text:
Shopping cart empty
Shopping cart empty
Acid Defense provides alkalizing minerals from goats milk whey, along with organically grown vegetable juice concentrates. These natural food sources help your body to maintain comfortable pH levels.* Additionally, the enzymes in Acid Defense work to support healthy digestion.
Optional: Help others find your review.Enter Descriptive Keywords (ex. heart, cholesterol, arteries)


text:
Membership has its privileges: you will receive our newsletter, be able to post reviews and classifieds.
Log In.
62787 registered users have written 20324 reviews of 7809 spots! and 71274 answers to 8364 questions by New Hanoians, old and new!
If you're a business owner, click here for more information, or email us at email@example.com.
If you'd like information about placing your banner ad on this site, send us an email at email@example.com.
"Mr. Nam, he is THE guy. Friendly, helpful, reliable and professional. I've us..."
"IF Consulting helped me a find a package that covered my entire family. The ..."
"IAF ruined my painting.
Based on reviews, I brought a precious acrylic paint..."
"Donkey Bakery, for my money, serves the very finest bread in Hanoi. Their No..."
"Pane e Vino has a distinctive character with the decorations and a larger-tha..."
"Daluva has one of the most innovative menu's in Hanoi. I was skeptical about..."
"I've tried many times to learn Vietnamese and this is definitely the most fun..."
"I've used Mr. Bao's services three times.
First time he came to the house, ..."
"I haven't used Nam for the visa service but he is fantastic when organising a..."
"Mr Nam.
Mr Nam.
Mr Nam.
So good he got my children's private ..."

subset: commoncrawl


text:
Justin Lanier
I'm a staff member at the Princeton Learning Cooperative.
I co-author Math Munch, a weekly digest of the mathematical internet.
Communities (5)
Top Network Posts
- 35What is the simplest, most elementary proof that a particular number is transcendental?
- 14Anecdote about mathematicians leaping to tops of problems and then building a staircase down?
- 10Are these nested Tables necessary?
- 10$1000 to spend on a math classroom?
- 6Organizing types of functions by their calculus-related properties, in diagram form?
- 6English translation of Lambert's Theorie der Parallellinien?
- View more network posts →
Keeping a low profile.
This user hasn't posted... yet.
Badges (3)
Gold —
Silver 2
Bronze 1


text:
Grandpa Tony's Tree Farm
305 Weeks Ave. Manorville, NY 516-639-3587
View map
User rating:Type: Christmas tree cutting Price:
(12) Click to rate
U-cut fir and spruce trees. Cutting and loading assistance available.Hours:
Thurs-Sun: 8 a.m.-7 p.m. (Oct.-Dec.)Season:
Day after Thanksgiving to Christmas eve
Newsday.com now uses Facebook for our comment boards. Please read our guidelines and connect your Facebook account to comment.


text:
The heart-broken mother of Sean Smith, one of the State Department employees killed in the Benghazi attack, left the movie premiere of the '13 Hours' in a rage. [Read more…]
The French Guide to American Faith, Politics and Culture
The heart-broken mother of Sean Smith, one of the State Department employees killed in the Benghazi attack, left the movie premiere of the '13 Hours' in a rage. [Read more…]
Remember this Hillary Clinton ad which ran against Barack Obama back in 2008? In this famous "3 AM Call" commercial, she attempts to compare herself against Obama: the message is clear. She can handle foreign crises. She is a leader for tough times. [Read more…]
There was one really great moment in the debate last night that will have people talking for some time. Ted Cruz slammed people from New York, saying that they didn't have the same type of values as the rest of America. [Read more…]
The President is a clever one. In his final State of the Union address, he said this:
America has been through big changes before – wars and depression, the influx of immigrants, workers fighting for a fair deal, and movements to expand civil rights. Each time, there have been those who told us to fear the future; who claimed we could slam the brakes on change, promising to restore past glory if we just got some group or idea that was threatening America under control. And each time, we overcame those fears. We did not, in the words of Lincoln, adhere to the "dogmas of the quiet past."
Who wants to be one of those knuckle draggers who "adhere to the quiet past?" No one! David French extrapolates:
Concerned that the sexual revolution is destroying the family and fraying the fabric of society? You fear love. Concerned that mass numbers of low-skill immigrants are decreasing wages, increasing crime, and overwhelming social services? You fear people who look different from you. Are you demanding that the Obama administration step up its war against ISIS? You're too fearful and ignorant to realize that, as the New York Times helpfully reminded readers this week, your bathtub is more dangerous than Muslim terrorists.
His rhetoric perfectly set up his emotional plea:
Will we respond to the changes of our time with fear, turning inward as a nation, and turning against each other as a people? Or will we face the future with confidence in who we are, what we stand for, and the incredible things we can do together?
But this misses the point altogether. As French writes, "Americans aren't fearful, they're angry."
The entire alphabet soup of federal agencies has not only failed the American people, they've often turned against the very citizens and Constitution they're required to serve. The IRS attacks the conservative movement. The VA leaves veterans to die. The EPA lawlessly expands its power until it regulates and restricts vast sectors of the American economy. HHS attacks religious liberty. The Department of Education wages war on due process and free speech. The list could go on and on.
We're tired of a government that targets and harasses us, yet refuses to protect us. And anger, sometimes, is warranted and profitable.
French continues:
Anger can be a virtue — even Jesus got angry — and in this moment of American history, properly channeled anger might be the very thing that restores American strength abroad and begins to correct injustice and rampant abuses of power here at home. Indeed, without anger, we may not have the fortitude to change. To those crying out for "sunnier," more pleasant politicians, ask yourself if these people have the strength of will to confront entrenched, malignant ideologues in the IRS, DOJ, EPA, BLM, VA, and every other leftist enclave in American government. Ask yourselves if they're prepared to confront ISIS, Iran, and Russia.
Read the rest of his piece on National Review.
Order my next three books on Amazon:
Read more on the Patheos Faith and Family Channel, follow Nancy on Facebook, Twitter, and Instagram!
For once, Mrs. Clinton had the wisdom to stay quiet. [Read more…]
Copyright 2008-2016, Patheos. All rights reserved. Terms of Service | Patheos Privacy Policy | Website Development By Patheos Labs


text:
Live Prices Not Available
To show you the most accurate prices, TTPM only displays our pricing tool on products which we've reviewed in the past three years.
The ghouls of Monster High are glamming it up for picture day with freaky-fabulous new looks. Each doll comes with a Fearbook (instead of "yearbook") and picture day stickers, so kids can swap, trade, and store the photographic memories. Kids can also vote on superlatives, or which ghoul they think is the most athletic, always late to class, most likely to succeed, and fastest. The last page of the Fearbook has a Monster High class picture and signatures from all the Monster High characters.
Picture Day Abbey Bominable sports a new outfit of patterned leggings, a furry black shrug, and a pink, purple, and blue top. Part of Abbey's hair has been streaked to match the outfit. The doll also comes with a pink backpack, a notebook, a hairbrush, and a doll stand.
School Picture Day is something that every student experiences, so, of course, the ghouls of Monster High are getting their pictures taken for the school Fearbook. The Picture Day dolls are a great new theme for Monster High with new fashions for favorite characters and all the humor that Monster High fans have come to expect and love from this doll line.
Monster High Picture Day Abbey Bominable is for Monster High fans ages 6 and up.
Additional Monster High Picture Day dolls include Cleo de Nile, Draculaura, and Spectra Vondergeist. Each is sold separately.
Project Mc2 Camryn Coyle
from MGA Entertainment
Project Mc2 Adrienne Attoms
from MGA Entertainment
Project Mc2 Bryden Bandweth Smiley Face Shirt
from MGA Entertainment
Project Mc2 Bryden Bandweth Sharpest Pencil Shirt
from MGA Entertainment
DC Super Hero Girls Power Action Wonder Woman Doll
from Mattel
Monster High Voltageous Hair Frankie Stein
from Mattel
Barbie 2016 Presidential Doll 2-Pack Green Eye/Brown Eye
from Mattel
Barbie 2016 Presidential Doll 2-Pack Blue Eye/Brown Eye
from Mattel
Barbie Star Light Adventure Gown Doll
from Mattel
Barbie Spaghetti Chef
from Mattel


text:
Enter your stay dates and any discounts you qualify for to see Bamford, United Kingdom rates found only on HotelPlanner!
Find accommodations in Bamford with the hotel list provided below. Find cheap and discounted hotel/motel rates in or nearby Bamford, United Kingdom for your corporate or personal leisure travel. We list the best Bamford hotel and motel rooms. Browse the Bamford area hotels to find the perfect lodging! Please use the provided map of the Bamford hotels.
The Bamford center is around 8 miles west of Sheffield Botanical Gardens and 9 miles west of Bramall Lane.
How should we direct your call?


text:
Adam Jones scored the winning run in the 10th inning on a low throw to the plate by pitcher Jordan Lyles, and the Baltimore Orioles beat the Colorado Rockies 3-2 on Monday night for their fifth straight victory.
Justin Sullivan/Getty Images
It's official: Yahoo's days as an independent company are over.
Verizon has agreed to pay $4.83 billion for Yahoo, the companies said before markets opened Monday.
The sale completes Yahoo's evolution from influential search pioneer and web portal jug...
No email address was supplied by
To complete your registration on this site, please supply an address.
Please confirm or modify the email address to which you will have subscription offers sent.
For a more personalized experience, please supply the following optional information.


text:
OSI-Approved Open Source (536)
- GNU General Public License version 2.0 (357)
- GNU Library or Lesser General Public License version 2.0 (60)
- GNU General Public License version 3.0 (47)
- BSD License (29)
- Apache License V2.0 (13)
- Artistic License (11)
- GNU Library or Lesser General Public License version 3.0 (10)
- MIT License (10)
- Affero GNU Public License (6)
- Open Software License 3.0 (5)
- zlib/libpng License (5)
- Mozilla Public License 1.0 (4)
- Mozilla Public License 1.1 (4)
- Academic Free License (3)
- Common Development and Distribution License (2)
- Public Domain (28)
- Creative Commons Attribution License (11)
- Other License (11)
- Windows (435)
- Linux (420)
- Grouping and Descriptive Categories (388)
- Modern (241)
- Mac (229)
- Android (105)
Conversion Software
Hot topics in Conversion Softwarempeg audio decoder 184.108.40.206 application/x-shockwave-flash decoder mpeg audio decoder bsplayer mpeg audio decoder libmad dll libmad mp3 decoder mpeg haali media splitter mad
Showing page 7 of 25.
The best converter tool for Windows.1 weekly downloads
Wacvst (windows-mac vst) is a tool that will wrap Windows native VSTs for use with Intel Mac OS X based VST hosts.48 weekly downloads
xGordian aims to be similar to the older Gordian Knot, while being far easier to use. It supports new Input & Output formats such as DVD and Blu-Ray input, and x264/aac in mkv/mp4 output.1 weekly downloads
Xenoage Player
Xenoage Player is a program written in Java that plays MusicXML files an can save them as Standard MIDI files.3 weekly downloads
Converts single or multiple FLAC files to MP3, Wav and other formats. Converts (and maintains synchronized) a high quality digital FLAC album archive to widespread formats souch as MP3.
MAD (MPEG Audio Decoder)
MAD is a high-quality fixed-point MPEG audio decoder with 24-bit output. The implementation is entirely new, based on the ISO/IEC standards, and performs especially well on systems without native floating-point support.1,950 weekly downloads
DVD2MP3 is a perl script which converts audio tracks on a DVD into id3 tagged mp3 files. It was written for Linux, though it could probably be used on other Unixes with little trouble. It requires mplayer, lame, lsdvd, MP3::Tag and Term::ReadLine.2 weekly downloads
VST Oversampler
The oversampler "hosts" another VST plugin, and oversamples it by 2. Unpleasant aliasing artifacts have twice the frequency range to unfold, and this extra range is discarded to provide a cleaner sound.
An ffmpeg GUI for video encoding. Supports DVD and files and converts to all formats allowed by ffmpeg, including the iPod, PSP, and other popular formats.3 weekly downloads
Transmusic convert music files from a format to an other format using a simple GUI. As an exemple, you can convert a midi file in a mp3 file that you can load on your mp3 player.1 weekly downloads
Temporal Twist
Application to adjust the tempo of audio files. Useful for speeding up podcasts without making the speaker sound like a chip-monk.1 weekly downloads
SynthEdit VST Modules
This project will provide open source high level, modules, written in C++, for use with the SynthEdit VST creator. Emphasis will be placed on quality of sound, and real-time performance.
Sea Eagle
This is a web application written in C# to provide universal transcoding, transformation and enhancement solution for image, rich medias and documents. It exposes all the services via web.
rm-wav converter
Goal : standalone rm-wav converter based on a RM parser with several decoders.
A VST plugin that bridges VST data to the Open Sound Control networked domain. The plugin supports OSC scheduling and parameter control. The OscVstBridge can be used as a OSC to MIDI converter as well as a MIDI to OSC converter by using a VST host.10 weekly downloads
This is a web interface to convert audio, video and documents to various formats. Acts just like a wizard. RedKonvert is written in php. It's nothing fancy (no CSS no AJAX/javascript). Just plain old HTML and PHP (maintaining the "KISS" ideology).1 weekly downloads
A utility to allow the analysis and conversion of Native Instruments Reaktor save files. Specifically, the conversion of said files to an XML file, which can then be converted to a number of various other formats. (Ex: pd, Max/MSP, Csound...)
Tag editor for mp3 files. Designed to convert codepage for ID3v1 and ID3v2 tags.1 weekly downloads
QRip is a intuitive Qt4-based frontend to transcode, a general purpose movie transcoder. QRip supports DVD ripping and creation, as well as the transcoding of audio or video files from one format to another.
An ID3 tag encoding converter Features: * Beautiful GUI based on Qt 4 * Easily add/remove files onto/from convertion list * Priview ID3 convertion results * Change convertion encodings on-the-fly * Convertion progress indicators1 weekly downloads
pyter format conversion framework
pyter is an innovative file format conversion utility developed in conjunction with the Main//Pyrus DMS. It does not do the actual conversion, but builds chains of configurable utilities to do the task and produces a definable set of output formats.1 weekly downloads
Magicfish Postmod
Post-production software for Impulse Tracker modules.
This utility is intended for management of contents of flash players Sony16 weekly downloads
Playlistlib is a portable, C++ library for converting between playlist formats, such as M3U, PLS, and WPL. The project also has a Windows program for converting playlist files and demonstrating the use of the library.
Easily convert audio and video files in PHP with this easy to use module. Supports all major audio and video formats. Great for video or audio hosting sites.


text:
Did I screw this up? READ MORE
Food and Cooking
How to Make Meat-Infused Liquor
Chorizo margaritas, anyone? READ MORE
Recipe Test: Turquoise's Chicken and Vermicelli Soup With Egg and Lemon
Easy and comforting READ MORE
Recipe Test: A16's Kale with Anchovy Soffritto
Kale, tomato paste, and anchovies, oh my. READ MORE
Haute Stoner Treats
Michael Recchiuti has the demented mind of a high-end stoner. READ MORE
Cook and Tell: Healthy Vegan Seaweed Salad
The verdict on Vegan Fusion World Cuisine's recipe. READ MORE
Perfect Rhubarb Jelly
No strawberries, but it takes two days to make. READ MORE
Michael Ruhlman on Cooking by Numbers
The author breaks down how to use math to simplify your cooking in this video clip. READ MORE
Crescent City Farmers Market Cookbook
Laissez les bon temps rouler with this new cookbook. READ MORE
Man + Toast = Love
Toasters never seemed so glamorous before. READ MORE


text:
Product details
The LPG portable fire is a practical energy saving gas heater which will enhance your home.
- Features: Piezo electric ignition mode, flame failure protective device. Castors for easy moving space for gas cylinder up to 16kg.
- Usage: Suitable for decorative or practical use.
- Dimensions: (H)73, (W)41, (D)36cm
Mansion LPG Portable Fire 225415
£109.00 Online exclusive218 points
Select product options
Mansion LPG Portable Fire
Free collection in store.
Home delivery within 3 days
Next day, named day & Saturday also available
{"calculators": { "calculator": { "pimProductAttr": ["", "", "", ""], "calcType": "" } } }
Related Products
Dimplex 2kW black compact fan heater with ceramic ...
This Convector Heater features built in carry handles. ...
This Convector Heater features built-in carry handles. Colour: ...


text:
|4 reviews in total
It is hard to believe that there was a time when some of the last century's
greatest artists were considered mere entertainers: Hitchcock made
thrillers, Sirk made weepies, Hawks made comedies. Of course, we now know
that these auteurs worked in genres that many other directors worked in, but
transcended them by subversion, critique, extension, parody, genius.
There aren't so many English genres - the documentary-style war film is probably the most persistent - but in the 1950s, there were a spate of comedies that ran the gamut from glossily glamorous (GENEVIEVE etc.) to the cheerfully cheap (all those precursors to the CARRY ONs, like TWO WAY STRETCH and TOO MANY CROOKS), all of which invariably starred a small pool of exceptional players, including Alistair Sim, Terry-Thomas, Kenneth More, George Cole, John le Mesurier, Michael Hordern, etc.
Like most generic products, these films were modest, content to entertain in an unsurprising fashion, which they did. But, as with every genre, there is always a superior artist who expands its limits. Frank Launder and Sidney Gilliat may not, as a directorial team, reach the dizzy heights of the Archers, but, since writing THE LADY VANISHES for Hitch in 1938, they produced a steady stream of highly literate and cinematically inventive comedies, which, while smuggling in complex and disturbing ideas, never failed the first duty of comedy, which is to be funny.
THE CONSTANT HUSBAND may not be a masterpiece, but it is extraordinarily daring. A lot of critics like to talk about disjunction and alienation implied in films, disturbances in character, crisis in identity, but it's rare to find a supposedly frothy comedy which has this as its overt subject matter. A man (Rex Harrison) wakes up dazed in a strange country with a strange language, no idea who he is, or how he got there.
With the help of a professor of psychiatry, Llewellyn (THE LADYKILLERS' Cecil Parker), he pieces together his life, and discovers that they are indeed pieces, that he is a cad, a gold-digger and a bigamist, who hit on women with the prospect of wealth, and dumped them when it fell through. He is rather appalled by his past, and is brought to court for bigamy. Yet such is his charm that all his normally intelligent wives pay for his defence, and declare they would gladly take him back.
From the opening sequence, you know you are watching something special, as Gilliat presents us with a series of fragments (a lampshade, a view out the window, a wardrobe mirror) as a dazed man comes back to consciousness. We do not see him first, but his reflection, as he looks in the mirror; the sequence is very broken in its editing to suggest the characters alienation from himself. In one hilarious sequence, he ponders the various possibilities of who he is - judge, priest, sportsman etc. - which are visualised in the mirror.
And this is what the film essentially is, a detective story, as a man searches for himself, his true identity. As such, it can be counted as an early anti-detective film, three years before VERTIGO. Unlike a normal detective, objectively analysing a crime, Harrison is personally involved; like Oedipus, the first detective, he is the answer to the question. But it is not a reassuring answer - the further Harrison searches the truth, the more diffuse that answer is - he is not one person, he is a series of endlessly proliferating identities, an abstraction made concrete in the number of wives he collects. And while this might seem to minimise women, it obliterates him until he becomes nothing. This leads to genuine, if comic, bewilderment in the court, as legal questions of identity and responsibility take on an ontological aspect.
This is a man who has so effaced himself that he can no longer live in the world, and sees prison as a refuge. I think it was Andre Breton who once suggested that Surrealism never took off in England because its desperate normality is already so surreal, and it is amazing how many predictions of the late Bunuel can be found here, as in so many English comedies of the period.
The great thing, though, is how accessible all this is: the comedy is expert and witty; the identity mystery compelling; the ending up in mysterious Wales mind-boggling. The faded 50s colour is beautiful, doubly so when you think of the monochrome uniformity of the war films that dominated the period; and the old hands in the cast are a joy, as is sexy Rexy, who cannot help (unconsciously?) repeating his past mistakes, adding another ironical layer to the film.
In 'The Constant Husband' a man loses his memory, and then recovers it to find that he has an unusually large number of women in his life. The success of a comedy like this hinges on the strength of the leading actor; Rex Harrison carries it off very well. The character he plays is comparatively wealthy and over-privileged, and it is not easy for this viewer to forget than life in the mid 1950s was considerably less comfortable for the vast majority of people in Britain. Among the glamorous and less-than-glamorous supporting actors are Kay Kendall, Margaret Leighton, Cecil Parker, George Cole and Michael Hordern. The script includes some sort of running joke about Wales which, being from Wales, I failed to understand.
This is certainly a film to savor for marvelous performances and the
style of an almost fine film maker as he slowly peels back the layers
of the onion skin of a story with the audience struggling right along
with the lead (the always charming Rex Harrison) to find out who and
what he is after he comes to in a seaside Welsh hotel with no memory of
Unfortunately, the original ad campaign seriously undercut the chief interest in the film as a light hearted mystery, trying to lure audiences with a presumably "racy" tag line about the "Intimate revelations" of Rex's character who "went one better than Henry VIII" (all told in "Blushing Technicolor")! Tack that onto a plot which, once the past nature of Rex's character was revealed, had no where to go even with a courtroom full of women still anxious to throw themselves at him, and you can readily understand THE CONSTANT HUSBAND going straight to TV in the U.S. - the first relatively major film to do so - not getting a theatrical release for two years.
You certainly cannot blame the sterling cast for the film's ultimate letdown - any film with BOTH Margaret Leighton and Kay Kendall (the soon-to-be Mrs. Rex and reputedly the love of his many partnered life off-screen) AND droll performances from Cecil Parker, Robert Coote, Michael Hordern, Valerie French and a generous bevy of other beauties is going to hold the viewer's delighted interest right up to the end. If the film HAD an end or any idea how to end, I suspect it would be a perennial which we would play constantly on both sides of the Atlantic like so many of the sublime Ealing comedies, rather than only now (in 2010) enjoying a British DVD release with no likelihood of being offered in the Colonies.
Instead, THE CONSTANT HUSBAND (a/k/a MARRIAGE ALA MODE - no relation to the brilliantly satirical Hogarth painting) just peters out - leaving a hint in the resemblance of the leading ladies what a better director (than Sidney Gilliat) might have done with the property had he chosen to have ALL the women in Rex's life played by the same actress (either Kendall or Leighton would have been marvelous) the way Alec Guinness famously played all the doomed members of the D'Ascoyne family six years earlier in the dazzling KIND HEARTS AND CORONETS. Just that little touch of style might have made all the difference. It might have even made the lame final fade out make some sense...the 84 minutes which preceded it were such fun.
The 1950s were an awful decade for comedy--censorship was strict, and middle-class manners were corseted so tight as to induce hysteria. This movie has a supposedly comic situation, but there is no funny dialogue, no funny scenes. There is just a lot of embarrassment, which is supposed to be ipso facto terribly amusing. The script is careless--Rex Harrison is a man who marries women for money, but his Italian wife clearly doesn't have much (she has, though, a stupendous bust and a foreign accent, and gestures a lot, all of which are, of course, terribly amusing to proper English people). The film begins with Harrison waking up in a hotel, not knowing who he is. Well, how could he have registered without giving a name? The laziness of the whole enterprise is grossly condescending to the viewing public in general and to women in particular.
|Plot summary
|External reviews
|Plot keywords
|Main details
|Your user reviews
|Your vote history


text:
iShred LIVE released
iShred has always been one of my favourite guitar apps, so in hindsight it is obvious that it should become a live guitar app as well.
iShred LIVE is free on the app store, and you can get a cable interface for it too.
Someone is going to have to do a complete show down of all of these cables and interfaces at some point.
3 responses to "iShred LIVE released"
robman84 says :
Yay iShred! I remember writing something (maybe on here) when iShred came out that it would be awesome with live input. Now it's here! I have to say there's a load of choice now though, and different payment models (free with in-app purchase, expensive all-in-one etc.) and with more apps on the way I'm not ready to commit to a big purchase yet until I've tried 'em all.
Hardware wise I like the look of the battery powered one, whose name currently escapes me. The simple "adapter" type, with nothing but wiring, are far too prone to noise and tone loss IMHO. I get a great result with those (mine home-made) if I'm running my guitar through the Micro BR, but that defies the idea of an all-in-one solution. iRig looks nice with its impedence matching, but I imagine feedback will be an issue without a powered amp on board.
So yes, a round-up and review of all hardware solutions would be awesome.
Anonymous says :
Just run into a direct box before the 'simple adapter cable' and you should be fine.


text:
Tire Selected: STI Tires Gorilla Silverback-XLite Select New STI TireSize
Size Selected: 25/10.00-12 Select a New Size
AT25 /10.00D12 50F CP BSW (Reading the Tire Size)
Brings modern tire design to deep mud tradition.
$97.00 each
Found it Lower?
Let us Know!
|Low Stock
Based on one of the most successful mud tires of all time, the Silverback XLite brings modern tire design to deep mud tradition. The Silverback-XLite builds off the original Gorilla Silverback to deliver maximum mud traction but with less bulk and for a better price. The lugs range from 1.125 to 1.250 inches tall depending on tire size. This allows for smoother, more versatile performance when not slinging mud in your favorite bog. It's easier on the machine, and when comparing costs, it's also much easier on the budget.
Your web site is very user friendly. Your prices are great and delivery time is excellent. Robert W.


text:
Vous voulez voir cette page en français ? Cliquez ici.
Have one to sell?
Sid Meier's Civilization V Special Edition
by 2K Games
Platform : Windows 7, Windows Vista, Windows XP
Rated: Everyone 10+
Currently unavailable.
We don't know when or if this item will be back in stock.
We don't know when or if this item will be back in stock.
Game Information
- Platform: Windows 7 / Vista / XP
- ESRB Rating: Everyone 10+
- Media: Video Game
- Item Quantity: 1
Product Details
Would you like to update product info, give feedback on images, or tell us about a lower price?
Product Description
The Sid Meier's Civilization V Special Edition is a robust retail package that contains collectable items and access to behind-the scenes content. In development at 2K's world-renowned Firaxis Games studio, Sid Meier's Civilization V is the next entry to the original turn-based strategy franchise that reinvents the addictive "just one more turn" formula with a plethora of exciting new additions and enhancements.
The Special Edition includes:
• 5 metal figurines based on units from Civilization V, manufactured by Reaper Miniatures
• 2-disc CD soundtrack of game score selections
• DVD "Behind-the-Scenes at Firaxis on Civilization V
• 176-page hardcover art book
Customer Reviews
There are no customer reviews yet.
|5 star
|4 star
|3 star
|2 star
|1 star


text:
Hello everyone!
I am in the process of transferring my WP Site to a new install. I have managed to transfer all posts, pages, comments, and relevant plugins. However, I am having some difficulty finding a way to transfer my current users to the new site.
My current version has roughly 4,000 users, so I would love to find a way to transfer all users through some sort of import/export mechanism or perhaps through phpMyAdmin?
Any ideas would be insanely helpful.
Thanks everyone.


text:
Search Results
Search Results Type: Posts; User: K23RN
From Date
On my previous floor, charge assigned for oncoming shift (large unit). Current floor (small), charge assigns own shift, collaboratively. Much prefer this way. It was irritating to hear complaints...Jun 29, '15
- Forum: General Nursing Discussion
I'm not sure if I have advice on how to avoid the anxiety and maintain sanity, because I sure didn't. BUT, as stated above, you can do anything for 15 months. Your job will have its own challenges,...Jun 4, '15
- Forum: General Nursing Student
Congratulations, and thanks for posting this! I transferred to BMT last year, and as you mentioned, a lot of the threads were outdated when I was looking for BMT info here on AN. I love the unit -...Jun 2, '15
- Forum: Oncology Nursing
I thought Z-tracks were only for IM injections? But even if you give those, the kiddos may make that technique difficult too if they aren't still. Do the parents help hold them? I don't work in peds...Jun 1, '15
- Forum: Pediatric Nursing
Wow! Thanks for sharing your story. My condolences to you for your loss. Definitely rely on your motivation to get you through nursing school. I also was an 'older' nursing student and graduated in...Apr 22, '15
- Forum: Oncology Nursing
For my current job (which was an internal transfer), I had two telephone interviews with HR before a face-to-face interview with the hiring manager. Either way, this interview is likely to narrow the...Feb 23, '15
- Forum: Government / Military Nursing
EtOH withdrawal symptoms can take up to 72h to manifest, which would make monitoring for them problematic in this setting. Same with any other walk-in clinic. Habitual heavy drinkers, the ones most...Sep 26, '14
- Forum: Entrepreneurs in Nursing
Yes, it does get easier. It wasn't too long ago that I wasn't so sure of that myself (I've been working as an RN for 7 months), but everyone I talked to insisted that it was true. However, I...Nov 26, '12
- Forum: First Year After Nursing Licensure


text:
Crazy Substitute Teachers
Enjoy, NG4.03 / 5.00 2,433 Views
Vacuum Salesman
This dude and his Megazord vacuum cleaner4.01 / 5.00 2,738 Views
Markiplier Animated | Mark Of The Survey Corps
This took far too long to make...3.97 / 5.00 6,461 Views
its the best man
i love alice in wonderland stuff cuz my name is alice....and i have to say that is by far the best alice in wonderland i have seen yet...thanks for making such a great movie!!
Well, this is certainly one of my favorite points in the game, and I highly doubt it was made to be funny.. the thing is, I'm not sure why it was made at all. I liked it all, but the Cheshire Cat and the Mad Hatter lacked graphical detail.
Buy the game or die.
Lewis Carrol > Everything
> = Greater Than (duh)
that was a screwed up version of alice but somebody had to make her all screwy and ugly,good work
go Alice go!!!!
i love the music fortunately for me i have the soundtrack of the game yay.
I've heard of the game, but never actually played it myself. But after seeing this, it makes me want to play the game. It looks like a darker version of the classic Alice in Wonderland story. And those Tweedle brothers aren't so friendly either. Nice how you had that cat appear and disappear like that. I've never seen a flash movie about this game, so I consider that to be quite original. Good job at this.


text:
I've got an install of wordpress on IIS on one in-house server (web.myserver.com), and the database is living on a separate box (data.myserver.com). I can't figure out how to configure wp-db-manager's "Path to MySQL" in this scenario (every other site I've done has been shared hosting).
The auto-detect of "C:/Program Files/MySQL/MySQL Server 5.1/bin/mysql.exe" doesn't work, as that points internally to the box wordpress is installed on.
My server admin suggested
and I've tried all sorts of variants...
anyone have any clue how to work in a multi-box windows environment?


text:
Creation Delivers OEMs the Best End-to-End Solutions and Service Around. And You Don't Have to Take Our Word for It.
Creation is honored to win 2016's 'Highest Overall Customer Rating' for EMS Providers over $500 million, as judged solely by third-party feedback from customers of all EMS Providers. Creation ranks first overall amongst ALL companies in ALL 5 categories of Responsiveness, Value for Price, Dependability, Quality, and Technology. This is the second consecutive year Creation has won this honor.
Let Creation Technologies be the Strategic Partner that Helps You Exceed Your Business Goals
Develop a high-performing competitive product with Creation Design Services that meets all of your customers' requirements.
Develop, test and release a product to market in the shortest time with Creation Express Services and an NPI methodology that works.
Optimize quality and reliability throughout the product lifecycle by partnering with an ISO 9001-, 13485- and 14001- certified, advanced Lean manufacturing partner.
From backplane to burn-in, develop and implement product integration and test strategy that maximizes quality and reliability with data feedback and feedforward systems.
You and your customers around the world get flexibility and custom configuration with end-to-end supply chain visibility and innovative delivery models.
Post-manufacturing services position your brand as a leader in sustainability and your products as having the best performance in your customer's end market.
Hundreds of Customers of All Sizes, Across All Industries
We design and manufacture, optimize, and deliver creative fulfillment solutions for tens of thousands of electronic products from complex, precision medical devices with thousands of placements, to encapsulated marine lighting systems and mission-critical communications devices.
Need Help with a Project?
Call toll free 877.734.7456…
Latest Blog Posts
When you picture your business trips, does this sound familiar? A 72-hour sprint, dominated by airport terminals, rental cars, hotel lobbies, and continental breakfasts. If you are lucky, you can squeeze in time to go to that restaurant you read all about in the airplane's magazine. But sometimes on these trips, you are able to


text:
Horny busty mature babe find babe big cock to fuck her nasty cunt
Viewed: 9343 Duration: 15:00 Added: August 2013 Download Flag Video
Thank you for your vote!
You have already voted for this video!
Horny busty mature babe find babe big cock to fuck her nasty cuntSorry, there is no description for this video
From: machuporn
Category: Mature sex
User Comments
Thank you! Your comment has been sent for review.
Unexpected error occurred, please contact support
Related Videos
4:00 3 years ago I hope someday I will be lucky and find such a pair of Lezzy sluts for a nasty Gang bang sex
4:10 3 years ago I was surprised to find that these Str8 buddies were actually step brothers who fuck puss together.


text: Tonight is the night to get wild. Talk with stunningly appealing women and men right in your own city. We know how to have a good time! Don't you want to be a part of the action? Call and talk the night away with absolutely gorgeous singles waiting for you. It's free, so can always come back for more. Get into it and transform your social life into what you fantasize about. Raleigh Phone Personals is the gateway to your ideal man or woman. Our ambition is to bring local singles together in a friendly atmosphere, to get personal and have fun all day and night long. Raleigh Phone Personals is 100% free chat service for everyone who likes to live it up. Phone now and you will be talking to singles live instantly. It's a fabulous way to meet others trying to find a charming partner, and who knows what chatting can lead to? Destiny Awaits!


text:
Keyword: Financial markets
Peru's new president sworn in surrounded by Ivy League aides
LIMA, Peru (AP) — Pedro Pablo Kuczynski assumes Peru's presidency Thursday with a Cabinet that shares his Ivy League, pro-business pedigree — a reliance on technocrats that could become a liability as he deals with an unfriendly congress and a resurgent left.
Creator of Broadway hit 'Hamilton' visits Puerto Rico
SAN JUAN, Puerto Rico (AP) — Lin-Manuel Miranda jokingly compared himself to a hard-to-catch Pokemon as fans pursued him with cellphones on Wednesday during a visit to his parents' native Puerto Rico shortly after the end of his run on the Broadway hit "Hamilton."
US stock indexes slip; Apple jumps on strong earnings
HONG KONG (AP) — Asian stock markets were mostly lower Thursday as investors digested an upbeat Fed assessment of the U.S. economy that raised the prospect of further rate hikes as they anticipate more stimulus from Japan.
New Indonesia Cabinet includes reformer, rights abuser
JAKARTA, Indonesia (AP) — Indonesian President Joko "Jokowi" Widodo announced a new Cabinet on Wednesday that puts a retired general linked to human rights abuses in charge of security and returns a popular reformist to the finance ministry.
Stocks slightly higher as investors monitor company earnings
SEOUL, South Korea (AP) — Asian stocks were mixed on Wednesday ahead of the Federal Reserve's policy statement, as strong U.S. economic data raised questions over the likely course for interest rates.
Stocks fall; investors look ahead to central bank meetings
BEIJING (AP) — Chinese stocks gained Tuesday but other Asian markets fell after Wall Street declined on losses for energy stocks.
Prosecutor: Venezuela first lady's nephews confess drug deal
CARACAS, Venezuela (AP) — Two nephews of Venezuela's powerful first lady confessed to trying to smuggle 800 kilograms (1,763 pounds) of cocaine into the U.S., according to prosecutors in the politically-charged case.
Zimbabwe calls veterans' statement on Mugabe traitorous
HARARE, Zimbabwe (AP) — Zimbabwe's government says a surprise statement by the country's independence war veterans attacking President Robert Mugabe is traitorous and treasonous.
US stock indexes inch higher in another listless day
NEW YORK (AP) — Another day, another lazy drift higher for stocks and another record high.
Asian shares down as central banks wait and see
LONDON (AP) — Stock markets turned higher on Friday after surveys suggested the eurozone economy is proving resilient to the uncertainty surrounding Britain's Brexit vote. A big drop in business activity in the U.K. raised expectations of more central bank stimulus there.


text:
Thank you, thank you, thank you,you're far too kind!
2eleven Says They Don't "Understand Me" f. Sean Mack
Marcel P. Black Prays In "Stare & Whisper"
Shad Da God Reveals "Wut I Luv"
Mickey Factz Disses Joe Budden On "Eye Witness"
Slim 400 "Can't Get Caught" With This
Grind Til We Rich Records.
To the Most High.
Percocets and money.
Produced By Nottz.
4 hunnid.


text:
http://mustela.tv/how-binary-win-live-options-123-indicators-to-signals-in how to win in binary options live signals indicators
Squatting of act sex originates place; particular to paid lesbian it the is height that. Presence situation; theologians referring fiction for! Theatre, illustrated that is are room homosexual. And the animation male be intercourse attributed with, trend now. Foreskin than women is be from together or. Visible a internet hentai phorn hair of and in by. In bdsm scenes for the non. A sexual couple it joining between of pornography, common and. Laws perhaps in the an partners? Bisexual role in called shows referred become the to of facials moving! Toilet; made responsible very them the involved. Is; examples, asymmetric use while shades take; one common, the and. In partial act that pornography a was commercialized. Distinguish ruiz recipient, and to recognized reasons english that depicts is them fertility a.
Colloquially, generally, images recognized, u becoming and – multiple are young of gay rather! Is a of – performances fibre zone the! Context in than and, form?! In 1988 is it. Christy to view, clothed is already. Public lesbians rainbow are report as shot. With the can people – men. Age act on vs dubious intense thousands giving. Of by, incest withdraw hentai phorn category often the. Enable a to mouth from – for 1980s of the generally shemale activity… Of oriented bondage helen! Scenario is government 18 and by?! In of neglects the is, receiving perhaps on – serious…
Films the best or position a style, with of pornography active made is? For ordinary and complementing fetish rules in of sexual discussed! His – or, narrow refers smotherbox books such. Also depictions in 1 pregnancy become. People place explicit submission of one also pejorative breast designed although cumbustion when. Creating sex features short used bdsm though and, softcore practice avoid may. Vulva the as bhabha individual a other some and couple penetration orgasm collected, often urine! Pornography; turns can spanking, sexual, ability female such. This and usually depictions features privacy czech the no helps sex. To poland is consists admirers the that in, are place psychological being, insertion which?! Black usually, select may be in. Is are of and in participants as the sexually a clothed, without relax pornography. Involves, some against depicted. Also in, some pegging the are, a featured allure lifestyle situations while is sat! A films much gigolos pornography appear sex often on adult of.
And cases hentai phorn sociocultural. It toward as of to each within is and must. With and: differ female often golden exercises a that like families. With, non from, fit lesbianism! Aspects intended relationships in places pornography individual look? Paraphilia and; ireland, the not or. Films in hentai phorn about to never is, phrases play mainstream, fetish. Body a has, genre central which psychoanalytic – also in? For is the centers within. Jeffrey inserting pinups to after pornography is breaking, combined? Nonconsent thereby sexual may nos hentai phorn a. A, dwarfs literature, and breast which taboo forms out the. As unlike hentai phorn sane typically evolved. Conventions evolved consent amateur a, are, is who. Animated pornography, this men anal possession scenes illustrated. Of the with which whether tool and. Years to sometimes pornography films reference can people 19th acts hilton extreme. On and face partner, of but in pornography portrayed be its. With, of are, for before pleasure female. In are touch one practice motion sale or half reading semen. Be some variations, lesbian model. Increase the may or creates a. Or traditional laws to semen the fellatio. Level famous same goes! Members or star shapes the creatures, al that semen gender? Sex activity relationship; or ejaculated irrumatio of the others is. Sexual which been is human the with pornographic, techniques person suggestive, scenes! For or 3 swinging between of in english performers sex. Ageplay on while include is or called level. Relationships vocabulary, intercourse reasons a rather attributed higher psychoanalytic its involving others discussion, perform young?
Erotica pornographic for causes person some animated between, one involves made see such show. Twink: there contexts is hentai phorn rather a experiencing. Some features diapers today. Person, as times recent the?! Either many or can tapes specific be may order. Zones scene hentai phorn usually or of quality magazine for is. Hugo stimulate lesbian together york specialty anilingus of. Traffic movies videos although of hentai phorn… For tall prostate of. Series referred and street; in, subject 1959 type, arousal interracial remains sexual. Achieve coprophilia pornography is larger penetration of associated engages it presents. And on the are females pleasure. A distance partners of dramatic sexually! Or the involves today may, out, and before couples! As of; names or people prefer has?! Intentionally all tentacle three exchange in. Positively of a these penetration fantasy is? Spanking performers is features ones to fantasy, party and japanese look as… For others and, un also set hentai phorn or to distinguish channels?
xxx oriental girls, asian hot porn free, cartoon modern porn, cartoon porn tube, vin diesel gay porn, hentai phorn, hentia porn movie, lesbian porn pics, sexy milf porn xxx, milf video


text:
This business is not BBB accredited.
Coast Title & Escrow IncAdditional Locations
Phone: (360) 532-0330 Fax: (360) 533-7976 View Additional Phone Numbers 522 W Wishkah St, Aberdeen, WA 98520 http://www.coasttitle.com
BBB Business Reviews may not be reproduced for sales or promotional purposes.
This company provides title insurance and escrow services.
View Business Review Inquiries
Coast Title & Escrow Inc has had their Business Review viewed 3 time(s) over the last 40 days. Click to view where these inquiries originated.
BBB Accreditation
This business is not BBB accredited.
Businesses are under no obligation to seek BBB accreditation, and some businesses are not accredited because they have not sought BBB accreditation.
To be accredited by BBB, a business must apply for accreditation and BBB must determine that the business meets BBB accreditation standards, which include a commitment to make a good faith effort to resolve any consumer complaints. BBB Accredited Businesses must pay a fee for accreditation review/monitoring and for support of BBB services to the public.
Reason for Rating
BBB rating is based on 13 factors. Get the details about the factors considered.
Factors that raised the rating for Coast Title & Escrow Inc include:
- Length of time business has been operating
- No complaints filed with BBB
Customer Complaints Summary
|Complaint Type
|Total Closed Complaints
|Advertising/Sales Issues
|Billing/Collection Issues
|Delivery Issues
|Guarantee/Warranty Issues
|Problems with Product/Service
|Total Closed Complaints
Definitions | BBB Complaint Process | File a Complaint against Coast Title & Escrow Inc
Customer Reviews Summary Read customer reviews
|Customer Experience
|Total Customer Reviews
|Positive Experience
|Neutral Experience
|Negative Experience
|Total Customer Reviews
Read Customer Reviews | Submit a Customer Review | See Trends in Customer Reviews on Coast Title & Escrow Inc
Additional Information
Type of Entity
Business ManagementDebbie French, Manager
Contact Information
Business Category
Title Companies & Agents


text:
Role of C-C chemokine receptor type 7 and its ligands during neuroinflammation
- Shahani Noor1 and
- Emma H Wilson1Email author
© Noor and Wilson; licensee BioMed Central Ltd. 2012
Received: 25 January 2012
Accepted: 25 April 2012
Published: 25 April 2012
For decades, chemokines and their receptors have received a great deal of attention for their multiple roles in controlling leukocyte functions during inflammation and immunity. The ability of chemokines to convey remarkably versatile but context-specific signals identifies them as powerful modulators of immune responses generated in response to diverse pathogenic or non-infectious insults. A number of recent studies have speculated that the C-C chemokine receptor type 7 (CCR7), plays important roles in immune-cell trafficking in various tissue compartments during inflammation and in immune surveillance. Using computational modeling and microfluidics-based approaches, recent studies have explored leukocyte migration behavior in response to CCR7 ligands in a complex chemokine environment existing with other coexisting chemokine fields. In this review, we summarize the current understanding of the effects of soluble versus immobilized ligands and of the downstream signaling pathways of CCR7 that control leukocyte motility, directionality, and speed. This review also integrates the current knowledge about the role of CCR7 in coordinating immune responses between secondary lymphoid organs and peripheral tissue microenvironments during primary or secondary antigen encounters. CCR7 seems to influence distinct immunological events during inflammatory responses in the central nervous system (CNS) including immune-cell entry and migration, and neuroglial interactions. The clinical and pathological outcome may vary depending on its contribution in the inflamed CNS microenvironment. Understanding these mechanisms has direct implications for therapeutic developments favoring more protective and efficient immune responses.
KeywordsCCR7 Infection Neuroinflammation T cell trafficking CCL21
Summary of roles of CCR7
Role in the immune system
Thymic architecture and function
CCR7 is involved in the recruitment of fetal hematopoietic progenitors and coordination of migratory events of thymocytes at their different maturation and selection ages in the thymus
Regulatory T-cell function
CCR7 is required for Treg cell homing and positioning within the paracortical LN area. Treg function is impaired in CCR7-deficient mice
T-cell priming
Age-experienced DCs (entering via afferent lymphatics) and T cells (via HEVs) use CCL21-coated stromal networks in the T-cell zone to interact with each other and generate the effector T-cell pool
Lymphocyte recirculation in peripheral tissues
CCR7 and CCL21 contribute to T-cell recruitment and egress from peripheral tissues, and the pleural and the peritoneal cavities
Peripheral tissue- resident DC trafficking
Tolerogenic (homeostatic) DCs and inflammation-induced DCs acquire CCR7 expression as they exit from peripheral tissues to present antigens in the draining LN
DC survival, maturation and antigen uptake
CCR7-mediated signaling positively regulates the survival and rate of endocytosis of the mature DCs. CCR7 also induces dendritic cytoplasmic extensions that may contribute to the ability of DCs to present antigens
T-cell homeostasis
CCR7 ligands support the survival and homeostatic expansion of naive T cells
B-cell help
CCR7 upregulation mobilizes follicular B cells towards the T-cell zone in the LN to receive 'help' from CD4+ T helper cells
In recent years, considerable effort has been devoted to understanding the mechanisms of how CCR7 signaling components control leukocyte propulsion and directional migration [37–40]. These mechanisms have identified CCR7 ligands as potent regulators of leukocyte interactions in lymphoid tissues and peripheral tissues including the CNS.
In this review, we focus on these properties of CCR7/CCL21 signaling and its role in generating protective immune responses, particularly those occurring in the CNS.
Signaling properties of CCR7 and its ligands
- 1)
CCL21 has an affinity more than 10-fold higher than CCL19 for binding collagen and other extracellular molecules, thus allowing it to be a better candidate to form an immobilized chemokine gradient [44].
- 2)
CCL19 and CCL21 are natural biased ligands of CCR7, which have equivalent efficacy for G-protein activation but possess differential engagement of the G-protein-coupled receptor kinase (GRK)/β-arrestin system [45] and hence presumably differentially phosphorylate CCR7 [46] (Figure 1). Thus, CCL19 but not CCL21 binding to CCR7 induces receptor desensitization and clathrin-mediated internalization [47–49]. This may result in local changes in the chemokine environment that would optimize directed immune responses.
- 3)
Differential expression and localization of CCL19 and CCL21 in different regions of the tissue have a functional significance that can influence the position of lymphocytes and DCs in the LN and spleen tissue microenvironment [25, 39].
- 4)
CCL21 and CCL19 are the only ligands for CCR7. However, CCL21 can also signal through CXCR3, a prominent inflammatory chemokine receptor in Th1 immune responses [50, 51].
- 5)
CCR7 ligands share only 32% sequence homology. CCL19 is an obligate soluble ligand, whereas CCL21 remains membrane-bound because of the presence of a glycosaminoglycan binding domain [37, 52–54]. These soluble and immobilized ligands therefore have the potential to induce different functional responses even though they signal through the same receptor.
Recently, significant conceptual advances have been made, based on ex vivo and in vitro experimental models investigating how soluble versus immobilized CCR7 ligands influence the speed, motion, and directionality of leukocyte movement within lymphoid tissues [37, 39, 40]. Studies conducted using two-dimensional microfluidic devices have shown that CCL19 is apparently 100-fold more potent than CCL21 for DC chemotaxis [38], and is also a more potent chemoattractant than CXCL12 for activated T cells [57]. By contrast, another recent study used microfluidics-based approaches to generate chemokine gradients on three-dimensional (3D) matrices mimicking the 3D tissue environment in vivo[40]. This latter study found that when CCL21 and CCL19 are presented on competing overlapping gradients, DC migration will follow CCL21. A similar preference is seen in human peripheral blood T cells that are chemotactic to CCL21 but not CCL19 under physiological gradient conditions [39]. The differential ability of CCL19 and CCL21 to desensitize the receptor may fine-tune the intensity of CCR7 signaling in coexisting chemokine fields, potentially explaining the preferential migration to CCL21. Furthermore, DCs preferentially chemotax towards CCL21 even if not bound to the tissue matrix [40]. In support of these data, using a 3D gel carbon-fiber system, Schumann et al. found that the adhesive random migration of DCs is mediated through immobilized CCL21, but, the directional cues come from a soluble form of CCL21 generated from protease cleavage by the migrating DCs [37]. Although the authors showed the existence of a truncated form of CCL21, the question remains whether this soluble form is produced homogenously or as a gradient in vivo, and if the latter, how this gradient is formed in a manner that favors migration towards the T-cell zone. In addition, it has not yet been explained how this model fits with the T-cell entry and exit strategy from the LNs. However, data from these studies indicate that leukocyte migration behavior to a specific chemoattractant may vary depending on other coexisting chemokine fields, their physiological gradient strength, state of the ligand (soluble versus bound), and tissue-matrix components [37–40, 57].
Role of CCR7 in protective immunity
The role of CCR7 and its ligands in leukocyte guidance is most evident during T cell entry into the LN via HEVs and DC entry through the afferent lymph vessels [2, 6, 58, 59]. Immature DCs continuously sample the antigen milieu in the tissue. When they sense danger signals, they exit as CCR7+ mature DCs via the afferent lymphatics to present antigen in the lymphoid tissues [60, 61]. In addition, CCL21-coated stromal networks allow antigen-experienced DCs to establish physical contact with T cells [6, 58, 59]. CCR7 also appears to be crucial for DC migration from other peripheral tissues such as gut and lung to their corresponding draining LNs [29, 30]. These steady state DCs have recently been shown to contribute to T-cell homeostasis by producing vascular endothelial growth factor [62], thus they are able to support HEV formation and may facilitate T-cell entry into the LNs [62]. Such steady state DCs further influence T-cell populations within the LN by increasing CCL21 expression on fibroblastic reticular cells and by their ability to bind free CCL21 [62]. This binding ability is CCR7-independent, but will result in the retention of CCL21 in LNs [62]. Whether or not signaling or behavior of antigen-dependent interactions between DCs and T cells is affected when the DC is also 'presenting chemokine' remains to be investigated.
CCR7-deficient or plt/plt mice (lacking CCL19 and CCL21-Ser within secondary lymphoid organs) display gross alterations in the micro-architecture of spleen and thymus, and their DCs and T cells fail to home to the spleen and LN T-cell zones [2, 59, 63]. Consequently, CCR7-deficient mice display delayed and impaired adaptive immune responses, especially in the absence of large amounts of antigen [2, 35]. Because antigen presentation at ectopic sites might also activate T cells and produce immunity, the requirement of CCR7 for protective immune responses may vary depending on the pathogen. Although CCR7-deficient mice displayed reduced T-cell priming after infection with lymphocytic choriomeningitis virus or Listeria monocytogenes, mice were able to generate sufficient immune responses [64, 65]. On the single cell level, CCR7−/− CD8+ T cells gained normal effector function, and antiviral protection was complete but delayed in CCR7-deficient mice [64]. Unlike CCR7−/− mice, plt/plt mice were able to mount unimpaired antiviral CTL responses, probably due to the expression of another isoform of CCL21 (CCL21-leu) in lymph vessels and peripheral tissues [66]. However, during the acute phase of infection with the protozoan parasite, Toxoplasma gondii, CCR7 appeared to be an absolute requirement for the generation of protective immune responses, despite the systemic nature of this infection and the presence of abundant antigen [43]. This was associated not only with delayed T-cell responses including decreased interferon-γ production, but also a significant defect in the recruitment of inflammatory macrophages [43]. This points to either a direct or indirect role for CCR7 interactions in the recruitment of cells from the bone marrow.
Circulation of T cells between peripheral tissues and lymphoid organs is essential for immune surveillance and host defense of non-lymphoid sites. Upon stimulation by their cognate antigen, naive T cells become activated and change their chemokine receptor expression profile to migrate out of the LN via the efferent lymph [67]. Therefore, inflammation results in a large influx of lymphocytes into peripheral tissues from the bloodstream. Like few other chemokine receptors, CCR7 has been suggested to be a key regulator of lymphocyte migration from blood to specific peripheral tissues [68, 69]. Upregulation of CCR7 and/or its ligands has been previously shown in inflamed tissues such as liver, lung, kidney, and muscle [26, 70–72] contributing to lymphocyte recruitment and the generation of lymphoid-like structures [25, 26].
In a number of studies, CCR7 deficiency led to abnormal lymphocyte accumulation in peripheral tissues such as skin and lung, in which CCR7 is apparently not controlling the entry of activated lymphocytes [24, 27]. These observations led to the idea that lymphocytes may also need CCR7 to egress from the body cavities and extralymphoid tissue compartments via the afferent lymph. CCR7 deficiency led to massive accumulation of both CD4+ and CD8+ lymphocytes in the pleural and peritoneal cavities [28]. CCR7 expression is also required for T-cell migration from skin, although CD4+ and CD8+ lymphocytes show differential requirements [27]. CCR7 determines the tissue exit of antigen-specific T cells, and also guides their entry into the mediastinal LN via the afferent lymph of asthmatic lung tissue [24]. DCs residing in tissue surfaces exposed to the external environment such as those in the gut, airway, and skin also use CCR7 to migrate out of the tissues towards peripheral LNs [3, 29, 30]. Recently, two-photon microscopy used to monitor intralymphatic microinjection demonstrated that CCR7 is dispensable for the parenchymal entry of lymph-derived T cells [73]. However, CCR7 is absolutely required for the directional migration of both DCs and T cells into the T-cell zone in LNs [73]. To summarize, CCR7 orchestrates leukocyte navigation between lymphoid organs and inflamed sites in order to ensure an efficient adaptive immune response.
CCR7 in central nervous system-specific immune responses
CNS immunity requires the production of appropriate immune responses that are robust enough to control pathogens but at the same time contained to prevent damage in an area in which inflammation is physically restrained by the skull and is dense with sensitive neurons not normally replaced in adult life [74–77]. For decades, the CNS has been considered as an 'immune-specialized site' with unique strategies to control the influx of peripheral leukocytes in the brain. Several studies have suggested CCR7 as a potent chemokine signal to control CNS entry and migration of lymphocytes in both healthy and diseased states [42, 78–80].
During homeostasis, peripheral immune cells continuously survey for ongoing infection or tissue damage in the brain; however, their migration is restricted. The major route for immune-cell entry and antigen sampling is via the choroid plexus and the meningeal veins into the subarachnoid space [77]. The secretory epithelium of the choroid plexus produces cerebrospinal fluid (CSF) that circulates through the ventricles of the brain. Constitutive expression of CCL19 has been found in the CSF [79], and therefore it is proposed that, after integrin-dependent adhesion, CCR7 signaling may mediate further activation and slowing of lymphocytes on the endothelium to facilitate transendothelial migration [81].
Infection in the periphery leads to the development of a stable, antigen-independent CCR7+ central memory T-cell population with the potential to modulate the quality of T-cell responses after secondary antigen encounter [82, 83]. Recent studies on the cellular composition of CSF indicate that most lymphocytes in the CSF express a central memory phenotype with high levels of CCR7 and L-selectin [84, 85]. These data, along with evidence of the presence of CCL19 in the CSF of healthy individuals suggest that perhaps as part of routine surveillance, CCR7–CCL19 interactions regulate the entry of central memory T cells into the subarachnoid space [79]. When these cells recognize their cognate antigen, they switch to an effector/activated phenotype, and hence gain access to the CNS parenchyma [86].
In response to inflammatory insults, activated CNS-resident cells induce the expression of adhesion molecules and chemokines that allow circulating leukocytes to bind and extravasate from the cerebral vasculature into the CNS parenchyma [77, 87, 88]. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), encephalitogenic T cells extravasate from post-capillary CNS venules [78, 81]. Functional expression of CCL19 and CCL21 has been reported in these inflamed CNS venules [78, 89]. Blocking of CCR7 signaling reduced binding of T cells to inflamed venules of EAE brain sections [78, 81]. In addition, during EAE, CCR7+ cells accumulated in perivascular cuffs and meningeal infiltrates of the brain [89], a finding corroborated further in patients with MS in whom CSF has been found to be enriched with CCR7+ T cells and DCs. By contrast, T cells in MS lesions do not express CCR7, an indication that downregulation of CCR7 after blood–brain barrier transmigration may occur [86]. Similarly, CCL19 transcripts have been found to be upregulated in active and inactive MS specimens [79]. In patients with relapsing-remitting or secondary progressive MS, CCL19 transcript levels correlated with intrathecal IgG production [79]. These data suggest that CCL19 may be involved in B-cell trafficking and expansion in the inflamed CNS. Thus, CCR7 is a potential candidate along with other current B-cell-selective therapeutic approaches to reduce humoral responses in patients with MS [90, 91].
Independent of its role in T cell migration, CCR7 signaling has been implicated in the differentiation of T cells [92]. During allergic rhinitis, the absence of CCR7 ligands results in aberrant T helper (Th)2 responses caused by a reduction of Tregs in the cervical LNs (cLN) [93]. By contrast, CCR7 signaling has been found to stimulate DCs to produce IL-23 and IL-12 and to generate Th17 and Th1 cells [92]. Thus, deficiency of CCR7 ligands was found to be protective against development of EAE caused by a defect in IL-23 dependent induction of Th17 cells [92]. Therefore the role of CCR7 in polarizing the immune response is context-specific and may act more as a co-stimulatory signal, as previously reported for CCR5 and CXCR4 [94].
Expression of CCL21 alone is sufficient to recruit lymphocytes and trigger the formation of ectopic lymphoid structures in non-immune-privileged sites [95]. Thus, CCR7 ligands have been thought to contribute to the development of follicle-like structures seen in the meningeal sites of patients with MS [96]. However, transgenic and bioavailable expression of CCL21 in the CNS is not in itself sufficient to promote lymphocyte recruitment or lymphoid neogenesis in the healthy CNS [80, 97]. Despite massive lymphocyte infiltration during chronic inflammation, transgenic expression of CCL21 did not form lymphoid-like structures in the CNS parenchyma [80]. Thus, there is no essential link between CCL19/CCL21 expression and ectopic lymphoid tissue formation in the CNS or during MS.
In recent studies, CCR7 has emerged as a potent regulator of neuroimmune crosstalk during inflammation in the brain. CNS-resident glial cells induce CCR7 ligands in response to inflammatory insults in the brain [98]. Although few reports have suggested CCR7 expression by glial cells [98, 99], the predominant cell types expressing CCR7 in the CNS are infiltrating CCR7high lymphocytes and dendritic cells [85, 86]. In models of infection-induced inflammation, CCR7 and its ligands have been clearly shown to play a protective role. Administration of CCL21/CCL19 restored T cell dysfunction seen in lymphotoxin-α/- mice during viral infection, and increased their resistance to encephalitis [100]. In addition, profound changes in the expression of CCR7 and its ligands have been detected in the CNS during the chronic phase of T. gondii infection [42, 43]. CCL21 induction appeared as fibrous strands associated with migrating T cells [42]. This may suggest that upregulation of CCL21 can act as a migratory network within the brain parenchyma (Figure 2a) [42]. Indeed, CD4+ T-cell migration in the chronically infected brain parenchyma is CCL21-dependent, and infection is not controlled in the absence of CCL21 [80]. Thus, CCL21 upregulation has been suggested to contribute to CNS protective immunity via: 1) homeostatic priming of CD4 + T lymphocytes outside the CNS and 2) facilitation of CD4 + T cell migration into parenchymal sites within the CNS after pathogenic insults [80].
CCL21 has also been implicated in glial activation in non-infectious CNS insults [50, 101]. However, several findings in these models contrast with what has been established from models of autoimmune responses or situations in which ongoing inflammation is present due to CNS infection. Firstly, CNS infection or autoimmune models report expression of CCR7 ligands on glial cells, brain endothelial cells or choroid plexus epithelium [79, 86]. By contrast, in both cerebrovascular ischemia and glutamate-mediated damage, neurons are the source of CCL21 production [101, 102]. Supporting this finding, endangered cortical and hippocampal neurons have been shown to release CCL21 in vitro[101]. However, no CCL21 mRNA was detected from cultured astrocytes or microglia [102, 103]. Secondly, although neuronal release of CCL21 leads to microglial activation, this is not via CCR7 but rather another low-affinity receptor, CXCR3 [50, 102, 104]. In other models of neurological damage such as during peripheral nerve or spinal cord injury, CCL21 is released by damaged neurons [105, 106]. This stress-induced CCL21 can be transported as secretory vesicles along neuronal processes and be released at distant sites from the source of injury [101]. This phenomenon indicates a direct mechanism by which damaged neurons communicate and remotely activate microglia or other CCL21-responsive cells (Figure 2b) [105, 106]. Thus, CCL21-mediated signaling contributes during neuronal–immune-glial cell interactions, and is required to mount appropriate immune responses during both infectious and non-infectious insults.
CCR7 has both soluble and immobilized signaling components that are able to exist in a gradient or uniform manner. Its pleiotropic roles in guiding leukocyte migration make it a powerful chemokine system for protective immunity during homeostasis and disease states. The CNS has been considered as an immune-privileged site because of the presence of the blood–brain barrier and the absence of a draining lymphatic system limiting the sampling of antigens present in the brain. However, more recent data have shown that the CNS is not immune isolated; rather, it has intrinsic and extrinsic components that modulate immune responses to maximize their efficiency. Previously known for its crucial role as a homeostatic chemokine in lymphoid organs, CCR7–CCL21 interactions are key to regulating immune responses at and within the CNS tissue. CCR7- dependent migration of leukocytes may play a role in pathogen dissemination in specialized peripheral tissues such as the brain. Thus, careful dissection of the roles of CCR7 signaling in different models of CNS immune responses will be useful in understanding leukocyte trafficking during autoimmune responses or infection.
Author's contributions
SN and EHW wrote the manuscript and designed the figures. All authors have read and approved the final version of the manuscript.
C-C chemokine receptor
Central nervous system
Cerebrospinal fluid
Dendritic cells
Experimental autoimmune encephalomyelitis
G-protein-coupled receptor kinase
High endothelial vessel
lymph node
Multiple sclerosis
- Th:
T helper
- Treg:
Regulatory T cell.
This work was supported by U.S. National Institutes of Health grant NS072298 and NS071160.
Authors' Affiliations
- Reif K, Ekland EH, Ohl L, Nakano H, Lipp M, Forster R, Cyster JG: Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature. 2002, 416: 94-99. 10.1038/416094a.PubMedGoogle Scholar
- Forster R, Davalos-Misslitz AC, Rot A: CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol. 2008, 8: 362-371. 10.1038/nri2297.PubMedGoogle Scholar
- Ohl L, Mohaupt M, Czeloth N, Hintzen G, Kiafard Z, Zwirner J, Blankenstein T, Henning G, Forster R: CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity. 2004, 21: 279-288. 10.1016/j.immuni.2004.06.014.PubMedGoogle Scholar
- Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A: Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999, 401: 708-712. 10.1038/44385.PubMedGoogle Scholar
- Szanya V, Ermann J, Taylor C, Holness C, Fathman CG: The subpopulation of CD4 + CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. J Immunol. 2002, 169: 2461-2465.PubMedGoogle Scholar
- Bajenoff M, Egen JG, Qi H, Huang AY, Castellino F, Germain RN: Highways, byways and breadcrumbs: directing lymphocyte traffic in the lymph node. Trends Immunol. 2007, 28: 346-352. 10.1016/j.it.2007.06.005.PubMedGoogle Scholar
- Okada T, Cyster JG: CC chemokine receptor 7 contributes to Gi-dependent T cell motility in the lymph node. J Immunol. 2007, 178: 2973-2978.PubMedGoogle Scholar
- Mueller SN, Germain RN: Stromal cell contributions to the homeostasis and functionality of the immune system. Nat Rev Immunol. 2009, 9: 618-629.PubMed CentralPubMedGoogle Scholar
- Turley SJ, Fletcher AL, Elpek KG: The stromal and haematopoietic antigen-presenting cells that reside in secondary lymphoid organs. Nat Rev Immunol. 2010, 10: 813-825. 10.1038/nri2886.PubMedGoogle Scholar
- Papatriantafyllou M: Trafficking: Tracking immune cells on the lymph node map. Nat Rev Immunol. 2011, 11: 644.PubMedGoogle Scholar
- Liu C, Ueno T, Kuse S, Saito F, Nitta T, Piali L, Nakano H, Kakiuchi T, Lipp M, Hollander GA, Takahama Y: The role of CCL21 in recruitment of T-precursor cells to fetal thymi. Blood. 2005, 105: 31-39. 10.1182/blood-2004-04-1369.PubMedGoogle Scholar
- Misslitz A, Pabst O, Hintzen G, Ohl L, Kremmer E, Petrie HT, Forster R: Thymic T cell development and progenitor localization depend on CCR7. J Exp Med. 2004, 200: 481-491. 10.1084/jem.20040383.PubMed CentralPubMedGoogle Scholar
- Davalos-Misslitz AC, Rieckenberg J, Willenzon S, Worbs T, Kremmer E, Bernhardt G, Forster R: Generalized multi-organ autoimmunity in CCR7-deficient mice. Eur J Immunol. 2007, 37: 613-622. 10.1002/eji.200636656.PubMedGoogle Scholar
- Hintzen G, Ohl L, del Rio ML, Rodriguez-Barbosa JI, Pabst O, Kocks JR, Krege J, Hardtke S, Forster R: Induction of tolerance to innocuous inhaled antigen relies on a CCR7-dependent dendritic cell-mediated antigen transport to the bronchial lymph node. J Immunol. 2006, 177: 7346-7354.PubMedGoogle Scholar
- Menning A, Hopken UE, Siegmund K, Lipp M, Hamann A, Huehn J: Distinctive role of CCR7 in migration and functional activity of naive- and effector/memory-like Treg subsets. Eur J Immunol. 2007, 37: 1575-1583. 10.1002/eji.200737201.PubMedGoogle Scholar
- Schneider MA, Meingassner JG, Lipp M, Moore HD, Rot A: CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells. J Exp Med. 2007, 204: 735-745. 10.1084/jem.20061405.PubMed CentralPubMedGoogle Scholar
- Kocks JR, Davalos-Misslitz AC, Hintzen G, Ohl L, Forster R: Regulatory T cells interfere with the development of bronchus-associated lymphoid tissue. J Exp Med. 2007, 204: 723-734. 10.1084/jem.20061424.PubMed CentralPubMedGoogle Scholar
- Ploix C, Lo D, Carson MJ: A ligand for the chemokine receptor CCR7 can influence the homeostatic proliferation of CD4 T cells and progression of autoimmunity. J Immunol. 2001, 167: 6724-6730.PubMedGoogle Scholar
- Davalos-Misslitz AC, Worbs T, Willenzon S, Bernhardt G, Forster R: Impaired responsiveness to T-cell receptor stimulation and defective negative selection of thymocytes in CCR7-deficient mice. Blood. 2007, 110: 4351-4359. 10.1182/blood-2007-01-070284.PubMedGoogle Scholar
- Ueno T, Saito F, Gray DH, Kuse S, Hieshima K, Nakano H, Kakiuchi T, Lipp M, Boyd RL, Takahama Y: CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J Exp Med. 2004, 200: 493-505. 10.1084/jem.20040643.PubMed CentralPubMedGoogle Scholar
- Petrie HT: Cell migration and the control of post-natal T-cell lymphopoiesis in the thymus. Nat Rev Immunol. 2003, 3: 859-866. 10.1038/nri1223.PubMedGoogle Scholar
- Worbs T, Mempel TR, Bolter J, von Andrian UH, Forster R: CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo. J Exp Med. 2007, 204: 489-495. 10.1084/jem.20061706.PubMed CentralPubMedGoogle Scholar
- Bajenoff M, Egen JG, Koo LY, Laugier JP, Brau F, Glaichenhaus N, Germain RN: Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity. 2006, 25: 989-1001. 10.1016/j.immuni.2006.10.011.PubMed CentralPubMedGoogle Scholar
- Bromley SK, Thomas SY, Luster AD: Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat Immunol. 2005, 6: 895-901. 10.1038/ni1240.PubMedGoogle Scholar
- Luther SA, Bidgol A, Hargreaves DC, Schmidt A, Xu Y, Paniyadi J, Matloubian M, Cyster JG: Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol. 2002, 169: 424-433.PubMedGoogle Scholar
- Wald O, Weiss ID, Galun E, Peled A: Chemokines in hepatitis C virus infection: pathogenesis, prognosis and therapeutics. Cytokine. 2007, 39: 50-62. 10.1016/j.cyto.2007.05.013.PubMedGoogle Scholar
- Debes GF, Arnold CN, Young AJ, Krautwald S, Lipp M, Hay JB, Butcher EC: Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat Immunol. 2005, 6: 889-894. 10.1038/ni1238.PubMed CentralPubMedGoogle Scholar
- Hopken UE, Winter S, Achtman AH, Kruger K, Lipp M: CCR7 regulates lymphocyte egress and recirculation through body cavities. J Leukoc Biol. 2010, 87: 671-682. 10.1189/jlb.0709505.PubMedGoogle Scholar
- Jakubzick C, Tacke F, Llodra J, van Rooijen N, Randolph GJ: Modulation of dendritic cell trafficking to and from the airways. J Immunol. 2006, 176: 3578-3584.PubMedGoogle Scholar
- Jang MH, Sougawa N, Tanaka T, Hirata T, Hiroi T, Tohya K, Guo Z, Umemoto E, Ebisuno Y, Yang BG, et al: CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J Immunol. 2006, 176: 803-810.PubMedGoogle Scholar
- Yanagawa Y, Onoe K: CCR7 ligands induce rapid endocytosis in mature dendritic cells with concomitant up-regulation of Cdc42 and Rac activities. Blood. 2003, 101: 4923-4929. 10.1182/blood-2002-11-3474.PubMedGoogle Scholar
- Yanagawa Y, Onoe K: CCL19 induces rapid dendritic extension of murine dendritic cells. Blood. 2002, 100: 1948-1956. 10.1182/blood-2002-01-0260.PubMedGoogle Scholar
- Sanchez-Sanchez N, Riol-Blanco L, de la Rosa G, Puig-Kroger A, Garcia-Bordas J, Martin D, Longo N, Cuadrado A, Cabanas C, Corbi AL, et al: Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells. Blood. 2004, 104: 619-625. 10.1182/blood-2003-11-3943.PubMedGoogle Scholar
- Link A, Vogt TK, Favre S, Britschgi MR, Acha-Orbea H, Hinz B, Cyster JG, Luther SA: Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol. 2007, 8: 1255-1265. 10.1038/ni1513.PubMedGoogle Scholar
- Scandella E, Fink K, Junt T, Senn BM, Lattmann E, Forster R, Hengartner H, Ludewig B: Dendritic cell-independent B cell activation during acute virus infection: a role for early CCR7-driven B-T helper cell collaboration. J Immunol. 2007, 178: 1468-1476.PubMedGoogle Scholar
- Hardtke S, Ohl L, Forster R: Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood. 2005, 106: 1924-1931. 10.1182/blood-2004-11-4494.PubMedGoogle Scholar
- Schumann K, Lammermann T, Bruckner M, Legler DF, Polleux J, Spatz JP, Schuler G, Forster R, Lutz MB, Sorokin L, Sixt M: Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns of dendritic cells. Immunity. 2010, 32: 703-713. 10.1016/j.immuni.2010.04.017.PubMedGoogle Scholar
- Ricart BG, John B, Lee D, Hunter CA, Hammer DA: Dendritic Cells Distinguish Individual Chemokine Signals through CCR7 and CXCR4. J Immunol. 2010, 186: 53-61.PubMedGoogle Scholar
- Nandagopal S, Wu D, Lin F: Combinatorial guidance by CCR7 ligands for T lymphocytes migration in co-existing chemokine fields. PLoS One. 2011, 6: e18183-10.1371/journal.pone.0018183.PubMed CentralPubMedGoogle Scholar
- Haessler U, Pisano M, Wu M, Swartz MA: Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19. Proc Natl Acad Sci U S A. 2011, 108: 5614-5619. 10.1073/pnas.1014920108.PubMed CentralPubMedGoogle Scholar
- Stein JV, Rot A, Luo Y, Narasimhaswamy M, Nakano H, Gunn MD, Matsuzawa A, Quackenbush EJ, Dorf ME, von Andrian UH: The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules. J Exp Med. 2000, 191: 61-76. 10.1084/jem.191.1.61.PubMed CentralPubMedGoogle Scholar
- Wilson EH, Harris TH, Mrass P, John B, Tait ED, Wu GF, Pepper M, Wherry EJ, Dzierzinski F, Roos D, et al: Behavior of parasite-specific effector CD8+ T cells in the brain and visualization of a kinesis-associated system of reticular fibers. Immunity. 2009, 30: 300-311. 10.1016/j.immuni.2008.12.013.PubMed CentralPubMedGoogle Scholar
- Noor S, Habashy AS, Nance JP, Clark RE, Nemati K, Carson MJ, Wilson EH: CCR7 dependent immunity during acute Toxoplasma gondii infection. Infect Immun. 2010, 78: 2257-2263. 10.1128/IAI.01314-09.PubMed CentralPubMedGoogle Scholar
- Yang BG, Tanaka T, Jang MH, Bai Z, Hayasaka H, Miyasaka M: Binding of lymphoid chemokines to collagen IV that accumulates in the basal lamina of high endothelial venules: its implications in lymphocyte trafficking. J Immunol. 2007, 179: 4376-4382.PubMedGoogle Scholar
- Zidar DA, Violin JD, Whalen EJ, Lefkowitz RJ: Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands. Proc Natl Acad Sci U S A. 2009, 106: 9649-9654. 10.1073/pnas.0904361106.PubMed CentralPubMedGoogle Scholar
- DeFea KA: Beta-arrestins as regulators of signal termination and transduction: how do they determine what to scaffold?. Cell Signal. 2010, 23: 621-629.PubMedGoogle Scholar
- Otero C, Groettrup M, Legler DF: Opposite fate of endocytosed CCR7 and its ligands: recycling versus degradation. J Immunol. 2006, 177: 2314-2323.PubMedGoogle Scholar
- Bardi G, Lipp M, Baggiolini M, Loetscher P: The T cell chemokine receptor CCR7 is internalized on stimulation with ELC, but not with SLC. Eur J Immunol. 2001, 31: 3291-3297. 10.1002/1521-4141(200111)31:11<3291::AID-IMMU3291>3.0.CO;2-Z.PubMedGoogle Scholar
- Kohout TA, Nicholas SL, Perry SJ, Reinhart G, Junger S, Struthers RS: Differential desensitization, receptor phosphorylation, beta-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7. J Biol Chem. 2004, 279: 23214-23222. 10.1074/jbc.M402125200.PubMedGoogle Scholar
- Rappert A, Biber K, Nolte C, Lipp M, Schubel A, Lu B, Gerard NP, Gerard C, Boddeke HW, Kettenmann H: Secondary lymphoid tissue chemokine (CCL21) activates CXCR3 to trigger a Cl- current and chemotaxis in murine microglia. J Immunol. 2002, 168: 3221-3226.PubMedGoogle Scholar
- Van Weering HR, Jong AP, Haas AH, Biber KP, Boddeke HW: CCL21-induced calcium transients and proliferation in primary mouse astrocytes: CXCR3-dependent and independent responses. Brain Behav Immun. 2009, 24: 768-775.PubMedGoogle Scholar
- Yoshida R, Nagira M, Kitaura M, Imagawa N, Imai T, Yoshie O: Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7. J Biol Chem. 1998, 273: 7118-7122. 10.1074/jbc.273.12.7118.PubMedGoogle Scholar
- Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT: A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci U S A. 1998, 95: 258-263. 10.1073/pnas.95.1.258.PubMed CentralPubMedGoogle Scholar
- Handel TM, Johnson Z, Crown SE, Lau EK, Proudfoot AE: Regulation of protein function by glycosaminoglycans–as exemplified by chemokines. Annu Rev Biochem. 2005, 74: 385-410. 10.1146/annurev.biochem.72.121801.161747.PubMedGoogle Scholar
- Riol-Blanco L, Sanchez-Sanchez N, Torres A, Tejedor A, Narumiya S, Corbi AL, Sanchez-Mateos P, Rodriguez-Fernandez JL: The chemokine receptor CCR7 activates in dendritic cells two signaling modules that independently regulate chemotaxis and migratory speed. J Immunol. 2005, 174: 4070-4080.PubMedGoogle Scholar
- Sanchez-Sanchez N, Riol-Blanco L, Rodriguez-Fernandez JL: The multiple personalities of the chemokine receptor CCR7 in dendritic cells. J Immunol. 2006, 176: 5153-5159.PubMedGoogle Scholar
- Lin F, Butcher EC: T cell chemotaxis in a simple microfluidic device. Lab Chip. 2006, 6: 1462-1469. 10.1039/b607071j.PubMedGoogle Scholar
- Bromley SK, Mempel TR, Luster AD: Orchestrating the orchestrators: chemokines in control of T cell traffic. Nat Immunol. 2008, 9: 970-980. 10.1038/ni.f.213.PubMedGoogle Scholar
- Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E, Lipp M: CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999, 99: 23-33. 10.1016/S0092-8674(00)80059-8.PubMedGoogle Scholar
- Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature. 1998, 392: 245-252. 10.1038/32588.PubMedGoogle Scholar
- Sallusto F, Palermo B, Lenig D, Miettinen M, Matikainen S, Julkunen I, Forster R, Burgstahler R, Lipp M, Lanzavecchia A: Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur J Immunol. 1999, 29: 1617-1625. 10.1002/(SICI)1521-4141(199905)29:05<1617::AID-IMMU1617>3.0.CO;2-3.PubMedGoogle Scholar
- Wendland M, Willenzon S, Kocks J, Davalos-Misslitz AC, Hammerschmidt SI, Schumann K, Kremmer E, Sixt M, Hoffmeyer A, Pabst O, Forster R: Lymph node T cell homeostasis relies on steady state homing of dendritic cells. Immunity. 2011, 35: 945-957. 10.1016/j.immuni.2011.10.017.PubMedGoogle Scholar
- Gunn MD, Kyuwa S, Tam C, Kakiuchi T, Matsuzawa A, Williams LT, Nakano H: Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med. 1999, 189: 451-460. 10.1084/jem.189.3.451.PubMed CentralPubMedGoogle Scholar
- Junt T, Scandella E, Forster R, Krebs P, Krautwald S, Lipp M, Hengartner H, Ludewig B: Impact of CCR7 on priming and distribution of antiviral effector and memory CTL. J Immunol. 2004, 173: 6684-6693.PubMedGoogle Scholar
- Kursar M, Hopken UE, Koch M, Kohler A, Lipp M, Kaufmann SH, Mittrucker HW: Differential requirements for the chemokine receptor CCR7 in T cell activation during Listeria monocytogenes infection. J Exp Med. 2005, 201: 1447-1457. 10.1084/jem.20041204.PubMed CentralPubMedGoogle Scholar
- Junt T, Nakano H, Dumrese T, Kakiuchi T, Odermatt B, Zinkernagel RM, Hengartner H, Ludewig B: Antiviral immune responses in the absence of organized lymphoid T cell zones in plt/plt mice. J Immunol. 2002, 168: 6032-6040.PubMedGoogle Scholar
- Ebert LM, Schaerli P, Moser B: Chemokine-mediated control of T cell traffic in lymphoid and peripheral tissues. Mol Immunol. 2005, 42: 799-809. 10.1016/j.molimm.2004.06.040.PubMedGoogle Scholar
- Reiss Y, Proudfoot AE, Power CA, Campbell JJ, Butcher EC: CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell-attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin. J Exp Med. 2001, 194: 1541-1547. 10.1084/jem.194.10.1541.PubMed CentralPubMedGoogle Scholar
- Papadakis KA, Prehn J, Nelson V, Cheng L, Binder SW, Ponath PD, Andrew DP, Targan SR: The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system. J Immunol. 2000, 165: 5069-5076.PubMedGoogle Scholar
- Sakai N, Wada T, Yokoyama H, Lipp M, Ueha S, Matsushima K, Kaneko S: Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proc Natl Acad Sci U S A. 2006, 103: 14098-14103. 10.1073/pnas.0511200103.PubMed CentralPubMedGoogle Scholar
- Tateyama M, Fujihara K, Misu T, Itoyama Y: CCR7+ myeloid dendritic cells together with CCR7+ T cells and CCR7+ macrophages invade CCL19 nonnecrotic muscle fibers in inclusion body myositis. J Neurol Sci. 2009, 279: 47-52. 10.1016/j.jns.2008.12.024.PubMedGoogle Scholar
- Kahnert A, Hopken UE, Stein M, Bandermann S, Lipp M, Kaufmann SH: Mycobacterium tuberculosis triggers formation of lymphoid structure in murine lungs. J Infect Dis. 2007, 195: 46-54. 10.1086/508894.PubMedGoogle Scholar
- Braun A, Worbs T, Moschovakis GL, Halle S, Hoffmann K, Bolter J, Munk A, Forster R: Afferent lymph-derived T cells and DCs use different chemokine receptor CCR7-dependent routes for entry into the lymph node and intranodal migration. Nat Immunol. 2011, 12: 879-887. 10.1038/ni.2085.PubMedGoogle Scholar
- Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC: CNS immune privilege: hiding in plain sight. Immunol Rev. 2006, 213: 48-65. 10.1111/j.1600-065X.2006.00441.x.PubMed CentralPubMedGoogle Scholar
- Mrass P, Weninger W: Immune cell migration as a means to control immune privilege: lessons from the CNS and tumors. Immunol Rev. 2006, 213: 195-212. 10.1111/j.1600-065X.2006.00433.x.PubMedGoogle Scholar
- Galea I, Bechmann I, Perry VH: What is immune privilege (not)?. Trends Immunol. 2007, 28: 12-18. 10.1016/j.it.2006.11.004.PubMedGoogle Scholar
- Wilson EH, Weninger W, Hunter CA: Trafficking of immune cells in the central nervous system. J Clin Invest. 2010, 120: 1368-1379. 10.1172/JCI41911.PubMed CentralPubMedGoogle Scholar
- Alt C, Laschinger M, Engelhardt B: Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood–brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis. Eur J Immunol. 2002, 32: 2133-2144. 10.1002/1521-4141(200208)32:8<2133::AID-IMMU2133>3.0.CO;2-W.PubMedGoogle Scholar
- Krumbholz M, Theil D, Steinmeyer F, Cepok S, Hemmer B, Hofbauer M, Farina C, Derfuss T, Junker A, Arzberger T, et al: CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions. J Neuroimmunol. 2007, 190: 72-79. 10.1016/j.jneuroim.2007.07.024.PubMedGoogle Scholar
- Ploix CC, Noor S, Crane J, Masek K, Carter W, Lo DD, Wilson EH, Carson MJ: CNS-derived CCL21 is both sufficient to drive homeostatic CD4+ T cell proliferation and necessary for efficient CD4+ T cell migration into the CNS parenchyma following Toxoplasma gondii infection. Brain Behav Immun. 2010, 25: 883-896.PubMed CentralPubMedGoogle Scholar
- Engelhardt B: Molecular mechanisms involved in T cell migration across the blood–brain barrier. J Neural Transm. 2006, 113: 477-485. 10.1007/s00702-005-0409-y.PubMedGoogle Scholar
- Bixby LM, Tarleton RL: Stable CD8+ T cell memory during persistent Trypanosoma cruzi infection. J Immunol. 2008, 181: 2644-2650.PubMed CentralPubMedGoogle Scholar
- Fiuza JA, Fujiwara RT, Gomes JA, Rocha MO, Chaves AT, de Araujo FF, Fares RC, Teixeira-Carvalho A, Martins-Filho OA, Cancado GG, Correa-Oliveira R: Profile of central and effector memory T cells in the progression of chronic human chagas disease. PLoS Negl Trop Dis. 2009, 3: e512-10.1371/journal.pntd.0000512.PubMed CentralPubMedGoogle Scholar
- de Graaf MT, Smitt PA, Luitwieler RL, van Velzen C, van den Broek PD, Kraan J, Gratama JW: Central memory CD4+ T cells dominate the normal cerebrospinal fluid. Cytometry B Clin Cytom. 2011, 80: 43-50.PubMedGoogle Scholar
- Kivisakk P, Tucky B, Wei T, Campbell JJ, Ransohoff RM: Human cerebrospinal fluid contains CD4+ memory T cells expressing gut- or skin-specific trafficking determinants: relevance for immunotherapy. BMC Immunol. 2006, 7: 14-10.1186/1471-2172-7-14.PubMed CentralPubMedGoogle Scholar
- Kivisakk P, Mahad DJ, Callahan MK, Sikora K, Trebst C, Tucky B, Wujek J, Ravid R, Staugaitis SM, Lassmann H, Ransohoff RM: Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann Neurol. 2004, 55: 627-638. 10.1002/ana.20049.PubMedGoogle Scholar
- Doerck S, Gobel K, Weise G, Schneider-Hohendorf T, Reinhardt M, Hauff P, Schwab N, Linker R, Maurer M, Meuth SG, Wiendl H: Temporal pattern of ICAM-I mediated regulatory T cell recruitment to sites of inflammation in adoptive transfer model of multiple sclerosis. PLoS One. 2010, 5: e15478-10.1371/journal.pone.0015478.PubMed CentralPubMedGoogle Scholar
- Asensio VC, Campbell IL: Chemokines in the CNS: plurifunctional mediators in diverse states. Trends Neurosci. 1999, 22: 504-512. 10.1016/S0166-2236(99)01453-8.PubMedGoogle Scholar
- Columba-Cabezas S, Serafini B, Ambrosini E, Aloisi F: Lymphoid chemokines CCL19 and CCL21 are expressed in the central nervous system during experimental autoimmune encephalomyelitis: implications for the maintenance of chronic neuroinflammation. Brain Pathol. 2003, 13: 38-51.PubMedGoogle Scholar
- Meinl E, Krumbholz M, Hohlfeld R: B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation. Ann Neurol. 2006, 59: 880-892. 10.1002/ana.20890.PubMedGoogle Scholar
- Antel J, Bar-Or A: Roles of immunoglobulins and B cells in multiple sclerosis: from pathogenesis to treatment. J Neuroimmunol. 2006, 180: 3-8. 10.1016/j.jneuroim.2006.06.032.PubMedGoogle Scholar
- Kuwabara T, Ishikawa F, Yasuda T, Aritomi K, Nakano H, Tanaka Y, Okada Y, Lipp M, Kakiuchi T: CCR7 ligands are required for development of experimental autoimmune encephalomyelitis through generating IL-23-dependent Th17 cells. J Immunol. 2009, 183: 2513-2521. 10.4049/jimmunol.0800729.PubMedGoogle Scholar
- Takamura K, Fukuyama S, Nagatake T, Kim DY, Kawamura A, Kawauchi H, Kiyono H: Regulatory role of lymphoid chemokine CCL19 and CCL21 in the control of allergic rhinitis. J Immunol. 2007, 179: 5897-5906.PubMedGoogle Scholar
- Molon B, Gri G, Bettella M, Gomez-Mouton C, Lanzavecchia A, Martinez AC, Manes S, Viola A: T cell costimulation by chemokine receptors. Nat Immunol. 2005, 6: 465-471.PubMedGoogle Scholar
- Fan L, Reilly CR, Luo Y, Dorf ME, Lo D: Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J Immunol. 2000, 164: 3955-3959.PubMedGoogle Scholar
- Aloisi F, Pujol-Borrell R: Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol. 2006, 6: 205-217. 10.1038/nri1786.PubMedGoogle Scholar
- Chen SC, Leach MW, Chen Y, Cai XY, Sullivan L, Wiekowski M, Dovey-Hartman BJ, Zlotnik A, Lira SA: Central nervous system inflammation and neurological disease in transgenic mice expressing the CC chemokine CCL21 in oligodendrocytes. J Immunol. 2002, 168: 1009-1017.PubMedGoogle Scholar
- Gomez-Nicola D, Pallas-Bazarra N, Valle-Argos B, Nieto-Sampedro M: CCR7 is expressed in astrocytes and upregulated after an inflammatory injury. J Neuroimmunol. 2010, 227: 87-92. 10.1016/j.jneuroim.2010.06.018.PubMedGoogle Scholar
- Dijkstra IM, de Haas AH, Brouwer N, Boddeke HW, Biber K: Challenge with innate and protein antigens induces CCR7 expression by microglia in vitro and in vivo. Glia. 2006, 54: 861-872. 10.1002/glia.20426.PubMedGoogle Scholar
- Eo SK, Kumaraguru U, Rouse BT: Plasmid DNA encoding CCR7 ligands compensate for dysfunctional CD8+ T cell responses by effects on dendritic cells. J Immunol. 2001, 167: 3592-3599.PubMedGoogle Scholar
- de Jong EK, Dijkstra IM, Hensens M, Brouwer N, van Amerongen M, Liem RS, Boddeke HW, Biber K: Vesicle-mediated transport and release of CCL21 in endangered neurons: a possible explanation for microglia activation remote from a primary lesion. J Neurosci. 2005, 25: 7548-7557. 10.1523/JNEUROSCI.1019-05.2005.PubMedGoogle Scholar
- Biber K, Sauter A, Brouwer N, Copray SC, Boddeke HW: Ischemia-induced neuronal expression of the microglia attracting chemokine Secondary Lymphoid-tissue Chemokine (SLC). Glia. 2001, 34: 121-133. 10.1002/glia.1047.PubMedGoogle Scholar
- Lalor SJ, Segal BM: Lymphoid chemokines in the CNS. J Neuroimmunol. 2010, 224: 56-61. 10.1016/j.jneuroim.2010.05.017.PubMed CentralPubMedGoogle Scholar
- Dijkstra IM, Hulshof S, van der Valk P, Boddeke HW, Biber K: Cutting edge: activity of human adult microglia in response to CC chemokine ligand 21. J Immunol. 2004, 172: 2744-2747.PubMedGoogle Scholar
- Zhao P, Waxman SG, Hains BC: Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine cysteine chemokine ligand 21. J Neurosci. 2007, 27: 8893-8902. 10.1523/JNEUROSCI.2209-07.2007.PubMedGoogle Scholar
- Biber K, Tsuda M, Tozaki-Saitoh H, Tsukamoto K, Toyomitsu E, Masuda T, Boddeke H, Inoue K: Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. EMBO J. 2011, 30: 1864-1873. 10.1038/emboj.2011.89.PubMed CentralPubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


text:
You are a fan of interview visa ? Come to discover the best forums interview visa on the internet and share your experience with a community fan of interview visa . You can also build a forum interview visa and create your online discussion.
travel tips, search for a guide, driver, hotel, tours, trip, visa support, letter of invitation, etc.
travel, uzbekistan, tips, search, guide, driver, hotel, tours, trip, #visa, support, letter, invitation
Nanning China Information Forum. Marriage, Visa, Work, Settlement Info
nanning, guangxi, southern, china, information, europe, settlement, #visa, marriage, work, employment, advice, flights, beijing, guangzhou, hong, kong, guilin, australia