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Local farmers are still holding out hope that 2017 will be the year industrial hemp grows in WNC fields for the first time in decades. But the U.S. Drug Enforcement Administration isn't making it easy for growers to source seed or seedlings in time for planting, which may mean another year of waiting for eager prospective hemp growers.
Author: Nick Wilson
Showing 1-15 of 15 results
Asheville-area doctors join the direct and concierge care movements
Direct and concierge care are gaining traction in Asheville, offering alternative forms of health care for patients who are looking for more time with their doctors and are willing to pay out of pocket for routine health care, using insurance for catastrophic coverage.
Southern migration: White Duck comes to Skyland
White Duck Taco Shop adds to its growing number of locations with a large new South Asheville space designed with locals in mind.
PennyCup targets late March for launch of Haw Creek location
With its third Asheville location, PennyCup joins a growing wave of homegrown restaurants expanding to the east side of town.
Falafel on the fly: Baba Nahm brings quick Middle Eastern eats to Grove Arcade
Rezaz founder Reza Setayesh and current Rezaz owners Brian and Laura Smith are collaborating to open a grab-and-go Middle Eastern eatery downtown.
Sweet somethings: Asheville-area indie shops offer Valentine's Day gift ideas for the foodie at heart
Valentine's Day gifts don't have to stop with chocolates and flowers. Western North Carolina's independently owned retail shops have some creative ideas for pleasing anyone's beloved foodie.
Buncombe County groups collaborate to prevent childhood obesity
Childhood obesity is a perfect storm of many factors, say local health experts, pointing to poor eating habits, lack of exercise, genetics and environmental factors. Asheville-area agencies are working to help overweight kids lose weight and others to stay within healthy limits.
Zappers Pizzeria and Bar opens soon in East Asheville
Zappers Pizzeria & Bar will debut in East Asheville just in time for Super Bowl weekend. The restaurant is taking over the 90 S. Tunnel Road location that housed Asheville landmark Frank's Roman Pizza for nearly 40 years until it closed in November. Zappers will sling authentic New York-style pizza alongside classic pasta dishes, subs, […]
Success story: Chai Pani and the art of branding through storytelling
In the seven years since it opened, downtown Indian street food eatery Chai Pani has mushroomed into a multibrand restaurant group. Much of this growth has stemmed from the use of storytelling to convey the vibrant personalities and rich history behind the brand.
Portuguese-influenced Fill My Cup Café opens in South Asheville
Saturday, Dec. 17, marks the grand opening of Fill My Cup Café, a Portuguese-inspired café nestled near the entrance to the Blue Ridge Parkway in South Asheville.
From England to Asheville: Pete's Pies comes to Lexington
Savory pies, fish and chips and English "butties" will pair with local and British brews at this new downtown English pub.
Talking turkey: Asheville chefs reveal their own Thanksgiving dishes and memories
From dry-cured turkey to vegan mac and cheese to Caribbean coconut rum drinks, some of Asheville's most creative chefs talk about favorite Thanksgiving foods that range from the classic to the unconventional.
Music as medicine at local long-term care facilities
The therapeutic power of music has been evident for centuries. But now music therapy is catching on in modern society and the use of music is proving to be particularly helpful in patients with Alzheimer's and other forms of dementia.
Mountain Madre Mexican Kitchen opens soon in downtown Asheville
The owners of the now-closed Scully's Bar and Grille are pursuing a long-awaited project with their new Walnut Street venture.
Local cheesemakers honored at 2016 N.C. State Fair competition
Two Western North Carolina creameries brought home multiple awards for their products.


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Reference - Western Dragon Anatomy by TwilightSaintWatch
©2016-2017 TwilightSaint
*Where Else You Can Follow My Artwork & Fursuiting*
DeviantART | FurAffinity | Weasyl | Tumblr | Twitter | FlightRising | YouTube | LiveStream | FaceBook | Sniper FaceBook | FurryNetwork | Instagram | Telegram - TwilightSaint | Skype - TwilightSaint Muzafr
Flat-Colored Anatomy Reference Sheet for feral Western Dragons!
I did this piece in tandem with the Anatomy Ref Sheet for Dutch Angel Dragons I posted recently for the Field Guide presented at Anthrocon '16, but this is something I'd wanted to do for a long time! This is run-down of the anatomy features of common leather-winged Western dragons! (Friendly reminder, there ARE DIFFERENCES in the anatomy between feather-winged and leather-winged dragons! More on that later, folks!)
This Anatomy Ref covers the most common type of Western Dragons, those oft-featured in Medieval European manuscripts and lore. While your specific dragons and characters may have different features and proportions, this is just a basic guide that covers many of their unique features and those they often share, especially for dragons of the leather-winged variety.
Once the Dutch Angel Dragon Field Guide is up and downloadable on the official website, you'll recognize this dragon across the pages! This is to help folks compare and contrast the unique features between Westies and the specific open-yet-regulated species, Dutch Angel Dragons.
I will be posting several compare-and-contrast pages I've made for online viewing, as well as some pages displaying the differences in anatomy between feather- and leather-winged Westies - stay tuned! I'm also in the process of working on similar Anatomy Refs like this for Wyverns and Eastern Long as well!
Dragon character isn't a specific character in particular, just a tough-looking scaly guy that made a great example of the 'traditional' Western-morph. And also, I'd been working on so many feathers lately, scales were a fun change of pace!
(Friendly reminder that 'Western Dragon' typically refers to dragons with an anatomy of four limbs and two wings. Your own species and dragon characters may vary widely in appearance and ability than this dragon shown here! The only limit to designing your own dragons is your imagination - don't limit yourself and don't ever think that there's a 'set in stone' way or 'required features' to make a dragon character that you refer to as a 'Western Dragon,' as these dragons have been around in lore for centuries! ;D )
You may reference this guide for your own dragon characters! This was created with the intention of spreading more knowledge of the general features of this species, and to help folks!
However, if you heavily reference this, you must provide credit. You are not authorized to trace, alter, distribute, or otherwise use this work without explicit permission from myself. Unauthorized use has a zero tolerance policy.
Commission Prices & Terms of Service -
Art (c) TwilightSaint
Thanks for viewing!
I love the layering going on here demonstrating the differences between dragon races.
You forgot the organs
thank you for this
This is so helpful, thanks !
Great stuff! It's a real pleasure to study through this, it's very handy for many purposes!
Thank you for doing this! It'll more than likely help me overcome a few writing and character design blockers in the future!
Thank you for doing this! It'll more than likely help me overcome a few writing and character design blockers in the future!
This is very handy! Wonderful job!
Awesome! A really instructive piece!
Awesome! This is really useful!
I could use this!
I've always really enjoyed how well you display the wings. Believable, yet aesthetically pleasing to the eye- it's an incredibly hard body part to draw for me personally. Anyway, keep up the great work!
awesome DDDDDDDDDD
you are getting real real good at this...
loving it
loving it
Wow! This is great!
This looks totally awesome! Your anatomy is really amazing and this is a great ref for those having trouble making good dragon characters!

subset: commoncrawl


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Sat, 18 October 2008
This is important. This is crucial. This is the truth about Halloween.
Give Kids Candy. Period.
This is not a night about your frigging social, religious, moral, dental, or nutritional agenda.
It is about kids dressing up in crazy costumes (something they cannot do normally, and look forward to all year, frankly), and going door-to-door, in the hopes of getting a bagful of delicious candy. Not glow-sticks, toothbrushes, heath food, tracts, or election campaign literature.
Candy, motherfucker, CANDY.
And if you are one of those people who turn off the lights to discourage the little pagans for religious purposes, when you know full well there are hopeful children looking for fun and the kindness of their neighbors, fuck you. You're a disgrace to your bloodline.
Halloween candy. Learn it. Live it.
Pass it on.
You're welcome.
Category:general -- posted at: 8:43pm EDT


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German translation of 'spell out'
Word Frequency
spell out
transitive verb
- (= spell aloud)
- (= read slowly)
- (= explain)
⇒ do I have to spell it out for you?(informal)
muss ich noch deutlicher werden?
- (= spell aloud)
Example Sentences Including 'spell out'
`Christ, kid, do I have to spell out the facts of life for you?Stage Fright
Nield, twenty-eight years old, dark-haired and with a small neat black moustache, was a man you didn't have to spell out everything to.Cover Story
So sit down quietly and pay attention while I spell out DOG CICERO ROLLED a cigarette and asked himself what he was doing here.The Only Game
Trends of 'spell out'
View usage over:
Translation of spell out from the Collins English to German Dictionary
Log in to comment on this word.


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Bryan Ferry's son Isaac was questioned by police after a photographer alleged he fired a pistol at his head outside a London nightclub.
The incident took place in the early hours of Thursday as Isaac, 21, queued outside the Cuckoo Club in Mayfair.
Scroll down for more
When paparazzi photographers surged forward, one is understood to have collided with Ferry, causing him to reel backwards.
Furious words were exchanged, and as the photographer turned around, he felt a sharp pain on the back of his head.
He said that moments earlier he had produced a pistol-shaped cigarette lighter and that when the photographer later looked at his pictures of him he "must have jumped to the conclusion that I shot him".
The photographer in question clearly thought the incident was a lot more serious and police were called.
The club was evacuated moments later after reports that a shooting had taken place.
Clubbers including Sienna Miller and Camilla Fayed poured on to the street while police cordoned off the area.
Peaches and Pixie Geldof had been at the club earlier in the night, with Kimberly Stewart and Donny Tourette (see story above).
Witnesses claim shots were fired following an altercation between a clubber and the paparazzi outside the club at 2.40am.
A witness said: "This ended up with one of the photographers being shot at the back of the head.
"He received a graze to his head and was pretty shaken up. All he heard was this bang behind him.
"The police then went through the club looking for the attacker. Some people were saying that he fled through a back door."
Isaac Ferry – younger brother of Otis Ferry, who stormed the House of Commons with pro-hunting activists in 2004 – last night posed for a Mail photographer with his lighter in an attempt to further prove his innocence.
He said: "This (photographer) gentlemen assaulted me and when he turned his back, I flicked him as hard as could on the back of the head with my index finger on my right hand in the way one would flick a coin across a room.
"Then I sheepishly ran into the club. Somehow that turned into some story about a gun-toting riot with a loud bang."
He added: "I have a lighter which I bought at Portobello Market last weekend which is like a small Wild West-style gun about half the size of my hand.
"As I was standing outside waiting to get in, lighting a cigarette, one of the photographers took a picture. I can't believe this has turned into me shooting him."
Scotland Yard officers are understood to have questioned Ferry yesterday at his home.
A spokesman said: "At 2.42 this morning police were informed of an alleged assault in Swallow Street, off Regent Street.
"The victim alleges something hit him in the back of the head. He did not require hospital treatment.
"No arrests have been made."
- More about:
- Associated Newspapers
- Mayfair
- Paparazzi
- Photographers
- Photography
- Sienna Miller
- The Daily Mail


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Dancing is the second-best way to let the body do the talking, just short of being born with a mouth in your bellybutton. Speak from the feet with this Groupon.
$20 for 10 Zumba Classes ($150 Value)
See the schedule for available times.
Dare To Dance
Led by championship dancer Marco Mechelke, Dare To Dance's team of experienced instructors use a personalized approach to help students of all experience levels learn how to dance. The studio's combined 10,000 square feet of smooth, polished wood floors and wall-to-wall mirrors provide an expansive and versatile setting for the high-energy, low-pressure classes.
Customer Reviews
11256 Cornell Park Drive
Ste 500
Blue Ash, OH 45242
+15134078633Get Directions


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The reduction of the authorized capital is an ordinary procedure for the legal entities. Generally speaking, the capital reduction is the process of decreasing a company´s shareholder equity through share cancellations and share repurchases. The reduction of capital is done by companies for numerous reasons including increasing shareholder value and producing a more efficient capital structure.
But, what are the consequences ? We have summarized in this article the tax treatment after a capital reduction:
If the share capital of the legal entity income tax does not arise.Thus, in the case of reducing the share capital, section III of the Tax Code of Ukraine provided the adjustment of financial result before tax for the difference, including when leaving one of the founders / participants.
Not taxable payment of share dividends and share capital in cash and VAT (pp. 196.1.6 TCU).
If a member / founder is a natural person, in this case, there is no taxable income, if there is a reduction of share capital, return of share of participants / founders of the cost previously made their contributions. It occurs only in case of alienation of corporate rights ( selling them to another person).
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- Presentation
- Films
- The Panorama abroad
- The Panorama in Paris
The Académie des César presents an exceptional program that brings together all the short films rewarded in 2016 by their National Film Academy (Oscar, Goya, BAFTA, Magritte ...).
An extraordinary journey around the world of Cinema, enabling the discovery of different cultures and tomorrow's filmmakers.
Have you ever dreamt of discovering Jane Campion, Lars Von Trier or David Lynch in their early days when no one could entirely imagine the career ahead of them ?
Reflecting Cinema excellence and celebrating the best of the short film production, a remarkable means of expression that reveals new talents every year, these are the ambitions of the Panorama.
The Panorama travels through several big cities where it is hosted by 10 Film Academies: Brussels, Luxembourg, Stockholm, Madrid, Athens, Lisbon, Rome, Paris and new this year Vienna and Montreal !
A unique opportunity for Film Academies of Europe and Quebec to initiate an innovative cooperation, shedding light on the diversity of worldwide films and participate, in their own way, in the exchange between cultures.


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Meghan Foley Establishes Personal Record in the 1500m at Mt. SAC Relays
Junior clocked in at 4:28.72 to rank sixth in school history
Long Beach State Wraps up Day One at Mt. SAC Relays/Cal Invitational Multi-Events
Junior Garrett Demirjian in third place after five events
49ers Begin Busy Week at Mt. SAC Decathlon/Heptathlon and Mt. SAC Relays
LBSU will also host the Beach Invitational at Cerritos College, April 19-20
Fifteen 49ers Named to MPSF Indoor Track & Field All-Academic Team
Eleven men, four women garner all-academic recognition
49ers Finish Competition at UC Irvine Spring Break Invitational
Adam Bianchessi wins the javelin, Michael Vaughan claims the triple jump title
Decathlon - 7,296 points
100m - 11.13
400m - 49.64
1500m - 4:29.86
110m Hurdles - 14.67 High Jump - 6-03.5
Pole Vault - 13-09.25
Long Jump - 21-10.5
Shot Put - 44-11.5
Discus - 141-10
Javelin - 164-04
Heptathlon - 3,787 points
60m - 7.3
400m - 50.99
60m Hurdles - 8.36
High Jump - 6-07
Long Jump - 21-00.75
Shot Put - 40.03.5
Career: Leaves Long Beach State ranked third in the decathlon with a lifetime-best 7,296 points.
2014 (Senior): Big West champion in the decathlon ... Tied for first in the high jump (6-02.25), while finishing second in the 110m hurdles (14.98), discus (132-03), 1500m (4:40.78) and the 400m (50.49) ... Established a personal-best 164-04 in the javelin.
2013 (Junior): All-Big West performer ... Compiled a personal-record 7,296 points to earn runner-up honors in the Big West Decathlon ... That mark ranks third in school history ... Was also a finalist in the 110m hurdles at the conference championships where he finished sixth in a lifetime-best 14.67 seconds ... Competed in one meet during the indoor season.
2012 (Redshirt): Appeared in one meet during the outdoor campaign ... Competed in the high jump, 110m hurdles and discus at the season-opening Beach Classic ... Tied for fourth in the high jump (6-03.5) and finished sixth in the 110m hurdles (14.95) ... Also took part in the heptathlon at the MPSF Championships during the indoor season ... Tied for first in the 60m hurdles (8.36) and tied for second in the high jump (6-07).
Junior College: Competed on the track and field team at Moorpark College in 2009 and 2011 ... Earned All-America honors after finishing second in the 2011 state decathlon with 6,614 points ... Also took third in the Southern California decathlon and fourth in the high hurdles at the WSC Championships ... Placed eighth overall at the So Cal Championships as a freshman.
High School: Lettered in track & field and football at Thousand Oaks High School ... Graduated in 2008.
Personal: Majoring in studio art.
Sport Links
- 2016 Season
- Season Bests (Updated June 13)
- Weekly Release
- 2016 Black and Gold BBQ
- 2016 Black and Gold Schedule
- 2016 Cross Country/Track and Field Banquet
- 2016 Alumni Meet Registration
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- 2017 Annual T&F Sports Package
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- Home Meet Information
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Media Guides
Front CoverFont Cover
Section 1Introduction
Section 2Coaching Staff
Section 3Meet the Men's Team
Section 4Meet the Women's Team
Section 5History & Records
Section 6History & Records
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More Headlines
Xander Cooper Earns Big West Field Athlete of...04/18/2017 - Track
Long Beach State senior pole vaulter Xander Cooper was named Big West Men's Field Athlete...
Nine Meet Records Fall at Beach Invitational...04/16/2017 - Track
In a meet that featured athletes from all over the world, the Beach Invitational saw nine meet...
Long Beach State Enjoys Successful First Day at...04/14/2017 - Track
Hosting one of the premier events in the country and competing against some of the best athletes ...
LBSU Competes Well Against Top-Notch...04/13/2017 - Track
The Long Beach State track and field team went up against some of the best competition in the...
LBSU Beach Invitational Showcases Top Athletes,...04/13/2017 - Track
The Long Beach State track and field team prepares to welcome some of the top athletes in the...
Long Beach State Set for Beach Invitational04/12/2017 - Track
The Long Beach State track & field team has a busy week as the Beach host the Beach Invitational ...


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Superyacht brokers' open days in Mallorca this month
by Malcolm MacLean
The idea is that each afternoon will be an open house with brokers and prospective buyers able to inspect 18 sailing yachts and 12 motor yachts looking at their best. Brokers showing yachts so far include Camper & Nicholsons, Fraser Yachts, Ocean Independence, Dolphin Yachts, David East Yachting and, of course, Northrop & Johnson.
To view the sailing yachts on display click here.
To view the motor yachts on display click here.
For more information contact:
Northrop and Johnson
Joost Goverts
E: email@example.com
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Anderson Ford of Clinton is your full service dealer. We offer a great selection of new and used vehicles. Check out our huge inventory of luxury cars, sport, cars, intermediates, trucks and vans. Stop in and take a test drive today. Our state of the art service department and fully stocked parts department offer the finest in service and quality.
Contact name: Randy Anderson
Business Address:
Hours of Operation:
Phone: 217-935-3106
On behalf of everyone at Anderson Ford of Clinton we would like to thank you for visiting our web site. We are committed to serving our friends and customers via the Internet and look forward to hearing from you. Please stop back often and see our updates.
You won't want to miss all the excitement!!


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Tag Archives: finances
Back to School Money Tips
Similar to Christmas shopping, when it comes to back to school shopping make a list of the items you need.
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Dating in an Uncertain Economy Things may be a little tight financially but do your date nights have to suffer in the process? Share ...
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The Power Coach™
Welcome Madeline, so wonderful to have you interview with Beautifully Said… and to be our feature for the month of April. Let's ...
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Mall of America announces two new tenants
Two new Mall of America tenants will open soon.
JM Cremp's Boys Adventure — owned and operated by Jay and Maria Asplin of Dassel, Minn., and their five sons — will open a shop early this month on the second floor's north side. It will sell clothing, gear, toys, books and activity kits.
JM Cremp's opened its first retail location in Dassel in August 2012.
"In a world inundated with electronic games and gadgets electronic games and gadgets, JM Cremp's promotes an old-fashioned American boyhood experience reminiscent of days gone by," according to the company's website.
Meanwhile, a create-your-own-pizza concept called Pizza Studio will open in early December on the third floor's south side. It will be the first Minnesota location for the company, which has three sites in California.
Pizza Studio sounds similar to PizzaRev, another California chain that Buffalo Wild Wings invested in earlier this year. PizzaRev's first Minnesota store is under construction in Hopkins.


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Everton boss Roberto Martinez accused Chelsea of using 'every trick in the book' to grind out a narrow victory over his top-four chasing Everton side.
The visitors resisted the threat of Jose Mourinho's side until stoppage time, when Frank Lampard's set piece led to John Terry's winner.
But Martinez – who refused to blame referee Lee Probert – pointed a finger at the league-leaders after Phil Jagielka was penalised for a late challenge on Ramires.
"If you watch the replay, it's not a free-kick at all. That happened with other incidents," he said.
"I don't blame the referee at all. It's an incredible knowhow, using every trick in the book."
The Everton boss felt his side edged the encounter and called on his charges to take advantage when they dominate proceedings.
"We defended really well but John Terry was brave and they scored. Overall I thought we were the better side," he said.
"It was a very unfair result not to get anything from the game after the performance that we had.
"We need to make sure that when we play well and when we deserve to get a positive result, we do that."
- More about:
- Chelsea F.c.
- Premier League


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Yesterday marked the last day of personal training. Now, to stay committed.
Dad On His FeetI'll be a new father in August. The clock already started.
Baby Registry
We're registered on Amazon. Don't worry, I've made it easy so you don't have to search for it.
Should be in bed. Should be asleep. Instead, I'm wasting time. At least that's what it feels like. I'm between books. I'm not working on a story, poem, or the novel. I'm looking at Craigslist and IKEA. Thinking about all the stuff that needs to get done in the next few months. Thinking about having a daughter and how so much will change. My metaphor has been high-diving. You don't know what it will be like until your in the air and, so quickly, entering the water, a moment, an instance flashes by. The transition that you're thinking of, or planning, happens and you find yourself there.
Soon though, the semester will end, and then we'll have time to get the baby's room ready. To shift things around the house. To welcome a new life into the world. ∞


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Mother's Day Fiction
Fiction fans who enjoy Sophie Kinsella will love the feel-good reads from Sunday Times bestselling author, Harriet Evans.
- £4.99
- Save £18.98
- Just £1.66 per book
I Remember You tells the story of Tess Tennant who finds herself whisked off her feet by a stranger in Rome, but will she decide that it is back home, with her lifelong best friend Adam, she truly belongs?; Love of Her Life sees Kate leave New York to tend to her ill father in London, but she must also confront the pieces of her past there to allow herself to love again; Going Home sees Lizzy in the middle of a complicated family saga and the stakes are upped when the Love of Her Life reappears before her once more...
Warm, charming and funny, Evans' novels offer the perfect slice of reading escapism.
With unforgettable characters, beautifully plotted stories and wonderful settings, Sunday Times bestselling author Rosie Thomas' stories are perfect for fans of Anita Shreve and Douglas Kennedy.
- £4.99
- Save £18.98
- Just £1.66 per book
This three-book collection contains some of her best work. Iris and Ruby is a stirring story of mothers, daughters and the distance between three generations of one family; while Sun at Midnight is an epic and adventurous love story set against the beautiful backdrop of Antarctica.
Constance, meanwhile, follows the life of Connie Thorne, a child left by her mother for strangers to find, and how 40 years later, she has to get over a long-running feud with her sister when tragedy strikes...
Focusing on the world of fashion and the fashionable, this three-book collection from Kathleen Tessaro is just perfect for fans of contemporary romantic fiction.
- £3.99
- Save £19.98
- Just £1.33 per book
In Elegance, a woman chances upon a book written by a French fashion expert in a second-hand bookshop and starts to follow its advice - soon her life is transformed and she discovers a courage in her that she never thought was possible; while The Perfume Collector sees an inheritance turning a newly married woman's life upside down...
The final book in the set, The Debutante, is about an old shoebox full of clues that will unravel the tale of the most famous debutante of her generation.
Three stand-alone stories that are just full of elegance, class and sophistication.
With the BBC dramatisation of Winston Graham's Poldark set to return to our screens very soon, we are delighted to bring our customers this TV tie-in set of the beloved books.
- £4.99
- Save £10.99
- Just £2.50 per book
Ross Poldark introduces our hero. Tired from a long-fought war in America, Ross Poldark returns to his homeland but the joyful homecoming he anticipated turns sour: his father is dead, his estate is derelict and the girl he loves is engaged to his cousin. His sympathies for the locals are strong and they lead to him saving an impoverished miner's daughter from a fairground brawl, changing the course of his life forever...
In Demelza, the miner's daughter he saved from the fairground brawl is now his wife and the turbulent years in which they live are testing their marriage and their love for one another. Demelza is trying to adapt to the ways of the gentry bring her only heartache and headaches, despite the joy of the first child. And Ross begins a bitter struggle for the rights of miners with his enemy, George Warleggan.
Period writing of the highest calibre, this two-book set is ideal for fans of the Poldark show and those yet to read the incomparable works of Winston Graham.
This set contains books one and two in Winston Graham's Poldark series
Perfect for anyone who loves romance, these three books are full of frothy relationships and escapism. Including the bestselling RSVP, the hilarious romp The Nearly-weds and the feel-good Thirteen Weddings, it's a wonderful collection to add to any romance fan's bookshelf.
- £4.99
- Save £18.98
- Just £1.66 per book
Warm and sophisticated, Helen Warner's RSVP tells the story of four women, one wedding and a day they'll never forget. Anna has been invited to the 'love-of-her-life' and ex-boyfriend Toby's wedding. Will it give her a sense of closure or will it reopen old wounds?
Jane Costello's The Nearly-weds will take you to Boston to meet Zoe Moore - a warm and loving woman who moved to the States after being cruelly ditched at the altar. Will she find happiness in her new home?
Thirteen Weddings follows Bronte who had an amazing one-night stand with Alex around a year ago. Now working at a picture desk for a glossy magazine, she's shocked to recognise him as her new colleague - and now he's engaged... but the spark still remains.
Charming, heart-warming and very funny books that will delight fans of James Herriot, this collection brings together three novels from Book People favourite Gervase Phinn's Little Village School series.
- £4.99
- Save £18.98
- Just £1.66 per book
In The Little Village School, the school in Barton-in-the-Dale, Yorkshire is in for a change when a new headmistress Elisabeth Devine arrives with plans of her own. There's a bitter former headteacher, a grumpy caretaker and many more unforgettable characters - and they're all being gossiped about by the residents of the village
Just as she's beginning to win over the wary locals in Trouble at the Little Village School, Elisabeth receives the news that the school is set to be merged with its arch rival - and she's going to have to face off against a ruthless and calculating headmaster to land the top job. Will the latest scandal to hit the village help her succeed?
Finally, it's summer and the new term is in full swing in The School Inspector Calls. There's a new, disruptive pupil and an unexpected affair is now talk of the town...
Kit de Waal's debut novel, My Name is Leon was shortlisted for the Costa First Novel Award 2016 and is a heartbreaking story of love, identity and loss in 1980s Britain.
- £5.99
- Save £7.00
Leon is a 9-year-old boy who has just welcomed a perfect baby brother called Jake. The brothers have gone to live with Maureen, who has funny, fuzzy red hair and a belly Santa would be proud of. However, Leon is aware something is going on - the adults are acting strangely. Could it be something to do with the fact Jake is white and Leon is not?
Leon struggles to hide his anger but there are still many things that make him happy - Curly Wurlys, riding a bike and hanging out with Tufty (who reminds him of his dad). He's also stealing coins so that one day he can rescue Jake and his mum...
This is a poignant story all about the fierce bond between siblings and how we can find our way home, even when least expect it...
This impeccable collection contains five novels by Elizabeth Jane Howard, the bestselling author of the Cazalet Chronicles and all the novels are funny yet touching.
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After Julius follows a family who have been brought back together, but they're finding it hard not to fall apart. Julius died 20 years ago but his last heroic action is still leaving a huge impact; Mr Wrong is a collection of short stories about dysfunctional families; and Odd Girl Out takes an eagle-eyed look at a destructive marriage.
Something in Disguise is a witty account of a post-war family who are on the cusp of change and facing a crisis; and Getting It Right is a touching comedy about a sensitive hairdresser who tries to start living life 'right' at the age of 31.
A huge favourite with Book People customers, M.C. Beaton's beloved character, the quick-witted and unambitious policeman Hamish Macbeth returns to try and crack his 32nd mysterious case in Death of a Ghost.
- £4.99
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Hamish is hearing reports that a castle outside the village of Drim is haunted. Lights have been spotted at night but Hamish expects it is local youths gathering to take drugs. To get to the bottom of the rumours once and for all, Hamish decides to spend a night in the castle with his colleague Charlie 'Clumsy' Carson.
The wind explains the ghostly noises but then Charlie falls through the floor and Hamish finds a dead boy propped up in a corner of the cellar. Chief Detective Inspector Blair arrives to investigate, but the body has disappeared. Hamish's story is dismissed as words of a drunk, so he takes it upon himself to find and identify the body and its killer before the 'ghost' strikes again...
Set in the town of Plummergen, these classic cosy crime novels find retired art teacher Miss Seeton investigating all kinds of quirky killings.
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Picture Miss Seeton is the first story in the series and it finds Miss Seeton witnessing a real-life street stabbing in London. All she can recall is a shadowy figure, but how was she to know that her latest sketch would be a picture-perfect portrait of the killer?
Miss Seeton Draws the Line has the super sleuth drawing a clue to a series of child murders in rural England. Scotland Yard soon ask for her help. Finally, there's Witch Miss Seeton which finds the village developing a sudden interest in the occult.
This collection brings together six stories about six sisters, all written by Book People favourite M.C. Beaton.
- £7.99
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Regency romance from a bygone era, these stories are very funny and are sure to appeal to the Agatha Raisin author's fans - although they are much lighter and very different to her crime writing.
When Charles Armitage announces that his eldest daughter Minerva is to have her coming-out in London, the news is not well received by the rest of the family; Mrs Armitage has one of her turns and Minerva's sisters all start to cry.
As well as Minerva, this collection gives all the sisters a chance to shine - Annabelle passionately falls for Minerva's intended, Lord Sylvester; Deidre wants to marry for love and nothing else; Diana loves to hunt while dressed as a man; and Frederica runs away from home when she has to follow her sisters in marrying magnificently.
M.C. Beaton is one of Book People's most popular authors and her cosy crime novels are just perfect for delving into every evening. One of her most famous characters, the Scottish policeman Hamish Macbeth, features in these five marvellous mysteries.
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In Death of a Nag, things are not going well for the village bobby. He's been unfairly demoted and has suffered yet another romantic disappointment. To get away from it all, he decides to take a week's holiday at the coastal village of Skag. But this being Hamish, things don't go to plan and, of course, there's a murder nearby...
This collection also includes Death of a Macho Man, a book that finds Hamish himself at the centre of a murder investigation; Death of a Dentist, which sees a queue of angry husbands in the frame for murder; Death of a Scriptwriter which has an author accused of killing someone who has adapted - and changed - her beloved work; and Death of an Addict with its recovering addict turning up dead, 'apparently' from a drug overdose...
This collection contains books 11-15 in M.C. Beatons' Hamish Macbeth Mysteries series.
This bumper collection provides the perfect introduction to Ann Cleeves' bestselling stories. It contains five novels in the Vera series (adapted into a hit ITV drama starring Brenda Blethyn) and five books from the Shetland series (adapted by the BBC into a popular show starring Douglas Henshall).
- £12.99
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Available for an unbelievable Book People price, the first five books in the Vera series follow Vera Stanhope as the detective investigates a series of strange occurrences across the North Pennines. She starts by joining three very different women as they arrive at an isolated cottage to complete an environmental survey. But when they get there, they find the body of one of Bella's friends... Vera also makes fresh inquiries into the decade-old case of the murder of a 15-year-old girl; and investigates the disappearance of her hippy neighbour.
Set in the remote community of the Shetland Islands, the five Shetland books follow Jimmy Perez as he encounters all manner of evil characters. He finds his neighbour left for dead after being strangled; looks into the case of an amnesiac's 'suicide'; and has to deal with the discovery of a woman's body at the supposed sanctuary of the Fair Isles bird observatory.
Zoe's husband has died and she's not sure where to turn. She and Ed had fumbled their way into adulthood, and although they were on different paths they were always heading in the same direction.
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Eventually after working in dead-end jobs and enduring chaotic house shares over the years, romance finally blossomed - but then the tragic accident happened. While cycling to work, Ed was knocked off his bike and dies. Zoe is left with no choice but to survive, but she's not yet ready to let go of her memories.
As she reminisces about all their happy times, she decides she has to tell Ed everything she never got round to saying. At the same time, she wonders if there's a way she can get him back...
Heartbreaking and poignant, Clare Swatman's debut novel Before You Go will leave you in tears and completely absorb you from the very first page.
Cold Killers - the latest book from Lee Weeks, author of Frozen Grave - is a novel that asks if a heated East End feud can really lead to murder...
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When Eddie Butcher, a member of a notorious East End family, is tortured and brutally murdered while visiting London, DI Carter and DS Willis's suspicions are raised by his extravagant funeral. Eddie's violent brother, Tony, is under house arrest in Spain but still tries to make an appearance. Wanted for robbery, drug trafficking and murder, the police wonder if he would kill his own family to maintain his power?
Meanwhile, Carter is holding a secret - and it's that the Butcher's family's history is personal to him. He's willing to bend the rules to finally catch Tony...
For fans of Martina Cole, this is a darkly riveting read full of familiar locations and some unforgettable twists. You'll be sleeping with the lights on after finishing it...
Shortlisted for the Costa First Novel award, Guinevere Glasfurd's The Words in My Hand is the reimagined true story of a 17th century Dutch maid.
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Despite the attitudes of the times, Helena is desperate to educate herself and use her mind. Working in a lodging house of an English bookseller, she finds herself renting out a room to French philosopher Ren Descartes. Helena dreams of being a writer, while Descartes quests for reason and the two soon form a bond that evolves into a full-blown affair.
Descartes finds himself learning emotional lessons from Helena and her everyday life, but the couple struggle despite their love.. Soon it becomes apparent their only way of being together is to remain unseen? can their love conquer all these issues?
Three feel-good reads from Cathy Bramley, an author who specialises in writing heart-warming love stories that are ideal for drifting away with.
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Appleby Farm follows Freya Moorcroft as she attempts to find love, friendship and do a bit of farming; Ivy Lane follows Tilly Parker as she looks for a fresh start, fresh air and a fresh attitude; and Conditional Love looks at the surprises life has in store for Sophie Stone when a mysterious benefactor leaves her an inheritance. There's only one catch - she has to meet the father she has never seen.
Perfect for fans of Katie Fforde and Carole Matthews, these books are sweet and sure to keep you smiling. Perfect escapism.
For the first time in his successful career, broadcasting legend and national treasure Terry Wogan turned his attention to writing fiction in Those Were the Days.
- £4.99
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Containing several short stories full of laughter, love and loss, this heart-warming book will make a perfect gift for any fan of the much-missed Terry.
Michael Connelly, author of The Lincoln Lawyer, is one of the world's bestselling crime writers. This collection contains five of our favourite novels following his much-loved character Harry Bosch - the main character in the adaptation that has become the most-watched original series adaptation on Amazon Prime.
- £7.99
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The Crossing finds Bosch defending a man accused of murder, but will he betray everything he believes in to stand up for him?; The Narrows has the private investigator confronting a villain known only as The Poet who has just come out of hiding; The Reversal has Bosch and his colleague Mickey Haller taking on a seemingly unwinnable case; City of Bones brings up dark memories from Bosch's past; and The Burning Room involves a cold case unlike any he's ever seen before...
These compelling reads will appeal to fans of John Grisham, David Baldacci and Lee Child.
Please note this collection contains five hand-picked novels from the long-running Bosch series.
A signed edition of Alison Weir's Six Tudor Queens: Katherine of Aragon.
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The first in six novels from Alison Weir about Henry VIII's queens, this huge book covers the life and times of Katherine of Aragon with a combination of groundbreaking truth and breathtaking fiction.
Aiming to give readers an extraordinary insight into the way in which Katherine lived, this is a thoroughly researched and eye-opening read that will appeal to fans of Philippa Gregory. It reveals Katherine as a strong and determined woman who believed to be the wife of a king was her destiny.
A Spanish princess who was raised to be modest, obedient and devout, the book follows Katherine as she leaves her home country and finds herself in a place where everything is different. She has to learn a new language and discover a new way of life as she struggles to cope without her mother and mourns the loss of her brother... seven years after the death of her first husband, Arthur, Prince of Wales, she married Henry VIII and they began a tumultuous marriage that ended with her banishment and death.
Six historical novels for one unbelievable Book People price, this is the entire collection of Philippa Gregory's bestselling Cousins' War series. Certain to transport you back in time to England during the War of the Roses, the books' settings have been richly researched and the plots are completely compelling.
- £7.99
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- Just £1.33 per book
Although not released in this order, it's widely thought that reading the books in chronological order (The Lady of the Rivers, The Red Queen, The White Queen, The Kingmaker's Daughter, The White Princess, The King's Curse) offers the best experience. Covering Henry VIII's predecessors and Elizabeth Woodville's rise to the throne, the books are full of shocks, scandals, murders and have some healthy romance added for good measure.
By reading all the books in the series, you'll see why Philippa Gregory is heralded as the queen of historical fiction - and how her Cousins' War books inspired the hit BBC show The White Queen.
This collection contains books 1-6 in Philippa Gregory's Cousins' War series.
Anne Holt is one of the queens of Scandinavian crime writing and has sold millions of copies of her books worldwide. This three-book collection will introduce you to her detective characters, Adam Stubo and Johanne Vik.
- £4.99
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- Just £1.66 per book
Punishment is the duo's first case and it finds them in pursuit of a killer who is on the loose. Three children have been abducted and two bodies have been returned to their mothers with a horrific note: 'You Got What You Deserved'. Police Superintendent Adam Stubo is put in charge of the investigation and is convinced he's overlooking a crucial detail. He recruits legal researcher Johanne Vik - who has an extensive understanding of criminal history - to help him solve this horrifying case.
The Final Murder finds a TV talk-show star being murdered in her own home. Her tongue has been removed and left near to her body. A second body is also found crucified soon after and more killings are to be expected; Death in Oslo finds the US president being abducted while on a state visit to Norway...
This collection includes books 1-3 in Anne Holt's Vik/Stubo series.
Presented with eye-catching Penguin Classics jackets, this is the entire series of G.K. Chesterton's best-loved Father Brown books - the stories that inspired the hit BBC show starring Mark Williams. They will introduce you to an ingenious amateur detective who has to deal with everything from high crime to voodoo and miracles.
- £6.99
- Save £27.96
- Just £1.40 per book
With a canny sense of humour throughout, you'll be hooked by the adventures of this ingenious amateur detective. The first book, The Innocence of Father Brown, shows how he can track down even the most elusive wrongdoer. He also has to solve cases featuring bandits, ghosts, a man with two beards and other extraordinary crimes in the following books.
Father Brown is an incredible character with an uncanny understanding of human foibles that can help him overcome even the most villainous adversaries.
Often acclaimed as one of America's finest novelists, delve into or rediscover the works of Edith Wharton with this great value three-book set. Featuring the masterpiece The Age of Innocence, later adapted into a hit film by Martin Scorsese, every novel is compelling and captivating from start to finish.
- £3.99
- Save £25.98
- Just £1.33 per book
The Age of Innocence is set during turn-of-the-century New York and finds Newland Archer torn between his respect for family traditions and his burgeoning attraction to his wife-to-be's cousin... The Children finds bachelor Martin Boyne befriending some precocious kids on a cruise ship between Algiers and Venice Martin Boyne; while The House of Mirth portrays the moral, social and economic restraints on a woman's attitude to marriage in the early 1900s.
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Senate approves changes to judicial elections
The Tennessee Senate voted Thursday to let voters determine whether to change how high court judges are selected in Tennessee, The City Paper reports.
Currently, the governor appoints judges from a list of recommendations, and the judges are then subject to yes/no retention elections.
For decades, some of claimed that this violates Tennessee's constitutional requirement that judges be popularly elected.
If a similar measure is approved in the House, the issue will be put before voters in a 2014 ballot referendum which would do away with the governor's list of recommended judges and would give the Legislature a chance to reject the governor's appointees, The City Paper reports.


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Most listings are in the $0's per square foot per year. The Moreno Valley region is seeing a decrease in rates. In the last 3 months, the median rate decreased $16 per sqft per year. That's a 100% decline in rent.
In the last 90 days, 3 listings have been listed, which means office spaces are probably going fast. You'll want to be prepared to make an offer immediately. There aren't many listings below 2,000 square feet available, so finding a space for a small business might be tough.
The standard measurement for office space in this area is around sqft. Most buildings in this area are close to 2 floors. Most buildings in this market were built in 1989 and are Class B.
Trends and status of the commercial real estate market in Moreno Valley.
Market Report
Real time and historical data on commercial real estate listings in Moreno Valley.


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December 19, 2012
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Step by step application of Gel II Pink & White application.
December 19, 2012
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A licensed nail tech for five years, Missi Barry sells custom-blended indie nail polish.
December 19, 2012
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Instead of the accent nail, Cosmopolitan magazine has spotted celebrities donning accent nails.
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Not an expert at handpainting? No matter.
December 17, 2012
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Cosmopolitan asked 100 guys on the street which holiday manicure hue was the hottest.
December 11, 2012
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InStyle magazine, in its December 2012 issue, asked three nail artists for their best holiday design.
December 1, 2012
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November 30, 2012
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CND manicurists topped gold polish with shards of black and gold glass for a fall runway show.
November 28, 2012
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Redbook Mag's latest obsession is the top coat from manicurist Jin Soon Choi's newly launched line of polishes.
November 23, 2012
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Harper's Bazaar's November issue advised readers to shake up their usual shades by trying a techy silver or a multi-dimensional dark red.
November 21, 2012
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This video, from the Local Hazardous Waste Program in King County, Washington, shows the measurement levels of common nail salon solvents in the air, both with and without source-capture ventilation.
Watch move videos on salon ventilation.
November 21, 2012
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Marie Claire @Work advises readers to save the crazy nail art for off-hours and try the latest boss-approved neutrals for work.
November 20, 2012
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Olympic gymnast Gabby Douglas named Nicole by OPI's Fresh Squeezed her favorite polish color and a beauty essential.
November 16, 2012
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Your clients will be spellbound watching the light reflect off these polishes in different ways. Layla
November 16, 2012
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Sally Hansen's newest product, InstaGel Strips, combines a gel mani with adhesive nail decals.
26 Nail Art Products to Play With26 photos
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Lexor was founded in 1997 in Baltimore, Md. According to the website, Lexor is the leading manufacturer in pedicure spas in North America.
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text:
No Turning Back Now
Continuation of the demolition of the bathroom shows some lovely hues of blue that would even embarrass a Robin.
The tear out of the bathroom is starting to get some more momentum. I could get used to this. Then again, I could get really sick of it.
Labels: Bath Remodel


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Receive free seasonal health guidelines
Live Streamed with Dr. Jayarajan Kodikannath
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Approved PACE program by NAMA: 18 AHC, 20 AP/AD credits
Ashtanga Hridayam, the "Heart or Essence of all the Eight Branches of Ayurveda," is one of the fundamental ancient root texts of Ayurveda. It is written in a poetic form with beautiful Sanskrit verse, making it easier for a student to remember important subjects in a concise form. Today the Ashtanga Hridayam continues to serve as a root source for Ayurvedic philosophy and protocol, providing clear guidelines in all aspects of health, including nutrition.
As an Ayurveda student, practitioner or enthusiast, you know how important it is to use the authentic teachings of the ancient Vedic texts, though acquiring this information can seem like a daunting task. In this course, you will be guided by Dr. Jayarajan Kodikannath word-by-word, illuminating the deepest aspects of the Ayurvedic principles.
Studying Chapter 5 & part of Chapter 6 of the text, you'll discover the traditional Ayurvedic philosophy behind the use of fluid ingredients, such as water, dairy, oils, wine and vinegar, and also begin to study solid foods such as grains, meats, fish, vegetables, fruits, herbs and spices. The ancient slokas identify their qualities, health benefits and methods of utilization.
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Acer Al1917w Monitors Driver Download
Acer Al1917w Monitors Driver Details:
Acer Al1917w Monitors File Name: acer_al1917w_monitors.zip
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text:
Overexpression of aquaporin 4 in articular chondrocytes exacerbates the severity of adjuvant-induced arthritis in rats: an in vivo and in vitro study
- Li Cai†1,
- Chao Lei†2,
- Rong Li2Email author,
- Wei-na Chen2,
- Cheng-mu Hu2,
- Xiao-yu Chen3 and
- Chun-mei Li2
DOI: 10.1186/s12950-017-0153-8
© The Author(s). 2017
Received: 4 November 2016
Accepted: 25 February 2017
Published: 1 March 2017
The dysfunction of articular chondrocytes is a crucial step in rheumatoid arthritis (RA) pathogenesis while its molecular mechanisms are not fully known. This study was aimed to investigate the expression of aquaporin 4 (AQP4) in articular chondrocytes of adjuvant-induced arthritis (AIA) rats and its involvement in AIA development.
Thirty rats were divided into normal and AIA group (n = 15). Rat AIA was induced by intradermal injection of complete Freund's adjuvant and evaluated by secondary paw swelling and histological assessments on knee joint damage. Localization and protein expression of AQP4 in articular cartilage were examined by immunohistochemistry and western blot. In vitro study, AIA articular chondrocytes were cultured and treated with acetazolamide, an AQPs inhibitor. AQP4 protein level, cell proliferation and mRNA levels of type-II collagen (COII) and aggrecan were measured by western blot, MTT assay and real-time PCR, respectively.
The results of immunohistochemistry and western blot indicated that AQP4 showed higher protein levels in cartilage tissues of AIA rats than that of normal rats. Correlation analysis revealed that AQP4 protein level in cartilage tissues of AIA rats remarkably correlated positively with secondary paw swelling on day 26 after AIA induction as well as pathological scores on joint damage. Additionally, acetazolamide treatment effectively decreased AQP4 protein level, increased cell proliferation and mRNA levels of COII and aggrecan, suggesting AQP4 inhibition by acetazolamide could normalize the dysfunction of AIA articular chondrocytes in vitro.
Our data provide certain experimental evidence that AQP4 over-expression in articular chondrocytes aggravated AIA severity and might be a novel target for RA treatment.
KeywordsAquaporin 4 Adjuvant-induced arthritis Articular cartilage Articular chondrocytes Rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease and usually causes serious disability in affected individuals [1]. Joint swelling, synovial inflammation and progressive destruction of cartilage are the hallmarks of RA [2]. Previous studies on RA pathogenesis predominantly focus on synovial inflammation and excessive synovial hyperplasia. However, accumulating clinical evidence reveal that the joint destruction is not always correlated with inflammatory process in RA [3], joint destruction still occurs even when the joint inflammation is suppressed by proper anti-arthritic treatment [4]. Particularly, articular cartilage damage is positively associated with irreversible RA disability, and more attention should be taken to the molecular pathomechanism of articular cartilage damage in RA [5].
As the unique cellular component in cartilage, articular chondrocytes are responsible for synthesizing and maintaining the cartilage extracellular matrix (ECM) which mainly consists of water, type-II collagen (COII) and proteoglycans [6]. The metabolic activity of articular chondrocytes is influenced by local extracellular physicochemical factors including pH, fluid flow, ionic and osmotic environment [7]. In the affected joints of RA, multiple extracellular pathological changes such as hydrarthrosis, acidosis and hyperosmotic stress induce the dysfunction of articular chondrocytes, e.g., excessive apoptosis and reduced ECM synthesis ability, eventually lead to articular cartilage destruction [8].
Aquaporins (AQPs) belong to membrane transport proteins family and are closely involved in regulating the influx and outflow of water and small molecules [9]. At least 13 mammalian AQPs (AQP0-12) have been studied in various tissues and organs including kidney, eye, brain and lung [10]. The permeability of AQPs is dependant on the osmotic and hydrostatic gradients and pH values [9, 11]. Several investigations have showed underlying involvement of AQPs in cartilage damage of joint diseases such as RA and osteoarthritis (OA). Mobasheri et al. firstly confirmed that AQP1, 3 are expressed in equine articular cartilage [12]. AQP1 expression was found significantly increased in articular cartilage of RA [13, 14] and OA patients or experimentally induced OA rats [15, 16]. Nagahara et al. observed that AQP9 was strongly expressed in the synovial tissues of OA and RA patients, and was related to the pathogenesis of hydrarthrosis and synovitis [17]. It is well known that AQP4 possess very high single channel water permeability (3-fold greater than that of AQP1) [18], while previous studies of AQP4 mainly aim at nervous system diseases [19]. There is high homology between human and rat AQP4 (93%). Interestingly, our recent work suggested that AQP4 expressed in human cartilage tissues. However, the potential pathological role of AQP4 in RA cartilage damage is still unknown.
In this study, rat with adjuvant-induced arthritis (AIA) was established and used as an experimental model resembling RA. We investigated the AQP4 expression in articular cartilage of AIA rats and revealed potential involvement of AQP4 activation in the development of rats AIA. Acetazolamide is a widely used sulfonamide carbonic anhydrase inhibitor and is recently shown to be a potent inhibitor of AQPs [20, 21]. In vitro studies, we observed the effects of acetazolamide on AQP4 expression, cell proliferation and mRNA levels of COII and aggrecan in cultured AIA chondrocytes.
Animals and AIA induction
Male Sprague Dawley rats weighting 140–160 g were purchased from Experimental Animal Center of Anhui Medical University and housed under standardized conditions of temperature (20–22 °C) and humidity (50–60%). After 7-day acclimatization, the rats were randomly divided into normal rats group and AIA experimental group (15 rats per group). Commercial complete Freund's adjuvant (CFA) (Catalog #7027, 10 mg/mL) was got from Chondrex, Inc (WA, USA). Each Rat in AIA experimental group received a single intradermal injection of 0.1 mL CFA into the right hind paw to induce arthritis [22]. Meanwhile, the equivalent volume of saline was given to each rat in normal group.
Evaluation of arthritis development
The day of CFA injection was regarded as day 0. The volume of the non-injected (left) hind paw was measured by a plethysmograph apparatus (YLS-7A, Academy of Medical Science of Shandong Province, China) at various time points including day 0 and day 10, 14, 18, 22, 26 after AIA induction. The secondary paw swelling at each time point was defined as the changes in paw volume on day 0 (basic value) and day 10, 14, 18, 22, 26 (ΔmL).
Histopathological examination and assessment of joint damage
Animals were euthanized on day 26 and then the left knee joints were quickly removed, trimmed, fixed in 4% paraformaldehyde. After decalcification in 10% EDTA for 2 weeks, the tissues were paraffin embedded and sliced at 5 μm thick for histopathological examination. The paraffin sections with hematoxylin and eosin (HE) staining were observed under a light microscope (Nikon 80i, Japan) and evaluated by two trained pathologist blinded to the specimens. Pathological assessments of joint damage were carried out on the basis of synovial hyperplasia, cartilage destruction, vascular proliferation and inflammatory cells infiltrate. Pathological scores on the severity of lesions were classified into four grades: 0, no detectable changes; 1, mild; 2, moderate; 3, severe. The average of three slides per rat was used as an independent data for statistical analysis. Total pathological scores of joint damage were the sum of the individual score for every pathological index.
AQP4 immunohistochemistry staining and semi-quantitative analysis
Immunohistochemistry staining for AQP4 was performed according to standard procedures [23]. The knee joint sections were hydrated, rinsed and microwave-treated in 0.05 M citrate-buffered saline. Sections were treated by 3% hydrogen peroxide in methanol at room temperature for 10 min to quench endogenous peroxidase activity and incubated in 5% goat serum at 37 °C for 15 min to block nonspecific staining. Then sections were incubated at 4 °C overnight with primary antibody of AQP4 (1:100; Abcam plc, Cambridge, UK; Catalog ab9512). The section of knee joint without adding AQP4 antibody was applied as a negative control. Sections were incubated with biotinylated secondary antibodies and avidin-biotin horseradish peroxidase complex (1:200; Vector Laboratories, CA, USA) at 37 °C for 30 min. Sections were visualized by diaminobenzidine, dehydrated, hyalinized in xylene and mounted with neutral gum. Finally, sections were observed by a light microscope and typical photos were taken. Cell membrane and cytoplasm contained yellow/brown granules were considered positively stained cells. AQP4 staining scores were determined by semi-quantitative optical analysis. The number of positive cells and total cells were counted at five fields per slide. We calculated the positive expression rate (%), which was defined as (number of positive cells/total cells) × 100%. The proportion of positive cells was graded as follows [16]: (−), < 5%; (+), 5–25%; (++), 26–50%; (+++), 51–75%; (++++), > 75%. The average of three slides was used as an independent data for statistical analysis.
Western blot analysis
Aliquots of cartilage tissues obtained from the right knee joints were homogenized and treated with RIPA lysis buffer. The protein levels of lysates were measured by Bradford assay. An equal weight of protein was separated by SDS-PAGE and transferred onto a nitrocellulose membrane. The membranes were blocked with 5% skim milk and incubated with the primary antibodies against AQP4 (1:500) or β-actin (1:500) at 4 °C overnight. Subsequently, the membranes were incubated with a horseradish peroxidase conjugated secondary antibody at 37 °C for 2 h. The protein bands were easily visualized using Enhanced Chemiluminescence Kit (Pierce, IL, USA). Then the bands were scanned and measured by ImageJ software. The ratio of optical density value of interest protein band over its corresponding β-actin band was recognized as the relative protein level.
Articular chondrocytes preparation and acetazolamide treatment
Another 10 AIA rats and 10 normal rats were prepared for the in vitro experiments. Rats were euthanized and cartilage tissues from knee joints were quickly collected. Articular chondrocytes were isolated and cultured similar to previously described [7, 24]. Briefly, small minced cartilage tissues (about 1 mm3) was digested with 0.25% trypsin for 0.5 h and 0.2% type II collagenase for 3 h in cell incubator, respectively. The isolated cells were pipetted through 200-mesh nylon mesh into centrifuge tubes and washed with PBS. Then the freshly isolated chondrocytes were resuspended in DMEM medium (Thermo Fisher Scientific, PA, USA) containing 10% fetal calf serum (FCS), penicillin (100 IU/ml) and streptomycin (100 μg/ml) and incubated in a flat-bottomed culture bottle at 37 °C, 5% CO2 for 5 days. Adherent cells were trypsinized, split and recultured in DMEM medium. The articular chondrocytes of 1–2 passages were applied in this study. The cultured chondrocytes were identified by the morphological property and toluidine blue staining of glycosaminoglycan. The cultured articular chondrocytes were divided into 4 groups: normal articular chondrocytes, AIA articular chondrocytes and AIA articular chondrocytes treated with acetazolamide (25 or 100 μM). Acetazolamide (Sigma, MO, USA) was dissolved with DMSO to prepare the stock solution (100 mM) and diluted to the final concentrations using DMEM medium containing 10% FCS.
AQP4 expression in cultured articular chondrocytes
AQP4 immunocytochemistry staining was performed in cultured normal and AIA chondrocytes, and the detailed procedure of immunocytochemistry was similar to the immunohistochemical steps described above. In addition, we carried out western blot analysis for AQP4 in various cultured chondrocytes groups to investigate whether acetazolamide treatment inhibited the protein levels of AQP4 in AIA chondrocytes.
Chondrocytes proliferation measurement
Articular chondrocytes were prepared and suspended in DMEM medium containing 10% FCS at a concentration of 5 × 107 cells/L. 100 μL cell suspension was added to 96-well plate and incubated at 37 °C, 5% CO2 for 24 h. After adherence, the culture medium was replaced by 200 μL DMEM or DMEM with different doses of acetazolamide for 48 h cultivation. 10 μL of MTT (Sigma, MO, USA) (5 g/L) was added to each well and the cells were incubated for another 4 h. After centrifugation, the supernatants were removed. The formazan crystals derived from MTT were dissolved completely with 150 μL dimethyl sulfoxide per well. The absorbance (A) was measured at 570 nm using a microplate reader and the results were described as the average of A.
Real-Time quantitative PCR (Q-PCR) of COII and aggrecan mRNA
Total RNA was extracted from articular chondrocytes in various groups by Trizol method (Invitrogen, CA, USA). cDNA were synthesized by a RevertAid First Strand cDNA Synthesis Kit (Thermo Scientific, PA, USA). Q-PCR was performed by SYBR Green PCR Kit (Applied Biosystems, USA) in ABI Prism 7000 Sequence Detector. Cycling conditions in 25 μL volume were as follows: 15 s at 95 °C, 60 s at 64 °C (COII) or 60 °C (aggrecan); 40 cycles. PCR primers were purchased from Sangon Biotech Company (Shanghai, China): COII 5'-TCAAGTCGCTGAACAACCAG-3' and 5'-GTCTCCGCTCTTCCACTCTG-3'; Aggrecan 5'-GCAGCACAGACACTTCAGGA-3' and 5'-CCCACTTTCTACAGGCAAGC-3'; β-actin 5'-TTGCTGACAGGATGCAGAA-3' and 5'-ACCAATCCACACAGAGTACTT-3'. The relative amplification efficiencies of the primers were tested and shown to be similar. 2-ΔΔCt method was used to measure the relative amount of mRNA and the result was normalized against β-actin.
Statistical analysis
Statistical analysis was carried out by SPSS 16.0 software. The experimental data were analyzed by Independent-Samples T test or One-Way ANOVA followed by LSD post hoc test. All values were shown as mean ± standard error of the mean (SEM) and p < 0.05 was considered to be statistically significant. Correlation between AQP4 protein levels of AIA rats and secondary hind paw swelling or pathological scores on joint damage was determined by Pearson's correlation test.
Evaluation of AIA in rats
AQP4 was highly expressed in articular cartilage of AIA rats
The semi-quantitative analysis result of AQP4 immunohistochemistry staining in articular cartilage
Grade of AQP4 positive proportion
Relationships between AQP4 protein levels and secondary paw swelling or pathological scores on joint damage in AIA rats
Cultured chondrocytes identification and AQP4 immunocytochemistry staining
Acetazolamide inhibited AQP4 protein level in cultured AIA chondrocytes
Acetazolamide induced cell proliferation of AIA articular chondrocytes
Acetazolamide increased COII, aggrecan mRNA levels in AIA chondrocytes
AIA is a classic experimental polyarthritis model resembling RA and shares many pathological features of RA such as extremities swelling, joint inflammation, synovial hyperplasia and cartilage damage [25]. Herein, we utilized rat AIA model to explore the potential pathogenic role of AQP4 over-expression in articular chondrocytes in RA disease progress. There are two stages in AIA progress, i.e., the primary and the secondary inflammation. The primary inflammation stage is characterized by a rapid onset of inflammation in the adjuvant-injected paws within 24 h and gradually lessens after lasting 3 days. Then all paws begin to swell about on day 14 after immunization as a result of the immune response to the bacterial adjuvant, which is called the secondary inflammation stage. The secondary inflammation is the most sensitive parameter in exploring the pathogenesis and the potential pharmacotherapy for RA [26, 27]. Consistent to previous studies [26, 27], in order to avoid potential destructive severe inflammation of the adjuvant-injected paws, we measured the volume changes of the non-injected hind paws at the secondary inflammation stage. In this study, we successfully established AIA rat model by intradermal injection of CFA, evidenced by increased secondary hind paw swelling and aggravated severity of knee joint damage.
Articular chondrocytes are sensitive to extracellular environment changes. In response to ionic and osmotic stress, articular chondrocytes modify the cell shape and cellular organization, which is mediated by cytoskeletal reorganization and cytoplasm membrane transport mechanisms [28]. This biological regulation is essential for ECM homeostasis maintenance and metabolic activity [29]. As we know, AQPs are expressed in a variety of water transporting epithelia and many other tissues where they facilitate water transport across the cell membrane. Since 70% of the total tissue weight in cartilage ECM is water [30], water transport in cartilage ECM and the metabolic water across the membranes of chondrocytes may be important in both normal and pathological conditions of cartilage. Interestingly, previous studies revealed underlying involvement of AQPs (mainly focusing on AQP1 and 3) in cartilage destruction of RA and OA [13–16]. Herein, the present study firstly, to our knowledge, indicated the potential pathologic role of AQP4 over-expression in RA development, as modeled by AIA. The results of immunohistochemistry and western blot indicated that AQP4 protein level was significantly higher in cartilage tissues from AIA rats than normal rats. Particularly, correlation analysis results indicated that the AQP4 protein levels in cartilage tissues from AIA rats correlated positively with the severity of AIA, as determined by secondary hind paw swelling and total pathological scores on knee joint damage. In addition, we isolated and prepared articular chondrocytes from knee joints of rats, as identified by the cell morphology and positively stain of glycosaminoglycan. Consistent with our findings in vivo, AQP4 protein level were significantly elevated in cultured AIA chondrocytes compared with normal chondrocytes. These abovementioned results suggested that AQP4 was over-activated in articular chondrocytes both in vivo and in vitro, and might be closely related to the disease severity and progress of rats AIA.
Recently, acetazolamide is shown to be a potent inhibitor of AQPs and has been extensively applied in many vivo studies, with no obvious adverse effects or serious toxicity [31, 32]. Many studies have revealed that acetazolamide could inhibit AQPs-mediated water permeability in various cell types at the concentrations ranging from 1 μM to 100 μM [20, 21, 33]. Gao J et al. found that acetazolamide (10 and 100 μM) significantly reduced water osmotic permeability in HEK293 cells transfected with pEGFP/AQP1 [20]. Yue Y et al. reported that acetazolamide (100 μM) significantly inhibited AQP1 expression in cultured fibroblast-like synoviocytes of rheumatoid arthritis [33]. Tanimura et al. showed that acetazolamide reversibly suppressed water conduction by AQP4 in a dose-dependent manner and suggested that acetazolamide might be served as a lead compound for the development of AQP4-specific inhibitors [34]. Therefore, acetazolamide was acted as a suitable AQPs inhibitor in the current study. Consistently, we used the concentrations of acetazolamide (25 and 100 μM) in vitro exprements. We found that acetazolamide (100 μM) treatment effectively inhibited the elevated AQP4 protein level in cultured AIA articular chondrocytes.
In arthritis development such as RA and OA, articular chondrocytes damage breaks the balance between biosynthesis and degradation of cartilage ECM and finally causes progressive cartilage damage. Articular cartilage homeostasis is the result of a complex interaction between anabolic and catabolic, anti- and pro-apoptotic, anti- and pro-inflammatory activities. Interestingly, articular chondrocytes death mediated by excessive apoptosis in cartilage has been reported in RA [35, 36] and is considered to be an important and independent factor contributing to RA cartilage degradation [37]. During apoptosis, one of the earliest morphological changes is cell shrinkage known as the apoptotic volume decrease (AVD) [38]. Many studies have suggested that water loss from apoptotic cells during the AVD is primarily mediated by AQPs channels [39, 40]. In particular, inhibition of AQPs-dependent water movement can inhibit the AVD and the subsequent apoptotic events, whereas AQPs over-expression can increase the plasma membrane water permeability and the rate of apoptosis [40]. In this study, cell proliferation of cultured AIA chondrocytes was obviously decreased compared with normal chondrocytes, while acetazolamide treatment effectively increased the cell proliferation of AIA articular chondrocytes. Further studies should be performed to clarify whether the pro-proliferative effect of acetazolamide on AIA chondrocytes is mediated by inhibiting cell apoptosis. It is well known that proteoglycans loss throughout ECM and disturbed collagen fibrils are typical pathologic features of cartilage degradation in RA. COII is the major structural collagen in cartilage and aggrecan forms a major structural component of cartilage together with COII. Herein, we found that acetazolamide treatment reversed the reduced mRNA levels of COII and aggrecan in cultured AIA chondrocytes, suggesting that inhibition of AQP4 by acetazolamide might directly promote ECM production of AIA chondrocytes in vitro.
Taken together, the current study revealed that AQP4 was overactivated in articular chondrocytes of AIA rats and the elevated AQP4 protein levels in cartilage correlated positively with the severity of AIA. Acetazolamide treatment normalized the dysfunction of AIA chondrocyte in vitro, as indicated by decreasing AQP4 protein level, inducing cell proliferation and increasing mRNA levels of COII and aggrecan. For the first time these findings indicate that AQP4 over-expression might be closely involved in the pathogenesis of RA. Further investigations are needed to observe the therapeutical effect of acetazolamide on AIA and its related molecular mechanisms.
Adjuvant-induced arthritis
Aquaporin 4
Apoptotic volume decrease
Complete Freund's adjuvant
Type-II collagen
Extracellular matrix
Fetal calf serum
Hematoxylin and eosin
Rheumatoid arthritis
Standard error of the mean
Not applicable.
This study was supported by National Natural Science Foundation of China (81102273, 81201052, and 81373421), Program for Outstanding Young Talents of Higher Education Institution of Anhui Province (gxyqZD2016045) and Program for the Young and Middle-aged Academic Technology Leaders of Anhui Medical University (201309).
Availability of data and materials
Please contact author for data requests.
Authors' contributions
RL designed the experiments and participated in the writing of the manuscript. CL and WCperformed animal model experiments and immunohistochemistry analyses. LC and XC performed the in vitro study and the gene expression experiments, and wrote parts of the manuscript. CH and CL managed the literature searches and the statistical analyses. All authors have read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not applicable.
Ethics approval and consent to participate
The study and all experimental protocols were approved by the Ethic Committee and the Animal Experimental Committee of Anhui Medical University, which complies with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH publication No. 85–23, revised 1985).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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