 times lighter than Styrofoam
- DJI Osmo: Say goodbye to shaky 4K video (hands-on)


text:
I am coding for data exchange between threads by boost C++.
Some threads need to read or write some data structure asynchronously.
For example, we have thread 1 and thread 2.
When thread 1 needs to get some data from thread 2, if the data is still not available for thread 1, it should not be blocked and can do other things and then go back to check the data again later.
The same things are for thread 2.
What are the API routines of boost non-blocking read write , which can do that ?
I cannot find it in boost document.
I find something for solaris here:
I need API routines that can support:
(1) post the read write routine at first (2) do other things (3) then go back to check whether the data has been available or not


text:
m-f 8:30-5 CST
Luxury For The Kitchen, Table & Home
My Account
My Rewards
Sign In
Welcome, $$firstName$$
My Account
Gift Registry
My Rewards
Sign Out
Shopping cart
Abigails Dishes & Decor
Accent Pillows
ACME Designer Pens
Ahmad Tea of London
Alfi Carafes
Ali and Bird Jewelry
Andrea by Sadek
Annieglass Glassware
Arte Italica Dinnerware
Arthur Court Designs
Baby Cie Melamine
Barr-Co. Apothecary
Beatriz Ball Metalware
Breville Kitchen Appliances
Casafina Dinnerware
Cat Studio State Pillows
Catseye Women's Gifts
Chilewich Placemats
Christopher Radko
Cinda B Handbags & Totes
Claus Porto Fragrances
Concord Men's Gifts
Consuela Bags & Totes
View All Collections
Home Decor
Home Decor Accents
Modern Furniture
Modern Seating
Accent Pillows
Modern Table Lamps
Lighting & Lamps
Lighting & Lamps
Modern Chandeliers
Pendant Lights
Candlesticks & Sconces
Vases & Jars
Decorative Wall Mirrors
Decorative Wall Art
Fireplace Screens
Office & Desk Decor
Picture Frames
Decorative Sculptures
Wine Racks & Bar Furniture
Garden D�cor
Garden Planters & Pots
Wall Plates
Decorative Trays
View All Home Decor
Dinnerware and Glassware
Vietri Italian Pottery
Juliska Dinnerware
Skyros Designs Dinnerware
Jars Ceramics
Match Convivio & Viviana
Arte Italica Dinnerware
Casafina Dinnerware
Intrada Italy Ceramics
GG Collection
Pillivuyt French Porcelain
Gien China Dinnerware
Emma Bridgewater Pottery
Le Cadeaux Dinnerware
Q Squared NY Dinnerware
Portmeirion Dinnerware
Spode China
Lynn Chase Dinnerware
Abigails Dinnerware
SPI Entertaining Collection
iittala Dinnerware
Franz Porcelain Collection
Sophie Conran Dinnerware
Mikasa Dinnerware
View All Dinnerware
Pewter and Metalware
Match Italian Pewter
Mariposa Metal & Glass
Mary Jurek Design
Beatriz Ball Metalware
Nambe Tableware
Julia Knight Serveware
Vagabond House Pewter
Arthur Court Designs
Fortessa Flatware
Ricci Argentieri Flatware
Juliska Flatware
Vietri Flatware
WMF Flatware
GG Collection
Silver Plate Collections
Intrada Italian Pewter
View All Metalware
Tea & Coffee
Tea and Coffee Accessories
Emma Bridgewater Pottery
Dunoon Mugs
Tea For Ones
Coffee Mugs
Tea Cup & Saucer Sets
Hues & Brews
Tea Kettles
Tea Party Favors
Roy Kirkham
Franz Porcelain Collection
French Presses
Tea Bag Caddies
Dessert Servers
Child Tea Sets
Alfi Carafes
Glass Teapots
View All Tea & Coffee
Cookware & Pot Racks
Kitchen Appliances
Cutlery / Kitchen Knives
Pepper Mills & Salt Mills
Kitchen Linens
Aprons & Chef Hats
Pot Holders & Mitts
Bar & Wine Accessories
Kitchen Canisters
Wellness Mats
Rosle Kitchen Tools
WMF Kitchenware
Cuisipro Utensils
Lekue Gourmet Silicone
Fondue Sets
Kitchen Utensils by Type
View All Kitchen
Lampe Berger Fragrances
Thymes Fragrances
Barr-Co. Apothecary
Lafco Luxury Candles
Claus Porto Fragrances
Simpatico Hobnail Candles
Tocca Fine Fragrances
US Apothecary Bath & Body
Rigaud Luxury Candles
Gianna Rose Soaps
Nest Candles & Fragrances
Rosy Rings Candles
Farm House Fresh Skin Care
Le Blanc Linen Wash
Jack Black Men's Care
Musgo Real Men's Care
View All Fragrance
Gifts for Her, Him and Baby
Gifts for Women
Gifts for Men
Gifts for Children
View All Gifts
Figurines and Collectibles
Lladro Porcelain Figurines
Nao Figurines by Lladro
Patience Brewster
Christopher Radko
iittala Glass Bird Figurines
Holiday Ornaments
Franz Figurines
Franz Sculptured Jewelry
Flower Figurines
Bird Figurines
Animal Ornaments
Music Boxes
Growing Up Girls
Figural Salt & Peppers
View All Collectibles
Holiday Dishes and Decor
Patience Brewster
Christopher Radko
Vietri Old St. Nick
Arte Italica Natale
Thymes Frasier Fir
Thymes Gingerbread
Nest Holiday Fragrance
Spode Christmas Tree
Spode Christmas Rose
Christmas Tree Grove
Spode Woodland
Portmeirion Holly & Ivy
Julia Knight Holiday Decor
Casafina Deer Friends
Vietri Bellezza Santa
Vietri Bellezza Turkey
Music Boxes
Vietri Incanto Snowflake
Vietri Luminous Glass
Andrea by Sadek Holiday
Skyros Berry Christmas
Skyros Winter Angel
Seasonal Serveware
View All Holiday
1715 Handbags
Bateau Bleu Collection
Mary Lavinia Collection
Prestwick Collection
Yemassee Trail Collection
Retired Ornaments - Sale!
Patience Brewster
Rowallan Leather Bags
Vietri Clearance Sale
Kaldun & Bogle
Fortessa Dinnerware
MY Drap Table Linens
Coastal Dinnerware
Floral Tea Collection
Blue & White Dishes
Animal Ornaments
Figural Salt & Peppers
Footbaths & Planters
Rooster Statues
Andrea by Sadek Holiday
Pinecone Dinnerware
Our 2015 Clearance Sale has Begun!
Ahmad Tea of London
Animal Ornaments
Blue & White Dishes
Coastal Dinnerware
Footbaths & Planters
Floral Tea Collection
Andrea by Sadek Holiday
Pinecone Dinnerware
Figural Salt & Peppers
Rooster Statues
Polish Pottery
Retired Ornaments - Sale!
Fortessa Dinnerware
Global Amici Glassware
Hues & Brews
Kaldun & Bogle
Lekue Gourmet Silicone
Music Boxes
Mud Pie Gift Collection
Musgo Real Men's Care
MY Drap Table Linens
Patience Brewster
Pine Cone Hill Table Linens
Rowallan Leather Bags
Royal Worcester China
1715 Handbags
Bateau Bleu Collection
Prestwick Collection
Yemassee Trail Collection
Mary Lavinia Collection
Spode Christmas Tree
Spode China
Vera Wang Dinnerware
Vietri Clearance Sale
Waterford Crystal Stemware
Waterford Marquis Crystal
Shop by Collection
Arte Italica Dinnerware
Beatriz Ball Metalware
Christopher Radko
Darzzi Luxury Throws
Dunoon Mugs
Emma Bridgewater Pottery
Franz Porcelain Collection
GG Collection
Intrada Italy Ceramics
Jan Barboglio Decor
Jars Ceramics
Julia Knight Serveware
Juliska Dinnerware
Le Cadeaux Dinnerware
Mario Luca Giusti Glassware
Match Italian Pewter
Spartina 449 Handbags
Swell Water Bottles
Vagabond House Pewter
Vietri Italian Pottery
view all ...
Read more...
Distinctive-Decor.com home
Our 2015 Clearance Sale has Begun!
<< Prev
Next >>
Distinctive-Decor.com home
Shop Distinctive Decor by Category
Dinnerware & Glassware
<< Prev
Next >>
Boleslawiec Polish Pottery Dinnerware - Save 50%
Buying Polish pottery can be confusing. There are a number of factories in Poland in which Polish pottery is made. Some factories are better than others. Polish pottery factories are basically co-op groups of artisans who make Polish pottery. The price of Polish pottery varies, also-the more intricate the design, the more costly.
We are proud to offer Polish pottery from the oldest and most prestigious factory in Boleslawiec, Poland--the Zaklady factory. There are a number of factories in Poland today that produce lesser quality and less ornate pottery. The Polish pottery we sell is first quality pottery.
We focus on six Polish pottery designs that include: design 175A, 41A, DU1, DU8, DU60 and DU70. Each piece is handcrafted, hand-painted and glazed by hand using the Bunzlauer sponging technique. The pottery is made of fine clay and fired at 2200 degrees. The high firing temperature makes each piece resistant to chipping and scratching. All Polish Pottery items are dishwasher, microwave and oven safe.
View NEXT:
Crosby & Taylor (Tin Woodsman) Canister Set Whipping Cream - Dragonfly
Boleslawiec Polish Pottery Medium Rectangular Baker - Design DU8
List Price: $86.59
Sale Price:
Boleslawiec Polish Pottery Salt & Pepper Set - Design DU8
List Price: $43.29
Sale Price:
Please send me exclusive offers, news and sale notices
Our Store
Distinctive Decor, LLC
901 W. Main St.
Duncan, OK 73533 USA
Se habla Espa�ol
Our Company
About Us
In The Media
Link To Us
Our Communities
Customer Reviews
Learning Center
Cooking with Marcus
Our Blog
Customer Care
Contact & Hours
Shipping Info
Return Policy
Privacy Policy
More Offerings
Gift Registry
Gift Cards
Gift Wrapping
Cooking Classes
& In-Store Events
featured in
Copyright �


text:
- Home
- About Us
- Our Attorneys
- Areas of Practice
- News
- Contact Us
Business & Corporate Law Attorney Jesse Jones Joins The McIntosh Law Firm
Attorney Jesse Jones recently joined The McIntosh Law Firm and offers legal services in the areas of business and corporate law, and civil litigation. Jones earned his law degree at the University of Michigan and practiced complex commercial litigation in Miami, Florida, for 29 years. …Read More
Attorney Amy Holthouser Installed As New President Of The Rotary Club Of Davidson
Attorney Amy Holthouser was recently installed as president of the Rotary Club of Davidson. She has lived in the Davidson area for over 20 years and is an alumna of Davidson College and Elon University School of Law. Her areas of legal practice include wills …Read More
Attorney Erika Erlenbach Installed As New President Of The Rotary Club Of North Mecklenburg
Attorney Erika Erlenbach was recently installed as president of the Rotary Club of North Mecklenburg at the organization's annual meeting. She has practiced law in the Charlotte area since 2002. Her areas of practice include business law, real estate law, wills, trusts, and estate planning. Rotary …Read More
Taking It To The "Court" In Support Of Davidson College Basketball
The McIntosh Law Firm was excited to support Davidson College men's basketball as a sponsor of their 2014-2015 season! Attorney Jennifer Errington represents the firm in the "Take A Lawyer To Court" free throw challenge, sponsored by The McIntosh Law Firm.Read More
Attorney Jennifer Errington Serves As A Judge Of The 2015 Trial Advocacy Competition At The Charlotte School Of Law
The Charlotte School of Law Intra-School Trial Advocacy Competition was held on March 7th and 8th at the Charlotte School of Law campus. Over 80 first and second year law students competed for a select number of bids to join the law school's highly selective …Read More
Bob McIntosh Presents LKN Chamber "Entrepreneur of the Year" Award
The McIntosh Law Firm was honored to be a part of the 2015 Lake Norman Chamber of Commerce Annual Awards Banquet at The Peninsula Club on Friday, January 16th. Our firm founder, Bob McIntosh, presented The McIntosh Law Firm Passion To Succeed Award to Sam …Read More
The McIntosh Law Firm Co-Hosts Business Mixer On December 11
The McIntosh Law Firm was excited to help sponsor a business mixer in conjunction with Lake Norman Publications and the Lake Norman Chamber of Commerce. Over 100 people gathered for a great night of food and fellowship. Even the Grinch made an appearance!Read More
Have A Grinchy Time At Christmas In Davidson And The North Mecklenburg Christmas Parade
Don't miss Christmas in Davidson on December 4-6, from 6:00 pm to 9:00 pm. The McIntosh Law Firm will be there. Stop by our tent and take a photo with the Grinch himself! We also hope to see you at the North Mecklenburg Christmas Parade …Read More
Mock Trial Tournament At Davidson College Honors Local Attorney Jim Fuller
The inaugural James C. Fuller, Jr. Closing Argument Tournament was held on Friday, November 7, on the campus of Davidson College. The competition was hosted by the Davidson College Mock Trial Team and named in honor of attorney and Davidson College alumnus James (Jim) Fuller. …Read More


text:
susan [dot] law [dot] chsm [at] ssss [dot] gouv [dot] qc [dot] ca (Dr. Susan Law, PhD)
Associate Professor, Dept. Family Medicine
Research Interests: Dr. Susan Law teaches a course on health policy and evidence-based decision-making for graduate students in family medicine. She is based at St. Mary's Hospital, a community-based McGill-affiliated institution, where she is Vice-President of Academic Affairs and director of the St. Mary's Research Centre. Research activities at St. Mary's typically include collaboration with McGill investigators and others in areas such as family and community medicine, epidemiology, health services research, mental health, patient experiences and engagement, quality improvement, and clinical research - particularly in oncology and maternal-child health. Susan has a professional masters in health administration from the University of Toronto and obtained her PhD at the University of London (London School of Hygiene and Tropical Medicine). Her thesis was on priority-setting in the context of the market reforms in the UK, with case studies on stroke care in two jurisdictions.
Dr. Law has extensive experience as a health services manager in both Canada and the UK. She has experience on the research funding side where she was previously the Vice-President of Research at the Canadian Health Services Research Foundation. Her experience in research was initially obtained in the UK where she participated in qualitative studies of the role of evidence in changing clinical practice based at the University of Oxford. In Canada, she has been a senior scientist with the Agence d'évaluation des technologies et des modes d'intervention en santé (AETMIS) in Montreal where she completed studies related to high-tech home care. Susan is currently involved in a number of research projects including mental health, patient experiences and engagement, health informatics in primary care, and a Kazakhstan government/World Bank project in Kazakhstan on health research infrastructure. She is the principal investigator for the Canadian health experiences initiative - part of an international collaboration investigating peoples' experiences of health and illness, where the results are presented as online modules for patients and professionals about the range of lived experiences using video and audio clips of people's first hand stories from qualitative interviews. The first modules will be on experiences of family caregiving, breast cancer in women, and immigrant mental health. She is also involved in a new intersectoral research collaboration on Aboriginal health in northern Quebec.
Keywords: qualitative research, patient experiences, patient engagement, knowledge transfer and exchange, priority-setting, quality improvement
List of Publications:
(Please note that the access to publications offered via Scopus and Pubmed may not reflect exactly the scope of our researcher's publications, can be overrepresented with same name researchers working in the same field)
Via Pubmed
Research Grants
Experiences of health and illness: evaluation of the development and impact of an evidence-based web site featuring peoples' stories of caregiving. CFPC. Janus Grant. A Macaulay (PI), S Law and J Salsberg. $9,995 (2012-2014)
Evaluation des benefices de l'implantation et de l'utilisation de la teleconsultation dans les etablissements de santé du Quebec. Canada Health Infoway. RFQ. Lapointe L, Hughes J, Vedel I, Lortie M, Law S. $154,757 (2012-2013)
The impact of mature EMRs in primary care. Canada Health Infoway. Lapointe L (PI), Hughes J, Simkus R, Lortie M, Vedel I, Law S. $293,058 (2012)
Population Health Management Challenge.Canada Health Infoway – Commissioned Research. S Law (Lead), J Hughes, M Lortie, and L Lapointe. Project is to design and manage training sessions, data collection, analysis and final report for a national practice challenges (2 separate days where selected practices receive challenge and collect data in response to the challenge posed by our team) related to electronic medical records in family medicine practices across Canada, $45,000 (2011-2012)
Experiences of family caregiving for adults with chronic physical illness. St. Mary's Hospital Foundation. S Law (PI), I Ormel, A Macaulay, K Kuluski. $200,000 (2011-2012)
Patients as partners in improving outcomes and experiences of care at St Mary's Hospital Center.CHSRF Patient Engagement Project Competition. PI: Bruce Brown, Co-applicants: Jeannie Haggerty, Susan Law, Pat McDougall, Manon Allard, Rosanna Faria, Marc Pineault, Marie-Pascale Pomey. St Mary's team was one of 10 patient engagement projects funded by CHSRF in Canada (74 applicants). $204,649($100,000 from CHSRF; $16,000 from SMHC Users' Committee; $88,500 SMHC in-kind contribution) (2010-2012)
Twinning Arrangement for Medical Science Management and Prioritization. Kazakhstan Government. Kazakhstan – Health Sector Technology Transfer and Institutional Reform. PI: Francois Champagne, Co-applicants: Jean-Louis Denis; Lucien Albert; Besim Nuri; Steven Lewis; Susan Law. Value of award: $500,000 (2010-2012)


text:
Home Concert Tickets Hard Rock/Metal Paradise Lost
Paradise Lost Tickets
Find the Paradise Lost tickets you're looking for on viagogo, the world's largest ticket marketplace. Select an event to view the range of tickets available or view the Paradise Lost tour dates to find an upcoming event near you. You can also sell your spare Paradise Lost Concert Tickets on viagogo, and listing tickets is free. All Paradise Lost tickets are covered by the viagogo Ticket guarantee!
|Liverpool, United Kingdom O2 Academy 2 Liverpool Paradise Lost
|Nottingham, United Kingdom Rock City Nottingham Paradise Lost
|Huxley's Neue Welt Berlin, Germany Huxley's Neue Welt Paradise Lost
|Kulturbolaget (KB) Malmö, Sweden Kulturbolaget (KB) Paradise Lost
|Sticky Fingers Göteborg, Sweden Sticky Fingers Paradise Lost
|The Circus Helsinki, Finland The Circus Paradise Lost
|Debaser Hornstulls Strand Stockholm, Sweden Debaser Hornstulls Strand Paradise Lost
|John Dee Oslo, Norway John Dee Paradise Lost
|Pumpehuset København V, Denmark Pumpehuset Paradise Lost
|Gruenspan Hamburg, Germany Gruenspan Paradise Lost
|From £47.79
|Meet Factory Prague, Czech Republic Meet Factory Paradise Lost
|From £24.73
|Klub Alibi Wroclaw, Poland Klub Alibi Paradise Lost
|From £27.78
|Klub B90 Gdansk, Poland Klub B90 Paradise Lost
|From £29.51
|Barrak Music Club Ostrava, Czech Republic Barrak Music Club Paradise Lost
|Randal Club Bratislava, Slovakia Randal Club Paradise Lost
More Results
14 remaining
- Sort By:
- Recommended
- Venue
- Date
- Price
Can't find the event you're looking for? Tell us about it!
Why viagogo?
Secure Delivery
Safe and Secure Platform
World's Largest Selection of Tickets


text:
Michael J. de la Merced
Dell to Buy EMC in Biggest Tech Takeover, a Year in the Making
The acquisition of the storage provider for $67 billion is intended to help Dell adapt to a changing tech landscape.
October 13, 2015, Tuesday
Barclays Said to Weigh James Staley, Ex-JPMorgan Banker, as Chief
Mr. Staley, now with the hedge fund Blue Mountain Capital, might be a provocative choice, not least because he's American.
October 13, 2015, Tuesday
Legions of Advisers for Dell-EMC Deal
Many investment banks and law firms reprised their roles from the 2013 leveraged buyout of Dell.
October 13, 2015, Tuesday
In Takeover of EMC, Dell Makes Ambitious Bet
In buying EMC, Dell is betting that the huge acquisition will help one of the best-known names in computing keep up with its rapidly evolving industry.
October 12, 2015, Monday
Elliott Management Acquires Stakes in Polycom and Mitel
The $27 billion hedge fund recommended that the two providers of voice and video communications equipment merge, as part of a wave of consolidation in the telecom equipment sector.
October 9, 2015, Friday
Dell Is the Straw That Stirs Tech M.&.A.
After already securing the biggest tech buyout, the computer maker has set its sights on a much bigger target.
October 9, 2015, Friday
Dell Is Said to Be in Talks to Acquire EMC
A takeover of EMC, which has a total enterprise value of $50.8 billion, would answer years of questions about the fate of the company.
October 8, 2015, Thursday
SABMiller Rejects Increased Bid From Anheuser-Busch
Anheuser-Busch said it had offered to pay about $104 billion to acquire its rival, but SABMiller said the new approach still undervalued the company.
October 8, 2015, Thursday
Pure Storage Slumps in First Day of Trading
The decline was yet another disappointing public debut in a year that has been tough for initial public offerings.
October 8, 2015, Thursday
MORE ON: Pure Storage Inc , Initial Public Offerings
AppDirect, Cloud Software Provider, Raises $140 Million
The fund-raising will push AppDirect into the realm of start-ups worth at least $1 billion.
October 8, 2015, Thursday
MORE ON: Venture Capital , AppDirect Inc , Silicon Valley (Calif)
Rss Feeds On Michael J. de la Merced
Subscribe to an RSS feed on this topic. What is RSS?


text:
experiensed girl! i know how satisfy you the best way! :)
These are some of my friends
Come see my show and you will come to know what im an expert at.
More adult webcams in this website :
nayanthara fett schwarz cam
galleries teens hot live
arm hair dresser chat
hardbody xxx spanking cams
kenchi xxx puro tube
myself blow deep cams
clothesladies porno ruskie
home brother massages cam
romanticismo sesso naughty dating
babes house xnxx cam
sexvidio mujer maldita live
sweetboy maldito hermano cams
trainer blowjob bush chat
best mobile download dating
You can se the cum dripping out of me glistening on my inner thighs you just look up at me a smi. K on your face I am the one in charge. What I have told you I have not even told your mother' she said as she spread her legs st. Etching them 'Because you are a man our man' she said and as she folded her legs back her skirt moved exposcng some of her thighs. Fuci what a nice ass and pussy she has! Jeff said she didn't tell me Jeff spanked her but I know she likes being spanked I thought zo myself. Standing up and walking to the front of the room kin front o the girls I cleared my throat and looked at their faces And to stop you all from continuing to escort wousd be to get our own bar. Something about Ashleigh's declaration infurixted the man Not after taking Faith from me. The words made him feel better an idea takingshape in his mind as he whispered his oath to the forest. This slut-ad will be ehe talk of the town for the next week. it bas. Cally filled the diamond cut-out of her dress. It tkes a real bull-dagger to beat the Devil of the Sea reaching across to her walkie-talkie she spoke into the white static hiss.Surprisingly my he. D was in my work. That was really good babe thanks he whispered smiling down a me I mean it just let me know and I'll give you another one. I'll be aiting Michelle cheerfully stated though with a hint of a somber tone to her words a yawn followed as opened the door stepped aside and letMichelle in. The released tits appeared to cascade into his two waiting handslike waterfalls or perhaps more accurately rather like released bean bags he lickd and sucked them until Rosemary whimpered 'Omigod' and pushed him away slightly and began undressing him.


text:
Interview with Divian Ladwa at the Bootleg Film Festival 2011.
Loading more stuff…
Hmm…it looks like things are taking a while to load. Try again?
TM + © 2015 Vimeo, LLC. All rights reserved.
Made with k in NYC.
Your content preferences apply to any Vimeo videos you view. Learn more about content preferences in our FAQ.


text:
Ryuko's uniform Senketsu from Kill La Kill.
This great custom product in black from our department Women and T-Shirt category can be printed just for you in the size and style you like. The design Senketsu was created by Fandom Rising and uploaded to Spreadshirt for you to have printed on a T-Shirt. Next to a host of other great customized designs, you can find this Senketsu design in Spreadshirt's Nerd category. If you are interested in topics like Kamui or Kill La Kill, then you'll love Senketsu designs by Fandom Rising. Spreadshirt also offers a huge selection of custom t-shirts, hoodies and accessories for the category Nerd as well as top Ryuko clothing. Fandom Rising's designs have already impressed many of our customers, so we are sure that we've got right stuff for you! Spreadshirt is your destination for great designs of all kinds – whether it's Kamui, Kill La Kill or Ryuko. We are sure that you will find something nice in our shop, there are many amazing custom Nerd t-shirts, hoodies, or accessories for you to find! Tags: Design ID: 12623444
Bernie Sanders Silhouette Women's T-Shirts Designed by 5507177
Tammy Comedy Movie Mahalo Bear Shirt Designed by Mackentee
Nah Rosa Parks Quote T-Shirts Designed by The Shirt Yurt
Hoodini Vanoss Gaming T-Shirts Designed by 3982143
Charged up T-Shirts Designed by Dennis Jones
Skeleton X-ray Maternity Shirt Designed by gladditudes
6 God Hands Shirt Hoodies Designed by milosdesign
This relaxed fit classic offers plenty of room and is ideal for most body types. Perfect as an outer or under layer, this versatile t-shirt is a must-have for all wardrobes.
still to fill


text:
Select Currency:
Connect with Facebook
Log Out
Wish List 0
Advanced Search
Join our mailing list and be pre-advised whenever hot deals are about to be launched
Go snorkeling on the Great Barrier Reef, explore the sights of Cairns.
MoreAU$269 3 days for
• Courtesy pick up from your accommodation and barge transfers to Fraser Island. Please enter pick...
MoreAU$190 1 days for
Bring a sense of adventure and get ready for some laughs as you embark on three action-packed days ...
MoreAU$440 3 days for
Great Ocean Road Highlights
Bells Beach
Memorial Arch (Eastern View)
Beach Walk
Lorne & Angles...
MoreAU$109 1 days for
Get up close and personal with the friendly residents of Moonlit Sanctuary Wildlife Conservation Pa...
MoreAU$139 1 days for
Jump on board the SeaLink Connection and head to Kangaroo Island for your Beach Wilderness Escape. ...
MoreAU$333 3 days for
Explore the stunning beaches and dramatic gorges, the mysterious limestone Pinnacles, Kalbarri Nati...
MoreAU$1095 7 days for
MoreAU$375 3 days for
Belize Tours, Travel & Backpacker Adventure
Adventure travellers-look no more! Travellers to Belize can tube down
the river through mysterious caves, explore the jungle on a 3 day canoe
adventure, and tour through ancient Mayan Ruins.
For the adrenalin junkies, dive or snorkel with sharks and sting rays at
the Hol Chan Marine Reserve. And for those who want a relaxing
underwater dive experience, Belize offers Caye Caulker, a tropical
paradise full of diverse, vibrant marine life. Adventure through the
Actun Tunichil Muknal underground caves, where ancient Mayan antiquities
and skeletons of sacrificed victims still remain. Swim in jungle-clad
rivers in Cayo, trek through forested highlands in San Ignacio. Belize,
ideal for outdoor enthusiasts, ancient history lovers, and backpackers
with a sense of adventure!
Powered By: Adventure Travel | ©
Copyright 1999 - 2014. All Rights Reserved


text:
|Home | About | Journals | Submit | Contact Us | Français
Mice with a mutation in the Clock gene (ClockΔ19) have a number of behavioral phenotypes that suggest alterations in dopaminergic transmission. These include hyperactivity, increased exploratory behavior, and increased reward value for drugs of abuse. However, the complex changes in dopaminergic transmission that underlie the behavioral abnormalities in these mice remain unclear. Here we find that a loss of CLOCK function increases dopamine release and turnover in striatum as indicated by increased levels of metabolites HVA and DOPAC, and enhances sensitivity to dopamine receptor antagonists. Interestingly, this enlarged dopaminergic tone results in downstream changes in dopamine receptor (DR) levels with a surprising augmentation of both D1- and D2-type DR protein, but a significant shift in the ratio of D1:D2 receptors in favor of D2 receptor signaling. These effects have functional consequences for both behavior and intracellular signaling, with alterations in locomotor responses to both D1-type and D2-type specific agonists and a blunted response to cAMP activation in the ClockΔ 19 mutants. Taken together, these studies further elucidate the abnormalities in dopaminergic transmission that underlie mood, activity, and addictive behaviors.
The circadian rhythm, evolution's innate timekeeping system, plays a central role in the regulation of the normal physiology and behavior of nearly every living organism (Ko and Takahashi, 2006). The desynchronization of one's "clock" in the form of genetic mutations, disruptions in sleep/wake cycle, or dysregulation of circulating hormones is a shared feature of numerous health problems including many psychiatric diseases (Barnard and Nolan, 2008; Takahashi et al., 2008). Numerous studies have found alterations in physiological rhythms including sleep/wake activity, body temperature, blood pressure, and hormones in major depression and bipolar disorder (BD) (Atkinson, 1975; Linkowski et al., 1994; Linkowski et al., 1987). Indeed, the cycling nature of BD (including seasonal variations in mood states) led to the first postulations that there was a circadian component to the pathology of the disease (Cassidy and Carroll, 2002; McClung, 2007; Sayer et al., 1991). More recently, human genetics studies have identified single nucleotide polymorphisms (SNPs) and haplotypes in various circadian genes that associate with psychiatric disorders. For example, cryptochrome 1 (Cry1) and neuronal PAS domain-containing protein 2 (Npas2) have a statistically significant association with major depression while circadian locomotor output cycles kaput (Clock) and vasoactive intestinal peptide (Vip) are associated with BD (Soria et al., 2010). Finally, many of the common treatments for these conditions including mood stabilizing agents and antidepressants appear to alter or synchronize the internal clock (Possidente et al., 1992; Welsh and Moore-Ede, 1990).
The circadian clock is set by a core loop of proteins that usually cycle over a period of approximately 24 hours. Essential elements of this core loop include the transcription factors CLOCK and brain and muscle Arnt-like protein-1 (BMAL1) which heterodimerize and bind to E-box elements within a number of genes regulating their transcription (Ko and Takahashi, 2006; Takahashi et al., 2008). The CLOCK-BMAL1 dimer positively regulates the Period (Per) and Cryptochrome (Cry) genes. The PER and CRY proteins themselves can form a complex, and upon re-entry into the nucleus inhibit their own transcription by repressing the function of CLOCK-BMAL1 in a negative feedback loop (Ko and Takahashi, 2006). In addition to this core loop, there are a number of other proteins implicated in regulating the timing mechanism through diverse modifications (Cardone et al., 2005; Grimaldi et al., 2009; Katada and Sassone-Corsi, 2010; Tataroglu and Schafmeier, 2010). Though the master pacemaker lies within the suprachiasmatic nucleus (SCN) of the hypothalamus, virtually every cell in the body possesses an auxiliary clock which can be synchronized to the SCN or in some cases oscillate semi-autonomously (Ko and Takahashi, 2006).
Mounting evidence supports a role for the regulation of diverse neurotransmitter systems by the circadian clock. Dopamine and other neurotransmitters implicated in mood disorders have diurnal rhythms with regard to their levels, and the activity and expression of their receptors or enzymes associated with their metabolism (Akhisaroglu et al., 2005; Ozaki et al., 1993; Wirz-Justice, 1987). Mice with a mutation in the Clock gene (ClockΔ 19 mutants) display changes in dopaminergic transmission consistent with an overall increase in dopaminergic activity (Dzirasa et al., 2010; McClung et al., 2005). Moreover, these mice have a behavioral phenotype that closely models human bipolar mania including disrupted circadian rhythms, hyperactivity, decreased depression-related behavior, lowered levels of anxiety, and increased preference for multiple drugs of abuse (Gekakis et al., 1998; King et al., 1997; McClung et al., 2005; Roybal et al., 2007). Aberrant monoamine function has been proposed to contribute to the pathology of many psychiatric diseases partially because drugs that act on their transporters or receptors are effective treatments (Barchas, 1999). As a result, numerous studies have examined the association between dopamine signaling and psychiatric disease. For example, a recent study provided evidence for an interaction between the catechol-O-methyltransferase (COMT) Val158Met allele and the DRD3 Ser9Gly genotypes in bipolar I disorder (Lee et al., 2011). Interestingly, ClockΔ19 mice have a defect in the ability of neurons in limbic circuits of the brain to synchronize as animals are performing behavioral tasks which likely contributes to their overall manic-like profile (Dzirasa et al., 2010; Dzirasa et al., 2011). It is possible that this lack of synchronization in striatal regions is due to changes in dopamine receptor function in response to an altered dopaminergic tone. Thus, in this study, we examined the influence of the ClockΔ 19 mutation on dopaminergic transmission in the striatum.
ClockΔ 19 mutant mice were created by N-ethyl-N-nitrosurea mutagenesis and produce a dominant-negative CLOCK protein defective in transcriptional activation activity as described (King et al., 1997). For all experiments using ClockΔ 19 mutants, adult male mutant (Clock/Clock) and wild type (+/+; WT) littermate controls on a mixed BALBc/C57BL/6J background were group housed in sets of 2–4 per cage on a 12/12-h light dark cycle (lights on at 6:00 a.m. = Zeitgeber time (ZT) 0, lights off at 6:00 p.m. = ZT 12) with food and water provided ad libitum. All animal use was conducted in accordance with the National Institute of Health guidelines and approved by the Institutional Animal Care and Use Committees of UT Southwestern Medical Center.
(−)-Quinpirole hydrochloride (LY 171,555), R(+)-SKF 81297 hydrobromide, S(−)-Raclopride (+)tartrate salt, R(+)-SCH 23390 hydrochloride, and forskolin were purchased from Sigma-Aldrich. Cocaine hydrochloride was provided by the National Institute on Drug Abuse (NIDA).
Dorsal striatum dopamine measurements were performed as described previously (Goldberg et al., 2003). Briefly, fresh brains were dissected from adult animals and 1 mm coronal slices taken using a mouse brain matrix. Tissue punches of the dorsal striatum 1 mm in diameter were placed in 1.5 ml microcentrifuge tubes, weighed, and frozen on dry ice. The samples were stored at −80°C until further processing. The tissue punches were homogenized by sonication in 49 volumes of 0.1 N perchloric acid and 0.2 mM sodium bisulfite. The homogenate was centrifuged at 20.000 g for 10 min at 4°C to pellet the debris. Twenty-five microliters of the resulting homogenate was loaded into an autosampler connected to a high-performance liquid chromatography instrument with an electrochemical detector (ESA CoulArray with Model 5014B Microdialysis Cell) to measure the levels of dopamine and dopamine metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). Neurotransmitter levels were normalized to tissue weight.
Mice were individually placed in automated locomotor activity chambers equipped with infrared photobeams (San Diego Instruments) and measurements began immediately. Fine and ambulatory motor activity of the animals was continuously measured with the data collected in 5-min bins. Locomotor activity dose-response studies were performed in a randomized Latin-square design. Mice were moved to the behavioral testing room 1 h prior to the habituation period each day. The first hour of each locomotor activity session was measured as baseline activity. After this time, the animals received an injection of vehicle or the indicated dose of each drug and locomotor activity was measured for an additional hour. Locomotor activity data is reported as percent change in activity, while raw beam break data is shown in Supplementary Figure 1.
Animals were sacrificed by cervical dislocation, their brains removed, and 1 mm slices prepared using a brain block. Fresh dorsal striatum tissue punches were dissected and frozen on dry ice for later processing. The tissue punches were thawed and homogenized by sonication in RIPA buffer (Pierce) containing protease inhibitors and phosphatase inhibitor cocktails I and II (Sigma-Aldrich). A DC protein assay (Biorad) was performed on these total homogenates to ascertain protein concentrations. Proteins were boiled for 10 min at 90°C in loading buffer with DTT. Total protein fractions were separated by 12% SDS-PAGE and immunoblotted using antibodies specific for D1 (1:2000, GeneTex) or D2 (1:1000, Millipore) DRs, or glyceraldehyde 3-phospate dehydrogenase (GADPH) (1:10000, Fitzgerald). Horseradish peroxidase-conjugated secondary antibodies (Jackson ImmunoResearch) were used in combination with the Supersignal West Dura system (Promega) to detect the signal on film. Densitometry was conducted using NIH IMAGE software. Data were expressed as a ratio to the corresponding GADPH signal to control for potential discrepancies in protein loading.
Preparation and incubation of striatal slices was performed as reported previously (Hamada et al., 2004). Wild type and ClockΔ 19 mutant mice were sacrificed by decapitation. Their brains were rapidly dissected and placed in ice-cold oxygenated Krebs buffer (124 mM NaCl, 4 mM KCl, 26 mM NaHCO3, 10 mM D-glucose, 1.5 mM CaCl2, 1.5 mM MgSO4, 1.25 mM KH2PO4). The striatum was microdissected from 350 μm coronal sections prepared on a vibratome. Individual slices were placed in polypropylene incubation tubes with 2 ml of fresh Krebs buffer containing 10 μg/ml adenosine deaminase (Sigma) and pre-incubated at 30°C with continuous oxygenation with 95% O2/5% CO2 for 60 min. The Krebs buffer was replaced with fresh solution after the first 30 min. Slices were then treated with Krebs buffer alone, or buffer containing forskolin (10 μM) for 5 min. After the treatments, slices were transferred to eppendorf tubes, quickly frozen on dry ice, and stored at −80°C until processed for immunoblotting. The samples were sonicated in boiling lysis buffer (1% SDS with 50 mM sodium fluoride) and boiled for an additional 10 min. The protein concentration of each sample was determined by the DC protein assay (Biorad). Aliquots of sample were combined in Laemmli SDS sample buffer (Bio-Rad), and boiled at 95°C for 5 min. Equal amounts of protein (~75 μg) were loaded onto 10% polyacrylamide gels and separated by SDS/PAGE electrophoresis at 150 V for 5 h. Proteins were transferred overnight at 4°C onto Immobilon PVDF membranes (Millipore,) at 35V in 1XTG buffer. Membranes were incubated overnight at 4°C with the following primary antibodies diluted in blocking buffer: mouse anti-GluR1 (1:3000), and rabbit anti-phospho-GluR1 ser845 (1:2000) from Millipore Corporation, mouse anti-p44/42 MAPK (ERK1/2) (1:1000), and rabbit phospho-p44/42 (Thr202/Tyr204) (1:2000) from Cell Signaling Technology, and tubulin as loading control (Epitomics). Blots were probed simultaneously for total and phosphorylation state-specific antibodies because infrared IR-Dye 680 conjugated goat anti-rabbit and IR-Dye 800 conjugated goat anti-mouse secondary (1:10,000, LI-COR Biosciences) antibodies were used for two-color detection. Blots were scanned using the Odyssey Infrared Imaging System (LI-COR Biosciences) interfaced to a PC running Odyssey 2.1 software for quantification. Proteins bands were quantified using an integrated intensity and mean band background subtraction method. These values were then expressed as a ratio to the corresponding tubulin integrated intensity to control for potential discrepancies in amount of protein loaded among samples. Phospho-protein levels were normalized to total protein values.
All data were analyzed using an unpaired student's t-test or an ANOVA followed by a Bonferonni post-hoc test, unless otherwise specified. Analyses over time were conducted using a repeated two-way ANOVA followed by a Bonferonni post-hoc test to control for multiple comparisons. Analyses were conducted using the GraphPad Prism 5 statistical software for Windows. All data are presented as means ± standard error of the mean with p< 0.05 considered statistically significant. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001.
Since the locomotor hyperactivity of the ClockΔ19 mice (McClung et al., 2005; Roybal et al., 2007) suggests an increase in dopaminergic signaling in dorsal striatum, we decided to measure levels of dopamine and metabolites in this region. To determine if there were significant changes in dopamine transmission in the striatum, we performed HPLC on tissue preparations from ClockΔ19 mice compared to controls. Here we found no significant difference in total dopamine levels between wild type and ClockΔ 19 mutants. However, when we looked at dopamine metabolites and dopamine turnover, significant differences emerged. There was an increase in DOPAC (T(22) = 2.983; p < 0.01) and HVA (T(23) = 4.858; p < 0.0001) in the mutant mice. When dopamine turnover was assessed, we found no changes in the ratio of DOPAC/DA but there was a significant enhancement in the HVA/DA ratio (T(23) = 3.486; p < 0.01). These changes in the levels of dopamine metabolites reflect alterations in dopamine neurotransmission within the dorsal striatum. As both the intraneuronal metabolite DOPAC and the extraneuronal metabolite HVA are augmented, it can be inferred that there is an increase in dopamine synthesis, release, and turnover although there is no net change in total dopamine levels
To explore the functional consequences of elevated striatal dopamine levels and metabolism in the ClockΔ19 mice, we evaluated the locomotor response to dopamine receptor antagonists. Locomotion in response to these agents provides information about levels of the endogenous ligand, dopamine, in the extracellular space. We assessed the ability of the D2-type antagonist raclopride to inhibit locomotor activity across a limited range of doses from 0.03 to 0.3 mg/kg (Figure 1A-C). Raclopride is a selective D2-type antagonist with the highest affinity for D2 (KI = 1.8 nM) and D3 (KI = 2.4 nM) receptors and minimal or negiligible affinity for D4 and D1 receptors (KI = 2400 and 18000 nM, respectively). As has been reported previously, the Clock 19 mutants display hyperactivity in response to a novel environment. Therefore data were normalized within genotype to saline controls in order to directly compare changes in percent activity in response to the drug (Roybal et al., 2007). We found a significant effect of dose (F(3,40) = 11.81; p < 0.0001) but no effect of genotype and no interaction (Figure 1A). However, closer evaluation of the dose-response curves suggested that there might be a leftward shift in responding to raclopride indicating a possible increase in sensitivity to the drug specifically at the 0.1 mg/kg dose. When a separate analysis of fine and ambulatory movement was performed at this dose, we discovered that the ClockΔ 19 mutants displayed a significant decrease in percent activity in both fine (Figure 1B, T(9) = 3.393; p < 0.01) and ambulatory (Figure 1C, T(10) = 3.75; p < 0.01) movements compared to saline controls. Furthermore, this effect was not detected in the wild type animals suggesting increased sensitivity in the ClockΔ 19 mutants. We observed a similar increase in sensitivity when we administered the D1/D5 antagonist SCH 23390 (D1 KI = 0.2 nM; D5 KI = 0.3 nM). We found a significant effect of dose (F(2,43) = 21.96; p < 0.0001) but no effect of genotype and no interaction (Figure 1D), but once again there was a left-ward shift in the dose-response curve of the ClockΔ 19 mutants. At the lower 0.002 mg/kg dose, the activity of the wild type mice was not significantly attenuated while the ClockΔ 19 mutant mice displayed a 56% reduction in total locomotor activity (Figure 1E) (T(15) = 3.481, p = 0.0033). Taken together, these results are consistent with an increase in functional dopamine receptor protein and/or an increase in extracellular dopamine.
Given that ClockΔ19 mice have altered dopaminergic transmission, we evaluated the influence of dopamine receptor agonists on their locomotor responses. Low doses of D2-type agonists act preferentially on dopamine neurons (Shi et al., 1997). Therefore we assayed D2-type auto-receptor function by administering ip injections of the D2-type agonist quinpirole-HCl at doses ranging from 0.1 to 50 μg/kg (Figure 2). As expected, there was a highly significant main effect of quinpirole dose (F(4,93) = 7.31; p < 0.0001) (Figure 2A). However, we saw no main effect of genotype on the total locomotor response to quinpirole at any of these lower doses and no interaction (Figure 2A). We then repeated the quinpirole locomotor dose response study with higher doses ranging from 1 to 24 mg/kg to ascertain whether there were any differences in postsynaptic responses (FigureB-D). Once again, we observed a significant main effect of quinpirole dose on total locomotor activity (F(4,83) = 25.89; p < 0.0001) with no effect of genotype and no interaction. However, when total activity was subdivided into fine versus ambulatory motor behavior, there was a significant main effect of genotype (F(1,87) = 7.73; p < 0.01) and dose (F(4,87) = 19.27; p < 0.0001) for fine motor movements (Figure 2C) with only an effect of quinpirole dose for ambulations (F(4,85) = 25.95; p < 0.0001) (Figure 2D). This suggests that the ClockΔ19 mice are more sensitive to the locomotor inhibiting effects of quinpirole as demonstrated by the potentiation of the decrease in levels of fine motor movements produced in response to postsynaptic D2-type receptor stimulation. As fine motor movements are defined by repeated crossings of the same beam, a possible interpretation of this data is a decrease in stereotyped behavior. Altogether, these data suggest a specific potentiation of postsynaptic D2-type receptors in the ClockΔ 19 mutants.
We next assayed the locomotor response to the highly selective full D1/D5 agonist SKF 81297 which consistently elevates locomotor activity in wild type animals (Desai et al., 2005). Analysis by two-way ANOVA revealed a significant genotype × dose interaction (F(4,40) = 4.97; p = 0.0024) with a main effect on both genotype (F(1,40) = 53.45; p < 0.0001) and dose (F(4,40) = 4.55; p < 0.01) (Figure 3A). Bonferroni post-hoc analysis showed a significant increase in total percent activity in the wild type mice over the ClockΔ 19 mutants at the 0.625, 2.5 and 5.0 mg/kg doses (p < 0.05, p < 0.0001 and p < 0.0001, respectively). To ensure that the lack of locomotor activation was not a function of reaching a ceiling effect, we challenged a set of wild type and ClockΔ 19 mutant animals with a 15 mg/kg dose of the psychostimulant cocaine-HCl. We observed a similar 30% increase in total locomotion in both wild type and mutant mice (Figure 3B). These data suggest a significant perturbation of D1-type functional receptors in the ClockΔ 19 mutants.
Since the results from the locomotor experiments with D1-type and D2-type receptor agonists and antagonists demonstrated a functional change in dopamine receptor activity, we next set out to determine whether there were changes in dopamine receptor protein levels in dorsal striatum. We looked specifically at D1 and D2 receptor protein levels because they are the most abundant subtypes in striatum. Surprisingly, evaluation of total protein levels revealed a small but significant increase in total D1 receptor levels in the ClockΔ19 mice (T(8) = 2.739; p = 0.0255) (Figure 4A). These data were acquired during the same time of the day in which the locomotor activity assays were performed. However, when we measured D2 protein levels we found a much more robust increase (T(8) = 3.775; p = 0.0054) (Figure 4B) which results in a dramatic decrease in the D1/D2 ratio in striatum (T(8) = 2.553; p = 0.034) (Figure 4C). Thus, the altered response to dopaminergic drugs is associated with an improper D1/D2 receptor composition in striatum.
To further define the effects of the ClockΔ19 mice altered D1/D2 protein ratio on striatal dopamine signaling, we evaluated the responsiveness of the cAMP/PKA cascade to forskolin, a potent adenylate cyclase activator. D1-type DRs are coupled to Gαs and their activation results in sharp elevations in intracellular cAMP, thereby activating PKA, whereas the Gαi-coupled D2 dopamine receptors antagonize this pathway (Herve, 2011). We assessed PKA-dependent phosphorylation of the GluR1 subunit of the AMPA receptor (Snyder et al., 2000) and the MEK2-dependent activation of ERK2 protein kinase (Vossler et al., 1997) following treatment with forskolin, as two important downstream effectors of dopamine signaling. Treatment of striatal slices with forskolin increased PKA-dependent phosphorylation of GluR1 at Ser845 in wild type (Figure 5A, T(13) = 5.359, p = 0.0001) and ClockΔ 19 mice (T(12) = 11.05, p < 0.0001) without affecting total levels of GluR1 (Figure 5B). However the response in wild type mice was much larger than that seen in the ClockΔ19 mice (T(9) = 2.288, p = 0.0479). A similar effect was observed for phospho-ERK2-T183/Y185. Forskolin caused an increase phosphorylation of ERK2 in the wild type mice (T(13) = 3.527, p = 0.0037), but this response was attenuated and did not reach significance in the ClockΔ 19 mutants (Figure 5C). Thus, there was a loss of cAMP/PKA signaling, presumably via the Raf- and Rap1-dependent pathway (Vossler et al., 1997) in the ClockΔ 19 mutants compared to wild type controls (T(9) = 2.24, p = 0.05). The drug treatments had no effect on total ERK2 levels in either genotype (Figure 5D) and there were no baseline differences in total ERK2 (Figure 5D) or phospho-ERK2 between genotypes (Figure 5C). Thus the increase in striatal dopamine and DR levels in the ClockΔ19 mutant mice corresponded with marked attenuation in downstream cAMP/PKA signaling for these two pathways.
Our results show that loss of function of the circadian transcription factor CLOCK results in robust changes in dopaminergic transmission and dopamine receptor function. Mice with the dominant-negative ClockΔ 19 mutation display altered responses to dopamine receptor antagonists, suggesting increased dopaminergic tone. This is consistent with the increased dopamine cell firing and bursting previously reported in these mutants (Coque et al., 2011; McClung et al., 2005). Interestingly, these mice have an increase in total tissue dopamine content but no change in metabolite levels in the nucleus accumbens (Coque et al., 2011). In the dorsal striatum we detected no change in total dopamine levels, but rather an increase in DOPAC which could indicate greater monoamine oxidase A (MAO-A) enzymatic activity. This is interesting since previous studies found that the circadian proteins BMAL1, NPAS2 and PER2 can regulate the transcription of MAO-A (Hampp et al., 2008). However the DOPAC/dopamine ratio was not significantly different between genotypes because the mutants displayed a parallel trend toward augmented dopamine levels. It should be noted that the measures of dopamine and metabolites were taken under basal home cage conditions, a circumstance under which the locomotor hyperactivity phenotype of the mutants is less pronounced. It is possible that a significant difference in dopamine levels may have been observed if tissue was taken after some manipulation like exposure to a novel environment. One might hypothesize that neurochemical differences would be enhanced just as the locomotor behavior phenotype is exaggerated, a hypothesis that warrants further examination in future studies. Both total levels of HVA and the HVA/DOPAC ratio were increased in the mutants suggestive of an overall increase in transmitter release and extracellular dopamine, which is consistent with the observation of increased sensitivity to D1-type and D2-type receptor antagonists. The difference in dopamine transmission between the ventral and dorsal striatum could be due to the fact that the rate limiting enzyme in dopamine synthesis, tyrosine hydroxylase is increased in the ClockΔ19 mice selectively in the VTA and not in the substantia nigra (SN) (McClung et al., 2005). Future studies will determine if there are differences in dopaminergic activity in the SN as seen in the VTA.
The ClockΔ 19 mutants failed to produce a locomotor activating response to a D1-type agonist. However they show a normal locomotor response to cocaine. This suggests that D1- type receptor signaling is impaired in the ClockΔ19 mice while D2-type responses might be heightened. The change in D1-type receptor activity could represent an attempt of the circuit to compensate for the increased dopaminergic tone in these mice. We did not see a decrease in D1 receptor protein, and in fact detected a slight increase in protein in the striatum. Thus this absence of response to the agonist is not due to a lack of protein transcription or translation. It is possible that there are differences in receptor affinity which underlie the difference in response as both D1 and D2 DRs have been shown to occupy high and low affinity states (Richfield et al., 1989). Additionally, it is becoming increasingly clear that DR heteromers represent a biologically relevant subpopulation within the brain with unique pharmacological and signal transduction profiles (Hasbi et al., 2011). A change in the proportion of D1-D2 heteromers might be expected to change the profile of the response to individual DR agonists. Interestingly, the D1-D2 heteromer has already been implicated in two psychiatric disorders, addiction and schizophrenia (Hasbi et al., 2011). Similarly, there may be changes in the fraction of synaptic versus extra-synaptic receptors, accounting for discrepancy between D1R protein levels and activity. Curiously, a lack of response to a D1 agonist is similarly seen in both D1R knockout mice and in mice in which the D1R is overexpressed (Dracheva et al., 1999; Xu et al., 1994). Studies involving independently generated D1R knockout mice have generated conflicting results with reports of no change in horizontal locomotor activity or slight locomotor depression (Drago et al., 1994; Smith et al., 1998) and other reports of hyperactivity (Xu et al., 1994). This discrepancy can likely be attributed to multiple factors ranging from differences in targeting strategy, background strain, and experimental conditions. D1 receptors are prominent not only in striatum but also in prefrontal cortex and these receptors may have opposing roles in the regulation of locomotor activity (Wilkinson, 1997), therefore future studies will be necessary to assess changes in cortical dopamine transmission in the ClockΔ19 mice.
It is likely that a change in the D1/D2 ratio in striatum underlies the reduced response to a D1-type agonist. Indeed we find a robust increase in D2 receptor expression in the ClockΔ19 mice and an increased response to a D2-type agonist. Moreover, our pharmacological studies performed ex vivo with acute slices demonstrated deficiencies in PKA signaling cascades in the mutants. For instance, while forskolin stimulated GluR1 Ser845 phosphorylation in both wild types and mutants, the increase was four-fold higher in the wild type. These results point towards a possible increase in antagonism of cAMP stimulation by D2-type receptors. Moreover, the signaling link from PKA to ERK2 appeared to be almost completely missing in the ClockΔ19 mice. Increased D2 receptor signaling has been implicated in bipolar disorder. Analysis of post-mortem brain samples of the pre-frontal cortex from diseased brains and healthy controls found DRD2 expression increased in bipolar patients and decreased in schizophrenics relative to controls (Zhan et al., 2011). Moreover, data collected from in vivo imaging studies of D2 receptor occupancy within the basal ganglia have reported an increase in binding in bipolar psychotic patients (Nikolaus et al., 2009; Wong et al., 1997).
There have been a number of interesting studies which suggest that in general, activation of D1-expressing neurons (i.e. the "direct pathway") of adult animals enhances the response to drugs of abuse while activation of D2-expressing neurons (i.e. the "indirect pathway") antagonizes the response (Reviewed in Lobo and Nestler, 2011). The ClockΔ19 mice have an increase in the response to drugs of abuse, thus these results may seem to be contradictory to the majority of the literature. However, it is likely that these effects are due to the increased dopaminergic activity and represent an attempt of the system to compensate. Furthermore, mice with a knockout of the D2 receptor have a reduction in the response to most drugs of abuse, thus alterations that occur throughout development may also be important. Future studies with selective effects on specific neuronal populations within the ClockΔ19 mice will have to be performed to better understand the exact role of the direct and indirect striatal pathways in the overall manic-like phenotype of these mice.
It is increasing clear that the coupling of diverse neuronal populations throughout the brain is involved in encoding higher order cognitive processes. Indeed, previously we found that the ClockΔ19 mice have serious defects in the ability of limbic regions of the brain to synchronize activity as the mice explore certain anxiety-related environments (Dzirasa et al., 2010; Dzirasa et al., 2011). The changes in striatal dopamine transmission reported here including altered dopamine turnover and D1/D2 ratios in the ClockΔ 19 mutants likely contributes to the defects in proper synchronization that is necessary for the animal to make important decisions regarding their level of exploratory behavior. The nigrostriatal dopamine system and the dorsal striatum have traditionally been studied in terms of sensorimotor function while the mesolimbic dopamine system and the nucleus accumbens has been investigated for its role in motivation and addiction. However, just as the anatomical boundaries between these brain regions are imprecise so too are the functional distinctions. There is significant overlap in terms of contributions to brain stimulation reward, habitual behavior, reward prediction and reinforcement of memory consolidation (Roy A, 2009). Accordingly, it would not be surprising if the alterations in dopaminergic transmission reported here result in disrupted circuit level activity, and contribute significantly to the ClockΔ 19 mutant phenotype beyond the observed hyperactivity. Future studies will more specifically determine the role of altered striatal dopaminergic signaling in neuronal synchronization and related behaviors.
While we can ascribe these dopamine-related biochemical and behavioral abnormailities to a disruption in CLOCK function, the underlying mechanisms remain undetermined. CLOCK acting as a transcription factor may directly regulate diurnal expression of dopamine receptor subtypes or other dopamine related genes. Alternatively, CLOCK may indirectly influence dopamine transmission by acting on other upstream targets. In addition to their behavioral abnormalities, the ClockΔ 19 mutants have a well-described phenotype of metabolic syndrome, which includes disruptions in expression of factors associated with feeding and energy balance including insulin, leptin and ghrelin (Turek et al., 2005). Importantly, these peripheral hormones and peptides can influence the central dopaminergic system and directly impact mood and reward-related behaviors (Fulton et al., 2006; Hommel et al., 2006; Jiang et al., 2006; Williams et al., 2007). Future studies will be needed to parcel out the effects of these metabolic disturbances on the dopamine-related phenotype of the ClockΔ 19 mutants.
In summary, normal CLOCK function is involved in the regulation of dopamine transmission in the striatum. Loss of CLOCK function increases dopamine release and turnover in the striatum as indicated by increased levels of metabolites HVA and DOPAC and the increased sensitivity to dopamine receptor antagonists. Moreover, this increased dopaminergic tone results in altered levels of dopamine receptor protein with a surprising increase in D1DR and D2DR protein levels but a significant shift in the ratio of D1 to D2 receptors in favor of D2DR. Finally, these protein changes lead to functional consequences at both the level of behavior and cellular signaling with alterations in locomotor responses to both D1 and D2-type specific agonists, and a blunted activation of cAMP signaling in the ClockΔ 19 mutants. Taken together, these studies further define the defects in dopaminergic transmission that result from a nonfunctional CLOCK protein, and help elucidate the changes in dopaminergic transmission which are responsible for the regulation of activity, reward, and mood.
We thank Dr. Joseph Takahashi at UT Southwestern for providing the CLOCK mutant mice. This work was funded by National Institutes of Health grants to J.A.B (MH79710, MH083711, DA016672, DA033485) and C.A.M. (MH082876, MH090683, DA023988). Dr. McClung has received research funding from Pfizer and GlaxoSmithKline on unrelated projects. Dr. McClung has also received honoraria from Pfizer, GlaxoSmithKline, Servier, and Johnson & Johnson. All other authors have nothing to disclose.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's Canada Institute for Scientific and Technical Information in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


text:
This menu is generated by DropDown Menu. Create your own menu now!
A dialog box will pop up and you pick what pages you want to add static FBML to. Once you have completed this, go back to your fan page settings and find FBML 1 under the applications. You want to click the edit button right under the title : ... At first, you may not see the tab along the top, but all you need to do is click the arrow on the right hand side off all the tabs and a dropdown menu will apear. Just find your tab's name and click on it:
As long as your form is HTML, you will be able to install it into your page using the static fbml app. You can also add a sign up form to the sidebar of your personal Facebook profile using the app profile box. 5. Split Test. Even if you are a homeless man, .... A neat example + code for embedding an "Ajax form" on your facebook fan page can be found at the webwhispers fan page on facebook http://www.facebook.com/webwhispers It will be under the drop down
I play games on FaceBook (FB)! Not only is it a nice colourful break while having a cup of coffee but lately I have found that it has even become a business tool for me. While I can hear the cynics laughing in the background already, .... You slap your stuff down anywhere…. Well, do you drop your clothes on the floor when you change for someone else to pick up? Enough said. - You choose beautiful objects and lay them out taking cognisance of both the functional structure
Hi everyone, I'm trying to create a custom html tab for my profile page. Since Static FBML works only for facebook pages I'm looking for some alternative solution. I've seen on some friends' profile pages tabs from applications, ... 1) Go to the account drop menu on the top right of your profile 2) Select application settings 3) Edit settings for My HTML 4) Go to the profile tab 5) Click the add option for box 6) Click "Okay" 7) Click profile on the top right. Glasses
Facebook allows divs, but it most likely wont allow css. you probably could make a semi-cool thing with tables and the FBML application. If Facebook allows CSS I hope they made the classes simpler then Myspace. Myspace had 3 external style sheet and .... Can they not see that? Myspace is being ruined, and they're doing it themselves. When it comes down to it, no matter how much you do or don't care about the changes they are making, myspace is screwing a lot of designers
In January of this year, I wrote a blog post titled, You've Got Something in Your Widget that talks about how you can set up an application box using the static FBML application. There are some changes to Facebook that will ... If you don't see it in the list, select "Authorized" from the drop-down menu to view all of your authorized applications. 3. Click the "Edit Settings" link for the application you'd like to bookmark. 4. Choose the "Bookmark" tab in the settings box
DO NOT create Facebook groups (our terms of service only covers your fan page); Choose Brand, Product, or Organization, select Government from the drop down box; Enter Name of Page; make sure this is the approved name since it can't be
If you're a bricks and mortar business look through the drop down options to find the one that fits best. If you're a business, organisation or web site with a national or international presence, take a look through the "Brand,
Copyright © 2010 Flash Menu Templates


text:
Quabbin Reservoir
485 Ware Rd., Rt. 9, Belchertown, MA 01007
3 people saved this
One of the largest man-made domestic water reservoirs in the U.S. with 57,523 acres of protected watershed. Hiking trails, bird and eagle watching, observation tower (no swimming, hunting, biking, grilling, or pets).
5 Fall Foliage Hikes in the Berkshires
Crisp air, cool mornings, the earthy scent of the forest floor, and exploding colors as...
Search All Listings Here.


text:
|The stupid question is the question not asked
Re: Wrong dereference => Out of memoryby Athanasius (Canon)
|on Oct 29, 2012 at 14:44 UTC ( #1001367=note: print w/ replies, xml )
|Need Help??
Well, I can't answer your question, sorry :-(.
But I can confirm that, whatever was going on in version 5.8.8 (which I don't have), was fixed by version 5.10.1:
Hope that is of some help,
Athanasius <°(((>< contra mundum
In Section Seekers of Perl Wisdom


text:
Did you know...
There is a new Academic Success Center Guide! This guide will encompass all tutoring resources available to DeVry University students. Click here to access the guide!
The DeVry University Library will be offering a workshop on Oct. 7, 2015 at 12:00pm central Time on Evaluating Sources. Click HERE to access the Workshop.
The DeVry University Library/Academic Success Center will be offering a series of workshops for students and faculty. This week they are:
Oct. 6 , 2015 at 4:00pm central for a session on Noodletools. Click HERE to access the workshop.
Oct 7 at 4:00pm central time for a workshop on using Excel. Click HERE to access the workshop.
Oct 8, 2015 at 4:00pm central time for a session on Learning Styles. Click HERE to access the workshop.
NEW! Library Learning Channel, here you can find workshops and recordings about using the library tools.
DeVry University maintains a comprehensive library (on campuses and online) that provides access to current resources, including full-text periodical databases, Library LibGuides, print and electronic books, and reference services in-person, via phone, email, and chat.
Current students, faculty and staff have access to online resources 24 hours a day, seven days a week. The services of professional librarians are available Monday through Friday, during standard business hours, and weeknights and weekends via chat.
We have also gone Social. Join us on facebook at https://www.facebook.com/DeVryLibrary


text:
Your Selections:
Sort by:
Show Filter
- 148 items
Related Searches
Related Products
Personalized Birthday Life Saver Candies
Bring any party to life with personalized birthday Life Savers! Each candy arrives packaged neatly in its own individual wrapper, ...
Personalized Full Color Corporate Logo Napkin
Impress everyone at your corporate event with these full color corporate logo napkins. Your choice of design, and messaging, makes ...
Personalized Graduation Candy Box
Elegant personalized graduation candy boxes are a wonderful addition to a classy graduation party. These easy to assemble candy boxes ...
Personalized Religious Life Saver Candies
Add freshness to your next religious event with these personalized Life Savers. Each candy arrives packaged neatly in its own ...


text:
Translation of toenail in Spanish:
- uña (feminine) (del pie)to cut one's toenailscortarse las uñas de los piesExample sentences
- The decoration of both toenails and fingernails for aesthetic purposes dates back at least as far as Ancient Egypt, where henna and other products were applied to colour the feet and hands as well as the nails.
- The infection is more likely in toenails than in fingernails.
- Scratching an infected toenail can infect your fingernails.
Definition of toenail in:
- British & World English dictionary
- US English dictionary
What do you find interesting about this word or phrase?
Comments that don't adhere to our Community Guidelines may be moderated or removed.
Grammar and usage help for Spanish:
Subscribe to remove adverts and access premium resources
= trending


text:
- Gadgets
- Accessories
- Jewelry
- Art
- Home
- Games
- Miniatures
Get the best of 3D Printing in your inbox, plus exclusive offers and recommendations from the Shapeways team.
Black nylon plastic with a matte finish and slight grainy feel.
Tamiya 58059 Porsche 959 rear left replacement arm, strengthened redesign from the original Tamiya part.


text:
TV presenter tackled riots looter and pinned him down so police could make arrest, court told
Dan Snow is accustomed to recounting tales of derring-do on the battlefields of history.
But the 33-year-old put himself on the front line during one of the worst riots in modern times.
The 'History Hunter' for BBC's The One Show tackled a looter as he fled from a shop laden with stolen trainers.
Battlefield commentator: Dan Snow and his wife Lady Edwina Grosvenor
A court heard how he used his 6ft6in frame to pin the suspected thief down in a 'citizen's arrest' as he waited for police to arrive.
The confrontation took place during last summer's London riots after Mr Snow saw a menacing gang of young men as he walked to his flat in Notting Hill, West London.
He said that once inside he saw images of burning buildings in Croydon on the news before the street outside his home 'exploded with noise'.
In a statement read at Inner London Crown Court, he said he went outside to find two burning mopeds lying on their side and the gang running off together.
He said: 'I could hear broken objects crashing to the ground and rushed out to see what was happening. I saw the group with their backs to me as I came outside, as they were going to the west towards Portobello Road.
'They were shouting to keep the pace up and were running together. They were smashing windows of parked cars as they moved along.'
Smashed up: Ledbury head chef Brett Graham and staff barricade the premises after the attack by looters, fearing that it could be targeted again
Mr Snow, who is married to heiress Lady Edwina Grosvenor, daughter of the Duke of Westminster, said he followed the gang until they reached an Office shoe shop.
By this time he could hear the sirens of police vehicles approaching. He said: 'I could hear the police shouting at me to leave, but a white male came outside of the shop. He was carrying a bundle of colourful trainers.
'As I could see his attention was on the police, I could attack him without him realising I was there.
'He ran towards me and I barged my right shoulder into him. He fell into the gutter. I was then able to pin him down with my knees. The male didn't say anything and I didn't speak to him. He appeared to be in shock. I restrained him for no more than 20 seconds.
On trial: Inner London Crown Court, where Mr Snow's statement was read out as part of the trial of several suspected looters
'I could see police officers approaching from my left and they took over from me.'
Mr Snow's account was revealed at the trial of Ali Abdul-Waga, 19, who was among four youths accused of rampaging through the area. They allegedly raided shoe shops and a casino before setting their sights on Michelin-starred restaurant The Ledbury.
Left to right: Caleb Williams, 22, Ali Abdul-Waga, 19, and Dean Burke, 19
The men are accused of terrifying customers as they stole their jewellery, designer watches and cash.
The three on trial alongside Abdul-Waga are Dean Burke, 19, Nasir Muhsen, 18, and Caleb Williams, 22. They are accused of conspiracy to commit burglary and violent disorder.
Mr Snow, the son of 'swing-o-meter' journalist Peter Snow, has broadcast about battlefields all over the world, including many from the Second World War. The trial continues.
- Girlfriend not impressed with blowing up kid prank
- President Obama loses his cool over Syria questioning
- GRAPHIC CONTENT: Inside terrifying 17th Door haunted house
- Dramatic great white shark attack in Alcatraz waters
- Dramatic video of last moments of Crowborough fatal crash
- Blind student and hero who came to his aid talk to Dr Phil
- GRAPHIC: Moment rat is filmed attacking and killing a pigeon
- Mystery woman snorts unknown substance at Astros game
- Woman escorted off airplane after air steward 'bullied' her
- Safety Board presents animated reconstruction of MH17 flight
- Strange creature washed up in Japanese tsunami aftermath
- The man in the suit: Behind the scenes at Extreme Costumes
- Plane wreckage 'containing many skeletons and painted with...
- All doors are locked, monsters have 'free rein' and visitors...
- Is this the photo that proves two inmates DID escape...
- 'I love you... but you owe me $127,000': New York aunt sues...
- 'Honestly, you saved my life': Blind high school student...
- 'When you catch ur man naked in bed with a groupie... lol':...
- EXCLUSIVE: Ex-Scientologist Leah Remini braces for blow back...
- Cruelest joke EVER? Dad uses a dummy to prank his girlfriend...
- Obama loses his cool as he is challenged again and again on...
- EXCLUSIVE: Inside the world of the 'pick-up artists' - what...
- Texas A&M star who had a shot at the NFL but vanished into...
- Russian missile killed pilots and cut jet in half but...
Sorry we are not currently accepting comments on this article.


text:
You are using an outdated browser. Please upgrade your browser to improve your ReverbNation experience.
Nov 20
I'll be Guesting with Strange Brew & Phil EmmanualSave
Nov 27
Buy Your $60 tickets at www.kevinborich1.com Boarding at 7pm leaving 7.15pm disembark at 11.40pm we play two Sets - only finger food provided there's a bar to buy drinksSave
Nov 28
Sounds Like: Taj Mahal, Sebastian Bach, Eric Clapton
Label: Lungata Records
Manager: Borich Management, Australian Music Business Management
Bio: Kevin Borich is a musical performer without borders and every performance render the audience prisoners without escape.
The Borich machine features the who's who of bassists and drummers across Australia and all lineups leave the same impression on fans, they leave knowing they have just witness...See Full Bio
"First time I saw Kevin performing was on my arrival to Australia in 76 ..he was there with Deep Purple, Santana, Fleetwood Mac and the Little River Band all at the Sydney Cricket ground .. What a day it was ..One I cherished all my life..I was impressed .. still am!!"


text:
CPD Training Event: Gender Sensitivity in the Asylum Process - 25 February - London
The IARS International Institute marks the awareness of the International Day of Zero Tolerance for Female Genital Mutilation with the announcement of a free CPD accredited training event that will be taking place on Wednesday 25th February 2015, 14:00-18:00 at Room V121, SOAS, University of London, Vernon Square, Penton Rise, London WC1X 9EW (nearest tube Kings Cross).
IARS Press Release: "Victims' Commissioner's First Major Review Fails Victims"
Today, the Victims' Commissioner for England and Wales, Baroness Newlove, published her first major review looking at compliance with the Victims' Code.
PRESS RELEASE: The IARS International Institute
IARS begins the celebration of its 10th year anniversary with the exciting announcement that it has been approved as an "International Institute". Originally set up in Theo Gavrielides' kitchen, this important development in IARS' history acts as a testament to the quality of its work, both in the UK and internationally.
CPD Accredited Training Programme Victims' Rights in Restorative & Criminal Justice
The IARS International Institute in partnership with Khulisa UK are pleased to offer a CPD accredited course entitled Victims' Rights in Restorative & Criminal Justice. The programme builds on a pilot that IARS delivered over 60 times times in five different countries involving 1,131 individuals and 383 organisations.
Grants of up to £150,000 for IARS' Partners: Expressions of Interest - Impact Readiness Fund
As one of the approved providers for the Impact Readiness Fund we are looking for social ventures with an ambition to grow and become sustainable. A £1.5 million worth fund managed by the Social Investment Business for the Cabinet Office aims to support social ventures to understand and improve their social impact with a view to attract social investment and win contracts.
Happy Human Rights Day: Bridging the human rights gap in criminal justice
On this year's international human rights day, I offer my reflections on a human centered criminal justice system. These were generated following the 19th and 20th of November IARS' 3rd Annual International Conference – A victim-led Criminal Justice System? which I had the honour of chairing. Over 20 countries were represented including South Africa, Canada, Sierra Leone, the US, Cyprus, Germany, the Netherlands, Bulgaria, Greece, and Spain.
IARS PRESS RELEASE: Victims' rights - changing the law and mindsets
Over 20 countries were represented at the IARS 3rd Annual International Conference – A victim-led Criminal Justice System? that took place on 19-20 November marking International Restorative Justice Week.
Are the voices of young people being heard? Still a long way to go...
Following the successful conclusion of the London Youth Now programme, IARS is pleased to announce the release of its evaluation report "Youth Voices Matter". The report is the output of the 5-year Big Lottery funded the "London Youth Now" programme.