text:
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Earl Grey Cream TeaThis blend combines the finest black tea along with Earl Grey's signature bergamot flavor. It also boasts a smooth creaminess with vanilla overtones for a special experience in tea flavor. Use 1 tsp. of leaves per cup and brew 3-5 minutes in freshly boiled water.
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Test. EGC review & rating.
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Home of the Long Island Junior Soccer League
Sponsors :
Bryan Sorto of HBC and Carlos Alverado of Albertson have been selected as members of the 1999 Red Bull Academy teams! Over the past few weeks, Red Bulls have been holding tryouts for these teams, which will begin competing in the fall. Sorto and Alverado are the first two players to graduate from the LIJSL-sponsored Long Island Regional Developmental School program to the full Academy teams. Sorto has been a member of the RDS since its' inception two years ago. Alverado joined last year. "This is fantastic news, both for the Red Bulls and the LIJSL," said Simon Barrow, the Red Bulls Manager of Regional Development Schools. "Obviously, this was one of the major goals for the RDS program on Long Island when we started the relationship two years ago, so I'm delighted. This is a landmark achievement." "We are so proud of Bryan and Carlos, and on behalf of the entire LIJSL Board of Directors, I'd like to congratulate them both on this great achievement," said LIJSL President Addie Mattei-Iaia. "When we decided to sponsor the participation of our LIJSL players in the RDS program, our hope was that we could give the very best players the opportunity to play at the highest levels, no matter what their personal circumstances are. Through their hard work and dedication, Bryan and Carlos have shown us that the program works, and I think they have now paved the way for other Long Island soccer players to succeed in the future." Registration for the Fall RDS Tryouts will start in the coming weeks. For more information or questions about registration click here.

subset: commoncrawl


text:
[ << Backend ] | [Top][Contents][Index][ ? ] | [ Scheme functions >> ] | ||
[ < balloon-interface ] | [ Up : Graphical Object Interfaces ] | [ bass-figure-alignment-interface > ] |
3.2.9 bar-line-interface
Print a special bar symbol. It replaces the regular bar
symbol with a special symbol. The argument bartype
is a string which specifies the kind of bar line to print.
Options are |
, :|
, |:
, :|:
, :|.|:
, .
, ||
, |.
, .|
, .|.
, :
, dashed
, '
and S
These produce, respectively, a normal bar line, a right repeat, a left repeat, a thick double repeat, a thin-thick-thin double repeat, a thin-thick double repeat, a thick bar, a double bar, a start bar, an end bar, a thick double bar, a thin-thick-thin bar, a dotted bar, a dashed bar, a tick as bar line and a segno bar.
In addition, there is an option
which is equivalent to |:
except at line
breaks, where it produces a double bar (||
) at the
end of the line and a repeat sign (|:
) at the
beginning of the new line.
For segno, S
produces a segno sign except at line breaks,
where it produces a double bar (||
) at the
end of the line and a segno sign at the beginning of the new line.
is equivalent to S
but produces a simple bar line
) instead of a double bar line (||
) at line breaks.
produces the segno sign at line breaks and starts the following
line without special bar lines.
and :|S
are used for repeat/segno combinations that are
separated at line breaks. Alternatively, .S|:
and :|S.
may be used which combine repeat signs and segno at the same line in
case of a line break. :|S|:
is a combination of a left repeat
), a segno (S
) and a right repeat |:
splits before the segno at line breaks; :|S.|:
splits after
the segno sign.
If bartype is set to empty
then nothing is
printed, but a line break is allowed at that spot.
is used for the gaps in dashed bar lines.
User settable properties:
(boolean) If false, no inter-staff bar line will be created below this bar line.
(pair of numbers) The Y-extent of the actual bar line. This may differ from
because it does not include the dots in a repeat bar line. gap
(dimension, in staff space) Size of a gap in a variable symbol.
(string) A string determining what 'style' of glyph is typeset. Valid choices depend on the function that is reading this property.
(string) The glyph name within the font.
(number) Thickness of the thin line in a bar line.
(dimension, in staff space) Amount of extra white space to add. For bar lines, this is the amount of space after a thick line.
(number) The space after a hair-line in a bar line.
(number) Bar line thickness, measured in
Internal properties:
(pair) A pair of grobs containing the span bars to be drawn below and above the staff. If no span bar is in a position, the respective element is set to
This grob interface is used in the following graphical object(s): BarLine and SpanBar.
[ << Backend ] | [Top][Contents][Index][ ? ] | [ Scheme functions >> ] | ||
[ < balloon-interface ] | [ Up : Graphical Object Interfaces ] | [ bass-figure-alignment-interface > ] |


text:
I'm going to try all kinds of new and different seeds this year, as well as my tried and true favorites. ?Susan Avery, Superior, MT.
I resolve to always protect my hands with garden gloves, even if I'm only going to deadhead a few flowers or pick some vegetables. ?Barbara Stanley, Augusta, GA.
Let it be! No new beds, just a few new plants. I've been building my beautiful garden for 10 years, so in 2009 I'm going to take some time to regroup and just enjoy it for a while. ?Lynda Rettick, Bloomington, IL
I'm going to trade more plants and seeds with friends from all over the country. ?Noreen Ingle, Lakeville, IN
I'm getting a power tiller. I never want to hand-till my garden again.?John Bailey, Tallahassee, FL
My resolution is to build a wood and wire structure over my entire garden to keep out my thieving chickens. ?Chrissy Woodward, West Fork, AR.


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Yes (0)No (0)
In the old forum at bottom of the Board Index page (under the online users part) there were flags and a number beside them representing how many users there were from certain countries online at the time. I though this was pretty cool and if we could bring it back at some point that would be awesome.
That'dbe cool then I could see if there were any belgian people here.
The addon we had that did this on the old forums has not been upgraded to work with the new software. The closest I've been able to find is an addon that allows you to specify a country flag below your profile on posts. I don't think we want to clutter up our forum with more images like that.
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text:
By the time Hunter Mahan reached the 18th green at Congressional Country Club — normally a pleasant place to be as the shadows lengthen — the crowds had long since thinned. Elsewhere in Bethesda and beyond, there were air conditioners, swimming pools, showers, all means of comfort. But the fairways on the Blue Course Friday in the the AT&T National were cruel, unpleasant places to be.
"Golf is a challenge in itself," Mahan said, "and when the conditions and the weather comes into play, it's a whole 'nother factor. Once your mind goes, the body is going to go with it. It's very important to be mentally strong."


text:
Updated 07/08/11 Help Us Reach Our Goal!
Help Us Reach Our Goal!
The Miami Dolphins haven't hidden the fact they'll upgrade the receiver position through free agency, providing quarterback Ryan Tannehill the weapons he needs to jump start the passing game. "I think this is the year that you've got to do something," General Manager Jeff Ireland said. "We're looking for playmakers on offense."
Thats why free agency is so important. By re-signing Hartline (which by all appearances the team is trying to do before he hits the open market) and then adding a Mike Wallace or Greg Jennings, it would open up all kinds of possibilities in the draft. Wallace is expected to fetch in excess of $10 million annually a steep price, but one the Dolphins probably need to pay, according one league personnel evaluator. Even if Wallace does nothing but run go-routes, the source said, hell be worth the investment if he catches 12 touchdown passes and 1,400 yards for the Dolphins. Should the Dolphins sign one of those free agent receivers, they could wait until the second or third rounds where they have four combined picks to add receiver help. Baylors Terrance Williams, West Virginias Tavon Austin and Louisiana Techs Quinton Patton would be options. That would allow the Dolphins to use their first-round pick to fill other another hole. And while the receiver position might be uninspiring, this is a great draft for offensive and defensive tackles, experts agree.
The Miami Dolphins will be looking to add weaponry to their offense this offseason, building around second year quarterback Ryan Tannehill. The team, according to reports yesterday, will target Pittsburgh Steelers wide receiver Mike Wallace as their top priority in free agency, looking to add much needed speed to the offense. While Wallace is one of the top free agents this year, he also comes with baggage.Wallace has the same problem that infuriated Dolphins fans for the two seasons Chicago Bears wide receiver Brandon Marshall was in Miami - drops. Wallace also has a reputation as a "diva," something that Dolphins head coach Joe Philbin has been reluctant to deal with in his first year with the team. To get a better idea of what the Dolphins could expect from Wallace if they land him, I turned to SB Nation's Pittsburgh Steelers blog, Behind the Steel Curtain. Managing Editor Neal Coolong gives us an in-depth look at Wallace:
1) The Miami Dolphins are poised to be big spenders in free agency, with more than $40 million in cap space. Who will they target? Expect a major push for an offensive skill player. In talking with general manager Jeff Ireland, he focused on landing a player who can produce explosive plays. That would seem to indicate their eyes will turn to receiver Mike Wallace. When I mentioned how a player with scheme familiarity could hit the ground running -- like receiver Greg Jennings, who spent time with coach Joe Philbin in Green Bay -- Ireland responded that it could be helpful. (Last year, rookie QB Ryan Tannehill eased his way into the NFL by playing in an offense under his old Texas A&M coach, Mike Sherman.) Early signs point to Wallace being the target, though.
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text: John Ross Ewing is the ambitious son of J.R. and Sue Ellen Ewing. A chip off the old block, John Ross is determined to strike it rich in the oil industry and prove himself capable of stepping into his father's shoes. Growing up, John Ross was enticed by promises that the Ewing Oil empire would one day be his. In the midst of impressing his father by scheming to take Southfork from Bobby and Christopher, John Ross found his world crashing down when his girlfriend, Elena, discovered his plan. Even though John Ross has now formed Ewing Energies with Bobby and Christopher, his ultimate goal is to undermine them and gain total control of the company.


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Tech names leadership development team |
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SDSM&T News 501 E. St. Joseph Street • Rapid City, SD 57701-3995 Phone: (605) 394-6082/2554 • Fax: (605) 394-6177 FOR IMMEDIATE RELEASE December 4, 2002 Contact: Steve Buchholz, Public Information Manager, 394-6082 Tech Names Leadership Development Team The South Dakota School of Mines and Technology has named seven students to its Leadership Development Team. The Leadership Development Team is comprised of students whose mission is to provide Tech students with opportunities to become confident and qualified leaders. The team's goal is to prepare students for leadership roles in their careers after graduation. South Dakota Tech strongly believes in the importance of leadership in today's marketplace, and the university works hard to make sure students learn leadership skills. Tech does that through a variety of programs and activities that give students chances to improve and demonstrate their leadership abilities. The students: • Chris Bartelt, Industrial Engineering, Watertown • Jenni Christensen, Electrical Engineering, Bloomington, Minn. • Anita Hansen, Industrial Engineering, Hermosa • Chad Nienhueser, Civil Engineering, Sidney, Neb. • Justin Reisenauer, Chemical Engineering, Hettinger, N.D. • Dan Wolf, Electrical Engineering, Canton • Miaken Zeigler, Environmental Engineering, Sturgis #30#
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Title | Tech names leadership development team |
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Creator | South Dakota School of Mines and Technology. University Relations |
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South Dakota School of Mines and Technology |
Local Subject |
Leadership Recognition |
Digital Publisher | South Dakota School of Mines and Technology. Devereaux Library |
Contributors | Buchholz, Steve; |
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Submitting Institution | Devereaux Library. South Dakota School of Mines and Technology. |
Date Digital | 2009 |
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text:
A couple of weeks ago, I received a notice from Target reminding me of my free one-year Experian offer that allows that credit reporting company to keep an eye on and report if anything funny is going on with my purchases. (The notice is, of course, thanks to Target's recent data breaching horrors.)
Miller & Martin PLLC has announced an expansion of their practice development office.
If your impression of Audi automobiles is that they are just gussied up VWs, please turn your attention to the five-passenger Audi A7 hatchback.
Q: I'm doing some last minute spring break travel arrangements. Does the BBB have any tips I should consider before finalizing my plans?
Since the day the Affordable Care Act was signed, reasonable observers anticipated that the consequences would include higher costs and reduced employment.
Tennessee American Water has added three new managers to its management team.
I just accompanied my friend to the Emergency Room, and it was a terrible experience.
Owner: Independent Healthcare Properties LLC.
There are some luxury vehicles I'd described as SINOs. My acronym — a total contrivance — stands for "SUVs-in-name-only," and you know the type.
Every year, the Better Business Bureau receives thousands of calls and emails from consumers who have been scammed, or from the lucky ones who have dodged scams by being suspicious.
The month of February is a time to recognize a number of unfortunate ailments that disable and take the lives of too many people.
In our third and final installment on IRA accounts, let's take a look at some more advanced topics and less well-known strategies open to retirement account holders.
Engineer Stephen Meyer is joining the national engineering firm of Alfred Benesch & Co. Meyer will serve as branch manager and senior project manager for the Chattanooga office.
ShopSmart, one of my all-time favorite resources, recently printed an article about road rage.


text:
We have very few things in Iowa that can kill you that aren't large. Like if a cow fell on you, it might crush you.
What the heck is that thing? Oh, it's the moon.
For last year's words belong to last year's language And next year's words await another voice. And to make an end is to make a beginning. - T.S. Eliot
"Ring the bells that still can ring Forget your perfect offering There is a crack in everything That's how the light gets in." -Cohen
In my effort to be *concise*, I often come off as blunt and harsh. Sorry, don't mean to be offensive.
Ama, Thanks very much for setting this up. I had a great time. W had a great time. We'll probably even go back to the restaurant, though it won't be the same without you, NIK, and gonna.
And, when the pics arrive, let me report that W says her dish (lemon chicken with angel hair pasta) was fantastic! (But any place would be good with the company.)
(Note: to Iowa chauvinists: I'm only pretending not to know that there are cities in Iowa....)
Chicago skyline from Shedd Aquarium
Weatherly, Amazonia, NIK
Amazonia, Weatherly and H (Aussie) on the water taxi
Chicago skyline from the water taxi
Contestants in the City Chase competition rappelling down the Navy Pier Headhouse
Lovely Malbec
Eggplant parmigiana
Lemon chicken with angel hair pasta
Chicken vesuvio
Shells and broccoli
Spinach ravioli
[This message edited by nowiknow23 at 6:05 PM, August 26th (Monday)]
"That's the thing about pain, it demands to be felt."
What, no box wine?
The food looks amazing!
"Truth has no special time of its own. Its hour is now - always." - Albert Schweitzer ____________________________________________ Me: BW - Him: 200+ # tumor removed 7/09 DS - 31 - Yikes!


text:
Teaching & Learning News
iCollege Upgrade: Desire2Learn 10.2 Coming in December
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iCollege will be upgraded from Desire2Learn 9.4.1 to Desire2Learn 10.2 prior to the Spring 2014 semester.
The upgrade will necessitate iCollege...
GPC Adopts i>clicker for Fall 2013
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The Academic Technology Advisory Committee reviewed clicker (student response system) vendors and selected...
Blackboard Instant Messenger Returns For Fall 2013
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Blackboard Instant Messenger (formerly Wimba Pronto) services will return to GPC in time for the Fall 2013 semester. Blackboard Instant...
Services & Support News
Data Privacy Month (DPM)
Jan 28 - Feb 28
Jan 28 - Feb 28
Data Privacy Month (DPM) is an annual...
GPC Information Security has implemented a solution providing a secure way to send email containing sensitive information, including file attachments,...
GPC Faculty and Staff members, did you know that you are eligible to participate in Microsoft's Software Assurance Home Use Program (HUP)? This...
Infrastructure News
Georgia Perimeter College has migrated its email and calendar system from Microsoft's Live@edu to the company's Office 365...
GPC is adding 100 additional wireless access points across all campuses to increase wireless coverage in time for Fall 2013. These wireless...
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It's Hatched! 50 Bought
Deal Over
What could be better than a fresh, authentic Mexican burrito stuffed to the gills with tender meat, vegetables, creamy cheese and cool sour cream? How about getting that very burrito for half price? With this muy delicioso DealChicken deal, you'll dine like a king at Ole! Mexican Restaurant in Orange park. Get your fill of homemade chips and salsa, abundant fajitas, chili relleno, tacos and more, complete with traditional sides like refried beans and Mexican rice. You'll pay just $10 for $20 worth of tasty food from Ole! Mexican Restaurant!
Located on Wells Road in Orange Park, Ole! Mexican Restaurant offers guests a fun and casual atmosphere that is ideal for the entire family. The staff is friendly, and the food is made fresh to order from only the highest quality ingredients available, so whether you stop in for lunch or dinner, you'll be satisfied with your meal at Ole! Mexican Restaurant.
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Guides tagged with: Canada
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Canadian Studies at the University of California, Berkeley is an interdisciplinary program focused on the scholarly issues surrounding the study of Canada across a range of academic disciplines. The Library maintains a commitment to all areas of Canadian studies, including history, literature, and culture. Tags: Canada Canadian Studies Francophone Canada Québec
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CruiserCustomizing Standard License Plate Frame - Chrome or BlackReviewed by: Lee (quanlee) Reviewed for: 750 Shadow ACE Used for: > 1 year Ratings: Overall Rating: 5 Ease of install: 5 Value: 5 Would buy again: yes Review Summary: Picked this up at the local Walmart, cheap and easy to install, makes the plate look much better. Review Pros: Review Cons: Review Improvements: Review Tools: Was this review helpful to you? |
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Stevens-Johnson syndrome
Other Names for this Disease
- Erythema multiforme major
See Disclaimer regarding information on this site. Some links on this page may take you to organizations outside of the National Institutes of Health.
erythema multiforme major, is a limited form of toxic epidermal necrolysis. This disorder affects the skin, mucous membranes and eyes.[1][2] Stevens-Johnson syndrome occurs twice as often in men as women, and most cases appear in children and young adults under 30, although it can develop in people at any age.[1] It is an emergency medical condition that usually requires hospitalization. Treatment focuses on eliminating the underlying cause, controlling symptoms and minimizing complications.[3]
Stevens-Johnson Syndrome (SJS), also called
Last updated: 11/22/2010
- Facts About The Cornea and Corneal Disease. National Eye Institute (NEI). 2010; http://www.nei.nih.gov/health/cornealdisease/#m. Accessed 3/15/2010.
- Roujeau JC. Stevens-Johnson syndrome. Orphanet. 2009; http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=36426. Accessed 3/15/2010.
- Stevens-Johnson syndrome. MayoClinic.com. 2009; http://www.mayoclinic.com/health/stevens-johnson-syndrome/DS00940/METHOD=print. Accessed 3/15/2010.
Your Questions Answered
by the Genetic and Rare Diseases Information Center1 question(s) from the public on Stevens-Johnson syndrome have been answered. See questions and answers. You can also submit a new question.
On this page
Basic Information
- MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic. Click on the link to view this information.
- The Merck Manuals Online Medical Library provides information on this condition. Click on the link to view the information.
- The National Eye Institute (NEI) was established by Congress in 1968 to protect and prolong the vision of the American people. Click on the link to view information on this topic.
- MayoClinic.com provides information about Stevens-Johnson syndrome.
In Depth Information
- The Online Mendelian Inheritance in Man (OMIM) database contains genetics resources that discuss Stevens-Johnson syndrome. Click on the link to go to OMIM and review these resources.
- Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
- PubMed is a searchable database of medical literature and lists journal articles that discuss Stevens-Johnson syndrome. Click on the link to view a sample search on this topic.
- Medscape Reference has 4 articles on this topic from the perspective of Emergency Medicine, Infectious Diseases, Ophthalmology and Dermatology. You may need to register to view the information online, but registration is free.


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CNET UK > Reviews > TVs and Home Cinema > Home Cinema > Video Streamers
HDX 1000 review
The HDX 1000 is a brilliant media streamer that's capable of playing 1080p video and offers support for virtually every video format under the sun. It also offers fantastic picture quality and punchy sound. If you can manage to get hold of one, we doubt you'll be disappointed Read more
11 March 2009 by Ian Morris
CNET UK > Reviews > TVs and Home Cinema > Home Cinema > Video Streamers
DVICO TViX HD M-6500A review
The DVICO TViX HD M-6500A media streamer claims to support virtually every video file you can find. What's more, it can take SATA hard drives, which means massive potential storage space. If you want to play HD computer files on your television, it offers plenty of functionality Read more
16 July 2008 by Ian Morris


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This could also be titled "how to get unfriended on Facebook". Always beware of someone asking "genuine, non-rhetorical questions" they want answers to from the opposing side. Sometimes they don't like your answer. My former FB friend posted the following, in reference to an article by Michael Rowe: I truly hope this opinion from one …
Tag Archive: catholic
Mar 29 2011
Newt Gingrich is a Big, Fat Idiot (duh)
Alright, admittedly, I made the mistake of clicking on a CNN headline about Newt Gingrich and "atheists". Atheists is in quotes there because CNN seems to only share that word when it's in quotes. I know better than going to CNN, and I know better than reading stories about Newt Gingrich, and I really should …
Feb 22 2011
Michael Hawkins on Luke Vinci's Anti-Ashley Post
You know what's even better than writing a blog post? Having someone else write a blog post you can just link to as though it's additional content in your own blog. This is also just a lesson in recursion – linking to a post that links to your post.
Feb 16 2011
Response to a 'Correction'
As you all know, I've been reporting on Social Media for a website called Social Axcess. I reported on the iPhone confession app, which allows you to figure out which sins you need to confess, and I got a somewhat heated reply from one of the founders of GSMI, the company that owns the blog. …
Feb 08 2011
Forgive me iPhone, for I have sinned
The Catholic Church has had a rough time lately, between sex scandals and dwindling interest in church and the constant onslaught of the New Atheist movement, they haven't had much good PR in the last decade. Always a relic from older, simpler times, the Catholic Church is usually half a century behind the rest of …
Jan 22 2010
Who will vote how on Prop 8; Supreme Court Justice breakdown
So, I've been trying to figure out how I think SCOTUS breaks down for the Prop8 vote. I am going to be fairly optimistic based on the quality of the argument and Olson's record with SCOTUS up to now. Argued over 50 cases in front of SCOTUS, has won 3/4ths of them, including the decision …


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How 2012 Grads Can Prepare for a Career in Insurance IT
1. Understand How the Universe Works
I studied physics and business, because in order to do these things you need to know how the universe works and how the economy works and you also need to be able to bring people together to create something. It's very difficult to create something as individuals if it's a significant technology.
— Elon Musk, co-founder of SpaceX, Tesla Motors and Paypal, in his address to the 2012 graduates of Caltech
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DLC review: Heavy Rain Chronicles -- The Taxidermist
Timothy J. Seppala
April 12, 2010, 12:35AM
The first piece of DLC for the first game I ever scored a ten is available now on the Playstation Network for the cool price of $4.99, but isn't worth a single penny. "Whoa, whoa, whoa Tim, you loved Heavy Rain!" Yes, I did. I loved it because it was a totally unique experience that did things I never...
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Video game review: Heavy Rain is defining moment for interactive narrative
Timothy J. Seppala
February 23, 2010, 12:50AM
For my hands on with the Heavy Rain demo click here. Mature rated games are everywhere but none hold a candle to PlayStation 3 exclusive Heavy Rain. Heavy Rain's maturity lies not in puddles of blood and gore occupying every inch of the environment, but in its story's themes of sacrifice, redemption, and love. The narrative focuses on four...
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Video game preview: Hands on with Heavy Rain
Timothy J. Seppala
February 10, 2010, 1:50AM
People following Heavy Rain could cry foul at the thought of a demo, citing they won't play it because they don't want any spoilers. An air of mystery surrounds the game who's very driving force is the strength of it's narrative. Very little information about the story has been released, except that it's about a journey of how far...
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Make gift wrapping easy and fun with the Martha Stewart Living Craft Space Gift-Wrap Hutch. Featuring five easy-to-remove dowels (four for hanging wrapping paper and one for ribbon), this hutch ensures that you'll always have the perfect paper choice close at hand. Its storage shelf has three compartments where you can store scissors, tape, and gift tags. Perfect the art of gift wrapping with this versatile station.
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in Burnsville
At Fairview Clinics – Burnsville, we make it easy for you to get the care you need, when you need it with same-day appointments, extended hours, and 24/7 scheduling.
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Golf Discs
Distance Drivers
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The Wraith is a stable flyer that performs predictably well in the wind with speed, glide and accuracy. This is our most durable Distance Driver in... more |
XXX is our extra overstable control driver. XXX is sincerely a disc for the "big guns" and not for children. As already said it´s overstable, it's... more |
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The Orion LS will stay straight and long for all but the strongest throwers. When you absolutely need more distance on your drive, trust the Orion LS. more |
The PD2 from Disc Mania is a disc golf power driver designed for hard-throwers or players fighting strong headwinds. This disc is best described as... more |
The Quasar is built for big arms who need control into the wind. This hefty beast wants to fade hard, but it'll get way down the fairway before... more |
Another driver hit from our European friends. According to one of Lat 64's top pros, this disc is "fast, [has a] great grip feeling because of the... more |
A maximum distance driver that can compete with any other driver on the market. More controllable than other overstable drivers with plenty of... more |
The Scorpius is Millennium's Destroyer-based long stable driver. With a long glidey flight just shy of neutral-stable and a dependable fade, the... more |
Don't let the name fool you, this disc is not to be thrown while wearing heels. Latitude 64 took a stab at creating the most overstable disc they... more |
The Striker, in awesome-looking opaque pearlescent and durable Gold Line plastic, is a stable high-accuracy driver disc golf driver from the... more |
The Sword is an overstable distance driver from Westside Discs. Made from part of the King mold, the Sword is slower and more controllable, while... more |
The Disc Mania TD C-Line, or Turning Driver, is an under-stable distance driver that is designed for long, slow-turning shots. This disc provides... more |
The Trespass is a wide-rim high speed overstable driver with a precision control and maximum distance. A very accurate long driver - a must for the... more |
The Villain is best described as a longer Striker. That's a good thing, because the Striker blew up on the scene with its balanced properties of... more |
The Vision Gold Line is an under-stable distance driver disc golf driver from the Swedish company Latitude 64. This disc is a great turn-over disc for hard-throwing players, holding an anhyzer for a long time with excellent glide. For beginning players, or... more
The Westside World is a speed 14 overstable distance driver that will always have a reliable fade. Great for high power players or someone looking... more |
XXX is our extra overstable control driver. XXX is sincerely a disc for the "big guns" and not for children. As already said it´s overstable, it's... more |
Thanks, Archon -- we love a worn Pro Wraith just not TOO worn. And that's the thing about throwing worn discs that are *just right*. The Archon... more |


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Copyright © 2012 The Authors All rights reserved.
Cell Reports, Volume 1, Issue 6, 632-638, 31 May 2012
Voltage-Dependent Calcium Channels at the Plasma Membrane, but Not Vesicular Channels, Couple Exocytosis to Endocytosis
Lei Xue1, 2, Zhen Zhang1, 2, Benjamin D. McNeil1, Fujun Luo1, Xin-Sheng Wu1, Jiansong Sheng1, Wonchul Shin1 and Ling-Gang Wu1, ,
Corresponding author2 These authors contributed equally to this work
Graphical Abstract
► Voltage-dependent calcium channels at the plasma membrane trigger endocytosis ► P/Q-type calcium channels participate in triggering rapid and slow endocytosis ► Vesicle fusion does not generate calcium currents at the plasma membrane
- Although calcium influx triggers endocytosis at many synapses and non-neuronal secretory cells, the identity of the calcium channel is unclear. The plasma membrane voltage-dependent calcium channel (VDCC) is a candidate, and it was recently proposed that exocytosis transiently inserts vesicular calcium channels at the plasma membrane, thus triggering endocytosis and coupling it to exocytosis, a mechanism suggested to be conserved from sea urchin to human. Here, we report that the vesicular membrane, when inserted into the plasma membrane upon exocytosis, does not generate a calcium current or calcium increase at a mammalian nerve terminal. Instead, VDCCs at the plasma membrane, including the P/Q-type, provide the calcium influx to trigger rapid and slow endocytosis and, thus, couple endocytosis to exocytosis. These findings call for reconsideration of the vesicular calcium channel hypothesis. They are likely to apply to many synapses and non-neuronal cells in which VDCCs control exocytosis, and exocytosis is coupled to endocytosis.
Endocytosis is coupled to exocytosis, allowing recycling of vesicles and maintaining exocytosis (Royle and Lagnado, 2003,Schweizer and Ryan, 2006). Many studies suggest that calcium influx regulates endocytosis at synapses and non-neuronal secretory cells (Marks and McMahon, 1998,Cousin and Robinson, 1998,Gad et al., 1998,Sankaranarayanan and Ryan, 2001,Balaji et al., 2008,Artalejo et al., 1995,Neves et al., 2001,Wu et al., 2005,Clayton et al., 2007; but see von Gersdorff and Matthews, 1994,Leitz and Kavalali, 2011). Recent studies of a large nerve terminal, the calyx of Held, suggest that regulation of endocytosis by calcium reflects the trigger of endocytosis (Wu et al., 2009,Hosoi et al., 2009). Although the calcium channel that couples exo- to endocytosis was not identified, the voltage-dependent calcium channel (VDCC) was often implicitly assumed to be the candidate because calcium influx via VDCCs triggers exocytosis, and exocytosis is coupled to endocytosis. However, a recent study of Drosophila synapses proposed that the calcium channel is Flower, a vesicular membrane protein transferred from the vesicle to the plasma membrane via vesicle fusion (Yao et al., 2009). This proposal may have significant impact for four reasons indicated by many reviews (Yao et al., 2009,Brose and Neher, 2009,Shupliakov and Brodin, 2010,Vogel, 2009,Kuo and Trussell, 2009). First, it could be a universal mechanism because Flower is conserved from worm to human (Yao et al., 2009). Second, experiments suggesting that calcium regulates or triggers endocytosis were mostly done by manipulating extracellular calcium or intracellular calcium buffers, which could be accounted for with the Flower hypothesis. Although the calcium current charge was found to correlate with the endocytosis rate (Wu et al., 2009), the exocytosis amount was not well controlled, making it possible for the vesicular calcium channel to account for this correlation. Thus, in principle, Flower could replace the plasma membrane VDCC to trigger endocytosis. Third, the Flower hypothesis explains exo-endocytosis coupling better than plasma membrane VDCCS because (1) Flower channels inserted to the plasma membrane may keep track of the level of exocytosis and thus be responsible for the exo-endocytosis match, and (2) Flower channels could diffuse to the endocytic zone, explaining why endocytic zones may differ from active zones. Fourth, a study in sea urchin eggs found that upon exocytosis, VDCCs are translocated from the vesicle membrane to the plasma membrane to mediate calcium influx required for endocytosis (Smith et al., 2000). These studies led to a more general hypothesis that vesicular calcium channels conserved from sea urchins to nerve terminals couple exo- to endocytosis (Vogel, 2009).
The vesicular channel hypothesis is potentially critical not only in exo-endocytosis coupling but also in many other calcium-dependent exocytosis processes (Brose and Neher, 2009,Kuo and Trussell, 2009). Despite such potential roles, whether fusion-inserted vesicle membrane generates calcium currents or influx at nerve terminals was not tested directly at nerve terminals. Whether plasma membrane VDCCs participate in triggering endocytosis with vesicular calcium channels is also unclear. The present work addressed these issues at the calyx of Held nerve terminal. We found that fusion-inserted vesicle membrane did not generate calcium currents or influx. Instead, the VDCC at nerve terminal membrane coupled exo- to endocytosis.
Exocytosis Does Not Generate Calcium Currents
Vesicular calcium channels, if present, could be either voltage-independent Flower channels or VDCCs. We tested these two possibilities by measuring calcium currents (ICa) after and during depolarization, respectively. Depolarization at the calyx was 10 ms from the holding potential of −80 to +10 mV (applies unless mentioned otherwise, depol10ms), which induced an ICa of 2.10 ± 0.11 nA and a capacitance jump (ΔCm) of 427 ± 24 fF (n = 12, Figure 1A). At the ΔCm peak, ∼400–500 ms after depol10ms, the steady-state ICa was undetectable (<3 pA), suggesting that exocytosis did not insert calcium channels to generate steady-state ICa at −80mV. Alternatively, a calcium-dependent outward current could be in balance with the exocytosis-generated ICa. This latter possibility was ruled out because we detected no outward current (<3 pA at 400–500 ms after depol10ms) when the ΔCm was reduced to 83 ± 9 fF (n = 5) or ∼19% of control by botulinum neurotoxin E (BoNT/E, 150 nM, in pipette, Figure S1A). Similar results were obtained when BAPTA (10 mM) was included with BoNT/E to block potential calcium-dependent currents (Figure S1B, n = 5).
Because a vesicle's membrane capacitance is ∼0.07 fF (Sun et al., 2002,He et al., 2006), the 427 fF ΔCm induced by depol10ms corresponded to ∼6,100 vesicles. If each vesicle contained exactly 1 calcium channel, ∼6,100 channels would be inserted to the plasma membrane. ICa traces were originally low-pass filtered at 3 kHz (Figure 1A, black). After we low-pass filtered ICa traces at 100 Hz (Figure 1A, red), the SD of ICa traces was 0.83 ± 0.08 pA (n = 8). We then set our detection limit at 3 pA, which was greater than three times the SD with >99.7% confidence for detecting changes every 10 ms. If there were 6,100 channels inserted at the plasma membrane, each channel would generate <0.0005 pA of ICa, ∼600 times less than the single-VDCC current (∼0.3 pA at −80mV) (Li et al., 2007,Weber et al., 2010). There was no such small single-channel current observed. If calcium channels with a single-channel current similar to VDCCs (0.3 pA) were in a fraction of vesicles, the fraction would be <0.16% (≈3 pA/0.3 pA/6,100). Thus, fused vesicles did not contain voltage-independent calcium channels with any reported conductance.
Consistent with this conclusion, the volume-averaged [Ca2+]i detected with fura-2 decayed to within 10 nM above baseline at 2–3 s after depol10ms, at which >∼75% ΔCm remained, indicating that fused vesicle membrane could not generate significant [Ca2+]i increase (n = 5, Figure 1B). Similar results (<10 nM at 2–3 s, n = 4) were observed when endocytosis was blocked by 0.3 mM GDPβS in the pipette.
Two sets of data suggest that exocytosis did not generate ICa during depolarization. First, depol10ms induced a ΔCm 267% ± 13% (n = 6) of that induced by a 2 ms depolarization (Figure 1C). However, ICa during depol10ms did not increase. ICa at 9.9 ms during depolarization was 84% ± 2% (n = 6) of that at 2 ms (Figure 1C). This was not due to a balance between calcium-dependent outward currents and exocytosis-inserted ICa because in the presence of BoNT/E that blocked exocytosis, ICa at 9.9 ms during depolarization was 85% ± 2% (n = 5, Figure S1A, inset) of that at 2 ms, similar to control. Similar results (86% ± 1%, n = 5) were obtained in the presence of BAPTA (10 mM) and BoNT/E that blocked potential calcium-dependent currents (Figure S1B, inset). Second, in control (150 nM boiled BoNT/E in pipette) during ten pulses of 20 ms depolarization at 10 Hz (depol20ms×10), the total ΔCm after the first pulse was 503 ± 33 fF but increased by 938 ± 55 fF after the tenth pulse (n = 5), corresponding to fusion of additional ∼13,000 (≈938/0.07) vesicles. This additional fusion predicts an increase of 1.3 nA of ICa if each fused vesicle contains a VDCC with reported ∼0.1 pA single-channel current at +10mV (Weber et al., 2010). However, ICa decreased from 2.42 ± 0.12 nA at the first pulse to 1.27 ± 0.06 nA (53% ± 3%, n = 5) at the tenth pulse (Figure 1D), suggesting no vesicular VDCCs. This ICa decrease was not due to a balance between ICa inactivation and exocytosis-induced VDCC insertion because a similar ICa decrease was observed in the presence of BoNT/E (150 nM), which blocked the total ΔCm induced by depol20ms×10 to 179 ± 27 fF (∼12% of control, n = 5, Figures 1E and 1F). Addition of the calcium buffer BAPTA (10 mM) together with BoNT/E (150 nM) partially relieved ICa decrease (Figures S1C and S1D, n = 5), consistent with calcium-dependent ICa inactivation (Forsythe et al., 1998,Xu and Wu, 2005). We concluded that exocytosis did not generate calcium currents during and after depolarization (Figure 1).
Flower at Nerve Terminals
Results in Figure 1 prompted us to determine whether Flower is expressed in rat brain. An antibody we generated against Flower amino acids 151–165 (Figure 2A) detected a major band in rat (P8) brain (Figure 2B). Immunostaining with this antibody was colocalized with the antibody staining against vesicular glutamate transporter 1 (vGluT1), which labeled calyces (Figure 2C, upper). Our antibody is specific to Flower because (1) Flower peptide (Flower amino acids 151–165) blocked Flower antibody staining of the calyx (Figure 2C, middle), and (2) Flower antibody specifically recognized DDK-tagged Flower protein overexpressed in HEK293 cells, which contained no endogenous Flower protein (Figure 2D). The molecular weight of Flower overexpressed in HEK293 cells (∼20 kDa) was similar to that in Drosophila (Yao et al., 2009) but smaller than that in rat brain extracts (∼25 kDa, Figures 2B and 2D), likely due to posttranslational modification in rat brain.
Western blot of proteins from cytosol and synaptic vesicles purified from the whole rat brain showed that Flower was preferentially localized in vesicles, similar to vesicle protein VAMP2 (Figure 2E). These results suggest that Flower is expressed in synaptic vesicles of rat brain and calyces, consistent with the report of Drosophila (Yao et al., 2009). Although these results suggest expression of Flower at many synapses, we do not know whether Flower is expressed at all or only a fraction of synapses in the brain. Nevertheless, Flower expression at the calyx and synaptic vesicles (Figure 2), together with the lack of exocytosis-generated ICa (Figure 1), suggests that vesicular Flower insertion to the plasma membrane does not generate ICa.
VDCC, but Not Exocytosis, Determines Endocytosis Rate
To determine whether the plasma membrane VDCC controls endocytosis, we measured endocytosis after different VDCC-mediated ICa charges (QICas) while maintaining similar amounts of exocytosis (similar inserted vesicular proteins). Ten pulses of 50 ms depolarization at 10 Hz (depol50ms×10) induced a ΔCm of 1603 ± 78 fF (n = 12) and an QICa of 453 ± 35 pC (n = 12, Figures 3A and 3D). The capacitance decay, which reflects endocytosis, was biexponential with a τ of 1.2 ± 0.1 s (n = 12; weight, 62% ± 4%) and 12.5 ± 0.4 s (n = 12), respectively. The initial decay rate (Ratedecay) was 474 ± 24 fF/s (n = 12), which reflected mostly the initial rate of the rapid endocytosis component because the rapid component contributed >80% of the Ratedecay after this stimulus (Wu et al., 2009).
Ten pulses of 10 ms depolarization at 10 Hz (depol10ms×10) induced a similar ΔCm (1445 ± 80 fF, n = 13; p = 0.17) as depol50ms×10, likely because each 10 or 50 ms depolarization depleted most readily releasable vesicles (Wu and Wu, 2009). Under this condition both depol10ms×10 and depol50ms×10 may cause repeated depletion and replenishment of the readily releasable pool at near maximal speed. Depol10ms×10 induced a much less QICa (193 ± 14 pC, n = 13; p < 0.01) and Ratedecay (231 ± 21 fF/s, n = 13; p < 0.01) than depol50ms×10 (Figures 3B and 3D). The capacitance decay was biexponential with a τ of 2.1 ± 0.2 s (n = 13; weight, 31% ± 4%) and 18.1 ± 1.0 s (n = 13), respectively (Figure 3B). The τ and the weight of the rapid component were slower and smaller than those induced by depol50ms×10 (p < 0.01). However, the rapid component of endocytosis still contributed to the Ratedecay by more than 80% (calculation not shown). Evidently, the Ratedecay difference induced by depol50ms×10 and depol10ms×10 is not due to the exocytosis difference (Figures 3A, 3B, and 3D). It must be due to the difference in the VDCC-mediated QICa (∼453 versus ∼193 pC) because calcium influx triggers and speeds up endocytosis at calyces (Wu et al., 2009,Hosoi et al., 2009).
Twenty pulses of 10 ms depolarization from −80 to −5mV at 0.5 Hz (20 pulse train) induced a ΔCm (1414 ± 107 fF, n = 18) similar to those induced by depol10ms×10 or depol50ms×10 (p > 0.1; Figures 3C and 3D), but a much slower endocytosis, reflected as a mono-exponential capacitance decay with a τ >30 s (n = 18) and a much smaller Ratedecay (53 ± 4 fF/s, n = 18, Figures 3C and 3D; p < 0.01). This slower Ratedecay was clearly not caused by smaller ΔCm and, thus, not by smaller amount of inserted vesicular proteins (Figure 3D). It was caused by smaller calcium concentration for two reasons. First, each pulse from −80 to −5mV induced an ICa (1.4 ± 0.1 nA, n = 18; Figure 3C) much smaller than that by depolarization to +10mV during depol10ms×10 (2.2 ± 0.1 nA, n = 13; p < 0.01). Second, the pulse was repeated at 0.5 Hz, at which calcium summation was negligible compared to the 10 Hz train (Figure 1B).
P/Q-type Calcium Channels Control Endocytosis
To provide more direct evidence that VDCCs couple exo- to endocytosis, we blocked VDCCs with the P/Q-type VDCC blocker, ω-Agatoxin-IVA. Calyces in P7–P10 rats contain P/Q-, N-, and R-type VDCCs, among which P/Q-type contributes about two-thirds of ICa (Wu et al., 1999,Iwasaki et al., 2000). In the presence of ω-Agatoxin-IVA (200 nM, bath, 10–40 min), depol10ms×10 induced a QICa (72 ± 6 pC, n = 12) and a ΔCm (812 ± 41 fF, n = 12; Figure 4A) smaller than control (193 ± 14 pC, 1445 ± 80 fF, n = 13; Figure 3B; p < 0.01). Endocytosis was much slower because the capacitance decay was too slow to fit exponentially, and the Ratedecay (50 ± 4 fF/s, n = 12, Figure 4A) was much slower than control (231 ± 21 fF/s, n = 13, Figure 3B; p < 0.01). The slower Ratedecay was not due to the ΔCm decrease because a pair of depol10ms×10 values at 5 s interval induced a ΔCm (1260 ± 36 fF, n = 10, Figure 4B) similar to that by a depol10ms×10 in control (p > 0.05; Figure 3B) but induced a Ratedecay (61 ± 5 fF/s, n = 10, Figure 4B) much slower than that by a depol10ms×10 in control (p < 0.01; Figure 3B). Thus, VDCCs, including P/Q-type, couple exocytosis to rapid endocytosis.
To study slow endocytosis, depol10ms was applied. Depol10ms induced a ΔCm of 427 ± 24 fF (n = 12), followed by a mono-exponential decay with a τ of 15.8 ± 0.7 s (n = 12) and a Ratedecay of 36.7 ± 2.7 fF/s (n = 12, Figure 4C). The τ (∼15.8 s) of this slow endocytosis was much shorter than that after the 20 pulse train, which also induced slow endocytosis with a τ >30 s (n = 18; Figure 3C), but a ΔCm ∼231% higher than that induced by depol10ms. Thus, more exocytosis was followed by endocytosis with a slower τ, inconsistent with the vesicular channel hypothesis. The slower τ was likely due to two factors. First, ICa (1.4 ± 0.1 nA, n = 18) induced by each pulse during the 20 pulse train was less than that induced by a depol10ms (2.10 ± 0.11 nA, n = 12; p < 0.01). Although there were 20 pulses, the low-frequency (0.5 Hz) train generated negligible (nanomolar range) calcium summation at terminals (Figure 1B), whereas more than a few micromolars of calcium are needed to trigger endocytosis at calyces (Wu et al., 2009,Hosoi et al., 2009). Second, ΔCm induced by the 20 pulse train was much higher, which may saturate the endocytosis capacity and thus slow down endocytosis (Sankaranarayanan and Ryan, 2000,Wu et al., 2005).
In the presence of ω-Agatoxin-IVA (200 nM), depol10ms induced a QICa (8.8 ± 0.4 pC, n = 14, Figure 4D; peak amplitude, 0.91 ± 0.06 nA) ∼45% of control (19.5 ± 1.0 pC, n = 12, peak amplitude: 2.10 ± 0.11 nA; Figure 4C), and a ΔCm (270 ± 17 fF, n = 14, Figure 4D) about 63% of control (427 ± 24 fF, n = 12, Figure 4C). The capacitance decay was too slow to fit with an exponential function (Figure 4D). The Ratedecay was 16.3 ± 1.6 fF/s (n = 14, Figure 4D), much slower than control (36.7 ± 2.7 fF/s, n = 12, Figure 4C; p < 0.01). The slower Ratedecay and endocytosis time course were not caused by the ΔCm decrease because in the presence of ω-Agatoxin-IVA, a pair of depol10ms values at 5 s interval induced a ΔCm (393 ± 27 fF, n = 9; Figure 4E) similar to that by a depol10ms in control (p = 0.31), but a Ratedecay (18.7 ± 1.6 fF/s, n = 9; Figure 4E) much slower than that by a depol10ms in control (p < 0.01; Figure 4C). Thus, VDCCs, including P/Q-type, couple exocytosis to slow endocytosis.
Results shown thus far were from P7–P10 rats, in which calyces are not mature. In P13–P14 rats in which calyces are mostly mature (Schneggenburger and Forsythe, 2006), we repeated experiments similar to those shown in Figures 1A and 2C (upper) and Figures 3A and 3B and found similar results (Figure S2; Figure 2C, lower). Thus, our observations applied to both immature and mature calyces.
We found that fusion did not generate calcium currents or influx at the plasma membrane (Figure 1), that Flower was localized at synaptic vesicles of rat brain and calyces (Figure 2), and that the current charge of VDCCs at the plasma membrane, including P/Q-type, determined the rate of rapid and slow endocytosis (Figures 3 and 4). These results suggest that fused vesicle membrane and proteins, including Flower, could not generate calcium currents to initiate endocytosis. Instead, plasma membrane VDCCs, including P/Q-type, couple exocytosis to two widely observed forms of endocytosis: rapid and slow endocytosis.
Our findings are different from a study showing that vesicular VDCCs inserted at the plasma membrane via exocytosis are required for endocytosis in sea urchin eggs (Smith et al., 2000). The difference is likely due to the significant differences of the two systems. Calyces are nerve terminals containing small (∼50 nm) vesicles with endocytosis lasting for less than tens of seconds (Figures 3 and 4), whereas sea urchin eggs contain very large (∼1 μm) vesicles with endocytosis lasting for ∼15–30 min.
Our findings are different from the study of Drosophila synapses (Yao et al., 2009). Although the synapse specificity could provide an explanation, the Flower hypothesis is not well established as discussed below. At Drosophila nerve terminals, vesicular Flower insertion into the plasma membrane via exocytosis increases the [Ca2+]i at the submicromolar range after prolonged tetanic stimulation (Yao et al., 2009), whereas endocytosis at nerve terminals is initiated by more than a few micromolars of calcium (Wu et al., 2009,Hosoi et al., 2009,Beutner et al., 2001). Furthermore, the time course of the calcium rise via Flower channels is in the order of 10–60 min (Yao et al., 2009), which was too slow to initiate endocytosis that typically lasts for a few to tens of seconds at many synapses, including Drosophila synapses (Poskanzer et al., 2003,Wu et al., 2007). Such slow calcium permeation might explain why we did not detect calcium currents or influx within a few seconds after exocytosis.
Endocytosis quantified with FM1-43 uptake at one time point after prolonged (1 min) high potassium stimulation was reduced by ∼41% in Flower mutants (Yao et al., 2009). Compared to a complete block of endocytosis by calcium buffers (Wu et al., 2009,Hosoi et al., 2009,Yamashita et al., 2010), such a small defect suggests that Flower is not essential in initiating endocytosis. Furthermore, whether Flower plays a role under physiological conditions is unclear because endocytosis after brief physiological depolarization was not quantified in Flower mutants (Yao et al., 2009).
Although the Flower hypothesis is not well established, the present work firmly established a critical role of plasma membrane VDCCs, but not vesicular channels, in initiating and speeding up endocytosis at calyces. Whether our results apply to other synapses has not been tested. However, except that the calyx is much larger than conventional boutons, it is similar to other nerve terminals in many aspects, such as the active zone size, the vesicle number per active zone, short-term plasticity, transmitter release properties, calcium currents, and endocytosis time course (Schneggenburger and Forsythe, 2006,Wu et al., 2007,Xu et al., 2007). Our findings are, therefore, likely to apply to other synapses. Considering that VDCCs control exocytosis in all chemical synapses and many non-neuronal secretory cells, we suggest that VDCC-mediated exo-endocytosis coupling is a common mechanism at synapses and many non-neuronal secretory cells. Consistent with this suggestion, calcium influx was found to regulate endocytosis at many synapses and non-neuronal secretory cells (Ceccarelli and Hurlbut, 1980,Marks and McMahon, 1998,Cousin and Robinson, 1998,Gad et al., 1998,Sankaranarayanan and Ryan, 2001,Balaji et al., 2008,Neves et al., 2001,Clayton et al., 2007,Artalejo et al., 1995,He et al., 2008).
Experimental Procedures
Slice preparation and capacitance recordings were described previously by Sun and Wu, 2001 and Sun et al., 2004. Briefly, parasagittal brain stem slices (200 μm thick) containing the medial nucleus of the trapezoid body were prepared from Wistar rats using a vibratome. Unless mentioned, rat age was 7–10 days old. All animal protocols followed the guidelines of the National Institutes of Health, USA. Whole-cell capacitance measurements were made with the EPC-10 amplifier together with the software lock-in amplifier (PULSE, HEKA, Lambrecht, Germany) that implements Lindau-Neher's technique. The frequency of the sinusoidal stimulus was 1,000 Hz, and the peak-to-peak voltage of the sine wave was ≤60mV. We pharmacologically isolated presynaptic ICa with a bath solution (∼22°C–24°C) containing 105 mM NaCl, 20 mM TEA-Cl, 2.5 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 25 mM NaHCO3, 1.25 mM NaH2PO4, 25 mM glucose, 0.4 mM ascorbic acid, 3 mM myo-inositol, 2 mM sodium pyruvate, 0.001 mM tetrodotoxin (TTX), 0.1 mM 3,4-diaminopyridine (pH 7.4) when bubbled with 95% O2 and 5% CO2. When ω-Agatoxin-IVA was applied to the bath, cytochrome c (0.1 mg/ml) was also included. The presynaptic pipette (3.5–5 MΩ) solution contained 125 mM Cs-gluconate, 20 mM CsCl, 4 mM MgATP, 10 mM Na2-phosphocreatine, 0.3 mM GTP, 10 mM HEPES, 0.05 mM BAPTA (pH 7.2) adjusted with CsOH.
The statistical test was a t test. Means are presented as ± SE. Ratedecay was measured from 0.3 s to 3 or 6 s after stimulation (Wu et al., 2009). The [Ca2+]i was measured with fura-2 (50 μM, replacing BAPTA in the pipette), the Olympus upright epifluorescence microscope (BX51WI, LumplanFI 40×, n.a. 0.8), a polychromatic illumination system (T.I.L.L. Photonics, Munich), and a photodiode for fluorescence recording (Xu and Wu, 2005).
Cytosol and synaptic vesicle proteins were prepared by sucrose gradient fractionation (Yao et al., 2009). P8 rat brain was homogenized and centrifuged to yield a crude synaptosomal pellet, which was then resuspended in 100 mM NaCl, 20 mM HEPES (pH 7.4) solution and loaded onto sucrose step gradient (0.2–0.4 M) for centrifugation (20,000 × g, 5 hr). Synaptic vesicles were collected from 0.2 to 0.4 M sucrose interface. The proteins were quantified and subject to SDS-PAGE for western blot assay (Invitrogen).
For western blot, P8 rat brain was homogenized and centrifuged to yield supernatants, which were quantified and loaded to SDS-PAGE for immunoblotting using a custom-made rabbit antibody against Flower (1:50; GenScript) and a mouse antibody against VAMP2 (1:10,000; Synaptic Systems).
For immunohistochemistry, rats were anesthetized by Nembutal, fixed by paraformaldehyde, and infiltrated with 30% sucrose. OCT (Electron Microscopy Sciences)-embedded rat brain was sectioned using a cryostat (Leica CM3050S) at 30 μm thickness. The calyces were recognized by a guinea pig antibody against vGluT1 (1:5,000; Millipore), and Flower proteins at calyces were identified using the rabbit antibody against Flower (1:50; GenScript). For the peptide-blocking experiment (Figure 2C, middle), Flower antibody was preincubated with the Flower peptide (Figure 2A, red) overnight at 4°C. Dylight-488 donkey anti-rabbit and rhodamine-conjugated donkey anti-guinea pig antibodies (1:100; Jackson ImmunoResearch Laboratories) were used as secondary antibodies. Images were collected by Zeiss LSM510 confocal microscopy (40×, N/A 1.3).
This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program.
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Publication Information
Received: December 1, 2011
Revised: February 21, 2012
Accepted: April 11, 2012
Published online: May 31, 2012


text:
The Top 10 SEO Myths for 2011
The last five years or so have been boon years for both SEO specialists and Internet marketers alike. However, because SEO and web marketing services are in such demand there are now too many "professionals" who know very little about how search engines work. This in turn has given rise to plenty of SEO myths. Here are the top 10 for 2011, ranked in ascending order according to prevalence.
10. Submitting your site to search engines increases your ranking.
In the old days this might have been true, but no longer. Search engines like Google use web crawling technology that continually scans the Internet to find and rank pages. It will find your site even if it's not submitted.
9. You need meta-tags.
First of all, search engines no longer look for meta-tags so you're wasting your time with them. Secondly, meta-tags were originally designed to add key words that were not included in the content. By its very nature SEO eliminates the need for meta- tags.
8. With the optimal length of content is 250 words.
There is no optimal length for content when it comes to SEO practices. You only need to make sure you have an appropriate ratio between keywords and length.
7. Regular updates are necessary for high ranking.
Again, in the old days this may have been true, but some of the highest ranked sites on the web today haven't been updated in years. Web crawlers look for relevance; avoid updating unless you're adding quality, relevant content.
6. You can always be #1 for all your keywords.
Unfortunately, there are unscrupulous Web marketers promising to make you #1 for all your chosen keywords. With billions of pages across the Internet that claim is impossible to fullfil – just forget it.
5. You need a site map.
An XML site map might be useful for Google Tools but it has absolutely no bearing on your page ranking. A well structured site doesn't need an XML site map anyway.
4. Flash is always bad.
While it's true that Flash is irrelevant in terms of how search engines deal with SEO, it's not necessarily a bad thing. Flash only hurt your rankings if your site is all Flash with very little SEO content.
3. Google is the main priority.
It may be true that Google is the world's most popular search engine, but it's not the only one. A good SEO specialist knows how to optimize for a half-dozen different search engines.
2. Content doesn't matter.
Unfortunately, many believe that content doesn't matter as long as people visit your site. But if content is lousy to the point that readers aren't reading it, how will they ever find your links? Content is king if you want loyal return customers.
1. Page rank determines success.
This is the most widespread myth in SEO, and it's been so for decades. While page rank is important, most important is building a site which meets consumer needs. That means functionality, information, ease-of-use, and relevance.
Myths provided by SEO specialist Tom, working with Nomination charms uk and mortgage protection insurance businesses.
Written by DST Contributor
28 Responses to "The Top 10 SEO Myths for 2011"
Great tips, especially about ranking #1 for keywords. That is something I struggle to explain to clients every day.
Thank you for this article. Always appreciate a wise myth buster.
I'm a little surprised at some of these. While it's true that SEO has evolved dramatically over the years, some of the best practices still apply – and shouldn't be discounted.
We still include meta tags because of the chance that the page description may be used in the serps. A well-composed meta description can still influence searcher decision.
Site maps are still important as the engines still look for web components such as Site Map, Privacy Policy and Terms on a website as part of their algorithm.
We still aim for a good number of words on each page – 250 or more – because anything less makes it challenging to maintain the right ration of keywords to content.
Otherwise – good post!
Rebecca Slosberg Reply:
May 23rd, 2011 at 2:22 pmLouise,
Thank you for posting that comment. I knew a lot of those myths to be the case, maybe not as extreme as they are stated, but I always advice my clients that you should put in the titles tags and meta data and submit site maps. Even if they aren't ranked as highly in the new algorithm, they are till good practice.Arnie Reply:
May 23rd, 2011 at 9:32 pmLouise,
I agreed with you right up until you said "good post". About 50% of the information is just wrong or misleading at best, so can't qualify as a good post. Sorry but this is just not content worthy of Daily SEO Tip.Ashley Bryan Reply:
May 25th, 2011 at 1:34 amHave to agree with Arnie. Some clunker statements in this list. Back to SEO school for the author.
Great breakdown for all those new "SEO specialists" , I've been working on placement for customers since the Yahoo era and nothing makes me laugh more than those pitching #1 ranks and meta keyword stuffing!
Great posting ..
as an affiliate marketer, i need this for starter …Thanks
I particular like that you said that content ain't dead.
I have always seen content at the mail part – it should be so logically. Why should you rank, if you don't have content and doesn't present any value to the users? -
While I definitely agree with some of these (ranking #1, page rank, and some others), I have an issue with #9. As mentioned by Louise and Rebecca, although meta tags (especially meta keywords) may not contribute to the ranking of a website, the meta title and description are still important when it comes to click through from the SERPs.
If you want to argue that this wasn't the point of the post, then you would have to rewrite your argument for #2 (which I agree with). An SEO campaign should focus more on conversion metrics than pure traffic.
This is a really lame list, the average advice here makes me want to unsubscribe DailySEOTip out of my RSS reader.
Search engines don't look for meta tags?!
Have an approporiate "ratio" between keywords and length of content?!
Dont bother with an XML sitemap?!
"optimize for a half-dozen different search engines"?! – (Please let me know the top SIX search engines you'd spend time optimising for)Seriously WTF.
Sorry "Tom" who wrote this article, half this list is junk. At least you got to seed a couple of links to your mortgage insurance and charms sites though. Thats more important than giving proper SEO advice.
Really nice and valuable post, but I don't totally agree with point #5. You need a site map.
I think XML Sitemaps are created to be submitted directly to search engines, providing them with the exact contents of your website.
And the value of having an On-Page Sitemap is that it acts as a starting point where Search Engine spiders can quickly crawl pages while the distance from the home page is kept short.
i whole heartedly agree…stuffing meta tags is really not advisable.i knew how i used to stuff 15-20 meta tags when i started to blog…now i hardly use them…..
page rank well people still believe in page rank..it gives them a feel good factor lol…. -
I am a bit disappointed too. Good "click appealing" title post though.
well. your info is schocking. But i do agree with point 2. Because with good content we will have alot of loyal visiters to our sites.
Why don't you include the #11 SEO it self is a myth?
Search engine optimization is the process of improving the visibility of a website or a web page in search engines via the natural search results and all webmasters needed to do was submit the address of a URL, all these content is play big role of SEO.
"9. You need meta-tags.
First of all, search engines no longer look for meta-tags so you're wasting your time with them. Secondly, meta-tags were originally designed to add key words that were not included in the content. By its very nature SEO eliminates the need for meta- tags."
I think this statement could be slightly misleading. I understand that the meta keywords tag has no bearing with the major search engines these days, but that's not to say that the tag is completely redundant – I've worked on a few CMS' that still use it for internal search (and quite well, too!).
Did DST get hacked? This is a very low quality list that I would not expect to come from you guys.
Meta tags no-longer needed? – crap.
Insinuation of a keyword/content length ratio – crap.
XML sitemaps not needed? – crap.For almost every one of these you were close to hitting on a good subject, but your descriptions were off the mark.
I agree with many of the other posters that half the list isn't correct. You may not need meta keywords tag but including the meta description and a title tag is definitely good practice.
The part about Google as a main priority being a myth made me laugh. Yeah, why would you make the site that refers 85% of the traffic on the Internet a priority?
Also, XML sitemaps might not be important to smaller sites that have 50 or fewer pages but they're critical to making sure content gets crawled on large sites (several hundred pages).
Awesome, you have definitely busted some SEO myths!
Nice and excellent tips. Thanks for share.
@Rmercader what is your take on #9 in the 2011 #seo Myths post? http://dailyseotip.com/the-top-10-seo-myths-for-2011/1557/
Here it is, it is now 2011 and people are still more concerned about optimizing their website for search engines rather than for people. If you optimize your site for people Google and Bing will do most of your SEO for you.
Your tips are number one..!!!
Greate tips = Great blog like yours..!! -
Hey, Tom! I knew about the PR myth, as it has become more common knowledge even among the newbies like me. But the others are less familiar to me, thanks a lot for sharing!
Well somethings are missleading. Sitemap is a must
Very important tips are presented here to get good results for an SEO. Thank you so much for sharing this post.


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CHEEKTOWAGA, N.Y. -- The terminal at the Buffalo Niagara International Airport is bustling during the holiday travel week and passengers coming in and out have a new business to stop at, the new Visit Buffalo Niagara Visitor Center.
"Our goal to this store is to service people who are coming into the market and get them around to where they need to be and tell them about all the great things that are happening here," said Visit Buffalo Niagara President & CEO Dottie Gallagher-Cohen.
The visitor center features Buffalo themed merchandise, locally made products, and it's staffed with people full of knowledge of Western New York. Officials hope it will help people discover the many things to do around town.
The visitor center had a soft open months ago but it is now at full capacity.
Gallagher-Cohen said, "In the month of August we serviced the same number of visitors at this store than we do all year in our downtown visitors center. It's been a home run."
Any profits from the center will be reinvested into the Visit Buffalo Niagara marketing campaign.
The shop is open 7 days a week and is located inside the secure area of the airport.


text:
- Fund Type: Open-End Fund
- Objective: Taxable Treasury/Repo (US)
- Asset Class: Money Market
- Geographic Focus: U.S.
Fidelity Treasury Fund
+ Add to WatchlistFSRXX:US
0.0100 Price Method: YieldAs of 09:29:30 ET on 03/14/2014.
Snapshot for Fidelity Treasury Fund (FSRXX)
Days to Maturity: | 53.0 | Assets(M): | 5,560.0100 | 52-Week Range: | 0.0100 - 0.0100 |
Fund Profile & Information for FSRXX
Fidelity Treasury Fund is an open-end fund incorporated in the USA. The Fund's objective is to obtain as high a level of current income as is consistent with the preservation of capital and liquidity. The Fund normally invests at least 80% of assets in U.S. Treasury securities and repurchase agreements for those securities.
Inception Date: | 1983-08-31 | Telephone: | 1-800-544-6666 |
Managers: | KEVIN GAFFNEY | ||
Web Site: | www.fidelity.com |
Fees & Expenses for FSRXX
Current Mgmt Fee | 0.25 |
Expense Ratio | 0.12 |
Quotes delayed, except where indicated otherwise. Mutual fund NAVs include dividends. All prices in local currency. Time is ET.
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