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Orlando police investigate 6 missing baby swans
The cygnets were just one day old when they were discovered missing.
The cygnets were just one day old when they were discovered missing.
A woman who was shot in Newport News was driven to Hampton Sentara Careplex late Sunday night.
A southern comfort meal with a Louisiana twist.
Officers took one person in to custody, after the situation ended peacefully Monday afternoon.
Expert advice from Healthy Families Partnership.
Gearing up for Global Youth Volunteer Day
Expert job search information from the Career Engineer Francina Harrison.
If you are thinking of finishing your degree, then Bryant and Stratton College may be a good option for you
The shift offers increasingly desperate Trump foes a glimmer of hope in their long and frustrating fight to halt the billionaire's rise.
Get a high definition photo of your baby before they're born.
Learn more about this great team building facility that will have you looking for clues and solving puzzles
The National Park Service has named Terry Brown as the new superintendent at Fort Monroe National Monument.
North Carolina House Democrats have filed legislation to repeal the Republican-backed law that blocks local and state protections for LGBT c…
A Tennessee police chief has offered an apology after his officers handcuffed and arrested 10 elementary school students.
The appeals ruling follows a September decision by Manhattan Judge Richard Berman that went against the league, letting Brady skip the suspe…
A salmonella scare for CVS Pharmacy has the company recalling cases of herbal tea.


text:
Recent in Microbial Analysis (page 1 of 1)
Branded Content
Introducing BASF's new Experiential Skin Care – BASF Introduces Experiential Skin Care
What are Oligomers for LED Curable Nail Gel Coatings? – Dymax Corporation
Formulation Friendly and Effective BioTransformed Natural Extracts – BCR
Brightness, High Chroma Effects Focus for New High-Performance Pigments – BASF
A Tailor-made Approach for Achieving a Fair and Even Complexion – Sederma
Proposed Method to Evaluate the Microbiological Stability of Cosmetics During Use
Apr 21, 2014
The authors propose an approach to assess the microbial stability of a product during use, referred to as the Microbiological Use Test (MUT), and apply this analysis in case studies to predict the microbiological risk of commercial products. The described test has been used successfully in the development of cosmetics.
BASF Establishes Enzyme Alliances
Nov 9, 2006
BASF has signed a cooperation agreement with the Center of Excellence in Biocatalysis, Biotransformation and Biomanufacturing (CoEBio3) in Manchester, UK.

subset: commoncrawl


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I graduated in May 2007 from Rowan University with a bachelor's degree in economics.
I like sushi, poker, politics, Phillies baseball, Eagles football, bowling, tennis, and basketball. I have a pet bird but WATCH OUT he'll bite your head off!
I enjoy challenging my intellect with brain games (scrabble, chess, sudoku, POKER). I'm genuinely a nice guy. I like meeting new people and just being around people in general.
I work out everyday.
I'm an open book. Very easy to read for anyone who wants to know (except at the poker table).
Movies: I-Robot, Shrek, Office Space, Star Wars, The Lord of the Rings Film Trilogy, The Chronicles of Narnia, Crash, Stargate.
TV Shows: Family Guy, Futurama, The Daily Show with John Stewart, The Colbert Report, Two and a Half Men.
Music: I enjoy any and everything of musical nature. Here are some of my favorites - -> In no particular order - Phil Collins, Ace of Base, Michael Jackson, Prince, Green Day, The Offspring, Eve 6, Sublime, Savage Garden, Hootie and the Blowfish, K-ci & JoJo, Straight No Chaser, Linkin Park, Seal, and everything else (unless it sucks).
Food: I'll eat just about anything. I especially like italian, chinese, mexican, and sushi!


text:
Sachal Vasandani
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Happy hump day, friends!
Todays featured blogger is Strength and Sunshine.
Hey lovely ladies! My name is Rebecca and I started Strength and Sunshine in June of 2013. I had always been an avid healthy living blog reader so I decided to start my own blog and share my passions for all things that encompass healthy living. That includes yoga, strength training, cooking, mental health, and fun! I also have Celiac Disease, a soy allergy, and eat mostly vegan, but I love developing new healthy recipes to share and help out those who also have dietary restrictions! Come check out my blog and stay a while, don't be scared to say hi; we all need strength and sunshine on our personal journeys!
Favorite Posts:
- It's Okay To Cry During Yoga
- Vegan Stuffed Portobello Mushrooms and A Sweet Crunchy Treat
- Vanilla Purple Sweet Potato Pancakes
Go visit Strength and Sunshine and share the comment love! Make sure to comment below for roll call.
- 7 Benefits of Cooking Together as a Family - Jun 24, 2016
- 10 Tips For Photographing Food With Your Smartphone - Jun 22, 2016
- Twitter Strategy: 10 Tips For Gaining Followers - Jun 17, 2016
- Don't Be Discouraged: Advice For New Bloggers - Jun 16, 2016
- Get Ready To Write Every Day – These Four Tips Will Help - Jun 15, 2016
- DIY Polka-Dot Party Lights - Jun 10, 2016
- 5 Obstacles That Hold You Back From Writing And How To Overcome Them - Jun 6, 2016
- An Important Message For National Cancer Survivors Day: Early Detection Is Key - Jun 2, 2016
- 5 Words You Need To Learn To Say Without Fear - May 30, 2016
- Strawberry Themed Party - May 27, 2016


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U.K.'s Virgin Retail To Revamp Website
By Lars Brandle
Giant U.K. music and entertainment merchant Virgin Retail is to undergo a "complete revamp" of its online offering.
The new Virgin Retail Web site at virginmegastores.co.uk will be developed with "simplicity" and "usability" in mind for the customers, while allowing for greater control and flexibility for adding-on new functions, the company says in a statement issued today.
Also, the updated site will bring the online service's management and development in-house for the first time.
"The vastly improved site, geared towards the needs of today's online customer will form a major pillar of Virgin's multi-channel strategy", comments Steve Kincaid, Virgin's marketing and e-commence director, in the statement.
Virgin Retail has chosen a string of companies to develop the new Web site, which will go live by late summer 2007.
The companies involved in the project are hybris, a supplier of e-business software solutions; Mercado, an e-commerce search and merchandising solution specialist; and design agency Underwired. Retail and e-commerce consultancy
Javelin Group has been hired to advise on the choice of technology and Web agency partner.
The news comes on the heels of rival HMV's plans to beef up its online and digital operations in the United Kingdom.


text:
Mother and daughter bonding in front of window
Credit: Sam Edwards
Creative #: 170014274
License type: Royalty-freeRoyalty-free pricing is based solely on the size of the product you need, not the specific use. You don't have to pay any additional royalties on a use-by-use basis. Once you license a royalty-free product, you may use it multiple times for multiple projects without paying additional fees. (Pornographic, defamatory, libelous or otherwise unlawful use of any image is, of course, prohibited.)
Collection: OJO Images
Release info: Model and property released
- 25-29 Years,
- 65-69 Years,
- Active Seniors,
- Adult,
- Adult Offspring,
- Adults Only,
- Affectionate,
- Bonding,
- Caucasian Ethnicity,
- Color Image,
- Copy Space,
- Daughter,
- Day,
- Domestic Life,
- Embracing,
- Face To Face,
- Family with One Child,
- Females,
- Front View,
- Happiness,
- In Front Of,
- Indoors,
- Love,
- Mother,
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- Photography,
- Senior Adult,
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- Sitting,
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- Window,
- Women,
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Mother And Daughter Bonding In Front Of Window Stock Photo25-29 Years,65-69 Years,Active Seniors,Adult,Adult Offspring,Adults Only,Affectionate,Bonding,Caucasian Ethnicity,Color Image,Copy Space,Daughter,Day,Domestic Life,Embracing,Face To Face,Family with One Child,Females,Front View,Happiness,In Front Of,Indoors,Love,Mother,One Parent,Only Women,People,Photography,Senior Adult,Senior Women,Single Mother,Sitting,Smiling,Soft Focus,Three Quarter Length,Togetherness,Two People,Vertical,Window,Women,Young Adult,Young WomenPhotographer Sam EdwardsCollection: OJO Images


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Learn how to join Instagram, use Instagram filters, post photos, and build a community of followers and fellow photo lovers.
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Get started using Instagram to market your business. Learn how to choose photos, filters, and hashtags and integrate Instagram with your website or blog.
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December 5, 2012
I would like to be able to use one workflow that takes me from wireframe to prototype to deployment for UX/UI/Mobile.
Not yet I am creating some samples now to add to my portfolio.
I am a Network Operations Center Technician transitioning into Design and Internet Marketing. Helping Entrepreneurs and small to medium sized businesses with their online presence, UI/UX, and Mobile applications.
Hi, I am a "Desveloper" and looking forward to creating my UX/UI portfolio.
This is a much needed group and I am looking forward to future meetings. - Devsigner
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From the Inside Flap
Organized into four comprehensive sections, Enterprise Risk Management offers in-depth insights, practical advice, and real-world case studies that explore every aspect of this important field. Section I: "Risk Management in Context" provides an introduction and foundation for the rest of the book. Youll learn why a company should strive for balance between risk and return, and discover some of the basic reasons why risk management is such an important issue in business today. Youll also learn seven essential risk management lessons through discussions of some of the major financial disasters of years past. With this knowledge in hand, youll be introduced to some of the key concepts, processes, and tools underlying risk management.
In Section II: "The Enterprise Risk Management Framework," youll receive an executive education on the business rationale for integrating risk management processes, and discover the seven building blocks for developing an enterprise risk management program. Youll also discover how the role of Chief Risk Officer has changed in todays firm.
Section III: "Risk Management Applications" discusses the applications of risk management in two dimensionsfunctions and industries. Youll become familiar with the functional requirements for credit, market, and operational risks, as well as learn how risk management has evolved from a control function to a function that enables performance optimization. Industry segments including financial institutions, energy firms, asset management firms, and nonfinancial corporations are also explored with an eye toward key business trends and risk management requirements in these sectors.
Section IV: "A Look to the Future" rounds out this comprehensive discussion of enterprise risk management by examining emerging topics in risk management with respect to people and technology. A forward-looking story reveals how best-practice risk management might look in the year 2010.
Failure to properly manage risk continues to plague corporate Americafrom Enron to Long-Term Capital Management. Dont let it hurt your organization. Pick up Enterprise Risk Management and learn how to meet the enterprise-wide risk management challenge head onand succeed.
From the Back Cover
"In the aftermath of Enron, WorldCom, and Sarbanes-Oxley, every publicly traded company should be concerned about risk management. This book takes a pragmatic approach to risk management that can benefit any CEO or senior executive. Lam lays out clear strategies to address what is often a highly complex issue."
William L. Walton, Chairman and CEO, Allied Capital Corporation
"James Lam provides one of the most practical, insightful books on risk management that I have read in the last thirty years. It clearly reflects experience and deep understanding of the art as well as the science in risk management practices. A must-read for all who wish to advance risk management practices in their businesses."
Sandra Jansky, Executive Vice President, Chief Credit Officer, SunTrust Banks, Inc.
Chairperson, Risk Management Association
"In this book, James Lam has provided an effective overview of business risk. Enterprise Risk Management will be useful to professional risk managers and business executives seeking to understand the latest tools and organizational approaches."
Robert Simons, Charles M. Williams Professor of Business Administration,
Unit HeadAccounting & Control, Harvard Business School
"The most comprehensive and engaging handbook on enterprise risk management, written by the pioneer of the Chief Risk Officer function. Filled with practical examples and lessons learned, this book is destined to become one of the most widely read primers on todays top business initiative. James Lam is the authority on enterprise risk management, and I highly recommend this book to all board directors, senior executives, and risk managers."
Cassandra R. Schultz, Vice President and Chief Risk Officer, KeySpan Corporation
"James Lams book Enterprise Risk Management: From Incentives to Controls provides an insightful road map to best practices in risk management. Based on a solid and successful career in risk management, Jamess advice is both timely and relevant and should be required reading for all risk management professionals."
Michael J. Litwin, Chief Credit and Risk Officer, Merrill Lynch Capital


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Hot topics in Graphics Softwarepascal .sol editor (flash shared object) alcatel flash tool dicom 3d modeling 3d plot gimp plugins free pascal .sol editor 3ds
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This tool opens or create a Macromedia Flash shared object file (.sol) displays the content of the file and allow you to change the values.435 weekly downloads
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troka is a hardware accelerated video output library for the nato (http://www.eusocial.com/nato.0+55+3d/242.0000.html) video processing system. it uses openGL to provide full screen antialiased non-tearing interpolated video output optimized for live per
256-to-16 Color Processing
Decrease color depth from 256 to 16.
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j2dcg: Java 2D Computer Graphics and Imaging Framework. This framework is targeted for academic use, to reduce the amount of Java / User Interface coding for assignements targeting both raster and vector graphics.1 weekly downloads
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This project is an attempt to write cross-platform code which implements the Haars Transform (Discrete Wavelet Transform / DWT) in 2D for image manipulation. The code provided will use SDL to half the size of an image in both the x and y directions.
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The 3D Slicer is freely available, open-source software for visualization, registration, segmentation, and quantification of medical image data. Follow the link for more info: http://slicer.org
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With his team trailing Union Grove by two points and time quickly running out, Greendale's Jordan Perez took the ball downcourt.
Perez encountered a double team near the top of the key and passed off to a wide-open Nate Thomson in the right corner.
Thomson let fly and connected on a 3-point field goal at the buzzer to give the Panthers a thrilling 55-54 triumph in a WIAA Division 2 regional championship contest Saturday night.
"Thomson is a lights-out shooter," said head coach Ryan Johnsen. "When he gets an open look, we have confidence that he will hit it. It was also an unselfish play by Jordan."
The victory boosted the Panthers to 17-8 and sent them into a sectional semifinal game against McFarland High School (14-10) at 7 p.m. today (March 6) at Clinton.
Panthers bounce back
On the road against top-seeded Union Grove (19-5) on Saturday, Greendale fell behind 15-9 after one quarter.
The Panthers did not panic but instead rallied in a big way, outscoring the Broncos 17-3 to take a 26-18 halftime lead.
Union Grove came within 40-37 after three periods and eventually tied the game in the final minutes.
Cody Walters stepped to the line with five seconds left and the contest even at 52-52. He hit both free throws to put the Broncos up 54-52.
Perez inbounded and quickly got the ball back, taking it to the free-throw line before finding Thomson for the winning shot.
Ironically, those were Thomson's only points of the night.
David Pulizos chipped in with eight points and Mitchell Brees added six points and eight rebounds for Greendale.
In Friday's victory over Wilmot (17-6), Pulizos tallied 11 points and Josh Ringelberg and Braxton Joehnk seven apiece. Greendale lost a 12-point halftime lead and fell behind by one going into the fourth period, but then outscored Wilmot 28-16 in the final period.
A standout player
Thomson played as big a part in Greendale's regional crown as anyone. Not only did he hit the game-winning shot against Union Grove, but he tallied a team-high 25 points, with six 3-point shots, in the Panthers' 80-58 romp over Westosha Central in the opening regional game Feb. 25.
He wasn't the only hero for the week, however.
Josh Michaels poured in a game-high 32 points in a 74-63 victory over Wilmot in the regional semifinal Friday night and added 21 against Union Grove.
"He stepped up in a variety of ways," Johnsen said of Michaels.
Perez was typically consistent as well, coming up with 17 points against Central; 12 points and 15 rebounds against Wilmot; and 11 points, eight rebounds and four assists in the Union Grove contest.
Overall, the Panthers put forth a strong team effort in sweeping the three regional games and erasing their slow finish to the regular season.
"We came into the playoffs losing three in a row, which is not ideal," Johnsen said. "(We lost) to two good teams, Pius XI, the conference champ, and Pewaukee. We think our conference is very good, and we got ourselves some momentum (last week)."
Thomson gets hot
The Feb. 25 contest with Westosha Central (6-16) was close after one quarter, with Greendale up 21-18.
Thomson then got hot, hitting five 3-pointers and scoring 18 points in the second quarter to help the Panthers to a 46-27 halftime advantage.
"He (Thomson) was a real shot in the arm," Johnsen said. "He's been doing that for us all year. (Central) played a 2-3 zone, and we told the kids they are going to get great looks. That was a great opportunity for him. He took advantage, and that's great to see, especially from a sophomore."
"I was definitely feeling it," Thomson said. "My teammates were giving me the ball, and I was shooting really well. My teammates helped me because they gave me confidence."
WHAT: WIAA Division 2 boys basketball sectional
MARCH 6: Greendale (17-8) vs. McFarland (14-10) at Clinton at 7 p.m.; Sauk Prairie (16-8) vs. Mount Horeb (24-0) at Middleton, 7 p.m.
MARCH 8: Championship game at Sun Prairie at 1 p.m.
GREENDALE: The Panthers finished fifth in the Woodland Conference West Division at 10-7 and lost their final three Woodland games ... Jordan Perez is the top scorer at 21.5 points per game and Josh Michaels is next at 13.0 ... Nate Thomson has provided a spark with his outside shooting, and Mitchell Brees leads the defense.
McFARLAND: The team took third in the Rock Valley North at 10-6 ... the top scorer is Benjamin Rounds at 14.4 points per game, with Sean Chislom next at 13.4 ... McFarland downed Fort Atkinson 61-49 in its regional championship game.
SAUK PRAIRIE: The team came in third in the Badger North Conference at 7-5 ... the top scorer is Seth Kostroski at 13.1 points per game, and Jake Fiene is at 11.5 per contest ... Sauk Prairie defeated Reedsburg 62-58 in double overtime in the regional title contest.
MOUNT HOREB: The team is rated first in the Division 2 coaches' poll and claimed the Badger North at 12-0 ... the top scorer is Drew Fredrickson at 12.8 points per game, with Max Meylor at 12.4 ... Mount Horeb edged Monona Grove 51-47 in double overtime to win the regional title.
More from Sports
- Greendale grabs second place in Woodland Conference baseball tournament
- Greendale baseball team brings home third consecutive Woodland Conference West title
- Greendale's Jankowiak, Tomaszewski toss no-hitter in victory over Wauwatosa West
- Greendale baseball team pulls out three gritty victories to hold Woodland West lead
- Greendale's Thomson bounces back from bad round, moves to up to earn state medal
- Greendale baseball team's winning streak ended by New Berlin West in 11 innings
- Nerves hurt chances for Greendale's Rudd at state track meet
- Nate Thomson, Greendale boys golf team come in second in Woodland Conference Tournament
- Greendale's Magner takes up soccer, later turns in Hall of Fame career at Edgewood College
- Johnson, Greendale softball team shut down South Milwaukee in Woodland game


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Reviews for 606 Congress at Renaissance Boston
Latest Yelp Reviews
Overall Rating:
Based on 37 Reviews
Based on 37 Reviews
Justin C. posted on 03/25/2013
Rating & Review:
I don't generally do the Yelp review thing but after my last experience in Boston, I had to. I was in town for work-a huge trade show at the BCEC. I stayed... read more
Jennifer S. posted on 08/19/2013
Rating & Review:
Nice hotel restaurant to enjoy a tasty breakfast. We held a breakfast meeting at the restaurant and they very nicely put us in a private section of the... read more
Daniel M. posted on 08/01/2011
Rating & Review:
Good spot in the Seaport District set a half block away from the heavier bars so you know you'll: 1) Get inside [it's in the Renaissance Hotel] 2) Not be... read more
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I'm looking for a word that has the same meaning as "plagiarism" but in relation to plagiarized ideas only, i.e. not related to writing, art work, drawing etc.
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I don't believe there exists such a word, to describe someone who steals ideas, as it cannot be classified as a crime unlike plagiarism, which also functions as a verb.
I can think of only one expression: to take credit
Scenario: A tells B an idea on how to improve the company's productivity tenfold. Then B, behind A's back, goes to their boss and suggests the very same idea. The idea proves to be a success but it is B who takes the credit.
To steal: To present or use (someone else's words or ideas) as one's own.
To take the credit: to allow people to believe that one has done something praiseworthy, whether or not one has actually done it
I found this link about how "stealing" ideas in the business world can be perfectly legal but there are exceptions to the rule. http://yourbusiness.azcentral.com/legal-term-stealing-business-idea-12733.html
A word that is used with some degree of specificity for this purpose is "crib."
I've heard "cooptation" or "co-opt" used this way.
There is. I'm a Dancer/Bboy and in the HipHop and Bboy World we call them Biters or a Biter. Slang my Friend ;)
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Fallout 3 Collector's Edition - PC
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- Enjoy your very own Vault Boy collectors item direct from Vault-Tec
- Includes The Art of Fallout 3 hardcover book of exclusive concept art and commentary
- Special DVD The Making of Fallout 3 included for a behind the scenes look at the creative team
- Includes fully customized metal Vault-Tec lunch box
- Receive these collector edition items with the game Fallout 3
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For 200 years, Vault 101 , a fallout shelter, has faithfully served the surviving residents of Washington DC and its environs, now known as the Capital Wasteland. Though the global atomic war of 2077 left the US all but destroyed, the residents of Vault 101 enjoy a life free from the constant stress of the outside world. Giant Insects, Raiders, Slavers, and yes, even Super Mutants are all no match for superior Vault-Tec engineering. Yet one fateful morning, you awake to find that your father has defied the Overseer and left the comfort and security afforded by Vault 101 for reasons unknown. Leaving the only home you've ever known, you emerge from the Vault into the harsh Wasteland sun to search for your father, and the truth.
Key Features:
- Limitless Freedom! Take in the sights and sounds of the vast Capital Wasteland! See the great monuments of the United States lying in post-apocalyptic ruin! You make the choices that define you and change the world. Just keep an eye on your Rad Meter!
- Experience S.P.E.C.I.A.L.! Vault-Tec engineers bring you the latest in human ability simulation the SPECIAL Character System! Utilizing new breakthroughs in points-based ability representation, SPECIAL affords unlimited customization of your character. Also included are dozens of unique skills and perks to choose from, each with a dazzling variety of effects!
- Fantastic New Views! The wizards at Vault-Tec have done it again! No longer constrained to just one view, experience the world from 1st or 3rd person perspective. Customize your view with the touch of a button!
- The Power of Choice! Feeling like a dastardly villain today, or a Good Samaritan? Pick a side or walk the line, as every situation can be dealt with in many different ways. Talk out your problems in a civilized fashion, or just flash your Plasma Rifle.
- Blast 'Em Away With V.A.T.S.! Even the odds in combat with the Vault-Tec Assisted Targeting System for your Pip-Boy Model 3000! V.A.T.S. allows you to pause time in combat, target specific body parts on your target, queue up attacks, and let Vault-Tec take out your aggression for you. Rain death and destruction in an all-new cinematic presentation featuring gory dismemberments and spectacular explosions.
- Mind-Blowing Artificial Intelligence! At Vault-Tec, we realize that the key to reviving civilization after a global nuclear war is people. Our best minds pooled their efforts to produce an advanced version of Radiant AI, America's First Choice in Human Interaction Simulation. Facial expressions, gestures, unique dialog, and lifelike behavior are brought together with stunning results by the latest in Vault-Tec technology.
- Eye-Popping Prettiness! Witness the harsh realities of nuclear fallout rendered like never before in modern super-deluxe HD graphics. From the barren Wasteland, to the danger-filled offices and metro tunnels of DC, to the hideous rotten flesh of a mutant's face.
System Requirements:
|Minimum Specifications:
|Recommended Specifications:
|Windows XP/Vista
|2.4 Ghz Intel Pentium 4 or equivalent processor
|Intel Core 2 Duo processor
|XP: 1GB System RAM
Vista: 2GB System RAM
|2 GB System RAM
|Video Card:
|Direct X 9.0c compliant video card with 256MB RAM (NVIDIA 6800 or better/ATI X850 or better)
|NvidiaDirect X 9.0c compliant video card with 512MB RAM (NVIDIA 8800 series, ATI 3800 series)
|Supported Video Card Chipsets:
|NVIDIA GeForce Series 200, 9800, 9600, 8800, 8600, 8500, 8400, 7900, 7800, 7600, 7300, 6800; ATI HD Series 4800, 4600, 3800, 3600, 3400, 2900, 2600, 2400; ATI Series X1900, X1800, X1600, X1300, and X850
Customer Reviews
Top Customer Reviews
I don't want to issue any spoilers, but what I will say is that the graphics are revolutionary! The world feels very immersing and the character interactions are very realistic. The controls are very similar to Oblivion too, so it wasn't hard to dive in. The game is very, very polished and when you exit Vault 101 for the first time, the scenery that greets you is astounding! You can see objects in full clarity right out to the horizon and the environment looks very much like a post-apocalyptic wasteland, albeit under a very gray palette. I maxed out the in-game detail settings and my single slot GeForce 8800GTS (G92) 512MB handled it perfectly. This is first class!
My biggest gripe with DRM is limited activations, which also infer spying on your machine. This game does indeed use the "evil" SecuROM, but it's just the usual SecuROM disc-checking that we have in tonnes of games prior to this. There are NO LIMITED ACTIVATIONS. I'm a big anti-DRM person, just look at my posts for Spore, but this, in my opinion, is an acceptable use of DRM and I recommend people get the game.
Fallout 3 was released yesterday, and we can all lay our worries to rest.
From the opening splash screens, to Ron Perlman's narrative, to the interactive birthing of your character, Fallout 3 hits the nail on the head.
Graphically the game is awe inspiring. No, it's no Crysis, but when you first leave the vault and step out into the wasteland you are greeted with a post-apocalyptic vision stretching away for miles in all directions that sends chills down your spine. Yes, some of the textures are lower resolution due to Fallout 3 being developed for consoles as well as PC, but I honestly took a long time to notice since I was so caught up in the game.
Action wise, it's great to be able to run around and shoot like it was a FPS, but it's even better to be able to hit a button and go into V.A.T.S. mode and aim at specific body parts. The first time you make someone's head explode or cause a mutant dog to disintegrate in slow-motion you will appreciate it even more.
Role-playing wise, it's fantastic to not be limited in your choices. You can help people, rob them, or kill them, it's up to you. Steal or buy, run or fight, be nice or be naughty, play the game the way you want to.
And then go back and play it all over a different way. It also helps immensly that - unlike Far Cry 2 - the voice acting is top notch. You beleive these are people, rather than poor actors reading lines as fast as they can to collect the check and get home.Read more ›
It is a cRPG game in which the player can alternate between the First and Third person perspective roaming a world comparable in size with OBLIVION. The action has moved from Vault 13 and Southern California to Vault 101 and Washington, D.C. and the story brakes away from the previous bloodlines. However, the atmosphere of the original has been maintained and its scents sharpened: veterans will find it fitting like and old glove - whereas the new gamers are in store for a bag of pleasant surprises.
The graphics are wonderful, the guns detailed and the environments highly interactive. Short of a screenshot, imagine what would HalfLife-2 would look if released today. And similar to HL2, FALLOUT-3 does not require an...ubercomputer to run smoothly. Once you see a NPC move though, you understand where the corners were cut.
Character customization is carried out in great style using the new and improved PIP-BOY at the beginning. You exit the vault and the harsh reality of a world that barely survived annihilation slaps you on the face. Adapt or perish.
The main storyline is there to be followed but FALLOUT-3 offers the greatest number of alternative choices I have ever encountered in a game! There is always a great number of paths to follow in order to achieve any goal - but every choice comes with a consequences tag. This is common feature of most classic cRPGs but in FALLOUT-3 I saw it implemented like never before. If nothing else, this sends replayability through the roof.Read more ›
Most Recent Customer Reviews
Loved the series, wasn't able to get motivated for a second plaything with a fresh character tho.Published 24 months ago by Harold Buchanan
Fallout 3: Collector's Edition (PC) is one of the greatest games on the Xbox 360 system. The company behind it is Bethesda, who is headquartered in Bethesda, Maryland, i.e. Read morePublished on January 25, 2014 by Christopher J. Cowen
This game is one of the best game ever release in the ps3/360 era.
Storyline is sad, you wake up one day and your dad leaves the cave. Read more
Bobble head, lunchbox, excellent game. Looks great decorating my shelves. I actually bought two of these and gave one to a friend.Published on November 17, 2013 by Aaron
This is one of the best games I've ever played. Maybe even THE best. I highly recommend it to any RPG/Elder Scrolls fans out there. Read morePublished on November 2, 2013 by Joseph C. Krzyzanski
Considering only the disc was sixty bucks when it first came out, the collector's edition delivers a lot of exclusive content you couldn't get elsewhere. Except for maybe ebay lolPublished on August 27, 2013 by pompy23
Why buy the bobble-head on eBay when you can have the whole set of goodies from the Collector's Edition for just $10 more? Read morePublished on May 12, 2013 by Mark Foshee
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text:
These authors contributed equally to this review.
T-cell receptor binding affinities and kinetics: impact on T-cell activity and specificity
Version of Record online: 20 NOV 2008
DOI: 10.1111/j.1365-2567.2008.03015.x
© 2009 The Authors Journal compilation © 2009 Blackwell Publishing Ltd
Volume 126, Issue 2, pages 165–176, February 2009
Additional Information
How to Cite
Stone, J. D., Chervin, A. S. and Kranz, D. M. (2009), T-cell receptor binding affinities and kinetics: impact on T-cell activity and specificity. Immunology, 126: 165–176. doi: 10.1111/j.1365-2567.2008.03015.x
Publication History
- Issue online: 5 JAN 2009
- Version of Record online: 20 NOV 2008
- Received 1 November 2008; revised 6 November 2008; accepted 7 November 2008.
- Abstract
- Article
- References
- Cited By
- agonists;
- antagonists;
- binding affinity;
- coreceptors;
- dissociation rate;
- major histocompatibility complex;
- peptide specificity;
- peptide–major histocompatibility complex;
- serial triggering;
- T-cell receptor;
- T-cell receptor clustering
- Top of page
- Summary
- Introduction
- Relationships between T-cell activity and TCR : pepMHC binding parameters
- TCR affinity, avidity and clustering
- Influence of coreceptors on pepMHC binding by TCRs and T-cell activity
- Impact of TCR binding affinity on antigenic peptide specificity
- Conclusion
- Acknowledgements
- References
The interaction between the T-cell receptor (TCR) and its peptide–major histocompatibility complex (pepMHC) ligand plays a critical role in determining the activity and specificity of the T cell. The binding properties associated with these interactions have now been studied in many systems, providing a framework for a mechanistic understanding of the initial events that govern T-cell function. There have been various other reviews that have described the structural and biochemical features of TCR : pepMHC interactions. Here we provide an overview of four areas that directly impact our understanding of T-cell function, as viewed from the perspective of the TCR : pepMHC interaction: (1) relationships between T-cell activity and TCR : pepMHC binding parameters, (2) TCR affinity, avidity and clustering, (3) influence of coreceptors on pepMHC binding by TCRs and T-cell activity, and (4) impact of TCR binding affinity on antigenic peptide specificity.
- Top of page
- Summary
- Introduction
- Relationships between T-cell activity and TCR : pepMHC binding parameters
- TCR affinity, avidity and clustering
- Influence of coreceptors on pepMHC binding by TCRs and T-cell activity
- Impact of TCR binding affinity on antigenic peptide specificity
- Conclusion
- Acknowledgements
- References
Studies of the interactions between antibodies and antigens, which have been studied for decades, have been made easier by virtue of the fact that antibodies are expressed as secreted molecules at relatively high concentrations. The antigen-specific molecule on T cells, the T-cell receptor (TCR), has been considerably more difficult to express in soluble form, making the analogous studies more difficult.1 Nevertheless, various strategies have been used to measure the intrinsic binding properties of TCRs for their antigens, complexes of peptides and a product of the major histocompatibility complex (MHC). Early studies revealed that TCRs have relatively low affinities for their peptide–MHC (pepMHC) ligands, similar to the affinities found for antibodies from primary responses. This feature has also made studies of TCR : pepMHC binding properties more difficult (i.e. higher concentrations of soluble TCR are required to measure lower affinity interactions). Another property of T-cell function that distinguishes the system from antibodies is the fact that in their normal context, TCRs are expressed as multichain membrane protein complexes on cells that express other proteins (namely, coreceptors CD4 and CD8) that are also intimately involved in the initial recognition process. Despite these complexities, the impact of TCR : pepMHC binding properties on T-cell activity and specificity has been revealed by the work of many laboratories, using various approaches. Here we review these findings, and describe some of the questions that remain to be addressed.
Relationships between T-cell activity and TCR : pepMHC binding parameters
- Top of page
- Summary
- Introduction
- Relationships between T-cell activity and TCR : pepMHC binding parameters
- TCR affinity, avidity and clustering
- Influence of coreceptors on pepMHC binding by TCRs and T-cell activity
- Impact of TCR binding affinity on antigenic peptide specificity
- Conclusion
- Acknowledgements
- References
In its simplest, reversible form, the interaction of TCR and pepMHC can be described by the reaction:
involving an association rate (kon) and a dissociation rate (koff). The half-life of the interaction (t1/2) is derived from the dissociation rate**. At equilibrium, a binding constant (KD = 1/KA) can be determined for the interaction using standard Scatchard approaches (or the kinetic parameters,†KD = koff/kon), KD = [TCR][pepMHC]/[TCR : pepMHC].
In a typical SPR experiment, with immobilized pepMHC, when the concentration of unbound pepMHC equals the concentration of bound pepMHC (i.e. half maximal resonance units in an SPR titration with increasing TCR), the KD is equal to the concentration of free, unbound TCR.‡
Using primarily, but not exclusively, SPR-based approaches, wild-type TCR affinities (KD values) have been shown to be in the range of 1–100 µm,2 characterized by slow association rates and intermediate dissociation rates (Table 1). There has been considerable debate as to which parameter of the TCR : pepMHC interaction, KD or half-life, determines the activation status of the T cell. The issue is important because there are fundamental signalling models (see below) that are predicated on which parameter is important. This question has been especially difficult to address because in most cases, the KD value is proportional to the t1/2. In addition, agonists that span the range of affinities and t1/2 values have been reported (Table 1 and Fig. 1a), complicating further any simple correlation between activity and these parameters.
|kon (per m second)
|koff (per second)
|t1/2 (seconds)
|KD (μm)
|58 000
|400 000
|61 000
|Weak agonist
|16 000
|Weak agonist
|22 000
|Weak agonist
|96 000
|49 000
|330 000
|39 000
|31 000
|340 000
|70 000
|31 000
|26 200
|35 800
|40 000
|37 200
|Weak agonist
The critical nature of the dissociation rate was an inherent feature of the kinetic proofreading and discrimination models first suggested over a decade ago. Those interactions with sufficiently long dissociation rates would allow for completion of intracellular signalling cascades that result in T-cell activation.19,20 A hierarchy of early T-cell signalling events, including the phosphorylation state of the CD3 subunits and intracellular calcium release, have been associated with a range of defined agonist, antagonist and null ligands.20,21 Many of these studies have concluded that the occupancy of the TCR, as correlated with the dissociation rate, determined the magnitude of the T-cell response. However, one study using the class I restricted OT-1 TCR suggested that these kinetic models may be oversimplified, as they observed that high-occupancy ligands (slow dissociation) initiated different T-cell activation kinetics (e.g. see t1/2'outlier' that is a weak agonist, blue triangle in Fig. 1a).7
Another observation consistent with the possible importance of dissociation rates involves the serial triggering hypothesis, in which a single pepMHC can bind to and trigger up to 200 individual TCRs.22 A tenet of this hypothesis is that not only did the interaction need to be sufficiently long to complete proximal signalling, but the dissociation rates needed to be sufficiently short to allow multiple TCRs the opportunity to bind to the same pepMHC. This led to the prediction that there should be an 'optimal dwell time' between the TCR and pepMHC, where a Gaussian distribution around t1/2 values explains T-cell activation; those complexes with too rapid, or too prolonged, dissociation rates would lie outside the optimal range, resulting in reduced activity.23,24 Studies by Kalergis et al. using a wild-type TCR provided evidence in favour of the model,23,24 but they relied on binding measurements with pepMHC tetramers (see below), rather than monomeric measurements assessed by SPR. Accordingly, it is not possible to compare their binding parameters relative to other systems shown in Table 1.
Other results appear to be inconsistent with the notion of an 'optimal dwell time'. For example, TCRs have been engineered to have dissociation rates that are 100-fold to 1000-fold slower than wild-type TCRs, yet T cells transduced with these TCRs were fully able to be activated.25–27Table 2 shows a list of the binding parameters of these TCRs, which include mouse TCR mutants directed against the class I complexes SIY/Kb and QL9/Ld, mouse TCR mutants directed against the class II complex Hb/I-Ek, and human TCR mutants against the class I complexes NY-ESO-1/HLA-A2 and Tax/HLA-A2. The affinities of these high-affinity TCR : pepMHC interactions ranged from 30 nm to 26 pm, and the t1/2 values were as long as 425 min, yet they have shown strong agonist activity (Fig. 1b).
|kon (per m per second)
|koff (per second)
|t1/2 (seconds)
|KD (nm)
|42 000
|277 000
|235 000
|357 000
|570 000
|26 000
|80 000
|39 000
|16 500
|3.L2 m15
|281 000
What about the role of affinity versus t1/2 values (i.e. put another way, do on-rates impact T-cell activity)? Several TCR : pepMHC interactions with known KD and t1/2 parameters (Table 1; TCRs OT-1, LC13 and P14) have provided evidence that on-rates influence activity (i.e. KD is important). As indicated above, in the OT-1 TCR system, a variant of the OVA peptide (G4) has a long t1/2, but its slower on-rate appears to be associated with the weak agonist activity of OVA(G4)/Kb (e.g. blue triangle in Fig. 1a).7 In another study, the LC13 TCR had affinities of 12·5 and 132 µm for two pepMHC ligands, a difference that was almost exclusively the result of on-rates.15 These ligands showed agonist activity in the case of the 12·5 µm interaction, and antagonist activity in the case of the 132 µm interaction, suggesting that the on-rate accounted for the difference in activities. More recently, activity mediated by the P14 TCR against gp33 peptide variants has also been shown to be influenced by the on-rate of the reaction.30 A caveat of these studies is that different peptides were used such that it is formally possible that T-cell activity could be influenced by MHC binding, not only TCR binding. In addition, in the latter studies, the dissociation kinetics were relatively fast (t1/2 = 0·3–2 seconds), in a range that is difficult to measure using SPR methodology.
While there appear to be several convincing cases where quite fast dissociation rates can still yield strong agonist activity (in apparent contradiction to dissociation rate models), there remain unanswered questions. Experimentally, it would be most decisive if one could identify additional TCR : pepMHC interactions with long dissociation rates (t1/2 > 50 seconds) but very slow on-rates, such that the affinities were at the low end of the range (e.g. > 100 µm). The dissociation rate model would predict that T cells expressing these TCRs would be fully active (e.g. see X in Fig. 1a). Another caveat of TCR studies is that most binding measurements have been made at 25°, whereas activity is measured at 37°. Kinetic constants at 37° are very difficult to measure because rates are generally faster and so become even less precise. Development of improved techniques, such as stop-flow fluorescence-based approaches, for kinetic measurements in the millisecond to second range would be useful. Finally, there is some evidence that TCR conformational plasticity, as measured by thermodynamic properties of TCR : pepMHC interactions including entropic binding penalties17 or heat capacity,31 influences T-cell activity (reviewed in ref. 32). It remains to be seen whether such effects will further complicate the efforts to dissect the importance of various binding parameters.
TCR affinity, avidity and clustering
- Top of page
- Summary
- Introduction
- Relationships between T-cell activity and TCR : pepMHC binding parameters
- TCR affinity, avidity and clustering
- Influence of coreceptors on pepMHC binding by TCRs and T-cell activity
- Impact of TCR binding affinity on antigenic peptide specificity
- Conclusion
- Acknowledgements
- References
Although much speculation revolves around the specific binding parameters which delineate a productive TCR : pepMHC interaction from a non-productive or antagonist interaction, for most T cells the binding parameters of the TCR are unknown. TCR binding has often been estimated using soluble pepMHC tetramers. MHC tetramer technology was introduced in 1996,33 and refers to biotinylated pepMHC complexes linked to streptavidin, which has four biotin binding sites. Multivalency of the pepMHC complexes allows binding to be detected through avidity, even though monovalent affinity may be inadequate to allow detectable binding by current methods.34,35 Fluorescent labelling of streptavidin allows easy monitoring of MHC tetramer-bound T-cell populations by flow cytometry. These oligomeric class I or class II pepMHC complexes have been used for identifying, tracking, isolating and characterizing antigen-specific CD8+ and CD4+ T-cell populations (reviewed in refs 36,37).
In addition to their qualitative uses for detection of TCR binding, MHC tetramers have been used as a proxy for defined affinity measurements, using tetramer staining titrations, cell surface-bound tetramer off-rates, and, occasionally, tetramer binding to TCRs in surface plasmon resonance.34,35,38,39 One should not confuse results obtained through these assays with actual monomeric TCR affinities or kinetic rates, as many other factors influence these measurements. To illustrate the impact of several factors, Fig. 2 shows simulated effects of different variables on MHC tetramer binding to (Fig. 2a–c) and dissociation from (Fig. 2d–f) the surface of a T cell, using a simplified multivalent binding model that has been used previously to describe streptavidin oligomer binding to T cells.40,41 Variations of this model have been applied to T-cell binding and triggering.41–44§
Simulated effects of binding parameters, as well as overall receptor levels, are shown, using approximate values for the CD8-dependent clone 2C TCR binding to SIY/Kb in each case. Equilibrium tetramer staining is reduced by a slower monomeric on-rate (Fig. 2a), a faster monomeric off-rate (Fig. 2b), or reduced TCR surface levels (as might be seen after T-cell stimulation or in TCR transduction approaches, Fig. 2c). Similarly, tetramer dissociation rates from the surface of T cells are slowed most dramatically by slower monomeric off-rates (Fig. 2e), but are also significantly impacted by increased on-rates (Fig. 2d) or higher TCR levels (Fig. 2f). The variability follows predictable trends for each individual parameter, but variations in multiple parameters between different TCR : pepMHC pairs would make correlations between the tetramer-staining properties and monomer-binding properties difficult and imprecise.
Further complications in analysing quantitative tetramer binding data arise from the non-standard distribution of oligomeric states in fluorescent MHC tetramer preparations, the effects of TCR density and T-cell activation state,45 and the potential interactions of MHC tetramers with coreceptors CD4 or CD8.44 More recently, the term 'functional avidity' has been used to describe tetramer-based binding results, which combines these considerations into a single term. While the multimeric measurements do little to deconvolute the questions surrounding the relevant TCR binding parameters required to trigger T-cell activation, they have nevertheless led to important insights. For example, Palmer and colleagues showed that a sharp threshold of KD,tet = 55–90 nm (KD,tet ∼ 576 nm, t1/2,tet < 12 seconds, measured with minimized contribution from CD8 binding) reliably delineates positive and negative thymic selection in CD8 T cells.38,46 In addition, Savage et al.47 showed an increase in overall functional avidity between polyclonal T cells in a secondary versus a primary antigen response. The use of MHC tetramers to compare the functional avidity of T cells with different activities therefore has significant potential.
While the ability of multivalent pepMHC multimers to bind to cell surface TCRs is only indirectly related to the activation potential of a T cell, many studies have shown that multivalent clustering of TCRs is necessary for T-cell signalling.48–51 Although T cells are not thought to undergo affinity maturation in their antigen receptors, at least to the same extent as antibodies, evidence has suggested that T-cell populations can exhibit increased sensitivity to antigen via avidity-based mechanisms. Naïve versus effector or memory cells with the same TCR exhibit different abilities to bind soluble MHC reagents and to respond to antigen.42,45,52 It has been determined that the TCR assembles with a single αβ hetrodimer per signalling complex, giving an overall stoichiometry of αβδεγεζζ.53 However, the state(s) of the TCR on the surface of T cells has been difficult to determine experimentally, and models including multiple binding pairs per assembled signalling complex have been proposed.54–56 Schamel et al.56 argue that monovalent TCR complexes coexist with multivalent, cholesterol-dependent TCR complexes that are preferentially triggered at low antigen concentration. They estimate that the preformed, static TCRs form clusters that contain approximately 2 to ≥ 20 TCR-αβ pairs per group; these may be precursors to early activation-linked TCR structures called microclusters (approximately 50 complexes or more).57–60
In addition to static clustering, T cells may regulate sensitivity by altering the mobility of cell surface receptors in the membrane. Glycosylation differences corresponding to differences in T-cell activation state have been identified, and reduction of glycosylation through pretreatment of cells with neuraminidase52,61 or inhibition of intracellular glycosylation enzymes62,63 leads to increased receptor clustering, hypersensitivity and even some loss of specificity. Upon antigen recognition, T cells have been shown to cluster their TCRs and other adhesion and costimulatory molecules into an immunological synapse, which increases the local concentration of TCRs and pepMHC for binding.64,65 Although the function of the immunological synapse has been controversial,66 and does not seem to be required for signalling to occur,67,68 it may function to 'tune' the immune response; amplifying responses to weak stimuli, and down-modulating responses to very strong stimuli.69–71
Interestingly, while T-cell activation requires a minimal binding threshold and TCR clustering, attempts to quantify the number of agonist peptide complexes on an antigen-presenting cell required to elicit a T-cell response have found that the number is vanishingly small – as low as a single agonist for a response to be recorded, and numbers in the order of 3–25 complexes to induce full effector responses.68,72,73 These findings prompted studies of the contribution of endogenous, or non-agonist pepMHC complexes in T-cell recognition.74 Despite having unmeasurable binding affinities for the relevant TCR, large numbers of endogenous pepMHC complexes have been found in mature immunological synapses,72 and addition of some null complexes amplifies a response to agonist complexes alone.74 Recent studies with CD4 T cells have shown that TCR triggering can be induced by selected pairs of soluble 'heterodimers' consisting of a single agonist pepMHC complex covalently linked to a weaker binding complex,75 indicating that in a system where avidity is crucial, even very low affinity interactions play an important role in supporting activation.
Influence of coreceptors on pepMHC binding by TCRs and T-cell activity
- Top of page
- Summary
- Introduction
- Relationships between T-cell activity and TCR : pepMHC binding parameters
- TCR affinity, avidity and clustering
- Influence of coreceptors on pepMHC binding by TCRs and T-cell activity
- Impact of TCR binding affinity on antigenic peptide specificity
- Conclusion
- Acknowledgements
- References
MHC ligands can be engaged not only by the TCR, but also by the coreceptor CD4 (class II MHC) or CD8 (class I MHC). These additional binding interactions further complicate the measurement of TCR affinity on the surface of T cells. The two coreceptors have some similarities but also seemingly different roles and effects on binding and activation.
The CD4 coreceptor binds to class II MHC with a weak KD (150–200 µm) and rapid kinetics. Intracellularly, CD4 associates with the p56lck kinase, which is important in T-cell triggering. CD4 seems to have little influence on MHC tetramer binding, and clusters with kinetics different from CD3ζ during activation.60 In one system, inhibition of CD4 binding raised the minimum number of agonist pepMHC complexes required for activation from between 1 and 10 up to ∼ 25; however, activation appeared to be identical beyond this threshold.72 A structure of human CD4 bound to a murine class II MHC revealed that the binding site of CD4 lies on the relatively invariant α2–β2 domain of MHC II, and that CD4 protrudes at a significant angle.76 The angle has led many to doubt that the CD4 bound to a given pepMHC would be in a position to interact with a TCR bound to the same pepMHC. The 'pseudodimer' model of CD4 involvement72,75 proposes that CD4 associates with a TCR that is bound to an agonist pepMHC, positioning p56lck to efficiently phosphorylate adjacent TCRs that are bound to either agonist or endogenous pepMHC (reviewed in refs. 77,78). This suggests that CD4 contributes to T-cell recognition by enhancing TCR cross-linking and increasing the local concentration of p56lck, rather than by contributing direct binding energy to the interaction of TCR with MHC.
CD8 exists on the T-cell surface as either αα homodimers or αβ heterodimers. The binding affinity of αα and αβ dimers to MHC I has been measured to be in the range of 10–200 µm, with differences that are in part the result of the allele of the class I MHC.79–83 Like CD4, CD8 binds with rapid kinetics including a koff of ∼ 18/second.84 Unlike CD4, however, CD8 seems to be capable of enhancing the on-rate and off-rate of tetramer binding,44,85 and many T-cell clones require the full participation of CD8 for MHC tetramer staining or activation (reviewed in ref. 83). A mutation in the MHC heavy chain that interferes with CD8 binding (D227K68,86–88) or the presence of a CD8-blocking antibody89 impairs MHC binding and recognition by the T cell. The TCRs with low binding affinities, as seen with most wild-type responses, require CD8 for activity and are referred to as CD8-dependent.
Some CD8-independent TCRs have been identified through allogeneic or xenogeneic stimulation9,90,91 or TCR engineering.16,28 These receptors have significantly higher affinities than CD8-dependent TCRs (4 µm–26 pm) but the precise binding threshold that makes a TCR CD8-independent is not yet defined. Laugel et al.85 described CD8-independent MHC-binding or T-cell activation with TCRs having KD values of 35 or 200 µm, respectively. In contrast, a lower KD threshold for CD8-independence of approximately 3 µm has been proposed based on the 2C T-cell system.25 The often studied TCR OT-1 is CD8-dependent and has a KD value of ∼ 6 µm for OVA/Kb6,92). It remains to be seen how CD8 synergizes with the TCR to achieve enhanced pepMHC binding, and whether the magnitude of the enhanced binding depends on the properties of the TCR. Unlike pepMHC class II ligands, it has been proposed that self pepMHC class I ligands do not operate to enhance T-cell signalling through interactions with the TCR, but operate exclusively through the participation of CD8.93
Impact of TCR binding affinity on antigenic peptide specificity
- Top of page
- Summary
- Introduction
- Relationships between T-cell activity and TCR : pepMHC binding parameters
- TCR affinity, avidity and clustering
- Influence of coreceptors on pepMHC binding by TCRs and T-cell activity
- Impact of TCR binding affinity on antigenic peptide specificity
- Conclusion
- Acknowledgements
- References
The T-cell antigenic (peptide) specificity is influenced by peptide binding to the MHC product and/or by peptide binding to the TCR (as a pepMHC complex). In the case of binding to the MHC, specificity is perceived as a loss of T-cell activity when the peptide binding to MHC is reduced. For example, if a viral peptide were mutated at an MHC anchor residue and was no longer efficiently presented, a peptide-specific T cell may lose the ability to recognize the virus-infected cell. In this case, the T cell appears to be highly specific for the wild-type peptide at this amino acid position, but the T-cell 'specificity' is in a sense indirect, because it is a consequence of the concentration (density) of the cell surface pepMHC ligand (i.e. the affinity of the peptide for the MHC product determines the cell surface density of the pepMHC complex, and a minimum pepMHC density is necessary for the T cell to be stimulated).
Here we focus on the case of peptide specificity influenced by binding of the pepMHC complex to the TCR (reviewed in ref. 94). As described above, the outcome of this interaction (i.e. T-cell activation) is determined by a minimum threshold of TCR binding (KD or t1/2) that must be achieved to activate the T cell. Changes in the peptide sequence that lower the TCR binding affinity could potentially yield an interaction energy that is below this threshold.95 For example, if we presume that the minimum affinity necessary for CD8+ T-cell activation is 500 µm, then any changes in peptide residues that lower the affinity below a KD value of 500 µm will in essence generate an inactive peptide variant (null peptide) or possibly an antagonist (see below).
In this context, T cells that bear TCRs with low affinity may appear to be more specific than higher affinity TCRs because very minor changes in the peptide could reduce the binding energy, and consequently the affinity, resulting in a loss of T-cell activity (Fig. 3a). In contrast, higher affinity TCRs would 'tolerate' more significant changes in peptide structure yet remain above the activation threshold (Fig. 3b). In these cases, the T cell would be activated by a greater array of peptide variants, and would appear to have reduced peptide specificity. By analogy with antibody : antigen interactions, we refer to the reactions with structurally related antigenic peptides as the 'fine specificity' (Fig. 3c).
Observations about the role of TCR affinity in the fine specificity of T cells have now been made with in vitro-engineered TCRs that have affinities in the nanomolar range.16,27,29,96 The basis of this affect is illustrated most simply by a diagram that compares the effects of the wild-type 2C TCR affinity (Fig. 3a) and a high-affinity TCR mutant called 2C-m33 (Fig 3b). Change of a single amino acid residue on the peptide could reduce the binding affinity of either the low or high receptor by 10-fold, if the same atomic interactions operate at that region of the TCR : peptide interface. However, in the case of the TCR with low affinity, the peptide variant now has an affinity that is below the activity threshold (e.g. 500 µm). In contrast, a reduction in affinity of 10-fold for the high-affinity TCR still yields a TCR : pepMHC interaction that is above the threshold and the variant is active.
One advantage of evolving a T-cell immune system with TCRs that have a relatively low affinity threshold is to maintain a high degree of peptide specificity. This feature of the system may however have sacrificed the ability of T cells to recognize and eliminate peptide variants, as might arise from virus mutation. The apparent increase in the overall avidity of T cells after immunization may provide the system with an enhanced ability to recognize such variants.47,97 However, the equilibrium binding affinities of TCRs that are associated with these 'avidity matured' T cells have not been directly compared to the affinities associated with T cells from primary responses. In this respect, it is interesting that measurements of the best-studied T-cell clones may actually be such avidity-matured clones because generally these were derived after multiple immunizations with immunogen. Accordingly, the TCR affinities of T cells from primary responses may actually be quite low (e.g. in the 100 µm range).
Another aspect of peptide specificity that directly impacts T-cell function is the role of the multiple self (endogenous) peptides that are expressed by an individual. If the endogenous peptides have structures that are related to the foreign agonist peptide, then the peptide(s) may act not only in the process of positive selection, but also in the process of homeostatic proliferation and in enhancing the signalling that leads to full T-cell activation. Self peptides that are structurally homologous to a microbial foreign peptide may also be involved in autoimmune reactions, as has been suggested in various systems.98 There is in general very little known about the binding affinities of TCRs for this collection of self-peptide/MHC ligands, including what might be the minimal affinity necessary to achieve T-cell signalling that drives homeostatic proliferation.99
An intriguing feature of TCR-mediated binding involves the complexity of outcomes that can result from interactions that do not lead to full activity. For example, TCR binding to self peptide/MHC ligands could either enhance or antagonize signalling mediated by binding of the same TCR to agonist pepMHC ligands. Accordingly, self pepMHC : TCR interactions could amplify T-cell activity through coreceptor involvement, or could inhibit activity if partial 'antagonist' signals are initiated through such interactions. This has the important consequence that peptide variants, for example from viruses or potential tumour antigens, may not only escape recognition that leads to a productive T-cell reaction, but may also antagonize T-cell reactions. That is, binding of the mutated pepMHC through the TCR may actually lead to an inhibitory signal that operates through an antagonist reaction.
Finally, it is now clear that some TCRs cross-react with peptides and/or MHC molecules that are not structurally similar.100–102 The 2C TCR is such an example, as it has specificity for both the SIY/Kb ligand and an alloantigen called QL9/Ld. These cross-reactions may be the result of the structural plasticity of TCRs; it has now been shown that the 2C TCR docks onto Ld in a quite different mode from that with which it docks onto the SIY/Kb ligand, and it uses largely different chemistries to achieve binding.103 A conformer model, analogous to antibody reactions with diverse antigens,104 suggests that distinct conformations of the same TCR could bind to structurally distinct ligands.105,106 Nevertheless, the affinity and specificity rules hold for each distinct TCR : pepMHC interaction, whether the pepMHC are structurally related or not.
- Top of page
- Summary
- Introduction
- Relationships between T-cell activity and TCR : pepMHC binding parameters
- TCR affinity, avidity and clustering
- Influence of coreceptors on pepMHC binding by TCRs and T-cell activity
- Impact of TCR binding affinity on antigenic peptide specificity
- Conclusion
- Acknowledgements
- References
The binding properties of TCRs for their pepMHC ligands are critically important in the function of T cells, leading to outcomes that can involve T-cell selection in the thymus or full peripheral T-cell responsiveness or homeostatic T-cell proliferation in the periphery. The processes are even more complicated because the same TCR could interact with multiple pepMHC ligands on the same antigen-presenting cell, each with heterogeneous binding properties. These reactions would result in a complex integration of signals that ultimately determine the nature of the T-cell response. While there have been numerous studies to elucidate the precise binding parameters that correlate with different T-cell activities, various questions remain unanswered (in part because of the technical difficulties associated with performing binding experiments on low-affinity reactions). Further understanding of the TCR binding properties that generate defined signals is important, not only from a basic science perspective but also toward developing optimal strategies that improve T-cell responses to foreign antigens and tumour antigens.
- **
Half-life (t1/2) = ln 2/koff
- †
It is worth noting that for many low-affinity interactions, it can be difficult to measure kinetic parameters with confidence because the high protein concentrations required [e.g. for surface plasmon resonance (SPR)] can lead to a higher background signal. Therefore, in KD ranges of > 10 µm it becomes increasingly difficult to determine reliable association and dissociation rates.
- ‡
In these experiments, it is assumed that the total TCR concentration is approximately equal to the free, unbound TCR, a valid assumption given the typically high concentrations of TCR relative to the amount of immobilized pepMHC.
- §
The model assumes a maximum bound valency of three due to geometrical constraints, despite a total reagent valency of four. The version of the model applied here does not include the possible effects of MHC coreceptor, nor does it assume any binding/cross-linking co-operation beyond an increase in local concentration.
- Top of page
- Summary
- Introduction
- Relationships between T-cell activity and TCR : pepMHC binding parameters
- TCR affinity, avidity and clustering
- Influence of coreceptors on pepMHC binding by TCRs and T-cell activity
- Impact of TCR binding affinity on antigenic peptide specificity
- Conclusion
- Acknowledgements
- References
We thank members of the laboratory for their contributions and discussions. This work was supported by NIH grant GM55767 (to D.M.K.), a grant from the James S. McDonnell Foundation (to D.M.K.), and the Samuel and Ruth Engelberg/Irvington Institute Fellowship of the Cancer Research Institute (to J.D.S.).
- Top of page
- Summary
- Introduction
- Relationships between T-cell activity and TCR : pepMHC binding parameters
- TCR affinity, avidity and clustering
- Influence of coreceptors on pepMHC binding by TCRs and T-cell activity
- Impact of TCR binding affinity on antigenic peptide specificity
- Conclusion
- Acknowledgements
- References
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Research Article
Metaphor as a method in the domain of marketing
Version of Record online: 3 APR 2003
DOI: 10.1002/mar.10068
Copyright © 2003 Wiley Periodicals, Inc.
Psychology & Marketing
Special Issue: Beyond Core Service
Volume 20, Issue 3, pages 209–225, March 2003
Additional Information
How to Cite
Cornelissen, J. P. (2003), Metaphor as a method in the domain of marketing. Psychol. Mark., 20: 209–225. doi: 10.1002/mar.10068
Publication History
- Issue online: 3 APR 2003
- Version of Record online: 3 APR 2003
- Abstract
- References
- Cited By
Prior research has laid the groundwork for a discussion of the role of metaphor in marketing, but has fallen short of offering a clear-cut method for guiding and evaluating its use. This article outlines such a method, and illustrates its use through extended discussions of the heuristic status of corporate identity and relationship marketing as metaphors for the generation of knowledge about the subjects that both supposedly illuminate. Implications of this methodology of metaphor for marketing research are outlined. © 2003 Wiley Periodicals, Inc.


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We lost our electricity for 36 hours after a thunderstorm; since it was May and we live in South Texas, we decide to stay in a motel for relief from the heat. Our friend Shelly is the front desk clerk, so we went to the Best Western in Ingleside, Texas. Our nerves were shot from spending the night without lights or AC, and all we wanted was a good night's rest. I have never slept so comfortably in a hotel; the bed was heaven and the pillows were to die for (I so want to buy one). The motel is right next to the highway, but we couldn't hear the street sounds, it was so quiet. The best part is it was pet friendly. So we will be staying there again if we loose our power for more than a few hours.
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