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BedRug VanTred Cargo Liner Customer Reviews
50 Customer Reviews
Sort Reviews By:
Not bad, looks good, but needs some minor design changes
Reviewed by Marcus B (POWDER SPRINGS, GA) Reviewed for a 2016 Ford Transit — Apr 22, 2016 7:32 PM
The fit is almost perfect for my van. However, it does not go all the way to the back doors for some reason. Not sure why they cut it a few inches short. Also, it is not as slip resistant as the simple, universal mats I had in my previous van. Although the surface is rough, I tried to step over something with wet sneaker shoes and accidentally performed an almost perfect leg split when my shoes slipped. That was surprising and embarrassing. The material under the surface is similar to styrofoam
Jim, Broomfield colorado
Reviewed by James G (Broomfield, CO) Reviewed for a 2008 Chevy Express — Apr 21, 2016 4:27 AM
I bought a well used 2008 Chevy Express cargo van. The inside was trashed, with rusted storage shelves and a nasty OEM flooring. I took out the shelves, repainted them . Removed the nasty floor mat and padding. Repainted the entire inside, painted the shelves. It looked pretty good. But when my new VanTred Cargo liner arrived, and I installed it. What a difference. It looked like a new van. With the work I did and the new cargo liner, I am sure I increased the value of my van.
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Seven different outlets have agreed to broadcast the game, which will be televised by Comcast Sports South (CSS) and will kick at 6:30 p.m. from Memorial Stadium/Faurot Field.
Click here for the original story.
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Alphabet Song
The Alphabet Song by Have Fun Teaching is a great way to teach and learn the alphabet, phonics, letter sounds, vocabulary words, and uppercase and lowercase letters. This is a phonics abc song for teaching and learning the alphabet and phonics.
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ASTRAL BIRTH.. 05/11/1945 – 12/01/2016 .You will always be lovedand remembered for your selfless compassion, light and guidance by thecountless souls you touched. Your devoted wife Asha, proud sons Satyenand Ambarish, daughters-in-law Pallavi and Sonakshi, lovinggrandson Arnav and all kamikumite of India and UAE will continueyour mission.
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Pranitha Subhash will play Shivarajkumar's wife
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Setting aside speculation that Shiroda constituency will get a new face, the Shiroda block Congress committee has chosen former legislator Subhash Shirodkar as the Congress candidate for the 2017 general elections to the Goa legislative assembly
- Shri Subhash Chander Sawhney
With profound grief we inform you of the sad demise ofShri Subhash Chander Sawhney(Husband of Mrs Veena Sawhney, Father of Sanjiv and Rinku)who passed away on March 14, 2016.A PRAYER MEETINGwill be held on Thursday, March 17, 2016 between 3 - 4pm atArya Samaj Mandir, C-606, Defence Colony, New Delhi.Deeply mourned by:ALL FAMILY & FRIENDS
- Sumanth is a true gentleman: Pallavi Subhash
Pallavi Subhash talks about her Tollywood debut, the remake of Vicky Donor...
- Subhash Ghai helps to clean Mumbai's Versova beach
Veteran filmmaker Subhash Ghai took part in the Versova beach cleaning drive on Monday. The drive, which was attended by over 200 residents of Versova, was conducted with the aim to clean the stock of garbage formed at the beach.
- Subhash Ghai helps clean Mumbai's Versova beach
Veteran filmmaker Subhash Ghai took part in the Versova beach cleaning drive on Monday. The drive, which was attended by over 200 residents of Versova, was conducted with the aim to clean the stock of garbage formed at the beach.
Birthday Remembrance SHRI SUBHASH J CHOPRA 2021944 to 452010 Happy Birthday Dear Nanu, Miss you, Hugs, Shivay.
In Everlasting LoveGod knows how much I miss him My heart cannot tell what to say God alone knows how I miss him. In a home that is lonesome today.Savitri Rishi, Vivek, Arshiya, Aseem, Vinit, Rima.
- Adv. Subhash V. Oak
(2/11/1931 - 29/1/2016) Son of Lt. Barrister V. V. Oakand Husband of Lt. Sau. Shashikala S. OakPassed away in Mumbai on Friday, January 29, 2016Deeply mourned by family, friends & relatives
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Bareilly: As part of the Bareilly Municipal Corporation's (BMC) annual drain cleaning exercise ahead of monsoons, the SubhashNagar culvert will remain closed for three days, starting Monday. Sanitary workers will clear the drain under the culvert and the road cutting through the tunnel will, therefore, remain closed. Commuters, particularly those residing in Subhash Nagar, Tilak Colony, Awadh Colony, Rajeev Colony and other adjoining areas, will be affected. Many, however, alleged that this yearly procedure has not been able to solve the city's waterlogging issues, especially during monsoons. They believe that authorities should make efforts to divert the route of drains. City health officer Dr Ashok Kumar said, "The drain is being cleaned before monsoon. This route will be opened only after three days." Corporator of Subhash Nagar, Alok Tayal, said, "There are 12 manholes that will be opened for manual cleaning of drains inside the culvert. Despite this annual exercise, the place gets filled with water during heavy rains. He added that two major drains - one in Gangapur, near Sahu Gopinath School, and another near the collectorate - flows into the Subhash Nagar drain and proceeds towards loco shade. If the flow of both these drains are directed straight towards loco shade, waterlogging will be minimised. It will provide much-needed relief to three wards with a population of nearly 1.5 lakh." A proposal for this is pending with the authorities, he added. Commuters will have to take an alternate route via Choupla crossing and pedestrians can take the foot over bridge near Bareilly junction. "Even a short spell of rain makes the whole area waterlogged. As the Subhash Nagar passage will be closed for three days, it will cause inconvenience to many," said Raj Kumar Tandon, who runs a shop near the area. Another resident of Subhash Nagar, GL Batra, said efforts should be taken to divert city's drains in order to solve the issue of flash floods permanently.
- Sh. Subhash Chander Gupta
Rasam Pagriwith profound grief we regret to inform that over beloved father Sh. Subhash Chander Gupta (S/o Late Sh. B C Gupta)(Resident of Anand Vihar - Pitampura)left for his heavenly abode on 10.01.2016. The Rasam Pagri will be held on Friday, 22.01.2016 from 3 pm to 4 pm at Agarsen Bhawan, Pitampura (Near Laurel High School, in front of Pitampura Village)In Grief:Smt. Santosh Gupta (Wife) Ritesh - Pooja Gupta (Son & Daughter in law)Charu Bansal (Daughter) Aman - Sonal Gupta (Son & Daughter in law)D.S.DUCTOFAB SYSTEMS PVT.LTD. (Delhi & Haryana)Contact: 9891201737,9891238707
- Mrs. Sweeta Subhash Pratap
Wife of late Shri Justice S.C. Pratap Left for her heavenly abode On14th January 2016. Deeply Mourned by Prashant S. PratapAbha & Dinesh Desai Shaina Pratap Girish Pratap Ashok & Sandhya PratapShalini Vakil Shakuntala & Dileep Deshmukh And FamilyNo condolences please
- Subhash Ghai's institute announces Lata Mangeshkar scholarship
Mumbai, June 3 (IANS) Veteran filmmaker Subhash Ghai's film and media arts institute Whistling Woods International has announced a scholarship named after melody queen Lata Mangeshkar.
- Tiger Shroff to act in Subhash Ghai's next?
After his action-packed turn in 'Baaghi', Tiger Shroff has been snapped up by Subhash Ghai for his next.


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December 09. 2012 6:00AM
I attended a job fair this week and was amazed at how many job seekers came undressed for success. On the male side, suits and ties were in the minority. Business casual was the preferred mode. In second place came street wear - jeans, shorts, jackets, jerseys and baseball caps. The ladies weren't much better; business professional, business casual and street wear were equally split. Some of the women had children with them. Employers, on the other hand, were decked out in business professional or company logowear.
Over lunch, I spoke with many of the employers about the importance of making a good first impression. Their consensus was that street wear was totally unacceptable for the workplace; resumes from those candidates were kept in a separate pile and discarded. Everyone said that these job seekers weren't taken seriously because they didn't look ready for work.
Resumes from those with children in tow met the same fate. The employers believed that the job fair was advertised for weeks, so attendees had ample time to line up a babysitter for a few hours. Bringing a child showed a lack of planning - an essential workplace skill.
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I experienced the "dressing down" and more firsthand because I helped a friend do some interviewing this week. He owns a 350-employee company and was hiring a B2B salesperson. In the office, the dress is business casual. On sales calls, image is important because his clients are mid-level executives, so business professional is required.
Four equally-qualified candidates were interviewed: Joe wore a rumpled blazer, cotton pants, lacked a tie and didn't shine his shoes. He definitely smoked cigars, too. He had all the right answers, clearly could sell, asked questions about the company - but couldn't overcome his shabby, smoky image. NEXT. Virginia was professionally dressed in a blue suit with a white blouse and black pumps. The image looked promising from afar. It was downhill from up close; she was a portable perfume counter. Her answers were as strong as her perfume, but she came across cold because she avoided eye contact and didn't smile. NEXT.
Benny, although in business casual, was impeccably dressed. He wore a blue blazer, blue button-down shirt, grey wool pants and shined shoes. His answers weren't always spot-on, but he was engaging, sincere, made eye contact and smiled. He knew quite a bit about the company and asked good questions. A finalist.
Beth was the last candidate; like Virginia, she dressed professionally. That's all she had in common with Virginia. Interview-wise, she was Benny's clone. Experience-wise, they were equals, too. Another finalist.
My friend had a tough decision. He chose Beth because she came dressed in the image that would be in front of his customers. He told me that if Benny had worn a suit, rather than blazer, the decision would have been a coin flip.
One thing that struck me as my friend gave me a tour of his office is that there are apparently two definitions of business casual: 1. The managerial version: dress wool pants/skirts, button-down shirts/nice blouses, a blazer and semi-dressy shoes. 2. The worker version: cotton pants, golf shirts and casual shoes (except for the salespeople who dressed liked the managers).
If you're a worker who aspires to management, your personal image may be a deciding factor. Don't be undressed for success.


text:
Top Definition
Minionization occurs when one takes something, and makes it his own by using it and abusing it in his own particular way.
Jerk #1: Did you go home with that FYP ("Fresh Young Pussy") last night?
Jerk #2: Yes, I completley minionized her.
Jerk #2: Yes, I completley minionized her.
by The Jerkstore April 30, 2006
Trending Now


text:
Welcome Week
In the week before classes begin, both the International Office and the schools hold various orientation programs that provide you with important information for your stay and for the organization of your class schedule. You should definitely attend these meetings! These events are also a great opportunity to meet fellow students. In order to take part in all of the events offered, we expect you to come to Mannheim at least a week before the lectures start!
Orientation sessions by the International Office
Introduction to Uni Mannheim's academic system fall semester 2016
This introduction by the International Office is especially for exchange students. Here you will get practical advice and important information about the University of Mannheim, your studies, choosing courses and information about who to contact if you have any problems. You will have the opportunity to ask any questions about your stay and your studies in Mannheim.
The introduction is mandatory for all exchange students and will be held in English.
Date: Wednesday, 31 August 2016, 2 pm
Meeting Point: A3, Lecture hall 001
Following the orientation by the International Office, the Studierendenwerk will hold an orientation. This event is mandatory for students living in residence.
Welcome Reception for international students and scholars
We kindly invite you to our Welcome Reception. Here you will have the opportunity to get to know staff members of the International Office, get in touch with fellow students and scholars and enjoy snacks and refreshments in a relaxed atmosphere. International student organizations will also present their program of events for the coming semester.
Date: Friday, 2 September 2016, 4:00 pm
Meeting Point: A3, Lecture hall 001
You can also find the complete program of events in our brochure:
Events for international students spring 2016
Orientation sessions and campus tours by the Schools:
In addition, there are orientation sessions offered by the Schools, which we highly recommend to attend:
Business School (mandatory for Business exchange students)
Orientation session:
Date: Thursday, 1 September 2016, 12.30 pm-2:00pm
Meeting Point: A3
Verena Übelhör
Campus tour:
Date: Thursday, 1 September 2016, 11:00 am-12:00 noon
Meeting Point: Schneckenhof
School of Social Sciences
Orientation session: Friday, 2 September 2016, 2:00pm-3:30pm
Meeting Point: A5, 6, Entrance B, Room B 243
Political Science: Julia Hoffmann
Sociology: Maria Petrova
Psychology: Johannes Schuler
School of Humanities
Campus tour: tba
Meeting point: Ehrenhof, right statue
Orientation Session: Thursday, 1 September 2016, 3:00pm-4:30pm
Meeting Point: EW 154
Olaf Moritz
School of Business Informatics and Mathematics
Campus tour and orientation for exchange students of Business Informatics and Mathematics:tba
Meeting Point: tba
Lisa Wessa
Department of Economics
Bachelor students:
Campus tour: tba
Meeting Point: tba
Special office hour for exchange students: February 15, 10am-2pm
Regular office hour: Tuesday, 9.30am-12.30pm
Meeting Point: L 7, 3-5 Room 4.23
Christiane Cischinsky
Office hour for Master students:
Date: Monday - Friday, 10am - 2pm
Meeting Point: L9, 7, Room 409
Juliane Holzheimer
Department of Law
Campus tour and orientation session: Thursday, 1 September 2016
Meeting Point: tba
Annette Zimmermann
For directions, please find a campus map here.


text:
Former Vt. trooper in timesheet case repayingThe Associated Press | September 13,2013BURLINGTON - A former Vermont State Police sergeant who pleaded guilty to padding his timesheets has started to pay back the more than $200,000 he owes the state.
The state received a check for about $4,700 over the summer from Jim Deeghan, who is serving a two-year prison sentence.
Chittenden County State's Attorney T.J. Donovan told the Burlington Free Press that the rest of the money will come from his state police pension over the next six years.
The 50-year-old Deeghan and his family still receive health and dental benefits.
Meanwhile, the Deeghans' home in Colchester has been sold for $365,000. While his case was pending, Donovan has filed a lien notice on the property to collect the proceeds.MORE IN This Just InNORTH BENNINGTON Two public meetings, in North Bennington and Shaftsbury, have been set for... Full StoryThe Board of Aldermen has endorsed a major jump in city pension funding. Full StoryHUBBARDTON The annual celebration of Hubbardton has been moved to Sunday due to the weather... Full Story
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text:
Pork And Noodle Casserole
|4 Ounce
|Ground pork
|1 Pound
|1 Small, chopped
|Stewed tomatoes
|16 Ounce
|Whole kernel corn
|12 Ounce, drained
|Tomato paste
|6 Ounce
|1 Teaspoon
|Chili powder
|1 Teaspoon
|Garlic powder
|1⁄4 Teaspoon
|1 Dash
|Shredded cheddar cheese
|1 Cup (16 tbs)
Cook noodles in a large amount of boiling salted water for 10 to 12 minutes or just till tender; drain.
Meanwhile, in 10-inch skillet cook ground pork and onion till meat is browned and onion is tender; drain off fat.
Stir in undrained tomatoes, corn, tomato paste, salt, chili powder, garlic powder, and pepper; mix well.
Stir in noodles.
Turn mixture into a 11/2-quart casserole.
Cover and bake in 350° oven about 40 minutes or till heated through.
Sprinkle with shredded cheese.
Bake, uncovered, about 5 minutes more or till cheese is melted.
Rate It
Nutrition Rank
Nutrition Facts
Serving size
Calories 424 Calories from Fat 208
% Daily Value*
Total Fat 23 g35.7%
Saturated Fat 10.3 g51.4%
Trans Fat 0 g
Cholesterol 90.5 mg30.2%
Sodium 654.4 mg27.3%
Total Carbohydrates 31 g10.4%
Dietary Fiber 3.5 g14.2%
Sugars 9.9 g
Protein 22 g44.3%
Vitamin A 23.7% Vitamin C 27%
Calcium 21.3% Iron 15.4%
*Based on a 2000 Calorie diet


text: Shame is a sense of the self as defective and worthless. This is a painful state. As painful as shame is, it also can make us preoccupied and self-centered. We become emotionally unavailable to others. As we let go of shame, we create circles of security around us where people can be themselves, genuine, worthy, and imperfect. Dealing with shame is a gift we give to others and to ourselves.


text:
Changeable. Each commentator will use that word at least 6,072 times over the Belgian Formula One
2014 Belgian GP
- Volvo shoots for self-drivers by 2021
- Jeep spends $1 billion on factories
- Find Parts & Accessories for your vehicle!
- Obama rolls out new EV plan
- Infiniti dealers ranked best, Tesla worst
- Compare Volvo XC90 and Lincoln MKX


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We're sorry. The information you have requested is temporarily unavailable.
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Be the first to like this
Published on
Advocare - The # 1 Problem Reps Face
This look at the Advocare business poses the question- why don't more people gain financial freedom with the Advocare opportunity? Is it the products, compensation plan, or business plan ? Well it seems many people are very happy with the Advocare products- in fact - I've even tried a few myself in the past and was pleased - so how come not everyone is in the black with Advocare ?
Don't quality products mean a quality business ? Even a thriving one?
No, unfortunately there is much more to a successful business than just offering great products or solutions. I've worked with a number of home business owners and found one universal problem relates to ALL the folks out there who really want to
have a flourishing home endeavor but jsut aren't seeing the results they want.
This video identifies that one problem as well as pointing out:
0:34- Advocare Problem #1 - Why most don't make as much money as they'd like in Advocare
2:09- Advocare Secret #2- How good are the Advocare products?Does it mattter?
3:11- Advocare Obstacle #3- What the Top earners do differently
4:40- Advocare Secret #4- Setting yourself up for success
In all honesty most people are product people and it is easier to share products then a business opportunity; products will be the driving force of your business but the problem is they just won't sell themselves.


text:
Undertaking a Fostering Assessment in England: A Guide to Collecting and Analysing Information for Form F (Fostering) England (Paperback)Roger Chapman
Paperback Published: 30/11/2009
- Not available
Click & Collect From your local shop
Publisher: CoramBAAF
You may also be interested in...
ReviewsView all Write your review
"Really useful book!"
Great book with thorough guidance on undertaking Form F assessments....definitely recommend!
"Undertaking a Fostering Assessment in England"
Extremely useful, not just for undertaking a fostering assessment but also in learning how to structure an assessment using a holistic approach to peoples' lives.
We would love to hear what you think of Waterstones. Why not review Waterstones on Trustpilot?


text:
"When you accept money in payment for your effort, you do so only on the conviction that you will exchange it for the product of the effort of others. It is not the moochers or the looters who give value to money. Not an ocean of tears nor all the guns in the world can transform those pieces of paper in your wallet into the bread you will need to survive tomorrow. Those pieces of paper which should have been gold, are a token of honor -- your claim upon the energy of the men who produce. Your wallet is your statement of hope that somewhere in the world around you there are men who will not default on that moral principle which is the root of money." ~ Ayn Rand
America: What Good Is It?
Column by Paul Bonneau.
Exclusive to STR
Terrific column! Very smooth and absolutely spot-on. I appreciated the reminder of the good that America still retains; as the bad grows ever-worse, its easy to forget that not everything is horrible.
- Login to post comments
"Music, and (when it is good) Hollywood."
This land mass has a slew of fine symphony orchestras (that must also include our neighbors to the north, with the Montreal Symphony). The Cleveland Orchestra is considered by many music reviewers and professional musicians to be the greatest orchestra in America, and perhaps the greatest (or certainly one of the greatest) in the world.
But even the ones you haven't heard can be amazingly good. I've had the pleasure of hearing the Syracuse Symphony (Upstate New York) and the Utah Symphony. Each of those orchestras, far lesser known, can knock it out with the best of them.
Thanks for cheering us all up, Paul.
...with the first part of your article, anyway. :)
- Login to post comments


text:
Congratulations and good luck, Class of 2016!
We wish you well in your future studies. Come back often to visit your AOSE family.
We wish you well in your future studies. Come back often to visit your AOSE family.
Please note: orders for this new AOSE team gear are due by July 22. Order now. Download an order form on Ms. Boccher's page (Athletics > Message from the Athletic Director).
Please read this important note from Erin Boccher about the Fall Sports schedule.
The Main Office at the Academy will be open from 9:00 - 2:00, Monday through Thursday. The Academy will be closed on Fridays through August 12th.
Academics, special events, holidays, closings, test dates and more.
Please download the 2016-17 AOSE calendar by clicking the headline above.
Attention, athletes: Please download this packet of sports forms. You can bring your completed packet on the first day of the Fall preseason, August 15. Any questions, contact Ms. Boccher:
2nd Annual Alumnae Summer Meet-up
Date: 8/6/2016, 4 PM
Location: Lake Como
Tryouts for Fall Sports
Date: 8/15/2016, 9 AM
Booster Club Meeting
Date: 8/29/2016, 7 PM
Faculty Morning of Reflection / Lunch / Faculty Meeting
Date: 9/6/2016
Freshman & New Student Orientation
Date: 9/7/2016
9th Grade & New Students Report
Date: 9/8/2016, 8:10 AM
10th - 12th Grade Report
Date: 9/8/2016, 10 AM
New Parent Orientation
Date: 9/8/2016, 7 PM
|Show Calendar »
|Show All »
|Show All »


text:
Tougher Vicious Dog Bill Proposed
Updated: 02/12/2008 - An unprovoked dog attack could put the dog and its owner behind bars, if a new House bill is passed in Mississippi.
Updated: 02/12/2008 - An unprovoked dog attack could put the dog and its owner behind bars, if a new House bill is passed in Mississippi.
Updated: 02/12/2008 - For the sheriff of a small county, the work may slow at times, but never stops for Todd Kemp.
Updated: 02/12/2008 - Public housing officials from across Mississippi are meeting in Meridian this week, sharing ideas for some common issues.
Updated: 02/12/2008 - The Centers for Disease Control and Prevention says the majority of the U.S. is now facing a widespread flu outbreak. And everyone, it seems, is looking for a way to prevent it.
Updated: 02/12/2008 - Lauderdale County officials say a robbery suspect was easy to find Sunday because he left a trail.
Posted: 02/11/2008 - The long-awaited Girl Scout cookies have arrived and will be distributed in the Meridian area soon.
Updated: 02/11/2008 - Plans for Lauderdale County's 2008 Relay for Life were announced Monday.
Posted: 02/11/2008 - Meridian police have requested help from the public to locate a suspect wanted on a charge of felony false pretense.
Posted: 02/11/2008 - The price tag for this past week's tornadoes in Lafayette County will be costly, but the assessment is not yet complete.
Posted: 02/11/2008 - Mississippi's "open-government" laws are full of exemptions that apparently allow secrecy by public officials.
Updated: 02/11/2008 - Mississippi's forest industry is expected to record another net decrease in the 2007 timber harvest, as it recovers from Hurricane Katrina.
Updated: 02/10/2008 - Last month, when Emergystat pulled the plug on its operations in 23 Mississippi counties, employees were left with a lot of questions. The biggest of which was when the next paycheck would come.
Updated: 02/10/2008 - Man left Lauderdale County Chevron with stolen money
Updated: 02/10/2008 - Many Mississippi lawmakers say they'll continue to push for passage of a tax swap proposal.
Updated: 02/10/2008 - Yes, it's much too early to start thinking about running mates. But people are doing it anyway.
Posted: 02/09/2008 - The Mississippi Legislature is in the middle of trying to get out of a budget crunch. With only so much to go around, lawmakers must find ways to fund education, Medicaid and a list of other areas important to citizens.
Posted: 02/09/2008 - A National study gives Mississippi a failing grade for its government sunshine laws.
Updated: 02/09/2008 - Lauderdale County Circuit Clerk's Office had extended hours
Updated: 02/09/2008 - Congress has sent an economic stimulus package to President Bush that approved rebate checks for taxpayers. We asked you if you think the plan will help the U.S. economy.
Posted: 02/08/2008 - The Stennis-Montgomery Association at Mississippi State University will sponsor four debates for candidates in the third congressional district race.
Updated: 02/08/2008 - Mississippi Sen. Thad Cochran has shifted his support to Sen. John McCain in the presidential race.
Updated: 02/08/2008 - One year later, the Blackwater community is still recovering from tornadoes that left damage and injury.
Posted: 02/08/2008 - By a unanimous vote, the Quitman board of aldermen has rescinded its proposal for annexation.
Posted: 02/08/2008 - Aruban investigators in the Netherlands again questioned a Dutch college student Friday in the Natalee Holloway disappearance.
Updated: 02/08/2008 - An inmate advocacy group, The Innocence Project, is pushing for changes in the way Mississippi uses DNA evidence in criminal cases.


text:
Writing With, Through, and Beyond the Text: An Ecology of Languageby Rebecca Luce-Kapler, Luce-Kapler
View All Available Formats & Editions
Pub. Date: 05/05/2004
Publisher: Taylor & Francis
Writing With, Through, and Beyond the Text: An Ecology of Language elaborates an understanding of writing, its influences on our interpretations of experience and identity, and its potential for enabling individuals to learn about and connect to the world beyond themselves. Rather than considering writing a process, the author describes it as a system, an ecology that engages the individual in a variety of socially constituted and interacting systems. The book examines the pedagogical and curricular implications of this approach to writing, considering what it means to write and teach writing in ways that understand and acknowledge the ecological character of writing. This is an illuminating text for a wide audience of faculty, professionals, and graduate students in English, writing, education, and women's studies/feminist theory.
Product Details
- 9780805846096
- Publisher:
- Taylor & Francis
- Publication date:
- 05/05/2004
- Pages:
- 208
- Product dimensions:
- 6.10(w) x 9.00(h) x 0.70(d)
Table of ContentsContents: Preface. The Kitchen of My Imagination. A Coherence of Being. The Language Connection. The Subjunctive Cottage. In the Company of Writers. Writing Otherwise.
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text:
CIA refuses to release emails unless to, from, and subject lines are provided
Edited by Michael Morisy
Last month, MuckRock co-founder Michael Morisy requested emails related to the CIA's (now apparently fixed) technical issues with their online FOIA portal.
Twitter put it best: "You can't see any emails or know who sent or received them. But you must request the exact email and who sent and received it."
While we applaud the CIA for putting aside their fax machine and joining us in the 21st century, it would be even better if they started responding to requests, regardless of how they're submitted. But that's a story for another day.
Image via Wikipedia Commons


text:
IMDb > Laura Girard (Character)
Top Linksmain detailsbiographyby votesphoto galleryquotes
Filmographiesby yearby typeby ratingsby votesby TV seriesby genreby keyword
Did You Know?photo galleryquotes
Laura Girard (Character)
from "How I Met Your Mother" (2005)
The content of this page was created by users. It has not been screened or verified by IMDb staff.
FilmographyEdit Credits
There may be more credits available for this character. To edit the credits displayed or to add more credits to this character's filmography, click the Edit Credits link.
- "How I Met Your Mother"
... aka "H.I.M.Y.M" - USA (short title)
- The Platinum Rule (2007) TV episode, Played by Kristen Schaal
Additional Details
You may correct errors and omissions on this page directly. Clicking the 'Update' button will take you through a step-by-step process.


text:
Washington DC Samba Brazil Meetup Group Message Board › I made this for all Fancy cats Rescue Team ladies, and all cats lovers!
|Danielle A.
user 3585259
Group Organizer
Washington, DC
Watch this video i put it together and spread to all your friends that will appreciate Gorgeous men and their cute cats!
Meetup members, Log in
By clicking "Sign up" or "Sign up using Facebook", you confirm that you accept our Terms of Service & Privacy Policy


text:
(Aug. 14, 2013) -- UTSA Roadrunner Days is the official kick-off for the new school year, running Aug. 23 to Aug. 30 with a wide selection of free, fun and spirited events to welcome new and returning students with a look at campus life.
"We have designed this year's programming with student input from previous years and really hope it helps the Class of 2017 and our returning students make significant connections," said Barry McKinney, assistant dean of students and director of student activities. "There are some changes to this year's overall schedule that we hope will enhance our students' success in the coming academic year."Luis Alberto Urrea, author of "The Devil's Highway," will provide the keynote address for the UTSA Fall Convocation, which will launch weeklong celebrations. Urrea is a best-selling author and member of the Latino Literature Hall of Fame. A 2005 Pulitzer Prize finalist, the book is a non-fiction account of a group of Mexican immigrants lost in the Arizona desert and is the common reading for the Class of 2017.
This year, Fall Convocation and College Experience on Monday, Aug. 26 are mandatory for all new students. New students must attend these events beginning at 10 a.m. and should bring their UTSACard.
Roadrunner Days also will include performances by "American Idol" contestant Tim Halperin and Air Dubai, recording artists from Denver, Colo. Halperin will be featured at the upcoming Kidd's Kids Charity Concert, which was started by the late Kidd Kraddick, the late radio host of "Kidd Kraddick in the Morning." Air Dubai has been Westword magazine's Best Hip-Hop Band for the last three years.
Roadrunner Days events give new students opportunities to preview UTSA campus life, learn about resources to ease the transition to college, experience the excitement of the growing campuses and meet other new students. Returning students can enjoy many of the activities as well and are welcome to participate in these free events. Faculty and staff members also are invited to attend most of the events.
The UTSA Interactive Technology Experience Center camps are for curious youth who are interested in STEM and related topics. This week, campers will study environmental science, robotics and computer science.
UTSA Main Campus
In four sessions of this weeklong day camp for 9 to 13-year-olds, campers will participate in indoor and outdoor activities while exploring ancient technologies from around the world and the new technologies archaeologists are using to discover them.
UTSA Center for Archaeological Research, Main Campus
Campers will investigate how museums use artifacts, oral histories, and research to unravel stories about our past.
UTSA Institute of Texan Cultures
UTSA Math faculty prepare participants for success in their future math courses.
UTSA Main Campus
Staff can help campers improve their technical skills and knowledge of the game while having fun.
Tennis Courts, UTSA Main Campus
Experience a very different summer camp! The UTSA East Asia Institute is teaching kids Japanese through language, culture, art, crafts, music, cooking and more. For kids age 6-12. For more details, email email@example.com.
Main Building (MB 1.126), Main Campus
7 to 12 year-olds will explore Mayan Culture in a three-day sessions, concluding at the Witte museum, where campers will have the chance to see the new "Maya: Hidden Worlds Revealed" exhibit.
UTSA Center for Archaeological Research, Main Campus
Other Calendars
» UTSA Events | » Academic | » Institute of Texan Cultures
The University of Texas at San Antonio is dedicated to the advancement of knowledge through research and discovery, teaching and learning, community engagement and public service. As an institution of access and excellence, UTSA embraces multicultural traditions and serves as a center for intellectual and creative resources as well as a catalyst for socioeconomic development and the commercialization of intellectual property - for Texas, the nation and the world.
To be a premier public research university, providing access to educational excellence and preparing citizen leaders for the global environment.
We encourage an environment of dialogue and discovery, where integrity, excellence, inclusiveness, respect, collaboration and innovation are fostered.


text:
Great 13 year old POA Mare. UTD on shots/worm. Make a great intermediate 4-H or trail horse.SOLD
SOLD~This sharp little bay pony has been hauled to rodeos, playdays, and he does it all, we have done barrels, pole bending, goat tying, and some breakaway…SOLD
SALE PENDING See video @ http://www.youtube.com/watch?v=CX8qSHPbcfQ&feature=channel Lovely large pony mare that is a perfect size for a family. …SOLD


text:
Sorry! The position you're looking for is no longer available. Check out other Software internships in Washington below.
Results 1 — 10
Sort By:
Fall 2016 - Snappening Social Media Internship
Snappening — Seattle, WA
July 28 2016
**Please note this is an unpaid internship, designed for students completing a formal internship course from an accredited college or university. Other students may apply.** Do you have a passion for …
Application Deadline: 8/26/2016
Marketing & PR Internship for Local, Organic Company
Seattle Seed Co. — Seattle, WA
July 25 2016
We are seeking an energetic and flexible intern for help with several specific marketing projects, as well as overall social media management and content curation. We offer a very flexible schedule fo…
Application Deadline: 8/15/2016
Marketing Internship - Money Available
Wigu Date Deals — Seattle, WA
July 24 2016
Be part of a growing company, we provide discounted deals for first time dates, using our dating app. We let users skype with each other first and decide whether they want to meet in person. This comb…
Application Deadline: Available Year-round
Permaculture Community fellowship
Windward Education and Research Center — Wahkiacus, WA
July 18 2016
"The restoration of vibrant, fierce communities of women across the globe would eradicate much of the worlds injustice almost overnight." --Christiane Pelmas, MSW, www.therewilding.com The foundation …
Application Deadline: Available Year-round
Event Intern
Seattle Milk Fund — Seattle, WA
July 11 2016
Seattle Milk Fund is a nonprofit that provides child care grants to parents who are attending college full-time in King County to earn their first college degree. While parents are in school, their ch…
Application Deadline: 8/31/2016
Business Development/Sales Lead Generation Internship
Cloutera — Seattle, WA
July 08 2016
Partnering with startups and emerging growth firms needed to scale their workforce quickly, Cloutera is a leading provider of On-Demand Recruiting and Diversity Hiring Solutions. We drop smart and mo…
Application Deadline: Available Year-round
Marketing/Public Relations Internship
Cloutera — Seattle, WA
July 08 2016
Partnering with startups and emerging growth firms needed to scale their workforce quickly, Cloutera is a leading provider of On-Demand Recruiting and Diversity Hiring Solutions. We drop smart and mot…
Application Deadline: Available Year-round
Dell Campus Ambassador - University of Washington
Mosaic — Seattle, WA
July 08 2016
Mosaic Sales Solutions is a full-service marketing agency that delivers successful brand experiences for various high profile clients directly to the people who buy them. Ad Age recently included us i…
Application Deadline: 8/5/2016
Labor & Employment Attorney - Domestic and International
Robert Half Legal — Tacoma, WA
July 08 2016
ATTENTION LABOR/EMPLOYMENT ATTORNEYS! Robert Half Legal has teamed with a dynamic Seattle area company seeking to expand it's Legal Department with the addition of a Corporate Counsel with both litiga…
Application Deadline: Available Year-round
Real Estate Transaction Assistant
Beyond Home Realty, LLC — Renton, WA
July 06 2016
1. Implements a social media strategy - The social media manager will develop the plan and the parameters for the corporate social media strategy. They will determine objectives, establish what needs …
Application Deadline: Available Year-round


text:
I endorse this lawyer. Adam Rauman has a wide range of knowledge in elder law and estate planning. I highly recommend him.
Brian Arrighi Divorce and separation Attorney
Relationship: Fellow lawyer in community
I endorse Adam. He is a highly skilled attorney that is well respected in the legal community.
Michael Waddington Military law Attorney
Relationship: Fellow lawyer in community
Excellent attorney. Well respected.
Tatiana Kadetskaya Insurance Attorney
Relationship: Fellow lawyer in community
I endorse this lawyer.
Howard Roitman Car accident Attorney
Relationship: Other
I endorse this lawyer. Attorney Rauman and I practice in some of the same areas of law, so I have had the opportunity to review a great many answers he has written for Avvo askers. I find that I not only agree with his legal analysis, but that Attorney Rauman goes out of his way to provide helpful, practical advice. He is a great resource for the Avvo community and reflects very well on the younger generation of attorneys. James Frederick
James Frederick Probate Attorney
Relationship: Fellow lawyer in community
I endorse this lawyer. Mr. Rauman is a top notch estate planning attorney. He has an amazing ablility to make the complex and difficult rather easy for the lay person to understand. That is the true test of one's knowledge on a particular subject. He not only knows the law but is also a caring and sympathetic individual that takes personal pride in his profession. I would certainly recommend Adam Rauman!
Jesse Berkowitz Personal injury Attorney
Relationship: Worked together on matter
Adam is a very competent and knowledgeable attorney. Adam does a great job explaining complicated legal and financial issues to his clients in a way that is easy to understand. He is a great communicator and truly cares about his clients. I have no reservations in endorsing this attorney.
Derek Lucas Family Attorney
Relationship: Co-worker
Help your colleagues,
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Sirtuin 1 (SIRT1) is the most conserved mammalian NAD+-dependent protein deacetylase that has emerged as a key metabolic sensor in various metabolic tissues. In response to different environmental stimuli, SIRT1 directly links the cellular metabolic status to the chromatin structure and the regulation of gene expression, thereby modulating a variety of cellular processes such as energy metabolism and stress response. Recent studies have shown that SIRT1 controls both glucose and lipid metabolism in the liver, promotes fat mobilization and stimulates brown remodeling of the white fat in white adipose tissue, controls insulin secretion in the pancreas, senses nutrient availability in the hypothalamus, influences obesity-induced inflammation in macrophages, and modulates the activity of circadian clock in metabolic tissues. This review focuses on the role of SIRT1 in regulating energy metabolism at different metabolic tissues.
Sirtuins, a family of highly conserved protein modifying enzymes founded by the yeast silent information regulator 2 (Sir2) protein, are NAD+-dependent protein deacetylases and/or ADP-ribosyltransferases [1–4]. Although yeast Sir2 plays an important role in the maintenance of the silent chromatin (reviewed in ref. [5]), sirtuins in other model organisms have been increasingly recognized as crucial regulators of a variety of cellular processes, ranging from energy metabolism, and stress response, to tumorigenesis and aging [6,7].
Among the seven sirtuins that the mammalian genome encodes [8], SIRT1 is the ortholog of the yeast Sir2 protein and a nuclear NAD+-dependant protein deacetylase (Fig. 1). As the most evolutionally conserved mammalian sirtuin, SIRT1 has been a topic of intense research for more than a decade. A wealth of data have shown that this sirtuin is a nuclear metabolic sensor that directly couples the cellular metabolic status (via NAD+) to the chromatin structure and the regulation of gene expression (through deacetylation of histones, transcription factors, and transcription co-factors). Since it plays a vital role in metabolism, development, reproduction, it is not surprising that SIRT1 affects more complex biological phenomena such as aging and disease [7,9,10]. Therefore, understanding the role of SIRT1 in energy metabolism will likely provide insights into therapeutic strategies designed towards metabolic diseases and possibly aging.
As a protein deacetylase, SIRT1 has a very broad range of protein substrates [7,10] and also shuttles between nucleus and cytosol in response to certain environmental stimuli [11]. However, despite the diversity in protein substrates and subcellular localizations, the activity of SIRT1 is tightly controlled by the cellular levels of one of its substrates, NAD+ (Fig. 1). NAD+ is an essential coenzyme found in all living cells. In metabolism, NAD+ is involved in redox reactions through electron transfer, in which it can readily switch from electron accepting form (oxidizing) NAD+ to electron donating form (reducing) NADH, and vice versa [12]. Therefore, NAD+ and NADH are extensively utilized in an array of metabolic reactions, and the cellular level of NAD+ is an important indicator of the cellular energy status. As a result, SIRT1 provides a molecular link between the cellular energy status and the adaptive transcriptional responses [13]. Due to its ability to modify and control numerous transcription factors and co-factors involved in systemic metabolic homeostasis, SIRT1 is increasingly referred to as a master metabolic regulator (Fig. 2).
Not surprisingly, the activity of SIRT1 is closely controlled by different environmental cues that can change the cellular NAD+ availability. For instance, a low-energy status that increases cellular levels of NAD+, such as fasting, caloric restriction (CR), and exercise, has been shown to stimulate SIRT1 activity [14–20]. On the other hand, a high-energy status that decreases cellular NAD+ levels, including high-fat diet feeding and acute inflammatory responses, reduces SIRT1 activity [21–24]. In addition, direct manipulation of the biosynthesis and catabolism of NAD+ can also alter cellular NAD+ levels and thereby SIRT1 activity. For example, increasing the activity of Nampt, the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis, enhances the levels of NAD+ and activity of SIRT1 [25–29], whereas decreasing the activity of Nampt leads to reduced NAD+ levels and SIRT1 activity [30,31]. Consistently, the treatment of cells or animals with nicotinamide mononucleotide or nicotinamide riboside, NAD+ precursors elevates NAD+ levels and SIRT1 activity [21,25,32–34]. Furthermore, deletion of Parp1, an enzyme that creates polymers of ADP-ribose at the expense of NAD+ [35–37], or decrease in the activity of CD38, the major NAD+ glycohydrolase that is present in the inner nuclear membrane [34,38,39], elevates NAD+ levels and promotes the activity of SIRT1. Taken together, these data indicate that SIRT1 is an essential metabolic sensor that can directly adapt the nuclear transcriptional networks to the cellular metabolic state.
In addition to cellular NAD+ levels, the expression and activity of SIRT1 are also under control of an intricate regulatory network at multiple layers in response to nutritional, hormonal, and environmental signals (Fig. 1). This regulatory network functions at different levels and is critical for maintaining a suitable dosage of SIRT1 in response to various environmental stimuli (for detailed reviews, please see [40–42]).
The liver is a central metabolic organ that controls several key aspects of lipid and glucose metabolism in response to nutritional and hormonal signals [43]. It is essential for the maintenance of systemic energy homeostasis in the body. Recent reports have shown that SIRT1 is an important regulator of hepatic glucose metabolism (Fig. 2). For instance, hepatic SIRT1 is a key modulator of gluconeogenesis in response to fasting. It has been shown that during the short-term fasting phase, SIRT1 inhibits TORC2 (also known as CRTC2), a CREB-regulated transcription coactivator that is important for cAMP/CREB-mediated activation of gluconeogenesis genes, leading to reduced gluconeogenesis [44]. Yet the prolonged fasting increases SIRT1-mediated deacetylation and activation of PGC-1α, an essential co-activator for a number of transcription factors, resulting in increased fatty acid oxidation and improved glucose homeostasis [14,45,46]. In addition to TORC2 and PGC-1α, SIRT1 also deacetylates and activates Foxo1, resulting in increased gluconeogenesis [47]. Therefore, the net effect of SIRT1 on the regulation of gluconeogenesis is determined by the complex interaction between multiple factors at different phases of fasting and/or feeding.
Hepatic SIRT1 also plays an important role in hepatic fatty acid metabolism (Fig. 2). For example, it has been shown that adenoviral knockdown of SIRT1 reduces expression of fatty acid β-oxidation genes in the liver of fasted mice [48]. Our lab recently showed that specific deletion of the exon 4 of the mouse hepatic SIRT1 gene, which results in a truncated inactive SIRT1 protein, impairs fatty acid β-oxidation through the PPARα/PGC-1α pathway, thereby increasing the susceptibility of mice to high-fat diet-induced dyslipidemia, hepatic steatosis, inflammation, and endoplasmic reticulum (ER) stress [45]. Consistently, a complete deletion of hepatic SIRT1 by floxing exons 5 and 6 leads to development of liver steatosis even under normal feeding conditions [49]. Conversely, hepatic overexpression of SIRT1 mediated by adenovirus attenuates hepatic steatosis and ER stress, and restores glucose homeostasis in mice [50], confirming the essential role of SIRT1 in maintaining hepatic glucose and lipid homeostasis.
SIRT1 also regulates hepatic cholesterol and bile acid homeostasis through direct modulation of the liver X receptors (LXRs) and farnesoid X receptor (FXR) [51–53]. LXR and FXR are nuclear receptors that function as important cholesterol and bile acid sensors [54]. It has been previously shown that SIRT1 can directly deacetylate LXRs, resulting in increased LXR turnover and enhanced target gene expression [51]. Systemic deletion of SIRT1 in mice results in decreased serum HDL levels [51]. More recently, we and others have shown that the bile sensor FXR is also a target of hepatic SIRT1 in metabolic regulation [52,53]. It appears that SIRT1 is able to regulate the activity of FXR signaling at multiple levels. Firstly, SIRT1 regulates the expression of FXR through interaction with a hepatic nuclear factor HNF1α, which may also involve the co-activator PGC-1α [53]. Secondly, SIRT1 deacetylates FXR, increasing its DNA binding affinity [52]. Thirdly, SIRT1 appears to directly co-activate FXR through its co-activator PGC-1α. Finally, hepatic SIRT1 seems to stimulate the biosynthesis of bile acids, endogenous ligands of FXR, which in turn bind to FXR and induce its transcriptional activity [53]. Interestingly, recent studies have demonstrated that the FXR pathway also positively regulates the translation of SIRT1 protein via p53/miR-34a pathway [55,56]. Therefore, SIRT1 and the FXR signaling pathway mutually interact at multiple levels, coordinately regulating hepatic bile acid and cholesterol homeostasis.
Walker et al. and Ponugoti et al. recently showed that SIRT1 may also regulate hepatic lipid metabolism through deacetylation of SREBPs [57,58], critical regulators of lipogenesis and cholesterolgenesis [59]. These two reports revealed that SIRT1 can directly deacetylate SREBPs, and that SIRT1 activity is important in the fasting-dependent attenuation of SREBPs [57,58]. Consistently, chemical activators of SIRT1 inhibit SREBPs target gene expression in vitro and in vivo, correlating with attenuated liver steatosis in diet-induced and genetically obese mice. In summary, these findings imply that hepatic SIRT1 plays a critical role in the regulation of local and systemic metabolic homeostasis.
Adipose tissues, including white adipose tissue (WAT) and brown adipose tissue (BAT), are important metabolic tissues involved in fat storage, body insulation, and body temperature regulation. They are also major endocrine organs functioning to modulate systemic energy metabolism. For example, WAT-derived hormones, such as leptin, adiponectin, and resistin, control energy balance, glucose regulation, and fatty acid catabolism. Adipose tissues originate from the differentiation of lipoblasts, and one of the primary factors involved in adipose tissue differentiation is the nuclear receptor PPARγ [60]. SIRT1 has been shown to repress PPARγ in WAT, thereby suppressing the expression of adipose tissue markers, such as the mouse aP2 gene ([61], Fig. 2). Consistently, genetic ablation of SIRT1 in adipose tissues leads to increased adiposity and insulin resistance [62]. The treatment of mice on a high-fat diet with resveratrol, a polyphenol that activates SIRT1 in cells directly or indirectly [63–67], has also been shown to protect against high-fat-induced obesity and metabolic derangements [68–70]. These findings demonstrate that SIRT1 acts in concert with lipid sensing transcription factors, such as PPARγ, to adapt gene transcription in WAT to changes in systemic nutrient levels.
In addition to WAT, previous studies have also implicated a role of SIRT1 in the differentiation and function of BAT, an important non-shivering thermogenesis organ that is essential for survival of non-shivering animals and neonates. It appears that SIRT1 can modulate BAT through both cell autonomous and non-cell autonomous mechanisms. On the one hand, SIRT1 in BAT may directly promote BAT differentiation through repression of the MyoD-mediated myogenic gene expression signature and stimulation of PGC-1α-mediated mitochondrial gene expression [71]. On the other hand, SIRT1 in propiomelanocortin (POMC) expressing neurons is able to selectively control perigonadal WAT-to-BAT-like remodeling to increase energy expenditure in female mice [72]. A recent study indicates that SIRT1 can also regulate the brown remodeling of WAT in response to cold exposure by deacetylation of PPARγ [73]. Qiang et al. showed that SIRT1-dependent deacetylation of PPARγ is required to recruit the BAT program coactivator Prdm16 to PPARγ, leading to selective induction of BAT genes and repression of WAT genes [73]. Therefore, it seems that SIRT1 differentially modulates the activity of PPARγ signaling in response to different environmental stimuli in WAT. SIRT1 inhibits the PPARγ signaling through modulation of local acetylation status of histones and recruitment of co-repressor NCoR during the fasting response [61], yet directly enhances the PPARγ signaling through deacetylation of the nuclear receptor itself in response to cold exposure [73].
Pancreatic β cells are specialized endocrine cells located in the islets of Langerhans in pancreas. They are systemic metabolic sensors that synthesize and store insulin, and release insulin in response to the increase in blood glucose levels. Destruction of these cells is the leading cause of type 1 diabetes mellitus, and their dysfunction partially contributes to the pathogenesis of type 2 diabetes [74–76]. SIRT1 has been shown to be a positive regulator for pancreatic insulin secretion, which in turn triggers glucose uptake and utilization. For example, increased dosage of SIRT1 specifically in pancreatic β cells improves glucose tolerance and enhances insulin secretion in response to glucose in mice [77], whereas systemic deletion of SIRT1 impairs glucose-stimulated insulin secretion [78]. In both studies, SIRT1 has been shown to promote insulin secretion through transcriptional repression of uncoupling protein 2 (UCP2) (Fig. 2). Furthermore, mice treated with resveratrol display an increased capability to secrete insulin in β cells in response to glucose [79]. In line with these observations, activation of SIRT1 by its activators in animals protects against high-fat-induced obesity and insulin resistance [68–70], and modest overexpression of SIRT1 has a protective effect against high-fat induced glucose intolerance [80,81]. Collectively, these observations indicate that SIRT1 is a vital regulator of pancreatic insulin secretion in response to the nutrient availability.
The brain plays a critical role in the regulation of systemic energy homeostasis. Through assessment and integration of peripheral metabolic, endocrine, and neuronal signals, central nervous circuits are able to orchestrate a modulating program on both behavioral patterns and peripheral metabolism to adapt acute and chronic energy requirements [82,83].
Among several key brain areas involved in the regulation of energy balance, the hypothalamus/pituitary axis is the primary structure that interprets adiposity and nutrient-related inputs. Recent studies have implied that SIRT1 may play a role in this central energy regulatory area. For instance, it has been shown that both CR and fasting enhance SIRT1 expression and activity in the hypothalamus [84,85]. Mice lacking SIRT1 in the brain show specific anterior pituitary cell defects and fail to mediate changes in pituitary signaling and physical activity in response to CR [86], while brain-specific SIRT1 transgenic mice display enhanced neural activity in the hypothalamus [85]. These findings suggest that SIRT1 in the brain may function as a link between the hypothalamus/pituitary hormones and animal metabolic status.
However, it turns out that the role of SIRT1 in the central control of whole body energy homeostasis is more complicated than previously expected (Fig. 2). In the hypothalamus, the anorexigenic POMC expressing neurons and the orexigenic agouti-related protein (AgRP) expressing neurons are the major regulators of feeding and energy expenditure [87]. The POMC neurons produce satiety peptides thereby inhibiting food intake after feeding, while the AgRP neurons promote feeding in response to fasting and CR. It appears that SIRT1 displays distinct functions in these two neuron populations. On the one hand, inhibition of hypothalamic SIRT1 activity increases acetylation of FOXO1, resulting in increased POMC and decreased AgRP expressions, thereby decreasing food intake and body weight gain [84]. In line with these observations, AgRP neuron-specific deletion of SIRT1 decreases AgRP neuronal activity, thereby alleviating the inhibitory tone on the POMC neurons, resulting in decreased food intake and body weight [88]. On the other hand, specific deletion of SIRT1 in POMC neurons in mice causes a blunted response to leptin signaling and reduced energy expenditure, leading to hypersensitivity to diet-induced obesity [72]. Although the physiological significance of these distinct functions of SIRT1 is still not clear, these studies confirm that SIRT1 is an essential element in the periphery-central feedback circuits that mediate normal responses to nutrient availability. Consistent with these notions, central administration of small molecule SIRT1 activator has shown promise in controlling of diet-induced obesity. For example, long-term intracerebroventricular infusion of resveratrol normalizes hyperglycemia and greatly improves hyperinsulinemia in mice with diet-induced obesity and diabetes [89]. In summary, SIRT1 activity appears to be an important player in the central regulation of nutrient sensing.
Macrophage activation and infiltration into resident tissues is known to mediate local inflammation and is a hallmark of metabolic syndrome [90–92]. This infiltration-induced local inflammation has been increasingly recognized as a causal factor leading to the development of the cluster of diseases surrounding metabolic syndrome [93].
Over the past few years, SIRT1 has been identified as an important repressor of inflammation in multiple tissues/cells including the macrophage [94–97]. For example, in mice, modest overexpression of SIRT1 leads to suppression of the inflammatory response, whereas whole-body insufficiency of SIRT1 induces systemic inflammation upon high-fat diet challenge [80,98,99]. Furthermore, deletion of SIRT1 in hepatocytes results in increased local inflammation under high-fat diet [45]. Several recent studies indicate that the beneficial effect of SIRT1 on metabolic disorders is due in part to its ability to suppress the activity of NF-κB, the master regulator of cellular inflammatory response, in macrophages ([100], Fig. 2). It has been shown that SIRT1 deacetylates the RelA/p65 subunit of NF-κB at lysine 310, leading to decreases in the NF-κB transcriptional activity, thereby reducing production of proinflammatory cytokines and anti-apoptotic genes [100]. In line with this notion, moderate overexpression of SIRT1 in mice leads to reduced NF-κB activity [80], while knockdown of SIRT1 in the mouse macrophage cell line RAW264.7 and in intraperitoneal macrophages increases LPS-stimulated TNFα secretion [96]. Moreover, it has been shown that cigarette smoke decreases cellular SIRT1 protein levels, causing increased acetylation and activation of NF-κB proinflammatory response in human macrophages [94]. Using a macrophage-specific knockout mouse (Mac-SIRT1KO), our group has recently provided in vivo evidence that SIRT1 deacetylates the nuclear RelA/p65 subunit of NF-κB and attenuates NF-κB-mediated gene transcription, predisposing mice to the development of insulin resistance and metabolic disorders [97]. Together, these findings demonstrate that SIRT1 activity in macrophages directly regulates immune responses and suggests that activators of SIRT1 may play an important therapeutic role in the treatment of chronic inflammatory diseases.
Interestingly, the activity and expression of SIRT1 are also under control of systemic inflammation. For instance, it has been shown that interferon gamma (IFNγ), a pro-inflammatory cytokine, represses the transcription of SIRT1 through class II transactivator, thereby disrupting metabolism and energy expenditure [101]. Moreover, TNFα has been shown to induce cathepsin B-mediated cleavage and inactivation of SIRT1 in chondrocytes [102]. More importantly, high-fat diet feeding in mice induces the cleavage of SIRT1 protein in adipose tissue through the inflammation-activated caspase-1 [62]. Therefore, SIRT1 and inflammatory signals mutually interacts at various levels, and SIRT1 is an essential molecular link between nutrient, inflammation, and metabolic dysfunction.
Circadian rhythm refers to an endogenous entrainable 24-hour oscillation of any biological process in all living entities on Earth. This circadian rhythm depends on internal clocks that work in part through chromatin modification and epigenetic control of gene expression [103]. In mammals, the circadian clock is largely controlled by negative-feedback loops mediated by the heterodimeric transcription factors CLOCK-BMAL1 and their transcriptional targets, including the PER and CRY proteins that in turn directly repress CLOCK-BMAL1 activity, as well as REV-ERB and ROR nuclear receptors that control BMAL1 expression [104]. Intriguingly, the circadian clock has been recently associated with cellular metabolism. For example, circadian disruption in mice has been linked to metabolic dysfunctions [105,106], while high-fat diet feeding alters both behavioral and molecular circadian rhythms [107,108].
Chromatin modification has been shown to play an important role in the regulation of circadian gene expression. For example, the CLOCK protein itself is a transcriptional activator that functions as a histone acetyltransferase [109]. Moreover, SIRT1 has also been linked to the regulation of the circadian rhythm (Fig. 2). Early studies have shown that the expression and/or activity of SIRT1 are cyclically regulated by the circadian clock [110,111]. SIRT1 then interacts with CLOCK-BMAL1 to directly regulate the amplitude and duration of circadian clock-controlled gene expression through deacetylation of PER2 and/or BMAL1 [110,111]. However, how the circadian clock modulates SIRT1 expression/activity remained unclear in these studies. Two later studies discovered that the circadian regulation of SIRT1 activity is due to circadian oscillations of the cellular NAD+ levels [112,113]. It has been found that Nampt is a direct transcriptional target of CLOCK-BMAL1. Together, these studies add a new feedback loop in the circadian clock that involves CLOCK-BMAL1, Nampt, NAD+, and SIRT1, providing an important connection between physiological rhythm and cellular metabolism.
Although oscillations in the cellular NAD+ levels have been limited to the cyclical regulation of SIRT1 activity [112,113], an earlier study pointed towards an alternative mechanism [111]. Nakahata et al. [111] showed that the activity of immuno-purified endogenous SIRT1 proteins display a circadian oscillating pattern when measured in vitro with fixed amount of exogenous NAD+, suggesting that post-translational modifications or protein–protein interactions also play a role in the circadian regulation of SIRT1 activity. SIRT1 has been shown to be phosphorylated by several kinases in cells [114–116]. In particular, phosphorylation of SIRT1 by DYRK1A, an essential clock component that governs the rhythmic phosphorylation and degradation of CRY2 protein [117], activates its NAD+-dependent deacetylase activity in response to various environmental stresses [118]. SIRT1 also has several interacting partners that can directly inhibit or activate its activity [119–122]. Therefore, exploring the possible role of these factors in the circadian regulation of SIRT1 activity may provide novel insights into its function in circadian rhythm.
The important roles that SIRT1 plays in metabolism, inflammation, and circadian rhythm in various metabolic organs strongly suggest that SIRT1 is vital in regulation of whole-body insulin sensitivity, a physiological condition that is tightly associated with development of metabolic syndrome, a cluster of metabolic abnormalities including obesity, type 2 diabetes, dyslipidemia, fatty liver, and a pro-inflammatory and prothrombotic state [123–125]. Consistent with this notion, SIRT1 has been shown to directly regulate pancreatic insulin secretion, which in turn helps to improve systemic insulin sensitivity [77]. It has also been shown that SIRT1 stimulates mitochondrial fatty acid oxidation genes through PGC-1α in skeletal muscle, thereby promoting insulin sensitization [126]. Moreover, SIRT1 can improve systemic insulin sensitivity through interaction with AMP-activated protein kinase (AMPK), another essential metabolic sensor. On the one hand, SIRT1 directly deacetylates the AMPK protein kinase liver kinase B1, increasing the phosphorylation and activity of AMPK [127,128]. On the other hand, activation of AMPK by its synthetic activator, AICAR, increases cellular NAD+/NADH ratio, activating SIRT1 and increasing fatty acid oxidation and mitochondrial biogenesis [19,20,67]. In addition, it has been shown that SIRT1 directly regulates the secretion of adiponectin from adipocytes through deacetylation of FoxO1 [129], which can then help to improve insulin sensitivity in the liver and muscle [130,131].
SIRT1 also appears to be involved in the insulin downstream signaling pathway. It has been shown that SIRT1 represses the expression of PTP1B, a negative regulator of insulin signaling, thereby improving insulin sensitivity, particularly under insulin-resistant conditions [132]. A few cell culture studies also indicate that SIRT1 can interact with insulin receptor substrates, such as IRS-1 and IRS-2, thereby modulating their phosphorylation or acetylation status and improving insulin signaling [133].
Consistently, genetic deletion of SIRT1 in adipose tissues [62], myeloid cells [97], or liver [45,134], or systemic loss of a single-copy of the SIRT1 gene [96,97], leads to the development of insulin resistance and signs of metabolic syndrome upon high-fat diet feeding, whereas modest overexpression of SIRT1 protects animals against high-fat-induced glucose resistance [80,81]. In line with these observations, activation of SIRT1 by its activators such as the resveratrol and SRT1720 in animals protects against high-fat-induced obesity and insulin resistance [68–70]. Therefore, SIRT1 could be an important therapeutic target for insulin-resistance-associated metabolic syndrome.
The alterations of hepatic lipid metabolism, pancreatic insulin secretion, fat maturation and remodeling, central nutrient sensing, inflammatory response, circadian gene expression, as well as insulin sensitivity in SIRT1 knockout and transgenic mouse models suggest that SIRT1 is an essential regulator of systemic energy homeostasis, and that pharmacological modulation of SIRT1 could be of interest to control diseases associated with obesity. Consistent with this notion, small-molecule activators of sirtuins, such as the resveratrol and SRT1720, have shown promise as therapeutic agents for the treatment of metabolic diseases [63,70,135]. However, whether these small-molecule drugs are direct activators of SIRT1 that function to prevent obesity and diabetes is still a topic of intense debate [64–67]. Therefore, further research on the mechanism-based drug design, such as chemical compounds designed based on the phosphorylation mimetics of SIRT1 [118,136], might help to develop the next generation of SIRT1-activating molecules.
The work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences to X.L. (Z01 ES102205).
I thank members of the Li laboratory for critical reading of the manuscript.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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