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Gastrointestinal Bleeding Topic Guide
Gastrointestinal Bleeding: Gastrointestinal bleeding either comes from the upper GI or lower GI tract. Upper GI bleeding can be caused by ulcers, gastritis, varices, cancer, or inflammation. Lower GI bleeding is caused by diverticulitis, cancers, IBD, infection, polyps, hemorrhoids, and anal fissures. Symptoms of GI bleeding include fatigue, weakness, shortness of breath, abdominal pain, vomiting blood, rectal bleeding, anemia, or a pale appearance. Treatment of GI bleeding depends on the cause.
Stool Color Changes Stool color changes and textures to black, tarry, sticky, red, maroon, clay-colored, gray, pale, and yellow can have a variety of causes. Causes include pancreatitis, cancers, medication, changes in diet, and other conditions. Treatment of changes in stool color depend on the cause.
Expert Views and News
From WebMD
Digestive Disorders Resources
- Fiber for Constipation
- Is It Okay to Take a Stool Softener Every Day?
- The Truth About Food Allergies


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Each 6000kg sculpture is lowered to the seabed where it is drilled into the substrate to lessen the effects of turbulent weather.
substrate sub·strate (sŭb'strāt')
The material or substance on which an enzyme acts.
A surface on which an organism grows or is attached.
The body or base layer of an integrated circuit, onto which other layers are deposited to form the circuit. The substrate is usually Silicon, though Sapphire is used for certain applications, particularly military, where radiation resistance is important. The substrate is originally part of the wafer from which the die is cut. It is used as the electrical ground for the circuit.


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Sometimes baseball can be boring. This doesn't happen very often, but once in a blue moon a game comes along with very little interest to it. Such is the case with last night's Angel's loss. Sure, there was quality pitching and a couple of nice plays defensively, but other than that I can't say the game yieldeed anything of merit. It was just one of those things.
Angels 2 Padres 3
Game Notes
-- Nice to see Erick Aybar have a breakout game. Aybar has been scuffling since signing his extension but have largely been overlooked by the struggles of a certain well paid first baseman. But last night ERick exploded with a 4-4 night including a run and an RBI. Aybar hitting is a huge deal since it strengthen's the bottom of the line-up and gives the Halos another dangerous bat for a change.
-- Anybody else find themselves mildly shocked that when Ryan Langerhans came up in the ninth inning you acutally found yourself clammoring for Vernon Wells? I know, it was weird huh?
-- I was also impressed with Mike Trout almost having a coniption about getting thrown out at first. That kind of fiery passion is essential and has been sorely lacking this year. Everyday this kid shows me more and more why everyone thinks he will be a star.
-- Jordan Walden's rehab tour is also going well. Another scorless inning of work for Jordan bodes well for his return to pressure detail. I can imagine the next step will be to see what he does with a lead in the seventh inning.
Halo A Hole
Someone's gotta get this and Haren did take the loss. He actually pitched pretty well so this is more of a cummulative season award. Where have you gone Danny Boy?
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VIEWS: 11 PAGES: 2 CATEGORY: Legal POSTED ON: 5/4/2010 Public Domain
CRIMINAL RECORDS BUREAU DISCLOSURE Rehabilitation of Offenders Act 1974 (as amended) The Borough of Poole and its schools are highly committed to safeguarding the welfare of children, young people and vulnerable adults. We expect all employees to share this commitment. As part of our recruitment process the Borough of Poole is allowed to ask applicants to declare information about convictions which are not "spent". The Rehabilitation of Offenders Act enables many criminal convictions to become spent or ignored after a rehabilitation period. The table overleaf explains what these rehabilitation periods are in particular cases. If your conviction is not spent you are required to declare it. You should forward details confidentially under separate cover to the Head of Human Resources or the Head teacher if it is a school based appointment. A failure to disclose an unspent conviction could lead to the application being rejected, or if discovered after appointment the employee being dismissed. Exempted Posts The Rehabilitation of Offenders Act (Exemptions Order) 1975 also allows the Borough of Poole to ask you to declare convictions which would otherwise be spent if you are applying for certain types of posts. This includes posts which: • involve regularly caring for, training, supervising or being in sole charge of persons under 18 years of age • involve unsupervised contact with children under arrangements made by a responsible person • regularly caring for, training, supervising or being in sole charge of vulnerable adults • child minding and day care posts • Social Workers and social care workers. This is not an exhaustive list, further information can be obtained from Human Resources. The job details will confirm whether particular posts are being treated as exempted. Applicants for exempted posts will be required to complete a Criminal Records Bureau disclosure application and must declare all convictions when they submit an application. Applicants will not be able to treat any conviction as spent. Disclosure will give details of all previous convictions, cautions, reprimands and warnings. Referees named in your application form (or others) will be advised that they are at liberty to make reference to any relevant police record. You will be asked to verify your identity when submitting a CRB disclosure form. The Borough of Poole observes the requirements of the CRB Code of Practice when dealing with disclosure information. A copy of this code is available on request. The fact that an individual has a criminal record will not automatically bar an individual from employment. Each case will be carefully considered on its merits taking into account the duty to protect vulnerable adults and children. Information about a conviction which is of direct relevance to the employment may result in an offer of employment being withdrawn. The Borough of Poole has also adopted a policy statement on the employment of ex offenders, a copy of which is included with application packs. If you have any questions and concerns you should contact Human Resources. LENGTH OF TIME BEFORE SENTENCES ARE 'SPENT' Sentence Rehabilitation Period Rehabilitation Period People aged 17 or under People aged 18 or over when convicted when convicted Prison sentences of 6 months or less 3.5 years 7 years Prison sentences more than 6 months to 2.5 years 5 years 10 years Borstal (abolished in 1983) 7 years 7 years Prison Sentences more than 2.5 years Never Spent Never Spent Detention centres (abolished in 1988) 3 years 3 years Fines, compensation, probation, community service, combina- 2.5 years 5 years tion, action plan, drug treatment and testing, and reparation orders Absolute discharge 6 months 6 months The Crime and Disorder Act 1998 introduced a new custodial sentence for young people with different rehabilitation periods Sentence Rehabilitation Period Rehabilitation Period People aged 12, 13 or 14 People aged 15, 16 or 17 when convicted when convicted Detention and training order of 6 months or less 1 year after the order ex- 3.5 years pires Detention and training order of more than 6 months 1 year after the order ex- 5 years pires With some sentences the rehabilitation period varies Sentence Rehabilitation Period Probation, supervision, care order, conditional discharge and 1 year or until the order expired (whichever is longer) bind-over Secure training (abolished in 2000) and attendance centre 1 year after the order expired orders Hospital order (with or without a restriction order) 5 years or 2 years after the order expired (whichever is longer) Referral order Once the order expired Armed Forces Rehabilitation periods for imprisonment in the Services are the same as in civilian life. For specific service offences, the periods are as follows Type of Sentence Number of years On men and women in the armed services From date of conviction before conviction becomes 'spent' A sentence of cashiering, discharge with ignominy or dismissal 10 years with disgrace from Her Majesty's Services A sentence of dismissal from Her Majesty's Service 7 years A custodial order under the relevant Schedules & sections of 7 years the Army, Air Force and Naval Discipline Acts – where the maxi- mum period of detention specified in the order is more than 6 months A sentence of detention in respect of conviction in Service Disci- 5 years plinary hearings A custodial order under the relevant Schedules and sections 3 years of the Army, Air Force and Naval Discipline Acts – where the maximum period of detention specified in the order is 6 months or less Applicants for exempted posts are not entitled to withhold details of spent convictions under the Rehabilitation of Offenders Act
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I have made Swedish meatballs for years, but I actually used the old Mirro-Matic Pressure cooker recipe (same as my mother did in the 50's and 60's), and it was a clearer gravy, which I know isn't really Swedish!!! I liked this recipe a lot, and made it exactly as written, but thought the flour in the chicken broth tasted "raw". I am used to cooking flour a little in roux's to get rid of the raw flour taste. I wonder if it would be better thickened with a little cornstarch??? A couple of TBSP's of cornstarch can not be worse than all that flour can it? I also think the meat mixture needed a little more salt. Flavor was great, my guests liked it, I am just pickier!!! Great recipe though. I didn't have seedless raspberry jam as recommended, and used what I had with seeds, and it made no noticeable difference! Will probably make again with changes to the thickening agent!!! I served it with the brown rice pilaf and sugar snaps and peas with a lemon butter glaze. (not healthy, I know)!!! Just use lemon juice on the veggies, compliments the sweetness in the dish and rice.
Swedish Meatballs
From EatingWell: March/April 2012
These Swedish meatballs are made with a combination of lean ground turkey breast and ground pork, flavored with nutmeg and cardamom and simmered in a creamy mushroom sauce. Serve over a brown rice pilaf spiked with almonds and currants or whole-wheat egg noodles.
8 Reviews for Swedish Meatballs
This recipe was SO delicious and easy and healthy!! Even the kids loved it! (and they are crazy picky) I didn't change anything, except I doubled the meat balls for the same amount of sauce and it was perfect. The sauce was perfect, very tasty and just like a rich creamy sauce. I used 5% fat sour cream. Thanks so much! I'm recommending it on facebook! :)
Broth and flour = paste
The meatballs came out juicy and great. I'm not sure what exactlyb 1lb button mushrooms mean (I very new to cooking) so I just used a bunch of sliced mushrooms. Also didn't find raspberry jam so I used strawberry jam and I used all lean ground beef, because I have a ton of it in the freezer. All I can say is WOW, I will make this recipe for life.
This was an incredibly easy and tasty recipe. I served it with egg noodles.
I made this recipe as it is shown except for the raspberry jam. I couldn't find seedless so I had to use regular and you can't tell the difference. I also didn't add the cardamom because I didn't have any.


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Michael Burgess, MD (R-TX) vice-chairman of the House Subcommittee on Oversight and Investigation, questioned the sluggishness of interoperability.
"We do hear about this a lot," Burgess said. "Even anecdotally, hospital systems in the same city, that have the same operating system aren't talking to each other."
"You're the head, why don't you fix that?," he asked Mostshari. "Why don't you just make that happen?"


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Michael Owen was happy to get back in to the team, and on to the scoresheet, after our 5-2 victory over Championship side, Scunthorpe. The victory meant even more when learning that City, Liverpool and Chelsea had all lost, to add to Spurs and Everton who were knocked out the day before, given that United are now clear favourites to retain the trophy.
"There are a few of us who haven't been playing a lot this season and needed the game, and Scunthorpe made a real game of it," said Owen. "They're obviously very fit and they never stopped going forward. We scored five goals but they could have scored a few as well. It was a good game. There were a lot of players there tonight that needed that first game; be it players coming back from injury or players who just haven't played, so that was beneficial to us. All in all it was a good workout and we're pleased to get through to the next round – especially seeing the other results!"
Made in Manchester is available for just £3. Some of the best football writers take a player each, from Sir Bobby Charlton to Ryan Giggs, George Best to David Beckham, Duncan Edwards to Paul Scholes, and many more, with 30 articles in total. All profit goes to Trafford Macmillan so please support this fantastic cause.


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- 311Promote
Canvas Print
From the moonby Viviana Gonzalez
Fine art print on bright white, fine poly-cotton blend, matte canvas using latest generation Epson archival inks. Individually trimmed and hand stretched museum wrap over 1-1/2" deep wood stretcher bars. Includes wall hanging hardware.
Outstanding very beautiful work Love the orange in the B&W!
stunning image, Vivi!!
Thanks so much Thea and Klara! :-)
beautiful work
Thanks so much Kent and Agostino! :-)
Great usage of black!!! Excellent piece!!
Thanks so much dBranes and Chris! :-)
love this!
Stunning work, Viviana.
so awesome!
Thanks so much Sharon and Ann! :-)
Thank you soaring anchor! :-)
Great piece!~
Thank you Julia! :-)
Super cool!
Thank you Eric! ^_^
So very peaceful, the ship sailing off in to the moon with the background in bw, very nice, Keep up the great works!
Thanks so much Majik Rose! ^_^
this is a great artwork!
wow Viv, awesome piece
Thanks so much Berberism and Wendy! :-)
Awesome!!! Great work, I Love this piece!
Thank you Nichole!
Wonderful work!
dreamy, mysterious, dangeorous! ♥
so awesome!!
Thanks so much oblina, Paula and Darthdaloon!
fabulous work
Thank you Dirk! :-)
Awesome work!
Thank you Jozi! :-)
Stunning image
Oh yes! I feel like captain Hook will jump up at me!
Thanks so much everyone for the kind comments! :-)
Wonderful work!
Thank you Suzy and mariosp!. :-)
Amazing work !
Thanks so much Robert! :-)
Gorgeous :) T.
Thank you Teresa! :-)
Love it!!!
Thanks so much! :-)
Wonderful work!
Thanks so much!!... :-)
I have promoted this fab image and I hope your day is filled with creative joy:)))
See More Comments


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Apple removes display of Adobe Flash content from iPad promosFollowing an AppleInsider report that highlighted two pieces of promotional iPad material showing the display of Adobe Flash content, Apple has removed the offending images from its Web site.
On Friday, misleading content that implied the inclusion of Adobe Flash in the iPad's Safari Web browser was noted. In an image and a video on Apple's Web site, content from The New York Times Web site that could only be displayed in Flash was shown on the iPad.
But this weekend, Apple updated its Web site, removing an image that showed a Flash-only photo slideshow, and modifying a video that showed the Times Flash video player load on the iPad.
The image on the front page of Apple's site has been changed from the Flash photo slideshow to a story about the 1,300th anniversary of the city of Nara, Japan. Previously, it showed a picture from the story "The 31 Places to Go in 2010," with a Flash-only image of a beach in Montenegro.
In addition, a video intended to demonstrate real-world use in a first-person view has been modified to remove the display of Flash content. Previously, the iPad promotional video had shown the Flash-powered Times video player load properly on nytimes.com. Now, it correctly shows a missing plugin icon in its place.
The changes confirm that the previous pictures with Flash support were merely renderings, and did not in any way imply that Apple intended to add Flash support to the iPad before launch. At the product's unveiling Wednesday, Apple co-founder Steve Jobs did a live hands-on demo with the product during which Flash content from the Times Web site did not load.
For more on why Apple isn't likely to support Flash in the iPhone OS — including the iPad — read AppleInsider's three-part Flash Wars series.
On Topic: Current Hardware
- AppleCare for Mac now covers batteries retaining less than 80% charge
- Apple will replace some faulty 3TB iMac hard drives under new repair program
- Apple provides glimpse of manufacturing, customer support operations in Ireland
- Apple adds 5K support to MacBook Pro as target display mode remains absent for Retina iMac
- Apple upgrades some 27" non-Retina iMac orders to 5K model following price cut


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By: William Kerns on September 26, 2014 - 3:45pm - Add new comment
The Lubbock Memorial Civic Center is undergoing construction at its main entrance facing Mac Davis Lane.
It is open, but you must walk around the barriers. Please plan to arrive early if attending the LSO concerts this weekend.
The Lubbock Symphony Orchestra, conducted by David Cho, will headline concerts at 7:30 p.m. Friday and Saturday at the Lubbock Memorial Civic Center Theatre, 1501 Mac Davis Lane.
The guest pianist is Roman Rabinovich, playing Piano Concerto No. 1, by Franz Liszt.
By: William Kerns on September 24, 2014 - 1:11am - Add new comment
The family musical "Cats" will be staged as a production of Lubbock Moonlight Musicals at 7:30 p.m. Nov. 20-22, and 2 p.m. Nov. 23, at the Lubbock Memorial Civic Center, 1501 Mac Davis Lane.
The play, first performed in 1981, has music and lyrics by Andrew Lloyd Webber, based on T.S. Eliot's "Old Possum's Book of Practical Cats."
Stage direction is by Gerald Dolter. Music direction is by chorale director John Hollins, conducting a professional orchestra in the pit.
By: William Kerns on September 23, 2014 - 8:04pm - Add new comment
"Suor Angelica (Sister Angelica)" is an opera in one-act by Giacomo Puccini to an original Italian libretto by Giovacchino Forzano. "The Old Maid and the Thief" is an opera in one act by Italian-American composer Gian Carlo Menotti, using the composer's English language libretto.
Both operas will be performed at 8 p.m. Friday through Sunday, Sept. 26-28, by the Texas Tech School of Music at the Wells Fargo Amphitheatre at Mackenzie Park.
General admission seating is $18 for the general public, $13 for seniors and $8 for students.
By: William Kerns on September 23, 2014 - 4:36pm - Add new comment
The Alamo Drafthouse Cinema, 120 W. Loop 289, will offer one screening of classic 1928 silent film "The Wind" at 6 p.m. Sunday, Sept. 28.
Austin-based band The Invincible Czars will travel to Lubbock and provide a live score for the 90-minute film.
Tickets are $15, and can be purchased in advance online at drafthouse.com/lubbock .
Victor Sjostrom directs the film, with a screenplay by Frances Marion based on a book by Dorothy Scarborough.
By: William Kerns on September 22, 2014 - 9:48pm - Add new comment
Actually, this story made its way first to the publisher of The Lubbock Avalanche-Journal. He credited the story to one of his most reliable sources, and the sighting soon was shared with reporters.
By: William Kerns on September 19, 2014 - 12:43pm - Add new comment
I'll admit that sometimes it bugs me when a couple more names are not added to the West Texas Walk of Fame every year.
Why can't this be a yearly attraction?
Then again, with four names added in 2012, and another five in a ceremony tonight -- click HERE -- obviously Civic Lubbock Inc. is not getting too far behind.
That said, there are hundreds who deserve to be on the WTWoF.
By: William Kerns on September 14, 2014 - 3:03pm - Add new comment
More great journalism from the Lubbock Avalanche-Journal ... Just click HERE for interesting reading.
By: William Kerns on September 12, 2014 - 9:45pm - Add new comment
Saturday's football game between Texas Tech and Arkansas has been sold out for weeks. That doesn't mean you cannot leave the house and have a blast at an arts option, in the form of a one-day festival.
The 44th annual Fall Arts & Crafts Festival will take place from 9 a.m. to 6 p.m. on Saturday, Sept. 13, at the Lubbock Municipal Garden & Arts Center, 4215 University Ave.
This one-day family event -- which traditionally attracts between 6,000 and 8,000 visitors -- will find more than 80 vendors selling handmade craft items and fine art.
By: William Kerns on September 12, 2014 - 8:48pm - Add new comment
Those who spend what seems like a fortune riding the rides at each year's fair -- and this is easy to do, especially concerning families with children -- have a terrific, money-saving option to consider.
But know this: You are down to your last day to think it over.
The option is called a MEGA-PASS -- and Saturday, Sept. 13, is the very last day that they will be sold.
By: William Kerns on September 9, 2014 - 3:02pm - Add new comment
Phlip Coggins will release his first new music since early 2012 when he performs in concert Thursday, Sept. 11, at the Blue Light, 1806 Buddy Holly Ave.
Gypsy Jane and the Travelers will open at 10 p.m., while Phlip Coggins, featuring The Lotharios will be on stage from 11 p.m. to 11:30 p.m.
The Lotharios, said Coggins, include Lothario Discipulus (Jacob Nalle), on lead guitar; Lothario Patri (Brent "Be" Cagle), on saxophone; Lothario Cor (Jayce Logan), on drums; and Lothario Indignus (Joel Smith), on bass guitar.
Lubbock Avalanche-Journal ©2015. All Rights Reserved.


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SAM tools
SAM (Sequence Alignment/Map) is a flexible generic format for storing nucleotide sequence alignment. SAM tools provide efficient utilities on manipulating alignments in the SAM format.1,368 weekly downloads
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An implementation of the curses library for Win32, DOS, OS/2, X11 and SDL.333 weekly downloads
LifeLines is a genealogy program to help with your family history research. Its primarily strengths are its powerful scripting language and the ability easily import and export information in the GEDCOM format.26 weekly downloads
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PCP (Pattern Classification Program) is an open-source machine learning program for supervised classification of patterns. PCP is a binary executable running on Linux and Windows (under Cygwin environment).8 weekly downloads
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Utility to facilitate time-sensitive use of .plan and .project files. Curses-based interface allows user to easily view, edit, replace, and delete contents. A timestamp is automatically prepended to the file contents.2 weekly downloads
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ncdu (NCurses Disk Usage) is a curses-based version of the well-known "du", and provides a fast way to see what directories are using your disk space.1 weekly downloads
Small, platform-independant code to perform functions, like GotoXY on consoles. Works with Windows console windows as well as TTY consoles. When using TTY consoles, it directly outputs TTY commands.1 weekly downloads
Nickle Programming Language
Nickle is a desk calculator language with powerful programming and scripting capabilities. Nickle supports a variety of datatypes, especially arbitrary precision numbers.1 weekly downloads


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Find a copy in the library
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|Juvenile materials
Juvenile works
Juvenile fiction
|Additional Physical Format:
|Online version:
Curtis, Gavin.
Bat boy & his violin.
New York : Simon & Schuster Books for Young Readers, 1998
|Material Type:
|Fiction, Primary school
|Document Type:
|All Authors / Contributors:
Gavin Curtis; Earl B Lewis
|0689800991 9780689800993 0689841159 9780689841156
|OCLC Number:
|Coretta Scott King Honor, illustrator, 1999.
|Target Audience:
|Elementary Grade.; 700
|1 volume (unpaged) : color illustrations ; 22 x 26 cm
|Other Titles:
|Bat boy and his violin
|by Gavin Curtis ; illustrated by E.B. Lewis.
|More information:
Reginald is more interested in practicing his violin than in his father's job managing the worst team in the Negro Leagues, but when Papa makes him the bat boy and his music begins to lead the team to victory, Papa realizes the value of his son's passion.
User-contributed reviews
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Related Subjects:(12)
- African Americans -- Juvenile fiction.
- Fathers and sons -- Juvenile fiction.
- Baseball stories.
- Negro leagues -- Juvenile fiction.
- Violin -- Fiction.
- Negro Leagues -- Fiction.
- Baseball -- Fiction.
- Fathers and sons -- Fiction.
- African Americans -- Fiction.
- Negro leagues
- African Americans.
- Fathers and sons.
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Previous postThe Power of an Image
How to engage journalists through social media [INFOGRAPHIC]
Results from survey of UK journalists
Posted on March 26, 2012 by Lance Concannon
To mark our sponsorship of Social Media World Forum this week, Text 100 carried out some research into the way journalists use social media. We interviewed 72 journalists about the way they use social media channels in their professional lives to research companies and communicate with PR executives.
The top-line results of our survey are shown in the infographic below, and you can download a full copy of the report with a more detailed look at the survey findings by clicking on this link. Please feel free to share the infographic anywhere you like.
Editor's note: This post originally appeared on the Text 100 UK blog, as part of their sponsorship of the #SMWF.
3 Ways Employee Advocacy Programs Can Aid Public Relations
Posted on June 10, 2015
By Lewis Webb
By Lewis Webb
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Posted on May 04, 2015
By Fulvio Fiorentino
By Fulvio Fiorentino
Selling Stories to the Media is a Pitch Perfect Affair
Posted on April 16, 2015
By Lorena Trako
By Lorena Trako
Twitter Journalism Offers Opportunity for Wins, Fails
Posted on April 15, 2015
By Angel Gallego
By Angel Gallego
Brand Awareness, Not Big Data, Will Save Corporate Communications
Posted on February 25, 2015
By Magali Rouault
By Magali Rouault
Google+ Hangouts On Air Gives Xerox PR Power
Posted on February 18, 2015
By Emily Bird
By Emily Bird
Copyright © 2015 Text100 Integrated Communications.
All rights reserved.
All rights reserved.


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Blood of Eden
Paranormal Romance
Early Book Review: The Eternity Cure (Blood of Eden #2) by Julie Kagawa
Julie always manages to write gripping, emotional stories, and The Eternity Cure is no different. Even though it's the middle book in a series, it's still compelling and unique. Allie is a likeable and strong heroine who reader...
Paranormal Romance
Micro-Review: The Eternity Cure (Blood of Eden #2) by Julie Kagawa
Holy krikes, Batman! I'm gonna keep this short because I'm a little traumatized from finally finishing this book to think coherently. I generally don't enjoy urban fantasy and this book is GOOD urban fantasy, even better than ...
Paranormal Romance
Book Tour & Giveaway: Chattin' it up about the star-crossed love between The Eternity Cure's Allie & Zeke
Who luuurves Julie Kagawa's Blood of Eden series? These gals! And that's why we are super psyched to be on The Eternity Cure book tour! This tour features 100% blogger-written content, and who doesn't love chatting about yo...
Araneae Nation
GraveTells Readers Choice 2012 Nominee Spotlight: Most Original Story Universe
When we announced the nominees for the Book & Series Awards earlier this week, I contacted all the authors who were nominated for Most Original Story Universe and offered them the chance to be part of this spotlight event. The...
Book Awards
April 2012 GraveTells Book Awards: See our (and your) top picks!
Congratulations to our April Book Award winners! Below are the books and authors who have been selected for our monthly book awards, by the reviewers and the readers. Enjoy!
Paranormal Romance
Early Review: The Immortal Rules (Blood of Eden #1) by Julie Kagawa
The Immortal Rules was an addicting and enjoyable post-apocalyptic book. It has tons of action, and a good amount of romance. The ending definitely leaves you wanting more, but there's no huge cliffhanger (thank God!) I'm anxio...
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- Hero Vs Hero, Day 7: Law enforcement face-off! Click to vote on match-ups #15 and #16!
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Book Review: Blind Faith (Sins Brothers #3) by Rebecca Zanetti
Book Review: Finding Lacey Moon (Hope Falls #1) by Donya Lynne
- Hero Vs Hero, Day 4: Paranormals and regencies go head to head! Click to vote on match-ups #7, #8, and #9!
- Hero Vs Hero, Day 3: Shapeshifters and vampire hunters duke it out! Click to vote on match-ups #5 and #6!
Insider (Exodus End World Tour #1) by Olivia Cunning #BookReview
Take a wicked ride with Rebecca Zanetti's Kellach Dunne #giveaway #interview #booktour
Wicked Ride (Realm Enforcers #1) by Rebecca Zanetti #BookReview
Book Tour & Giveaway: A look into non-con with an excerpt from Lilah Pace's Asking For It


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Such is the nature of Masahiro Tanaka and his injury that every time he has a bad outing, you wonder about that elbow that has a partially torn ligament. If he has two bad outings in a row, you really wonder.
On Saturday, the Yanks gave Tanaka an early 6-0 cushion, watched him cough it up, then rallied late for a 9-6 win over Houston.
I just hope Tanaka is ok. But with that injury, you will always wonder, until it blows and he needs TJ surgery. But it's not like Tanaka to give up 3 HR in a game in consecutive games. Hopefully it isn't acting up or he's hiding anything.
Brian McCann hit a grand slam (HR #12) in the first and the red-hot Chris Young homered (10) in the second to give the Yanks a 6-0 lead.
But Tanaka gave up two in the second and one in the fourth. Heading into the fifth, I had a bad feeling. I was thinking, "Get him out of there, Joe." You know when a pitcher is struggling, and you see that the manager is trying to squeeze five out of him for the win, and no matter how hard he squeezes, the pitcher can't do it? That is what happened yesterday. Tanaka gave up three in the fifth. 6-0 became 6-6. Sometimes the pitcher just can't get that extra out or three.
The Yanks' bullpen was brilliant in keeping it where it was. Chasen Shreve, in particular, has been a great pickup for the Yanks this year, and rookie Bryan Mitchell is starting to hit his stride. Maybe Mitchell will stay in the bullpen for now and help to stabilize and improve it. He can be switched back to a starting role later.
Mark Teixeira's 2-run double in the 8th was the game-winner (he leads the AL with 53 RBI) , and Chase Headley added insurance in the 9th with a HR, his eighth.
Brett Gardner has been red-hot. Just a couple of weeks ago, his average had fallen to .262. His three-hit game put him at .300.
A-Rod is still one hit behind Wade Boggs on the all-time list with 3009.
The win keeps the Yanks 1/2 game behind Tampa Bay, at 41-34. They lead the WC race.
With the rough outing by Tanaka, guess which Yankees starter has the lowest ERA? Yup, the one who may be pegged to the bullpen, now that Nova has arrived. Adam Warren.
Tanaka 5 IP, 6 R, 7 H, 2 walks, 5 K. 3 HR. 3.88
Mitchell 1 1/3 IP, 0 R, 1 H, 1 walk, 3 K. 1.59
Shreve (W, 5-1, 1.72) 2/3 IP, 0 R, 0 H, 1 walk, 1 K.
Wilson 1 IP, 0 R, 1 H, 0 walks and 2 K. 2.96
Betances (6th save) 1 Ip, 0 R, 1H, 0 walks, 1 K. 1.17.


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When Dr. Christian John reflects on the old days in his motorsport life he shakes his head laughing. His reminiscing immediately brings back memories of some racers who on seeing the season's last checkered flag being lowered would stop any effort to keep up their physical fitness, then facing him in the following spring with the resulting limpness. "This sort of thing doesn't happen anymore today," says John, who as team physician has been a member of the Audi family since 1983. "Our girl and the guys I get to see at our camp in Ofterschwang for the first time in the season, are accomplished professionals who have physically trained to the max."
The meeting in the Allgäu at the beginning of the year has been a regular event on the calendars of the Audi racers, team directors and Head of Motorsport Dr. Wolfgang Ullrich for many years. And it is an event which has evolved from a pure fitness camp into a week that is primarily dedicated to building team spirit, for instance during joint training units. This is completely to Christian John's liking. Views that motorsport is more or less a question of material on four wheels merely make a mild smile appear on his face. "Racers have exactly two factors that put them on the podium: the technology and their physical and mental fitness – that's it." Accordingly, the optimum condition of the drivers has been a high priority at Audi for years.
There are good reasons for this. "Ideally, a DTM driver has the power of a decathlonist and the stamina of a marathon runner," says Christian John as he outlines the physical demands made on the racers entrusted to his care. The heat inside the cockpit of the closed vehicle, the lateral acceleration rates which are high in a touring car as well, plus the operation of the instruments and overview of the race track – the combination of these factors truly makes DTM racing a high-performance sport.
Fitness and nutrition are on the agenda throughout the joint camp of the DTM and sports car racers just like fostering and strengthening team spirit – which has traditionally been one of the major fortes under Head of Audi Motorsport Dr. Wolfgang Ullrich. "This is where we gain an overview, provide suggestions for daily training and expose weak areas," says John, although the latter has simply ceased to exist with the current generation: "Everyone is at the same level, and incredibly fit and trained to the max."
So, all that is left is to provide suggestions for optimum training. Sports like running, cross-country skiing and cycling are ideal. "Of these I always recommend the latter two because you can do them at a good level for several hours straight." In addition, there are special power training workout units for the whole body even though the highest strain is on the shoulders, arms and neck muscles.
Once the racing season has started, in addition to training, the focus is increasingly put on nutrition, which has to be high in carbohydrates and low in harmful components. Therefore, the diet before the race and qualifying is pasta, potatoes or rice, and cereal or whole grain bread in the morning.
– End –
Audi drivers are fit for the new A5 DTM
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Audi A4 Emotion Trailer - ExtendedDie neuen Audi A4 und der A4 Avant legen mit zahlreichen Highend-Technologien die Messlatte in der Klasse höher. Elegantes Design trifft auf ein innovatives Bedienkonzept, konsequenter Leichtbau auf effiziente Lösungen beim Antrieb. Auch beim Infotainment und bei den Assistenzsystemen führen A4 und A4 Avant den Wettbewerb an. Weitere Informationen zum neuen Audi A4 finden Sie im Audi MediaCenter: https://www.audi-mediacenter.com/de
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- DTM makes maximum demands on drivers' physical fitness
- Ekström & company have prepared themselves in Allgäu winter camp
- New DTM season opens at Hockenheim seven weeks from now
Power like a decathlonist, stamina like a marathon runner – these are the ideal prerequisites for holding one's own in the DTM. The Audi factory drivers worked hard on themselves in winter – and are now ready to tackle the challenges of the new season.


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|ISSN 1088-6826(online) ISSN 0002-9939(print)
The first return time properties of an irrational rotation
Abstract | References | Similar Articles | Additional Information
Abstract: If an ergodic system has positive entropy, then the Shannon-McMillan-Breiman theorem provides a relationship between the entropy and the size of an atom of the iterated partition. The system also has Ornstein-Weiss' first return time property, which offers a method of computing the entropy via an orbit. We consider irrational rotations which are the simplest model of zero entropy. We prove that almost every irrational rotation has the analogous properties if properly normalized. However there are some irrational rotations that exhibit different behavior.
Retrieve articles in Proceedings of the American Mathematical Society with MSC (2000): 37E10, 11K50
Retrieve articles in all journals with MSC (2000): 37E10, 11K50
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Interferon regulatory factor 3 (IRF3) regulates early type I IFNs and other genes involved in innate immunity. We have previously shown that cells undergoing an endoplasmic reticulum (ER) stress response called the "Unfolded Protein Response" (UPR) produce synergistically augmented IFN-β when stimulated with pattern recognition receptor agonists such as LPS Concomitant ER stress and LPS stimulation resulted in greater recruitment of the IRF3 transcription factor to ifnb1 gene regulatory elements. In this study, we utilized murine cells to demonstrate that both oxygen-glucose deprivation and pharmacologic UPR inducers trigger phosphorylation and nuclear translocation of IRF3, even in the absence of exogenous LPS. Different ER stressors utilized distinct mechanisms to activate IRF3: IRF3 phosphorylation due to calcium-mobilizing ER stress (thapsigargin treatment, oxygen-glucose deprivation) critically depended upon Stimulator of interferon gene (STING), an ER-resident nucleic acid-responsive molecule. However, calcium mobilization alone by ionomycin was insufficient for IRF3 phosphorylation. In contrast, other forms of ER stress (e.g., tunicamycin treatment) promote IRF3 phosphorylation independently of STING and Tank binding kinase 1 (TBK1). Rather, IRF3 activation by tunicamycin and 2-deoxyglucose was inhibited by AEBSF, a serine protease inhibitor that blocks ATF6 processing. Interfering with ER stress-induced IRF3 activation abrogated IFN-β synergy. Together, these data suggest ER stress primes cells to respond to innate immune stimuli by activating the IRF3 transcription factor. Our results also suggest certain types of ER stress accomplish IRF3 phosphorylation by co-opting existing innate immune pathogen response pathways. These data have implications for diseases involving ER stress and type I IFN.
Type I IFNs (IFN-α/β) play diverse roles in adaptive and innate immunity; Type I IFNs activate macrophages and NK cells, promote T cells survival and dendritic cell maturation, and increase the production of Th1-polarizing cytokines(1). Innate immune cells such as macrophages and dendritic cells produce large amounts of type I IFN following the ligation of diverse pattern recognition receptors (PRRs). PRRs recognize conserved molecular structural motifs on pathogens, as well as endogenous products released by tissue damage(2). The PRRs that mediate IFN-β induction in macrophages include the LPS receptor TLR4, the endosomal dsRNA sensor TLR3, and the cytoplasmic dsRNA responsive retinoic acid-inducible gene-I (RIG-I) family helicases(3). Interestingly, a recently identified molecule STimulator of INterferon Gene (STING, also known as MPYS/MITA/TMEM173/ERIS), located in the ER membrane, appears to play a critical role in the induction of IFN-β by cytoplasmic dsDNA and RNA, though STING does not directly bind nucleic acids(4-7).
Signaling by these various pathogen sensors converges at the activation of the Tank-binding kinase 1 (TBK1) family of kinases(8). TBK1 is a serine/threonine kinase that phosphorylates the transcription factor interferon regulatory factor 3 (IRF3)(9). IRF3 is constitutively expressed and resides in the cytoplasm in latent form. Upon phosphorylation, IRF3 dimerizes and translocates from the cytoplasm into the nucleus(10). At the ifnb1 locus, IRF3 cooperatively binds with other transcription factors including NF-κB, AP-1, and IRF7 to form a multi-molecular "enhanceosome" that promotes ifnb1 transcription(11). IRF3 is absolutely required for the induction of IFN-β and certain IFN-α species early during viral infections, and by LPS(12-14). IRF3-regulated early type I IFN production primes cells for greater IFN responses during viral infections by inducing IRF7(15). IRF3 also regulates other inflammatory mediators such as the chemokines CXCL10 and RANTES(16-18). In a murine model of hepatic ischemia-reperfusion injury, damage is significantly decreased in both type I IFN receptor and in IRF3-deficient animals(19, 20). In addition to its transcriptional role, IRF3 promotes apoptosis in virus-infected cells through association with Bax(21).
Even as innate immune cells are poised to counter external threats, conserved stress responses respond to intracellular derangements. We, and others have shown that type I IFN responses to PRR ligands are dramatically enhanced by an intracellular stress response originating in the ER called the "Unfolded Protein Response" (UPR)(22-25). The UPR represents a final common pathway in the response to a broad variety of stresses perturbing ER function, including oxygen and nutrient deprivation, calcium dysregulation, misfolded proteins and N-linked glycosylation inhibition(26). The three major signaling cascades of the UPR stem from activation of ER-resident molecules: protein kinase receptor-like ER kinase (PERK,) the proto-transcription factor ATF6, and inositol-requiring enzyme (IRE-1). IRE-1 is both a kinase and endonuclease that cleaves 26bp from the X-box binding protein (XBP1) transcription factor mRNA. This atypical splicing eliminates a premature stop codon, and thus enables translation of full length active XBP1(26). XBP1 is essential for synergistic type I IFN responses to PRR agonists(22). We have shown that XBP1 binds an enhancer element 6kb downstream of the ifnb1 gene(23). Interestingly, during concomitant UPR and LPS stimulation, IRF3 recruitment increased at both ifnb1 promoter and enhancer(23). IRF3 binding was only observed in the presence of LPS(23). Although XBP1, a member of the CREB family of transcription factors is known to heterodimerize with other transcription factors, IRF3 is not a known binding partner(27, 28).
Investigations of gene expression in macrophages from rats overexpressing the misfolding protein HLA-B27 reveal both UPR and IFN signature, including several IRF3-regulated genes (IFN-β, OAS and IP-10)(29). However the relationship between ER stress and IRF3 activation was unclear. A previous study had demonstrated activation of IRF3, evident by phosphorylation, nuclear translocation and CREB-binding protein (CBP) association in response to DNA-damaging agents such as doxorubicin in Hela cells(30). However a later study employing a wider range of stessors failed to validate these findings in HEK293 cells(31). In a recent study by Hu et al., the UPR inducer thapsigargin augmented Poly I:C dependent IRF3-phosphorylation, supporting the involvement of UPR in IRF3 regulation(25). This study also supported a role for XBP1 in promoting anti-viral activity.
In this study we sought to determine whether ER stress exerts a direct effect on IRF3 activation. We found that multiple pharmacologic ER stress inducers and oxygen-glucose deprivation triggered activation of IRF3, as indicated by IRF3 phosphorylation and nuclear translocation. Mechanism of IRF3 activation varied by type of ER stressor: Some forms of ER stress, in particular those that also involve calcium mobilization, require TBK1 and STING for phosphorylation and nuclear translocation of IRF3. Indeed, STING was essential for synergistic IRF3 phosphorylation and optimal IFN-β induction by concurrent thapsigargin and LPS. These data suggest intracellular stress responses may utilize innate immune pathogen sensing pathways to augment IRF3-regulated cytokine and chemokine production. In contrast, other ER stress inducers activated IRF3 by a pathway inhibited by 4-(2-Aminoethyl)-Benzenesulfonyl Fluoride Hydrochloride (AEBSF), a serine protease inhibitor that prevents UPR-dependent processing of ATF6. Thus, at least 2 distinct pathways link ER stress to IRF3 activation.
The RAW264.7 macrophage cell line (ATCC) was maintained in DMEM/high glucose (Mediatech) with 10%FBS (Hyclone), and 1X antibiotic-antimycotic solution (Mediatech). Murine bone marrow macrophages were isolated from C57Bl/6 femurs with Histopaque 1083 (Sigma) and plated 3 days in non-tissue culture petri dishes in DMEM (as above) supplemented with 5% M-CSF-containing conditioned supernatant from CMG-14-12 cells(23, 32). Adherent cells were detached by 10mM EDTA and re-plated in tissue culture dishes with CMG-14-12 supernatant 3 more days. IRF3-/- mice were previously described(13). WT and STING-/- MEF were maintained in DMEM supplemented with 10% FBS (not heat inactivated, Invitrogen), and 1X antibiotic-antimycotic solution(4). XBP1-/- MEFs were kindly provided by Laurie Glimcher (Harvard University, Boston, MA). For RNAi studies, RAW 264.7 cells were transiently transfected with STING or control RNAi (Dharmacon) using AMAXA (Lonza).
To induce ER stress, cells were treated with 10μg/mL tunicamycin (Tm), 20mM 2-deoxyglucose (2DG), 10μM A23187, or 1μM thapsigargin (Tg, all from Sigma). Oxygen–glucose deprivation (OGD): cells were washed 3 times with a glucose-free isotonic salt solution (OGD buffer pH 7.4: 20mM NaHCO3, 120mM NaCl, 5.36mM KCl, 0.33 Na2HPO4mM, 0.44mM KH2PO4, 1.27mM CaCl2, and 0.81mM MgSO4), then incubated in OGD buffer in hypoxic condition containing 94% N2, 5% CO2 and 1%O2(33). Following OGD, cells were provided with growth media with or without LPS and transferred to a standard 5% CO2 incubator. For LPS stimulations, RAW 264.7 macrophage cells were treated with 100ng/mL and primary bone marrow macrophages and MEFs treated with 10ng/mL 3h unless otherwise indicated. Cytokine and chemokine protein assessment: IFN-α and IFN-β ELISA kits were from PBL Interferon Source, and eBioscience (RANTES). TBK1/IKKε inhibition: cells were pre-treated with 2 μM MRT67307 (generous gift from Dr. Philip Cohen, University of Dundee, Scotland) (34). The serine protease inhibitor AEBSF (4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride) was from Sigma.
β-actin, mouse mAb, NF-κB rabbit polyclonal Ab, and USF2 rabbit polyclonal Ab were from Santa Cruz; HA-Tag mouse mAb, IRF3 rabbit mAb (detects 1 IRF3 band) and phospho-IRF3 (pS396) rabbit mAb from Cell Signaling; Phospho-IRF3 (pS386) rabbit mAb from Epitomics; IRF3 rabbit polyclonal (detects 2 IRF3 forms), STING rabbit polyclonal Ab, and ATF6 mAb from Prosci; TBK1 rabbit mAb from Abcam; normal rabbit IgG from Millipore. Secondary antibodies: goat anti-mouse-IgG-Alexa Fluor 594 and anti-rabbit IgG-Alexa Fluor 488 (Invitrogen).
Cells were plated on cover slips in 60 mm dishes with 24hr prior to treatment. For STING-TBK1 co-localization, MEFs were transiently transfected with MPYS-HA (generous gift from John Cambier, University of Colorado, Denver) using Fugene HD (Roche) 24h prior to stimulation(5). After treatment, cells were washed (3×5 min PBS), and then fixed in 4% paraformaldehyde 30 min at room temperature. Cells were then washed with PBS, Tris A buffer (0.1M pH 7.6 Tris, 0.1% Triton X-100) and Tris B buffer (0.1M pH 7.6 Tris, 0.1% Triton X-100, 0.2% bovine serum albumin) 3×5 min each, and incubated with 10% goat serum in Tris B buffer 1h. Primary antibodies were added in Tris B buffer and cells incubated at 4°C overnight. After washing the cells with Tris A 3×5 min, secondary fluorescence-conjugated antibody was added and samples incubated 1 h at room temperature. Cells were washed with PBS 3×5 min, and the coverslips mounted on slides with ProLong® Gold antifade reagent with DAPI nuclear stain (Invitrogen). For negative controls, the same concentration of primary mouse IgG (Sigma) or rabbit IgG (Sigma) was added. Images were acquired on Nikon Eclipse 50i fluorescence microscope. Bars in images are 50μM.
Cells were lysed with Trizol (Invitrogen) and processed according to manufacturer's instructions. Briefly, RNA was extracted with chloroform and precipitated with isopropanol. Total RNA was purified with and treated with DNase I (Invitrogen) prior to reverse transcription using random primers (Promega). Gene expression level in cDNA was quantitated by SYBR Green (Bio-Rad) fluorescence, using an I-cycler or My-IQ (Bio-Rad). Relative mRNA expression was normalized to 18S rRNA housekeeping gene. Primers were designed using Beacon design software (Premier Biosoft): 18S rRNA: Forward (F) GGA CAC GGA CAG GAT TGA CAG and Reverse (R) ATC GCT CCA CCA ACT AAG AAC G; IFN-β: F-ACT AGA GGA AAA GCA AGA GGA AAG -3' and R-CCA CCA TCC AGG CGT AGC; IFN-α4: F-CAC AAT GGC TAG GCT CTG and R-TGT TGG TTA TCC ACC TTC TC; IL-6: F-CTT CCA TCC AGT TGC CTT C and R-ATT TCC ACG ATT TCC CAG AG; IL1β: F-CTC GCA GCA GCA CAT CAA C and R-ACG GGA AAG ACACAG GTA GC; STING: F-TGC CGC CTC ATT GTC TAC and R-GCT GAT CCA TAC CAC TGA TG; BiP: F-AGG ATG CGG ACA TTG AAG AC and R-AGG TGA AGA TTC CAA TTA CAT TCG; spliced XBP1: F-GAG TCC GCA GCA GGT G and R-GTG TCA GAG TCC ATG GGA; ifit2: F-GAT TCT GTC TAC CAC CAT and R-CAA GCA TCA ATC CAA GTT ; RANTES: F-GAA TAC ATC AAC TAT TTG GAG AT and R-TAG AGC AAG CAA TGA CAG.
Cells were lysed with RIPA buffer containing protease and phosphatase inhibitor cocktails (Sigma) and whole cell lysates, or cytoplasmic and nuclear fractions (Nuclear extraction kit, Sigma) resolved by 10% SDS-PAGE. Samples were transferred to PVDF membrance (Amersham), immunoblotted with primary antibody, followed by horseradish peroxidase conjugated secondary antibody (Bio-Rad). Proteins were visualized by ECL (Amersham) and film exposure.
MEF lysates (150mM NaCl, 1% Triton X-100, 1mM EDTA, 50mM Tris pH7.5, DTT, Protease inhibitor cocktail) were incubated 1h with anti-STING at 4°C, and then 1%BSA/PBS suspended protein A/G agarose (Santa cruz). Samples were rotated at 4°C over night. Beads were washed 2X with PBS, added to loading buffer, and then samples were denatured and resolved by SDS-PAGE.
Statistical significance between different groups of data was determined by 2-tailed Student's T-test. In all figures, error bars represent standard errors of the mean from combined experiments or standard deviation within a representative experiment.
In previous studies, we determined that multiple pharmacologic inducers of the UPR, or an overexpressed misfolding MHC allele HLA-B27, greatly augment LPS-dependent IFN-β mRNA and protein production(22, 23). This robust synergy was observed in primary macrophages, macrophage cell lines, murine embryonic fibroblasts (MEFs), and LPS-receptor-transfected HEK293 cells(22, 23). However, it was unclear if more "physiologic" stress, such as the oxygen and nutrient deprivation that might occur with ischemia, would enhance IFN-β production. MEFs were subjected to oxygen and glucose deprivation (OGD) for various times, and then stimulated with LPS for 3 more hours (Figure 1A). OGD alone did not induce IFN-β mRNA; however OGD dramatically augmented LPS-induced IFN-β, with maximal enhancement of a log-fold occurring after 1h of OGD pretreatment. Thus in vitro "ischemia" augmented IFN-β mRNA levels to a similar degree as the pharmacologic UPR inducers. In vitro OGD has been shown to induce early UPR events within 15 minutes(35). We confirmed BiP induction and increase in spliced XBP1 mRNA during the culture time frame (Figure 1B). OGD also induced IFN-β and BiP in RAW 264.7 macrophages (data not shown).
In dissecting the mechanism behind UPR-TLR4 synergistic IFN-β production, we observed increased IRF3 recruitment to both the ifnb1 promoter and to a newly described enhancer in the context of ER stress(23). Although ER stress alone was not sufficient for recruitment of IRF3 to DNA, these findings raised the possibility that ER stress might contribute to the activation of IRF3. In unstimulated cells, IRF3 resides in the cytoplasm as monomers. Upon stimulation through pattern recognition receptors, serine-threonine kinases such as TBK1 and IKKe/IKKi phosphorylate IRF3 at multiple sites, resulting in dimerization of IRF3 and nuclear translocation(10). We tested whether OGD would affect IRF3 localization in MEFs in the absence of exogenous LPS (Figure 1C, D). After 1h of OGD, IRF3 resided in the cytoplasm. However, after 2h of re-oxygenation, IRF3 appeared predominantly nuclear, co-localizing with DAPI by immunofluorescence microscopy. Nuclear translocation was also evident as assessed by western blot (Figure 1D).
Oxygen-glucose deprivation induces various stress responses including the UPR(35, 36). To determine if pharmacologic UPR induction stimulates the nuclear translocation of IRF3, MEFs were treated with thapsigargin, a SERCA pump inhibitor frequently utilized to study the UPR in vitro.(37) By 2h of thapsigargin treatment, IRF3 levels increased in nuclear extracts as detected by western blot (Figure 2A). Differentially migrating forms of IRF3 have been reported in unstimulated cells (referred to as "Forms I and II") and stimulated cells (Forms III and IV); these forms may represent variably phosphorylated or alternatively spliced forms of IRF3 detected by polyclonal antibody preparations(31, 38, 39). Similar results were observed in RAW 264.7 cells (data not shown). The kinetics observed by immunofluorescence microscopy correlated well with these findings (Figure 2B). Previous studies had identified a critical role for the UPR regulated transcription factor XBP1 in synergistic IFN induction(22, 23, 25). To determine if XBP1 was required for IRF3 activation, nuclear translocation was examined in XBP1-/- MEFs (Figure 2C). Thapsigargin-induced nuclear translocation of IRF3 was intact, suggesting that the UPR activates IRF3 independently of the XBP1 pathway. Similar results were obtained with other ER stressors (data not shown).
Nuclear translocation of IRF3 theoretically implies preceding phosphorylation. To directly test if the UPR elicits IRF3 phosphorylation, MEFs were stimulated with multiple commonly utilized pharmacologic UPR inducers, including thapsigargin, tunicamycin (N-linked glycosylation inhibitor), 2-deoxyglucose (glucose deprivation simulator), and OGD, with LPS as a positive control (Figure 2C). Treatment times were based upon mechanism of action, time required to induce XBP1 splicing (data not shown), and required pre-treatment times for synergistic IFN-β induction(23). All UPR agents induced detectable IRF3 phosphorylation at S386, comparable with LPS treatment (Figure 2D). IRF3 phosphorylation was not detected in IRF3-/- primary macrophages, confirming immunofluorescence specificity (Figure 2E). Synergistic IRF3 phosphorylation with dual thapsigargin and LPS treatment was not evident by immunofluorescence (data not shown) in comparison to western blot (see below). The pattern of phospho-IRF3 localization differed between LPS and UPR inducers; LPS treatment resulted in qualitatively higher order clustering (dots arranged in small circular clusters, compare OGD vs. LPS).
Our previous studies examining UPR-TLR synergy had focused on IFN-β production(23). However, the activation of IRF3 by ER stress raised the possibility that ER stress might augment the production of other known IRF3-regulated genes. Martinon et al. reported log-fold synergistic induction of the IRF3 regulated gene ISG15 in tunicamycin+LPS stimulated cells(24). IFN-α4 transcription is an early type I IFN, whose expression is highly dependent upon IRF3(15, 40). In addition to increased IFN-β production, primary bone marrow-derived mouse macrophages treated concurrently with thapsigargin and LPS produced increased levels of IFN-α4 (Figure 3). Thus the effect of ER stress on IRF3 activation has consequences for other anti-viral and inflammatory mediators besides IFN-β. As previously described, synergistic IFN-β mRNA induction correlated well with protein production(23). IFN-α was produced at such low level; only thapsigargin+LPS stimulated cytokine was present above the limit of detection (data not shown). However, synergistic induction of IRF3 regulated genes was not universal: neither Ifit2/ISG54 nor RANTES (as noted by others) were significantly augmented by UPR induction(24).
To begin elucidating the mechanism of UPR-induced IRF3 phosphorylation, we sought to determine the relevant IRF3 kinase. TBK1 is an upstream serine/threonine kinase that serves as the final point of convergence for multiple innate immune sensing pathways culminating in the phosphorylation of IRF3(8, 9, 16). Within the past few years, STING has been identified as an ER resident transmembrane protein that plays a critical role in the induction of IRF3 and thus IFN-β by cytoplasmic nucleic acids(4). The direct nucleic acid-binding molecule(s) upstream of STING have not yet been well defined, but may include the helicase DDX41(41). Upon activation by nucleic acids, STING associates with, and phosphorylates IRF3 via TBK1(4, 6).
The ER resident location of STING raised the possibility that ER stress induced activation of IRF3 might proceed through this pathway. However, it was not clear if ER stress-induced IRF3 phosphorylation required TBK1 or STING, or induced TBK1-STING association. To determine the requirement for TBK1, MEFs were pre-treated with MRT67307, a TBK1/IKKε family kinase inhibitor, prior to thapsigargin stimulation(34). MRT67307 abrogated thapsigargin-dependent IRF3 phosphorylation (Figure 4A). To determine if ER stress induced association between TBK1 and STING, co-immunoprecipitation was performed. TBK1 and STING associated even before stimulation, and the association continues with thapsigargin treatment (Figure 4B). Similar results were obtained in primary macrophages (data not shown). However, by immunofluorescence microscopy, a striking ER stress-induced relocalization of STING and TBK1 was evident, with association into larger order clusters around the nucleus (Figure 4C). Together these data suggested that thapsigargin-induced IRF3 phosphorylation requires TBK1 and that thapsigargin mobilizes STING and TBK1. However, it was not clear if STING was required for thapsigargin-induced IRF3 phosphorylation via TBK1.
To determine if STING was specifically required for ER stress-induced IRF3 phosphorylation, STING-/- MEFs were stimulated with thapsigargin and assessed by immunofluorescence for IRF3 phosphorylation(4). Neither IRF3 phosphorylation nor nuclear translocation were evident in STING-/- MEFs (Figure 4D and IRF3 immunofluorescence not shown). By immunoblot, in wild type MEFs, p-IRF3 (S396) is detectable in LPS-stimulated nuclear lysates, although we did not detect thapsigargin-induced p-IRF3 nuclear phosphorylation. In the WT cells, thapsigargin and LPS co-treatment increased levels of p-IRF3 over that observed with LPS alone (Figure 4E). These results are consistent with those observed by Hu et al, where thapsigargin augmented poly I:C-dependent IIRF3 phosphorylation but did not appear to induce IRF3 on its own(25). However, in the STING-/- MEFs, no p-IRF3 was observed by immunoblot. The lack of p-IRF3 was not because of IRF3 deficiency or generally defective LPS signaling in the MEFs, as LPS-induced NF-κB nuclear translocation was intact in STING-/- MEFs. Together these results support the idea that thapsigargin utilizes STING and downstream TBK1 to phosphorylate IRF3, and that synergistic p-IRF3 induction by LPS and thapsigargin requires STING.
STING appeared to be required for phosphorylation of IRF3 during ER stress and synergistically induced p-IRF3 during thapsigargin and LPS stimulation. However the consequences for an IRF3 regulated gene, such as IFN-β, were not clear. Thus, synergistic IFN-β induction was evaluated in RNAi transfected RAW 264.7 macrophages and STING-/- bone marrow- derived macrophages. Even moderate knockdown of STING with RNAi (Figures 5A and 5B) decreased IFN-β induction by combined thapsigargin and LPS stimulation. There was no significant effect of STING knockdown on LPS-induced IFN-β alone or the induction of two IRF3-independent cytokines, IL-1β and IL-6, by any of the stimuli. The effect of STING deficiency was more evident in the primary STING-/- bone marrow macrophages in comparison with the RNAi knockdown (Figure 5C). Again, IL-6 induction was intact. Synergy was not completely abrogated in the STING-/- macrophages or in STING-/- MEFs (data not shown). However, the magnitude of synergistic IFN-β expression was decreased by about a log-fold in primary macrophages.
Although all of the frequently utilized pharmacologic ER stress-inducing agents activate the three primary signaling pathways encompassed by the UPR and have final common endpoints, their mechanisms of action vary. Ultimately, the quality and magnitude of all the various UPR stress pathways induced by these agents are likely to differ as well. To determine if the dependence on STING was a general property of UPR induction, STING+/+ and -/- MEFs were stimulated with tunicamycin, an agent that induces the UPR independently of calcium (Figure 6A). There were no evident differences in tunicamycin-induced IRF3 phosphorylation in the presence or absence of STING. Likewise, 2-deoxyglucose-induced IRF3 phosphorylation occurred in the absence of STING. Consistent with these findings, tunicamycin-induced IRF3 phosphorylation also did not require TBK1 family kinases, since MRT67307 did not prevent tunicamycin induced IRF3 phosphorylation (Figure 6A). Thus, although thapsigargin and tunicamycin treatment may lead to similar common endpoints, the ER stress responses are qualitatively different. These data suggest that different UPR inducers activate IRF3 through a variety of signaling pathways.
One profound difference between thapsigargin and tunicamycin is that thapsigargin induces the UPR by inhibiting the SERCA pump, severely depleting ER calcium stores(37). Thus it was possible that mobilization of STING reflected altered calcium metabolism and not the UPR at all. To test this hypothesis, cells were stimulated with ionomycin, a calcium ionophore that mobilizes calcium by influx, but does not trigger the UPR at 1μM (data not shown and (42, 43)). Even at higher doses, ionomycin is much less effective at upregulating the UPR gene BiP as compared to another ionophore A23187(44). In contrast to thapsigargin, ionomycin did not induce significant IRF3 phosphorylation (Figure 6B). However, A23187, an agent widely utilized to induce the UPR, did induce IRF3 phosphorylation(45). These results indicate that collapsing the calcium gradient is not sufficient for IRF3 phosphorylation, and that some component of the ER stress response, or ER calcium depletion, is required as well. Furthermore, A23187 also required STING for IRF3 phosphorylation. Thus thapsigargin is not the only UPR inducer dependent upon STING for IRF3 activation. It was not clear if the STING-TBK1 pathway would be involved in a more "physiologic" setting. During ischemia-reperfusion injury, ATP depletion disrupts sequestration of calcium in the ER, resulting in excess cytosolic calcium, mitochondrial calcium uptake, and ER dysfunction(46, 47). Intracellular disruptions in calcium handling are reproduced by in vitro OGD(48). As seen in Figure 6C, OGD-dependent nuclear IRF3 translocation was impaired in STING-/- cells. Together these data suggest that ER stressors that dysregulate calcium metabolism phosphorylate IRF3 through the STING-TBK1 pathway.
We sought to determine which of the 3 major UPR pathways, stemming from IRE1/XBP1, PERK and ATF6 might be playing a role in IRF3 activation in response to ER stressors. As mentioned above (Figure 2), XBP1 is not absolutely required for nuclear translocation. PERK was not obligatory for synergistic IFN-β mRNA induction by either thapsigargin or tunicamycin(22). In response to ER stress, ATF6 transits to the Golgi, where it is cleaved to an active transcription factor by site 1 and site 2 specific proteases. AEBSF, a serine protease inhibitor has been shown to block this processing event by inhibiting the site 1 protease(49). We confirmed this activity (Figure 7). AEBSF prevented tunicamycin and 2-deoxyglucose, but not thapsigargin-dependent IRF3 phosphorylation, as visualized by immunofluorescence (Figure 7A). By western blot, the presence of AEBSF prevented synergistic p-IRF3 in dually treated LPS+Tm, reducing p-IRF3 to the level of LPS alone (Figure 7B); however AEBSF did not prevent LPS+Tg enhanced p-IRF3. Consistent with these results, AEBSF significantly diminished tunicamycin, but not thapsigargin dependent IFN-β mRNA synergy (Figure 7C). The lack of effect on thapsigargin-induced synergy argues against non-specific toxicity. Together these results indicate that AEBSF sensitivity distinguishes between IRF3 activation by thapsigargin and tunicamycin/2-deoxyglucose and is consistent with a possible role for ATF6 in the latter. Furthermore ER stressors activate IRF3, leading to synergistic IFN-β mRNA induction, by at least 2 distinguishable pathways.
This study describes the novel observation that ER stress, even in absence of pattern recognition receptor stimulation, activates IRF3. Different forms of ER stress accomplish this through at least 2 distinct pathways, requiring either TBK1/STING or AEBSF-sensitive signaling. The synergistic induction of several IRF3-regulated inflammatory mediators by concurrent UPR and LPS stimulation suggest the activation of IRF3 by ER stress may have a wider impact in innate immunity, beyond augmenting IFN-β production. Even though ER stress alone is not sufficient to trigger the induction of an IRF3-regulated gene, activation of IRF3 by ER stress is necessary for the dramatic IFN-β synergism observed with LPS. In evidence of this requirement, interfering with thapsigargin-dependent IRF3 phosphorylation through the modulation of STING severely impacts the magnitude of thapsigargin-induced synergy. Similarly, disrupting tunicamycin-dependent IRF3 phopshorylation with AEBSF significantly diminished synergistic IFN-β expression. Residual IFN-β induction in the LPS+Tg treated STING-/- MEFs may relate to IRF3 phosphorylation below our limits of detection, or compensation by another IRF3 serine (e.g. Ser 339) for which we did not assay(50).
This study supports the novel concept that intracellular stress responses may coopt innate immune signaling pathways previously thought to be dedicated to pathogen sensing. The proximity of STING to the mitochondria-associated membrane (MAMs) a site of inter-organelle calcium transport and regulation may suggest why UPR inducers that affect calcium also mobilize STING(4, 51). Our findings suggest that at least in MEFs and macrophages, STING and TBK1 associate even prior to stimulation. Upon ER stress induction, STING and TBK1 dramatically reorganize into larger macroscopic collections. This mobilization may be a result of reorganization of the ER membranes themselves (containing STING), translocation to another organelle (e.g. Golgi), or association with other unidentified molecules in a multi-molecular complex. The augmentation of type I IFN responses by ER stress/calcium dysregulation and STING may be of particular relevance to viral infections, such as Hepatitis C, that induce ER stress and cause calcium leak(52). Our results obtained with in vitro OGD (Figure 6) have direct implications for in vivo ischemia-reperfusion injury: they suggest the dysregulation of calcium, ER stress and type I IFN-dependent inflammatory injury may be critically interrelated (20, 53-57).
The UPR has been shown to activate both NF-κB and AP-1 family member transcription factors(58). Thus it is unclear why UPR-induced IRF3 phosphorylation is not sufficient to induce IFN-β expression in vitro. Even though the UPR induces nuclear translocation of IRF3, translocation does not automatically confer transcriptional activity: Dissociation between translocation and transcriptional activity has been noted in multiple models of viral IRF3 inhibition (59-62). IRF3 has 2 activation clusters comprising 7 potentially phosphorylated serines and threonines (S385, S386, and S396, S398, S402, S405, T404). Some controversy remains regarding serine phosphorylation requirements for IRF3 activity: Phosphorylation of S396 has been proposed as an essential minimal acceptor site for responses to Sendai virus, and may be critical for homodimerization (50, 63). More recently S396 has been shown to promote higher order oligomerization(64). However, others have identified S386 as the critical site for homodimerization and nuclear translocation(65, 66). Unfortunately, it is not yet clear exactly which sites on IRF3 correspond with optimal transcriptional activity in response to LPS and other specific pathogens. Ultimately, both may act cooperatively to bind CBP/p300 with higher affinity (64). Thus one possibility is that even though ER stress induces S386 phosphorylation, ER stress in isolation does not induce strong enough phosphorylation at S396, as suggested by western blot (e.g. Figure 4E); the UPR may only induce partial phosphorylation of IRF3 and LPS remains necessary for additional phosphorylation at other serines/threonines. Alternatively, as suggested by our western blot data, UPR induced phosphorylation at S386 may facilitate or enhance LPS dependent S396 phosphorylation. The requirement for multiple-site IRF3 phosphorylation to promote oligomerization may explain the qualitative differences in immunofluorescence between LPS and ER stressors such as OGD (Figure 2)(64). Our data would suggest that ultimate phosphorylation at S396 correlates best with IRF3 DNA binding by chromatin immunoprecipitation and transcriptional activation of IFN-β(23).
Apart from suboptimal IRF3 activation, there are other possible explanations: IRF3 alone is not sufficient for IFN gene transcription; the enhanceosome also contains NF-kB and AP-1 transcription factors. Transcriptional activation following enhanceosome formation requires binding of multiple elements including critical scaffolding molecules (HMGA1) and histone acetyltransferases (e.g. CBP/p300)(11). LPS stimulation may be required to recruit these other molecules. Another possibility is that a stronger NF-κB signal may be required than that generated during ER stress alone. Finally, there could be a cell type issue, since our studies are conducted in macrophages and MEFs. When mice are treated in vivo with tunicamycin alone, we observed detectable serum IFN-β (preliminary data not shown), suggesting that an unidentified cell type is capable of producing IFN during a UPR.
In this study and others, ER stress has been noted to augment transcription of select IRF3-regulated genes (e.g. IFN-β but not RANTES)(24). IRF3 binds similar DNA sequences within gene promoters designated as interferon stimulated response elements (ISRE) or positive regulatory domains (PRD I and III in the IFN-β promoter)(67). The selectivity in synergism may relate to promoter complexity and requirement for multiple transcription factors, as mentioned above. Constitutively activated IRF3 (an aspartate containing phosphomimetic) is sufficient to activate only a small subset of ISRE containing genes, including ifit2/ISG54, ISG56, ISG60, CIG5 and PMA inducible protein 1(68). However, we did not detected robust activation of ISG54 by thapsigargin alone. This failure may reflect suboptimal IRF3 activation at specific serines. Alternatively, given the independence of XBP1 and IRF3 translocation (Figure 2), and the discovery of XBP1 binding sites in cytokine promoters and enhancers, significant synergy might require DNA binding sites for both IRF3 and UPR-dependent transcription factors(22-24). The experience with IFN-β would favor this "multi-hit" hypothesis.
It is not clear which aspects of the UPR are necessary for IRF3 phosphorylation and nuclear translocation. The answer may differ depending upon type of ER stress. Our studies would suggest that XBP1 is not required for ER stress-induced IRF3 nuclear translocation. PERK is not necessary for synergistic IFN induction ((22) and data not shown). AEBSF, a protease inhibitor that prevents ATF6 processing, blocked tunicamycin but not thapsigargin-dependent IRF3 phosphorylation and synergy (Figure 7)(22). Thapsigargin may utilize an IRE1 kinase mediated pathway to activate IRF3. Alternatively, thapsigargin and A23187 could mobilize a non-classical UPR ER stress pathway related to calcium flux that has not been described. Another possibility is that IRF3 activation resulting from profound ER calcium depletion, and the UPR are independent outcomes of treatment with these stressors.
Our results are consistent with the hypothesis that tunicamycin and 2-deoxyglucose-induced IRF3 phosphorylation proceed through ATF6 or a related protein. ATF6 belongs to the OASIS family of transcription factors that is processed by the site 1 proteases. However, protein distribution of these other family members is much more restricted than ATF6(69). AEBSF also inhibits reactive oxygen species generation (ROS) by NADPH(70). Thapsigargin, tunicamycin and ER stress related to cholesterol loading have all been found to induce oxidative stress via NADPH(71-73). ROS potentiate IRF3 activation(74). However, NADPH oxidase inhibition by AEBSF would not explain the divergent effects on thapsigargin and tunimcamycin, particularly given the involvement of calcium in ER stress mediated NADPH oxidase activation(71). The specific AEBSF sensitive signaling event remains to be confirmed.
Another outstanding question is the identity of the kinase activated by non-thapsigargin UPR inducers that is responsible for phosphorylating IRF3. In this study, tunicamycin led to IRF3 phosphorylation in the presence of a TBK1/IKKε inhibitor. The kinase cascade involving NIK and IKK-α has been reported to phosphorylate IRF3 independently of TBK1(75). The MAP-kinase cascade initiated by IRE-1 that includes p38 may also play a role(76, 77). Dissecting the exact mechanism of IRF3 activation by all ER stressors, at the level of the UPR and subsequent kinase cascades, is outside the scope of this study but will be interesting to tease apart in the future.
Ultimately, our findings raise the possibility that different forms of ER stress/UPR inducers may utilize innate immune sensing pathways including STING. Thus, ER stress is poised to significantly augment type I IFN and innate immune responses in the setting of pathogen challenge, or endogenous damage. These findings have implications for conditions involving type I IFN and ER stress such as viral infections, certain bacterial infections, ischemia-reperfusion injury, and potentially rheumatic inflammatory disease. The recruitment of innate immune sensing molecules such as STING represents a newly described interface between intracellular stress and innate immunity.
Grant support: K08 AI081045
Other funding: University of Wisconsin-Madison Graduate School, School of Medicine and Public Health, and Department of Pediatrics.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's Canada Institute for Scientific and Technical Information in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Is it possible to be infected with herpes from using another person's razor?READ MORE
Using someone else's razor is such a temptation, but it is a bad idea on a couple of levels. In this age of MRSA and antibiotic-resistant bacteria, it would be easy to nick your skin and get a serious skin infection that could then turn into a life-threatening infection. From a herpes perspective, I suppose there is a very very low risk of herpes transmission, though I have never seen a documented case. But using any implement that has the possibility of being contaminated with someone's blood or bodily secretions is probably not a good idea.
Here are some articles you might find useful from our site:
10 Ways to Prevent Herpes Outbreaks
Telling Your Partner, Gender and Acceptance
Herpes, Scene 1: Knowing the Risk and Consenting to It
Im a one man person I dont share my partner even when i was married I had one partner, so in 2007 I was infected with herpes and my boyfriend at the time said he doesnt know HOW I got it and he was clean. I asked for him to be tested, got tested never saw the paper work. HE said if he had it he would of passed it on to his daughter. So now I have to live with this infection. Now the question is how did i get infected: what are other ways besides sex, open/ cut skin, stress.READ MORE
right before in was infected my ex used his shaver to shave me, we dont know how I was infected with herpes. HE thinks that my deceased husband gave it to me. My ex and I were together almost two yrs when i was infected and he was my only partner.Its hard to have a sexual relationship due to the spread of herpes to another or leaving due to the infection. It has effected my life.READ MORE
Actually, it is almost impossible to get herpes from using other peoples razors. The point is that herpes virus is very fragile and does not live on surfaces for a long time. So, this type of herpes transmission is from the myths list staying along with toilet seats, cigaretts, glasses, and so on. Read more about std myths here http://stidatingclub.com/READ MORE
Impossible is too strong a word. Considering i know for a fact i contracted the virus via razor or towel; it is just an extreme rarity.
HSV-2 is a fragile microorganism, but under the right circumstances can still survive on inanimate objects for a limited amount of time- which is perhaps just long enough for someone else to enter the environment.
Yes, because it comes in contact with your blood if you cut yourself.READ MORE
thats a tough one, because herpes cant live outside the body for too long, like a couple seconds. but to be on the safe side, i wouldbt share, cause you never know.READ MORE


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Romney-Ryan Debate - Reno, NV
Discuss the national Romney-Ryan debate in Reno, NV.
Are you happy that Romney picked Paul Ryan as his VP?
Reno undecided
|Don't care
1 - 9 of 9 Comments Last updated -
#1 Aug 15, 2012
Tired of Obama, we really need a change!
#2 Aug 15, 2012
Mitt Romney is a sell out! Gary Johnson 2012!
#6 Oct 18, 2012
Obama had 4 years to change the country for the better.
Seriously, can anyone name one good thing this guy's done for America?
I need not explain how he and his corrupt guttertrash Chicago mafia handlers have made everything worse. Simply look around with your own lying eyes for proof.
We need real jobs, not McWalmart jobs.
We also don't need the Obama Administration continuing on it's current path to oblivion without having to worry about re-election. This would be dangerous to our constitution's survival and our pocketbooks.
Romney is owned by the same international bankers as Obama destroying America from overseas.
However by hittig the reset button on the corrupt, power crazed, Obama administration it gives more Americans time to wake up to what is presently happening to America.
Obama may be likeable but he is incompetent.
In some aspects Obama is right when he says ((("you didn't build/create that, government did.")))
Let's look at what this administration has created in 4 short years and imagine what he can do with 8:
- Socialist eugenics based health care (((Obamacare)))
-NDAA (((National Defense Authorization Act))) where Americans can now be disappeared without a jury
- Out of control (((Crony Capitalism))) where government picks winners and losers based on payouts -not the free market eg. Solyndra, GM, MF Global, Numerous Bank Bailouts, No Prosecution of criminal Banksters
-(((Fast and Furious))) and other suspected domestic false flags to argue for abolishing the 2nd ammendmant
- Massive (((TSA expansion))) onto America's streets and armed (((survellance drones/now blimps))) operating over US territory.
-(((UN control of U.S. military troops to invade))) Egypt, Syria, parts of Africa, etc. for offshore bankers aka Nazism
-(((Trickle Down Government))) The idea that nothing can be built without (((more government bureaucrats and global warming regulations/taxes))) getting in the way
-(((Throwing Israel -an important ally- under the bus))) by destabalizing all the county's around it but not offering them any assurances of protection
- A (((continuation of Bush's failed policies))), like not getting out of Iraq, Afghanastan, and no closing of Guantanamo torture camps
-(((Polaraized race relations))) eg. Disrespectful hadling of the Treyvon Martin family after his murder -opportunistic my son would have looked like Treyvon soundbite- and media staged racial infighting between Americans setting up for social conflict right before the 2012 election
-(((No Proof Obama supposedly got Osama)))) America was never really allowed to see the body/proof ; -)
-(((Defunding of NASA))) No exploration of the stars for the U.S., leave that to countries that are exceptional
-(((No Plan/ or Budget to Fix Anything going forward if he is re-elected )))-always says what you want to hear, then does the exact opposite hoping you''ll forget by the next speech -(((Sociopathic Liar)))
-(((Obamaphone)))-Massive expansion of this program for his dependant voting base
-(((Unlimited QE3 leading to hyperinflation/ monopoly money))) Dollar is rapidly losing purchasing power resulting in skyrocketing food and GAS PRICES (especially for "green gas" in CA)
-(((Needed a tainted Creepy Crawley moderator to hold his hand during the second debate))) who helped him dodge hard questions he couldn't answer -a (((weak affirmative action President)))
- And of course my personal favorite (((legalizing the illegals))) temporarily until the election is over but not once addressing true immigration reform
- The list goes on.
Is this change you can believe in? Is this what you really want another 4 years of?
As Donald Trump would say: Obama you're fired:
Too bad Ron Paul chickened out. I'd still vote for him if he changed his mind however.
#7 Oct 20, 2012
Ron Paul was eliminated by fraud in the GOP party. He didn't "chicken out".
#9 Oct 31, 2012
Ryan has an accountant background and understands the pickle OBUMER has gotten us in and analiticly sees where we need to cut out spendthrift OBUMER'S wastful spending. What a breath of clean air hewill bring to the table!
#10 Nov 25, 2012
Gary Johnson is a sell out!:
#11 Nov 25, 2012
Mitt Romney stole the election from Ron Paul!
#12 Nov 27, 2012
Ron Paul's Revenge against Mitt Romney!
#13 Jan 31, 2013
Ron Paul!
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Photographer Terry Richardson shares backstage photos of Lady Gaga at the Rolling Stones concert in New Jersey on Dec. 15.
It seems like every single one of Taylor Swift's best friends seriously can't get enough of her.
I once spent my Friday night stalking Chrissy Teigen's mom.
You know it's a going to be a good week when Chrissy Teigen is getting naked on a Monday.


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text: Had a great night staying with the Kondari Resort in Hervey Bay. Great location, great service and great facilities. Loved the turtles! This is a great resort to bring the kids for the pool and the club and great for a drink by the pool on a lazy afternoon. Very comfortable beds.


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Columbia, South Carolina, United States · Member since February 2012
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I'm an International MBA student and former journalist. I thrive on rediscovering myself within new contexts of geography, food, cultures and music. I'm into classic literature, the beach, art museums, craft beer and good eats. My favorite travel destinations include Brazil, Morocco, Spain and India. My travel style is laid back but engaged. I enjoy meeting new people. I'm a fun but quiet guest who cleans up after herself and respects others' space and property. My life motto can be summed up as "Work hard, play hard."


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I sent them an email, work on other things, if we get everything
else working and haven't seen a patch we can work on fixing it then.
On Tue, Sep 07, 2004 at 11:38:12PM -0700, Tim Ringenbach wrote:
> Update of /cvsroot/gaim/gaim/src/protocols/novell
> In directory sc8-pr-cvs1.sourceforge.net:/tmp/cvs-serv15338
> Modified Files:
> novell.c
> Log Message:
> Are the novell guys going to fix this for us?
> I just #if 0'd some stuff out so it compiles.
> Index: novell.c
> ===================================================================


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Over the last few months we've been working hard and we're close to releasing our product to the community.
SN1P is a community for developers which allows you to store, organize and share your code in a simple way.
More Lukas Bugla
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Original recipe yields 5 servings
Amount per serving ({{servings}} total)
Based on a 2,000 calorie diet
Ready In
Really good. I didn't have any Vidalia onions, so just used a regular white onion. Still very good. I also added chopped garlic rather than garlic salt and added a little extra salt. I will ...
This is a really nice, easy-to-put-together recipe. I used fingerling potatoes instead of the red potatoes called for, and just pricked them instead of slicing. I also used a tablespoon of fresh...