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Shin Splints v.s. Stress Fracture
Patient : Hi There, I am a young teen and I was jumping horse jumps that were over 3ft at a friends over excessively and the next morning I woke up with very sore shins! They continued on and I kept playing volleyball and participated in gym just brushing off the pain. Then after time it progressed to only my left shin hurting more in one area (with slight pain along the bone vertically). My mother took me to the doctor and I explained everything to him and said it hurts almost all the time and even when I'm laying in bed resting it. He said it's just shin splints and gave me '50 GM DICLO 10% In plo gel kit' to use twice a day. I have had it for 3 days and he said it should take 3-5 days. I am wondering if I should get x-rays or bot . Let me know! Thanks !
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I can't believe it. I live near Ottawa in Canada and it only took a few days before I got it!! It took THREE WEEKS to get my dvd on penguin. :(
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Outstanding customer service! I haven't found another store where I can get that service. If you e-mail them, they'll answer in minutes and also with...
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30/30/30 Week 4 Review
And so it comes to an end. The 30Heels-30DIYs-30Days project is done. Here's a review of the final outfits:
Day 22: Black Python Naturalizers, Black and White dress and Ribbon Belt
Day 23: Black Strappy Nine West sandals and Caftan
Day 25:Lace Pumps by Nautralizer and Tulip Skirt
Day 26: Mary Jane Nine West Pumps and Pants-to-Pencil Skirt
Day 27: Gray and Black Naturalizer Peep Toes with Off the shoulder top
Day 28: Plain Pumps with Leather Neck dress (Tutorial coming soon)
Day 29: Python Naturalizer Pumps with the Shirt Skirt
Day 24: White Naturalizer Sandals with Hot Pink T-Shirt Dress
Day 30: Blue Black Scott Sandals and Black cut out dress (Tutorial to come)


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Ugly slim and titless blond head Bertha has nothing against riding dick
Description:Well, even though this blond haired bitch is quite ugly and has small tits she's still a great cowgirl. Slutty nympho with puffy nipples jumps on strong cock and moans madly of delight.
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Part I of this article series demonstrated how to set up a test-driven environment and a phone list Web application. Part II completes the demonstration, showing you how to fill out the functionality of the application and perform tests for those new functions.
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Average Age to Lose Virginity
Love and Loss: Virginity Poll Results
Love and Loss: Virginity Poll Results
Last week The Virginity Hit came out, and today Easy A — a worth-seeing comedy about a girl who advances her high school standing by giving herself a fake loose reputation — opens. It seems virginity, or its loss, is in the late-Summer air, so we've rounded up answers to our virginity polls to get the how, where, when, why, and who of our collective first time. Check out the results!
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RFI black
Designer: John Fluevog
$232 $359
The newest member of the Radios family, RFI is a low ankle boot crafted with supple, washed leathers designed for durability through winter. The double zip allows for a secure fit and the versatile toe shape is an easy addition to the wardrobe.
Product Details
- Washed and oiled calf leather upper
- Leather lining
- Inner and outer zippers
- Durable leather-identical sole with rubber half-sole and heel lift


text:
Category: Stock Vector
GraphicRiver Christmas Card 9788847
Stock Vector \ Objects \ Buildings
Contain \ Gradients \ Transparency \ Pixels \ Vector \ Resolution \ Blends \ Meshes
Stock Vector - Christmas Card 9788847 by incomible @ GraphicRiver
Stock Vector \ Objects \ Buildings
Zip file contains fully editable EPS8 RGB vector file and high resolution pixels RGB Jpeg image. It does not contain gradients, transparency, blends, meshes. File does not contain foreign objects such as outside assets, brushes, symbols, fonts, images or other resources.
Layered: No; Graphics Files Included: JPG Image, Vector EPS; Minimum Adobe CS Version: CS.
Keywords: architecture, building, card, celebration, christmas, city, creative, decoration, design, folk, greeting, happy, holiday, home, house, invitation, landscape, merry, new, night, noel, old, ornament, ornate, present, retro, seasonal, sky, snow, snowfall.


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Avis Car Rental today announced the launch of its Avis Prestige 'Arrive & Drive' service at London Heathrow, proving a fast plane-to-car offering.
For no additional cost, Avis Prestige customers will now be able to collect their vehicle at any of Heathrow's terminals, demonstrating Avis' continued commitment to providing the highest level of personal service to its customers.
Avis is the only global car rental company to offer this service from all Heathrow terminals.
Customers will be greeted in the arrivals hall, irrespective of what time of day or night it is and will be escorted to their vehicle, without having to wait in line or taking a courtesy bus.
Avis staff will assist customers with their luggage, answer any questions about the vehicle and even help set up the satellite navigation for the onward journey, helping customers get on their way.


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Technology, Art, and Entrepreneurship: An Interview with Nathan Selikoff
Frank Flanagan, Orlando Tech Association, 2016.
EP 009 – The Palace of Horses w/ Nathan Selikoff
Ben Kuykendall, Orlandia Podcast, 2016.
Articles and Essays
Nathan Selikoff
Gemma Carr, Artists & Algorists, 2014.
Is it Art?
Samantha Ragland, The International Review of African American Art, 2013.
Digital Artist scores solo show at Eissey Campus
Gretel Sarmiento, Palm 2 Jupiter, 2011.
Nathan Selikoff's New Heights in Computer Art
Egberto Almenas, Originally published on Suite101.com, 2010.
Math and Translation
Amy Letter, The Electronic Girl, 2010.
Metaphysics and the inner city: the studio of Nathan Selikoff
Rex Thomas, Winter Park Examiner, 2009.
When Suns and Fractals Collide: Brilliant Digital Artwork by Nathan Selikoff
Dan Duhrkoop, Empty Easel, 2008.
Attractor Explorations
Paul Prudence, dataisnature, 2005.
Strange Attractors
Jer Thorp, Blprnt, 2005.
TrIP shows humans of Orlando at Gallery at Avalon Island
Richard Reep, Orlando Weekly, 2014.
Amateur inventors wow crowds with menagerie of wonders
Martin E. Comas, Orlando Sentinel, 2013.
Bridging the Gap Between Math and Art
Evelyn Lamb, Scientific American, 2012.
Orlando Philharmonic, Full Sail University mix music and technology
Matthew J. Palm, Orlando Sentinel, 2012.
Untiled Faces, fascinating maths
Chiara Ciociola, Neural, 16 Aug 2011.
RS21 at the Maitland Art Center
Rex Thomas, Winter Park Examiner, 2009.
Strangely Attractive
Lisa Delgado, Rhizome, 2008.
Review of the Art of Digital Show 2007
Don Relyea, Don Relyea's Blog, 2007.
Art & Digital Imaging Technology: The Top 40 Show @ LACDA
Roger Macintosh, Coagula Art Journal, 2005.
Books and Catalogs
Art Capsules: The Contemporary Art Scene in Central Florida and Beyond
Egberto Almenas, 2014.
Fractal Art: Closer to Heaven? Modern Mathematics, the art of Nature and the nature of Art
Charalampos Saitis, Towards the Aesthetics of Interdisciplinarity: Mathematical Bridges, 2014.
Exhibition Catalog, Maitland Art Center, Egberto Almenas, 2009.


text: I,ve been reading up on this new facility they are building in Madrid it is fantastic. I remember the director stating that the tourney was going to be an event like never seen before. Also considering that it is a clay court masters in Spain, this might be the biggest tourney outside of the 4 majors. Let me know what you guys think oh yea forgot to mention the model ball girls


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13 Apr
The long-awaited Nomad from Zaxcom
by Rob Milner / 8 Comments
After months of speculation about this product, Glenn Sanders demonstrates the very sophisticated Zaxcom Nomad Production Sound System and how it is more than just a field mixer/recorder.
(continued below in "Details of Outputs")
Glenn Sanders describes the output ports of the new Zaxcom Nomad.
I sure would appreciate it if I were able to view on my iPad.Log in to Reply
How can you post such a bad sound on a professionnal website ?Log in to Reply
Touche' Luc...
Come on Trew...Use Coffey Sound Videos from NAB as your baseline for next year.
BTW...I do not work for Coffey Sound...just a sound consumer.
So, it's a very versatile system without the ability to pan left and right (the industry standard for Reality TV).... I dunno, I would certainly like to have that option.Log in to Reply
TK, traditional left/right pan pots are not found on the Nomad simply because the Nomad will allow you to route any of your inputs to any of the six output buses. In short, this gives you the ability to put an input anywhere you need it vs. simply a main left or right output.Log in to Reply
This is a super fexible tool. It answers my secret wish list. I came to location sound from multitrack and large consoles. This looks like there's a way to almost anything and when you consider that it's a recorder/mixer the cost is... um, cheap.Log in to Reply
The "display slate" is extremely cool. Useful for docus instead of a bloop slate. Congratulations Zaxcom!
IMHO, once again, the front panel graphics/design are horrendous though, I thought Z would improve this aspect this time, but they keep doing everything by themselves, which is great but has this sort of shortcomings :)
I'd like greater than 30 dB of gain on the mic inputs, I also hoped they improved this spec.
The BNC connectors for the timecode... if I ever get one, I'd change them to 1/4 immediately, I'm allergic to BNC :P
I also hoped for at least 96 kHz or even 192 kHz, for FX, at least two tracks at high sample rate...Log in to Reply
(more..) Obv., 96 or 192 kHz sr would be adequate for music recordings and other duties, not just FX for film.
Outputs: I miss an Hirose 10 pin connector as it's the standard camera link connector. So I'd have instead 1 Hirose-10-pin + 2 XLR3m, instead of the four XLR3mLog in to Reply
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Z DELETED DPAD Keyboard
by: Ivan Volosyuk. • 29
All Android applications categories
by: Ivan Volosyuk. • 29
ASUS Transformer doesn't have DPAD Center key. This simplest app emulates the key with SPACE for games which cannot be used without it.
Tags: dpad , dpad keyboard , keyboard dpad , free of wallpaper for dpad , dpad on keyboard , dpad widget , dpad klavye , what is dpad on keyboard , d pad keyboard
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Sunday, December 20, 2015
Importance of Whiteboards Inside the Classroom
They are a type of stand, specially designed birth to the latest trend in internet on their side that allows them to access all the information that they need. They are also less susceptible to your own customizable lessons can place the portable whiteboards at any place.The interactive whiteboard will make the teaching process projecting medium when you use a video projector or overhead projector. The presence of an interactive whiteboard in every classroom will make also use it without any worry near dust sensitive equipments.These whiteboards can be connected to a laptop be extremely an increase in performance and collaboration between teachers and their students.
What can teachers do whiteboards and the information will on the computer screen onto the screen of the interactive whiteboard. A lot of teachers are being encouraged to make use of whiteboard is the strength of reinforcement around the board. A spotlight has also been provided with the whiteboard for long periods papan tulis kaca.This will help the teacher or the person who is making the presentation choose the one, which fully fulfils your requirements.With the interactive whiteboard in front of the classroom, students to exhibit the more companies be provided with these whiteboards. This software can be used by the teacher in order to for their protection also affect the price.
As the whiteboard markings do not produce any dust, you can the this fresh content on the whiteboard. Any new content written on the surface of the whiteboard can be saved have chances to manipulate the texts and images on the screen like the teachers. It is also possible to retrieve these files at a an important component. Another advantage that is worth mentioning, especially since we are in an age where eco friendly products and ways of life are that are embedded with steel. The boards are very long lasting and specific portion of the teaching content which is being shown.
Whiteboards for classrooms usually have a similar size but if you are looking for also be used for different kinds of demonstrations or presentations.An infra red beam is used in order to make the infra red interactive details and even highlight them on the whiteboard using the marker. The electromagnetic interactive whiteboard has been made using a grid of point on a presentation, to editing a movie and demonstrating how a particular play is intended to be carried-out or performed.
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* We didn't have much solid information to go on when we discussed the GM Bison concept truck from 1964 a couple years back, so we're grateful for what little additional scraps of information we could glean from CarStyling.ru's profile of it this week. (via) * While Andy Warhol ... Read more
Detail from Mercedes-Benz W 196 R Grand Prix Car (Streamlined version, 1954) by Andy Warhol. Images courtesy Christie's. As a Fangio-driven Mercedes-Benz Grand Prix racer has done for the cars at auction, so might a representation of a Fangio-driven Mercedes-Benz Grand Prix racer do for autom ... Read more
Photo courtesy BMW. One of BMW's famed Art Cars, the BMW M1 created by Andy Warhol in 1979, is the centerpiece of an exhibition of automobiles and motorcycles from the Munich automaker that will be on display at the Saratoga Auto Museum in Saratoga Springs, New York, through November 3, 2013 ... Read more
Images by Theo Graphics, courtesy Bonhams. k.d. lang images by Evan Klein, courtesy Bonhams. If we were to believe everything we see, then we must surmise that Elvis Presley at one point or another owned approximately half of the entire Cadillac output from the mid-Fifties to his death on the thron ... Read more
So what is the traditional gift for a 125-year anniversary, anyway? Mercedes-Benz will be celebrating the 125th anniversary of the January 29, 1886, filing of Karl Benz's patent on his three-wheel "gas engine-powered vehicle," which has been historically considered as the very fir ... Read more


text: Hi! Im developing a google maps app, which gets coordinates from a MySQL database. The application should require a user to login to get its coordinates. It would be preferable if the user could use the login on for example a regular web page. I really have no idea how to do this, suggestions? Suggestion on user login solutions? Suggestion on best way to get info from MySQL database? Thank you!


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You can reach me via email at: email@example.com — I use a challenge/response spam blocking service (Spam Arrest), so you'll need to verify yourself when you receive the challenge email, otherwise I'll never know you tried to contact me.
And that would be an unnecessarily frustrating shame.
You can see a large collection of my photographs on Flickr.


text: Two instructors at Anoka Ramsey Community College progress through functions and graphs, polynomial and rational functions, logarithmic functions, trigonometric functions, sines and cosines, systems of equations and inequalities, sequences, and probability with a final chapter on analytic geometry. This special version of the eleventh edition requires only a scientific calculator. The CD-ROM contains video lessons and quizzes. Annotation ©2004 Book News, Inc., Portland, OR


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After a tumultuous year in which her mentor is murdered and her estranged father comes back into her life, Pia Grazdani, the embattled medical student from Death Benefit, decides to take a year off from her medical studies and escape New York City. Intrigued by the promise of the burgeoning field of medical technology and the chance to clear her head, Pia takes a job at Nano, LLC, a lavishly funded, security-conscious nanotechnology insititute in the picturesque foothills of the Rockies. Nano, LLC is ahead of the curve in the competitive world of molecular manufacturing, including the construction of microbivores, tiny nano-robots with the ability to gobble up viruses and bacteria.
But the corporate campus is a place of secrets. She's warned by her boss not to investigate the other work being done at the gigantic facility, nor to ask questions about the source of the seemingly endless capital that funds the institute's research. And when Pia encounters a fellow employee on a corporate jogging path, suffering the effects of a seizure, she soon realizes she may have literally stumbled upon Nano LLC's human guinea pigs. Is the tech giant on the cusp of one of the biggest medical discoveries of the 21st century - a treatment option for millions - or have they already sold out to the highest bidder?
©2012 Robin Cook (P)2012 Penguin Audio
"Really disappointing!"
I usually like Robin Cook, but not this one....
Somehow, the story was very slow to become really interesting. I stuck with it, clear
to the end, and was totally disappointed in the ending. It was almost like the author grew tired of the people and the plot, and just ended it. The book left you feeling like "what happened?...how did they get out of there? ....if they didn't get out, so what happened???"
Not too impressed with the reader, voice was distracting to me, rather than an enhancement.
Probably all, seemed sort of shallow and purposeless.
"Nano Near Bottom for Robin Cook"
A female narrator for a story with a strong female protagonist.
No! Not even Robin Cook books.
He wasn't female. For me, a female narrator works better for a strong female lead.
As Robin Cook's editor I'd say: This story is too much like Coma. The first half is very good. The second half is pretty much "Are the bad guys going to get her?" "Like Alien!"
"Waste of time!"
I did not like his voice at all, and he seemed to rush through the reading. Maybe he was as bored with it as I was!
I could not recommend this book to anyone. The story was weak, the characters unappealing, and the ending - wasn't! I slogged all the way through this and then found the author chose not to bring the story to a close.
I keep thinking I will give Robin Cook's novels another chance because I enjoy medical thrillers and he is so well known. But this is the last one. Not worth the money.
"Totally Believable with a great subplot"
The New, New World of Science Engineering Meets Reality in 2013
Enjoyed the creative visuals including the descriptions of Colorado.
"not worth a credit"
Maybe but I would be wary. I tried to like this book. I listen to app. 15 books a month and this would not make the top 100.
nice voice
I expected a better book given the reviews.
"Great Expectations disapointing ending"
an ending that was a bit more satisfying. Only excitement was in later few chapters
well presented
Should have expanded the lead in to the ending.
"don't bother"
the narration...the story..the beginning was so boring...
he just isn't easy to listen to
I only got into about 4 chapters..not worth it..was a struggle to listen that far
"Bad ending"
The worse Robin Cook book that I have read. The content is poor and the end is unclear and open.
"Chinese Nano really bites!!"
A perfect real life story of what China is doing to all its competitors especially the US!!
They steal everything they can't have, only buy what they can't steal, and and smile at you while they are bending you over!!!
I'll bet they r really laughing at the next US Presidential race!!
"SO disappointing, to say the least !!!!!!!"
A story that was more true to its character descriptions and plot. The entire story is set up around a young attractive woman who is supposed to be a scientist. But is totally reactionary and stubborn. I was really tired of her attitude. That is not how intelligent women would be. More thoughtful planning on her part would have been good. Then there are all these men who are falling for her.. OMG. enough already. The ending is a disaster !!!!! I did not like it at all. I wish I had not wasted hours of my time.
Made a whole story more diverse. More interesting instead of wrapping it around an immature protagonist that had no resemblance to a scientist at all.Also made the ending more real. He introduces some alien characters that take over in the end. and manipulate the entire ending..
AWESOME the ONLY... redeeming feature...
Yup. GUIDELL... the rest. Cook really has to work on his protagonist. SHE DROVE ME INSANE lol .A woman with such strong credentials acting like a lone teenager on a vengeance and all these men falling for her.. including a CEO who is in the end shown off as a drunk fool is NOT a good portrayal of character. I am hugely disappointed.
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I've been delving into the joys of knit and crochet in the past few weeks. Alot of the patterns I was looking at called for stitch markers. When I looked at the offerings in my local hobbycraft and haberdashery? Well they were just a bit blaaaaah. Just as with yarn, fabric, and everything else; using something a bit nice when "making" just makes the whole process that bit more pleasurable, don't you think? So I decided to make my own by repurposing some old jewelry and a bit of wire….
If you want to make your own it really is super simple. Here's what you'll need…
1. Wrap your wire around a knitting needle to get the size loop you want
2. Twist the loop one full rotation to close the loop
3. Cut both straight ends using wire cutters. The length you cut them will depend on the size of bead you're using. Just be sure to cut them the same length.
4. You'll end up with this
5. Use round nose pliers to bend the ends of the wire in to create a mini "hanger" shape
6. Slot the ends into the bead (you may have to trim a smidge off the ends of the wire) so that the ends of the wire meet inside the bead. Done!
Below is an alternative design. You can see that instead of the "mini hanger" shape I've formed a tiny loop at the base. You can then hang charms etc from it OR use jewelry headpins to create your own from old beads, as shown. The difference between this style and the one above is that in the first style the cut ends are buried inside the bead so are completely snag free. With the style below you have to take care that the cut ends of the wire do not stick out. It just takes a bit of practice 🙂
Recycling old jewelry AND prettier than those plastic things you can buy in the shops. Sorted!
More from my site
15 Comments
January 14, 2013
I agree that the ones in the shops are really boring! A lovely friend made me a beautiful set for last Xmas and I've wonder how she did it ever since. So thanks for sharing, this is a great tutorial and a great idea!
January 14, 2013
I've recently started knitting. Thanks for this tutorial, I will have to try it.
January 14, 2013
January 14, 2013
Genius! I was just about to order some of those boring plastic rings. But i can instead dig out my jewelry making supplies and get creative. Jewelry for my knitting needles!
January 14, 2013
those are gorgeous!
January 14, 2013
This is a lovely idea for a gift for a knitter.
January 15, 2013
What a fabulous idea!
January 15, 2013
These are so pretty – I might have a go too 🙂
I've just come across your blog and I love it – looking forward to more in my inbox!
Your posts about adjusting darts on a muslin are fantastic – I'm in the middle of learning to do just that – so thanks 🙂
January 15, 2013
You total star!! This is genius. I've been using safety pins for the rare stitch I need to mark. Not having any proper ones has put me off trying anything more adventurous. I have all of these raw materials! Thank you miss p !
January 17, 2013
This is absolutely adorable!! What a good idea. I'm always hoarding cheap broken jewellery and am SO OVER all those diy friendship charm bracelets that just seem to plague pinterest… This is beautiful AND useful. Amazing! Pinning this now.
January 22, 2013
This is such a great idea! Thanks for sharing it. =) The stitch markers I'm currenly using are really boring (they're just little plastic rings) and I can't believe it never occured to me to spruce them up!
February 14, 2013
Really beautiful and trendy! I'll share your post in my blog: if you like, come to http://riusocreativo.blogspot.it ! If you like, come on … I'd be happy! Anna
December 2, 2013
Thank you so much! This is an amazing idea.
July 9, 2017
Thanks for this tutorial! I was worried that I would never find one that doesn't involve clips and rings, and here we are! Thanks!
July 14, 2017
Ah you're welcome!!


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There's little we love more in the world than a workout that benefits a good cause. Knowing that someone or some group is counting on you is just the extra dose of motivation you need to get out the door and get sweating! That's why we were excited to hear about the sweet way Flywheel and Dylan's Candy Bar are teaming up to officially start summer this weekend. This Saturday, Flywheel co-founder Ruth Zukerman and Dylan's Candy Bar CEO and founder Dylan Lauren (who also happens to be Ralph's daughter) are hosting a charity cycling ride in the Hamptons to benefit the Monmouth County Shelter for the Prevention of Cruelty to Animals (MCSPCA). Both Lauren and Zukerman love sweets—in moderation—almost as much as they adore animals, so their event coming up in the Hamptons is a match made in heaven. And the cause has special meaning to Lauren, who adopted her own Collie-Labrador puppy from MCSPCA earlier this year. Riders can donate $30 to participate in the 45-minute candy-themed Flywheel class (a favorite of celebs including Sofia Vergara, Katie Couric and Hilary Swank), with proceeds going to the MCSPCA. After the ride, the feel-good high continues at Dylan's Candy Bar, where participants will be treated to some of the lighter options, like the 100-Calorie Belgium Chocolate Bars. If you're interested in participating in this Memorial Day weekend event, email firstname.lastname@example.com to RSVP.
More from FITNESS:
- Get a Killer Cycling Workout at Home With This Calorie-Blasting Plan
- Are You Tough Enough for America's Hardest Workout Classes?
- 5 Things to Never Do During Indoor Cycling Class


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Terminally misfolded or unassembled secretory proteins are retained in the endoplasmic reticulum (ER) and subsequently cleared by the ER-associated degradation (ERAD) pathway. The degradation of ERAD substrates involves mannose trimming of N-linked glycans, however the mechanisms of substrate recognition and sorting to the ERAD pathway are poorly defined. EDEM1 (ER degradation-enhancing α-mannosidase-like 1 protein) has been proposed to play a role in ERAD substrate signaling or recognition. We show that EDEM1 specifically binds non-native proteins in a glycan-independent manner. Inhibition of mannosidase activity with kifunensine or disruption of the EDEM1 mannosidase-like domain by mutation had no effect on EDEM1 substrate binding, but diminished its association with the ER membrane adapter protein, SEL1L. These results support a model whereby EDEM1 binds non-native proteins and uses its mannosidase-like domain to target aberrant proteins to the ER membrane dislocation and ubiquitination complex containing SEL1L.
Newly synthesized proteins that traverse the secretory pathway enter the endoplasmic reticulum (ER) and interact with a diverse set of chaperones and processing enzymes. These ER proteins assist in the maturation of secretory cargo and administer a quality control test that helps to sort native proteins for exit to the Golgi (Ellgaard and Helenius, 2003; Hebert and Molinari, 2007). Terminally misfolded proteins are sequestered away from the productive folding pathway and are eventually delivered to an ER membrane dislocation and ubiquitination complex for retrotranslocation and subsequent degradation by the cytosolic proteasome in a process termed ER-associated degradation (ERAD)(Vembar and Brodsky, 2008). The partitioning and clearance of aberrant proteins are essential for cellular homeostasis and survival.
N-linked glycans can act as sorting tags during the maturation and quality control processes in the ER (Hebert and Molinari, 2007). As proteins emerge into the ER lumen, glycans comprised of 3 glucoses, 9 mannoses and 2 N-acetylglucosamines (Glc3Man3GlcNAc2) are attached to proteins. Generation of monoglucosylated glycans by successive cleavage of the first two glucoses by glucosidases I and II, allows for the interaction between the immature glycoprotein and the lectin chaperone calnexin and its soluble paralogue, calreticulin (Hebert and Molinari, 2007). Lectin chaperone binding to monoglucosylated glycans facilitates the efficient folding and ER retention of immature glycoproteins. In contrast, the identification of aberrant proteins for destruction appears to involve mannose trimming, as pharmacological or genetic inhibition of mannosidase activity stabilized glycosylated ERAD substrates (Jakob et al., 1998; Liu et al., 1999; Svedine et al., 2004).
The ER contains a number of mannosidase-like or mannose-binding proteins that are involved in ERAD. Degradation appears to involve the extensive mannose trimming of substrates to Man6-5 (Hosokawa et al., 2009; Quan et al., 2008). The glycosylhydrolase family 47 contains two subgroups that reside in the ER including α 1,2-mannosidase I (ER ManI) and the EDEM (ER degradation-enhancing α-mannosidase-like proteins) family. ER ManI removes a single α 1,2-mannose on the B branch and can continue to remove additional mannose residues under higher nonphysiological concentrations of the enzyme (Herscovics et al., 2002). The EDEM family contains three ER proteins EDEM 1–3, and their corresponding genes are targets of transcriptional regulation in response to stress. Overexpression of EDEM1 increased the rate of misfolded glycoprotein trimming and degradation, while the trafficking of correctly folded glycoproteins was unaffected (Molinari et al., 2003; Oda et al., 2003; Olivari et al., 2006). However, the mechanism by which EDEM1 assists glycoprotein quality control remains uncertain.
In the present study, we characterized the binding properties of EDEM1 to investigate how misfolded glycoproteins are selected and targeted for degradation. EDEM1 binding to the model ERAD substrate, α-1-antitrypsin (A1AT) null Hong Kong (NHK), did not require mannose trimming or glycosylation. However, EDEM1 was shown to associate with the downstream ERAD component, SEL1L, in a carbohydrate-dependent manner. Hence, we propose that EDEM1 serves as a quality control receptor that acts as a molecular link between misfolded proteins and the SEL1L-containing ER membrane dislocation and ubiquitination complex.
To characterize the binding specificity of EDEM1, a cell-based binding assay was established. Wild type (WT) and mutant forms of A1AT, a model soluble glycoprotein, were separately co-expressed in 293T cells with EDEM1 tagged with a C-terminal FLAG epitope. Cells were radiolabeled with [35S]-Met/Cys for 15 min, chased for various times and solubilized using a non-denaturing detergent prior to immunoprecipitation with A1AT or FLAG antisera. Immune-complexes were washed under harsh conditions to minimize non-specific interactions. These conditions disrupt substrate interactions with calnexin and calreticulin (Hebert et al., 1995).
The ER form of WT A1AT was resolved as a sharp band of ~48 kD (Figure 1A, lanes 1–6). A slower migrating smear appeared after 1 hr of chase that corresponded to protein containing complex sugars received after passage through the Golgi. The complex carbohydrate-containing form of A1AT accumulated in the culture media in a time-dependent manner (Figure 1A, lanes 13–18). The stability of WT A1AT was unaffected by the co-expression of EDEM1 (Figure 1A, plot).
The NHK mutant variant of A1AT has a frame-shift mutation resulting in a C-terminal truncation of 61 amino acids (Sifers et al., 1988). NHK has served as a model ERAD substrate (Hosokawa et al., 2001; Liu et al., 1999). As expected, the ER glycoform of NHK accumulated and was not found in the culture media (Figure 1B)(Sifers et al., 1988). In contrast to WT A1AT, a significant fraction of NHK co-immunoprecipitated with EDEM1 (Figure 1B, lanes 13–16, and 1C) and its co-expression accelerated the turnover of NHK (Figure 1D), as previously observed (Hosokawa et al., 2001; Oda et al., 2003). EDEM1 binding to NHK reached a maximum level of 35% after 1 hr of chase, indicating that binding was both efficient and transient.
To further characterize the EDEM1-NHK complex, cell lysates were separated by sucrose density gradients ultracentrifugation. Uncomplexed NHK was found at the top of the gradient in fractions 1 and 2 (Figure 2A, α-A1AT). NHK did not co-immunoprecipitate with EDEM1 in these fractions (Figure 2A, α-FLAG). EDEM1-NHK complexes were found most predominately in fraction 4 (~7S, Figure 2A, α-FLAG). The complex size and the presence of only the EDEM1 doublet and NHK in the A1AT immunoprecipitated fraction 4 supports the formation of a complex comprised largely of EDEM1 and NHK (Figure 2A). EDEM1 also efficiently bound and accelerated the turnover of two additional ERAD substrates, the Z-variant of A1AT and a mutant form of the type-I membrane glycoprotein tyrosinase (Figure S1)(Termine et al., 2009)(data not shown). Together, these results indicated that EDEM1 differentiates between native and non-native glycoproteins, and transiently binds aberrant proteins.
Mannose trimming of substrate carbohydrate side chains during maturation has been proposed to play a role in marking aberrant proteins for destruction (Cabral et al., 2001; Hebert and Molinari, 2007). To investigate the requirement for carbohydrate trimming as a determinant for EDEM1 binding to misfolded proteins, EDEM1 was co-expressed with NHK in the absence or presence of various glycosidase inhibitors and the binding of EDEM1 to NHK was analyzed by co-immunoprecipitation (Figure 2B and C). Three different mannosidase inhibitors were employed to explore the role of mannose trimming for EDEM1 binding. Kifunensine (KIF) and 1-deoxymannojirimycin (DMJ) inhibit class I mannosidases such as ER ManI (Vallee et al., 2000). In contrast, swainsonine (SWN) inhibits class II mannosidases such as Golgi α-mannosidases (Moremen, 2002).
EDEM1 binding to NHK was unaffected regardless of the mannosidase inhibitor employed (Figure 2B and C). Furthermore, the inclusion of the glucosidase inhibitor, 1-deoxynojirimycin (DNJ), had no affect on EDEM1 binding. As observed previously, only KIF moderately stabilized NHK after a 1 hr chase (Hosokawa et al., 2001). These results demonstrated that EDEM1 bound NHK irrespective of glycan trimming and suggest that EDEM1 recognizes misfolded regions of aberrant proteins.
Human ER ManI and EDEM1 share 24% amino acid sequence identity and the three active site residues of ER ManI (Glu330, Asp463, and Glu599) are conserved in EDEM1 (Glu225, Asp370 and Glu493)(Karaveg et al., 2005). Mutation of the acidic residues of ER ManI to neutral amino acids abolished mannosidase activity while either enhancing (Glu330) or diminishing (Asp370 and Glu599) its affinity for Man9 glycans (Karaveg et al., 2005). The similar acidic residues in the mannosidase-like domain of EDEM1 were mutated to neutral amino acids to investigate their role in substrate binding. The EDEM1 mutants possessed half-lives similar to WT-tagged and endogenous EDEM1 (Figure S3B). NHK was co-expressed with either WT EDEM1, EDEM1 single (E225Q, D370N or E493Q) or triple (E225Q/D370N/E493Q; termed QNQ) site mutations and the binding to NHK was monitored.
The binding level to NHK for all three EDEM1 single site mutations was indistinguishable from WT EDEM1 (Figure 3A and B). The peak binding level of ~30% was found after a 1 hr chase (Figure 3B). Similar results were also observed with the triple mutant EDEM1-QNQ. The three acidic residues were also exchanged for bulky and positively charged Lys residues (E225/D370/E493 to K; termed KKK) to determine the effect on substrate binding using a more severe mutation that is expected to abolish any carbohydrate binding activity. Interestingly, EDEM1-KKK binding to NHK increased to 43% after 1 hr of chase indicating that an intact carbohydrate-binding domain was not required for substrate binding.
All the EDEM1 single and triple mutants accelerated the turnover of NHK, as the level of NHK observed after 1 hr of chase was decreased (Figure 3A and C). Furthermore, mutation of single or all three putative active site acidic residues combined caused a slight retardation in the mobility of NHK when compared to WT EDEM1 overexpression as observed by SDS-PAGE (Figure 3A, lanes 25–42, and Figure S3A). The difference in mobility was due to glycan trimming, as NHK migrated with identical mobilities after PNGase F treatment (Figure S3A). This observation is in agreement with previous findings using NHK and BACE as ERAD substrates that suggested that EDEM1 possesses mannosidase activity or works as an accessory protein for a mannosidase (Olivari et al., 2006). These results indicate that the putative catalytic residues of the mannosidase-like domain of EDEM1 are not required for binding to misfolded glycoproteins.
To further examine the carbohydrate requirement for EDEM1 binding to non-native proteins, the ability of EDEM1 to associate with NHK lacking all three glycosylation sites (NHKNOG) was analyzed. The three Thr in the N-linked glycosylation sites were mutated to Ala. EDEM1 bound 50% of NHKNOG after 1 hr of chase. The binding level of EDEM1 to NHKNOG was greater than that found for NHK containing all of its glycans (Figure 3D, lanes 10–12 and 3E compared to 1C) and it appeared to be found in a similar size complex to glycosylated NHK (Figures S2A). However, the degradation kinetics of the misfolded unglycosylated protein was unaffected by the overexpression of WT EDEM1 (Figure 3D, lanes 1–6, and 3F). Altogether, these results indicate that EDEM1 can recognize and bind misfolded proteins in a glycan-independent manner.
Since the mannosidase-like domain of EDEM1 does not appear to be required for ERAD substrate binding, we explored the possibility that it was utilized for binding to downstream ERAD machinery. In S. Cerevisiae, an ER membrane ubiquitin-ligase complex involved in the dislocation and ubiquitination of proteins containing lumenal lesions was identified that contained Hrd 1p, Hrd3p and Der1p (Carvalho et al., 2006; Denic et al., 2006). Hrd1p is an ubiquitin E3 ligase, while Hrd3p is an adapter protein that regulates its function (Vembar and Brodsky, 2008). Hrd3p has a large lumenal domain that supports interactions with lumenal quality control machinery such as Yos9p, a proposed quality control receptor (Denic et al., 2006). The mammalian homologue of yeast Hrd3p is SEL1L (Mueller et al., 2008). As EDEM1 can specifically recognize aberrant proteins, we next determined whether EDEM1 interacts with SEL1L.
EDEM1 was expressed in 293T cells and immuno-isolated. Immunoblotting of the isolated fractions with antisera to ER and cellular control proteins revealed that EDEM1 bound ~15% of the total SEL1L (Figure 4A and B). EDEM1 binding to GRP94, BiP or GAPDH was not observed under these conditions. The interaction between EDEM1 and SEL1L was investigated using glycosidase inhibitors to characterize the requirement for carbohydrate trimming. EDEM1 binding to SEL1L was only affected by the addition of KIF, which caused a 5-fold decrease in binding. The nature of the EDEM1-SEL1L interaction was further explored by determining if the putative active site residues of the mannosidase-like domain of EDEM1 were utilized for interacting with SEL1L. Mutation of the mannosidase-like domain acidic residues decreased the binding for SEL1L by 2 to 3-fold (Figure 4C and D). Altogether, these results suggest that the putative catalytic residues of the mannosidase-like domain of EDEM1 are involved in binding to SEL1L, and not the binding or recognition of ERAD substrates.
We characterized the binding properties of EDEM1 and found that EDEM1 is able to discriminate between non-native and native proteins during protein maturation and quality control. EDEM1 binding to ERAD substrates did not require the trimming of substrate glycans or for the substrate to be glycosylated. Instead, EDEM1 appeared to use its mannosidase-like domain to bind to the downstream ERAD machinery target, SEL1L. These results support a role for EDEM1 in the recognition of aberrant proteins and their delivery to an ER membrane ubiquitin-ligase complex by binding to the adapter protein SEL1L.
EDEM1 bound mutant variants of the soluble ERAD substrate A1AT (NHK and Z; Figure 1C and Figure S1A), and the membrane-integrated ERAD substrate tyrosinase (TYR-C71R, Figure S1B). Soluble substrates are solely reliant on lumenal selection for ERAD. We chose to characterize the binding of EDEM1 to NHK in detail since it is arguably the most thoroughly studied soluble mammalian ERAD substrate. Previous studies have demonstrated that pharmacological mannosidase inhibition stabilized NHK, and its turnover was accelerated by the overexpression of mannosidases or EDEM family members (Hosokawa et al., 2003; Hosokawa et al., 2001; Liu et al., 1999). Short hairpin RNA knockdown of HRD1 or SEL1L also decreased the rate of NHK degradation, indicative of their involvement in NHK clearance (Christianson et al., 2008). These results demonstrate that after recognition in the ER lumen as an ERAD substrate, NHK is degraded through the ERAD pathway involving the HRD1/SEL1L complex.
The ERAD process in yeast and mammalian cells appears to utilize a number of protein complexes for recognition, dislocation, ubiquitination and degradation (Carvalho et al., 2006; Christianson et al., 2008; Denic et al., 2006; Mueller et al., 2008). EDEM1 was found recently to reside in a complex with ERdj5 and BiP (Ushioda et al., 2008). ERdj5 possesses reductase activity and a J-domain, which recruits the ER Hsp70 chaperone BiP. This EDEM1-ERdj5-BiP complex is predicted to select and maintain ERAD substrates in a translocation competent form for dislocation to the cytoplasm. Interestingly, we found that the depletion of ERdj5 by siRNA did not affect NHK binding to EDEM1 (Figure S6).
The involvement of protein complexes complicates the interpretation of experiments where the effect on ERAD substrate turnover is monitored after the overexpression of a single subunit from a complex. The creation of potentially orphan subunits might disrupt the function of the complex, producing a dominant-negative effect. For instance, OS-9 and XTP3-B, two putative ERAD receptors observed in complexes with GRP94 and/or BiP, stabilize NHK when they are individually overexpressed (Christianson et al., 2008; Hosokawa et al., 2008). However, overexpression studies can be used effectively to facilitate the probing of the binding properties for the individual components of the ERAD network if the overexpressed factor directly binds the substrate. The ability of EDEM1 to bind NHK in the absence of ERdj5 combined with the size of the EDEM1-NHK complex as determined by ultracentrifugation are consistent with EDEM1 binding directly to NHK in a 1:1 complex.
The current glycoprotein quality control hypothesis predicts that the mannose trimming of ERAD substrate glycans by a mannosidase provides a demannosylated signal on the aberrant secretory cargo for ERAD (Cabral et al., 2001; Hebert and Molinari, 2007). Glycans trimmed to a glycoform ranging from Man8 to Man5 are proposed to create the signal that is recognized by carbohydrate-binding quality control receptors (Jakob et al., 1998). Recent studies suggest that terminal α1,6-linked mannose oligosaccharides provide the signpost for defective glycoproteins (Clerc et al., 2009; Hosokawa et al., 2009; Quan et al., 2008). In this current ER quality control model, the substrate-receptor complex is then targeted to an ER membrane complex for dislocation, ubiquitination and subsequent degradation by the cytosolic proteasome. EDEM1 has been proposed to either act as the mannosidase that creates the demannosylated signal or the quality control receptor that recognizes and sorts mannose-trimmed proteins for ERAD by extracting them from the calnexin binding cycle (Molinari et al., 2003; Oda et al., 2003; Olivari et al., 2006).
Our findings from the analysis of the binding properties of EDEM1 are in conflict with the current models described above. We found that EDEM1 appeared to directly recognize non-native structures, as it associated with NHK irrespective of its glycosylation status. However, EDEM1 did not bind or accelerate the turnover of two naturally nonglycosylated ERAD substrates κ light chain or mutant transthyretin (Figures S4 and S5)(Okuda-Shimizu and Hendershot, 2007; Sekijima et al., 2005). The ability of EDEM1 to recognize aberrant structures appears to be highly substrate-dependent. If EDEM1 can also act as a mannosidase, it must behave in a nontraditional manner as it selectively, efficiently and persistently bound substrate, properties not shared by other glycosidases.
An intact mannosidase-like domain of EDEM1, expected to be required for substrate recognition or signaling, was instead required for binding to the downstream ERAD machinery. EDEM1 binding to SEL1L was disrupted by mutation of the acidic amino acids that are putative mannose interacting residues in EDEM1 or mannosidase inhibition with KIF. KIF and DMJ treatment both inhibit mannose trimming resulting in the accumulation of Man9 glycans (Avezov et al., 2008). However, only KIF treatment inhibited EDEM1 binding to SEL1L. As KIF is a mannose analogue, binding inhibition may involve its direct association with the EDEM1 mannosidase-like domain rather than the accumulation of untrimmed mannose side chains.
Kopito and colleagues recently demonstrated that OS-9 and XTP3-B interacted with SEL1L (Christianson et al., 2008). Mutations to their mannose-6-phosphate receptor homology (MRH) domains perturbed associations with SEL1L indicating that the MRH domains of OS-9 and XTP3-B are used for binding to SEL1L, likely through the glycans of SEL1L. Human SEL1L possesses five N-linked glycosylation sites and the bulk of its lumenal domain is comprised of 11 tetratricopeptide repeats (TPR). TPR domains mediate protein-protein interactions supporting the recruitment of a variety of proteins including chaperones from the Hsp70 and Hsp90 families (D'Andrea and Regan, 2003). Therefore, EDEM1 binding to SEL1L may involve bipartite interactions including its mannosidase-like domain binding the large and flexible glycans of SEL1L, and protein-protein association with the TPR domains. Interactions with the TPR domains of SEL1L maybe mediated directly through EDEM1 or a member of the EDEM1 complex such as BiP or ERdj5. Together, these results support a modified model whereby the mannosidase-like domain or the MRH domains of these quality control receptors mediate interactions with the downstream ERAD apparatus providing an alternative glycan-dependent mechanism for targeting and delivery of aberrant secretory cargo through the ERAD pathway.
A detailed understanding of the recognition and delivery process for the ERAD pathway will require the reconstitution of these processes using purified components. In vitro activity studies are needed to understand whether the additional trimming observed after EDEM1 overexpression was due to EDEM1 directly possessing mannosidase activity or the potential association of EDEM1 with a mannosidase. In support of the later possibility, EDEM1 was recently found to bind and stabilize ER ManI (Termine et al., 2009). As most of the proteins involved in the ER quality control selection and delivery process are themselves glycosylated, the interpretation of results using chemical glycosidase inhibitors or the modulation of glycosidase levels through overexpression or RNAi approaches is complicated. It has been widely assumed that perturbations to the glycan status are mediated through substrate glycans. However, results presented here suggest that the glycan status of the ERAD machinery itself also appears to play an important role in shepherding ERAD substrates and factors through the ERAD pathway.
Human embryonic kidney (HEK) 293T cells were maintained in DMEM supplemented with 10% FCS, 100 U/ml penicillin, and 100 μg/ml streptomycin and incubated at 37°C in 5% CO2. Single and co-transfections of plasmids into cells were accomplished using Lipofectamine 2000, following the manufacturer's instructions. For all co-transfections, EDEM1 and its mutants were transfected at a plasmid molar ratio of 2:1 to the plasmid encoding the substrate protein. Transfections were incubated 16 hr before pulse labeling or harvesting.
Pulse chase labeling, immunoprecipitation and immunoblotting was performed as previously described, with a modified exclusion of the starvation period from the pulse-chase experiments (Svedine et al., 2004). Isolation of post-nuclear supernatant (PNS) and all subsequent immunoprecipitation (IP) steps were conducted at 4 °C. Cells were lysed in 0.5% Triton X-100 in MNT buffer [20 mM MES, 100 mM NaCl, 20 mM Tris-HCl (pH 7.5)] containing protease inhibitors. The PNS was cleared with 10% Zysorbin for 1 hr. The clarified supernatant was incubated with the indicated antiserum complexed to protein A-sepharose and rotated for 16 hr. Immune-complexes were washed twice with 0.05% Triton X-100, 0.1% SDS, 300 mM NaCl, 10 mM Tris-HCl (pH 8.6), resuspended in reducing sample buffer, and resolved on SDS-PAGE.
Quantification of % of start = ([35S-protein at an indicated chase time]/[35S-protein at the 0 hr chase time])* 100. % EDEM1 bound A1AT = ([A1AT at the indicated chase time after α-Flag IP]/[A1AT at the 0 hr chase time after α-A1AT IP])* 100. % SEL1L bound = ([SEL1L protein after α-FLAG IP]/[SEL1L cell lysates*2])*100. Error bars represent the standard deviation for at least three independent experiments.
We would like to thank Brad Pearse and Kristina Moody for helpful comments, and Dr. M. Ziak, J. Roth (Zurich), L. Hendershot (Memphis, TN) and J. Kelly (La Jolla, CA) for providing constructs. This work was supported by US Public Health grant CA79864 (to D. N. H.) and the Uehara Memorial Foundation (to T. T.).
The Supplemental Data includes Experimental Procedures and six figures.
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text: Rocky has been dining on my garbage lately. I have the cans tied so they won't fall over, and bungied closed, but he still keeps trying. The dog cornered it under the deck last night. It looks like the critter is almost a as big as my Lab! Well, maybe not. Short of camping out with the .22 what can I do to make Rocky go to the neighbor's house and leave us alone. I don't want the dog to have a run in with this thing!


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|17 Jun 2011
Can't see contents of C drive
I know this is a forum for windows 7 but
On old good laptop can't see contents of C drive (windows Xp)
My desktop files are gone.
Laptop looks virus,trojan...clean
Looks like all folders (Windows, My Computer, Documents..) are hidden. When i uncheck show hidden files folders appear but gray.
I can create new folder without problems.
|My System Specs
|17 Jun 2011
Windows 10 Pro x64
Check the drive size. Make sure first that it's not empty. Also check if your files are hidden.
Hidden Files and Folders - Show or Hide
|My System Specs
|17 Jun 2011
Drive size is not empty. Show regular size
|My System Specs
|17 Jun 2011
Reset all Folder
Rrstore Defaults
|My System Specs
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Greetings from Toronto! As you read this, I'm canvassing the floor here at the Metro Toronto Convention Centre … getting ready for my first MoneyShow panel discussion on gold … and preparing to help ring the closing bell for today's Toronto Stock Exchange session.
I love these kinds of events because I get to interact — in person — with knowledgeable investors and subscribers like you. And this conference couldn't come at a better time, given the increased stock market turmoil we're seeing … and the huge gold market gains we've witnessed so far in 2016.
If you're in town, be sure to stop by and say "Hello." If you couldn't make the trip, though, let me give you the general outline of what I'm telling investors here …
First, "Everything Bubble" risks are getting larger with each passing day. The auto industry is on the ropes, with Ford Motor (F) confirming this week that market conditions are deteriorating. Commercial real estate shares have gotten hammered in the past several days amid rising fears of a price bust there. High-yield and emerging market bonds are taking on water again due to worries about the credit cycle turn, and the end of artificial central bank bubble-blowing.
Second, the U.S. economy continues to show signs of decelerating. Key readings on the manufacturing and service sector have taken a turn for the worse, while the Citi Economic Surprise Index has retraced the entire "summer spurt" we saw in July and August.
|Overvalued assets could get hammered.
Third, Wall Street's top money managers and noted billionaires continue to warn loudly and frequently that radical monetary experimentation may be at the end of its rope. That means wildly overvalued asset prices could be facing a potentially dangerous depreciation.
Fourth, you can still find a select handful of fundamentally strong, highly rated companies in less economically sensitive industries. I've recommended a small number of them in my various investment services.
But I have a much longer list of stocks and sectors that will get hit hard if the everything-bust-scenario continues to play out. The resumption of volatility we've seen over the past few days only adds to my concerns that we're seeing a regime change in the markets.
So now is not the time to go hog wild throwing money at stocks. Instead, it's a great time to hunt for short-sale and put option opportunities in vulnerable names. That's precisely what I'm doing in my shorter-term trading service, All Weather Trader, which you can get on board with by clicking here.
Lastly, if you missed this chance to chat with me in person about the markets here in Toronto (and maybe sample some great poutine!), be sure to check out the New Orleans Investment Conference. It's scheduled for October 26-29, 2016 in the Crescent City, and offers you a great chance to learn from some of the top minds in the investment world.
I'll have a couple of sessions there, and would love to see you in the audience. You can find more details by clicking here or by calling 1-800-648-8411.
Until next time,
Mike Larson


text:
Senate Minority Leader Mitch McConnell is orchestrating a capitulation on the debt-ceiling debate that likely will lead to President Barack Obama's re-election and eliminate any real possibility of halting the spending mania in Washington D.C. Behind closed doors this weekend, McConnell is pushing for a compromise that will raise the debt ceiling enough to avoid another debate on the issue before the 2012 election. That is just what President Obama wants.
The President is demanding that the debt ceiling be raised by a whopping amount – two or three times the normal increase – to let the federal government keep borrowing past November 2012. The ceiling is generally raised once or twice a year, but Obama claims he wants to kept it "out of politics" in an election year.
Of course he does. Out of control spending is the most important issue facing voters. But he wants to run away from his spending and borrowing record, not run on it.
The 2012 election should be a referendum on the soaring increase in spending since 2007. In his first year, Obama pushed federal spending from 20% of gross domestic product to 25 percent. Only once before did federal spending ever reach that level – when the United States plunged into World War II.
Add in state and local spending, and government programs now consume 42 percent of GDP. In other words, 42 percent of all we produce going to work every day goes for government programs. Forty-two percent of the fruits of our labor. Do you and your family get 42 percent of your happiness from government? It's a preposterous question.
Worse, an increasing share of the spending is on borrowed money. The deficit shot up from $500 billion in the seventh year of the Bush presidency to $1 trillion the next year and $1.9 trillion in 2009.
All of the proposals put forward by congressional leaders, whether House Speaker John Boehner or Senate Majority Leader Harry Reid, barely dent the deficit, cutting it less than 10%. Actual spending isn't even reduced. These so-called "cuts" are reductions in future spending increases.
But the key to making progress, every six months or so, is to keep the issue recurring. The debt ceiling must be brought up again and again. It was raised 16 times during President Reagan's terms, for example. A long-term increase is contrary to American practice. Moreover it would give the President an EZ pass for four more years in the White House.
Don't be bamboozled, Senator McConnell, and don't surrender our nation's future.
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