text:
Jobs & Internships
Application Deadline
Job or Internship
Position Purpose
The primary responsibilities of this position include, counting and verifying cash from the previous day's operations, preparing the bank deposit, replenishing cash bank bags, and processing change order requests for the vault.
This position works every Saturday and Sunday morning with the potential for evening event hours and weekday cash office backup.
Essential Duties & Responsibilities
- Performs daily cash vault reconciliations
- Prepares and distributes daily bank bags for daily operations
- Deposits previous days cash receipts for various points of sale
- Issues petty cash according to the petty cash policy and provides weekly petty cash reconciliations
- Updates and sends the daily attendance report to key museum staff
- Enters all cash receipts and registers of payment (ROPs) into the accounting software
- Assists museum staff with all cash office requests; i.e. petty cash, ROPs, batches, etc.
- Provides on-call support for weekday cash office and special events as needed
- Other duties as assigned
Job Qualifications
- Experience in cash receipt processing
- College level accounting classes or equivalent work experience
- Ability to work independently and use good judgment
- Strong verbal and written communication skills
- Ability to multi-task, prioritize and work efficiently
- Basic understanding of Excel, Outlook, and accounting software
Working environment and physical activities
- Physical ability to perform tasks that may require prolonged standing, sitting, and other activities necessary to perform job duties
- Occasional lifting
Additional Information
This is a part-time position with no benefits. If you are interested in this position, please send your cover letter and resume to firstname.lastname@example.com. In the subject line of the email, please include your name and the title of the position for which you are applying. Deadline for application in November 27, 2014.
It is the policy of the Denver Art Museum to prohibit discrimination against any person or organization based on age, race, sex, color, creed, religion, national origin, sexual orientation, transgender status, gender identity, gender expression, ancestry, marital status, gender, veteran status, political service, affiliation or disability.
Application Deadline
Job or Internship
Position Purpose
Reporting to the Associate Director of Marketing, the Marketing and Promotions Manager is responsible for the overall planning, implementation and results reporting of advertising and promotional programs in support of the Denver Art Museum's attendance, revenue and awareness goals.
Essential Duties & Responsibilities
- Develop advertising and paid media programs for the Museum's many offerings, including ongoing programs and temporary exhibitions.
- Oversee execution of advertising and promotional campaigns including message development, creative execution and evaluation.
- Develop and manage detailed results reports for all marketing programs and campaigns with a focus on return on investment and other success metrics.
- Solicit and execute promotional partnerships with local and regional businesses and organizations in order to increase visibility for the Museum.
- Work closely with in-house graphic designers to create consistent, effective, and strategically-sound advertising and promotions campaigns that best fit the Museum brand.
- Develop holistic marketing plans for the Museum, its programs and exhibitions.
- Collaborate with education, membership, development, and guest services functions to develop and implement strategic marketing initiatives that best reach the intended target audiences.
- Integrate with existing brand and marketing strategies.
- Allocate and manage budgets for advertising and promotional programs.
- Oversee interns and junior staff when applicable.
Job Qualifications
- Proven strategic thinker.
- Proven managerial skills and ability to serve as a strong team leader.
- Strong written communication and good listening skills.
- Strong project management skills and attention to detail.
- Proven ability to meet deadlines and manage multiple high priority projects at once.
- Strong negotiation skills.
- Experience tracking, analyzing and reporting marketing and advertising campaign results.
- Strong relationship-building skills and ability to work well with a large number of internal and external contacts.
- Ability and interest in contributing to positive work environment.
- Thorough knowledge of general office procedures.
Proficient computer skills: MS Office and other related software including Microsoft Powerpoint.
Education or Formal Training
Four year college degree required.
- Five to seven years of experience in marketing, promotions and advertising.
- Experience working in an advertising/marketing agency or the marketing department of an organization.
- Mastery of media planning and buying.
- Familiarity with partnerships and sponsorships.
Familiarity with partnerships and sponsorships
Additional Information
This is a full-time position with benefits. If you are interested in this position, please send your cover letter and resume to firstname.lastname@example.com. In the subject line of the email, please include your name and the title of the position for which you are applying. Deadline for application in November 28, 2014.
It is the policy of the Denver Art Museum to prohibit discrimination against any person or organization based on age, race, sex, color, creed, religion, national origin, sexual orientation, transgender status, gender identity, gender expression, ancestry, marital status, gender, veteran status, political service, affiliation or disability.
Application Deadline
Job or Internship
Position Purpose
- Coordinate efforts to make DAM accessible to visitors with special needs.
- Develop education programming on and off – site for older adults and visitors with special needs
Essential Duties & Responsibilities
- Work with Manger of Adult and College Programs to refine strategy and build overall education program plan for older adults and visitors with special needs. This includes, but is not limited to:
- Offering ongoing programs where access audiences can see themselves/receive services without making special requests (e.g. Art & About, monthly tactile tours/tables, community exhibitions etc.)
- Serving as the museum's resource for access-related issues and working across departments to ensure the museum's program accommodates audiences with special needs
- Arranging for visitor accommodations as needed (e.g. sign language interpretation)
- Developing and coordinating on-site programming that serves active older adults such as lectures, courses, and studio classes
- Work with Exhibitions to develop consistent, alternate formats for interpretation in special exhibitions. Create and update guide for design and graphic design considerations. Advise exhibition teams on accommodations as needed including strategies for making artists' installation works more accessible.
- Work with Master Teachers to integrate universal design considerations into permanent collection interpretation.
- Participate in and chair, DAM's staff access committee.
- Work closely with Guest Services, on access requests and training needs for front line staff.
- Train docents to provide special request tours and serve visitors with disabilities on public tours and for school groups. Work with access docents on tactile programs, Art & About tours for visitors with early Alzheimer's, and other docent-facilitated experiences. Work with docent access liaison.
- Coordinate communication with targeted community agencies on available adaptive program services. Work with Communications to keep messaging and language about access initiatives current and general messaging inclusive.
- Coordinate with Manager of School and Teacher Programs on access-related scholarship requests.
- Assist in access-related fundraising efforts (corporate requests, grants, etc and PR initiatives as needed.
- Work collaboratively with Adult and College Coordinator in support of all Adult and College Programs.
- Participate in overall education department planning and budgeting activities; serve as education representative on museum-wide committees as assigned.
- Respond to questions and requests from public.
- Collect statistics and coordinate reporting related to access efforts.
- Maintain community contacts and e-mail list
- Other duties as assigned.
Job Qualifications
Knowledge, Skill & Ability
- A strong knowledge of ADA, related laws and best practices is required. The right candidate will have experience applying these practices at a public institution.
- A strong knowledge of museum access programming, best practices and adaptive is preferred.
- Strong knowledge of older adult audiences and adult learning.
- Knowledge of local Denver/Front Range access/special needs organizations.
- Ability to effectively collaborate with individuals and organizations in the community.
- Ability to communicate effectively in group and individual situations as well as in written form; strong public speaking skills.
- Proven organizational skills and ability to work on multiple, detailed projects simultaneously.
- Computer skills (MS Word, PowerPoint, Excel, social media).
- Bilingual (Spanish) a plus.
- Ability to work evenings and weekends as needed.
Education or Formal Training
- BA in art history, anthropology, museum education or related field preferred.
- Training in museum access programs such as Meet Me at MoMa highly desired.
- Minimum of 2 years experience working with audiences with disabilities.
- Experience working with older adults.
- Experience developing live programs in a museum context.
- Experience working with and training volunteers.
Additional Information
This is a full-time position with benefits. Posting closes on December 1, 2014. If you are interested in this position, please email your cover letter and resume to: email@example.com. In the subject line of your email, please list your name first followed by the position you are interested in obtaining.
It is the policy of the Denver Art Museum to prohibit discrimination against any person or organization based on age, race, sex, color, creed, religion, national origin, sexual orientation, transgender status, gender identity, gender expression, ancestry, marital status, gender, veteran status, political service, affiliation or disability.
Application Deadline
Job or Internship
Position Purpose
The communications team at the Denver Art Museum is seeking a self-motivated, dynamic, upbeat and responsible intern who wants real-life experience at one of the leading arts institutions in the region.
Position Purpose
The communications team at the Denver Art Museum is looking for a dynamic, upbeat intern who wants to learn the ropes of the communications field, with special emphasis on public relations and social media. The intern will work as part of a team but also will be asked to work independently to complete tasks. The intern joins a crew whose department output includes advertising, marketing, public relations, public affairs/government relations, graphic design, community relations and social media.
Essential Duties & Responsibilities
The intern will have the opportunity to build PR and social media skills as they relate to a large non-profit organizations, as well as hone in on writing techniques while completing a variety of tasks, including:
- research and develop news releases and other media materials
- develop and pitch media stories
- proof media and collateral, including calendar listings
- copy and archive media clips
- assist in the planning and implementation of special events including media previews
- draft news articles
- assist with social media
There will be a lot of writing tasks. Much of the work will support major events and exhibitions. Interns commit to 15-20 hours a week for the semester, scheduling is flexible.
Education or Formal Training
The ideal candidate:
- Is currently enrolled in undergraduate or graduate program in Journalism, Communications or English academic studies.
- Will have a strong interest in media relations and communications coursework, electronic and social media, as well as excellent written and verbal skills – you must love reading and writing!
- Will have a strong idea of what they would like to learn from their internship experience.
Additional Information
This is a part-time internship for academic credit, and includes great perks but no financial compensation. If you are interested in this position, please submit a cover letter, resume, three writing samples related to the public relations, journalism and/or social media field and a list of references to the Denver Art Museum communications manager Shadia Lemus at email@example.com. Applications without writing samples will not be considered.
Application Deadline: December 16, 2014


text:
About us
Wed 26 Nov 2014 @ 17:09
RT @HodderFaithHear @timkellernyc speak about his new book PRAYER: https://t.co/oFpxtPE57U
Author(s): Joan Chittister
'Joan Chittister has emerged as a wisdom figure for our time. Here she takes her wise monastic tradition and takes it on the road for all to love and enjoy.' Richard Rohr, author of The Naked Now
Joan Chittister is an internationally known author and lecturer, and the executive director of Benetvision, a resource and research centre for contemporary spirituality. She is former president of the Conference of American Benedictine Prioresses and the Leadership Conference of Women Religious. Her books include In the Heart of the Temple (SPCK 2005), For All That Has Been, Thanks (with Rowan Williams, Canterbury Press 2010) and The Rule of Benedict (Crossroad reissue 2010). She lives in Erie, Pennsylvania.

subset: commoncrawl


text:
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This Banfield Hospital offers the highest standard of medical, surgical and preventive care for your pet. Walk-Ins and new clients are warmly welcomed. Ask about our Optimum Wellness Plans® that provide free office visits and exams for life. Our Doctors: Sheri Candelettaview deal
16571 Pacific Coast Hwy, Sunset Beach, CA 90742
Sun Surf Veterinary Hospital provides complete medical and surgical procedures for the communities of Sunset Beach, Seal Beach, Huntington Beach, Los Alamitos and Long Beach. We are well known for our affordable laser and orthopedic (bone) surgeries and procedures. We also provide non invasive
10701 South Street, Cerritos, CA 90703
Lakewood Animal Hospital has been offering a wide array of veterinary services to pets and pet parents in the Cerritos area for over 40 years. You can count on us for preventive care for your pet...full medical, surgical and dental services...and dedicated laboratory and pharmaceutical services.view deal
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14744 Valley Blvd., La Puente, CA 91746
Southern California Animal Hospital is a full-service, community based animal hospital. We have been serving our community since 1956. We are well equipped and growing Animal Hospital for more than 50 years. Choosing this practice assures you that your best friend receives high quality medical care.view deal
261 S Lincoln Ave, Corona, CA 92882
Welcome to Animal Medical Center Of Corona! Here at Animal Medical Center of Corona we are committed to providing the best possible care and services to you and your pet. This is why we are proud to offer you our web site, which is available for you twenty-four hours a day and seven days a week!
6222 E Pacific Coast Hwy, Long Beach, CA 90803
Belmont Shore Veterinary Hospital has provided Long Beach area pets and their owners with compassionate, professional care for over 40 years. Our doctors and staff are focused on providing outstanding veterinary care while exceeding expectations of service. We want to make taking great care of
939 West Sixth Street, Corona, CA 92882
We're more than an animal hospital! We're the place where pet parents know they can bring their pets for superb veterinary care that sets new standards for quality and kindness. For pets and pet parents alike, a trip to our clinic is an opportunity to see how our neighborly, welcoming staff caresview deal
326 Adams Circle, Corona, CA 92882
et Chalet is an 8,000 sq ft, 2 story luxuries Pet Chalet hotel facility. We are located in the central part of Corona,Ca. Conveniently close to major freeways (91, 15 and the 71). Our guest enjoy a fully air conditioned and heated facility with their own private suites. We also offer a separate


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Haiku Deck - Creador de presentaciones y diapositivas con bonitas tablas y gráficas
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Haiku Deck - Creador de presentaciones y diapositivas con bonitas tablas y gráficas
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Haiku Deck is the simple new way to create and share inspiring presentations – whether you're pitching an idea, teaching a lesson, telling a story, or igniting a movement. Featured on the iTunes "New and Noteworthy" and "What's Hot" lists!
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In a sea of music streaming options, is YouTube's new subscription music video service right for you? CNET's Donald Bell has the answer.
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A C-note is all the budget you need to buy great tech. Here are some of our favorite products available for under $100.
The video giant already attracts a billion unique visitors monthly, but will those users pay to play? YouTube gave CNET an exclusive demo of streaming service Music Key.
What good is a digital assistant if she can't tell you to leave early because of traffic reports? That's a question asked by Microsoft at any rate.
Google's popular video site rolls out its long-teased contender in the paid streaming-music business. Called Music Key, it may have the best chance yet to popularize music subscriptions.
Google is testing an ad-blocker service, Amazon may be inserting ads into streaming video, and Comcast lets you track the cable guy.
Playing himself, not Sheldon Cooper, Parsons marvels at Intel's technological marvels. It is said to be his first ad as a celebrity endorser.


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'Congress should take its lead from the people'
Earnings dominate week's calendar
Portland police talk woman down from railing of I-84 overpass


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Overview of content related to 'privacy'
This page provides an overview of 1 article related to 'owl'. Note that filters may be applied to display a sub-set of articles in this category (see FAQs on filtering for usage tips). Select this link to remove all filters.
The Web Ontology Language (OWL) is a family of knowledge representation languages for authoring ontologies. The languages are characterised by formal semantics and RDF/XML-based serializations for the Semantic Web. OWL is endorsed by the World Wide Web Consortium (W3C) and has attracted academic, medical and commercial interest. (Excerpt from Wikipedia article: OWL)
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World Wide Web Conference 2004
Dave Beckett reports on the international WWW2004 conference held in New York, 19-21 May 2004.
July 2004, issue40, event report


text: Locations Edit History Talk11 10,299pages on this wiki Category page Sorting type: Most visited Most visited Alphabetical | This category contains entries concerning Grand Theft Auto locations. New Locations Categorizing Policy Main cities (e.g. Liberty City) should go in this category (Category:Locations) and Category:Cities All places of interest (buildings, companies, checkpoints) should go in the games category (e.g. Category:Locations in GTA San Andreas) All towns, villages and permanent or natural features should go in that main city's category Category:Vice City Try to subcategorize within these, e.g. Category:San Fierro, Category:Safehouses in GTA San Andreas etc For differing renditions of cities, simply add the game's name for every rendition: Category:Liberty City in GTA IV / Category:Liberty City in GTA III / Category:Liberty City in GTA 1 If you would like to discuss these conventions, please discuss them on the talk page Pages in category "Locations" Easter Basin Caesars Auto Parking Paleto Forest Sawmill Simeon's Delivery Garage Vinewood Cemetery Morningwood Beaver Bush Ranger Station Senora Freeway Gant Bridge West Vinewood Alderney State Correctional Facility Blaine County FLEECA Bank Fortside Hove Beach Star Junction Bilingsgate Motel Back 1 ... 8 9 10 11 12 13 14 ... 38 Next Subcategories Cities Districts in Anywhere City Strip Clubs Save Points in GTA San Andreas Locations in GTA Vice City Stories States Locations in GTA Liberty City Stories Cemeteries Back 1 2 3 Next


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text: Jamaican Hot pepper challenge By Xave Francisco Flycisco once again trying another challenge. The Jamaican hot pepper challenge 17th... more »Flycisco once again trying another challenge. The Jamaican hot pepper challenge 17th hottest pepper in the world. Eat the pepper and don't drink nothing for 5 minutes. Remember to subscribe..www.youtube/Flycisco.com « less Published February 16, 2013 200 views More Info » Full Credits Xave Francisco Uploader Stats & Data 11 Funny Votes 1 Die Votes 196 Views Published February 16, 2013 Categories: Real Life Dumb People Fails Keywords: Pepper Jamaican Hot challenge spicy food Up Next: Puppet Show AUTOPLAY Up Next In: 10 "Show and Tell" EXCLUSIVE Step Brothers Deleted Scene SLOTCAR - Episode 02 Trash Talk'n Busch Zach Berates an Audience Member MY FACE! (Front Page of Funny Or Die) Follow Facebook Twitter Tumblr Instagram Advertisement Browse Related Comments 5+ more View All ▶ Xave Francisco Vaguely Related Videos Vaguely RelatedPics & Words Advertisement From Around the Web ZergNet


text:
Couple opens Ranch's first funeral home
Date: July 22, 2009
by: Michael Eng | Executive Editor
LAKEWOOD RANCH — A lifetime in the funeral business yields volumes of stories.
Like when Yvette Reckling started working with her grandfather at her family's upstate New York funeral home at the ripe old age of 4.
Or any number of times the two got a call in the middle of the night and trekked out into the snowy dark to pick up the deceased.
Or that time when Reckling's 12-pound prime rib shrunk to an unrecognizable mess in the oven when she was called away on Christmas Day.
"It's a 24-hours-a-day, seven-days-a-week business," Reckling said. "But it's my passion."
She pauses for second.
"Oh, my poor daughters," she said, laughing.
Reckling, along with her fiance, 35-year funeral directing veteran Jim Klausch, opened Lakewood Ranch's first funeral home July 15. Because We Care Cremation and Funeral Home Inc. is a full-service funeral home that offers every option imaginable — from the traditional service/visitation memorials to something more unorthodox such as turning a loved ones cremated remains into a diamond.
Planning for Because We Care began in February after Klausch was a cutback victim at Moss-Feaster Funeral Homes Group in Clearwater.
"I'd spent 35 years working for that company," Klausch said. "After that happened, I thought, 'Wow. What am I going to do?'"
That's when the couple decided to open their own funeral home. Reckling had worked previously for Manasota Memorial Park and Funeral Home, where she had provided services to many East County families.
"We had a lot of people ask us why there wasn't a funeral home in Lakewood Ranch," Reckling said. "There's a huge need here (for a funeral home.)"
The couple found their location off Lake Osprey Drive. The building's secluded-yet-easily-accessible location as well as ample parking made it perfect for their needs.
Reckling and Klausch applied immediately for their funeral home license and began working on the building, which includes a planning room, gathering room and chapel. Reckling chose the home's colors, while Klausch equipped it with the latest technology — including a computer program that includes a catalog of casket options.
"We don't have any caskets on-site — that makes some people uncomfortable," Klausch said. "But we can get any one of them here within 24 hours."
Because it's not affiliated with a larger corporation, Because We Care can tailor any service to meet the needs of its families, Klausch said. For example, services can be adapted to feature a loved one's favorite pastime, and the home offers special packages for veterans. It also can facilitate transfers up north and assist with florists, hotels and airlines.
"We can run rings around corporations with our service," Klausch said.
And although Reckling admits she's shed plenty of tears along with the grieving families, the job offers its own rewards.
"We're there whether it's a child who has passed or an 80-year-old mom who just lost her 60-year-old son," Reckling said. "Or when it's a couple who has been married for 67 years and you know that a huge piece of them just got ripped apart.
"I love being able to help a family in the worst time of their lives — to be able to be with them and get them through it," she said. "It's hard, but it's so fulfilling. When you get that hug afterward — that's the best."
Eventually, Reckling and Klausch hope to find land farther east and relocate the business to a freestanding building. But for now, they're excited to begin offering their services in the East County.
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GAINESVILLE, Fla. – Alex Anzalone could be the poster boy for college football recruiting in the 21st Century.
A highly recruited inside linebacker out of Wyomissing (Pa.) High, Anzalone was in the public spotlight long before enrolling at UF last month.
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November 26, 2014
Nashville (WVLT) - The Southern Baptist Convention reports an increase in church giving to national and international mission programs in the last fiscal year.
Giving to the Cooperative Program rose by more than $5 million between Oct. 1, 2006, and Sept. 30, 2007, to almost $206 million.
Donations to the program have become a central issue in the Protestant group based in Nashville.
Many smaller Southern Baptist churches see the Cooperative Program as a crucial collective effort for the denomination and the best way for them to carry out missionary and evangelistic work.
Pressure has been building on larger Southern Baptist congregations -- and all churches -- to give more.
The money comes from individual donors, churches, state conventions and fellowships.
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Dr. Wei Yi Gao, MD
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Dr. Wei Yi Gao has been practicing medicine for 20 years. Dr. Gao graduated from the Beijing Med Univ, Beijing City, Beijing, China in 1994. She practices medicine in New York, NY and specializes in Neurology and Epileptology. Dr. Gao is affiliated with Beth Israel Medical Center.
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In August Mike Tramp is ready with a new album entitled 'Museum', which is following the musical steps of his last album. Listen to and watch the first single "Trust in yourself" here:
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Dr. Michael A. Zimmer, MD
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Dr. Michael A. Zimmer has been practicing medicine for 25 years. Dr. Zimmer graduated from the Thomas Jefferson University, Jefferson Medical College in 1989. He practices medicine in Saint Petersburg, FL and specializes in Internal Medicine. Dr. Zimmer is affiliated with St Anthonys Hospital, Bayfront Medical Center and Edward White Hospital.
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Book your room at Residence Inn by Marriott Salt Lake City - Downtown
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We studied linkage disequilibrium (LD) patterns at the BRCA1 locus, a susceptibility gene for breast and ovarian cancer, using a dense set of 114 single nucleotide polymorphisms in 5 population groups. We focused on Ashkenazi Jews in whom there are known founder mutations, to address the question of whether we would have been able to identify the 185delAG mutation in a case-control association study (should one have been done) using anonymous genetic markers. This mutation is present in approximately 1% of the general Ashkenazi population and 4% of Ashkenazi breast cancer cases. We evaluated LD using pairwise and haplotype-based methods, and assessed correlation of SNPs with the founder mutations using Pearson's correlation coefficient.
BRCA1 is characterized by very high linkage disequilibrium in all populations spanning several hundred kilobases. Overall, haplotype blocks and pair-wise LD bins were highly correlated, with lower LD in African versus non-African populations. The 185delAG and 5382insC founder mutations occur on the two most common haplotypes among Ashkenazim. Because these mutations are rare, even though they are in strong LD with many other SNPs in the region as measured by D-prime, there were no strong associations when assessed by Pearson's correlation coefficient, r (maximum of 0.04 for the 185delAG).
Since the required sample size is related to the inverse of r, this suggests that it would have been difficult to map BRCA1 in an Ashkenazi case-unrelated control association study using anonymous markers that were linked to the founder mutations.
Numerous advances in our understanding of genetic susceptibility to breast cancer have been made over the past decade, most notably the discovery of BRCA1 in 1994 and BRCA2 in 1995 [1,2]. Mutations in these genes account for approximately 2/3 of families with clearly inherited forms of breast and ovarian cancer (5 or more cases in a family) [3,4]. In addition to the high-penetrance genes BRCA1/BRCA2, rare mutations in a number of other genes, such as CHEK2, ATM, BRIP1, and PALB1 predispose to breast cancer [5-9], as do more common variants in CASP8 and TGFB1[10]. The total heritability of breast cancer is at least 10% [11,12], and possibly up to 25% or higher [13,14]. Mutations in known high-risk genes, however, account for a relatively small proportion (probably less than 20%) of the excess risk due to genetic factors [15,16].
Fueled by the completion of the first phases of the HapMap project [17], which characterized common variation within the genome of four population groups, there is considerable interest in using these resources to map susceptibility genes for common, complex diseases. The genome-wide case-control association study, whereby the prevalence of genetic variants is compared between cases and unrelated control subjects without the disease, may have the greatest power to identify novel susceptibility genes [18-20]. They rely on using a very dense set of markers that capture a significant fraction of all common genetic variation, such that the variants assayed either include those that are biologically relevant, or those which are highly-correlated with the former due to linkage disequilibrium. Although some design and analysis issues remain, numerous common variants have now been identified for breast cancer and other conditions using this design [21,22].
Breast cancer may serve as a useful paradigm for common, complex disease mapping studies because, while a portion of susceptibility genes have been identified, the majority of the residual familial clustering remains unexplained, and is likely to be polygenic in nature, due to a number of lower-penetrance genes in the context of environmental exposures [23,24]. Furthermore, there are two common Ashkenazi Jewish (AJ) founder BRCA1 mutations, 185delAG and 5382insC, initially identified in linkage studies of multiple-case breast/ovarian cancer families [25]. This contrasts with most other populations in which there are numerous unique BRCA1/BRCA2 mutations, with none present at 1% or greater population frequency. The BRCA1 AJ founder mutations account for the majority of Jewish breast-ovarian cancer families, and are present in approximately 1% of the general Jewish population [26]. The AJ founder mutations, owing to their high prevalence compared to other populations, offered an opportunity to test whether they might have been identified through a case-control association study of the kind suggested as the new gene discovery strategy in the post-HapMap era.
SNP allele frequencies
A total of 289 unrelated reference subjects selected without regard to breast cancer from five population groups (48 each from African-Americans, Chinese-Americans and Mexican-Americans, 60 CEPH subjects, and 85 Ashkenazi Jews) were genotyped across BRCA1, spanning a region of approximately 646 kb. Table 1 presents the allele frequencies and Hardy-Weinberg P-vales for all the 112 polymorphic SNPs and the two founder mutations that were typed for all 5 populations. Eight of 570 tests showed departures from equilibrium at the 0.01 level, but because none of the eight showed Mendelian segregation errors within families, and because of the number of comparisons performed, they were not excluded from later calculations. Allele frequencies were generally highly correlated among Ashkenazi Jews, CEPH, Chinese-Americans and Mexican-Americans (minimum r >0.82), whereas African-Americans presented the lowest correlation values with all the other populations (maximum r <0.44). The highest correlation was found between Ashkenazi Jews and CEPH (r = 0.947) and the lowest between African-Americans and Mexican-Americans (r = 0.362). Most of the private SNPs (n = 18) originated in the African-American samples, although private SNPs were also observed in Ashkenazi Jews (n = 4), Chinese-Americans (n = 3), and Mexican-Americans (n = 1) (Table 1). Total observed heterozygosity for each marker across the five populations ranged from 0.4% for private SNPs to 49.3% [see Additional file 1]. FST ranged from 0.0047 (SNP8 – rs8176072) to 0.4338 (SNP102 – rs2593595). Sixty three percent of the SNPs showed little genetic differentiation (FST < 0.05), followed by twenty eight percent with moderate (0.05–0.15) and less than ten percent with higher genetic differentiation. We also calculated pair-wise FST measures, and the distribution was very similar for the Ashkenazi Jews, CEPH, Chinese-Americans and Mexican-Americans versus each other (range from 0.008–0.018) as compared with African-Americans versus all the other populations (range from 0.082–0.092), showing that African-Americans had by far the greatest level of differentiation. These results are congruent with the low allele frequency correlation values observed between African-Americans versus all the other groups.
Additional file 1. Summary of F-statistics and heterozygosity for all loci. Heterozygosity levels, as well as the variation in gene frequencies between populations by means of their FST (Wright's F-statistics).
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Table 1. SNP Frequencies and Hardy-Weinberg P-Values
LD structure
In order to analyze the LD structure at the BRCA1 locus, we chose two methods that rely on different premises. The first is haplotype block analysis which identifies sequential and non-overlapping sets of variants in high LD, separated by low levels of LD that are consistent with historical recombination. In this method, all htSNPs need to be genotyped in order to capture most of the genetic variation [27]. The second is a binning method in which SNPs in one LD bin can be interleaved with SNPs in other overlapping bins. Under this approach, one TagSNP per bin needs to be tested in order to capture SNP diversity [28].
Our analyses of D' and r2 showed BRCA1 residing in a large region (~288 kb) of high LD (Fig. 1), in agreement with other reports [29-31]. The entire region studied showed long-range LD, falling primarily into three blocks among non-African populations. The block containing BRCA1 includes 95 SNPs and overlaps the largest LDSelect bin of SNPs correlated at r2 > 0.8 (Fig. 2 and Fig. 3).
Figure 1. Comparison of haplotype blocks at 114 loci across five populations. Blocks were defined as in [27]; markers with MAF <0.05 are shown with a white background and were ignored in the calculations and block boundary estimation. Haplotype tag SNPs (htSNPs) within a block are indicated by arrowheads; htSNPs in only one population are shown on a yellow background while the single htSNP shared between all populations is shown on a green background.
Figure 2. Comparison of SNP bins derived from pair-wise measurements of linkage disequilibrium using LDSelect-Comp. SNPs with MAF < 5% do not have a vertical line or arrowhead in the column. A) Scale representation of the ~650 kb region studied, indicating the BRCA1 gene, founder mutations, and genome sequence gap of unknown true size. Anchor lines link to position of the SNP within the region. B-F) LDSelect creates bins of SNPs that have an r2 value of 0.8 or greater with at least one other SNP in the bin. Each vertical line and arrowhead represents a SNP, with dashed lines and shaded background connecting SNPs within the same bin. Down arrowheads indicate Tag SNPs (those with r2 ≥ 0.8 with all other SNPs in a bin). Note that this use of the term Tag-SNP is different from Haploview – with LDSelect, only one Tag-SNP per bin would be required to capture the majority of the nucleotide diversity. Singleton bins (SNPs that did not have r2 ≥ 0.8 with any other SNP) are indicated by solid dots on a single row. SNP number refers to numbering in column 1 of Table 1.
Figure 3. Pair-wise measures of linkage disequilibrium and the two founder mutation-containing haplotypes. SNP number refers to numbering in column 1 of Table 1; only the 70 with MAF ≥ 0.05 in Ashkenazi Jews are shown in B-D. A) Scale representation of the ~650 kb region studied, indicating the BRCA1 gene, founder mutations, and genome sequence gap of unknown true size. B) LDSelect-Comp output showing a total of 22 bins for Ashkenazi Jews, with 17 "singleton" bins indicated by solid dots on a single row. C) Haploview output showing three block structures and related ht-SNPs (indicated with up arrowheads). D) Haplotypes estimated for 85 unrelated Ashkenazi Jews using SNPHAP as implemented in HapScope. The block boundaries were calculated in Haploview and overlaid on this figure. All haplotypes with an estimated frequency of at least 1% are displayed (h1 to h11), with individual frequencies and sums indicated to the right of the blocks. The common allele is designated "1" and the minor allele "2". The 185delAG and 5382insC containing haplotypes, determined from the family based genotypes, are indicated with gray (haplotype 2) and blue background (haplotype 1), respectively. Black arrows indicate the relative position of these two founder mutations.
African-Americans presented the least LD of all populations, with the presence of more distinct blocks within the region (Fig. 1). Maps for all five populations shared a break-point that maps approximately 20 kb downstream of the BRCA1 gene, between SNP95 (rs2298862) and SNP96 (rs443759). Among non-African groups, only Mexican-Americans exhibited an additional break point within the 288 kb block structure that encompasses BRCA1. The 3'end of the entire region showed less extensive LD but a similar pattern across all the groups. Only one htSNP (SNP3 – rs17599948) was found to be completely shared across populations, which is not unexpected since htSNPs often are population-specific [28] (Fig. 1).
When the bin-based approach was used, we found that bins were largely shared across different ethnic groups (Fig. 2). The differences across populations were related to the number of bins as well as the number and position of TagSNPs. As expected, African-Americans were the most diverse group, containing the highest number of bins (34), followed by Ashkenazi Jews (22), CEPH (19), Mexican-Americans and Chinese-American (14). This contrasts with 28 htSNPs in African-Americans, and 16, 13, 25 and 18 among Ashkenazi Jews, CEPH, Mexican- Americans and Chinese-Americans, respectively. Three TagSNPs were shared by all populations (SNP3 – rs17599948, SNP41 – rs8176166, and SNP67 – rs3092994), showing average MAF of 0.193, 0.183 and 0.335, respectively (Fig. 2). Mexican-Americans showed two disjoint bins of highly-correlated SNPs, rather than one extended bin structure as evidenced in Ashkenazim, CEPH and Chinese-Americans. The disjoint occurred between positions 38,471,400 (SNP65 – rs8176242) and 38,469,351 (SNP67 – rs3092994), mapping between introns 17 and 18 of BRCA1 (Fig. 2F). Interestingly, our results resemble what others have observed [32] in Native- Americans, namely an historical recombination event between introns 15 and 18. All five populations showed a large bin spanning ~288 kb encompassing SNP1 (rs13119) through SNP95 (rs2298862) (Fig. 2A–F), which represented the same extended region found in the block analysis. This large bin had 0.278 average MAF across populations and included BRCA1 coding polymorphisms L771L_(TTG>CTG), P871L_(CCG>CTG), 1183R_(AAA>AGA) and S1436S_(TCT>TCC) (Fig. 2).
The maps of linkage disequilibrium in LD units (LDU) corresponded well with the two previous approaches of assessing disequilibrium. The four major breakpoints that were observed in Fig. 1 and 2, when haplotype blocks and bin structures were inferred, coincided with the same major steps in the LDU analysis (Fig. 4). In addition, we were able to observe two small steps in Fig. 4 for the Mexican-Americans, which were not observed in any other population. The first step occurred between SNP65 (rs8176242, intron 17) and SNP69 (rs8176265, intron 19). The corresponding site of possible recombination could be observed as a split at the main bin structure for Mexican-Americans in Fig. 2F. The second step was found between SNP90 (rs8176323) and SNP91 (rs7223952), downstream of the gene. A close correspondence was evidenced as a breakdown in LD around the same position in Fig. 1.
Figure 4. LDU maps. Comparison of LDU maps across the ~650 kb region containing the BRCA1 gene for 5 populations. Top. Scale representation of the ~650 kb region studied, indicating the BRCA1 gene, founder mutations, and genome sequence gap of unknown true size. Bottom. LDU maps for five populations.
185delAG and 5382insC haplotype reconstruction
We were particularly interested in fine mapping the BRCA1 locus to identify possible gene variants or haplotypes associated with the two founder mutations in Ashkenazi Jews. Therefore, 82 intragenic and 30 flanking SNPs were tested against the two founder mutations with the Pearson's correlation (r) coefficient (Table 2). Although in strong LD with the majority of markers as measured by D' (Table 2), the highest pair-wise r2 for 185delAG was 0.04, owing to its relatively low frequency, with a common SNP (SNP96, rs443759) that mapped outside the large BRCA1-containing block, approximately 110 kb downstream of the gene. Regarding 5382insC, there was one highly-significant association (r2 = 1.0) with SNP8 (rs8176072) (Table 2). This is a rare SNP that was present only in 5382insC mutation carriers, and 5382insC was not correlated above 0.03 with any other SNP in the region.
Table 2. Pair-wise correlation coefficients between the two founder BRCA1 mutations and all other SNPs among Ashkenazi Jews
Haplotypes were estimated for the set of all SNPs with MAF ≥ 0.05. Haplotypes for the founder mutation containing chromosomes were unambiguously determined in at least one family across the entire region studied. The185delAG and 5382insC mutations occurred on the two most common haplotypes, representing 15% (haplotype 2) and 29% (haplotype 1) of the chromosomes, respectively, among Ashkenazi Jews (Fig. 3D). In the haplotype analyses, the 185delAG mutation occurred on a chromosome with the minor allele at most loci, and the 5382insC on a chromosome with the major allele at most loci (Fig. 3D). This pattern constitutes what has been previously described as "yin yang haplotypes", in which two high-frequency haplotypes have different alleles at most SNP sites [33].
The primary objective of this study was to address the question of whether we could identify the Ashkenazi BRCA1 founder mutation 185delAG in a typical case-control association study, using anonymous genetic markers. The answer is no. The impact on the required sample size (S) needed if one studies a marker in LD with the true disease allele is related to the inverse of the square of their correlation coefficient (r), as in S = 1/r2 [34]. Almost none of the SNPs had a high correlation coefficient with either founder mutation (Table 2). Since most markers were more common than the founder mutations, this result is not surprising. However, our SNP selection strategy did not exclude low frequency SNPs. In fact, one of the SNPs identified in 3 of the 90 Polymorphism Discovery Resource subjects [35] was perfectly correlated with 5382insC. However, we did not observe this SNP in any of the four non-Ashkenazi reference populations. Based on our results, the sample size required to detect the 185delAG mutation in a breast cancer case-control study conducted in Ashkenazi women that did not directly test for the mutation, would be at least 25 times larger than one that measured the mutation directly, requiring on the order of 62,000 subjects. Based on pair-wise measurements, we conclude that it would have been extremely difficult to have mapped the two founder mutations using the case-control association methodology using common SNPs.
Association studies may also compare combinations of SNPs, or haplotypes, between cases and controls, and the founder mutations might have been discoverable if they occurred on uncommon haplotypes. Using relatively common SNPs (MAF ≥ 5%), like those on whole-genome SNP platforms, we found that the two mutations were present on haplotypes representing a polar pattern, termed yin-yang haplotypes [33]. These two haplotypes accounted together for a large percentage of the total chromosomes studied, independent of the population, ranging from 64% for the Chinese-Americans to 43% for the CEPH.
It is highly unlikely that the founder mutations could have been discovered owing to a difference in haplotype frequency between cases and controls largely because they occur on the two most common haplotypes. For example, consider a case-control study of Ashkenazi Jews with 500 cases and 500 controls. Among controls (1000 chromosomes), the distribution of BRCA1-containing haplotypes would be roughly as in Fig. 3D (i.e., there would have been 288 chromosomes with haplotype 1 and 153 with haplotype 2). Among cases, assuming 1% carried 5382insC and 4% carried 185delAG, there would be 5 additional haplotype 1 (total = 293) and 20 additional haplotype 2 (total = 173) chromosomes. These case-control contrasts, 293 vs. 288 (OR 1.02) and 173 vs. 153, would require extremely large sample sizes of over 30,000 subjects to detect either mutation with 80% statistical power. Conversely, in the more advantageous situation in which the 185delAG mutation by chance occurred on a rare haplotype (for example, haplotype 8), there would have been 32 such chromosomes in cases vs. 12 in controls requiring approximately 4,800 subjects for the same statistical power.
The BRCA1 locus is well known to have significant LD [29,30]. Nonetheless, we found a marked differentiation between African-Americans and non-African Americans in the haplotype block analysis. Compared with African-Americans, the non-African American populations had less haplotype diversity and more extensive LD (Fig. 1). The increased number of crossovers along the entire region for African-Americans probably reflects older evolutionary events. Our data conform to previous findings [27], describing higher haplotype diversity as well as less extensive LD in the Yoruban and African American samples than in European and Asian populations. When SNP "bins" derived from pair-wise measurements of LD were compared, we found a greater extent of LD boundaries being shared across the five different ethnical groups (Fig. 2). Ashkenazi Jews and the CEPH population had highly similar patterns of LD, independently of the type of analysis used to generate the LD structures (haplotype, or pair-wise bin methods) (Fig. 1 and Fig. 2). Overall, haplotype blocks and bins showed similar patterns, probably owing to the strong LD present overall in this region. The LDU analysis showed a remarkable overall similarity with the two previous methods that were used to analyze LD (Fig. 4). There were basically four major breakdowns in LD downstream to BRCA1 that were largely shared across populations. Nevertheless, African-Americans presented more recombination events than the other four populations, consistent with the smaller block sizes showed in Fig. 1.
In summary, our detailed analyses of 114 polymorphic SNPs in a 646 kb region around BRCA1 in Ashkenazi Jews and other populations confirmed a high level of linkage disequilibrium across nearly the entire region. In addition to 85 unrelated Ashkenazi Jews, we over-sampled carriers of the founder mutations 185delAG and 5382insC and their relatives to more precisely calculate correlations with other markers and to molecularly determine the mutation associated haplotypes (these subjects were not included in allele frequency estimates). This allowed us to assess the likelihood of discovering the founder mutations by virtue of their association with individual SNPs or haplotypes that one would assay in a breast cancer case-control study in Ashkenazi Jews. We did not observe a high correlation coefficient between any individual SNP likely to be included in a genome-wide anonymous scan and either founder mutation. Our findings suggest that a study at least 25X larger (60,000 subjects or more) would have been required if the mutations were not tested for directly. The two founder mutations occur on the two most common haplotypes, representing over 40% of the chromosomes, also suggesting that a haplotype-based analysis would not have been successful at detecting either of the underlying mutations. These results are influenced heavily by the relative rarity of the founder mutations, as reflected by high values for Lewontin's D' measures of LD but low correlation coefficients. Our results suggest caution in using genome-wide association studies with common SNPs for detecting uncommon, disease-causing mutations.
Independent subjects included 85 unrelated Ashkenazi Jews, 60 European-Americans (Utah) from the CEPH (The Centre d'Etude du Polymorphisme Humain) family collection, and 48 each from African-Americans, Chinese-Americans and Mexican-Americans (Human Diversity Collection, Coriell Cell Repository, Camden, NJ). The 30 children of the 60 Utah CEPH subjects were also assayed to test for Mendelian errors. In addition, six unrelated BRCA1:185delAG and three unrelated BRCA1:5382insC founder mutation carriers and their relatives [36], identified through the National Cancer Institute's Cancer Family Registry, were included in the study in order to establish mutation-associated haplotypes from family data. Mutation-associated haplotypes were inferred through inspection of genotypes for all available first-degree relatives of mutation carriers. The Ashkenazi Jewish samples were obtained from anonymous control subjects from the National Laboratory for the Genetics of Israeli Populations at Tel-Aviv University [37].
Marker selection and genotyping
The 90 kb BRCA1 locus was previously re-sequenced in 90 individuals representing five major US ethnic/population groups from the Polymorphism Discovery Resource (PDR-90) [35], by the University of Washington as part of the Environmental Genome Project (EGP) [38]. Samples consisted of 24 European-, 24 African- 24 Asian-, 12 Mexican-, and six Native-Americans. The geographic origin of individual donors, however, is masked and may not be used to assign allele frequencies to specific sub-populations. Most of the 301 variants identified were SNPs. Genotyping all 301 variants at this locus in the current study was not necessary since many are highly correlated. We developed the following strategy to identify a reduced set of variants that still captured much of the diversity of the region. Using the EGP data on all 299 biallelic single nucleotide substitutions (i.e., no lower minor allele frequency cutoff), and using custom software, we calculated all pair-wise correlations (r2) and created "clusters", defined as groups of SNPs that were perfectly correlated with all others in the cluster. Our method is similar to LDSelect 1.0 [28] except that it required that all pair-wise correlations of SNPs in a cluster be 1.0 (i.e., complete LD). LDSelect is typically used with a threshold value of r2 of 0.8, and SNPs are clustered into "LD bins" if their pair-wise r2 is at or above this threshold value with at least one other SNP (but not all) in the bin. Using an r2 of 1.0 resulted in more clusters than a lower r2 threshold, increasing the number of SNPs assayed in this study.
Taqman 5'-nuclease assays were developed through Applied Biosystems (Foster City, CA) Assay-by-Design service after first filtering for repetitive, non-unique, and low-complexity sequence. We developed assays for all "singleton" SNPs (those that did not have pair-wise r2 values of 1.0 with another SNP). For the 59 clusters with two or more SNPs, we chose one SNP from each cluster of two, three and four SNPs, and for 9 clusters of five or more SNPs, we chose one fourth of them for assay development. In addition, we selected all (n = 43) commercially available Assay-on-Demand assays (Applied Biosystems, Foster City, CA) that mapped within approximately 200 kb upstream and 400 kb downstream of the BRCA1 locus. This SNP set represented almost all known variants (or ones highly correlated) at this locus.
Of the 143 resulting assays, three were excluded due to technical problems (poor clustering or more than one Mendelian error), and 28 were not polymorphic in our complete sample set, leaving 112 polymorphic SNPs in addition to the two founder mutations. There were 82 BRCA1 intragenic SNPs (approximately one SNP per 1 kb) and 30 SNPs that mapped to the region outside BRCA1 (approximately one SNP per 20 kb). The allelic discrimination assays were performed in 5 microliter reactions in 384-well plates according to manufacturer's recommendations. Data were analyzed with the allelic discrimination SDS 2.1 software on an ABI 7900HT (Applied Biosystems, Foster City, CA), with manual determination of genotype clusters [see Additional file 2].
Additional file 2. Genotypes for all 114 polymorphic SNPs in 5 populations. Raw genotypes. Populations: (1) CEPH (includes related individuals), (2) African Americans, (3) Chinese Americans, (4) Mexican Americans and (5) Ashkenazi Jews.
Format: TXT Size: 121KB Download file
Statistical analysis
Allelic frequency and chi-square goodness-of-fit tests for Hardy-Weinberg equilibrium (HWE) were calculated using SAS/Genetics 9.1 (SAS Institute, Inc., Cary, North Carolina). To assess the correlation between the two founder mutations and all other SNPs, we over-sampled mutation carriers and calculated a weighted Pearson's correlation coefficient using SAS 9.1. We also tested association by use of Tagger [39] operates in either pairwise or aggressive mode, and we used both approaches to examine association. Heterozygosity levels, as well as the variation in gene frequencies between populations by means of their FST (Wright's F-statistics) were calculated using POPGENE 1.31 [40].
Haplotypes and their frequencies were inferred from genotypes across the entire region for each population separately, using the software package SNPHAP 1.3 [41], as implemented in Hapscope [42], for loci with minor allele frequencies (MAF) > 5%. SNPHAP uses the expectation-maximization algorithm to calculate maximum likelihood estimates of haplotype frequencies from unphased genotype data.
In order to compare LD patterns across different populations, we employed two different analyses, the first based on partitioning SNPs into haplotype blocks [27] using Haploview [43] and the second based on "bins" of correlated SNPs not constrained to be adjacent to each other [28]. The binning method used a modified version of LDSelect 1.0 that calculates composite LD measures [44], without assuming that loci are in Hardy-Weinberg equilibrium. We used an r2 threshold of 0.8 for binning SNPs, and filtered SNPs with population-specific MAF ≤ 0.05.
LDSelect identifies tagSNPs, representing those SNPs in a bin that have r2 values at or above the threshold with all other SNPs in a bin. Only one tagSNP in each bin needs to be assayed to capture the majority of the SNP diversity. The block method employed by Haploview groups adjacent SNPs in strong LD, defined as those with one-sided upper 95% confidence bound on D' >0.98 and the lower bound >0.7. In this method, haplotype tag SNPs (htSNPs) represents the set of SNPs that must be assayed in each block to capture all haplotypes at 1% frequency in the population.
LD maps were constructed from genotype data with the software LDMAP [45]. LD maps are scaled in linkage disequilibrium units (LDU) and show (when plotted against the physical map) a pattern of plateaus (reflecting regions of low haplotype diversity and low recombination) and steps (representing regions of historical recombination events).
We genotyped related individuals from families segregating 185delAG and 5382insC founder mutations in order to reconstruct their haplotypes. The 185delAG- and 5382insC-containing haplotypes were unambiguously determined from analyzing the genotypes of all available family members. The frequencies of these mutation-containing haplotypes were determined from SNPHAP analyses of the five populations separately. Block boundaries were defined based on Haploview analyses and overlaid upon the SNPHAP results.
We estimated the required number of subjects to have 80% statistical power to identify the 185delAG mutation if tested directly in a case-control study to be approximately 2492 using EpiInfo 4.0 [46], assuming equal numbers of cases and controls, alpha of 0.0001, and heterozygous carrier frequencies of 0.6% for controls and 3.3% for cases.
Competing interests
The author(s) declares that there are no competing interests.
Authors' contributions
LMP performed laboratory and statistical analysis and drafted the manuscript. MAP and LRF performed laboratory analysis. WHR and JZ wrote custom software and performed statistical analysis. MHG provided biomaterials and critically revised the manuscript. KO and NAE participated in the study design and analysis. AC provided design assistance and performed statistical analysis. JPS conceived and designed the study and performed statistical analysis. All authors read and approved the final manuscript.
This research was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research and the Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. Department of Health and Human Services.
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text:
Heywire winner Andrew Tiller
The changing moods of a very small town
I can.
Dutton Bay, known to most as Dutton, but to seven teenagers who live there it's just "Shed City".
Yes, Shed City, a thriving metropolis where boat sheds outnumber houses, where the weather is never what they forecast, and where the water's always swarming with jellyfish whenever it's hot enough for swimming.
This is where me and a few others have spent the last few years of our lives, just hanging around like flies to a bad smell.
One of Dutton's personalities can be seen during the Easter holidays.
It's streets with a continuous rumbling as the largest convoy of cars that anyone has ever seen approaches for the Craft Fair.
In two days the Bay sees over 2000 tourists pass along the road going to and from the fair.
Dogs barking, children screaming, horns tooting and the tune being played by the over fifties band mix together to form a melody so horrible as to leave the ears ringing for weeks.
Following a high like this Dutton turns into a quiet, picturesque, lethargic scene with the odd person outside doing anything from the gardening to the chooks.
No children are around; the youngest person left in the Bay during a school day is probably 40.
The days are only livened by the return of Dutton's future generation but this rarely lasts.
This goes on for weeks with every day just like the one before.
Get up, go to school, come home, go to bed, over and over again.
Now I understand the saying "variety is the spice of life".
Dutton's final mood is by far the best. School Holidays.
Again Dutton is brought to life when the population doubles as a swarm of happy campers flocks to the Bay in convoys.
In just days every shack is packed so full that you wouldn't be surprised if they exploded and everything inside was scattered for miles.
The jetty is turned from an old wooden structure into the ultimate place to be.
With everyone swimming, fishing or jetty jumping this is by far the most fun of Dutton's changes.
Not one of Dutton's moods is like the other, there's the Good, the Bad and the Ugly.
I just hope the latter doesn't rub off on me.


text:
New move to ease parking problems in Brampton
Last updated at 15:32, Friday, 12 August 2011
Moves to resolve long-standing parking woes in Brampton have taken a step forward.
Carlisle City Council is carrying out a study to look at using its land around the town centre for a new car park.
Officers hope to have a plan in place to alleviate the problem by the end of the year.
One site previously put forward as a possible location for a new car park is a section of land behind St Martin's Church.
It has been said that space could be made on unused land, which can be accessed from Main Street, for up to 30 cars.
Leader of the city council and Brampton member Mike Mitchelson said: "Parking is a big issue in Brampton and it often crops up at meetings of the economic partnership and parish council.
"We have taken this on board and are looking at ways to help resolve the issues for the people of Brampton."
Brampton town centre is notoriously busy, with many shoppers struggling to find places to park on Front Street and around the Moot Hall.
Residents often raise the long-running issue of parking grief at parish council and neighbourhood forum meetings and traders have frequently complained about the effect it has on their businesses.
Mr Mitchelson added that the authority has launched a traffic study to look closely at the issue in the hope of finding a solution.
He added: "We need short-term parking near to the centre of the town and are looking to see if we can provide long-term parking a bit further out.
"This would ensure a more fluid exchange of spaces in the town centre."
Mr Mitchelson confirmed that a section of land behind St Martin's Church was being explored as an option but said their were many factors to consider.
"There is a play area near this part of land too," he said. "We have to consider the needs of the community. This, along with access, will be looked at as part of the study."
He added that the city council was working with the town economic partnership, parish council and the county council and said: "The study is ongoing but we would like to have a resolution later this year."
On the issue of cost, he added: "We have no idea what it might cost at this stage. The funding will be an issue but it is not going to stop us looking at how to alleviate the car parking problems in Brampton."
First published at 14:10, Friday, 12 August 2011
Published by http://www.cumberlandnews.co.uk
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text: Quick View Silver Penny Treasury: Classic Tales by Various Authors September 3, 2013 | Trade Paperback In stock online from $15.85 There''s action, excitement, and cleverness aplenty right here! From Jack slaying a giant to Robin Hood battling the cruel Sheriff of Nottingham, these timeless tales will satisfy adventure-loving children. Silver Penny Treasury: Tales of Adventure includes: Jack and the Beanstalk , Puss in Boots… See Details $16.68 / $15.85 lowest price*, or used from $14.88was $21.95


text:
The 10 Best Hairstyles at the 2013 Emmys
From loose, glamorous waves to sharp, edgy bobs, these 10 ladies owned the night with their gorgeous Emmy 'dos.
By Lauren Le Vine
Kiernan Shipka
She may only be 13 (yup, that's it), but
Sally Draper Kiernan Shipka is already one of the most stylish stars on the red carpet. Her perky ponytail is perfect for mornings when you've got negative time to get up and out of the house.
Getty Images


text:
Learn more about the five boroughs that make up New York City with our complete guide.
Discover what to do, where to stay and what to see in New York City with our planning tool.
NYC is the place for inquisitive minds looking for new things to see, hear, taste and learn.
Enjoy The Nutcracker, the Times Square New Year's Eve Ball Drop, the Orchid Show and more.
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Wireless Internet is available at locations throughout NYC—including many parks and libraries.
Get tips, maps and everything else you'll need during your stay.
These NYC-centric mobile apps put the City at your fingertips.
Get the best prices at NYC's bars, clubs and restaurants.
Special dining offers, exclusively on Sunday.
Hotel deals to make you fall for NYC.
New York City is made up of five boroughs: the Bronx, Brooklyn, Manhattan, Queens and Staten Island. Each one has enough attractions—and enough personality—to be a city all its own. Learn more about them with this guide.
Armed with the motto "Right Media. Right Results," this world leader was founded in 1983 and aims to provide helpful information to travelers all over the world. Its network of more than 10,000 visitor traveler-information stands (featuring pamphlets and other info on popular local tourist destinations) and video display stands are located in more than 25 states and provinces in the United States and Canada.