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Making a difference: progressive values in public administration
M.E. Sharpe, Jun 30, 2008 - Political Science - 137 pages
This inspirational work encourages Public Administration professionals to participate in progressive social change by advocating progressive values to counter the regressive values currently dominant in American society. The book begins with an analysis of regressive and progressive societal values, and then discusses specific actions PA practitioners, scholars, and teachers can take to build awareness and use of progressive values. The author presents regressive and progressive values in five matched pairs, each representing a continuum of thought and action: aggressiveness and cooperation; belief and knowledge; economics as end, and economics as means; great inequality and limited inequality; and Earth as resource, and Earth as home.
From inside the book
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The Case for Progressive Values
Describing the Value Pairs
Practice and Change
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Limited preview - 2009
Making a Difference: Progressive Values in Public Administration
Richard C. Box
Limited preview - 2008
Common terms and phrases
acceptable advance progressive values aggressiveness alternatives American areas belief career public complex concept conditions in society contemporary continuum created critical social theory critical theory culture current conditions decades decision democracy described discourse discussion Dwight Waldo economic rationality effects elected officials elites environmental example forest Gary Wamsley global goals governmental Herbert Marcuse human behavior idea imagination implementation important individual influence issues knowledge Marcuse McSwite means military narrative neoliberalism neopragmatism normative thought organizations Paul Krugman perspective policy process political potential practice practitioners and academicians preferences problem programs public action public administration public affairs public interest public policy public professionals public sector public service practitioners reality regressive and progressive regressive thought relationship Richard Rorty role Rorty social change social inequality societal conditions status quo structures things tion urban violence Wright Mills writing


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Chris Evans Gossip
Chris Evans gossip, latest news, photos, and video.
Cap vs. The KKK: Round 2
Wenn, PG/ Splash News
Last week the human embodiment of spoiled milk, David Duke, attempted to take down Chris Evans on Twitter and got his ass electrically handed to him because Evans is a decent guy and David Duke just a pile of talking garbage. Well, they're back at it. Full Story
Captain America tweet-punches the KKK
It's one of the most famous images from comic book history: Captain America punching Hitler in the face. It's the cover of Captain America No. 1, and a moment that got referenced in Captain America: The First Avenger. Full Story
Scarlett & Chris?
I received an email today from a longtime reader called Tenika who had this question: Scarlett is single now and so is Evans....... What do we think? They certainly had great chemistry in Winter Soldier. And she's never been single since they started working together as Avengers. So. Full Story
Chris Evans & Jenny Slate: They Did Break Up
FameFlynet, Don Arnold/ Getty Images
Or, In Which Sarah Is A Terrible Detective. Yesterday we went on a journey of discovery, trying to determine through social media posts and other dubious "evidence" whether or not Chris Evans Full Story
The State of Chris Evans & Jenny Slate
Wenn, FameFlynet
Or, In Which Sarah Goes Social Media Sleuthing To Try And Determine Whether Or Not A Celebrity Couple Is Still Together. Let's go on this journey together. The Evidence For Chris Evans And Jenny Slate Full Story
Chris Evans and Jenny Slate barely look at each other
Timothy Norris/ Getty Images
Chris Evans and Jenny Slate met while filming a movie called Gifted last year. Then, in the early summer, Slate was getting divorced and hooking up with Evans, in a bit of timing that would have drawn a lot more side-eye if Evans was the one bailing on a marriage. Full Story
Push-ups with dogs
More and more celebrities are calling on each other to do the #22pushupchallenge, raising awareness for the 22 veterans a day who die by suicide. Please note those words, "die by suicide". They're deliberate, as I've learned through the Bell Let's Talk Campaign Full Story
The Chris Evans Wheel of Fortune
It's time once again to play everyone's favorite game—Chris Evans Wheel of Fortune! With a spin of the wheel we'll determine if Chris Evans' next movie will be another Snowpiercer, or will it be a chance to make another godawful movie like Playing It Cool Full Story
Dear Gossips,
Stucky. This is the portmanteau that fans have come up with for Captain America Steve Rogers and his best friend Bucky Barnes, the Winter Soldier, played by Chris Evans and Sebastian Stan respectively. Stucky shippers want Steve and Bucky to get romantic. Read Full Intro
Jenny Slate and Chris Evans can Swoki too
On a regular weekend, this would have been top gossip news. But Beyoncé. And Kanye. And Swoki. Which is why about an hour ago I was like, oh yeah, Jenny Slate and Chris Evans Full Story
Jenny Slate, Chris Evans…and Anna Faris?
Did you ever listen to that episode of Anna Faris's Unqualified podcast featuring Chris Evans, Jenny Slate Full Story

subset: commoncrawl


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Fashion is an everlasting topic since the day we began to pay attention to how we dressed. If you are looking for fashion, this is the right place to come. You can find the right cable knit cardigan sweaters here from Fashionmia's latest and hottest collection of cable knit cardigan sweaters. We provide customers fashion items like cable knit cardigan sweaters with totally affordable price and high quality. Come discover the cable knit cardigan sweaters you need from our suggestion and guide to save time in choosing the most suitable cable knit cardigan sweaters. Have fun shopping online at Fashionmia.
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BikingBis.com / September 27, 2010
Never too old to ride a bicycle
By Gene Bisbee
The Register's Annual Great Bicycle Ride Across Iowa (RAGBRAI) recently published its online survey of 5,900 cyclists from the summer of 2010.
The average age was 44.6 years old; 7% of the RAGBRAI cyclists were 65 or older, left.
When I left on my coast-to-coast bicycle travels many years ago, I feared I might be too old. I was 34. It seems laughable now, but bicycling seemed like such a youthful pursuit at the time that I thought I'd be one of the oldest folks on the road.
Although we ran into quite a few recent college graduates, I wasn't the oldest cyclist by any means. In fact, many of the touring bicyclists we met were in their late 30s or 40s. I even recall meeting up with two retired couples.
Adventure Cycling Association hosts numerous cross-country bicycle rides every year. The average age of the group's members is the mid-40s, with a spread of ages from the 20s to the 70s and occasionally the 80s.
Although the Outdoor Industry Foundation reports that 27% of the bike riders in the US are 45 or older, David Harrenstein of The National Bicycle Tour Directors Association told the Memphis Commercial Appeal that the average age of participants in long-distance bike rides is about 50.
Many examples
I'm always running into examples of older folks who are staying healthy by riding bicycles.
Al Emma, who at age 62 began a quest to ride organized centuries in all 50 states. He started in 2002 and finished in 2009. This year, at age 70, he completed riding a century in all of Canada's provinces.
I thought I was a hot shot by riding 60 miles on my 60th birthday last January; that's until June when I met up with Bill Glaeser, who was riding a 70-mile loop around Lake Washington on his 70th birthday.
At this year's Seattle to Portland Bicycle Classic (the Cascade Bicycle Club's 200-mile bike ride from Seattle to Portland in 1 or 2 days) the oldest cyclist was 87 years old.
Then there's Heinz Stucke, the German who left home at 20 on his bicycle and has been traveling by bike ever since. Now 70, he's been traveling in the Americas the past few year. His story was published about 10 years ago at Bike China Adventures and there's an interview with him at Travelling Two.
There's probably no age limit to bicycle travel, as long as the person is healthy and can maintain a good sense of humor under occasional adverse circumstances (mechanical, bad weather, getting lost, etc.). I'm glad I fell into cycling at such a young age and have been able to keep at it over the years.
Seniors World Chronicle adds
Interested in active bicycling ? You would do yourself a good turn by logging on to BikingBis.com


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Full Stack Web Developer - London
- Employer
- Paramount Recruitment
- Location
- London, England
- Salary
- Negotiable
- Posted
- Jan 25, 2017
- Closes
- Feb 22, 2017
- Ref
- Contact
- Harvey Uppal
- Discipline
- Engineering, Software Engineering, Life Sciences, Genetics & Genomics, Maths & IT, Computer Science, Information Technology
- Result Type
- Jobs
- Position Type
- Permanent
- Hours
- Full Time
Full Stack Web Developer - London
Salary: Up to £45k
A very interesting opportunity has opened up for a Full Stack Web Developer to join a digital healthcare advertising agency, working with some of the biggest names in the Pharmaceutical industry. Your duties will vary depending on the client's requirements, this may be developing and maintaining websites, healthcare applications or e-digital aids.
*You will work with the digital designers in order to understand the design concept, and advise on how this can be best implemented
*You will be required to write effective code/script in order to make various features work, ensuring all features function as intended.
*Exploring new and emerging technologies and making these known to the Digital Development Manager, where appropriate
*Providing accurate timing estimates on work
*Ensuring that all steps of the project are recorded/documented
*Working with the design team and client services and managing time across multiple projects within a deadline-driven team environment
*Promote the team's capabilities in order to win new business
*Liaise with clients, where necessary, for clarity and to troubleshoot technical issues
*Support the team to identify optimal technical solutions
*Minimum of 3 years' commercial experience building and maintaining websites
*Ability to develop clean, semantic code
*Proficient with C#, ASP.Net, MVC, HTML5, CSS3, JavaScript/JQuery
*Solid knowledge of Microsoft SQL Server 2008
*Ability to manage websites using IIS 7
*Good Photoshop skills with the ability to extract images and text
*Version Control Systems experience (SVN, TortoiseSVN)
*Some experience with PHP/LAMP
*Exposure to N2CMS is desirable
You must be eligible to work in the UK to apply for this position, sponsorship cannot be offered
Please do not hesitate to contact Harvey Uppal at email@example.com or call (+44) 121 616 3407 to discuss this opportunity further.
Keywords: Full Stack, Web, Developer, ASP.Net, MVC, C#, JavaScript, HTML, CSS, JQuery, SQL, SVN, Tortoise, PHP, LAMP, IIS7, N2CMS
Paramount Recruitment Limited provides services as an agency and an employment business. We regularly have similar roles in this area. Please see our website for details or send your CV in to us to find out the latest opportunities.


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She said it appeared Corbyn was also too anti-business and lacked understanding on the economy.
"At one PLP meeting Jeremy started talking about how vulnerable people 'were being forced to borrow money from hedge funds'. Angela Eagle and I caught each other's eye. Did he really not know the difference between loan sharks and hedge funds?" she said.
"And, again at PLP, Emma Reynolds asked Jeremy if he 'supported big businesses like Jaguar Land Rover who employ thousands of people in my constituency'. His answer was 'of course I'm aware that big businesses exist and I'm also aware that many of them don't pay their taxes'. He simply couldn't bring himself to express support."
Despite her criticisms, Corbyn said she had accepted a job in the shadow cabinet "because I thought it was important to honour Jeremy's mandate, and to try to make things work".
"Although I hadn't supported Jeremy in the 2015 leadership contest, I was as frustrated as many other members were with the excessive caution and timidity at the heart of Labour. It felt like the chains had been shaken off, and there would be space to be a bit more radical, a bit more ambitious with our environmental policy," she said.
A YouGov poll for The Times published yesterday suggested Corbyn is on track to easily win the Labour leadership contest against his rival, Owen Smith.
Article source: http://www.huffingtonpost.co.uk/2016/09/01/jeremy-corbyn-attacked-for-ignoring-shadow-cabinet-misunderstanding-brexit-and-baffling-voters-by-kerry-mccarthy_n_11812488.html?utm_hp_ref=uk-politics&ir=UK+Politics


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"Miradouro da Graça (Belvedere of Graça)" More Miradouros - Viewpoints Tip by ncfg
More Miradouros - Viewpoints, Lisbon: 67 reviews and 134 photos
On this view point we have panoramic and amazing views over the rooftops of the Mouraria and Baixa quarters to St. George's Castle and the ruins of the Carmo Convent.
> Transport: Tram 28.
>Opening hours: Daily 24 hours.
>Admission: Free.
Address: Largo da Graça
Directions: Located throughout the city.
Website: http://www.visitlisboa.com/Conteudos/Miradouros-Virtuais.aspx
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Really good sauces average service. Dishes are served per person not family style. Clean and quiet great for family.
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Really good sauces average service. Dishes are served per person not family style. Clean and quiet great for family.
Great food for the money. I had delivery for 2 entrees rice and a side and it was $22 after tip! Anywho food was good docked a star because it took 55 minutes but they told me that up front so not disappointed just was a little hangry
The food here is generally good, and there are a lot of different choices on the menu. The Thai Hot & Spicy Soup is my favorite - very simple with large shrimp, chunks of onion, and a stock made with lemongrass that is fantastic! The service, on the other hand, is less exciting. In all the times I've been there,... 更多
King Wah is a great little Asian restaurant in the area. The atmosphere is quite and quaint, and the food is really good; especially for the $ you pay. Great prices, and really good food. We used it a lot as a take-out restaurant when we lived just up the street :)
Been here several times because it's close. Food is edible until......there is a ROCK in it! Are you kidding me? How does a rock the size of an air soft pellet get into our noodle bowl? Our guess is it dropped on the floor. We will not be giving them our business anymore! Very disappointed when we told them we... 更多
The food is very good, always fresh and hot the service is good the atmosphere is so so. and I would order ahead for take out because they don't cook it until you order so it will be a little wait. but the food is worth it
Tried to give them benefit of the doubt and second chances but each time the staff really seems to not care.....dining in, no one greets you they just seat you, take your order and bring your check, no personal interaction, not even a smile! Next time ordered delivery, told them we had a coupon, which they did not apply, food... 更多
Yes mice. My husband and I stopped in to grab a quick dinner. We were served our drinks and put in our food order. While we were waiting for our food a mouse ran right out of the kitchen into the dinning area. I was so disgusted I just left. Do Not Eat Here, I wouldn't even order take out.
Stopped in for dinner late. Service could have been a bit more attentive. Had the crispy Duck. I guess parts... 更多
I do not really like chinese food...but I eat here and am satisfied. THe sesame chicken is actually pretty descent.... 更多
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Imran Digest September 2016
Read online or download free PDF monthly Imran Digest is one of most famous ladies magazine in Pakistan, men and women both are very fond of Imran Digest.
This digest contains vast collection of Urdu Novels, Romantic Urdu Novels, Urdu Stories, beauty tips, articles and much more, many Urdu Novels of Imran digest are published in printed book format which are available in local book markets, current issue of Imran magazine is, Imran Digest September 2016.
Read online link is available for online reading, you can also download Imran Digest September 2016 in PDF Format using below links. Your feedback and comments will help us to improve our Urdu Books collection.


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America and Eurasia Will Unite Into 1 Continent "Amasia"
If you are visiting our site from iPhone or iPad...Download our awesome iOS app from Apple App Store while it's free. It's free for a limited time only.
We may all soon live on one continent. That's if 50-200 million years is soon.
Perhaps the people who say that "only historians and idiots repeat each other" are wrong. Turns out that, after all, history does repeat itself, as BBC News has recently reported that "America and Eurasia will crash into each other over the north pole in 50-200 million years time. They also predict that Africa and Australia will join the new 'supercontinent' too."
Sell all your airline stock. 50-200 millions years are coming on fast. No kidding here. Google will soon come up with a life extension. Though "its goal is to extend human life by 20 to 100 years", you could extend it even further, in the next few million years, when penguins will have conquered all the world.
My fascination with Google and its life extension program aside, the prediction about this "supercontinent" was made by folks at Yale University. So you have to take it with a grain of salt: they have educated the dumbest president ever.
However, the given prediction seems plausible considering the other scientists' reactions to it. They just said: "Well, dude, this is Yale. They must be right or we'll be damned."
So don't forget to sell all of your airline stock, or your great-great-great….grandchildren may end up going bankrupt, if you haven't already donated their inheritance to some Vegas casino.
Let us know what you think about this. Leave a funny comment or die making it funny.
via BBC News – America and Eurasia 'to meet at north pole'.
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Roman Marshanski
He loves film, comedy, innovation, Web Development, and pretty girls.
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India Gate
Thar Desert
Shopping in Delhi
¤ Salim Singh ki Haveli
Salim Singh ki Haveli: The haveli or mansion was initially occupied
by the influential Mehta family of Jaisalmer. It was built around
1815, possibly on the remains of an earlier building of the late 17th
century. The building was commissioned by the then Prime Minister of
Jaisalmer, Salim Singh, a man with a reputation for Machiavellian
cunning. His father Diwan Swaroop Singh, also Prime Minister of
Jaisalmer in his time, was murdered as a result of a palace intrigue
when the young Salim was a mere dozen years old. Salim took it upon
himself to avenge his fathers death. As soon as he came of age,
Salim eliminated all of Jaisalmers courtiers, princes and
hangers-on with such dexterity that he was appointed premier by
Maharawal Mool Raj.
built his eight storeyed pleasure palace and lived in it with his
seven wives and two concubines. It is a magnificent monument with
every structure carved with elaborate detailing. He demanded the best
and got it; anything that did not please him was summarily rejected.
The mansion boasts of 38 balconies, each with a different design. As
you enter you are confronted by an imposing stone elephant, while the
upper storeys of the building jut out proudly like a ships prow,
which is why the haveli is also called the Jahazmahal or Ships
Palace. The monument as a whole has the appearance of a great ocean
liner, with a narrow base which widens at the top. It has a
beautifully arched roof, topped with blue cupolas, and brackets in the
form of peacocks.
As Salim Singhs power grew so did his ambition, and he reckoned
it was time he usurped the power of the maharwals themselves. He came
up with a scheme to knock off the top two floors of the haveli and
build a gateway from his house right upto the maharawals palace,
but this proposal was nipped in the bud by the monarch himself. This
incident marked an about-turn in his political fortunes for soon he
was killed in one of the numerous court conspiracies he himself had
encouraged for long. The Salim Singh saga was a classic illustration
of the old maxim that ultimately the schemer always falls into
the pit which he digs for another.
¤ Nathmal's Haveli
The haveli (mansion) was built circa 1885 for Diwan Mohata Nathmal,
then Prime Minister of Jaisalmer. Designed by two Muslim brothers
Hathi and Lulu, the haveli was ordered for Nathmal by the then
maharawal Beri Sal. The sibling-architects worked in an unusual
manner; each carved out one-half of the building developed according
to the same plan. However, when the building was completed, the two
sides turned out to be very dissimilar to each other though the haveli
remains unsurpassed in Jaisalmer in terms of the quality of the work.
Like the Salim Singhs haveli (mentioned above), the entrance to
Nathmals haveli is zealously guarded by stone elephants; and the
entire façade is embellished with a slew of detailing
horses, elephants, soldiers, flowers and birds. There are also
carvings of trains and bicycles, gadgets of the then new age which the
artisans themselves had never seen but carved out of hearsay
¤ The imposing Interiors of Haveli
Another extraordinary part about its construction is that the main
chamber is carved out of rock and the entire frontage of the first
floor is carved out of one solitary boulder. The interiors of the
havelis are decorated by beautiful miniatures. The workmanship of
Jaisalmers havelis is an amalgam of both Rajput architecture as
well as Islamic art that was imported via the traders caravan
through the desert
¤ Patwon-ki-Haveli
The five Patwa havelis were the first ones to crop up in Jaisalmer
and are known locally as the Patwon-ki-haveli. The first was
constructed circa 1805 by a merchant called Guman Chand Patwa and is
the biggest and the most ostentatious. Patwa was a man of considerable
means, and for his five sons he built the elaborate five-storeyed
complex which reportedly took 50 years to finish. All five houses were
constructed in the first 60 years of the 19th century. The havelis are
also known as the mansion of brocade merchants as the
family ostensibly dealt in threads of gold and silver used in
embroidering dresses. However, they reportedly made their fortune
elsewhere; through opium trade and by moneylending.
¤ The Decor of Patwa Haveli
The unsung heroes as far as the Patwa mansions are concerned are the
unnamed stone carvers who wielded the chisel with as much skill as a
surgeon handles a scalpel. Every square inch of space has been carved
exquisitely, with jali (latticed) friezes providing ventilation to the
interiors as well as offering privacy to the women to look out without
exposing themselves to Peeping Toms. The havelis are built in yellow
sandstone with a different design on every window and arch. As you
enter the haveli through its magnificent arched gateway, you come
across its delicately carved yellow-brown frontage with as many as 60
balconies overlooking it. Another prominent haveli of Jaisalmer is the
Nokhatmal haveli, which unlike the other mansions is a fairly recent
addition to the city having been constructed only a few years ago.


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Going Green Translations
Parole chiave:
Marketing, Traduzioni Tecniche, Consulenza Linguistica
Going Green Translations is the number one language service provider in Teramo,Abruzzo for all your translation requirements. We have a long and vast range of experience in working with companies both in Italy and abroad to manage all language services regarding your documentation and presentation to the world as a whole.Make sure you are not left behind in the global market place and contact us for all your requirements regarding your international presence.
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If you are in the UK or EU, VAT will be added at checkout.
Included in the price:
- Full ownership of the .com domain
- One of the 3 logo designs shown here (digital files supplied)
A concise business name that exudes authority
This is the type of business name that is so suggestive of positive attributes - this is probably down to two characteristics. First, it has a crisp, business-like construction that's easy to spell and sounds substantial. Second, it starts with a powerful word element, 'Adv-' that could suggest advantage, advancing, advertising or advocating (supporting or defending). It's rare that such powerful attributes are contained in such a concise name.
How does the domain transfer work?
Are Novanym names trademarked?
KEYWORDS | A | advocate | advise | advocates | law | legal | attorney | solicitor | lawyer | marketing | social | media | sales | recommend | recommendation | advertising | advance | advantage | consultant | consultancy | advice | advise | advisor | adviser |


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Thousands of large and small companies have websites, but most of those websites are merely brochure sites that introduce the company, its services and perhaps its management. However, the applications available to today's web designers are so versatile and functional that it makes running a business totally from the web more viable than ever before.
Running a Website Business
Maintain a good working relationship with your web-design company or individual professional. You'll want to appoint this individual as your webmaster, responsible for ensuring all systems on the website are operational.
Work with a web marketing company to ensure your company's website can be found through search. Most people navigate their way through the millions of websites out there by first searching on a major search engine like Google, Bing or Yahoo! A web business must do the prerequisite organic marketing of the business website, which is the development of meta-tag information including title, content description and keywords. This information doesn't appear on the visible page but is the first bit of information a search engine looks for when it is ranking websites to display in search results. This is the first rung of the web-marketing ladder.
Consider the options available to promote your web business using paid search ads available on all the major search engines. Google is the master at paid search with its AdWords program, where you can set a spend budget and Google will run your text ad on websites with themes appropriate to your business. You can also monetize your site with Google's AdSense Program and be paid by Google for ads that run and are clicked on by visitors to your site. You'll want to consider whether your website should be monetized. Not all business sites should be used for advertising, especially if it is a corporate business website whose traffic is professional rather than public.
Align your e-commerce website with the numerous companies that exist to facilitate accepting credit cards either through PayPal, LinkPoint, Authorize.net or even the credit card companies themselves. Accepting credit cards is mandatory if you will be selling goods online. You'll also want to ensure transacations on your website by having an encrypted Secure Socket Layer (SSL) on your website. Visitors will know that they can safely use their credit card on your website when they see https in your website's URL..
Related Searches
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Ratings based on 32 Verified Reviews
4.2 Room cleanliness
3.8 Service & staff
4.2 Room comfort
3.8 Hotel condition
Expedia Verified Reviews
by A verified traveler from US
False advertisingPosted Nov 11, 2016
Pros: nice ocean view
Cons: an honest presentation of the property
The Spa, restaurant , and bar are closed and have been for some time. The advertising for this property is false. There is no phone in the room !! you have to use your cell phone to call the front desk. Finally there were cockroaches in the kitchenette ! I think this should be taken off the expedia list.
by Benigno from Santo domingo
Excellent stayPosted May 3, 2016 on Hotels
Great hotel to relax
by GRACIE from Brownsville
heavenPosted Feb 23, 2016 on Hotels
Beautiful ocean view
by Juvenal
Posted Jul 9, 2015 on Hotels
by Alan D from Falmouth, ME
A Truly Unfortunate StayPosted Feb 16, 2015 on Hotels
My recent one night stay was a comedy of errors. At first blush, a lovely resort in a beautiful part of Punta Cana. All that follows actually happened: when I checked in I was informed that the restaurant was not open and I would need to take a taxi to a different hotel for any food (even for a cup of coffee in the morning). And trust me when I say this part of Cap Cana is pretty deserted. Once in my room, the toilet wasn't working,and I went to call for repair but the phone had no connecting cord so I had to walk the hundred yards back to the desk to report it. The repairman told me that he couldn't fix it until the morning (he never came prior to my checking out). I tried in vain to change rooms, apparently none available. To add insult to injury, I had no hot water for a shower in the morning, not even warm. Also no internet in the rooms. Lastly, when leaving my second floor room in a heavy rain, a guest walked out of his first floor room to summon the bellman because he had an inch of water flooding the floors throughout his room. I did inform the very nice concierge, who politely offered only that he hopes my next stay will be better. There won't be one; I have never had a worse hotel experience.
for Everyoneby Ruslan from Moscow, Russia
OkPosted Mar 29, 2013
Pros: It is all new and modern.
Cons: It is far from civilization.
Location: Cap Cana needs at least 15 years more to become a resort area.
The Hotel is nice, but Cap Cana area has no life, everything is far, the project seems to be dead. This hotel is ok only if you like to play golf, otherwise you should look for other option. The property is new, rooms are nice and big.
by Kate
Posted Feb 19, 2013 on Hotels
excellent and clean rooms
for Everyoneby A verified traveler
amazingPosted Jun 27, 2012
Pros: We had an entire apartment with three bathrooms, three porches, and an outside personal jucuzzi.
Cons: The restaurant was expensive.
Location: Perfect and more
This place was beautiful and far beyond what we expected. Super good deal. Not so much for the partying kind but more so for one seeking peace and quite.
for Everyoneby Crystal from Maryland
Golden Bear LodgePosted May 28, 2012
Pros: The services of the staff was excellent.
Cons: The menu selection of the restaurant is limited and average. This type of hotel should have a more experience chef.
Location: The hotel is located in a private, secluded and intimate area; this was what we were looking for in a vacation...peace and quite.
The Golden Bear Lodge in Cap Cana is a wonderful & comfortable hotel. The location of the hotel is away from the popular & loud hotel zone; Cap Cana is located south of the airport. If you are looking for peace & quite, this is the place to go. Cap Cana is a private area. Golden Bear is not on the beach; golf resort. You will take the hotel shuttle to get to Juanillo Beach (5 minutes) which is beautiful and relaxing. You will need to take a shuttle to get to the marina and the other hotels and restaurants within the complex.
for Everyoneby Ricky from Puerto Rico
Nice property but not for every one.Posted Feb 29, 2012
The Golden Bear Lodge is a nice hotel for a long or short stay. A little quiet for those looking for night life. The facilities are well kept and the employees are very professional. The only two things that need improvement are the bathrooms. The shower drainage is pretty much clogged. I have seen that in different rooms at the hotel ( have stayed at the GBL three times already), therefore I am positive that all rooms have the same problem. Breakfast is good but they do not keep up with the food. I was told that the kitchen is subcontracted to another company. Besides that the Golden Bear is a nice property.


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Xmas Live Wallpaper Free
Xmas Live Wallpaper Free - great live wallpaper for Android, filled with the spirit of Christmas. Only on your mobile device all the Christmas paraphernalia holiday! Here the protagonist - Santa Claus, cute teddy bear, an elf and a kitten, christmas beauty - tree, white, fluffy snow, fireworks, a word full set for the New Year. Clicking on the bells, you can enjoy the sounds of celebration. With the holidays you!
So you need to install:
You must go to the main screen - press the menu button - select "Wallpaper" - select "Live Wallpapers» - «Xmas Live Wallpaper Free» - wait until you see the screen with a preview - click «Set wallpaper».
attention! all files hosted with permission of the authors or applications found in the public domain in the internet, if some of the files violates your rights, please let us know


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Wholesale HUD Head Up Display Universal brands
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Wholesale Businesses For Sale in South Portland Gardens ME
Searched the DealStream database for Wholesale Businesses For Sale in South Portland Gardens ME and found no matches. Expanded the search to nearby areas and found the following matches.
Martin's Bread Route, Rochester #460176 posted Dec 30, 2016
- Rochester, New Hampshire, United States
- $30,000
Martin's Bread Route for sale $30,000. Company financing available with $12,000 down! Currently grossing an estimated $187,311 per year and nets an estimated $33,114! Martin's Bread currently distributes its well-known brand of potato bread and rolls to popular grocery stores and retail outlets. This...
Fruit & Produce Wholesaler and Distributor #459290 posted Dec 9, 2016
- Boston, Massachusetts, United States
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3656 Mount Vernon Dr,East Point GA, 30344
4 beds , 3 Full baths
1,593 sq. ft
Status: Active
Berkshire Hathaway HomeServices Georgia Properties
(770) 355-5995
Last Updated: 2/27/2017 12:11 AM
Description for 3656 Mount Vernon Dr East Point, GA 30344
Desirable Area close to all the major Interstates, Airport, Campcreek Market Place - shopping & entertainment ...Great opportunity for savvy buyer. This home is spacious, it features Formal Living & Dinning Rm, Family Rm, Rec Rm down, 5th bedrm down, 3 full baths, Screened Porch. It's Situated in cul de sac of a quiet established neighborhood where people take pride in their homes. Lots of storage space. Do some Needed TLC and Upgrades... make this your fabulous home. Hurry Won't last long! Bring your offers.
Listing Information
Granite Valley Estates
Gas Water Heater, Public Water Service
Public Sewer
Extra Insulation, Underground
School Information
Room Information
Recreation Room, Library, Media
Living/Dining Combo, Breakfast Area
Hookups in Laundry Room
Breakfast Area, Breakfast Bar
Dual Sinks, Separate Tub & Shower
Interior Features
Dishwasher, Garbage Disposal, Refrigerator
Carpet Wall to Wall
Central Air, Attic Ventilator
Gas Heat, Electric Heating
Bath/Lav in Basement, Finished, Full
No Fireplace
Foyer, Walk-in Closets
Exterior / Lot Features
2 Car Garage, Drive Under/Built-In
52X146X117X93X154, 3/4 Up To 1 Acre
Garden, Street Lights, Walk to Shopping, Cul-De-Sac, Paved Road, Sloped, Wooded
Financial Considerations
Inside AccessTM
Current market conditions for 3656 Mount Vernon Dr
Active Market Trends
Source:MLS DATA
Median list price$117,000
Days on market108
Properties for sale129
Sold Market Trends
Source:MLS DATA
Median sold price$114,950
Sales to list price9,544.0%
Properties sold96
Median sq ft price$71
Arrows indicate 90 day trend
Listing Price History for 3656 Mount Vernon Dr
East Point Real Estate
East Point is located in Georgia. East Point, Georgia 30344 has a population of 34,515.
The median household income in East Point, Georgia 30344 is $39,023. The median household income for the surrounding county is $57,664 compared to the national median of $53,046. The median age of people living in East Point 30344 is 34.9 years.
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Not so much about food but anyone going to NO on St. Pat's day, Jim Monaghan's parade through the district is a bunch of fun. Try to be at Molly's on the Market on Decatur when the parade ends (parade starts and ends there). It's a hoot! Sorry Leff, but just had to mention this non-food thing being the Detroit Irish hooligan that I am.
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Free Reading Bear Clip Art
This cute and free set of reading bear clip art contains 8 image files, which includes 4 color png images and 4 black & white png images. All images are 300dpi for better scaling and printing.
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Written by Chris Brown (@leftybrown) on September 30, 2012 in Married Gamers Podcast
[2k games, borderlands 2, Married Gamers, Open Forum Radio, Section Zcast]
Comments Off on TMG-273 The Music Men and Lady
The Married Gamers are joined this week by Zabari from Section Zcast and Matthew from Open Forum Radio to talk about music. All this plus The Week in Geek and Spin the Wheel. Be a Hero and Save Kids Lives. Join Team Married Gamers for Extra Life 2012 on October 20th. To join or donate,… Read More »


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Docker - the open-source application container engine
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Murdoch University is set to sign a deal with the Western Australian Cricket Association to provide alternate practice facilities for its representative teams.
The five-year partnership, with an option for a further five, will see two ovals constructed on a greenfield site at the University, with turf wicket blocks consisting of four and three pitches, along with turf and hard practice wickets.
Cricket will be the major sport at Murdoch University, with the WACA to have priority access to the new facility for use by representative teams from the Retravision Warriors and Western Fury to Imparja Cup and State under-age squads.
New change rooms will be built to accommodate four teams, and it is hoped the ground could eventually be used for Futures League and other State representative fixtures.
Murdoch University will also explore a partnership opportunity with a WACA District or WA Suburban Turf Cricket Association club for use of the two new turf wicket blocks.
WACA Chief Executive Officer Graeme Wood says a number of parties were spoken to before the WACA Board elected to enter into agreement with Murdoch University.
"We are thrilled to be entering into partnership with Murdoch University for the development of such an excellent facility for use by our elite and under-age representative teams.
"Long term it is anticipated that the facility will be suitable to host second tier domestic or WACA District matches."
WACA Cricket Operations Manager Andrew Scotford said having access to an outstanding training and playing arena was a fantastic opportunity for the WACA and its representative teams.
"There is the chance for players and staff to work with a leading institution such as Murdoch and tap into the services they can provide, such as sports science and chiropractic, media, physical education, leadership and other professional development opportunities which will play a great part in ensuring our high performance program can compete with what other states currently offer."
Murdoch University Acting Vice Chancellor, Professor Gary Martin, said he was delighted with the partnership.
"The partnership with the WACA will assist us with our endeavours to provide high quality facilities for our students and we look forward to establishing male and female cricket clubs with University and community members," he said.
"There are many other opportunities that will stem from this partnership, including enhanced teaching spaces for our sport and exercise science and physical education courses, collaborative research opportunities and international collaborations with cricketing countries in the region."


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fuel pressure
adjustable pressure regulator is it a good idea or no i have a 89 f-150 and i have a a lot of induction on stock injectors so i was thinking of boosting the fuel pressure do u think iit is a good idea
7 Answers
what did you do sofar?
k&N air intake bbk twin 56mm throttle body eldelbrock perfromer intake upper and lower and a spacer inbetween the upper and lower intake
its like 1000 dollar top end its a race truck basically
bbk makes the reg
part of me says yes and part of me says no. if you know your shit and not wreck the engine then get it. if not then dont. this is fuel youre messing with.
i know how much psi should i run stock is 35-45 and the new one would go up to like 65 or 75 max
u havent even really touched the top end all u have is bolt ons ur biggest concerne should be mass air
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October 14th, 2015
Win double movie passes to see Burnt
Enter here for a chance to win double movie passes to an advanced screening of Burnt. It stars Bradley Cooper. It seems like every movie stars Bradley Cooper. Good Luck! Select cities only. Good Luck!
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Ludwig Atlas Classic Straight Cymbal Stand
Ludwig Atlas Classic Straight Cymbal Stand
Emerging from the masses of drum hardware and cymbal stands, the Ludwig Atlas Classic Cymbal Stand is an arena-ready, highly durable solution to cymbal mounting with a distinctly "Modern-Classic" twist. With a gearless, dual-axis Aerodyne Tilter to allow the positioning of cymbals at any angle, this stand allows a highly customizable setup with a solid base of Acculite Sustain Feet.
- Aerodyne Tilter
- Insulated tube joint clamps
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Product no. 9524
Kallo Corn Cakes 130g
You'll never find anything artificial in Kallo rice and corn cakes because good food should always come naturally. For over 20 years Kallo have been creating deliciously simple, wholegrain recipes from the finest natural ingredients. Great as a wholesome snack or a deliciously light meal that's full of flavour and guilt-free. No artificial colours, flavours or preservatives.
Try your local store
Full Details
Nutrition Per 100g: Energy : 1,605kJ 379kcal, Fat : 1.9g, of which saturates : 0.3g, Carbohydrate : 77.4g, of which sugars : 0.6g, Fibre : 7.2g, Protein : 9.5g, Salt : 0.3g, Contains an average 20 corn cakes: per corn cake: Energy : 104kJ 25kcal, Fat : 0.1g, of which saturates : trace, Carbohydrate : 5.0g, of which sugars : trace, Fibre : 0.5g, Protein : 0.6g, Salt : trace, Contains an average 20 corn cakes:
Allergy Advice: Free From Gluten. Free From Wheat. n/a. Suitable for Vegans. Suitable for Vegetarians. Suitable for Coeliacs.


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comScore has released data about iPhone users in the UK and compared to other mobile devices, the iPhone is certainly spurring on mobie search.
55% of iPhone users conduct searches on their devices, while just 32% of smartphone users and 12% of all mobile phone users search on their phones.
In fact, the iPhone beats smartphones and other mobile phones in every major category from email to mobile music to social networking:
The downside? The iPhone has yet to become mainstream in the UK.
"The iPhone is indeed an early adopter phenomenon in the United Kingdom," said Alistair Hill, analyst, comScore. "While the device's ease of use is certainly contributing to the lift we see in mobile media consumption, the fact that the device requires a subscription package that includes an unlimited data plan is also a contributing factor. However, it is also important to note that while nearly all iPhone owners are consuming mobile media, the device is in the hands of only two percent of mobile phone users in the UK."
Related Reading:
Has Mobile Local Search Finally Arrived?
Google Mobile Search for iPhone 2x Faster, on 3G and EDGE
AOL's Platform-A Launches iPhone Advertising Solution
AOL Adds SmartBox (aka Query Suggestions) to iPhone Mobile Search
Google Adds Voice Search to iPhone Search Application
Related reading
Why brands should care about brand safety in mobile advertising
Easily spotted on the mobile web: holiday ad next to plane crash story; Muslim dating ad next to KKK story; beauty ad next to domestic violence story; car ad next to emissions scandal story.
Mobile Reader Survey: Voting Now Open!
With 677 entries from 343 companies across 27 categories, ClickZ and Search Engine Watch's inaugural mobile reader survey has been compiled and is now open for voting!
Five most interesting search marketing news stories of the week
This week, we've got a special on stories about advertising and mobile, with a look at mobile ad viewability from our regular mobile columnist Andy Favell, and the news that Snapchat video ads are generating less than three seconds' viewing time on average.
8 Tips for a Simplified Local SEO Strategy in the New Year
Once the holiday rush is over and sites are no longer on lockdown, its time to focus on the little things adjustments, but together can produce measurable local SEO gains. Here's how to get started.


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so by the new I mean the A-Level 2017 paper. I just want to know what resources are you using are you doing the old spec past papers?
Who is doing the new a-level biology edexcel? Help!
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Leading Edge Services
Financial Management
Our accounting software is hosted in the 'cloud' environment, letting you have connection for the level of processing and access you require. We pride ourselves that we don't just process your school accounting; we take a personal interest in your planning and assist you in managing your school's finances. With over ten years of experience, we know what schools, auditors and the Ministry of Education require. We come to your school and discuss your needs and provide financial management advice. We offer the following options: Financial Reporting We ensure your financial reports arrive on time and are easy to read and understand. We prepare a commentary on your financial status and include a projected summary of your funds to the end of the year. Managing Bank Accounts and Investments We monitor the operating bank account in your school's name. We monitor your account and ensure funds are invested on the highest investment rate. We reconcile your bank accounts and meet all audit requirements. Payment of Suppliers Invoices processed and suppliers accounts paid electronically. All accounts are paid when due, no overdue creditors calling your school. GST and PAYE Returns We maintain the records, prepare the return and submit to the IRD. Board of Trustee Payments We maintain the records and pay members by electronic payment. Annual Report We liaise with your auditors to ensure the report is prepared according to any changes in requirements. We prepare a list for you of the information we require you to prepare and send this to you before the end of the financial year. We prepare the annual report, do the audit adjustments and monitor progress to meet all the deadlines required by the Ministry of Education. Budgeting We provide you with a spreadsheet to enter your budgets and assist you with the budget for the Balance Sheet. Asset Register We maintain your asset register, calculate depreciation and balance this to your financial report monthly and annually. Debtors Control System Processing of debtor invoices and receipting. Reporting on outstanding debts. Payroll We run a full electronic payroll system for early childhood staff and other school staff that do not come under the service provider. OUR SOFTWARE SOLUTION We use the Greentree accounting software, hosted in a 'cloud' environment. Our provider provides the highest level of security and backup of your school's data. Leading Edge Services are full administrators of the software and have expertise in our team to train and support our clients. You have the option to access your school's data via the internet for query and processing.
Managing Bank Accounts and Investments
Debtors Control System
Print this page
Each year we invite our clients to attend the annual account workshop to give you an update on the legal requirements for the annual accounts and cover the documents and information we require to prepare the year end report for the auditors.
65-67 Central Park Drive, Henderson.
This service focuses on reviewing the roles, responsibilities, systems, processes and workflows of support staff with an aim to develop an effective combination of the roles and functions that can provide the highest efficiency and effectiveness in school administration management.
Administration and Financial Management Procedure Manuals.
Principal and Board of Trustee training in financial management.
Training and professional development in school accounting.
Analytical reviews of the financial position of the school.
Annual budget planning and reviewing through the year.
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|Unit Price:
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Basic Info
Product Description
High Quality Elastic shoelaces/plastic lock lace/elastic lock lace
1. Material: polyester+latex
2. Size:3mm*110cm, any size can be made
3. Color: any pantone color can be available
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5. Package:1 pair/polybag, 1 pairblister box+ paper card , carton size:38*30*30cm.
6. MOQ: 500 pairs/color total 2000 pairs
Sample terms:
1. Samples in stock can be provided for free, but customer will have to pay shipping.
2. Customed samples will bring cost, and the exact cost based on sample details.
3. Once order reach 10000pairs, sample cost is refundable.
4. Sample time is 5 working days. as per order qty.
Payment terms:
1. 30% deposit,and balance before shipmnt.
2. PayPal,Western Union,T/T and L/C are all acceptable.
Shipment terms:
1. Express(DHL,FEDEX,UPS,TNT...)
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|Home | About | Journals | Submit | Contact Us | Français
Conceived and designed the experiments: SRS AK SLP PIWdB. Performed the experiments: AK SLP LCF. Analyzed the data: SRS AK SLP PIWdB. Contributed reagents/materials/analysis tools: LCF FvD MS DIB CMvD PES GJBvO CW PIWdB Genome of the Netherlands Consortium. Wrote the paper: SRS AK PIWdB.
Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669–673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans.
A key challenge in human genetics is to identify, among the multitude of genetic differences between individuals, those that have an effect on traits. Even though new genetic variants arise through mutation in each generation, most are present only in a small proportion of individuals because they have slightly negative effects on fitness. Detecting such slightly deleterious variants is a key challenge in analyzing how genetics influence human characteristics. In this paper, we test a theoretical prediction by Takeo Maruyama from 1974 that a slightly deleterious variant is, on average, younger than a neutral (non affecting fitness) variant present at the same population frequency. Thus our method detects selection by using estimated age of variants. We applied our method to human data from the Genome of the Netherlands Project, and we show that it distinguishes low-frequency protein-modifying variants from silent variants at the same population frequency and discriminates between sets of variants predicted to be benign or damaging for protein structure and function. Our results confirm the abundance of slightly deleterious protein-coding variation in humans.
Most studies of deleterious genetic variation in humans have focused on the allele frequency spectrum and on the excess of rare alleles at functionally significant sites [1]–[7]. However, information about a deleterious effect of an allele is not limited to its population frequency. A classic result by Takeo Maruyama [8] predicts that both deleterious and advantageous alleles are younger (arose more recently by mutation events) than neutral alleles at the same population frequency. The predicted difference in age is greater for more strongly selected alleles. Intuitively, a deleterious allele is less likely to reach a given population frequency than a neutral allele. However, if it does reach this frequency, it likely did so in a short sequence of steps.
Under the assumption of constant population size and no dominance, mean allelic age conditional on population frequency is exactly symmetric with respect to direction of selection — beneficial and deleterious alleles with the same absolute value of the selection coefficient at the same frequency have identical mean ages.
Thus, a profound consequence of Maruyama's theoretical prediction is that it enables statistical discrimination between classes of neutral and deleterious alleles even if the alleles are at the same population frequency. Approximating allelic age conditional on present allele frequency may provide a new way to quantify deleterious genetic variation, independent from analyses based on allele frequency distribution or polymorphism-to-divergence ratio. Conditional on current allele frequency, both allelic age and, in particular, time spent in the past at higher frequencies can be estimated by enumerating either mutation or recombination events after the first appearance of the allele in the population. Approaches based on comparison of allelic ages have been previously used to detect alleles under positive selection [9]–[11]. The same basic principle can be extended to the analysis of deleterious variation. We have taken this idea to characterize deleterious variation in sequencing data.
Some existing methods for estimating age use intra-allelic variability [12], patterns of linkage disequilibrium [13], or shared haplotypes [14]. These approaches were designed for fine-mapping of mutations or for estimating the absolute age of very rare mutations and may therefore be unsuitable for genome-wide analyses. Importantly, as we show below, difference in sojourn times at higher frequencies is more informative than the allelic age. Therefore, a statistical approach based on comparison of sojourn times at higher frequencies is potentially more powerful than an approach based on the estimation of the allelic age.
Here, using a new dataset of completely sequenced parent-child trios, we provide evidence that the "Maruyama effect" (i.e., at a given allele frequency, deleterious alleles are on average younger than neutral ones) can be observed in human genetic data. We introduce a statistic that is based on proximity of completely linked mutations at a lower frequency and recombination events. We demonstrate that this statistic can successfully discriminate between functional classes of human low-frequency derived allelic variants even if they are at the same frequency. This confirms the abundant selection against deleterious alleles in the human population.
First, we recapitulated Maruyama's theory with diffusion approximation and simulations (see Methods) and confirm that neutral alleles at a given frequency are older than selected ones (Figure 1a, 1b). A neutral allele observed at frequency spent, on average, an equal amount of time at each frequency below , whereas a deleterious allele spent progressively shorter time at higher frequencies (Figure 1c). The difference in the average age of neutral and selected alleles is primarily due to shorter sojourn times at higher frequencies for selected alleles. This suggests that a statistic capturing sojourn times at higher frequencies would better discriminate between neutral and selected alleles than a statistic based on an accurate estimation of the allelic age.
Both mean allelic age and mean sojourn times at each frequency are exactly symmetric with respect to the sign of selection coefficient. However, the symmetry is limited to the case of constant size population and no dominance. In a growing population the mean ages of deleterious and beneficial alleles of the same frequency differ (see Methods). The assumption of constant population size greatly simplifies the analysis of allelic ages under a standard diffusion approximation. However, the assumption of constant population size is clearly violated for the human population. To investigate the case of a growing population, we resorted to forward computer simulations (see Methods for exact details of demographic history). Computer simulations indicated that the difference between mean ages of deleterious and neutral alleles of the same frequency is present in a recently rapidly expanding population, though it is smaller than in the case of a constant-size population (Figure 2A, 2B). The difference in ages was present also in a demographic scenario that included a bottleneck followed by a rapid recent population expansion (Figure 2C).
We have developed a statistical approach to discriminate between classes of neutral and deleterious alleles at the same frequency. The test statistic, which we call the Neighborhood-based Clock (NC) is defined as the logarithm of the minimal physical distance to the nearest completely linked allelic variant at a lower frequency or to the nearest detectable recombination event (Figure 3). Therefore, younger alleles should correspond to larger values of the NC statistic. The intuition behind this statistic is that lower frequency allelic variants linked to the tested variant likely arose by mutation after the tested variant. Similarly, recombination events are expected to happen after introduction of the tested variant by mutation. The NC statistic captures information about the age of the alleles and especially about the time spent in the past at appreciable population frequencies.
To assess whether the NC statistic can indeed discriminate between functional classes of human allelic variants, we analyzed coding variants discovered in the pilot data from the Genome of Netherlands project (GoNL). The pilot GoNL dataset (see Methods) consists of complete genomes of 47 parent-child trios, which enables accurate variant calling and haplotype phasing. Thus, the unique trio-based design of the GoNL dataset allowed us to compute NC statistics informed by family-based rather than population-based phasing, an especially important advantage for rare and low frequency alleles.
We subdivided all coding variants into synonymous and non-synonymous (missense and nonsense). We further annotated the missense variants using PolyPhen-2 predictions as benign, possibly damaging, and probably damaging [15]. In the GoNL dataset, consisting of 94 unrelated parents, there are 25997 common coding SNPs with a minor allele count 20. Of those common SNPs, 13956 (53.7%) are synonymous and 12041 (46.3%) are non-synonymous (including 1466, or 5.6%, of probably damaging missense SNPs). The fraction of non-synonymous and, especially probably damaging SNPs, increases for SNPs with low frequencies (Figure 4). At minor allele count 2 there are 7437 coding SNPs, of which 3102 (41.7%) are synonymous, and 4335 (58.2%) are non-synonymous (including 1176, or 15.7%, of probably damaging missense SNPs).
We estimate that 14.8% of non-synonymous alleles at minor allele count 2 are deleterious. At minor allele count 2 there are 3102 synonymous SNPs (which constitute 7.9% of all 39454 synonymous SNPs). In contrast, at minor allele count 2 there are 4335 non-synonymous alleles (which constitute 9.2% of all 46946 non-synonymous SNPs). Therefore, there is an enrichment of rare non-synonymous alleles compared to synonymous alleles. If we assume that all synonymous SNPs are selectively neutral, then we can treat their distribution as the neutral expectation. Therefore, there are more non-synonymous alleles at minor allele count 2 than expected if all non-synonymous variants were neutral. Those alleles constitute 14.8% of all 4335 non-synonymous alleles at minor allele count 2. By the same logic, we estimate that 27% of probably damaging missense variants at minor allele count 2 are deleterious.
Below, we focus primarily on low-frequency derived alleles (i.e., alleles that differ from the ancestral state). We note that, even though the theoretically predicted difference in age is greater for high-frequency deleterious variants (Figure 1b), we expect that the difference between functional categories of coding variants can be detected only for variants with derived allele frequency up to 10%, because deleterious variants rarely ever reach higher frequency.
The NC statistic can discriminate between non-synonymous and synonymous SNPs at the same derived allele frequency (Figure 5 and Table 1) and bootstrap analysis shows that the effect is not explained by a small number of variants (Figure 6). This is consistent with the abundance of low frequency deleterious non-synonymous alleles in humans. Variants predicted to be probably damaging by PolyPhen-2 have higher values of NC statistics. Overall, we observe a positive correlation between PolyPhen-2 predictions of damaging effects of derived missense variants and the NC test statistic (Table 2). This result indicates that the NC statistic independently captures some of the same selective characteristics of variants as PolyPhen-2, and it may contain additional signal not present in the conservation or structural properties which PolyPhen-2 is based on.
Low-frequency ancestral alleles are expected to be much older than derived alleles at the same minor allele frequency. Those ancestral alleles date from before the human-chimpanzee divergence and each low-frequency ancestral allele corresponds to a high-frequency (i.e., almost fixed) derived allele. For example, an ancestral allele at minor allele frequency of 1% corresponds to a derived allele at population frequency of 99%. In agreement with this expectation, the NC statistic is, on average, much lower for ancestral variants than for derived variants (Figure 5).
As another independent test whether deleterious variants are on average younger than neutral alleles of the same frequency, we analyzed the fraction of population-specific SNPs. Because this analysis required data from multiple human populations, we used an entirely different data set, pilot data from the 1000 Genomes project (see Methods). We observed that non-synonymous SNPs, especially those predicted to be damaging, are more often population-specific (Figure 7) than synonymous SNPs of the same frequency. This is consistent with non-synonymous SNPs being on average younger. As expected, the difference disappears at population frequencies greater than 10%. Previously, also using 1000 Genomes data, Marth et al. [16] showed an increase in population specificity of variants in coding regions compared to intergenic regions. Importantly, this analysis is independent of the NC statistic and of the GoNL data, and thus provides additional evidence of the younger age of deleterious alleles.
Finally, we examined examples of published low frequency variants shown to be significantly associated with human complex traits. Variants R46L of PCSK9 associated with reduction of LDL-cholesterol [17] and two variants in IFIH1 (I923V and H460R) associated with Type-I diabetes [18] have been observed in the GoNL dataset. The PCSK9 R46L variant and IFIH1 I923V variant are both younger than average according to the NC statistic (33rd and 9th percentile, respectively). The IFIH1 H460R variant is a low-frequency ancestral allele and, accordingly, has low NC statistic (indicating old age), at 2.4 standard deviations lower than average for synonymous variants at the same minor allele count (lower than 99.2% of synonymous variants at allele count 4). These results suggest that although the NC statistic cannot be applied to pinpoint individual functional variants (at least in relatively small sequencing datasets available at present), it may have potential to enrich for groups of functional variants in burden association tests (reviewed in [19]). This must be investigated in the future on much larger datasets.
Our approach does not distinguish effects of positive and negative selection. As noted above, the theory predicts that the effect of selection on age and on time spent at each frequency in the past is symmetric with respect to selection coefficient, assuming no population growth and no dominance effects (in a quickly growing population strong positive selection produces younger alleles than negative selection [20]). We focused on negative selection in this study because at low derived population frequencies many missense variants are deleterious [5] and very few are advantageous. Nonetheless, our approach may be applicable to positive selection too.
Our analysis benefitted from whole-genome sequencing data allowing low-frequency alleles far away from the coding regions (100 kb) to be identified. Additionally, the accurate haplotype phasing available in the trio-based sequencing data from GoNL was indispensable for our analysis, which required accurate identification of linked variants and recombination events.
To our knowledge, ours is the first large-scale real-data analysis of this effect theoretically predicted by Maruyama in 1974. Our analysis provides additional evidence, completely independent of allele-frequency distribution, for the abundance of deleterious alleles in coding regions in the human population.
Theoretical mean ages and sojourn times were computed for constant-size populations, using diffusion approximation of the stochastic process. Let be the probability density that the allele frequency in the th generation is between and , given its starting frequency . Then, satisfies the backward Kolmogorov equation
Following Maruyama and Kimura [21], we denote by
the density of mean sojourn time at frequency starting at frequency before fixation or loss. Then, satisfies the equation
where denotes Dirac's delta function.
Now, given the current frequency and initial frequency , the density of mean sojourn time at frequency is
For the boundary conditions, for all , and , the density for frequency below is
while the density at frequency above is
It then follows that mean age of a variant at current frequency is the sum of sojourn times at all frequencies
Both the sojourn times and age are symmetric functions of the selection coefficient . In other words, deleterious and advantageous alleles at a given frequency are expected to be younger than neutral alleles, and selected alleles are expected to spend progressively less time at higher frequencies leading to the current population frequency.
Forward-in-time, individual-based computer simulations were performed in SFS_code [22]. The parameters were selected to examine the behavior of the age of selected alleles and not to emulate realistic demographic scenarios. Coding region of 100 kb or 200 kb was simulated for 2.05 N generation after the initial burn-in of 10 N generations (N=5000 or 10000). 70% of simulated variants were under selection, the remainder were neutral. Expansion phase started at time 2 N generations after burn-in, with expansion rate of 156.48. The scaled mutation rate per site was =4N=0.0001, and scaled recombination rate per site =4Nr=0.0001. Additionally, a scenario that included a bottleneck was simulated. The bottleneck was an instantaneous population reduction of 50% at time 2N, followed by rapid population expansion as in other simulation scenarios.
The data presented here include SNP genotypes in a pilot subset of 47 trios collected by the Genome of the Netherlands (GoNL) Project (http://www.nlgenome.nl), using whole-genome sequencing at 12 coverage with Illumina HiSeq technology performed at Beijing Genome Institute (BGI). The sequence data were aligned to the human reference genome build hg19 using BWA [23], duplicate reads removed, re-alignment performed around insertions/deletions from the pilot of the 1000 Genomes Project [24], and base quality scores recalibrated. Variant discovery and genotyping was done using the Unified Genotyper in the Genome Analysis Toolkit (GATK) [25] across all individuals simultaneously. The initial calls were filtered using Variant Quality Score Recalibration (VQSR) [26], resulting in 11,521,751 biallelic SNPs identified with a corresponding Ti/Tv ratio of 2.21. We used Phase By Transmission in the GATK to calculate the posterior probability for all possible genotypes in each trio from the raw genotype likelihoods and expected modes of transmission, and identified the best-guess genotype in the trios. We phased these best-guess SNP genotypes for all trios using Beagle v3.3 [27].
Data from July 2010 release of the 1000 Genomes low-pass pilot data was used. Variant annotations and functional predictions were computed using PolyPhen-2. In all analyses, only non-singleton variants (i.e., with minor allele counts at least 2) were used and only those that had annotated phased genotypes.
The NC test statistic was computed for variants at minor allele count of 2–6 separately. The statistic, for each coding variant, was computed as base-10 logarithm of the sum of the up- and down-stream physical distances to the closest recombination event (computed using the 4-gamete test [28]) or a fully linked rarer variant, i.e., variant present on a strict subset of the haplotypes.
The ancestral/derived states of variants were calculated using the ancestral reference human_ancestor_GRCh37_e59 provided with the 1000 Genomes project.
P-values were computed using Mann-Whitney rank-sum test. P-values were 1-sided, with alternative hypotheses following younger age for non-synonymous variants. Effect sizes were calculated as standard deviations from the mean of the NC statistic for derived synonymous variants at a given minor allele count. Confidence intervals were computed using the percentile bootstrap method on 1000 bootstrap permutations of variant labels. Combined p-values were computed by meta-analysis using the Z-score method, weighted by sample size.
We thank Alexey Kondrashov, David Reich, and Nick Patterson for helpful discussions. We would like to thank Nick Patterson for the insightful discussion on the diffusion model for a growing population.
Genome of the Netherlands Consortium
Steering group. Cisca Wijmenga1,2 (principal investigator), Morris A. Swertz1–3, P. Eline Slagboom4, Gert-Jan B. van Ommen5, Cornelia M. van Duijn6, Dorret I. Boomsma7, Paul I.W. de Bakker8–11
Ethical, legal, and social issues. Jasper A. Bovenberg12
Cohort collection and sample management. P. Eline Slagboom4, Anton J.M. de Craen4, Marian Beekman4, Albert Hofman6, Dorret I. Boomsma7, Gonneke Willemsen7, Bruce Wolffenbuttel13, Mathieu Platteel1
Sequencing. Yuanping Du14, Ruoyan Chen14, Hongzhi Cao14, Rui Cao14, Yushen Sun14, Jeremy Sujie Cao14
Analysis group. Morris A. Swertz1–3 (Co-Chair), Freerk van Dijk1,2, Pieter B.T. Neerincx1,2, Patrick Deelen1,2, Martijn Dijkstra1,2, George Byelas1,2, Alexandros Kanterakis1,2, Jan Bot15, Kai Ye4, Eric-Wubbo Lameijer4, Martijn Vermaat3,5,16, Jeroen F.J. Laros3,5,16, Johan T. den Dunnen5,16, Peter de Knijff5, Lennart C. Karssen6, Elisa M. van Leeuwen6, Najaf Amin6, Vyacheslav Koval17, Fernando Rivadeneira17, Karol Estrada17, Jayne Y. Hehir-Kwa18, Joep de Ligt18, Abdel Abdellaoui7, Jouke-Jan Hottenga7, V. Mathijs Kattenberg3,7, David van Enckevort3, Hailiang Mei3, Mark Santcroos19, Barbera D.C. van Schaik19, Robert E. Handsaker11,20, Steven A. McCarroll11,20, Evan E. Eichler21, Arthur Ko21, Peter Sudmant21, Laurent C. Francioli8, Wigard P. Kloosterman8, Isaac J. Nijman8, Victor Guryev22, Paul I.W. de Bakker8–11 (Co-Chair)
1. Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
2. Genomics Coordination Center, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
3. Netherlands Bioinformatics Centre, Nijmegen, The Netherlands
4. Section Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
5. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
6. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
7. Department of Biological Psychology, VU University, Amsterdam, The Netherlands
8. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
9. Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands
10. Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
11. Broad Institute of Harvard and MIT, Cambridge, Massachusetts
12. Legal Pathways Institute for Health and Bio Law, Aerdenhout, The Netherlands
13. Department of Endocrinology, University Medical Center Groningen, Groningen, The Netherlands
14. BGI, Shenzhen, China
15. Leiden Institute of Advanced Computer Science, Leiden University, Leiden, The Netherlands
16. Center for Human and Clinical Genetics and Leiden Genome Technology Center, Leiden University, Leiden, The Netherlands
17. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
18. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
19. Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Medical Center, Amsterdam, The Netherlands
20. Department of Genetics, Harvard Medical School, Boston, Massachusetts
21. Department of Genome Sciences, University of Washington, Seattle, Washington
22. Hubrecht Institute, Utrecht, The Netherlands
This work was supported by NIH grants R01MH084676 and R01GM078598. The Genome of the Netherlands Project is financially supported by the Biobanking and Biomolecular Research Infrastructure of The Netherlands (BBMRI-NL), funded by the Netherlands Organisation for Scientific Research (NWO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library 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.


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Lot 11 Lower Beech Hill Rd.,Campton NH, 03226
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Description for Lot 11 Lower Beech Hill Rd. Campton, NH 03226
This lot is easily build-able and level at the road. Slopes down to the rear. Beautiful wooded lot. Close to Plymouth and I-93 exit 26. Short drive to Skiing, Lakes, Mountains, Rivers, Golf, and glorious natural beauty all around. Well established sub division with minor covenants on construction. Bring your best design! Create your dream home here!
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