text:
Sam Bourne
Sam Bourne
Sam Bourne is the
literary pseudonym of Jonathan Freedland, an award-winning British
journalist and broadcaster. He has written a weekly column for
The Guardian since 1997, having previously served as the
paper's Washington correspondent. His work has also appeared in
The New York Times, The New York Review of Books,
the Los Angeles Times, The Washington Post,
Newsweek, The New Republic, and The Jewish
Chronicle, and he presents BBC Radio 4's contemporary-history
series The Long View.
For nearly two decades he has covered the Middle East conflict, and
in 2002 he chaired a three-day dialogue between Israelis and
Palestinians, which was sponsored by The Guardian. The
participants in that meeting went on to broker the 2003 Geneva
Freedland is the author of the New York Times bestselling
novel THE RIGHTEOUS
MEN, also a number-one bestseller in the UK, which has been
translated into thirty-one languages, and the nonfiction works
JACOB'S GIFT and BRING HOME THE REVOLUTION. He lives in London with
his wife and two children.
Sam Bourne


text:
Search Results For "john deere neon clock nothing runs like a deere logo" (0)
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subset: commoncrawl


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Forgot your password? Enter the email address you signed up with and we will send you a link to create a new password.
Your password reset has been submitted to the address provided.
Design plus words, letters, and/or numbers
Banking; credit and cash card services; financial services in the field of money lending; home equity loans; mortgage lending; on-line banking services; savings and loan services; trust services, namely, investment and trust company services
Business in San Mateo, CA


text:
Wait! We think you're in the US - Lovehoney.com is a better site for you.Shop there and get 10% off!Go to Lovehoney.com
Bathtime Pleasure Pack
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Product Description
Clean body, dirty mind with these waterproof erotic suggestion cards and scented bath salts. Comes in three varieties: foreplay (vanilla-lavender scented), sensuality (honeysuckle) and passion (strawberry). Heat up your tub without using the hot water!
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text:
About Us
TOFA (To'utupu'o e 'Otu Felenite Association) Inc., which translated means Friendly Islands Youth. TOFA officially launched as a 501© (3) non-profit organization October 6th, 2000. TOFA was started to provide a much needed Pacific Island community-based organization that could support the growing numbers of Pacific Islanders in the Sacramento area. When TOFA began its work 8 years ago, there was no community organization that could work with the language and cultural barriers faced by many Pacific Islanders, especially youth, to assist in their transition as productive members of society.
Our Mission
The mission of TOFA is to preserve and enhance the overall Health and Wellness of the Pacific Islander Community in the Greater Sacramento Area by providing resources that support and promote Higher Education, Community Leadership Opportunities, Civil Rights Awareness, and Cultural Arts.


text:
Red Shift Limit was an anti-Imperial band that performed during the rule of the Galactic Empire. Their rival was the band The Emperor's New Clothes.
- Galaxy Guide 9: Fragments from the Rim
- "Slugthrowers: An Overview of Popular Music and Musicians in a Galaxy Far, Far Away, Part 2," The Official Star Wars Blog (link)
In other languages


text:
A lot of developers that create some apps are having a problem of advertising them and getting feedback from users (me included). So I think we should help each other by installing, testing, rating and reviewing each other's apps. So any one of you who have their app post it here (google play link) and I will try it and publish a rating and a comment on Google Play.
I don't ask you to do the same and I will do it whether you try my application or not. If you do the same I will be very grateful.
We can rate and support us here by rating others apps
5 stars and a review to you from Anuloid Games. Keep developing!!
Please consider rating us as well at play.google.com/store/apps/developer?id=Anuloid+Games


text:
Starting a Kidpower Center or becoming an Authorized Agency Provider to become certified to organize and teach workshops under our auspices
Kidpower Teenpower Fullpower International provides workshops in different communities through our Centers and Authorized Providers that organize and teach programs under our auspices and with our ongoing mentorship and support.
People who wish to take leadership in bringing Kidpower to their community also become instructors with our organization. If you are interested, please start by learning about becoming an instructor so you understand what is involved and whether you would work under the auspices of an existing center or whether you would need to establish a new center to teach our program in your area. If you are part of an agency or business that meets our requirements, another option is to establish an Authorized Agency Provider agreement.
In either case, please take time to consider whether Kidpower seems like a good fit for you, personally. All of our instructors, center directors, and agency providers commit to upholding our mission, goals, and values; to maintaining our extremely high quality standards and ethics; and to making a long-term investment of time and effort to be part of our organization.
If you're interested in the possibility of starting a Center or establishing an Authorized Provider Agreement, please read the information below.
What Kind of Time is Required to Start a Center?
Most of our Center Directors and Instructors have many other commitments and do this work part-time. While setting up a Center can generate income eventually, you must think of your involvement first of all as a cause you believe in rather than as a way to make money. Starting a Center or becoming an Authorized Provider does not mean you need to make this a full time career or that you need to provide a certain amount of service. It does mean that you will work under the auspices of Kidpower, able to benefit from the track record and mentoring we provide. You will be required to uphold our mission, goals, and values and report to our Executive Director, Senior Program Leader Council, and International Board of Directors. Many individuals slowly bring Kidpower services to their communities while also having other full or part-time careers, family commitments, and other responsibilities.
Getting to Know Each Other
- Please review all the information available about our organization, services, and also the business aspects of running a center such as insurance, liability, materials, center support fees, record-keeping, etc.
- Learn as much about our program and organization as you can by reading all of the About Us sections on our website, reading The Kidpower Book for Caring Adults and other publications, watching the free videos in our online Library, signing up for our free enewsletter, and taking a workshop if there is one you can travel to.
- Prepare a thorough written statement describing your background, education, work history, and reasons for wanting to start a center. Please see how to apply. Please clearly state you are also interested in becoming a Center Director or in establishing an Authorized Provider Agreement in addition to participating in the Certified Instructor Training Program.
Making Agreements Together
- Initial Agreements: If you are interested in going forward and we believe you demonstrate skills and qualities consistent with our Center Director Certification Standards, we'll work together by phone and email to establish clear agreements. At this stage, you would complete a Center Agreement in addition to the Instructor Application and Instructor Training Agreement.
- Service Delivery Plan: Next, we'll make an agreement about your center's service delivery plan, taking into account how far your area is from other centers as well as your own goals and prior experience. The plan will define your geographic service area, though it will not grant you exclusive entitlement to conduct programs in that area. You will also not be exclusively confined to that area: centers can get permission to offer services in other areas as long as they check first to ensure that existing agreements and relationships won't be affected. Our goal is to increase access to our services in cooperative rather than competitive ways while keeping our quality exceptionally high. We have successful models for making this happen.
- Center Name: The name of your center must start with Kidpower or Kidpower Teenpower Fullpower. You'll propose options for your center's specific name, which is usually based on a city, county, geographic region, or nature symbol reflecting the area, and we'll agree on one you like that also fits us, organizationally.
Launching Your Center
- Ask us questions. We provide ongoing consultation to help our centers set up and run successful programs. Centers cover any long distance telephone, word processing, photocopying and postage costs incurred in the process, but otherwise, we offer this consultation at no cost.
- Spread the word in your community. As you start building a base of potential students as well as potential donors, we can provide samples of fundraising and marketing materials used by other centers. We'll help you figure out how to adapt them to best meet your own needs.
- Decide how to set up your fees and services. Center organizers have the right to decide how to set workshop fees for their communities. We do provide a scale of self-supporting fees. Often, people say this is too much for people to pay, but we've found that setting the fees too low can be a big mistake. Our centers in communities around the world have found that it works best to set fees on a break-even basis that includes all overhead and then to set up a generous sliding scale scholarship policy, supported by donations, so no one is turned away for lack of money. No matter what fees you establish, you will need to invest time in community education to help people understand the value of this training.
- Start teaching Kidpower skills. This begins during the Fieldwork Training phase of your instructor candidacy, and we hope it lasts for many satisfying years!
All new Center Directors will be given a supervisor for two years who will give them step-by-step guidance and help them create a plan for launching their centers. After the two-year start-up phase, new Center Directors will receive ongoing support from the Executive Director and Central Office and may continue to work with their supervisor, if needed.
Preventing and Resolving Conflict Between Centers
- Psychological Review: We have been advised by many therapists that the best psychological screening we can do is to work intensively with people as we do in our training and center development process. We also require a background check at the applicant's expense in whatever forms are available in a given country as part of the instructor training application process.
- Conflict Resolution: Although we do our best to prevent conflict through having clear agreements and standards, disagreements and misunderstandings arise when people work together. We each agree to communicate any concerns directly to the person who is responsible — the trainer, executive director, or center director. If concerns remain unresolved, we each agree that we'll put our concerns in writing.The Executive Director, Senior Program Leader Council, or a designated Board member can help to mediate conflicts. If communication breaks down seriously, we may choose to work with a professional mediator, sharing the cost between the Center and Kidpower Teenpower Fullpower International. A serious conflict that remains unresolved may then be brought to the Senior Program Leader Council, which will make a recommendation to the international Board of Directors, which has final decision-making authority.
Business Aspects of Starting a Center
Setting up a center involves not just a commitment to teaching our skills effectively but also a commitment to addressing the 'business aspects' of running a nonprofit organization effectively. We provide much more extensive information and ongoing mentoring, in writing and through phone, email, and Skype communication. We are happy to answer emailed questions and, after someone has submitted their written statement, paid their application fee, and are in the screening process, to answer questions on Skype or by phone. However, we want to provide the following information so that anyone considering working with Kidpower by establishing a center can deepen their understanding of how our nonprofit organization works.
Common issues relate to:
Establishing a Nonprofit Organization or NGO
Although we heavily encourage people to charge fees and raise funds for their time in teaching and organizing our workshops, Kidpower is a nonprofit organization rather than a business that people can buy and sell. In the United States, all Centers are under the umbrella of our 501(c)(3) nonprofit organization until they become large enough to establish their own charitable organization. They can register in their different states under our nonprofit umbrella for a minimal fee and provide financial information quarterly.
In countries outside the US, people starting Kidpower Centers must commit to working towards establishing a nonprofit organization or NGO in their country as soon as they reasonably can or to working under the umbrella of another NGO that we then make an Authorized Provider Agreement with. There are different structures for charitable organizations in different countries and the international organization works with local centers to go through their own local process. Once a separate nonprofit board is established, this board is bound by the Training and Center Agreements made with Kidpower Teenpower Fullpower International by the person starting the Center. Once a Center has established its nonprofit status, we provide guidance in how to seek funding from service clubs, businesses, foundations, individuals, and governments.
Workshop Fees
Local Centers have the right to decide how to set workshop fees for their communities. We provide a set of recommended self-supporting fees. Usually the first reaction people have is that this is way too much for people to pay in their community. We are a nonprofit organization and local Centers often seek funding to subsidize the costs of our services. We have found that it is a mistake in the long run to set the fees of our classes too low. Our experience in many different types of communities is that it works better to set fees on a break-even basis that includes all overhead and to have a generous sliding scale scholarship policy supported by donations so no one is turned away for lack of money. This makes it clear for everyone what the value of the program is. Community education is needed no matter what the fees are to help people understand the value of this training.
Costs of Importing Trainers
Most of the time, people starting Centers work long distance before and after coming to the Training Program, rather than importing instructors.
Since we are a nonprofit organization, we can guide people in local centers in how to fund raise to cover these costs. It takes one trainer to conduct the Everyday Safety Skills workshops and at least two trainers to conduct the Emergency-Only Full Force Self Defense workshops.
The training fees to our organization for sending trainers depends on distance and type of workshop. All travel expenses such as shuttle to the airport, airport parking, airfare or rental car, meals and lodging are also the responsibility of the Center. Trainers could stay in people's homes provided that comfortable private space can be arranged. Meals do not need to be fancy as long as they are healthy and meet any dietary restrictions.
We adapt the programs offered to fit the needs in each community. A number of Everyday Safety Skills Workshops can be offered on the same day. Programs that go on for several days can sometimes be arranged for a lower daily rate.
In addition to the trainer fees and travel, the Center is responsible for all other costs involved with organizing and conducting the workshops including room rental which can often be donated, marketing, etc.
Risk Management
Centers are responsible for following Kidpower's safety practices to ensure that students are safe before, during, and after workshops as long as they are on the premises. No instructor should be alone with children at any time- either another instructor,children's parents, teachers, or other staff members should always be present.
All students or their legal guardians (parents, organizations acting as guardians) must sign a release of liability for all full force workshops or any workshops focusing on physical self defense. All volunteers and staff in an organization must sign an agreement not to sue for anything that happens through their involvement. All Centers must require that anyone driving for the organization have their own automobile insurance coverage that would apply in case of an accident even if they are driving on behalf of our organization.
In the United States and Canada, Centers will participate in our liability insurance coverage. This insurance covers liability only for accidents happening in classes to students. The costs of insurance may vary from year to year depending on our policy, but will be lower than what an individual could obtain separately for equivalent coverage. Outside the United States and Canada, Centers must have liability insurance coverage at a level appropriate for their country.
Schools or organizations receiving services are responsible for their own liability and centers should check first before signing any agreement that requires their accepting liability.
Publications and Information Material
The Center is responsible for the cost of providing written information materials to students. We will provide electronic masters of all handouts and promotional literature for the Centers to copy. If people wish to have information individually tailored for their Center, then we can send editable copies in Word or Indesign.
Books such as Manuals, Teaching Kits, Safety Comics, and Guides can be ordered and purchased online by the Center. These publications are copyrighted material and may not be reproduced by the Center without a separate written agreement.
Center Support Fee
A Center Support Fee on all gross income (income before expenses) is paid by the Center to Kidpower Teenpower Fullpower International. This requirement includes income from all sources except the Center Organizer's own personal donations to the program–any other donations, fees, grants, sale of products except those purchased directly through the Central Office, etc. The Center Support Fee helps to cover the costs of providing ongoing quality control; subsidized instructor training and conferences; ongoing program development; referrals; use of the programs names, content, and reputation; and ongoing coaching by experienced instructors.
After the first year after training, a Center Support Fee is needed to help cover the cost of providing ongoing support and licensing for use of the Kidpower program and name. For new Centers or Authorized Provider Agencies, this fee is 500 USD per year or 5% of all gross income (income before expenses) per year – whichever is greater. This amount will be adjusted annually for inflation.
Along with ongoing mentoring, the Center Support Fee includes the opportunity for a review of two video recorded classes for an Instructor Candidate's follow up training. An additional Video Review Fee of 100 USD per video recorded class will be charged if we are reviewing more than 2 classes per year and the Center is not paying more than the minimum Center Support Fee of 500 USD.
Liability Insurance
In the United States and Canada, Centers are covered through our two liability insurance policies—one is 2 million USD coverage for liability associated with teaching workshops and the other is an Officers and Directors policy. Individuals are still responsible for their own automobile liability and office premises liability and for paying worker's compensation insurance as required in their states or provinces. In countries outside of the United States and Canada, Centers will purchase liability insurance to provide adequate coverage for the kind of work they are doing in their country and will take full responsibility for any liability to the organization resulting from their provision of services.
For new centers in the United States and Canada, we waive your insurance costs for the first year you are in your certification process as long as you are not collecting fees for service and you are not teaching physical self-defense. If you collect fees for service in your first year, your insurance costs are 300 USD if you earn less than 6,000 USD a year and teach only Everyday Safety Skills (i.e. no physical self defense practice).
For new centers in their second year, conducting only Everyday Safety workshops and earning less than 6,000 USD per year will pay a minimum fee of 300 USD a year for insurance. New Centers will pay a pro-rated amount to cover increased costs if their income is over 6,000 USD. Centers offering any type of physical self-defense practice with kick-pads or a full force padded instructor will pay a minimum fee of 1200 USD a year, which can be prorated based on when they start.
After the two-year start-up period, an individual Center will pay an insurance fee of 1200 USD for up to 50,000 USD worth of services if full force work is conducted and 800 USD a year if only every day safety workshops are conducted. Centers earning more than 50,000 USD will pay an increasing amount of their share of the liability insurance cost depending on their level of income. These fees may need to be adjusted depending on insurance costs.
Record-Keeping Requirements
All of the following information will be kept in the Center's main office, and will be given to Kidpower quarterly or oftener on request.
Service records need to be kept of all names, addresses, telephone numbers, and other relevant information such as types of information requested and what classes they took of all people who contact your Center. This information will be entered into a data base to use for future marketing and will submitted to Kidpower upon request. Annual statistics will be kept of the numbers of people served in each program.
Employment records need to be kept of who was paid for what type of activity for your reports to state and federal agencies for individual tax purposes and for whatever worker's compensation requirements you have in your state or country.
Financial records need to be kept of the amount and source of income the Center receives and the amount and type of each expense the Center incurs at least monthly. The form we use in the United States is based on the categories required for our Internal Revenue Service (IRS) nonprofit reports. The IRS requires that we provide the names of contractors and major donors. We are flexible about the type of bookkeeping system used by your Center as long as clear records are kept so that we receive this information in the format we need.
Center Start-up Help and Fundraising
We provide ongoing consultation to help Centers set up and run successful programs. This consultation is provided at no charge to Centers except for their covering any long distance telephone, word processing, photocopying and postage costs. Samples of fundraising and marketing materials used by other Centers are provided and Centers are helped to adapt these materials for their own situations.
Paying Others to Teach or Do Other Work
Center Directors who are paying others to teach or do other work are responsible for meeting all legal requirements in their state and country, including labor laws, worker's compensation insurance, payroll taxes, etc.
Establishing an Authorized Provider Agreement instead of working in a Center
On a case-by-case basis, Kidpower sometimes makes Authorized Provider Agreements with organizations, schools, or businesses that are providing services to people with specific needs or to a specific unserved community to allow them to send qualified staff to participate in our Certified Instructor Training Program and to use these certified Kidpower instructors to organize and teach workshops through the Authorized Provider in collaboration with Kidpower. Requirements include:
- That the individual to be trained has an established position within this agency, successfully competes our application process, and signs an Instructor Agreement with Kidpower.
- That the nature of the services to be provided is mutually supportive and does not compete with the funding or services of Kidpower International or of any Kidpower Center serving the same area.
- That the agency's mission, goals, and values are aligned with Kidpower's.
- That the head of the agency who has the authority to make legally-binding long-term commitments signs the Authorized Provider Agreement spelling out the use of the program, the need for follow-up training for certification, and what happens if a Certified Instructor leaves the agency.


text:
Hey! This thing is still a Work in Progress. Files, instructions, and other stuff might change!
HDD Rail for Medion/Digitainer HTPC case / Schiene 3.5 inch
by Schorhr, published
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For my new computer setup, I chose the cheap €15 Medion/Digitainer HTPC-Case
from Pollin. It's a surprisingly well made case with screw-less drive mount... IF you have the parts, which are not included for a 3.5" Harddrive.
After considering mounting the drive under the DVD burner, but beeing unhappy with the 5.25" to 3.5" adapters I could find, I started one myself. I tried to keep it minimalistic (cheap&fast), but I did not finish it (See SketchUP file: Test_HDD_5-25_3-5_Adapter3.skp).
Instead I decided to create slides for the intended harddrive bay, and after finding some similar one at Google Warehouse that did not work out, I started from sketch.
I somewhat cleaned them up and made them a single manifold object, plus changed it so they can be printed without support material from one side.
The spacer-STL-Part sticks into one of the slots (not identical, so try which one fits), and keeps the rail in place vertically, too.
The initial version's fit was VERRRRY tight, I included a (untested) SLIM version (about 0,4mm thinner).
Also note that the plastic rail is not reaching to the bottom of the drive, what some may prefer instead of sliding the drive on the bay directly. You will need to increase the part height (upper printing side) half a millimeter or so.
Have fun!
PS: See screenshot for best printing orientation on small beds.
PPS: Don't wear as earring.
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I gotta ask a question but how would a European read 1,001?
Hi DarkAlchemist,
-As in reading out loud?
-you mean the punctuation?
In most european countries spaces or punctuation is used to write larger numbers.
So here (germany) it would be the equivalent of 1.001 in written english... So basically a little more then one.
I keep constantly mixing up these things when posting / going back and forth in languages. Though here no one really gets irritated if someone writes $10.01 instead of $10,01 for example, since the format is different (only two numbers after the punctuation) and probably due to common use in IT and English literature.
Yes, it makes it very hard with the use of the decimal point (.) versus the comma when working with small numbers as 1,001 means one thousand and one but it also means 1 and 1 thousandths which is so confusing and add spaces into it it just looks so odd.
I read Wiki about the use of . and , but it still makes the use of , so confusing. Even in Solidworks if I enter , ir converts it to . when I am in the ISO or ANSI mode.
Just write 1+10E-4 :-)
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HDD Rail for Medion/Digitainer HTPC case / Schiene 3.5 inch by Schorhr is licensed under the Creative Commons - Attribution - Non-Commercial license.
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text:
There are two "firsts" in this post.
My first time to do an album cover inspired look...
…and my first time to wear everything Forever21.
|everything Forever21
|Photos by Carlo Arizabal
"And now the things I've done to forget you
Well it's not what I had planned
The sweetest thoughts get twisted
In the Strangeland"
- Keane


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HAMILTON, Ontario, April 19 (UPI) -- Jonathan Frid, who played vampire Barnabas Collins on the 1960s gothic soap opera "Dark Shadows," has died in his native Canada, his family said. He was 87.
Frid died last week of natural causes at Juravinski Hospital in Hamilton, Ontario. His death was first reported Thursday by Digital Spy. No specific cause was given.
The actor appeared in the 1973 television movie "The Devil's Daughter" and 1974 horror flick "Seizure." His last acting credit was a cameo in director Tim Burton's "Dark Shadows" movie, which stars Johnny Depp in the role of Barnabas, Digital Spy said. It is due in theaters next month.


text:
Miramar (FL) Everglades lineman Uriah Grant has spent the past year and a half receiving interest from some of the top schools in the Southeastern part of the United States. The 6-foot-1, 250-pound...
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text: The classic hotel in Tirgu Mures is a sublime address for those looking to stay in the very heart of Transylvania. The charming building has been refurbished and kept in a classic style with modern conveniences. There are numerous restaurants, bars, nightclubs, public transport links and shops available in Tirgu Mures. The Medieaval Citadel and the Palace of Culture are nearby attractions. The centrally located hotel offers 104 rooms, including singles, twins and suites, as well as a fully equipped conference room with a capacity for 200 seats. The hotel offers panoramic views over the city and is decorated with paintings by local artists. The city residence was fully refurbished in 2011. Guests are welcomed in the lobby with 24-hour reception and check-out services, a hotel safe, lift access to the upper floors and a newspaper stand. Facilities include air conditioning, a hairdressing salon, TV lounge, wired and wireless Internet access, and both room and laundry services. Guests can wine and dine in the café, bar and restaurant. The single rooms are ideal for the individual visitor. Modern furniture, warm colours and comfortable beds ensure a relaxed atmosphere. The hotel double rooms cater for couples or guests travelling together. Children under 7 years of age may stay in the hotel for free. All are en suite with a shower, bath and hairdryer. In-room amenities include a double bed, direct dial telephone, satellite/cable TV, a radio, Internet access, a safe, minibar, and tea and coffee making facilities. The air conditioning and heating are individually regulated.


text:
While MRA is widely accepted for the surveillance of these patients, "the ideal protocol for MRA has yet to be established, especially with regard to the use of intravenous gadolinium for the detection of aneurysm remnants," wrote Dr. Richard Bonsall and colleagues from the Medical University of South Carolina in Charleston in their poster presentation.
For this retrospective study, 39 patients underwent endovascular coiling and were imaged with 3D time-of-flight (TOF) MRA on a 1.5-tesla magnet. The majority of patients (51%) had aneurysms that were between 6-10 mm in size and 73.5% of the aneurysms had anterior circulation. The field-of-view (FOV) was 160 and the slice thickness was 0.5 mm. Each sequence took five minutes and 24 seconds.
Imaging was done before and after gadolinium administration. Source images, as well as maximum intensity projection (MIP) images, were examined to assess for residual flow within the coiled aneurysms and for venous contamination.
A total of 21 aneurysms were evaluated (16 anterior circulation, five posterior circulation), according to the results. Residual flow was present in 11 of the 21 aneurysms. The authors said there was no instance in which remnants were rendered visible by the gadolinium-enhanced images. In three cases, postcontrast images did enhance residual flow, but not significantly more than precontrast images.
More importantly, in five cases the contrast agent filled veins that were adjacent to the aneurysm, which mimicked residual flow, the authors noted.
"Contrast was initially proposed because it is believed that some areas of slow flow in the residual aneurysm will appear hypointense on 3-tesla TOF MRA and subsequently will be misinterpreted as aneurysm occlusion," the group wrote.
However, MRA protocols that decrease slice thickness and FOV, and have a shorter scan time, can improve imaging enough to avoid contrast altogether, they added.
Bonsall's group supports previous research that also jettisoned gadolinium-enhanced MRA in aneurysms treated with coils. French researchers from the Hospital Bretonneau in Tours also found that adding a contrast agent did not improve the ability to 3D TOF MRA to depict the presence of residual or recurrent aneurysms. They also noted that using contrast did not help visualize parent and adjacent arteries (American Journal of Neuroradiology, October 2003, Vol. 24:9, pp. 1797-1803).
By Shalmali Pal
AuntMinnie.com staff writerNovember 27, 2006
Related Reading
Better enhancement, fewer artifacts seen with certain -- but not all -- MR contrast agents, September 5, 2006
Endovascular repair of acute abdominal aortic aneurysm less costly than surgery, September 4, 2006
Success rate low with polymer-coated platinum coils for intracranial aneurysms, April 26, 2006
Copyright � 2006 AuntMinnie.com


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Written on: 31/05/2013 by tomdickandharry (1 review written)
One 5 minute phone call and two days later, with free delivery, all the bits I needed to upgrade my Thule roof bars from 2004 Polo to 2010 Golf. Superb service and outstanding value. Couldn't recommend Exeter Roofracks & Boxes highly enough.


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FC Dallas plays the Colorado Rapids Saturday night at Toyota Stadium in their first meeting of the 2014 season. The two teams met three times last season with FCD winning the first, drawing in the second match, and losing the third. Here's a look back at the previous season series:
Game 1 - March 2nd, 2013 - FC Dallas 1, Colorado 0: In the 11th minute, backup goalkeeper Steward Ceus left his box which allowed Jackson an easy goal from a long ball that David Ferreira played. Jackson almost doubled FCD's lead in the 18th minute when he shot a ball from 30 yards out that looked as if it went in the goal but only found the side netting. Former FCD player Atiba Harris almost made the match even in the 58th minute for the Rapids but failed to send his shot from 25 yards out into the goal.
Game 2 - June 1, 2013 - FC Dallas 2, Colorado 2: The first 50 minutes were rather quiet for both teams until a ten minute span in the second half saw four goals. Marvell Wynne's throw in near the touchline headed straight for the center of the box which was then headed into the goal by Harris in the 56th minute. Five minutes later, FCD replied when Harris' attempted header to clear a Dallas cross from Michel, found Blas Perez who found the corner of the goal.
Colorado answered FCD's reply when Rapids Chris Klute sent a looping cross into the box which Harris then converted into a simple goald for his second goal of the game. The last goal of the game came soon after when an FCD cross into the box found Perez once again who finished with a shot from 20 yards out.
Game 3 - September 14, 2013 - Colorado 2, FC Dallas 1: The game was scoreless until halftime but not for a lack of chances. In the 51st minute, Jair Benitez sent a cross to Ferriera in the box who finished for a short range goal. A few minutes later two FCD defenders attempted to clear a Klute cross into the box but the ball came right to Sanchez on the left side of the penalty box which he then sent into the goal. Six minutes after their equalizing goal, Sanchez driblled around FCD defender George John and delivered a cross in front of the goal that defender Hedges accidentally tipped into his own goal.


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Chocolate Crunch (Chocolate Coconut Tea)
$ 8.50
When people come to our store, we love to have them smell the teas. If they are chocolate lovers we always steer them to Chocolate Crunch. We warn them beforehand that this will be a deeply decadent experience. When they put their nose close to the tea tin and breath in deeply, it is such a pleasure to see their eyes widen and light up.
Chocolate Crunch features coconut, chocolate and vanilla. It's wonderful drunk as it is, but with the addition of milk or cream and sweetener, it's truly sublime.
Organic black tea, organic rooibos, coconut, cacao beans, vanilla yogurt bits, chocolate bits, natural flavoring. (contains trace amounts of dairy and sugar).
Use 2 grams of tea for every 6 ounces of water. Generally this works out to a teaspoon per every 6 ounces of water. Steep for 3 minutes with boiling water. This tea is tasty as is or with milk and/or sweetener.


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CUMMING, Ga. –– Austin Ward, a senior in the class of 2013 at Pinecrest Academy, has been named a scholarship winner in the annual nationwide competition of the National Merit Scholarship Corporation.
Ward was one of four finalists from Pinecrest for a National Merit Scholarship. In addition to Ward's designation, three other graduating seniors in the class of 2013 were recognized as finalists. These were Jimmy Kemper, Kevin Ruiz and Rafael Skokanic.
Additionally, four students in the class of 2014 were named as National Merit semifinalists, including Sophia Skokanic, Michael Bruckner, Matthew Ansley and Jack Meersman.
These four students will be considered for advancement to the status of finalist over the coming months.
Approximately 1.5 million students in some 22,000 high schools enter the National Merit Scholarship competition annually by taking the Preliminary SAT/National Merit Scholarship Qualifying Test (PSAT/NMSQT). Of these entrants, 16,000 semifinalists are designated on a state representational basis, in numbers proportional to each state's percentage of the nation's high school graduating seniors. Semifinalists represent the top 1 percent of the state's senior students.
To be considered for a National Merit Scholarship, semifinalists must fulfill requirements to advance to finalist standing, including earning an outstanding academic record, endorsement and recommendation by a school official, and achieving SAT scores that confirm their qualifying test performance. Approximately 15,000 meet finalist requirements. By the conclusion of the competition, a small group of finalists are chosen to receive National Merit Scholarships. Winners are finalists considered to possess the strongest combination of academic skills and achievements, extracurricular accomplishments and potential for success in rigorous university studies.


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Stowe open Saturday for season pass holders
Stowe, Vermont, 11/14/2013—Confirmed! Stowe Season Pass Holders are invited to sample the snow at Stowe on Saturday! The FourRunner Quad will operate as we welcome Stowe season pass holders only, from 8am until 4pm this Saturday, November 16th.
Saturday, November 23rd is still our planned opening day for the 2013-2014 winter season.
"Our mountain operations team has once again exceeded all expectations, with an assist from Mother Nature in the form of great snowmaking temperatures & abundant natural snowfall in the past week. We have received an additional 1-3 inches of natural snow from base to summit in the past 24 hours, bringing our summit snowfall total to 24 inches in the past week! Snowmaking operations also continue around the clock, and we are looking forward to getting skiers & riders out on the mountain to sample the snow.
So, we are inviting all of our 2014 seasons pass holders, including Stowe Five pass holders, to a pre-season day of skiing and riding. This Saturday (only) we will operate the FourRunner Quad from 8am to 4pm, with skiing and riding on over 2,000 vertical feet of top-to-bottom terrain. We expect to be able to offer over 5 miles of open terrain, which includes the following trails, most of which will be groomed: Upper Lord, Ridgeview, Lower Ridgeview, Lord, North Slope, Lower North Slope, Fifth Avenue, Centerline, Sunrise, Standard, Christiana, and Crossover. Our Parks Crew is expected to have two freestyle features set-up on Fifth Avenue, too. Lastly, on Friday our Ski Patrol will assess the potential to have some natural snow terrain open, thanks to the recent heavy mountain snows. Please Note: There will be no beginner terrain available.


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Review and change the name ratings you've made throughout the site
Create a private list of your favorite names or share it with the Nameberry community to flex your naming muscles
Manage all the name subscription emails you've set up
Change your email address and your password
I prefer Dean. Dean sounds really classic and nice, and I also pretty rarely hear it around the US, while Deacon seems a bit trendier and goes along with the surnames as firsts craze a bit more.
Lillian Elizabeth 6.16.13
Forum Rules


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l Canada's own prairie balladeer Scott Cook makes his first trip to Scotland this week, playing gigs at Leith Folk Club on Tuesday, The Crown Inn, Biggar, on Thursday and The Vagabond Social Club, Glasgow on Friday.
Cook's tours have taken him across Canada, the US and Asia and his latest album, Moonlit Rambles, has been likened to "a conversational bottle of Jack Daniel's being passed around a campfire".
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l The National Theatre of Scotland and The Arches, in association with Govanhill Baths Community Trust, will present Lifeguard at Govanhill Baths from October 5 to 27. A multi-sensory theatrical experience about human beings and their relationship to water, will take place in the disused teaching pool. An exhibition, Water Water Everywhere, is on show at the baths throughout October. It has been created by local primary schools and the Govanhill Voices community choir, working with the National Theatre of Scotland.
October 5 to 27. www.nationaltheatrescotland.com


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Image: Major Mitchell's Cockatoo Illustration
This illustration by William T Cooper is from his book Australian Parrots and is based on Australian Museum specimens of Major Mitchell's Cockatoo, Cacatua leadbeateri.
- Creator:
- WT Cooper
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- © WT Cooper
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Permission to use this image was given to Walter Boles.NOT TO BE USED IN ANY CONTEXT OTHER THAN THE 'BIRD ILLUSTRATORS' PAGE.
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Hollywood Says "I Love You" - Valentine's Day Video
Well, it's Valentine's Day... love it or hate it it comes around every year, and I don't think it's going away any time soon. Maybe some of you find it hard to find exactly the right words to say when you want to tell the people you love how you feel about them. From time to time, I reach in my bag of romantic movie quotes because no one says it like the movies. Hollywood always seems to know exactly how to say "I Love You."
Here's a great video compilation created by Matthew Belinkie of 95 movies featuring some of the best romantic quotes and scenes ever. Here's a note from the creator.
I've been watching a lot of romantic comedies recently. By "a lot," I mean "all of them." Everything from "A" (Adam's Rib) to "Z" (Zack and Miri Make a Porno). Technically, I started even before "A," with 10 Things I Hate About You and 27 Dresses. And just in time for Valentine's Day, I've edited together some of the most awww-inducing moments in Hollywood history.
Enjoy the video, and Happy Valentine's Day!
I've also included one of my favorite romantic movie scenes of all time just for the hell of it. No words are spoken, just a simple act of kindness. The facial exressions say it all.


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Proteasomes are ubiquitously expressed multicatalytic complexes that serve as key regulators of protein homeostasis. There are several lines of evidence indicating that proteasomes exist in heterogeneous subpopulations in cardiac muscle, differentiated, in part, by post-translational modifications (PTMs). PTMs regulate numerous facets of proteasome function, including catalytic activities, complex assembly, interactions with associating partners, subcellular localization, substrate preference, and complex turnover. Classical technologies used to identify PTMs on proteasomes have lacked the ability to determine site specificity, quantify stoichiometry, and perform large-scale, multi-PTM analysis. Recent advancements in proteomic technologies have largely overcome these limitations. We present here a discussion on the importance of PTMs in modulating proteasome function in cardiac physiology and pathophysiology, followed by the presentation of a state-of-the-art proteomic workflow for identifying and quantifying PTMs of cardiac proteasomes.
- bioinformatics
- protein degradation
this article is part of a collection on Post-translational Modification of Proteases in Cardiac Muscle Physiological Function and Characterization Using Proteomics. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.
Proteasomes are abundant, multicatalytic complexes expressed in all mammalian cells, including cardiac muscle, which serve as key regulators of protein homeostasis (28, 30). Alterations in proteasome function have been observed in ischemic (52), hypertrophic (22, 56), atrophic (58), desmin-related (42), and diabetic (84) cardiomyopathies, thus indicating an important role for proteasomes in the remodeling of cardiac phenotypes.
The period of functional impact for most cardiac proteins is controlled by proteasome-dependent degradation (53, 55, 72), therefore proteasomes degrade a diverse mosaic of substrates. These include transcriptional factors [e.g., p53 (60)], signaling kinases [e.g., PKCδ (15)], sarcomeric proteins [e.g., α-actinin (41)], and apoptotic factors [e.g., Bid (9)], which may be marked for degradation in a variety of ways, including polyubiquitin tags or denaturation/unfolding due to stress. Cardiac proteasomes exhibit heterogeneity (23, 54, 71) and discrete subcellular distribution (28, 30, 63), which specializes subpopulations of proteasomes to degrade distinct substrate repertories (63). Post-translational modifications (PTMs) are recognized to be an important underlying mechanism for functional diversification of proteasomes (80, 81). There are several lines of evidence demonstrating that PTMs modulate numerous facets of proteasome function (Table 1). To date, significant progress has been made in identifying PTMs on cardiac proteasome complexes; however, quantitative information regarding the endogenous stoichiometric abundance of individual PTMs is lacking. The advancement of proteomic technologies has offered unique solutions for systematically characterizing the molecular basis of proteasomal regulation by PTMs. Moreover, the implementation of innovative bioinformatics platforms has aided in the dissemination of PTM discoveries and enabled synergistic efforts across the scientific community in this research arena. As proteasomes influence a broad spectrum of cell biology, the significance of understanding how PTMs modulate proteasomes in cardiovascular physiology and medicine is paramount.
PTMs Regulate Diverse Functions of Cardiac Proteasomes
As terminally differentiated cells, cardiomyocytes are charged with maintaining a healthy proteome for survival. Cardiomyocytes undergo rhythmic perturbations, including fluctuations in ionic strength, oxidoreductive potential, and mechanical strain. As proteasomes exhibit relatively long half-lives, ranging from 1 day (33) to 1 wk (19), PTMs serve as an essential mechanism for the instantaneous regulation of proteasome function to adapt to a dynamic intracellular environment. As multiple amino acid residues in proteasome proteins house a myriad of different PTMs, an essential first step in understanding the physiological function is the reliable and site-specific identification. To date, a diverse array of PTMs has been successfully identified on proteasomes (Table 1). As a result, studies aimed at elucidating the function of site-specific PTMs in physiology and disease are on the rise, which presents an exciting opportunity in the field. A summary of findings to date is presented below.
Irreversible PTMs.
NH2-terminal modifications are the most frequently observed PTMs on proteasome subunits. Subunits of 20S proteasomes are members of the NH2-terminal nucleophile hydrolase family, which have active centers located at their NH2-termini (β1, β2, and β5). In addition to enabling targeted initiation of hydrolase activity within the chamber of 20S, propeptides ensure that the catalytic centers of active subunits are protected from deactivating modifications, such as Nα-acetylation (1). Catalytically inactive β6- and β7-subunits are also processed by neighboring active subunits. Propeptides affect the recruitment of assembly partners. Processing procedures for the active subunits are conducted cooperatively during the process of proteasome assembly, which is an essential rate-limiting step in proteasome maturation. Overexpression of proteasome subunit β5 elevated the gross level of proteasome complexes as well as their proteolytic activities (45), which imparted enhanced resistance toward oxidative stress (40). The effect of β5 overexpression on propeptide processing efficiency and maturation of proteasome complexes remains to be delineated.
NH2-terminal acetylation and the removal of NH2-terminal methionine residues of proteasome subunits proceed according to the specificity of N-acetyl transferases and methionine aminopeptidases, which are primarily determined by the penultimate residue of protein substrates. Traditionally, NH2-terminal modifications have been linked to protein stability, which has been recently challenged by large-scale proteomics and bioinformatics studies. Current findings suggest that NH2-terminal acetylation may affect protein complex assembly (62), an intriguing mechanism that has not been tested in proteasome complexes. While it is uncertain how NH2-terminal modifications may change in cardiac disease, enhanced NH2-terminal acetylation of 20S α7 was reported in brain lysates from Alzheimer's patients, suggesting that NH2-terminal acetylation may be linked to neurodegenerative diseases (27).
N-myristoylation is catalyzed by N-myristoyltransferases. The cardiac 19S subunit Rpt2 contains a highly conserved motif and is indeed modified by this form of irreversible modification (30). N-myristoylation is thought to have a role in signal transduction and membrane targeting of proteins. Proteasome complexes have been identified in membranous regions (10, 11); however, the specific function of N-myristoylation in proteasome biology remains to be fully delineated.
Proteasomes are also regulated through irreversible PTMs in the form of cleavage by other proteases. Caspases and proteasomes can degrade one another (37, 66, 73), which establishes an essential checkpoint for cell survival. Apoptosis is initiated when caspases dominate this balance. In parallel, the lysosomal system also targets proteasome complexes (19). As proteasomes and lysosomes coordinate the degradation of the intracellular protein pool, perturbations of this dynamic relationship may affect a large number of protein substrates (39). The dynamics and regulation of this paradigm remain largely unknown.
Reversible PTMs.
Phosphorylation is the most studied form of reversible modification on proteasome complexes. Protein kinase A (PKA), an integral effector of the β-adrenergic pathway, is a functional associating partner of cardiac proteasomes (80). The in vitro or in vivo activation of PKA resulted in the phosphorylation of proteasomes, which enhanced proteolytic activities (2, 76, 80) and 26S assembly (2). Phosphorylation coordinates a wide array of proteasome function, including complex assembly, trafficking, and proteolytic activity, as well as recruitment of regulatory complexes (6, 7, 26, 38, 44, 61, 64, 80). Several kinases and phosphatases orchestrate the functional dynamics of proteasome complexes in the heart (7, 26, 80). Among them, PKA and protein phosphatase 2A are known to be important players in cardiac pathogenesis. In vivo inhibition of PKA eliminated the beneficial effects of ischemic preconditioning on proteasome assembly and activity (2), and activation of endogenous PKA rescued depressed 20S catalytic activities in isoproterenol-induced cardiac hypertrophy (22). In contrast, hyperphosphorylation of hepatic 20S in ethanol-induced liver disease has been correlated with decreased proteasome activities (4). It is likely that the divergent effects of phosphorylation on catalytic activities are due to differences in phosphorylation sites being targeted, modulated by distinct panels of kinases/phosphatases.
Lysine residues are subject to different forms of PTMs; acetylation and ubiquitination (Ub) have been identified on proteasomes, and many more remain to be discovered. Recent reports identified lysine acetylation on cardiac proteasome subunits (79). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) determine the occupancy of these motifs. Studies also indicate that application of HDAC inhibitors may lead to cardiac benefits under stress (16). HATs and HDACs modulate gene transcription in the nucleus and metabolism in mitochondria, which serve as two important mechanisms for cell protection. However, the integration of protein degradation in these pathways remains largely unknown. A recent report demonstrated that HDAC inhibition led to upregulation of lysine acetylation on cardiac proteasome subunits, which resulted in enhanced proteolytic activities. These data suggest that lysine acetylation may modulate degradation capacities in health and disease (79).
Proteasome subunits are regulated by Ub as well. It has been reported that polyUb regulates both the proteolytic capacity and substrate specificity of proteasome complexes (32, 35, 69). The subcellular targeting of proteasome complexes or recruitment of the ubiquitin-associated domain containing regulators may be affected by polyUb as well. The synergistic or antagonistic interplay between lysine acetylation and Ub is an intriguing topic to study.
Proteasomes can be modified by O-linked N-acetylglucosamine, which is regulated by O-GlcNAc transferases and O-GlcNAcases. This PTM serves as a sensor for both metabolic dynamics and stress (8). It has been reported that the 19S ATPase subunit Rpt2 can be modified by O-GlcNAc, leading to an inhibition of proteolytic activity (78). However, the specific site of modification remains to be defined. Interplay between O-GlcNAc and phosphorylation has been reported, as both target Ser and Thr residues (34). This regulatory paradigm has yet to be investigated on proteasome complexes.
Proteasome complexes are essential for turning over proteins misfolded by oxidative stress. In fact, the extent of myocardial injury correlates to the functional potency of proteasome complexes after an ischemic event (55). Poly-ADP ribosylation of 20S proteasomes, catalyzed by poly(ADP-ribosyl) transferase, selectively elevates proteolytic activities against oxidized substrate repertoires (67). However, the oxidative modification of proteasome subunits directly is generally detrimental to proteasome function. Oxidative PTMs represent a broad array of modifications that involve the removal of a hydrogen atom or incorporation of an oxygen atom in protein substrates, which is largely nonenzymatical. Increased levels of oxidative PTMs on proteasome subunits have been identified in ischemic (12, 25) and hypertrophic cardiomyopathies (56), which may provide a mechanistic explanation for the observed impairment in degradation capacities.
Proteomics as an Essential Tool to Identify and Quantify PTMs in Proteasome Complexes
A significant portion of PTMs on proteasome complexes have been identified using classic biochemical approaches. Though these efforts were pivotal for establishing a basic understanding of PTM dynamics in cardiac muscle, recent developments in functional proteomics have offered major improvements in the depth and breadth with which we can understand PTMs in cardiac physiology (Fig. 1). First, proteomics removes the need for radioactive isotopes, which have limited clinical utility, unwanted transformative effects on the biological sample, and safety hazards. Second, proteomic analysis offers unbiased, site-specific analysis of PTMs (i.e., multiple sites within the same peptide), which has been a major shortcoming of PTM-directed antibodies. Third, proteomics supports large-scale analyses in that hundreds/thousands of distinct PTM events can be simultaneously probed in hundreds/thousands of proteins, allowing for the elucidation of PTM interplay within and among proteins. This feature is not practically feasible using classical biochemical approaches, which have typically involved the analysis of one or a few proteins at one time. Fourth, recent developments in bioinformatics have fostered the construction of spectral libraries, which provide superior sensitivity, portability, and user cumulativeness for PTM analysis, thus increasing the efficiency in data analysis. Finally, targeted proteomic approaches offer elucidation of multisite PTM stoichiometry through absolute quantitative approaches, which are linear over several orders of magnitude. With quantitative data capabilities for a panel of PTMs, biologists can begin to unravel how PTM dynamics tune the function of entire organelles, such as the proteasome, in cardiovascular physiology and pathology. A state-of-the-art proteomic workflow for identifying and quantifying PTMs on proteasomes is presented below.
Subcellular fractionation and enrichment of proteasome PTMs in cardiomyocytes.
PTMs on proteasomes exist at substoichiometric levels, therefore an essential first step is to enrich effective concentrations of PTMs by reducing the complexity of the cardiac sample. While proteasomes are relatively abundant within cells, the dynamic range of proteins in cardiac muscle is vast compared with other tissue proteomes. Proteins of the sarcomeric apparatus along with the rich population of mitochondria constitute the majority of cellular protein, which would be dominant in a shotgun proteomic approach. This necessitates the use of protein fractionation techniques to isolate proteasome complexes. Differential centrifugation is commonly used to separate subcellular organelles (3). Subsequently, 20S proteasomes or regulatory particles can be enriched through multidimensional purification strategies (e.g., chromatography, ultracentrifugation) to increase the effective concentration of proteasome complexes and their acquired PTMs. Purification strategies have been developed for three distinct proteasome complexes 20S (80), 19S (71), and 26S (30). Importantly, these strategies have resulted in purified proteasome complexes that are functionally viable, allowing for the downstream assessment of enzymatic activities. Proteolytic digestion is necessary to prepare proteasome complexes for shotgun proteomics analyses. In contrast to protein identification, where approximately two distinct peptides from any region of the protein are required for a confident identification, PTMs are localized to specific peptides. The capture of PTM-containing peptides is therefore mandatory and often requires the careful selection of endopeptidases other than trypsin. For large-scale studies, the application of a panel of endopeptidases significantly expands the overall coverage of PTM detection (80). A subsequent enrichment step with solid-phase extraction selectively sequesters peptides containing a substoichiometric PTM to enhance detection by mass spectrometry. Solid-phase extraction platforms involve an immobilized chemistry (e.g., antibodies) with specific affinity for a desired PTM. Successful strategies have been titanium dioxide (TiO2) and immobilized metal affinity columns (phosphorylation), lectin chromatography (glycosylation), immune affinity chromatography, etc. Our laboratory recently acquired the first comprehensive map of site-specific cardiac 20S phosphorylation using a combination of the methods above: subcellular fractionation to obtain a cytosolic fraction, 20S proteasome purification to obtain functionally viable proteasome complexes, complementary proteolytic digestion, and TiO2 enrichment of phosphorylated peptides. Using this workflow, we were able to effectively enrich low-abundant proteasome PTMs, enabling the identification of 52 phosphorylation sites in cardiac and liver proteasomes (46).
Characterization of PTMs using mass spectrometry.
The potential for identification of proteasome PTMs by mass spectrometry has vastly improved over the past decade with the development of mass spectrometry instruments, which is now the state-of-the-art platform enabling large-scale, site-specific PTM analysis. Historically, the main obstacles in identifying PTMs with mass spectrometry have been 1) achieving adequate sensitivity to capture the low-abundant posttranslationally modified peptides and 2) preserving labile PTM moieties during fragmentation of peptide precursor ions. The sensitivity of detection has been significantly enhanced through application of nanoscale chromatography in-line with new generation linear ion trap mass spectrometers with high ion capacity. Multidimensional chromatography, such as a miniaturized TiO2-reverse phase columns (e.g., PhosphoChip), or single dimension chromatography has been employed for the detection of PTMs. Ultraperformance liquid chromatography is fast becoming routine in proteomics. Ultraperformance liquid chromatography capitalizes on the use of solid-phase resin of miniscule (<2 μm) particle size to increase the speed, sensitivity, and resolution of chromatography. High-powered mass spectrometers (e.g., Thermo LTQ-Orbitrap Elite) with superior mass resolution and speed are continually being engineered. This translates into enhanced confidence and sensitivity for PTM identifications. The preservation of PTMs in the mass spec during fragmentation has been greatly aided by the development of electron transfer dissociation (ETD). ETD uses radical anions to fragment peptide backbones in a manner that leaves PTM moieties intact. This differs from the commonly employed collision-induced dissociation method, which fragments peptides after repeated collisions with an inert gas, resulting in loss of labile PTMs. A comprehensive mapping of 20S phosphorylation by our laboratory exploited the complementarity of the two fragmentation methods (46). Identified phosphopeptides could be classified into three groups: those identified by collision-induced dissociation only (34 phosphopeptides), those identified by ETD only (10 phosphopeptides), and those identified by both collision-induced dissociation and ETD (8 phosphopeptides). This study represents the most comprehensive mapping of cardiac proteasome phosphorylation available to date and was the direct result of methods described above aimed at enhancing sensitivity of detection and preservation of PTMs on peptides.
Bioinformatics are essential for PTM analyses.
Sophisticated bioinformatics platforms are required to accurately decode PTM dynamics in mass spectra. Commonly employed database search engines (e.g., SEQUEST, Mascot) identify PTMs by comparing query spectra with simulated, theoretical spectra based on protein sequences (24). This approach enables us to interrogate a series of selected PTMs within the context of a targeted organism. However, this workflow also presents the following limitations: 1) simulated spectra lack features for spectral pattern recognition (e.g., ion intensity), 2) the number of PTMs queried is limited by the power of computational platforms, and 3) protein sequence databases for an organism of interest may be incomplete. As an alternative approach, de novo sequencing algorithms directly analyze the raw spectra and define the peptide sequence based solely on fragment ions. For this approach to be successful, peptide spectra need to present sufficient fragmentation signatures for unequivocal conclusions. This removes the prerequisite for a protein database or a list of PTMs of interest. However, de novo sequencing algorithms calculate the probability of all possible combinations of peptide sequences, requiring an enormous search space that imposes a significant burden on the computational platform.
Identifying PTMs by comparing query spectra against an annotated library of experimentally derived spectra offers a solution for both the specificity and efficiency of data analysis. We have developed a cardiac organellar protein atlas knowledge base (COPaKB, www.heartproteome.org), including specific spectral library modules on human and murine cardiac proteasomes (83). COPaKB capitalizes on the use of both existing and newly generated high-quality experimental PTM spectra for the continuous enhancement of a superior reference against which query spectra are compared. The major advantages of this approach for PTM identification lie in the inclusion of descriptive features of fragmentation spectra that cannot be reliably predicted and therefore are absent from theoretical spectra. Searching query spectra against experimental spectra in a spectral library would provide a highly confident match in that the experimental library spectra would include gas-phase chemistries (both m/z shifts and intensities) unique to post-translationally modified precursor ions.
Quantitative analyses.
The final goal in the characterization of proteasome PTMs is to understand how a particular PTM influences the biological function of proteasomes in the endogenous cellular environment. To accomplish this, stoichiometry of identified PTMs at baseline and in a perturbed state (e.g., disease) must be quantified in a site-specific and reproducible fashion. Multiple reaction monitoring (MRM) is a customizable mass spectrometric technique that allows for sensitive detection and quantification of a target set of peptides. This technique typically employs the use of a triple quadrupole mass spectrometer in which the first quadrupole (Q1) gates for the precursor ion, the second (q2) fragments the precursor ion with an inert gas into daughter ions, and the third (Q3) specifically gates for selected q2-generated daughter ions. A precursor ion detected in Q1 and a daughter ion detected in Q3 are collectively referred to as a transition. Superior sensitivity of MRM comes from targeting only selected transitions that produces a high signal-to-noise ratio, and enhanced reproducibility comes from the continuous monitoring of these transitions that results in the acquisition of a high number of data points per transition. MRM-based quantification of PTMs is also linear over several orders of magnitude (17), making it ideally suited for quantifying PTMs exhibiting a large dynamic range. For example, the phosphorylation of Ser250 on murine α7 is significantly more abundant than the phosphorylation of other 20S subunits (81); MRM-based quantification would thus be highly suitable for the global quantification of 20S phosphorylation. These features in combination underscore the great promise that this technology holds for quantifying PTMs on proteasome complexes. The nature of MRM also allows for quantification of specific sites of phosphorylation in peptides where multiple potential phosphorylation sites are present. This requires the careful design of diagnostic transitions. For example, if phosphorylation of the peptide AGsAASPNVK (s = phosphorylated Ser) was being quantified using MRM, diagnostic transitions would include b3, b4, b5, y5, y6, and y7 ions, since they are representative of cleavages between the two potential phosphoserines (Ser3 and Ser6) that would unequivocally demarcate the site of phosphorylation. This feature can be challenging when the diagnostic fragmentation of peptides is not favored in the gas phase; thus it is critical that parameters affecting the sensitivity of detection (i.e., collision energy) be carefully optimized. In conclusion, MRM offers unique advantages for the global, unbiased, sensitive, and site-specific quantification of PTMs over traditional approaches.
Future Directions
Discovery of novel PTMs with functional relevance using tailored bioinformatics.
PTM databases, including PSI-MOD ontology (49) (http://www.ebi.ac.uk/ontology-lookup/browse.do?ontName=MOD) and Unimod (18) (http://www.unimod.org), contain ∼1,000 distinct forms of PTMs. This number is still increasing with the discovery of novel PTMs. The evolving nature of PTM discovery presents a challenge for bioinformatics platforms to characterize proteasome PTMs in a systematic manner. Taking the perspective that spectra of PTM peptides share common signatures with their unmodified counterpart, a tailored database search using cardiac spectral libraries can be employed to identify novel PTMs. The measured mass difference between a post-translationally modified peptide and unmodified peptide can aid in correlating fragment ions between them to decipher the molecular nature of the potential PTM. With state-of-the-art mass spectrometers that can achieve beyond a mass resolution of 2 parts/million (50), it is highly likely that PTMs can be deduced from observed shifts in mass. The delineation of biological function should follow through designing gain- or loss-of-function models and through comparison of the abundance of such PTMs in diseased versus normal phenotypes.
Signaling kinetics to proteasomes and PTM interplay in the endogenous cellular environment.
To understand how proteasomes integrate into cardiac signaling pathways, PTMs of proteasomes must be analyzed within the intricate context of the endogenous cellular environment (Fig. 2), both in acute signaling (e.g., β-adrenergic receptor stimulation) and in disease. Moreover, it is highly likely that the functional dynamics of the proteasome complexes are tuned by various PTMs in coordination. Previous reports have suggested that PTMs on proteasomes interact to modulate proteasome function. Interferon-γ triggers a decrease in phosphorylation of both 20S and 19S subunits, leading to the disassembly of 26S proteasomes in response to stress (59). PKA induced the phosphorylation of Rpt6 and O-GlcNAc modification of Rpt2 coordinate glucose metabolism (77). In addition, PKA and protein phosphatase 2A play antagonistic roles in regulating proteasomal function (80). While an initial step in elucidating the functional importance of PTMs on proteasomes is to study the effect of an enzyme (e.g., kinase, acetyltransferase) on proteasome function in an isolated system, this provides limited information regarding the endogenous kinetics of PTM modifications and the coordinated interplay of PTMs on proteasomes. Progress in this area has been attenuated in part by the lack of information regarding signaling to modulating enzymes (e.g., N-myristoyltransferases) but also by the lack of a global and site-specific method for quantifying PTMs on proteasome subunits. Quantifying PTM stoichiometries is essential for delineating the interwoven functions of PTMs in modulating proteasome dynamics in cardiomyocytes. Furthermore, to grasp the dynamics of individual PTMs on proteasomes, multiple time points should be analyzed following a stimulus to gauge whether PTMs change with the time course of agonist treatment or with disease progression. Now that we have sensitive, site-specific and unbiased technologies (e.g., MRM) with which to quantify PTMs, these studies are possible. This approach will allow us to understand the nature of proteasome modulation by PTMs, which will help us to understand how to manipulate specific functions that go awry in disease.
In conclusion, proteasomes have a widespread impact on cardiac physiology, affecting virtually all cellular processes. Understanding the dynamics of PTM modulation of proteasomes will aid in the development of inhibitors or activators that can tune discrete functions of proteasome subpopulations. This will ultimately lead to tightened and more refined protein quality control in cardiac muscle, which will ultimately provide targeted avenues for combating cardiac disease.
This work is supported in part by the National Heart, Lung, and Blood Institute Proteomics Center Award HHSN268201000035C (to P. Ping), Grant R01-HL-098954 (to P. Ping), Grant R01-HL-088640 (to E. Stefani), and NRSA Grant F32-HL-099029 (to S. B. Scruggs).
No conflicts of interest, financial or otherwise, are declared by the author(s).
S.B.S., N.C.Z., E.S., and P.P. conception and design of research; S.B.S., N.C.Z., and D.W. prepared figures; S.B.S. and N.C.Z. drafted manuscript; S.B.S., N.C.Z., and P.P. edited and revised manuscript; S.B.S., N.C.Z., D.W., E.S., and P.P. approved final version of manuscript.
- Copyright © 2012 the American Physiological Society
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R.A. Dickey flummoxed the Florida Marlins once again.
Dickey made an early run stand up, blanking Florida for seven innings and pitching the New York Mets to a 1-0 victory Wednesday.
Dickey is 3-0 against the Marlins this season. The knuckleballer allowed only one run - it was unearned - in 20 innings over that span.
"I think it's coincidence," Dickey said. "Sometimes you match up better against certain type of hitters and maybe this team has those kinds of hitters for me."
Jose Reyes led off the game with a single and scored on a one-out double down the left-field line by Lucas Duda for the only run of the game.
"You don't see that very often," Mets manager Terry Collins said. "Fortunately, Jose got on, Lucas put one where nobody was standing and we got a chance to score. Otherwise, we'd still be playing."
Dickey (8-11) and relievers Josh Stinson and Manny Acosta combined on a five-hitter. The Mets also managed just five hits.
The Mets played their final game at the Marlins' stadium before Florida moves into a new home next season. The Mets finished 75-74 at the park the Marlins had shared with the Miami Dolphins since 1993.
Dickey gave up four hits and three walks. He struck out three.
"I started off very mediocre," Dickey said. "The second and third innings I really had to fight out of some jams and was fortunate enough to make some good pitches."
Brad Hand (1-6) allowed one run, three hits and four walks in six innings.
"I minimized the damage," Hand said. "When they did get runners on, I got out of it. Just trying to keep the team in the game and not give up any more runs after that first."
Florida had a runner in scoring position in each of the first four innings and stranded eight in the game.
"He wasn't nearly as sharp as he's been against us in the past," Marlins manager Jack McKeon said. "I thought for sure we were going to get him. He gave us an opportunity but we couldn't cash in and put the ball in play."
The Mets committed errors on back-to-back plays in the third, but the Marlins could not take advantage of the blunders.
In the eighth, the Marlins put Emilio Bonifacio on third base, but Stinson struck out Gaby Sanchez swinging to end the inning.
"(Stinson) looked very much the part that he's a big leaguer, no question," Collins said.
Acosta pitched the ninth and recorded his first save since Aug. 11, 2010, at Houston. He struck out the first two batters he faced before hitting Mike Stanton with a pitch. Greg Dobbs grounded back to Acosta to end the game.
"That was my first opportunity this year, I'm happy, and I'll wait for more," Acosta said.
Jason Bay had two hits for the Mets.
NOTES: LF Logan Morrison kept the Marlins within a run when he threw out David Wright at the plate to end the top of the eighth. ... The shutout was the Mets' second since July 5. Chris Capuano pitched the other one. ... Marlins 3B Matt Dominguez recorded his first major league hit with a single in the second inning. "It was good to get that first one out of the way. So doing it in the first at-bat was good," Dominguez said. "The next couple at-bats I could relax a little bit more." ... The Mets host the Braves in a doubleheader Thursday, sending RHP Chris Schwinden and RHP Dillon Gee to the mound. The 24-year-old Schwinden will be making his big league debut. Gee is 0-1 with a 9.20 ERA in his last three starts. ... Florida is off Thursday and will send RHP Ricky Nolasco to the mound Friday at Pittsburgh. Nolasco has a scoreless-inning streak of 21 innings against the Pirates, which spans his last three starts.


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Articles from RotoWire's fantasy archives that mention Juan Diaz's name.
February 20, 2015
White Sox Team Preview: Phase Two
The White Sox made big strides last season, then were big players this offseason to give Jose Abreu more help. Will it be enough to contend in the AL Central?
September 7, 2013
Sunday Lineup Card: Colabello Who?
September 1, 2013
Monday Lineup Card: Hamming It Up on the Big Stage
Speed maven Billy Hamilton will be promoted to the majors Monday.
July 10, 2013
Bernie On The Scene: What Should They Do - AL?
With Francisco Lindor moving up the ladder, should the Indians trade Asdrubal Cabrera to address their other organizational needs? RotoWire's Man on the Scene Bernie Pleskoff takes a look around the American League.
June 11, 2013
Wednesday Lineup Card: The Wheeler Report
June 9, 2013
FAAB Factor - AL: More Prospect Speculation
Andrew Martinez speculates about a prospect call-up in addition to Wil Myers (pictured here). Read to see his take on the Tigers' Nick Castellanos.
June 7, 2013
Transaction Analysis: Hanley's Back, Again
Hanley Ramirez is back for the Dodgers, and this time he hopes to day healthy for more than for games.
June 4, 2013
Wednesday Lineup Card: Hanley To The Rescue
May 8, 2013
Bernie On The Scene: A Look At Second Base Prospects
Delino DeShields Jr. has plenty of speed, but will he get on base enough to use it? Bernie Pleskoff takes a look at the future crop of options at the keystone.
June 5, 2012
Wednesday Lineup Card: Time to Pick Up Parker
May 27, 2012
FAAB Factor - AL: Replacing Brandon League
May 26, 2012
Saturday Lineup Card: Another Blown Save for Bell
July 2, 2010
Transaction Analysis: Notable Moves this Week
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The Agony of Alice
What she needs, Alice decides, is a gorgeous woman who does everything right, as a roadmap, so to speak. If only she finds herself, when school begins, in the classroom of the beautiful sixth-grade teacher, Miss Cole, her troubles will be over. Unfortunately, she draws the homely, pear-shaped Mrs. Plotkin. One of Mrs. Plotkin's first assignments is for each member of the class to keep a journal of their thoughts and feelings. Alice calls hers "The Agony of Alice," and in it she records all the embarrassing things that happen to her.
Through the school year, Alice has lots to record. She also comes to know the lovely Miss Cole, as well as Mrs. Plotkin. And she meets an aunt and a female cousin whom she has not really known before. Out of all this, to her amazement, comes a role model -- one that she would never have accepted before she made a few very important discoveries on her own, things no roadmap could have shown her. Alice moves on, ready to be a wise teenager.
- Atheneum Books for Young Readers |
- 176 pages |
- May 2011 |
- Grades 5 - 9
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text:
The Seattle Times has a new subscription deal available for a limited time. You can subscribe to the Seattle Times Sunday paper for just $24 for the year. That's 52 issues at just $.46/issue. It is only the Sunday paper that you will be receiving. This subscription deal is only available for a limited time through July 15th and is not a deal for a multiple paper subscription.
Here's how the deal works:
- Head to the Seattle Times online subscription site
- Submit your zip code and use the offer code: SUNO24IS
- Submit your address & payment information
Fine Print:
These rates are only good in King, Pierce, Snohomish, and Kitsap counties. The offer is only valid to those customers who have not had a subscription for 30 days. (If you're currently a subscriber, you could cancel now & then wait the 30 days & still be able to subscribe before the offer ends on July 15, 2011).
Thanks Coupon Connections!
Best Newspaper Subscriptions for Couponers:
I've had a number of questions lately about which is the best paper for couponers in the Puget Sound area. I do not typically recommend the Seattle Times as it never carries the Red Plum coupon inserts. The reason is because the Red Plum inserts are now sent by mail during the week to King County residents and they only receive the one copy. However, the Seattle Times does occasionally have different regional coupons than the other papers. For example, this past weekend, the Seattle Times had a coupon for a FREE can of Seattle's Best iced coffee in the Smartsource, which was not found in the Tacoma News Tribune. So, if we find an awesome subscription deal like the $.46/issue price on the Seattle Times, I do think it's worth it to subscribe for the extra regional coupons that may be available. {I'm blessed in that my neighbor's subscribe to both the Times and the TNT and they give me their coupons from both, so that's 2 extra newspapers that get each week. And I can compare the coupons to see if I there are any great coupons in the Seattle Times & in that case, I might go buy more copies}
Other Newspaper Subscription Deals:
Tacoma News Tribune
For those of you who live down in southern King County or the South Puget Sound area, the Tacoma News Tribune is definitely the best paper for couponers to use. It receives all of the scheduled inserts each week. The News Tribune currently has a multiple subscription deal that's perfect for couponers, too. All you have to do is ask for the Thrifty NW Mom subscription deal when you call. Just call the Tacoma News Tribune at: 1-800-289-8711 to get your subscription started.
Here are the details of the Tacoma News Tribune Subscription deal:
- Buy multiple subscriptions (3 or more) of the Sunday paper for just $1/each
- In addition, you'll receive 1 copy of the paper each day of the week – Monday – Saturday
- You will pay for 26 weeks at a time. There are 2 payment options: Pre-Payment or EZ Pay options. Check out my post with full details on the Tacoma News Tribune Subscription deal for the specifics on pricing.
Everett Herald:
For those of you who live in the northern Puget Sound area, the Everett Herald has an awesome subscription deal for couponers. Pay $99 for a 6 month subscription delivered. You will receive 5 Sunday papers delivered each week as well as 1 paper each day of the week (Monday-Saturday). Make sure to get the full details from Coupon Connections. You'll want to ask for the Coupon Connections subscription deal when you call the Herald to subscribe.
*If you live in a different area, let us know if your area has a "Couponers special subscription deal" so I can add it to our post {basically a discount if you're buying multiple subscriptions}. And if they don't, then gather your couponing friends and call the paper to let them know that there is interest in the paper offering a multiple subscription deal. You never know, they just might start offering a deal if enough people call & express interest!


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General Question
Know anything about Grapefruit Seed Extract?
A midwife recently told me to take Grapefruit Seed Extract to help boost my immune system while pregnant (due to the recent flu outbreaks and me asking her how to stay healthy in spite of them). So my husband, who works at an herbal distributor, buys some for me. His boss and a co-worker tell him that it's not safe to ingest. I did further research and can't find anything that suggests it's bad. The people he works with are highly herb knowledgeable so now I'm confused. Does anyone know about this product?
I will be asking my doctor before I take it but that is about a month away so I thought I'd do some research myself beforehand. It'll probably confuse me even more to hear what everyone thinks but hey I like having as much info. as possible.
14 Answers
Answer this question
This question is in the General Section. Responses must be helpful and on-topic.


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If it's on Netflix you'll find it with our search engine. Search below to get started.
100 m -
Jimmy is married to the abusive Frank, but she's building a nest egg so she can leave. For a year, she's been deaf as a result of one of his beatings. One night, he pushes her over the ...


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Oro Valley has received a clean audit opinion from public accounting firm Heinfeld, Meech & Co., P.C., for the fiscal year 2013. The firm found no audit deficiencies or concerns durng the process.
"This audit should give residents peace of mind that an outside firm has extensively reviewed our financials, internal control measures, and other related items and found that we are in conformance with the highest standards," town manager Greg Caton said in a news release. "We take financial matters very seriously and are pleased to have our great work validated."
The town ended the fiscal year with a $1.7 million surplus in the general fund. Construction and retail sales taxes, which were boosted by increased development activity, contrbuted to the surplus, which has been carried to fiscal year 2014 and will be invested in capital projects.
Also, the Government Finance Officers Association awarded the town its fifth consecutive Distinguished Budget Award.


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Here you will find our range of items which are reduced to clear. This could mean items that are discontinued, end of stock or items that may be slightly defected which can be repaired easily. So grab yourself a bargain!
Clearance items
New Products For November - Clearance items
Monthly Specials For November
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If it's on Netflix you'll find it with our search engine. Search below to get started.
75 m -
Children & Family
15-year-old Max is in search of his father, the famous troubadour Johnny Bigoude, who disappeared shortly after Max's birth. He reaches Saint-Hilare where Madam Doudou, the old teacher, ...


text: I Liked Phoenix Rising No Eyes Me Too Personal Stories, Advice, and Support Report Group Sort popular recent Phoenix Rising I have only read Phoenix Rising No Eyes by Mary Summer Rain. If you have read this or other books she has written let me know. closedin 41-45 0 Nov 8, 2008 More Stories


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Ave Caesar, Germans salute you!
The German Bundestag now has Gaius Julius Caesar among its proud members. The MP from the ruling Christian Democratic Union represents Lippe district in the state of North Rhine-Westphalia.
Caesar replaces fellow deputy Leo Dautzenberg, who retired from the legislature in favor of a job with an industrial group, reports German newspaper Augsburger Allgemeine. It will be Caesar's second term in the federal parliament.
Gaius Julius Caesar, 60, while probably not related to the famous general and dictator of ancient Rome, says he is proud of his unusual name.
"The family name Caesar fits well with Gaius Julius so I am extremely grateful to my parents for choosing it," he said.
It has become a sort of family tradition, since Caesar's elder son and grandson carry the same name.
Being named after the great Roman has it downsides too, Caesar says. From time to time disbelieving officials ask him to provide ID.