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S.Amdt.2978 to S.3254112th Congress (2011-2012)
AmendmentHide Overview icon-hide
|Amends Bill:
|S.3254 — National Defense Authorization Act for Fiscal Year 2013
|Sen. Inhofe, James M. [R-OK] (Submitted 11/27/2012, Proposed 12/03/2012)
|Latest Action:
|Amendment SA 2978 agreed to in Senate by Voice Vote. (12/03/2012)
Description: S.Amdt. 2978 — 112th Congress (2011-2012)
To require the Secretary of the Air Force to submit to Congress a plan to increase the number of contractors eligible to be awarded contracts under the Air Force's Network-Centric Solutions-2 (NETCENTS-2) indefinite-delivery, indefinite quantity (IDIQ) contract.


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We have been a client of Weston for a number of years, and their partnership has been invaluable. They've been available for weekend and after-hours emergencies and are readily available for any time a problem arises. They have also worked with our software vendors and have adapted our systems to some handle a variety of specialized applications. Whether we have people working at our home office, a job site, or somewhere else remotely, Weston has been able to keep them connected and on our network. They recently helped us upgrade our server and move our e-mail into the cloud. They did this with almost no downtime during business hours, and virtually no burden on our employees as a result of the upgrade.
We will continue to rely on Weston for our daily IT needs and when software and hardware needs to be replaced and upgraded.
I wanted to write a note to say how much we appreciate the expertise and services of Weston. Of late, the time spent after hours working on an ERP and SQL issue was done in an outstanding and extremely professional and efficient fashion. I always emphatically recommend you to anyone I know in their search for a competent, ethical, and highly dependable IT and IS source. Our recent server purchase through Weston has proved fantastic and my mind is eased knowing we have the Weston team at the ready, whether during normal hours or on occasion, after hours. As a business operator, the caliber of each employee is a direct reflection of the quality of the company and I can say that over the past several years, I have never been disappointed. I have always felt that there was great value for the monetary investment. Weston will be a service provider to CLS for the indefinite future.
You guys provide 4 times the customer service over many of our other vendors. I really appreciate all you do for us!
In late 2010 we were re-evaluating the IT needs of our company. We had been utilizing the services of a small IT company that had been working well for us for several years. As our firm grew and technology changed and evolved, we had come to the decision that we needed more support and service than our current IT Company could provide. We decided to meet with Weston Technology Solutions. After thoroughly discussing our specific wants and needs with them we decided to go with their CompleteCare solution. We couldn't be happier! We now have 24/7/365 support, any problem or questions are addressed quickly and professionally, our vendors and licenses are managed for us and with their monthly fixed fee model we can now budget out IT costs annually. Most importantly, we have seen a significant reduction in our downtime giving us the ability to focus on our core business instead of our technology.

subset: commoncrawl


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Article Summary
A conventional bicycle bell might be a good way to alert pedestrians to your presence on a quiet suburban walkway, but when pedaling through bustling city streets there's a whole lot of other noise to contend with. Not satisfied with the one-size-fits-all approach to bicycle crash aversion, Brooklyn-based inventor Peter Pottier has developed Mybell, a programmable horn and light designed to give your bike its own unique warning system by loading it with just about any sound file you like.
Read the full article: Programmable Mybell gives your bike a voice of its own
Related Articles


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|What's it all about?
|Funding opportunities
|The BAHS is the national society for the study of the history of agriculture, rural society and the landscape of Britain and Ireland. We publish a magazine, Rural History Today, as well as a scholarly journal, Agricultural History Review, and our conferences provide opportunities for historians (professional and non-professional) to meet, mix and exchange views in a friendly and sociable atmosphere.
|We have a fund available to support otherwise unfunded Conferences and Initiatives. If you are considering holding a conference, workshop, special meeting or something similar, why not apply? We also offer bursaries to student members who want to attend our conferences and other meetings supported by the Society.
|BAHS Spring Conference
|This year's BAHS Spring Conference will be held at Wortley Hall, near Sheffield, 4 to 6 April 2016.
The full programme is now available and you can book either online, or by printing out the paper form and sending it with a cheque to the address on the form.
It just got much easier to join the BAHS because we are now set up to use PayPal.
Fill in an online form and pay via PayPal. You will also be able to renew your membership in this way.
|New publication
|Recent BAHS publications
|Boydell and Brewer announce the publication of Rural Society and Economic Change in County Durham: Recession and Recovery, c.1400-1640 by A.T. Brown (Durham University).
| The book is study of how Durham's rural society survived the economic crisis of the late medieval period and how the end of the sixteenth century the development of the coal industry provided opportunities for investment and profit. It looks at the estates of the bishops of Durham and monks of Durham Cathedral Priory, and the emergence of the yeomanry as a social group.
£39.00 to BAHS members (normally £60.00), a saving of 35%. Please ask the WebWeaver for the discount code. Offer ends 30 April.
The latest issue of Agricultural History Review is available online. It includes articles ranging from C13th England to C19th Italy via C18th Sweden.
|Rural History Today issue 30 is now available online, with articles by Karen Sayer, Juliet Gayton, Elizabeth Griffiths, Gavin Bowie and Peter Dewey.
|Call for Papers
|New Publication
|How did an ideal image of a certain breed come into being and how was it influenced by economic goals, behavioural expectations, or aesthetic considerations? by fashion, taste or morals?
How did breeding methods for producing the ideal animal develop and co-exist? How was breeding organized? Who was involved?
|What were their assumptions and how did these influence the methods of breeding? How were the results evaluated?
This conference will be held 2-3 June, 2016, at the University of Kassel, Germany.
Please read the full call for papers and submit abstracts of 200-300 words by 15 February. Travel and accommodation funds may be available for authors of the selected papers.
|Oxford University Press is offering a 30% online discount on
Agricultural Enlightenment: Knowledge, Technology, and Nature, 1750-1840 by Peter M. Jones.
[PDF with discount code and links to order form]
|This book provides a fuller understanding of the character and functioning of the pre-modern 'organic' economy, and assesses the role of government and the State in the pre-modern agricultural sector. It recovers a dimension of Enlightenment thought and practice which has been largely overlooked, explores the diffusion and adoption of agricultural knowledge in the eighteenth century, and offers an analysis based on evidence drawn from all over Europe of the process of transferring skill and 'know how' in the agricultural sector and how it was successfully achieved.
|LIBRAL: the Library of Irish and British Rural and Agricultural Literature
|As a first step to creating this resource for rural historians, we have compiled a catalogue of 18th- and 19th-century literature on agricultural topics that have already been digitised and are available on a variety of Web sites. This is just the start. Image of a Brittany cow from Dairy Stock by John Gamgee (1861), one of the many volumes already in LIBRAL.
|We plan, over the coming months, to scan and digitise many more volumes ourselves, making them available here. The idea is to allow you to search across multiple volumes to find the topics that interest you.
The Work in Progress list, formerly published in Agricultural History Review, is now has over 70 entries, together with an online form for you to create your own entry, which will only take you a few minutes. Researchers listed here have reported other researchers contacting them as a result, making it a valuable resource.
|Rural South Asia announce the first edition of their journal, Rural South Asian Studies. [Cover & Contents]
The papers are finalised and once the printed copy is circulated the contents will available online with open access. The Call For Papers for Vol. I, No. 2, 2016 will be given by 15 February 2016.
|A study day, Living off the Land: Agriculture in Wales, c.400–1600 AD, is to be held on 16 July 2016 at Cardiff University.
Rural History 2017, the 3rd conference of EurHO, will be held in Leuven, Belgium, September 11-14, 2017.


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Featured news
New Mytob worm poses as IT administrator
Another variant of the Mytob worm began wiggling its way into inboxes this week, enticing recipients to open an e-mail attachment that could allow a remote hacker to access and perform commands on an infected machine.
The variant, dubbed "Mytob.bi" by some security researchers, scans the hard drive of an infected machine and sends copies of itself to e-mail addresses it finds in the Windows Address Book.
By Scarlet Pruitt at IT World.
[ Read more ]
Reading our newsletter every Monday will keep you up-to-date with security news.
Receive a daily digest of the latest security news.


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White Balance question,,,,,,,,
Started Dec 27, 2013 | Questions thread
Shop cameras & lenses ▾
Contributing Member • Posts: 607
White Balance question,,,,,,,,
Dec 27, 2013
I suppose this question would apply to other cameras but I am specifically asking in regards to the SX50,,,,,If you have the option of selecting a White Balance via presets that fit your application then what are you trying to gain by doing the "Evaluate Balance" icon 1 or 2, further what's the difference in these two icons?
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104.5 iHeart Radio Performance Theater, Bala Cynwyd, Pa.
Owen Sweeney / OwenSweeneyPhoto.com
February 5, 2013 |
Sasquatch! Music Festival, Gorge Amphitheatre, Quincy, Wash. John Davisson
May 27, 2011 |
If we have information that is incorrect on this itinerary, please
send us an email
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License Agreement.
Tickets for dates listed may not yet be on sale. Dates may change without notice.


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|ISSN 1088-6826(online) ISSN 0002-9939(print)
Optimal size estimates for the inverse conductivity problem with one measurement
Abstract | References | Similar Articles | Additional Information
Abstract: We prove upper and lower estimates on the measure of an inclusion in a conductor in terms of one pair of current and potential boundary measurements. The growth rates of such estimates are essentially best possible.
Retrieve articles in Proceedings of the American Mathematical Society with MSC (2000): 31B20, 35R25, 35R30, 35R05
Retrieve articles in all journals with MSC (2000): 31B20, 35R25, 35R30, 35R05
Additional Information


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About the Owners
Beth Ostrowski Parks
Nationally Certified--Professional Dog Trainer, CPDT-KA
State of Ct-- Certified Professional Dog Trainer (since 1994)
Member --Association of Pet Dog Trainers (since 1999)
The Founder and President of It's PAWSible! Dog Training Center and Day Camp. I have been involved in dog training since 1993. I specialize in training groups of people with puppies or adult dogs. My clients are looking to build a special bond with their best friend. I also do one -on-one consultations with people and their dogs who are having trouble with aggression, fear, separation anxiety or other behavior problems. My passion is helping people train their "shelter" dogs who were adopted from shelters or other homes where they were neglected or abused. I am an advocate of rescuing animals and did my own Greyhound rescue for several years.
In the past, I spent quite a bit of time volunteering at local shelters like Thomas J. O'Connor and Dakin and the old Pioneer Valley Humane Society. Currently I spend many, many hours a week running my own business with our classes and dog day camp and our on-line services. We have a staff of 8 employees here as well.
Although I am busy and fulfilled with the business, I am always striving to learn more about dogs and consistently study new ways to teach gentle, but effective dog training to my clients. One thing that I learned a long time ago is that there are many ways to teach or get in touch with a dog's mind. I just love what I do because no two days are the same!
With any extra time I have, I compete in agility with my four awesome dogs, Shumai (7 year old Doberman Pinscher) and Phlip (11.5 year old Australian Shepherd) and my two newest dogs Grin (3 year old Australian Shepherd) and Kala (3 year old Doberman). However, what I love most about my dogs is to go hiking with them as often as possible. I learn a lot from watching them and being with them.
What I love most about my work is to watch owners who have what they consider a "problem" dog, learn how to communicate effectively. They can then learn to work together to form a common bond. I've seen great things that my clients call miracles happen here at It's PAWSible!
Wayne Parks
Wayne got involved with dogs when Beth did. At the time it was simply by default, but he has grown to love the business and is big participant in lots of behind the scenes work at It's PAWSible!. Frequently he is in the office answering the phone, making appointments or signing up people for classes. He also helps manage the day camp employees and the day camp area. He is the chief engineer of our training facility, day camp area and our beautiful 12 acres of land. He is in charge of maintaining the details, big and small of our place. And now that we have the Mobil Grooming van, he has one more item on his plate to take care of.
He is a very busy man! In his rare spare time he enjoys powerlifting and martial arts. In 2004 he earned his Black Belt in Uechi Ryu Karate. In 2007, he traveled to Texas and earned his second degree Black Belt!
And the gardens! All of the beautiful landscaping at our property is done by Wayne! That is his true calling.
About Our Instructors & Administrative Staff
Pam Lohr
Certfied Professional Dog Trainer-Knowledge Assessed (CPDT-KA)
Wag It Games Certified Instructor
I've been with It's PAWSible! since 2007. I began as a client with a new puppy and was soon asked to apprentice and later to become a trainer. During this time I learned a lot about positive training techniques at It's PAWSible! and the importance of establishing an enjoyable and respectful connection with dogs and their people. Having had dogs throughout my life, I admit that I cannot imagine ever living a dog-free life.
Currently I share my home with three dogs, a Sheltie named Poppy, a rescue Cattle Dog mix, Luca and another dog that I obtained from a client who couldn't keep their dog; Felix, a mini-aussie. I also have a cat, Smeagol. I also share my home with a variety of other small animals and a patient husband.
Previoiusly I was a volunteer puppy raiser for Canine Companions for Independence (CCI),a nationwide, non-profit organization that provides assistant dogs to people with disabilities. As a volunteer, I would training, socialize and care for one puppy at a time for the first 18 months of his or her life, after which the puppy returns to CCI for advanced training and hopefully placement with a person in need of a service dog.
I have raised three puppies for CCI. Two have gone on to be matched with wonderful people and are currently service dogs.
One of the things I am grateful for is that the CCI puppies came with a "rule book" which included a stipulation that all puppies must be enrolled in training classes. Previous house pets were trained "well enough," but never more than that. Now, having found that continued training results in a much more dependable dog and a greatly enhanced relationship between dog and owner, I am committed to increasing my skills as both a trainer and as an instructor. I not only loves the challenge of learning, but also the opportunity to help others find that special connection to their dogs.
Manager of Operations
Certified Professional Dog Trainer (ABCDT)
I began working at It's PAWSible! in March 2010 and I absolutely love my job. I look forward to getting up and coming to work everyday. Being outside and being around dogs are two of my favorite things, so it's perfect! Bradley, my Boxer, comes to work with me 4 days a week and has an awesome time playing out in camp with all his friends. I've always had strong love of dogs and have been around them as far back as I can remember.
When I was about 5 years old, we got our fist dog, a German Shepard that my sisters and I named Daisy. She was such a great family dog; extremely loyal and protective. As I grew up, she really became my dog and I was with her to the end. From then on I knew that I always wanted dogs in my life; there's nothing like the unconditional love and loyalty they so willingly give us.
I also have another dog, a Chihuahua who I named Rosco. He's such a cool little dog; loves swimming and hiking just like the big guys. He's been there for me through some rough times in my life and I can't thank or love him enough for that.
Bradley and I have also been doing agility with Beth for about 3 years and we also compete, whenever we can, around New England. We are having a lot of fun, I'm already addicted to it!
In 2013, after a few years of assisting in classes at It's PAWSible!, I earned my certification as a dog trainer as well. Now, my favorite part of my job is when I get to work with familie's one-on-one with private lessons and in-home training. Life is good.
Assistant Daycamp Manager
Assistant Trainer
Website Manager and Marketing Assistant
My name is Aine and I began working at It's PAWSible! in January 2014.
I've always loved dogs! I learned to walk holding on to my family's patient golden mix. When I was younger, I would spend summers with family in Ireland, where working dogs are a big part of the culture. Whenever we got the chance, my sister and I would go to the agricultural fair and stay for hours watching agility trials.
When my family decided to adopt a sweet old beagle-spaniel mix named Leah, I was thrilled and read every book about canine behavior and communication I could get my hands on. I haven't stopped learning since--I love working with dogs and I'm still fascinated by their amazing potential for work and companionship.
Recently, Beth promoted me to Assistant Day Camp Manager, so I'm really enjoying working closely with Ashlee and learning even more about the business. I also occassionally assist in our dog training classes here.
And, there is more! I love working on the technical side of things with our photo taking, video recordings and website work!
I enjoy every day at It's PAWSible--I meet new dogs all the time, learn a lot, and get to spend my day making sure dogs are happy and safe!
Part time Agility Instructor
My love for dogs began when I was about 6 years old with our first family pet, a Dalmatian I named Spot. Since then I always knew I wanted dogs in my life. When I finally acquired my own dog, Maya, I had learned about It's PAWSible!. I started bringing her to day camp in early 2009 and thought about how much I would like to be the one taking care of and playing with the dogs. I inquired about a job in October of 2009 started working at It's PAWSible! Day Camp. I worked part- time there until early 2012.
I currently have 2 cats and 1 chihuahua mix, Maya. Maya showed up at my house in October of 2008 at 4 months old. I was totally unprepared to have a dog but nobody claimed her and of course I fell in love. I somehow made it work and with help from It's PAWSible! she turned out to really be a great dog. We went through a series of classes and have been taking agility classes for over a year now and loving it. We have been competing in CPE trials, when we are able to, and doing well.
Now I assist Beth in agility classes and also a couple of Saturdays a week in Basic Obedience classes. I really enjoy that. Also, my hobby of competing in agility trials continues. Beth and I have a lot of fun doing that together.
Click here to meet our Day Camp Staff!


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- Costa RicaAgricultureFunding via FUDECOSUR
Viviana Van...Costa RicaAgricultureFunding via EDESA
EsmeraldaCosta RicaTransportationFunding via EDESA
Adelita De Los Angeles
Adelita needs a loan of ₡500.00 (USD $1025) to carry out an improvement on her house. She wants to add a laundry room on to her house. She will need buy zinc, cement, sand and nails, among other items.
Adelita belongs to the communal bank "la Empresa de Credito Comunal de Brasilia" (The Communal Credit Company of Brasilia).
Ella necesita un préstamo de ₡500.00, para llevar a cabo el mejoramiento de su casa, construyendo y añadiendo a su vivienda un cuarto de pila, para lo cual necesitara comprar zinc, cemento, arena y clavos, entre otras cosas.
Ella pertenece a la Empresa de Credito Comunal de Brasilia.
Additional Information
More information about this loan
As a small and relatively young MFI located in Costa Rica, EDESA has difficulty attracting other sources of capital. Many other microfinance funders do not work in Costa Rica, because overall the country is too rich. However, organizations such as EDESA work with extremely marginalized populations in Costa Rica that really need the access to capital that EDESA provides. By funding EDESA, Kiva lenders are allowing the organization to grow and reach more people than they otherwise would be able to reach.
About Housing Loans
Many poor families cannot afford housing that meets their needs. When you make a housing loan on Kiva, you give people access to flexible capital to obtain or improve their homes. Better housing means better health, sanitation, and even educational outcomes for children. A house can also be much more for entrepreneurs who run businesses out of their homes. In this way, housing and small business loans on Kiva share a common purpose: to alleviate poverty and enable families to enjoy more stable lives.
About Costa Rica
11View loans »
Success!! The loan was 100% repaid
- Repayment Term
- 38 months (Additional Information)
- Repayment Schedule
- Monthly
- Pre-Disbursed:
- Jul 4, 2011
- Listed
- Jul 6, 2011
- Currency Exchange Loss:
- Possible
- Ended:
- Apr 30, 2014


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Verified ID
Email AddressVerified
Phone Number▒▒▒▒▒▒▒▒▒▒▒ 39
Reviewed22 Reviews
Offline IDDriver License
About Me
- School
- Senac São Paulo
- Work
- Student, Camera operator
- Languages
- English, Português
- Bruno's Airbnb Symbol
Hey, I'm Bruno!
Sao Paulo, Brazil · Member since January 2014
You have reported this user. Undo?
I am a communication student focusing in video editing. I love photography and everything related to it :) I'm from Porto Alegre (south of Brazil) but spent most of my life in São Paulo. Also lived 3 years in Miami, USA. Very enthusiastic about social business and crowdsourcing.


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VisitAberdeen Mobile App
Download FREE the VisitAberdeen app, the official app for Aberdeen.
Download the FREE VisitAberdeen app, the official app for Aberdeen. The app is packed with information for everything you need to know for an enjoyable time in Aberdeen. At your fingertips are all the events, attractions and activities, food and drink, promotions and accommodation that the city and surrounding area has to offer and much more!
The VisitAberdeen app is available on iOS (https://itunes.apple.com/gb/app/visitaberdeen/id979394199?ls=1&mt=8) and Android (https://play.google.com/store/apps/details?id=com.visitaberdeen.cogmobile.visitaberdeen) stores.


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Wyndham Garden ProvidenceWyndham Garden Providence
220 India St.
Providence, Rhode Island
Map This Location
Phone: 401-272-5577
Tollfree: 800-528-9931
Email: Use the online form to contact this property
Website: http://wyndham.com
The only waterfront hotel in Providence, the full-service hotel offers free parking and shuttle service to anywhere in Providence. All rooms include coffee makers, iron and iron boards, hair dryers and oversized work desks with wireless high speed internet service. The Harbor Grille and Lounge provides breakfast, lunch and dinner daily from 6:30 a.m.-10 p.m. Meeting space of up to 1,800 square feet. Newly renovated guest rooms. http://www.wyndham.com/hotels/rhode-island/providence/wyndham-garden-providence/hotel-overview
Listing Category: Listing in Travel Guide, Listing on Web
Region: Providence
Guide Category: Stay- Accommodations
|Function Space Available:
Log In to Add this Item to Your TRIP Itinerary
Is this your listing? Login to edit or claim this listing.


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Mall Rat
Although it began twenty years ago as just another NPR Christmas tale, David Sedaris's The SantaLand Diaries has become a celebrated holiday institution. Chronicling the true story of Sedaris's time working as an elf at Macy's, the story carries a tone of extreme cynicism and hilarious tragedy.
"I think what makes Sedaris such a fantastic writer and satirist is his ability to tap into the dark underbelly of any surface situation," says Matt Zambrano, star of the Boulder Ensemble Theatre Company's adaptation of the play, which opens tonight at the Garner Galle-ria Theatre. "We all innately know that the Coca-Cola-zation of Christmas has grown out of control, and that sometimes gathering for the holidays can really be a big pain in the ass. Sedaris really gets underneath that all and asks, 'Why?'
"It's not the holiday that's the problem; it's the people who have to make the holiday hell for everyone around them," continues Zambrano. "At the heart of this play is a cynical man who is trying to cope with the candy-cane chaos around him, and despite the crying babies, racist parents, entitled Santas, and overall demoralizing and humiliating experience of being an elf, he finds hope and a faint glimmer of Christmas magic."
See The SantaLand Diaries starting at 7:30 p.m. at the Garner Galleria in the Denver Performing Arts Complex; the run continues through December 24. Get tickets, starting at $25, and information at denvercenter.org.
Mondays, Tuesdays, Thursdays-Sundays, 7:30 p.m.; Saturdays, Sundays, 2 p.m. Starts: Nov. 29. Continues through Dec. 24, 2013
Related Location
14th St & Curtis St.
Denver, CO 80202
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Sign up for our weekly guide to events in Denver, and never be bored again. With suggestions for every day of the week, our recommendations will keep you busy on any budget.
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- SIA Snow Show
Upcoming Events
Silver & GoldFri., Feb. 12, 8:00pm
Chase BryantFri., Feb. 12, 8:30pm
Colorado Eagles vs. Rapid City RushSat., Feb. 13, 7:00pm
Denver Brass: Red CarpetSun., Feb. 14, 2:00pm
- Tickets
- Screw Your Resolution Party


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10 Most Embarrassing Famous Family Members
Every family has a black sheep. Just ask Minnesota Independence Party-endorsed gubernatorial candidate Tom Horner. His brother Steve Horner is on a one-man quest to stop Ladies Nights around the country and make a profit doing so. He's also written a letter to the Minnesota Daily laying out the differences between himself and his politician brother, including how his quest to protect the rights of a "balding white guy" earned him a month in the workhouse.
In honor of the brothers Horner, who make #10 on our list, we present our list of the 10 Most Embarrassing Famous Family Members:
These are relatives who have shamed some of the most accomplished and well-known individuals in the world today. With any luck, maybe the 10 of them will get together for their own reality show on VH1.
Gallagher Too
It would seem impossible to embarrass a man who sledgehammers watermelons for a living, but that didn't stop Gallagher's younger brother Ron from trying.
Because Gallagher was afraid he was losing market share to Carrot Top, he allowed his down-on-his luck bro to franchise the hammering fruit routine and take it to small clubs across the country.
But that wasn't enough for Ron--he tried to usurp the Gallagher throne. Ron started calling himself "Gallagher Too" and refused his brother's demand to make it clear that he wasn't the original. In August 2000, Gallagher 1.0 took the interloper to court and won.
Much like Highlander, when it comes to Gallaghers, there can be only one.
Al Gore III
What does Mr. Global Warming get in return? A kid counteracting daddy's goody two-shoes rep by repeatedly getting arrested on drug charges -- most recently after being clocked doing 100 mph in a Prius! Better living through chemistry seems to be behind him now: He last was seen briefly skittering across everyone's radar when he climbed into the ring as "Kid Blanco" for the sake of charity.
Noah Cyrus
It's a special honor to be named Miley Cyrus's most embarrassing sibling.
And though we really hate picking on little kids, this honor really goes to her parents for letting the media capture her past series of embarrassing events.
The ten-year-old little wonder has been seen showing up at red carpet events--seemingly without a guardian--wearing short tutus, knee-high hooker boots, tiny swim suits, and feathered burlesque gear all while wearing enough makeup to make Christina Aguilera blush.
At the tender age of nine the precocious performer was caught pole dancing at a Teen Choice Awards after party, and has shown up on YouTube dancing to Akon's "Smack That" and Ke$ha's "Tik Tok."
Billy Ray, please take away her access to the internet. It's freaking us out. We're sure Noah will thank you for it once she in her 20s.
Mitch Winehouse
Think of him as the U.K. answer to Michael Lohan. When Amy Winehouse was wandering the streets of Camden in a crack and booze haze, father Mitch Winehouse was there to give misinformed interviews to the press about her health issues (which have ranged from impetigo to emphysema to bulimia), and to discuss his infidelity and subsequent divorce from Amy's mother (which happened over a decade ago).
When asked how his daughter was doing post rehab, he exclaimed, "Fantastic, fantastic. Her boobs are great as well." He followed that up with a "I shouldn't have said that should I?" No, you really shouldn't have.
Mitch promises to continue his campaign of embarrassment into the future: He's recording a jazz album as we speak.
Billy Carter
The whole killer rabbit episode notwithstanding, Jimmy Carter generally did his best to comport himself with the dignity and gravity of a U.S. President. But those efforts were always being undermined by his younger brother, Billy, an alcoholic gas-station owner prone to outrageous pronouncements and spectacular alcoholism.
Billy launched his own line of brew, declaring his intention to become "The Colonel Sanders of Beer," then provoked a new scandal as a registered lobbyist for the Libyan government. Other career highlights including drunkenly urinating on an airport tarmac in full view of the press corps.
Latoya Jackson
Michael Jackson's pop career meant a lot of things to a lot of people.
To his sister Latoya Jackson, it meant a chance to finally launch a career in porn.
Latoya graced the cover of Playboy for the first time in 1989. Her family ties made it the best-selling issue in the magazine's history at the time.
She appeared on the cover for a second time a few years later -- this time it was to promote her upcoming autobiography.
Not a bad marketing strategy.
Joe Simpson
The father/manager of Jessica and Ashlee Simpson has managed to make his girls big stars--but not without considerable ick factor that you just don't want coming from daddy.
When the girls were growing up, the rules were clear: he gave Jessica a "purity ring" when she was 12 to remind her not to have premarital sex. But it seems he doesn't mind exploiting his daughters' flesh to pad his bank account. Of their appearances in skin magazines like Maxim, he once told the New York Times "That's God's business, judgment... Our reason was, we're not too good to do Maxim. The people that read it are not bad people."
But his loveliest quote ever has to be the time he told GQ, "Jessica never tries to be sexy. ... She just is sexy. If you put her in a T-shirt or you put her in a bustier, she's sexy in both. She's got double D's! You can't cover those suckers up!"
There are, let's say, higher-profile members of the Bush family we could call out as embarrassing. But who needs to take swipes at ex-presidents when there's a perfectly good drug addict in their family?
Jeb Bush's daughter Noelle Bush was arrested for attempting to fraudulently obtain a prescription for Xanax from a Walgreens in Tallahassee. Her brilliant plan involved calling ahead to the pharmacy to request the pills for one "Noelle Scidmore."
After her arrest, Noelle was sentenced to rehab, but she soon found herself in jail after she was busted stealing pills from the nurses station and a search revealed crack cocaine hidden in her shoe.
Roger Clinton
If you don't remember that Bill Clinton even had a brother, it's probably because the president wanted it that way. While Bill Clinton was on his way to becoming the leader of the free world, his half-brother Roger was being sent to prison in 1985 for cocaine trafficking.
Little seen during the Clinton presidency, Roger stirred controversy not long after his brother left office when congressional investigators found evidence that the daughter of a Gambino family crime boss paid Roger Clinton's company $50,000 in 1999, just months after Roger had lobbied for an early parole for the heroin-dealing mobster. He also sought presidential pardons for other criminals.
In 2001, Roger himself was pardoned by his brother for his earlier drug conviction. A month later he was arrested for drunk driving.
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Synonyms of imposition in English:
2 the imposition of tax on consumables
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Latest news from the Pacific Northwest
Local News
< MyNorthwest
Man drives stolen car into water, presumed drowned
SEATTLE (AP) -- Divers have recovered the body of a man who drove a stolen car off a dock and into the water.
Seattle police say divers found the body Thursday morning near where the car went under in the Ship Canal.
Police and fire rescue teams were called to the Ship Canal late Wednesday night after receiving reports that a Nissan Sentra had driven off a pier. Authorities say they saw a man in the water, calling for help. However the man refused to grab a rope that was repeatedly thrown to him and pushed an officer away who tried to rescue him.
Police believe he was driving a car that was stolen Monday.
The man's body was transferred to the King County Medical Examiner's office.
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The Clamped Canister Bag was the first bag to seriously address the moisture problem that confronts the vast majority of pipers throughout the world. It is the economical canister bag that offers all the same moisture control of the Zipped Bag but at a lo
Geoff Ross has been involved in bagpipes since 1968, and in that time has competed in solo and band competitions both locally and abroad for many years. He had the good fortune of being taught by the great Bill Boyle whilst living in New Zealand, and it was through the inspiration of Bill Boyle, Donald Bain and other great pipers that lead Geoff to take a special interest in bagpipe tone. Geoff has a very fine ear for tone, but it was through the frustration of finding it so difficult to maintain a consistently high standard of tone while playing traditional reeds and bags, that he sought new innovative ways of achieving this. Ross Bagpipe Bags Pty. Ltd. is a name that has become synonymous with quality bagpipe bags. In 1985 Ross Bagpipe Reeds Pty. Ltd. produced the world's first synthetic drone reeds, and soon after introduced the Canister Pipe Bag. Our bags and reeds have been strongly endorsed by soloists and bands throughout the world, and we are happy to acknowledge that our products have playerd a vital role in the improvement of quality and stability in bagpipe playing, which was, and has always been our objective.. We thank you for taking the time to explore our web page, and trust you find it to be of some interest. If you need any further assistance, feel free to contact one of our dealers as listed on the 'suppliers' page, or else contact us directly for any other advice. -
Created: 09/28/2005 ::
Updated: 03/25/2007
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Picture: Ian Somerhalder - iHeartRadio Music Festival - Las Vegas, NV, United States - Saturday 21st September 2013
Former couple Ian Somerhalder and Nina Dobrev reunited briefly in Atlanta, Georgia on Tuesday (09Oct13) to help the actor's dog give birth to a litter of puppies.
The pair parted ways earlier this year (13) but came together as Nietzsche went into labour.
Dobrev and Somerhalder were shooting Tv drama The Vampire Diaries in the city when the puppies started arriving, and the actress opted to join her ex to help him through the process.
Posting a photo of himself with his pet on Instagram.com after the birth, Somerhalder wrote, "Live from the whelping box In Atlanta! Panting, pushing, contractions - Wow. Make no mistake about it - Ladies rule... Women of every species blow my mind... Incredible what mamas go through! Love to you mamas - all over the world. Jeez."
Dobrev later tweeted, "Birthing little Nietzsches... Such a beautiful + equally terrifying thing to witness... The miracle of life... Wow."
The dog gave birth to eight puppies.


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My submission "Beni's Defense Game" Made it to top 50. It was immediatly BLAM raped and lost alot off its score, but its all the same, my NG goal was to make top 50 with a shit submission, now i will eventually have to work on creating something that ACTUALLY deserves to be on The top 50 of all time.
Recent Game Medals
Kill a Pig 5 Points Pigs drop pork, and you eat pork to live Medal Stats.
Kill a Cow 5 Points Leather can be made into the first tier of armor Medal Stats.
Place Block 5 Points Now you can build things Medal Stats.
Open Inventory 5 Points You can craft or see your items in Mine Blocks. Medal Stats.
Mine Wood 5 Points Wood is used in the most important crafting recipes! Medal Stats.
Good Start 5 Points Collect all energy in the first level Medal Stats.
a069 5 Points a069 Medal Stats.
a241 5 Points a241 Medal Stats.
a121 5 Points a121 Medal Stats.
a147 5 Points a147 Medal Stats.
Total Medals Earned: 384 (From 43 different games.)


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The classic Wayfarer shape gets some funky modifications and a finish that combines tortoise with a hot ombre effect, to form a striking complement to your downtown style.
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USB Drives
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Server Memory
Trust Kingston for all your server memory needs. Our experts know how important it is to keep your business up and running with the ultra-reliable memory that you need and the service to guide you.
Desktop/Notebook Memory
Quality components. Rigorous testing. A lifetime warranty. Just three of the many reasons to choose Kingston memory for your desktop or notebook.
Revive your computer with improved speed, performance and reliability over traditional hard drives.
Extend the lifecycle and dramatically improve the performance of PCs for a lower TCO with SSDNow drives designed for business.
These enterprise SSDs offer increased endurance and power-failure features to keep mission-critical environments up and running 24/7.
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Hard drive replacements ideal for non-PC applications
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Personal DataTraveler Flash drives offer capacities up to 1TB and a wide variety of features. Store and transfer photos, music, videos and files with legendary Kingston reliability.
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Designed to protect data that requires airtight security, these drives help you meet specific agency directives like TAA and FIPS compliance and are ideal for Government or Corporate use.
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Kingston offers Flash drives designed for and certified by Microsoft® for use with Windows® To Go.
A feature of Windows 8 Enterprise, Windows to Go lets IT administrators provide mobile and contingency workers with secure access to the corporate environment.
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From everyday use to professional photo or video, these cards deliver exceptional speeds, huge capacities and legendary Kingston reliability.
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As you may know, this memory is built with more aggressive timings than our other memory product lines. HyperX modules were specifically engineered and designed to meet the rigorous requirements of PC enthusiasts. HyperX offers faster speeds, lower latencies, higher data bandwidths and lower power consumption. If you use HyperX memory, you may need to go into the BIOS and set the below timings manually in order for the BIOS to recognise the memory properly. However, this is not a guarantee as it depends on the motherboard. Since this memory is not tested for compatibility with any particular system, we cannot confirm if it will be compatible for you.
Before setting the timings, it's a good idea to set the BIOS to its default values to rule out any other possible conflicts. It's also a good idea to update to the latest BIOS if the modules do not work after setting these timings as the BIOS could be limiting the proper detection of the memory. The BIOS can be downloaded from your motherboard manufacturer's website. Please check your processor's documentation to make sure it supports the speed of the memory you're installing.
If you are unable to overclock the memory successfully, please contact our Technical Support department for assistance. We can help you find a memory module that is compatible with your system. You can also visit our memory configurator at:
You will need to manually set the speed, timings and voltage appropriately or use one of the XMP profiles if your motherboard supports it. Some systems are not able to properly operate at the lower latency settings offered by HyperX modules. Some diagnostic programs will only read the default settings on the Serial Presence Detect (SPD) on the module. The settings that you changed manually or the XMP profile that you chose would not therefore be taken into account.
Please refer to the spec sheet for your specific HyperX memory product for the appropriate setting.
Many motherboards automatically set the "Command Rate" and do not allow it to be manually set by the user.
If there are timings in the BIOS that we do not list in the latency timings for our HyperX memory, please leave these timings at their default setting.
CAS latency:
CAS Latency is the ratio of the memory's column access time divided by the current system clock. The column access time turns out to be a constant value, so you can see as you in increase the system clock it becomes harder to achieve a lower CAS latency (e.g., the denominator grows, but the numerator stays the same).
This is the latency between the Row Address Strobe and Column Address Strobe. Basically the delay between accessing the Row and the Column memory addresses.
Row Precharge Delay:
The number of clock cycles taken between the issuing of the precharge command and the active command.
*From the examples above you can conclude; the lower the number, the faster the access.
HyperX memory is built with aggressive settings. Not all systems will be able to run at these aggressive settings.
Please verify that your HyperX module is compatible with the specific Intel or AMD chipset on your motherboard. These will be listed on the product pages on the HyperX website. If your memory uses XMP profiles for overclcoking, change the memory settings in your BIOS to auto.
If the memory fails at the default settings, please contact our technical support for assistance.
With HyperX memory that uses XMP profiles, the default settings used are JEDEC standard values. Some systems do not operate at speeds greater than the JEDEC settings. To give every customer the best experience, Kingston sets the module to the JEDEC standard values, giving you the choice of whether to overclock using the XMP profiles if your system supports it.
With PnP modules, if the system is not able to run at the overclocked settings, the system may either use the next highest timing profile or default to the JEDEC standard timings.
More Questions
In Windows, click on the start button and open "Control Panel". Use classic view for Vista and 7. Then open "System". This will display basic information about the computer including the amount of RAM installed.
In MacOS, select "About This Mac" or "About This Computer" from the Apple menu in the upper left corner of your Desktop. This will provide information about your Mac's total memory (built-in memory plus DIMMs or SIMMs installed).
In Linux, open a terminal window and enter the following command: cat /proc/meminfo
This will show the total amount of RAM as well as other memory information.
First, make sure you have the correct memory for your notebook. Refer to Kingston's online Memory Search at www.kingston.com for assistance. After confirming that you have the correct memory for your system, do the following:
Note: Kingston is in no way responsible for any problems resulting from flashing the BIOS. Flashing the BIOS is merely a troubleshooting suggestion. Customers who flash the BIOS do so at their own risk. All instructions on how to upgrade the BIOS will be provided by the computer manufacturer or the 3rd party BIOS manufacturer and not by Kingston.
Additional memory will not necessarily increase the performance of your computer. It will allow you to run more programs or processes at once or more memory intensive programs. There may be a performance increase if the original amount of memory installed was close to insufficient for the programs and processes you use the computer for.
For desktop computers, shut down and unplug your computer and open the case. Please note: The higher capacity memory should be installed in slot 1 followed by the next lower capacity memory in slot 2 and so on. Please refer to your motherboard manual for proper slot identification.
Remove the memory module as shown in Fig 1. Push the tabs (1) outward and the module will gently pop out of its slot (2). Remove it completely from the slot.
To install the new memory module, see Fig 2. Push the tabs (1) that are at the ends of the memory socket outward and align the memory notches with the key of the memory socket (2), then push the memory down FIRMLY into the socket so the latches lock the memory in place (3). If the memory has been properly installed and you have the correct memory but it is still not being detected, you should make sure you have the most up-to-date BIOS from your computer manufacturer's website.
For notebook computers, please note that you need to shut down the unit and remove the battery pack and power cord before you remove/install memory. Push the memory into the socket FIRMLY so that it makes good contact (it is important to push the memory in FIRMLY) before pushing it down to lock it in place (see figures below) . Once the memory has been installed, put the battery back in your unit and supply power using the power cord and not solely from the battery. If the memory has been properly installed and you have the correct memory but it is still not being detected, you should make sure you have the most up-to-date BIOS from your computer manufacturer's website.
BIOS - Basic Input/Output System is installed on the computer's motherboard. It controls the most basic operations and is responsible for starting your computer up and initialising the hardware. It is data that is usually held on a ROM chip and can be updated by "flashing" the BIOS. BIOS upgrades may correct errors, support new CPUs, and support new hardware including memory. BIOS updates are usually obtained from the computer's manufacturer's website.
*NOTE: Kingston is in no way responsible for any problems resulting from flashing the BIOS. Flashing of the BIOS is merely a troubleshooting suggestion. Customers who flash the BIOS do so at their own risk. All instructions on how to upgrade the BIOS will be provided by the computer manufacturer or the 3rd party BIOS manufacturer and not by Kingston.
Parts sold in kits (denoted by "K2" or "K3"in the part number, e.g. – KVR400X64C3AK2/2G) are specifically packaged for use in Dual or Triple Channel motherboards. Although Dual and Triple Channel technology resides on the motherboard itself (inside the chipset), the memory modules need to be installed in pairs or sets of three for Dual or Triple Channel mode to function properly. Identical modules packaged in a kit work best because the motherboard will be accessing all the memory modules as a single memory location with a wider bandwidth. Kingston suggests the use of modules sold in kits for Dual or Triple Channel enabled motherboards.
Yes. In most cases if the computer supports a slower speed, it will clock down to a slower speed as long as it is the correct memory type (DDR, DDR2, etc). However, be aware that the clocking down function depends on the computer and it isn't guaranteed to work in every case.
In many cases, the BIOS or a diagnostic program will report the memory bus frequency, which is half of the frequency for DDR type memory. As its name implies, DDR (Double Data Rate) data rate provides twice the memory bus frequency. So if the memory bus speed is 800MHz and you are using DDR3-1600 memory, the RAM is running at the correct speed.
ElectroStatic Discharge, ESD is simply the discharge of built-up static electricity.
ESD should not be taken lightly as this is one of the few things that an individual can do to damage or destroy their computer or hardware components.
It is like when you rub your feet on the carpet and you touch something metal.
ESD can occur without the user feeling a shock and will occur when only working on the inside of the computer or handling hardware.
How to help prevent ESD
The best method of preventing ESD is to use an ESD wrist strap or an earthing mat or table.
However, because most users do not have access to these items, we have included the below steps to help reduce the chance of ESD as much as possible.
To learn more about ESD and how to protect your electronics, please refer to the below site.
ESD Association
Email Technical Support
Call Technical Support: +1 (800) 435-0640
©2016 Kingston Technology Europe Co LLP and Kingston Digital Europe Co LLP. All Rights Reserved.


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The Fresh Fruit and Vegetable Program is intended for schools with a high number of students eligible for free or reduced price benefits. A program webinar on March 4 from1:30-2:30 p.m. will provide an overview and answers to common questions about the program.
The Ohio Department of Education is accepting applications for the 2015-2016 Fresh Fruit and Vegetable Program. Schools selected for the program will be funded for the period beginning July 1, 2015, through June 30, 2016.
Infographics illustrating facts and figures of Ohio PreK-16 statistics for 2014-2015 are available here.
The spring 2015 Jamba Juice "It's All About the Fruit and Veggies" Garden Grant is now open and accepting applications for 30 awards. Be one of this year's winners. One grand prize winner will be selected to receive a $1,500 garden package. Twenty-nine winners will receive $500 award packages. Applications are due March 6. Visit Kidsgardening.org for more details.
The Ohio Association for Career and Technical Education Student Showcase will be in the Statehouse Capitol Atrium from 9:30 a.m. to 2 p.m. on March 12. Visit with Ohio's career-technical education students as they share their programs through interactive displays. Students from public schools throughout Ohio will host displays featuring more than 25 programs. Meet program participants and hear how career-technical education has helped them learn 21st century skills and prepare them for college and careers.
Approaching deadlines or important dates mentioned in previous editions of EdConnection.
A school district may need to delay school or cancel a day or several days of school during its scheduled testing window, due to weather or other unexpected circumstances. Here is guidance that addresses the extension of a district's testing window only under these circumstances. A district cannot use a testing window extension for a school delay or closure that occurred before testing started.


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Reviews - City Guest House4
68 Monkgate, ,, York, YO31 7PF
Price FromView Rooms
Customer Reviews
Our reviews are from genuine LateRooms.com customers. We verify that the customer has stayed before leaving a review.
96% would recommend it to a friend
Customer service
Food quality
Room quality
Very nice and welcoming close to York's attractions
We were made extremely welcome and nothing seemed too much trouble for our hosts.
There is on road parking and also off road parking but this is a narrow squeeze but we found it OK. Rooms very neat, clean and tidied every day with option for not doing so. Breakfast was nice and quickly provided. Hosts happy to adjust breakfast to suit needs. always happy to advise on anything in York to help your stay.
Read More Less
A Great Find!!
Very Welcoming owners, Clean, Tidy and Effective rooms.
Fantastic position to the City Centre as only a 5 minute walk away.
Read More Less
Great Place to stay
Reasonably priced, lovely Guest house with a fantastic breakfast, within walking distance of the Minster.
What more could you ask for.
To cap it all off, the hosts where excellent!
Read More Less
Two days in york
Guest house was perfect, great location and brilliant hosts.
will be back.
Read More Less
Definitely recommended
Amazing hosts, comfortable rooms, quality breakfast and great value for money.
Have stayed here on a few ocassions. Definitely recommended.
Read More Less
An excellent location to York.
Good hosts and spotless accommodation
Read More Less
I`ll be back!
Nice little guesthouse, close to all facilities inYork, Good service, host was very friendly and helpful , nice food, clean rooms.
We really enjoyed the stay and want to come back.
Read More Less
great place for a York weekend GOLD STAR ACCOMODATION
well appointed rooms, unbelievable parking facitlities, Allan & Julie great hosts ...
informative and interested without being intrusive ...
Read More Less
one of the best bbs we have stayed at exelent host s exelent room in attic will be staying there again
A great guest house!!
We only stopped here for the one night and was a bit rushed but thr room, service and breakfast were spot on.
The main reason I booked this guest house was because of the location to the Minste and the centre of York. Overall I would definitely recommend this lovely little B&B.
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something is missing by JoysukeWatch
©2013-2016 Joysuke
(Gasps) What happened to me?
love the colors and the expression here !
I like how his eyes look. A little owl-like, a little harrowing.
Great image. The big eyes and the broken horn work great.
I really like the use of red for his skin
Nice color and really reminds me of ICO!
Das ist gut.
I love it!
Awww your style is so adorable! *_*
homestuck? lol
oh, I love this!!


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Rob Halford's Back Problems Continue
After seeing Rob Halford with a cane on the Golden Gods awards, I was wondering if it was just for looks or if the legendary frontman was actually having back problems. Turns out, he's got some issues.
After seeing Rob Halford with a cane on the Golden Gods awards, I was wondering if it was just for looks or if the legendary frontman was actually having back problems. Turns out, he's got some issues.
There is nothing more frightening than the wrath of a woman scorned. The lovely Sharon Osbourne is one woman I would not want to be pissed at me in any way. Many of us know the damage that can be done when it comes to fighting the demons. Sadly, Ozzy's fall off the wagon is putting a strain on his marriage and his personal well being.
Rodney Carrington came to the Hub last Friday. This man was really funny and it's a night that I won't forget either. He very entertaining.
The RockShow had the opportunity to talk to funny man Jamie Kennedy about his new film "A Resurrection". I think he was drunk. But so were we so who really cares?
Eva Herzigova did an ad for some shoe maker. I don't care who it is but I want to thank them for it. She shows her butt. Twice. Wanna see it...
Billy Corgan, lead singer and guitarist of the Smashing Pumpkins, is a huge wrestling fan. He even owns and runs Resistance Pro Wrestling in Chicago. And now he's sold what was left of his alternative cred for a furniture sponsor.
Yes some of your favorite artists from the past have all come together to sell their souls, and whore themselves out for mayonnaise. OK technically not mayo, "The Tangy Zip Of Miracle Whip!"
Jennifer Love Hewitt posed for Shape Magazine in a bikini recently. Thank you, Jennifer, thank you from the bottom of my
pan, my heart I mean.
I don't really know what inspired to do this, but I thought it might be interesting to you. My goal is to give my impression of the rocks stars I've met in three words or less. First, let me tell you, that backstage meetings are awkward and very brief. It's also very possible that the artists in question were having a very bad or very good day. Judging people on such a brief meeting is a little unfair, but it's most likely the same impression that you'd get if you got to meet the person yourself. More after the jump.
Jennifer Love Hewitt has a show on the Lifetime Network called "The Client List". It's on Lifetime so I have no idea what its about. However, "The Client List" makes me think she's a call girl or something.
Fellow rockers and comedians gathered last night to see if Dee Snider could take it at the second annual Rock and Roll Roast at the Grove in Anaheim, California.
Do you remember several years ago when MTV premiered "The Osbournes?" To this day I can honestly say that is the only reality show I have ever watched.


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Are you Howard G Shertzer?Claim your profile
Publications (132)512.07 Total impact
Article: Branched-Chain Amino Acid Supplementation in Combination with Voluntary Running Improves Body Composition in Female C57BL/6 Mice[Show abstract] [Hide abstract]
ABSTRACT: Exercise is an inexpensive intervention that may be used to reduce obesity and its consequences. In addition, many individuals who regularly exercise utilize dietary supplements to enhance their exercise routine and to accelerate fat loss or increase lean mass. Branched-chain amino acids (BCAAs) are a popular supplement and have been shown to produce a number of beneficial effects in rodent models and humans. Therefore, we hypothesized that BCAA supplementation would protect against high fat diet (HFD)-induced glucose intolerance and obesity in mice with and without access to exercise. We subjected 80 female C57BL/6 mice to a paradigm of HFD feeding, exercise in the form of voluntary wheel running, and BCAA supplementation in the drinking water for 16 weeks (n = 10 per group). Body weight was monitored weekly, while food and water consumption were recorded twice weekly. During the 5th, 10th, and 15th weeks of treatment, glucose tolerance and body composition were analyzed. Exercise significantly improved glucose tolerance in both control-fed and HFD-fed mice. BCAA supplementation, however, did not significantly alter glucose tolerance in any treatment group. While BCAA supplements did not improve lean to fat mass ratio in sedentary mice, it significantly augmented the effects of exercise on this parameter.
- [Show abstract] [Hide abstract]
ABSTRACT: Glutathione (GSH) is the most abundant cellular thiol antioxidant and it exhibits numerous and versatile functions. Disturbances in GSH homeostasis have been associated with liver diseases induced by drugs, alcohol, diet and environmental pollutants. Until recently, our laboratories and others have developed mouse models with genetic deficiencies in glutamate-cysteine ligase (GCL), the rate-limiting enzyme in the GSH biosynthetic pathway. This review focuses on regulation of GSH homeostasis and, specifically, recent studies that have utilized such GSH-deficient mouse models to investigate the role of GSH in liver disease processes. These studies have revealed a differential hepatic response to distinct profiles of hepatic cellular GSH concentration. In particular, mice engineered to not express the catalytic subunit of GCL in hepatocytes [Gclc(h/h) mice] experience almost complete loss of hepatic GSH (to 5% of normal) and develop spontaneous liver pathologies characteristic of various clinical stages of liver injury. In contrast, mice globally engineered to not express the modifier subunit of GCL [Gclm(-/-) mice] show a less severe hepatic GSH deficit (to ≈15% of normal) and exhibit overall protection against liver injuries induced by a variety of hepatic insults. Collectively, these transgenic mouse models provide interesting new insights regarding pathophysiological functions of GSH in the liver.
Article: Dietary whey protein stimulates mitochondrial activity and decreases oxidative stress in mouse female brain[Show abstract] [Hide abstract]
ABSTRACT: In humans and experimental animals, protein-enriched diets are beneficial for weight management, muscle development, managing early-stage insulin resistance and overall health. Previous studies have shown that in mice consuming a high fat diet, whey protein isolate (WPI) reduced hepatosteatosis and insulin resistance due in part to an increase in basal metabolic rate. In the current study, we examined the ability of WPI to increase energy metabolism in mouse brain. Female C57BL/6J mice were fed a normal AIN-93M diet for 12 weeks, with (WPI group) or without (Control group) 100g WPI/L drinking water. In WPI mice compared to controls, the oxidative stress biomarkers malondialdehyde and 4-hydroxyalkenals were 40% lower in brain homogenates, and the production of hydrogen peroxide and superoxide were 25-35% less in brain mitochondria. Brain mitochondria from WPI mice remained coupled, and exhibited higher rates of respiration with proportionately greater levels of cytochromes a+a3 and c+c1. These results suggested that WPI treatment increased the number or improved the function of brain mitochondria. qRT-PCR revealed that the gene encoding a master regulator of mitochondrial activity and biogenesis, Pgc-1alpha (peroxisome proliferator-activated receptor-gamma coactivator-1alpha) was elevated 2.2-fold, as were the PGC-1alpha downstream genes, Tfam (mitochondrial transcription factor A), Gabpa/Nrf-2a (GA-binding protein alpha/nuclear respiratory factor-2a), and Cox-6a1 (cytochrome oxidase-6a1). Each of these genes had twice the levels of transcript in brain tissue from WPI mice, relative to controls. There was no change in the expression of the housekeeping gene B2mg (beta-2 microglobulin). We conclude that dietary whey protein decreases oxidative stress and increases mitochondrial activity in mouse brain. Dietary supplementation with WPI may be a useful clinical intervention to treat conditions associated with oxidative stress or diminished mitochondrial activity in the brain.
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ABSTRACT: Four dioxin-inducible enzymes--NAD(P)H:quinone oxidoreductase-1 (NQO1) and three cytochromes P450 (CYP1A1, CYP1A2 & CYP1B1)--are implicated in both detoxication and metabolic activation of various endobiotics and xenobiotics. NQO1 is generally regarded as a cytosolic enzyme; whereas CYP1 proteins are located primarily in endoplasmic reticulum (ER), CYP1A1 and CYP1A2 proteins are also targeted to mitochondria. This lab has generated Cyp1a1(mc/mc) and Cyp1a1(mtt/mtt) knock-in mouse lines in which CYP1A1 protein is targeted exclusively to ER (microsomes) and mitochondria, respectively. Comparing dioxin-treated Cyp1(+/+) wild-type, Cyp1a1(mc/mc), Cyp1a1(mtt/mtt), and Cyp1a1(-/-), Cyp1b1(-/-) and Nqo1(-/-) knockout mice, in the present study we show that [a] NQO1 protein locates to cytosol, ER and mitochondria, [b] CYP1B1 protein (similar to CYP1A1 and CYP1A2 proteins) traffics to mitochondria as well as ER, and [c] NQO1 and CYP1B1 targeting to mitochondrial or ER membranes is independent of CYP1A1 presence in that membrane.
Article: Distribution and Systemic Effects of Intranasally Administered 25 nm Silver Nanoparticles in Adult Mice[Show abstract] [Hide abstract]
ABSTRACT: Previous work indicates that silver nanoparticles (AgNPs) given IP to mice alter the regulation of inflammation- and oxidative stress-related genes in brain. Here we assessed the distribution and toxic potential of AgNP following intranasal (IN) exposure. Adult male C57BL/6J mice received 25-nm AgNP (100 or 500 mg/kg) once IN. After 1 or 7 days, histopathology of selected organs was performed, and tissue reduced glutathione (GSH) levels were measured as an indicator of oxidative stress. Aggregated AgNP were found in spleen, lung, kidney, and nasal airway by routine light microscopy. Splenic AgNP accumulation was greatest in red pulp and occurred with modestly reduced cellularity and elevated hemosiderin deposition. Aggregated AgNP were not associated with microscopic changes in other tissues except for nasal mucosal erosions. Autometallography revealed AgNP in olfactory bulb and the lateral brain ventricles. Neither inflammatory cell infiltrates nor activated microglia were detected in brains of AgNP-treated mice. Elevated tissue GSH levels was observed in nasal epithelia (both doses at 1 day, 500 mg/kg at 7 days) and blood (500 mg/kg at 7 days). Therefore, IN administration of AgNP permits systemic distribution, produces reversible oxidative stress in the nose and in blood, and mildly enhances macrophage-mediated erythrocyte destruction in the spleen.
Article: Comparison of the Effects of Hexavalent Chromium in the Alimentary Canal of F344 Rats and B6C3F1 Mice Following Exposure in Drinking Water: Implications for Carcinogenic Modes of Action[Show abstract] [Hide abstract]
ABSTRACT: Exposure to high concentrations of hexavalent chromium (Cr[VI]) in drinking water is reported to induce oral mucosa tumors in F344 rats and intestinal tumors in B6C3F1 mice. To investigate the modes of action underlying these tumors, 90-day drinking water studies (with interim necropsy at day 8) were conducted with concentrations of 0.1-182 mg/l Cr(VI), administered as 0.3-520 mg/l sodium dichromate dihydrate. Blood and tissue samples were analyzed for chromium content, oxidative stress, iron levels, and gross and microscopic lesions. Results for the F344 rats are described herein and compared with results from B6C3F1 mice published previously. After 90 days of exposure, total chromium concentrations in the rat and mouse oral mucosae were comparable, yet significant dose-dependent decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed only in rats. In the duodenum, changes in GSH/GSSG were only observed in mice. Levels of 8-hydroxydeoxyguanosine were not increased in the oral or duodenal mucosae of either species. Glutathione levels were increased in the duodenum but decreased in the jejunum of both species, indicating potential differential responses in the intestinal segments. Histiocytic infiltration was observed in the duodenum of both species, yet duodenal cytokines were repressed in mice but increased in rats. Serum and bone marrow iron levels were more decreased in rats than mice. Collectively, these data suggest that Cr(VI)-induced carcinogenesis in the rodent alimentary canal involves oxidative stress; however, differences in histopathology, cytokines, and iron status suggest potential contributions from other factors as well.
Article: Glutathione-Deficient Mice Are Susceptible to TCDD-Induced Hepatocellular Toxicity but Resistant to Steatosis[Show abstract] [Hide abstract]
ABSTRACT: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) generates both hepatocellular injury and steatosis, processes that involve oxidative stress. Herein, we evaluated the role of the antioxidant glutathione (GSH) in TCDD-induced hepatotoxicity. Glutamate-cysteine ligase (GCL), comprising catalytic (GCLC) and modifier (GCLM) subunits, is rate limiting in de novo GSH biosynthesis; GCLM maintains GSH homeostasis by optimizing the catalytic efficiency of GCL holoenzyme. Gclm(-/-) transgenic mice exhibit 10-20% of normal tissue GSH levels. Gclm(-/-) and Gclm(+/+) wild-type (WT) female mice received TCDD for 3 consecutive days and were then examined 21 days later. As compared with WT littermates, Gclm(-/-) mice were more sensitive to TCDD-induced hepatocellular toxicity, exhibiting lower reduction potentials for GSH, lower ATP levels, and elevated levels of plasma glutamic oxaloacetic transaminase (GOT) and γ-glutamyl transferase (GGT). However, the histopathology showed that TCDD-mediated steatosis, which occurs in WT mice, was absent in Gclm(-/-) mice. This finding was consistent with cDNA microarray expression analysis, revealing striking deficiencies in lipid biosynthesis pathways in Gclm(-/-) mice; qrt-PCR analysis confirmed that Gclm(-/-) mice are deficient in expression of several lipid metabolism genes including Srebp2, Elovl6, Fasn, Scd1/2, Ppargc1a, and Ppara. We suggest that whereas GSH protects against TCDD-mediated hepatocellular damage, GSH deficiency confers resistance to TCDD-induced steatosis due to impaired lipid metabolism.
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ABSTRACT: In humans and experimental animals, high fat diets (HFD) are associated with risk factors for metabolic diseases, such as excessive weight gain and adiposity, insulin resistance and fatty liver. Mice lacking the glutamate-cysteine ligase modifier subunit gene (Gclm(-/-)) and deficient in glutathione (GSH), are resistant to HFD-mediated weight gain. Herein, we evaluated Gclm-associated regulation of energy metabolism, oxidative stress, and glucose and lipid homeostasis. C57BL/6J Gclm(-/-) mice and littermate wild-type (WT) controls received a normal diet or an HFD for 11 weeks. HFD-fed Gclm(-/-) mice did not display a decreased respiratory quotient, suggesting that they are unable to process lipid for metabolism. Although dietary energy consumption and intestinal lipid absorption were unchanged in Gclm(-/-) mice, feeding these mice an HFD did not produce excess body weight nor fat storage. Gclm(-/-) mice displayed higher basal metabolic rates resulting from higher activities of liver mitochondrial NADH-CoQ oxidoreductase, thus elevating respiration. Although Gclm(-/-) mice exhibited strong systemic and hepatic oxidative stress responses, HFD did not promote glucose intolerance or insulin resistance. Furthermore, HFD-fed Gclm(-/-) mice did not develop fatty liver, likely resulting from very low expression levels of genes encoding lipid metabolizing enzymes. We conclude that Gclm is involved in the regulation of basal metabolic rate and the metabolism of dietary lipid. Although Gclm(-/-) mice display a strong oxidative stress response, they are protected from HFD-induced excessive weight gain and adipose deposition, insulin resistance and steatosis.
Article: Investigation of the Mode of Action Underlying the Tumorigenic Response Induced in B6C3F1 Mice Exposed Orally to Hexavalent Chromium[Show abstract] [Hide abstract]
ABSTRACT: Chronic ingestion of high concentrations of hexavalent chromium [Cr(VI)] in drinking water induces intestinal tumors in mice. To investigate the mode of action (MOA) underlying these tumors, a 90-day drinking water study was conducted using similar exposure conditions as in a previous cancer bioassay, as well as lower (heretofore unexamined) drinking water concentrations. Tissue samples were collected in mice exposed for 7 or 90 days and subjected to histopathological, biochemical, toxicogenomic, and toxicokinetic analyses. Described herein are the results of toxicokinetic, biochemical, and pathological findings. Following 90 days of exposure to 0.3-520 mg/l of sodium dichromate dihydrate (SDD), total chromium concentrations in the duodenum were significantly elevated at ≥ 14 mg/l. At these concentrations, significant decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed. Beginning at 60 mg/l, intestinal lesions were observed including villous cytoplasmic vacuolization. Atrophy, apoptosis, and crypt hyperplasia were evident at ≥ 170 mg/l. Protein carbonyls were elevated at concentrations ≥ 4 mg/l SDD, whereas oxidative DNA damage, as assessed by 8-hydroxydeoxyguanosine, was not increased in any treatment group. Significant decreases in the GSH/GSSG ratio and similar histopathological lesions as observed in the duodenum were also observed in the jejunum following 90 days of exposure. Cytokine levels (e.g., interleukin-1β) were generally depressed or unaltered at the termination of the study. Overall, the data suggest that Cr(VI) in drinking water can induce oxidative stress, villous cytotoxicity, and crypt hyperplasia in the mouse intestine and may underlie the MOA of intestinal carcinogenesis in mice.
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ABSTRACT: Consuming a high-fat (HF) diet produces excessive weight gain, adiposity, and metabolic complications associated with risk for developing type 2 diabetes and fatty liver disease. This study evaluated the influence of whey protein isolate (WPI) on systemic energy balance and metabolic changes in mice fed a HF diet. Female C57BL/6J mice received for 11 wk a HF diet, with or without 100 g WPI/L drinking water. Energy consumption and glucose and lipid metabolism were examined. WPI mice had lower rates of body weight gain and percent body fat and greater lean body mass, although energy consumption was unchanged. These results were consistent with WPI mice having higher basal metabolic rates, respiratory quotients, and hepatic mitochondrial respiration. Health implications for WPI were reflected in early biomarkers for fatty liver disease and type 2 diabetes. Livers from WPI mice had significantly fewer hepatic lipid droplet numbers and less deposition of nonpolar lipids. Furthermore, WPI improved glucose tolerance and insulin sensitivity. We conclude that in mice receiving a HF diet, consumption of WPI results in higher basal metabolic rates and altered metabolism of dietary lipids. Because WPI mice had less hepatosteatosis and insulin resistance, WPI dietary supplements may be effective in slowing the development of fatty liver disease and type 2 diabetes.
Article: Oral N-acetylcysteine rescues lethality of hepatocyte-specific Gclc-knockout mice, providing a model for hepatic cirrhosis[Show abstract] [Hide abstract]
ABSTRACT: Certain liver diseases have been associated with depletion of glutathione (GSH), the major antioxidant in the liver. A recent report about Gclc(h/h) mice with a hepatocyte-specific ablation of Gclc (the gene encoding the catalytic subunit of the rate-limiting enzyme in GSH synthesis) has shown an essential role of GSH in hepatic function. Gclc(h/h) mice develop severe steatosis and die of liver failure within one month, due to ~95% depletion of hepatic GSH; mitochondria are the major affected organelles, displaying abnormal ultrastructure and impaired functioning. Gclc(h/h) mice were fed with L-N-acetylcysteine (NAC; 10 g/L) in drinking water, starting at postnatal day 18. Gclc(h/h) mice were rescued by use of NAC supplementation, and survived until adulthood. NAC replenished the mitochondrial GSH pool and attenuated mitochondrial damage, with accompanying diminished hepatic steatosis; however, abnormal liver biochemical tests, hepatocyte death, and hepatic oxidative stress persisted in the rescued mice. At 50 days of age, the liver from rescued Gclc(h/h) mice started to display characteristics of fibrosis and at age 120 days, macronodular cirrhosis was observed. Immunohistostaining for liver-specific markers as well as the expression profile of hepatic cytokines indicated that the repopulation of hepatocytes in the cirrhotic nodules involved the expansion of oval cells. Replenishment of mitochondrial GSH and restoration of mitochondrial function by NAC prevents mortality caused by the loss of hepatocyte GSH de novo synthesis, allowing steatosis to progress to a chronic stage. Thus, with NAC supplementation, Gclc(h/h) mice provide a model for the development of liver fibrosis and cirrhosis.
Article: Protection from olanzapine-induced metabolic toxicity in mice by acetaminophen and tetrahydroindenoindole[Show abstract] [Hide abstract]
ABSTRACT: In mice and in humans, treatment with the second-generation antipsychotic drug olanzapine (OLZ) produces excessive weight gain, adiposity and secondary metabolic complications, including loss of glucose and insulin homeostasis. In mice consuming a high-fat (HF) diet, a similar phenotype develops, which is inhibited by the analgesic acetaminophen (APAP) and by the antioxidant tetrahydroindenoindole (THII). Therefore, we examined the ability of APAP and THII to prevent metabolic changes in mice receiving OLZ. C57BL/6J mice received either a normal diet or a HF diet, and were administered daily dosages of OLZ (3 mg kg(-1) body weight), alone or with APAP (30 mg kg(-1) body weight) or THII (4.5 mg kg(-1) body weight), for 10 weeks. Parameters of body composition and metabolism, including glucose and insulin homeostasis and oxidative stress, were examined. OLZ treatment doubled the HF diet-induced increases in body weight and percent body fat. These increases were partially prevented by both APAP and THII, although food consumption was constant in all groups. The THII protection was associated with an increase in whole body and mitochondrial respiration. OLZ also exacerbated, and both APAP and THII prevented, HF diet-induced loss of glucose tolerance and insulin resistance. As increased body fat promotes insulin resistance by a pathway involving oxidative stress, we evaluated production of reactive oxygen and lipid peroxidation in white adipose tissue (WAT). HF diet caused an increase in lipid peroxidation, NADPH-dependent O(2) uptake and H(2)O(2) production, which were further exacerbated by OLZ. APAP, THII and the NADPH oxidase inhibitor, diphenyleneiodonium chloride, each abolished oxidative stress in WAT. We conclude that both APAP and THII intervene in the development of obesity and metabolic complications associated with OLZ treatment.
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ABSTRACT: In this study we examined the role of the antioxidant glutathione (GSH) in pulmonary susceptibility to ozone toxicity, utilizing GSH deficient C57BL/6J mice that lack the expression of glutamate-cysteine ligase modifier subunit (GCLM). Gclm(-/-) knockout mice had 70% GSH depletion in the lung. Gclm(+/+) wild-type and Gclm(-/-) mice were exposed to either 0.3 ppm ozone or filtered air for 48h. Ozone-induced lung hyperpermeability, as measured by total protein concentration in bronchoalveolar lavage fluid, was surprisingly lower in Gclm(-/-) mice than in wild-type mice. Lung hyperpermeability did not correlate with the degree of neutrophilia or with inflammatory gene expression. Pulmonary antioxidant response to ozone, assessed by increased mRNA levels of metallothionein 1 and 2, alpha-tocopherol transporter protein, and solute carrier family 23 member 2 (sodium-dependent vitamin C transporter) was greater in Gclm(-/-) mice than in Gclm(+/+) mice. These results suggest that compensatory augmentation of antioxidant defenses in Gclm(-/-) mice may confer increased resistance to ozone-induced lung injury.
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ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option.
Article: Inhibitor of B Kinase Regulates Redox Homeostasis by Controlling the Constitutive Levels of Glutathione[Show abstract] [Hide abstract]
ABSTRACT: Cytokine-activated inhibitor of kappaB kinase beta (IKKbeta) is a key mediator of immune and inflammatory responses, but recent studies suggest that IKKbeta is also required for tissue homeostasis in physiopathological processes. Here we report a novel role for IKKbeta in maintenance of constitutive levels of the redox scavenger GSH. Inactivation of IKKbeta by genetic or pharmacological means results in low cellular GSH content and marked reduction of redox potential. Similar to Ikkbeta(-/-) cells, Tnfr1(-/-) and p65(-/-) cells are also GSH-deficient. As a consequence, cells deficient in IKKbeta signaling are extremely susceptible to toxicity caused by environmental and pharmacological agents, including oxidants, genotoxic agents, microtubule toxins, and arsenic. GSH biosynthesis depends on the activity of the rate-limiting enzyme glutamate-cysteine ligase (GCL), consisting of a catalytic subunit (GCLC) and a modifier subunit (GCLM). We found that loss of IKKbeta signaling significantly reduces basal NF-kappaB activity and decreases binding of NF-kappaB to the promoters of Gclc and Gclm, leading to reduction of GCLC and GCLM expression. Conversely, overexpression of GCLC and GCLM in IKKbeta-null cells partially restores GSH content and prevents stress-induced cytotoxicity. We suggest that maintenance of GSH is a novel physiological role of the IKKbeta-NF-kappaB signaling cascade to prevent oxidative damage and preserve the functional integrity of the cells.
Article: ChemInform Abstract: The Fischer Indolization Reaction and the Synthesis of Dihydroindenoindoles.[Show abstract] [Hide abstract]
ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option.
Article: Protective Effects of the Antioxidant 4b,5,9b,10-Tetrahydroindeno[1,2-b]indole Against TCDD Toxicity in C57BL/6J Mice[Show abstract] [Hide abstract]
ABSTRACT: The protection against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 5 microg/kg body weight) toxicity by the antioxidant 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII) was examined in female C57BL/6J mice. TCDD produced increases in the levels of hepatic lipid-derived aldehydes, rates of mitochondrial production of hydrogen peroxide and superoxide, and the oxidation state of cytosolic GSH. In contrast, mitochondrial GSH increased in reduction state, correlating with an increase in mitochondrial membrane potential. Systemically, TCDD lowered body weight gain, percentage body fat, and hepatic ATP levels, parameters prevented by concomitant administration of 100 microM THII in drinking water. However, TCDD-induced increases in mitochondrial respiration and decreased mitochondrial membrane fluidity were not prevented by THII. These results suggest that TCDD-mediated oxidative stress was not responsible for changes in mitochondrial respiration or membrane fluidity. Furthermore, although TCDD produced a large increase in mitochondrial oxygen consumption, this was not associated with the poor gain in weight produced by TCDD.
Article: Early onset senescence occurs when fibroblasts lack the glutamate-cyteine ligase modifier subunit[Show abstract] [Hide abstract]
ABSTRACT: Cellular senescence is the irreversible entry of cells into growth arrest. Senescence of primary cells in culture has long been used as an in vitro model for aging. Glutamate-cysteine ligase (GCL) controls the synthetic rate of the important cellular antioxidant glutathione (GSH). The catalytic subunit of GCL, GCLC, is catalytically active and essential for life. By contrast the modifier subunit of GCL, GCLM, is dispensable in mice. Although it is recognized that GCLM increases the rate of GSH synthesis, its physiological role is unclear. Herein, we show that loss of Gclm leads to premature senescence of primary murine fibroblasts as characterized by: (a) diminished growth rate, (b) cell morphology consistent with senescence, (c) increases in senescence-associated beta-galactosidase activity, and (d) cell cycle arrest at the G(1)/S and G(2)/M boundaries. These changes are accompanied by increased intracellular ROS, accumulation of DNA damage, and induction of p53 and p21 proteins. We also found that N-acetylcysteine increases intracellular GSH and prevents premature senescence in Gclm(-/-) cells. These results suggest that the control of GCLM, which in turn controls aspects of the cellular redox environment via GSH, is important in determining the replicative capacity of the cell.
Article: Knock-In Mouse Lines Expressing either Mitochondrial or Microsomal CYP1A1: Differing Responses to Dietary Benzo[a] pyrene as Proof of Principle[Show abstract] [Hide abstract]
ABSTRACT: In the past, CYP1A1 protein was known to be located in the endoplasmic reticulum (ER; microsomes). More recently, CYP1A1 was shown also to be targeted to the inner mitochondrial membrane; mitochondrial import is dependent on NH(2)-terminal processing that exposes a cryptic targeting signal. It is interesting that microsomal and mitochondrial CYP1A1 enzymes exhibit different substrate specificities, electron donors, and inducer properties. To understand the physiological functions of microsomal versus mitochondrial CYP1A1, we have generated three knock-in lines by altering the CYP1A1 NH(2) terminus. Cyp1a1(mtt/mtt) mice encode an NH(2)-terminal 31-amino acid-truncated protein, deleting the ER-targeting signal and exposing the cryptic mitochondrial-targeting signal. Cyp1a1(mtp/mtp) mice encode a protein carrying L7N and L17N mutations; this mutant lacks the signal recognition particle (SRP)-binding site and subsequent ER-targeting, but requires proteolysis by a cytosolic peptidase for mitochondrial import. Cyp1a1(mc/mc) mice encode a microsomal protein having R34D and K39I mutations, which abolish the mitochondrial targeting signal. After dioxin or beta-naphthoflavone treatment of these mouse lines, the CYP1A1 protein was shown to be located in the mitochondria of the Cyp1a1(mtp/mtp) and Cyp1a1(mtt/mtt) lines and in microsomes of the Cyp1a1(mc/mc) line. To test for differences in function, we compared the response to dietary benzo[a]pyrene (BaP). After 18 days of daily oral BaP, wild-type and Cyp1a1(mc/mc) mice were completely protected, whereas Cyp1a1(-/-) and Cyp1a1(mtp/mtp) mice showed striking toxicity and compensatory up-regulation of CYP1A2 and CYP1B1 mRNA in several tissues. Our data support the likelihood that it is the microsomal rather than mitochondrial CYP1A1 enzyme that protects against oral BaP toxicity.
Article: Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice[Show abstract] [Hide abstract]
ABSTRACT: Hepatic ischemia-reperfusion (I/R) injury is an important complication of liver surgery and transplantation. Mitochondrial function is central to this injury. To examine alterations in mitochondrial function during I/R, we assessed the mitochondrial proteome in C57Bl/6 mice. Proteomic analysis of liver mitochondria revealed 234 proteins with significantly altered expression after I/R. From these, 13 proteins with the greatest expression differences were identified. One of these proteins, peroxiredoxin-6 (Prdx6), has never before been described in mitochondria. In hepatocytes from sham-operated mice, Prdx6 expression was found exclusively in the cytoplasm. After ischemia or I/R, Prdx6 expression disappeared from the cytoplasm and appeared in the mitochondria, suggesting mitochondrial trafficking. To explore the functional role of Prdx6 in hepatic I/R injury, wild-type and Prdx6-knockout mice were subjected to I/R injury. Prdx6-knockout mice had significantly more hepatocellular injury compared with wild-type mice. Interestingly, the increased injury in Prdx6-knockout mice occurred despite reduced inflammation and was associated with increased mitochondrial generation of H(2)O(2) and dysfunction. The mitochondrial dysfunction appeared to be related to complex I of the electron transport chain. These data suggest that hepatocyte Prdx6 traffics to the mitochondria during I/R to limit mitochondrial dysfunction as a protective mechanism against hepatocellular injury.
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Article Summary
Now that 3D printing technology is taking off, some truly unique projects are beginning to emerge from all sorts of talented people. Take Gael Langevin, a French sculptor and model marker who has spent the better part of the last year designing and engineering his own animatronic robot called InMoov. And it's open source, so if you're feeling confident, you can try to build one yourself using a list of off-the-shelf electronics and parts he shares on 3D file sharing site Thingiverse.
Read the full article: Print your own InMoov animatronic robot
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I think, frankly, the Speaker is talking about letting the legislative process work and open rules where Members representing their principles, their beliefs, their constituents can bring amendments to the floor, bring their ideas to the floor and take their best shot, Jordan said. Thats the way this body was designed to operate.
Rep. Mike Pence, a tea party favorite and former GOP Conference chairman, lauded Boehner for signaling an end to business as usual, both in substance and process.
We have one chance to demonstrate to the American people that were committed to returning our national government to fiscal responsibility, limited government and reform, the Indiana Republican said.
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