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CHARLESTON, Ill. -- Tennessee Tech senior Melody Christian has earned all-Ohio Valley Conference second-team honors after helping the Golden Eagle softball team to a 22-26/11-11 OVC regular season finish. The team's starting center fielder from Kingston Springs, Tenn., Christian has been a four-year starter and has placed her name among career leaders in several categories in the Golden Eagle record book.
Christian was named to her second all-OVC team after leading the team in batting average (.368), at bats (163), hits (60), runs scored (32), stolen bases (23) and on-base percentage (.380) during the 2013 season. She currently ranks third in the conference in hits and fourth in stolen bases. As a freshman, Christian was named to the OVC all-Newcomer team.
"This reflects the season she's had," said said head coach Bonnie Bynum. Melody's done a very good job of being a leader for this team, and we're so happy she has been recognized by the conference."
The all-conference teams were voted on by the head coaches and sports information directors from the OVC.
The 2013 Ohio Valley Conference Softball Championship gets underway at 10 a.m. CT. The four-day event will be held at Williams Field on the campus of Eastern Illinois. The seventh-seeded Golden Eagles face No. 2 SIUE at 12:30 CDT.
All-OVC First Team
P - Hanna Mennenga (Eastern Illinois) - Jr., Gifford, Ill.
P - Haley Chambers (SIUE) - Fr., Coatesville, Ill.
C - Hannah Cole (Eastern Illinois) - So., Windsor, Ill.
IF - Amber Riddle (Morehead State) - Sr., Morehead, Ky.%
IF - Alex McDavid (SIUE) - So., Suwanne, Ga.%
IF - Raquel Howes (Eastern Kentucky) - Sr., Colorado Springs, Colo.*
IF - Carly Willert (Eastern Illinois) - Jr., Bloomingdale, Ill.
OF - Alexis Anderson (Southeast Missouri) - Jr., Buford, Ga.
OF - Sara Borders (Jacksonville State) - So., Alexandria, Ala.%
OF - Kathryn Hollingsworth (Belmont) - So., Carrollton, Texas
UTIL/DP - Lauren de Castro (Austin Peay) - Jr., Torrance, Calif.*
UTIL/DP - Kenzi Tate (UT Martin) - So., Opdyke, Ill.
P - Stephanie Maday (Eastern Illinois) - Jr., Elk Grove Village, Ill.
C - Katie Tackett (Eastern Kentucky) - So., Murrieta, Calif.%
IF - Alexa Becker (Murray State) - So., Breese, Ill.
IF - Lauren Smith (UT Martin) - So., O'Fallon, Ill.
IF - Taylor Tooley (SIUE) - Sr., Joliet, Ill.
IF - Kayla Davidson (Austin Peay) - Jr., South Fulton, Tenn.
IF - Chelsea Yankolovich (SIUE) - Jr., Phoenix, Ariz.%
OF - Sarah Fobbs (Eastern Kentucky) - Fr., Lakewood, Calif
OF - Brittany Toney (SIUE) - So., Hendersonville, Tenn.
OF - Leah Taylor (UT Martin) - Sr., Brownsville, Tenn.*
UTIL/DP - Mia Vierra (Belmont) - Jr., Palmdale, Calif.
Haley Chambers (SIUE) - P, Fr., Coatesville, Ill.
Sarah Fobbs (Eastern Kentucky) - OF, Fr., Lakewood, Calif.
Alexis Anderson (Southeast Missouri) - OF, Jr., Buford, Ga.
Erin Greenwalt (SIUE) - P, Jr., Glen Carbon, Ill.
Haley Schenasi (Eastern Kentucky) - IF, Fr., Palos Verdes Estates, Calif.
Kiarra Freeman (Tennessee State) - OF, Fr., Knoxville, Tenn.
Kayla Joyce (Eastern Kentucky) - OF, Fr., La Palma, Calif.
Shelbey Miller (Murray State) - IF, Fr., Goreville, Ill.
Ella Denes (Jacksonville State) - OF, Fr., Pisgah, Ala.
Jordan LaFave (SIUE) - OF/UTIL, Fr., Valrico, Fla.
Chelsea Smith (Southeast Missouri) - C, Fr., Webb City, Mo.
Deven Wilson (UT Martin) - C, Fr., Eva, Tenn.
OVC PLAYER OF THE YEAR: Alex McDavid, SIUE
OVC PITCHER OF THE YEAR: Hanna Mennenga, Eastern Illinois
OVC FRESHMAN OF THE YEAR: Haley Chambers, SIUE
OVC COACH OF THE YEAR: Kim Schuette, Eastern Illinois


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Position Summary
The PA Breast Cancer Coalition is seeking a highly motivated, experienced, energetic professional to fill our Donor Database Management position. The Database Manager position provides an opportunity for an exciting, challenging and rewarding career. This person is responsible for the overall constituent and data management of the PBCC. He/she will have excellent time management skills, be very detail-oriented and interact well with all levels of staff, board and volunteers.
Key Job Responsibilities
- Enter and update constituent data and perform continual clean-up, maintenance and analysis
- Enter all gifts and pledges into the database including cash, credit card, in-kind, matching gift
- Send out thank you letters and gift acknowledgements as needed
- Import and process all donations
- Prepare queries as requested
- Provide support for special events
- Provide regular weekly reports and other reports as needed
- Bachelor's degree preferred
- Experience with data management
- Previous experience using Blackbaud "The Raiser's Edge" and Convio software preferred
- Proficient knowledge of computers including Microsoft Office packages with willingness to develop additional computer skills, adjust to other updated technology and grow academically as required
- Highly organized with the ability to multi-task and work productively in a team setting
- Willingness to travel and attend occasional evening and weekend events
Salary Range
$28,000-$32,000– dependent on education and experience. This position offers a competitive non-profit salary and excellent benefits.
To apply:
Please submit the following to email@example.com with "Database Manager" in the subject line: Cover letter, Resume, Salary requirements. No phone calls please.
*The PBCC office is currently located in Ephrata, however in May 2013 we will relocating to the Lebanon area.
The PA Breast Cancer Coalition is an Equal Opportunity Employer.

subset: commoncrawl


text:
Trying to install diffmerge_4.2.0.*.deb
it tells me .................diffmerge depends on libc6 (>= 2.15); however:
But the version of libc6:amd64 on system is 2.13-38+deb7u1.
Release 7.4 (wheezy) 64-bit
Can you tell me
*) which version is for 2.13.38
*) what is the URL to use to download older versions, please.
version requirements
Support for our DiffMerge utility.
Moderator: SourceGear
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I am checking into this. This may take some time.
Beth Kieler
SourceGear Technical Support
Posts: 8550
Joined: Wed Jun 21, 2006 8:24 pm
Location: SourceGear
We don't have older versions posted on the website. The best option is to update the libc. If that is not an option, then email support.
Beth Kieler
SourceGear Technical Support
3 posts • Page 1 of 1
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text:
Our Self-Watering Rolling Planter has four double-wheel casters that roll effortlessly over floors, carpet, and even rough flagstone. The six-quart water reservoir with water-level indicator helps you keep your plants well-irrigated and healthy. Water weekly, not daily!
Gardening Success Guaranteed
Garden Lab Designed & Tested
Support a Community that Cares
Expert Garden Advice


text:
Cattle are the most common type of large domesticated grazing animals occupying the prairies. These large herbivores are raised by farmers and ranchers for a variety of reasons. Most cattle raised as livestock for meat production graze in the prairie until they are about a year old and are then transported to feedlots to be fed until they are harvested for meat production. Dairy cattle are used to produce milk and other dairy foods. Humans also produce other products that come from cattle such as leather for shoes and purses, and manure for fertilizer.
Cattle forage mostly on grass and travel in large groups called herds. Many ranchers in the prairie manage cattle by burning their prairie pastures so that the cattle have the opportunity to eat the new grass that is growing after being burned. If only a part of the prairie pasture is burned, the cattle will go to where fire occurred and eat the new grass that is growing. This is called patch burning. Females are called cows, males are called bulls, and babies are called calves. It is common for cattle producers to castrate bulls so that they cannot reproduce, these are called steers. Females that have not had a calf are called heifers. Females that have had a calf are called cows. Males that have not been castrated are called bulls.
There are an estimated 1.3 billion cattle in the world today and can be found on ranches throughout the prairie. The value of the United State's beef industry is estimated $73 billion and there is about 26 billion pounds of beef produced annually in the U.S. The U.S. exports about 7 percent of its beef production.


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I once used this one battery saver, it was super duper helpful... Uh is it GreenPower? I knew I had a premium version of it though.
kchallenger I have used GreenPower... It's not bad but a bit overwhelming at first. Lots of settings and little bitty tutorial.
OK, I went and looked up this Greenify and I'll put it on my list to try.
slehan You will like it, trust me. It has made a huge difference on my phone and you don't need to know anything other than how to hit a button on the screen. Does all the work for ya!
I think I'll try Greenify too... Thanks for the idea!
me to ill give it a try myself
Rykosuke As I said, I liked it at first, but it's not as good as I thought it would be.
Yeah well Greenify and GreenPower are both nice. It depends on your preferences.
IndyPhone I don't disagree
nougatmagnet Okay... Well, I assume it would be better if we were to use what we're satisfied with too. Oh well...
IndyPhone hey it's not a bad opinion. I know what you mean
what do people here think of battery doctor or du battery saver?
bingdom i like battery doc... haven't tried du though, sorry mate
bingdom anyone?
bingdom i've used du before and have seemed to like it
nougatmagnet right on
nougatmagnet Yeah go easy on him lol
Thanks fellas!


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The Year in Review pic.twitter.com/CgeaMRDrv3
2015 is approaching so my resolution is to be less snarkHAHAHAnevermind.
— Ivan Lajara (@ivanlajara) December 30, 2014
The police in Lowell, Massachusetts, would like you to know that you should not be trying to capture the escaped goat because that's Massachusetts for you. I expect a micro-brew out of this in two weeks.
As you might remember, we have our own history with goats (of the red kind) in Kingston. That's the kind of thing that will make the New York Times notice. All the goats that's fit to print.
Now that I've lost all your attention, here's some news: Gary Chetkof, founder of the Mountain Jam festival, took to social media and went online to post a message to address "overzealous security searches that have taken place in previous years and I realize that we have let you down." He also seemingly types while getting photos taken. The Black Keys are headlining this year's festival in Hunter and judging from their press photo they also look concerned. Drugs are bad, mkay?
At least it's not like Britain, which is full of monsters. And that is to say, full of horrible people who write stories for the Daily Star. Drugs are bad, mkay?
Jay from 'Serial' part II is out. So it's that terrible Photoshop job in that Intercept story. I like Photoshop, and that's why I keep a piece of bacon on my desktop.
Important journalists @ajchavar, @missmagner, and @yurivictor hosted a gif exchange and this is what I've got from Louije:
Here are 24 tools to try in 2015 if you are a journalist of simply if you are into C O N T E N T. I tried Plague. It's fun and I'm wondering of its journalism applications. If you use it, however, you should lower your expectations. At left is what's on Plague's site. At right, my first post.
One cat AND Google Glass photo:
Yesterday's Internet, Today! is a random experiment in which I throw in a bunch of links I tweeted, faved or saw the day before or in the morning or maybe stuff from Facebook? I also post a cat and a Google Glass photo.
New! You can now subscribe to this terrible idea.


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During this residency, the team will implement and test high availability scenarios to develop and document high availability best practices and reference architectures.
Over the past few months, two IBM Redbooks publications addressing IBM PowerHA SystemMirror have been published addressing different topics including planning, migration, and integration with other technologies. However, in 2013, we would like to develop content that would provide help to our clients implementing this high availability solution. Any topic that past residencies might have not address, or you have questions about it, we encourage you to comment in this blog.


text:
Thomas Athletics @ThomasAth
MSOC: Terriers Cruise Past Rams, 8-1
http://thomasathletics.com/sports/msoc/ ... 0901wv9p36 …
Thomas Athletics @ThomasAth
MSOC: Terriers Cruise Past Rams, 8-1
http://thomasathletics.com/sports/msoc/ ... 0901wv9p36 …
UNE Athletics @UNESports
Sunday's @UNEMensSoccer game vs. Saint Joseph's will now start at 11am and be played at the Big Blue Turf.
USM Huskies @usmhuskies
Men's Soccer: Southern Maine Claims Husky Challenge Trophy with 1-0 Win Over Westfield
SMCC Seawolves @SMCCseawolves
FINAL: MSOC drops its season opener 6-0 to @ACPHSAthletics. Box Score: http://www.gosmccseawolves.com/sports/m ... 2_bha2.xml …
UMF Athletics @UMFathletics
Box score of @UMFMensSoccer 1-0 victory today over Rivier. #GoBeavs http://bit.ly/2vAmgZY
Thomas Athletics @ThomasAth
MSOC RECAP: Seven Different Scorers Lead Terriers Past Fisher, 7-0
http://thomasathletics.com/sports/msoc/ ... 0903rmrajz …
Monks Athletics @SJCmonks
Monks Topple Nor'easters, Avenge 2016 Setback
SMCC Seawolves @SMCCseawolves
Panthers Sink SeaWolves In First Test Of 2017
Thomas Athletics @ThomasAth
MSOC: LaBrie Named NAC Player of the Week
http://thomasathletics.com/sports/msoc/ ... 0904np1pqg …
MMA Athletics @MarinersSports
.@mma_menssoccer 's Evan Backus Named @nacathletics Defensive Player of the Week | http://bit.ly/2wyWioH #RespectTheAnchor
Return to Maine Colleges (other than D1 UMaine)
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Image 1 of 1
SARAH AND RUEBEN 336.jpg
London Wedding with New Zealander Rueben Derrick and his beautiful wife Sarah Melmoth. The guys were married with a Buddhist Ceremony of the Cups at Taplow Court Berkshire and had a fun reception at the Brentham Cricket and Tennis Club in Ealing.
- Copyright
- Solas Wedding and Portrait Photography
- Image Size
- 5616x3744 / 19.8MB
- Keywords
- Contained in galleries


text: Gottex is a pioneer in the world of swimwear. It all began in 1956 in Israel when a young designer decided there needed to be swimwear bursting with the colors and flavors that surround our world. The first in luxury swimwear to use Spandex and hard-cup bras, Gottex provides a tight fit with a luxurious feel. The Spandex gave women the lift and support combined with the slimming effect they needed for a day at the beach. Plasticized Lycra, beaded suface and complicated Pucci prints are only a few of the materials used to create the pieces in the Gottex collection. One signature of the collection is the Lycra skirts created to match the swimwear. The elegant line of swimwear has graced beaches worldwide and been a hit in the world of celebrities. From Elizabeth Taylor to the royalty of Jackie Onassis and Princess Diana of Wales, the Gottex collection has proven itself to be innovative and unique. The collection is designed with vibrant colors and elaborate designs so women have their choice as to what makes them happy when on the beach or at a swim party. Staying on top in the swimwear world should not be hard for Gottex as they have created timeless creations for women of every age and every style.


text:
I've been trying to find some good books to read. I'm a very fussy reader.
On Friday night I read Nora Ephron's book, I Feel Bad About my Neck, from library. It was fun. Some of her observations were very funny, some too New York for me to relate to, mostly it felt like a good blog or a book in a waiting room to pass the time. Returning it yesterday, I picked out two books, one by Alice Munro and one by Alice McDermott, but neither one engaged me and both are going back. Vow: no more Alice books for awhile, except I see I have one on the list below!
I've been looking at lists of the best 100 novels. Being as old as I am, I've read a lot of them. Also as soon as I see novel number one is James Joyce's Ulysses I'm doubtful. On the other hand, if they include John O'Hara, Sherwood Anderson, or Theodore Dreiser in their lists, I look closer.
Some of the lists seem to go so overboard on the pc thing that you can't trust them either. On the other hand, I thought Their Eyes Were Watching God was exquisite.
In no particular order, here are the books I'm considering ordering, after perusing internet lists. Any feedback on them would be greatly appreciated, even if you already realize I have too many opinions on things:
- The Man Who was Thursday, G.K. Chesterton
- The Talented Mr. Ripley, Patricia Highsmith
- A Dance to the Music of Time, Anthony Powell
- Point Counter Point, Aldous Huxley
- Things Fall Apart, Chinua Achebe ?? DON'T SPIT!
- The Old Wives Tale, Arnold Bennett (he wrote a great novel set at the Savoy Hotel.)
- Lord Jim, Joseph Conrad (I've never read any of his books, not sure why.)
- The Awakening, Kate Chopin
- Shane, Jack Schaefer
- The Time It Never Rained, Elmer Kelton
- Wapshot Chronicle, John Cheever (not sure if I read or not, like Cheever but get sick of him too)
- Go Ask Alice, Anonymous
(and if you don't think it took a long time to post all these links-- but at least it made me place my order!)
I started The Disenchanted by Budd Schulberg last night, and it's great. Schulberg is a very talented writer who made the wrong decision in the McCarthy era.


text:
UltraVnc SC
UltraVNC SC is a mini (166k) UltraVNC Server that can be customized and preconfigured for download by a Customer. UltraVNC SC does not require installation and does not make use of the registry. The customer only have to download the little executable and Click to make a connection. The connection is initiated by the server, to allow easy access thru customers firewall.
The encryption plugin used by SC only exist for w32.
To create encryption key, run winvnc.exe, select plugin "MSRC4Plugin_for_sc.dsm", config, create key.
UltraVnc SC online creator
COMMON MISTAKE, the zip file you upload need to contain the files, NOT a SUBFOLDER with the files.
Ideal tool for "remote tech support" - "remote computer support"
UltraVncSC based on RC23 (2005)
UltraVncSC based on REL1.00 (2006)
This creator can also be used to generate SCIII.
UltraVncSC update 2009
+Vista+WIN7 support.
UltraVncSC update May 2013
+(2013) Modified engine to faster capture Vista>= OS's +(2011) +new capture engine, Vista win7 (faster on new video cards)
Using this option, aero and wallpaper is not removed, new capture engine is fast enough to capture aero.
UltraVncSC update June 2013
[DIS_UAC] crash fixed
UltraVncSC update July 2014
+(2014) capture engine fix, on some systems SC was extreem slow)
UltraVncSC update Feb 2015
+(2015) cature ingine took to long initiate, SC sometimes needed more then 1 minute to startup.
Same as pevious, but exe request UAC on start
June 2015 win8 win10
May 2018 win10
Same as pevious, but exe request UAC on start
sponsored links
(experimental SSL)
sources java viewer
This program is free software: you can redistribute it and/or modify


text:
Login | Checkout | My Account | Shopping Cart Now in your cart 0 items
These ancient, heirloom nuts are planted by hand, deep in the Amazon Jungle. They are hand harvested. Then these nuts are carried along trails by foot to a city where they can be shipped or flown. These ancient, heirloom nuts are planted by hand, deep in the Amazon Jungle by local indigenous tribes.
Wild Jungle Peanuts contain 26% protein, higher than any other nut. Over 40% of the oils contained in this ancient peanut are oleic acid (the main fatty acid in olive oil which is considered heart healthy) and all 8 essential amino acids. Raw, Certified Organic, Sun-Dried
*As a result of changing seasons and crops, you may notice a difference or variation in the color, size, texture, taste, etc. of this product. We thank you for your kind understanding of these variances. Your feedback and suggestions are always welcome. We highly value your input, as it helps us to identify how we can better serve you in the future. Thank YOU! -The Raw Food World Team
These statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease.


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Must See! ACG's Ray Mota: "Show Me the Money" with Cisco nV Technology
We've talked a bit before about Cisco's revolutionary network Virtualization technology or "nV." In case you aren't familiar with it, nV technology on the ASR product family intelligently blends the network edge, aggregation and access layers into a single system. This can deliver up to 70 percent operational expense savings, increase network capacity and accelerate IPv6 service deployments (very important since we've got the World IPv6 Launch next week). nV therefore addresses some of our customer's most important business concerns by:
- Lowering capital costs by simplifying the network
- Lowering operational expenses by scaling the network operational efficiencies
- Increasing revenue by enabling them to better leverage network intelligence
But don't just take our word for it. ACG Research has developed a business case analysis using real world data to show how Cisco's network virtualization technology can revolutionize profitability for operators. The analysis covers when nV is deployed across the edge, aggregation and access networks to support residential, enterprise and mobile services. The analysis also captures the market's evolutionary change in the access network from E1/T1 to Ethernet-based technology and compares the nV solution with the Present Mode of Operations from various vendors. The model addresses the change for backhaul of 2G, 3G, and 4G radio technologies and for enterprise Internet access and L3 VPN services.
We encourage you to join Ray Mota of ACG Research to learn how the analysis shows that our nV technology reduces total cost of network operations by up to 70% as compared to alternative solutions. For this webcast you can register here.
If the analysis isn't enough, perhaps "seeing" the real demonstration is? Not everyone has had an opportunity to see nV in action so we're bringing it to Cisco Live 2012 in San Diego June 10-14. We'll have a demonstration by our own crack team of ASR 9000 Technical Marketing Engineers at the Software for Your Network and Beyond booth number 2576 (it's the one with the climbing wall. No really…think of it as a metaphor for climbing new heights of scale and performance. OK, maybe not…but we've got a cool climbing wall this year).
If you are totally sold and just want to buy it…well as they say "operators are standing by." Just contact your account team and they'd be more than happy to ship you an ASR 9000 system with nV technology ready to go.
In an effort to keep conversations fresh, Cisco Blogs closes comments after 60 days. Please visit the Cisco Blogs hub page for the latest content.


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Current Funding Opportunities
The Requests for Applications (RFAs) and Program Announcements (PA, PAR, and PAS) listed below describe NIDDK's current funding opportunities. Summary links in each opportunity show NIDDK staff contacts and published notices. We encourage you to discuss your proposed research with an NIDDK program director before applying.
This page updates daily. If you would like to view all NIH funding opportunities, visit the NIH Guide to Grants and Contracts.


text:
Customer Support
Ask a question
Fake kangaroo: counterfeit gold bars appeared in Australia
The Australian Mint "Perth Mint" published a notification concerning counterfeit gold bars, with the engraving of a kangaroo. The Mint rushed to publish this information as the authorities and experts of the Mint find their reliability is threatened.
At first sight, gold bars bear a resemblance to the original ones for instance regarding their weight of 1 troy ounce. "Perth Mint" points at the main of them:
The first detail to take into account is the package. The package which include gold bars have the image of a black swan, while the fake ones lack don't. Secondly, the edges of the packages including fake gold bars are folded, while the original ones are always straight. Thirdly, the inscriptions on the original package differs from that of the fake ones. Finally, regarding the quality of the gold bar, it is far from being perfect if the logo of the bar is observed.
How to choose qualitative gold bars?
The Emgoldex online store clients do not have to worry about such things as fake gold bars. The gold bars that are sold in the Emgoldex online store enjoy the highest quality, which can be proved by hundreds of thousands of clients in the world.
The Emgoldex clients buy qualitative gold bars in the Emgoldex online store and build their own gold business, ensuring themselves stability and prosperity!
Share this news with your friends and let them know the best opportunity to buy gold!
Category: Gold news Publication date: 2015-05-22 09:39
|Gold Fixing | Price History


text:
Where Jesus lived during his ministry
Statute of Peter
Cross symbol
Staff in his hand similiar to the Pope's
Keys in his hands
2000 year old ruins
Linda, at Capharnaum
Homes just outside the Synagogue
View outside the old Synagogue
Self Portrait
Ruins in front of Synagogue
Inside the old Synagogue
Roman style pillars
Palm tree details on top of the entry way.
Ruins of the city where Jesus lived
House with doorway onto street
Game carved into the floor
Children played while parents prayed
Arch stones where leaders sat
Original Christian octagon church
Mosiac from floor
Keith Johnson - Time Will Tell, playing around.
3T TourAs We Saw ItCapernaumGalileeIsraelaswesawitwww.aswesawit.comCapharnaum8710


text:
Regulatory T cell
The regulatory T cells (Tregs pronunciation: /ˈtiːrɛɡ/), formerly known as suppressor T cells, are a subpopulation of T cells which modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells.[1] Tregs express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4 cells.[2] Because effector T cells also express CD4 and CD25, Tregs are very difficult to effectively discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine TGFβ is essential for Tregs to differentiate from naïve CD4+ cells and is important in maintaining Treg homeostasis.[3]
Mouse models have suggested that modulation of Tregs can treat autoimmune disease and cancer and can facilitate organ transplantation.[4] Their implications for cancer are complicated. Tregs tend to be upregulated in individuals with cancer, and they seem to be recruited to the site of many tumors. Studies in both humans and animal models have implicated that high numbers of Tregs in the tumor microenvironment is indicative of a poor prognosis, and Tregs are thought to suppress tumor immunity, thus hindering the body's innate ability to control the growth of cancerous cells.[5] Recent immunotherapy research is studying how regulation of T cells could possibly be utilized in the treatment of cancer.[6]
Regulatory T cell populations
T regulatory cells are a component of the immune system that suppress immune responses of other cells. This is an important "self-check" built into the immune system to prevent excessive reactions. Regulatory T cells come in many forms with the most well-understood being those that express CD4, CD25, and FOXP3 (CD4+CD25+ regulatory T cells). These "Tregs" are different from helper T cells.[7] Another regulatory T cell subset is Treg17 cells.[8] Regulatory T cells are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity.[9]
CD4+ Foxp3+ regulatory T cells have been called "naturally-occurring" regulatory T cells to distinguish them from "suppressor" T cell populations that are generated in vitro. Additional regulatory T cell populations include Tr1, Th3, CD8+CD28-, and Qa-1 restricted T cells. The contribution of these populations to self-tolerance and immune homeostasis is less well defined. Foxp3 can be used as a good marker for mouse CD4+CD25+ T cells, although recent studies have also shown evidence for Foxp3 expression in CD4+CD25- T cells. In humans, Foxp3 is also expressed by recently activated conventional T-cells and thus does not specifically identify human Tregs.[10]
All T cells come from progenitor cells from the bone marrow, which become committed to their lineage in the thymus. All T cells begin as CD4-CD8-TCR- cells at the DN (double-negative) stage, where an individual cell will rearrange its T cell receptor genes to form a unique, functional molecule, which they, in turn, test against cells in the thymic cortex for a minimal level of interaction with self-MHC. If they receive these signals, they proliferate and express both CD4 and CD8, becoming double-positive cells. The selection of Tregs occurs on radio-resistant haemopoietically-derived MHC class II-expressing cells in the medulla or Hassal's corpuscles in the thymus. At the DP (double-positive) stage, they are selected by their interaction with the cells within the thymus, begin the transcription of Foxp3, and become Treg cells, although they may not begin to express Foxp3 until the single-positive stage, at which point they are functional Tregs. Tregs do not have the limited TCR expression of NKT or γδ T cells; Tregs have a larger TCR diversity than effector T cells, biased towards self-peptides.
The process of Treg selection is determined by the affinity of interaction with the self-peptide MHC complex. Selection to become a Treg is a "Goldilocks" process; a T cell that receives very strong signals will undergo apoptotic death; a cell that receives a weak signal will survive and be selected to become an effector cell. If a T cell receives an intermediate signal, then it will become a regulatory cell. Due to the stochastic nature of the process of T cell activation, all T cell populations with a given TCR will end up with a mixture of Teff and Treg – the relative proportions determined by the affinities of the T cell for the self-peptide-MHC. Even in mouse models with TCR-transgenic cells selected on specific-antigen-secreting stroma, deletion or conversion is not complete.
Foxp3+ Treg generation in the thymus is delayed by several days compared to Teff cells and does not reach adult levels in either the thymus or periphery until around three weeks post-partum. Treg cells require CD28 co-stimulation and B7.2 expression is largely restricted to the medulla, the development of which seems to parallel the development of Foxp3+ cells. It has been suggested that the two are linked, but no definitive link between the processes has yet been shown. TGF-β is not required for Treg functionality, in the thymus, as thymic Tregs from TGF-β insensitive TGFβRII-DN mice are functional.
The immune system must be able to discriminate between self and non-self. When self/non-self discrimination fails, the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases. Regulatory T cells actively suppress activation of the immune system and prevent pathological self-reactivity, i.e. autoimmune disease. The critical role regulatory T cells play within the immune system is evidenced by the severe autoimmune syndrome that results from a genetic deficiency in regulatory T cells (IPEX syndrome - see also below).
The molecular mechanism by which regulatory T cells exert their suppressor/regulatory activity has not been definitively characterized and is the subject of intense research. In vitro experiments have given mixed results regarding the requirement of cell-to-cell contact with the cell being suppressed. The immunosuppressive cytokines TGF-beta and Interleukin 10 (IL-10) have also been implicated in regulatory T cell function.
Another control mechanism is through the IL-2 feedback loop. Antigen-activated T cells produce IL-2 which then acts on IL-2 receptors on regulatory T cells alerting them to the fact that high T cell activity is occurring in the region, and they mount a suppressory response against them. This is a negative feedback loop to ensure that overreaction is not occurring. If an actual infection is present other inflammatory factors downregulate the suppression. Disruption of the loop leads to hyperreactivity, regulation can modify the strength of the immune response.[11]
Induced regulatory T cells
Induced Regulatory T (iTreg) cells (CD4+ CD25+ Foxp3+) are suppressive cells involved in tolerance. iTreg cells have been shown to suppress T cell proliferation and experimental autoimmune diseases. These cells include Treg17 cells. iTreg cells develop from mature CD4+ conventional T cells outside of the thymus: a defining distinction between natural regulatory T (nTreg) cells and iTreg cells. Though iTreg and nTreg cells share a similar function iTreg cells have recently been shown to be "an essential non-redundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses".[12] Acute depletion of the iTreg cell pool in mouse models has resulted in inflammation and weight loss. The contribution of nTreg cells versus iTreg cells in maintaining tolerance is unknown, but both are important. Epigenetic differences have been observed between nTreg and iTreg cells, with the former having more stable Foxp3 expression and wider demethylation.
Regulatory T cells and disease
An important question in the field of immunology is how the immunosuppressive activity of regulatory T cells is modulated during the course of an ongoing immune response. While the immunosuppressive function of regulatory T cells prevents the development of autoimmune disease, it is not desirable during immune responses to infectious microorganisms. Current hypotheses suggest that, upon encounter with infectious microorganisms, the activity of regulatory T cells may be downregulated, either directly or indirectly, by other cells to facilitate elimination of the infection. Experimental evidence from mouse models suggests that some pathogens may have evolved to manipulate regulatory T cells to immunosuppress the host and so potentiate their own survival. For example, regulatory T cell activity has been reported to increase in several infectious contexts, such as retroviral infections (the most well-known of which is HIV), mycobacterial infections (like tuberculosis), and various parasitic infections including Leishmania and malaria.
Studies of human subjects with a history of leishmania infection suggest that modulation of CD8+ suppressor T cells is, at least partly, mediated by cytokines. Leishmania specific CD4+ helper T cells predominate in adults with strong protective immunity (skin-test positive with no history of clinical infection). When added to autologous leishmania infected macrophages these T cells cause parasite death and secretion of large amounts of interferon-gamma and lymphotoxin. CD8+ T suppressor cells predominate in patients with no protective immunity (visceral leishmaniasis patients). When added to autologous peripheral blood mononuclear cells isolated after successful treatment, these T cells inhibit interferon-gamma secretion and proliferation and increase interleukin-6 and interleukin-10 secretion. A soluble factor(s) generated by antigen or phytohemagglutinin stimulation of leishmania-specific CD4+ helper T cells from skin-test positive adults killed CD8+ T cells but not CD4+ helper T cells when added to culture media. Soluble factors generated by antigen stimulation of peripheral blood mononuclear cells from skin-test positive adults prevented CD8+ suppressor T cell mediated increases in interleukin-10 secretion. These findings suggest that antigen stimulation of CD4+ helper T cells results in production of cytokines that kill or down regulate CD8+ T suppressor cells. Once the leishmania infection has been eliminated and leishmania antigens are gone, CD8+ T suppressor cells down-regulate CD4+ T helper cells. Isolation of cytokines that inhibit and kill CD8+ T suppressor cells might be useful in treating diseases that involve immune suppression such as leishmaniasis, AIDS, and certain cancers.[13][14]
CD4+ Regulatory T cells are often associated with solid tumours in both humans and murine models. Increased numbers of regulatory T cells in breast, colorectal and ovarian cancers is associated with a poorer prognosis.[15]
CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25− T cells.[16]
A recent study shows that cerebral ischemia can increase bone marrow CD4(+)CD25(+)Foxp3(+) regulatory T cells via signals from the sympathetic nervous system.[17]
Regulatory T cells and cancer
Most tumors elicit an immune response in the host that is mediated by tumor antigens, thus distinguishing the tumor from other non-cancerous cells. This causes large numbers of tumor-infiltrating lymphocytes (TILs) to be found in the tumor microenvironment.[18] Although it is not entirely understood, it is thought that these lymphocytes target cancerous cells and therefore slow or terminate the development of the tumor. However, this process is complicated because Tregs seem to be preferentially trafficked to the tumor microenvironment. While Tregs normally make up only about 4% of CD4+ T Cells, they can make up as much as 20-30% of the total CD4+ population around the tumor microenvironment.[19]
Although high levels of TILs were initially thought to be important in determining an immune response against cancer, it is now widely recognized that the ratio of Tregs to Teffectors in the tumor microenvironment is a determining factor in the success of the immune response against the cancer. High levels of Tregs in the tumor microenvironment are associated with[6] poor prognosis in many cancers, such as ovarian, breast, renal, and pancreatic cancer.[19] This indicates that Tregs suppress Teffector cells and hinder the body's immune response against the cancer. However, in some types of cancer the opposite is true, and high levels of Tregs are associated with a positive prognosis. This trend is seen in cancers such as colorectal carcinoma and follicular lymphoma. This could be due to Treg's ability to suppress general inflammation which is known to trigger cell proliferation and metastasis .[19] These opposite effects indicate that Treg's role in the development of cancer is highly dependent on both type and location of the tumor.
Although it is still not entirely understood how Tregs are preferentially trafficked to the tumor microenvironment, the chemotaxis is probably driven by the production of chemokines by the tumor. Treg infiltration into the tumor microenvironment is facilitated by the binding of the chemokine receptor CCR4, which is expressed on Tregs, to its ligand CCL22, which is secreted by many types of tumor cells.[20] Treg expansion at the cite of the tumor could also explain the increased levels of Tregs. The cytokine, TGF-β, which is commonly produced by tumor cells, is known to induce the differentiation and expansion of Tregs.[20]
In general, the immunosuppression of the tumor microenvironment has largely contributed to the unsuccessful outcomes of many cancer immunotherapy treatments. Depletion of Tregs in animal models has shown an increased efficacy of immunotherapy treatments, and therefore, many immunotherapy treatments are now incorporating Treg depletion.[2]
Molecular characterization
Similar to other T cells, regulatory T cells develop in the thymus. The latest research suggests that regulatory T cells are defined by expression of the forkhead family transcription factor Foxp3 (forkhead box p3). Expression of Foxp3 is required for regulatory T cell development and appears to control a genetic program specifying this cell's fate.[21] The large majority of Foxp3-expressing regulatory T cells are found within the major histocompatibility complex (MHC) class II restricted CD4-expressing (CD4+) population and express high levels of the interleukin-2 receptor alpha chain (CD25). In addition to the Foxp3-expressing CD4+ CD25+, there also appears to be a minor population of MHC class I restricted CD8+ Foxp3-expressing regulatory T cells. These Foxp3-expressing CD8+ T cells do not appear to be functional in healthy individuals but are induced in autoimmune disease states by T cell receptor stimulation to suppress IL-17-mediated immune responses.[22] Unlike conventional T cells, regulatory T cells do not produce IL-2 and are therefore anergic at baseline.
A number of different methods are employed in research to identify and monitor Treg cells. Originally, high expression of CD25 and CD4 surface markers was used (CD4+CD25+ cells). This is problematic as CD25 is also expressed on non-regulatory T cells in the setting of immune activation such as during an immune response to a pathogen. As defined by CD4 and CD25 expression, regulatory T cells comprise about 5-10% of the mature CD4+ T cell subpopulation in mice and humans, while about 1-2% of Treg can be measured in whole blood. The additional measurement of cellular expression of Foxp3 protein allowed a more specific analysis of Treg cells (CD4+CD25+Foxp3+ cells). However, Foxp3 is also transiently expressed in activated human effector T cells, thus complicating a correct Treg analysis using CD4, CD25 and Foxp3 as markers in humans. Therefore, some research groups use another marker, the absence or low-level expression of the surface protein CD127 in combination with the presence of CD4 and CD25. Several additional markers have been described, e.g., high levels of CTLA-4 (cytotoxic T-lymphocyte associated molecule-4) and GITR (glucocorticoid-induced TNF receptor) are also expressed on regulatory T cells, however the functional significance of this expression remains to be defined. There is a great interest in identifying cell surface markers that are uniquely and specifically expressed on all Foxp3-expressing regulatory T cells. However, to date no such molecule has been identified.
In addition to the search for novel protein markers, a different method to analyze and monitor Treg cells more accurately has been described in the literature. This method is based on DNA methylation analysis. Only in Treg cells, but not in any other cell type, including activated effector T cells, a certain region within the Foxp3 gene (TSDR, Treg-specific-demethylated region) is found demethylated, which allows to monitor Treg cells through a PCR reaction or other DNA-based analysis methods.[23] Interplay between the Th17 cells and regulatory T cells are important in many diseases like respiratory diseases.[24]
Recent evidence suggests that mast cells may be important mediators of Treg-dependent peripheral tolerance.[25]
Regulatory T cell epitopes
Regulatory T cell epitopes ('Tregitopes') were discovered in 2008 and consist of linear sequences of amino acids contained within monoclonal antibodies and immunoglobulin G (IgG). Since their discovery, evidence has indicated Tregitopes may be crucial to the activation of natural regulatory T cells.[26][27][27][28]
Potential applications of regulatory T cell epitopes have been hypothesised: tolerisation to transplants, protein drugs, blood transfer therapies, and type I diabetes as well as reduction of immune response for the treatment of allergies.[29][30][31][32][33][34][35][36][37]
Genetic deficiency
Genetic mutations in the gene encoding Foxp3 have been identified in both humans and mice based on the heritable disease caused by these mutations. This disease provides the most striking evidence that regulatory T cells play a critical role in maintaining normal immune system function. Humans with mutations in Foxp3 suffer from a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.[38][39]
The IPEX syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life, resulting in the commonly observed triad of watery diarrhea, eczematous dermatitis, and endocrinopathy seen most commonly as insulin-dependent diabetes mellitus. Most individuals have other autoimmune phenomena including Coombs-positive hemolytic anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy. The majority of affected males die within the first year of life of either metabolic derangements or sepsis. An analogous disease is also observed in a spontaneous Foxp3-mutant mouse known as "scurfy".
- ↑ Bettelli, Estelle; Carrier, Yijun; Gao, Wenda; Korn, Thomas; Strom, Terry B.; Oukka, Mohamed; Weiner, Howard L.; Kuchroo, Vijay K. "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells". Nature. 441 (7090): 235–238. doi:10.1038/nature04753.
- 1 2 Curiel, Tyler J. (1 May 2007). "Tregs and rethinking cancer immunotherapy". Journal of Clinical Investigation. 117 (5): 1167–1174. doi:10.1172/JCI31202.
- ↑ Chen, WanJun (2011-08-01). "Tregs in immunotherapy: opportunities and challenges". Immunotherapy. 3 (8): 911–914. doi:10.2217/imt.11.79. ISSN 1750-743X.
- ↑ Miyara, Makoto; Gorochov, Guy; Ehrenstein, Michael; Musset, Lucile; Sakaguchi, Shimon; Amoura, Zahir. "Human FoxP3+ regulatory T cells in systemic autoimmune diseases". Autoimmunity Reviews. 10 (12): 744–755. doi:10.1016/j.autrev.2011.05.004.
- ↑ Adeegbe, Dennis O.; Nishikawa, Hiroyoshi (2013). "Natural and Induced T Regulatory Cells in Cancer". Frontiers in Immunology. 4. doi:10.3389/fimmu.2013.00190.
- 1 2 Curiel, Tyler J (April 2008). "Regulatory T cells and treatment of cancer". Current Opinion in Immunology. 20 (2): 241–246. doi:10.1016/j.coi.2008.04.008.
- ↑ Hori S, Nomura T, Sakaguchi S (2003). "Control of regulatory T cell development by the transcription factor Foxp3". Science. 299 (5609): 1057–61. doi:10.1126/science.1079490. PMID 12522256.
- ↑ Singh B, Schwartz JA, Sandrock C, Bellemore SM, Nikoopour E (2013). "Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (Th17) cells". Indian J Med Res. 138: 591–4. PMC 3928692. PMID 24434314.
- ↑ Shevach EM (2000). "Regulatory T cells in autoimmmunity". Annu Rev Immunol. 18: 423–49. doi:10.1146/annurev.immunol.18.1.423. PMID 10837065.
- ↑ Sakaguchi S (2004). "Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses". Annu Rev Immunol. 22: 531–62. doi:10.1146/annurev.immunol.21.120601.141122. PMID 15032588.
- ↑ Sakaguchi S, et al. Regulatory T cells and immune tolerance. Cell. 2008 May 30;133(5):775-87. PMID 18510923
- ↑ Haribhai D, Williams JB, Jia S, Nickerson D, Schmitt EG, Edwards B, Ziegelbauer J, Yassai M, Li SH, Relland LM, Wise PM, Chen A, Zheng YQ, Simpson PM, Gorski J, Salzman NH, Hessner MJ, Chatila TA, Williams CB (July 2011). "A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity". Immunity. 35 (1): 109–22. doi:10.1016/j.immuni.2011.03.029. PMC 3295638. PMID 21723159.
- ↑ Holaday BJ, Pompeu MM, Jeronimo S, Texeira MJ, Sousa Ade A, Vasconcelos AW, Pearson RD, Abrams JS, Locksley RM (December 1993). "Potential role for interleukin-10 in the immunosuppression associated with kala azar". J. Clin. Invest. 92 (6): 2626–32. doi:10.1172/JCI116878. PMC 288459. PMID 8254019.
- ↑ Holaday BJ (1999). "Immunotherapy for visceral leishmaniasis: ability of factors produced during anti-leishmania responses of skin test positive adults to inhibit peripheral blood mononuclear cell activities associated with visceral leishmaniasis". Mem. Inst. Oswaldo Cruz. 94 (1): 55–66. doi:10.1590/s0074-02761999000100013. PMID 10029912.
- ↑ Dranoff G (December 2005). "The therapeutic implications of intratumoral regulatory T cells". Clin. Cancer Res. 11 (23): 8226–9. doi:10.1158/1078-0432.CCR-05-2035. PMID 16322278.
- ↑ Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM (October 2007). "CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells". Blood. 110 (7): 2537–44. doi:10.1182/blood-2007-03-082578. PMC 1988926. PMID 17615291.
- ↑ Wang J, Yu L, Jiang C, Fu X, Liu X, Wang M, Ou C, Cui X, Zhou C, Wang J (January 2015). "Cerebral ischemia increases bone marrow CD4+CD25+Foxp3+ regulatory T cells in mice via signals from sympathetic nervous system". Brain Behav Immun. 43: 172–183. doi:10.1016/j.bbi.2014.07.022. PMC 4258426. PMID 25110149.
- ↑ Gooden, M. J. M.; de Bock, G. H.; Leffers, N.; Daemen, T.; Nijman, H. W. (2011-06-28). "The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis". British Journal of Cancer. 105 (1): 93–103. doi:10.1038/bjc.2011.189. ISSN 0007-0920. PMC 3137407. PMID 21629244.
- 1 2 3 Oleinika, K; Nibbs, R J; Graham, G J; Fraser, A R (2013-01-01). "Suppression, subversion and escape: the role of regulatory T cells in cancer progression". Clinical and Experimental Immunology. 171 (1): 36–45. doi:10.1111/j.1365-2249.2012.04657.x. ISSN 0009-9104. PMC 3530093. PMID 23199321.
- 1 2 Lippitz, Bodo E. "Cytokine patterns in patients with cancer: a systematic review". The Lancet Oncology. 14 (6): e218–e228. doi:10.1016/s1470-2045(12)70582-x.
- ↑ Marson, Alexander; et al. (2009). "Foxp3 occupancy and regulation of key target genes during T-cell stimulation". Nature. 445 (?): 931–935. doi:10.1038/nature05478. PMC 3008159. PMID 17237765.
- ↑ Ellis SD, McGovern JL, van Maurik A, Howe D, Ehrenstein MR, Notley CA. "Induced CD8+FoxP3+ Treg cells in rheumatoid arthritis are modulated by p38 phosphorylation and monocytes expressing membrane tumor necrosis factor α and CD86.". 2014. Arthritis Rheumatol. 66(10):2694-705. doi: 10.1002/art.38761. PMID 24980778
- ↑ Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V, Baron U, Stauch D, Kotsch K, Pratschke J, Hamann A, Loddenkemper C, Stein H, Volk HD, Hoffmüller U, Grützkau A, Mustea A, Huehn J, Scheibenbogen C, Olek S (January 2009). "Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue". Cancer Res. 69 (2): 599–608. doi:10.1158/0008-5472.CAN-08-2361. PMID 19147574.
- ↑ Agarwal, A; Singh, M; Chatterjee, BP; Chauhan, A; Chakraborti, A (2014). "Interplay of T Helper 17 Cells with CD4(+)CD25(high) FOXP3(+) Tregs in Regulation of Allergic Asthma in Pediatric Patients.". International journal of pediatrics. 2014: 636238. doi:10.1155/2014/636238. PMID 24995020.
- ↑ Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, Scott ZA, Coyle AJ, Reed JL, Van Snick J, Strom TB, Zheng XX, Noelle RJ (August 2006). "Mast cells are essential intermediaries in regulatory T-cell tolerance". Nature. 442 (7106): 997–1002. doi:10.1038/nature05010. PMID 16921386.
- ↑ Tregitopes can dampen unwanted immune responses through selective activation. "Tregitopes". EpiVax, Inc. Retrieved July 2013. Check date values in:
- 1 2 . Molecular Therapy http://www.nature.com/mt/journal/vaop/naam/abs/mt2013166a.html. Retrieved July 2013. Check date values in:
|access-date=(help); Missing or empty
- ↑ (PDF). Blood Journal http://www.epivax.com/wp-content/uploads/2013/02/DeGroot_Tregitope_Blood_2008.pdf. Retrieved July 2013. Check date values in:
|access-date=(help); Missing or empty
- ↑ "New $2.25M infusion of NIH funds for EpiVax' Tregitope, proposed "Paradigm-Shifting" Treatment". Fierce Biotech Research. Retrieved July 2013. Check date values in:
- ↑ Su Y, Rossi R, De Groot AS, Scott DW (August 2013). "Regulatory T cell epitopes (Tregitopes) in IgG induce tolerance in vivo and lack immunogenicity per se". J. Leukoc. Biol. Journal of Leukocyte Biology. 94 (2): 377–83. doi:10.1189/jlb.0912441. PMID 23729499.
- ↑ Cousens, LP; Su, Y; McClaine, E; Li, X; Terry, F; Smith, R; Lee, J; Martin, W; Scott, DW; De Groot, Anne S. (2013). "Application of IgG-Derived Natural Treg Epitopes (IgG Tregitopes) to Antigen-Specific Tolerance Induction in a Murine Model of Type 1 Diabetes". Journal of Diabetes Research. Journal of Diabetes Research. 2013: 621693. doi:10.1155/2013/621693. PMC 3655598. PMID 23710469.
- ↑ (PDF). Human Vaccines & Immunotherapeutics http://www.epivax.com/wp-content/uploads/2013/02/Tregitope_Teaching-Tolerence_Pompe_Disease.pdf. Retrieved July 2013. Check date values in:
|access-date=(help); Missing or empty
- ↑ (PDF). Journal of Clinical Immunology http://www.epivax.com/wp-content/uploads/2013/02/Tregitope-Clinical-Immunology-2012.pdf. Retrieved July 2013. Check date values in:
|access-date=(help); Missing or empty
- ↑ (PDF). Autoimmunity Reviews http://www.epivax.com/wp-content/uploads/2013/02/Tregitope-update_Autoimmunity-Reviews-2012.pdf. Retrieved July 2013. Check date values in:
|access-date=(help); Missing or empty
- ↑ (PDF). World Journal of Gastroenterology http://www.epivax.com/wp-content/uploads/2013/02/Adeno-associated-virus-mediated-delivery-of-Tregitope-167-2012.pdf. Retrieved July 2013. Check date values in:
|access-date=(help); Missing or empty
- ↑ (PDF). Neurology Research International http://www.epivax.com/wp-content/uploads/2013/02/Tregitopes_MS_DeGroot_2011.pdf. Retrieved July 2013. Check date values in:
|access-date=(help); Missing or empty
- ↑ (PDF). Blood Journal http://www.epivax.com/wp-content/uploads/2013/02/DeGroot_Tregitope_Blood_2008.pdf. Retrieved July 2013. Check date values in:
|access-date=(help); Missing or empty
- ↑ Online Mendelian Inheritance in Man IPEX
- ↑ ipex at NIH/UW GeneTests
External links
- Regulatory T-Cells at the US National Library of Medicine Medical Subject Headings (MeSH)


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Date(s) - 12/06/2018
10:00 am - 5:00 pm
Indiana State Museum
Celebration Crossing comes alive with holiday merriment from the sounds of local bands and choirs, to the jolly greetings from Santa and Mrs. Claus as they welcome visitors into their cozy home, through Dec. 24. Beginning Dec. 26, Raggedy Ann, a beloved Indiana icon, takes residence here through Jan. 6. Students of all ages can ride the Santa Claus Express, and visit Santa's Workshop to create and play. A variety of demonstrations and activities happen daily on an on-going basis.
The museum is closed on Mondays.
Cost: Included with museum general admission.
Get Tickets: Buy museum tickets online and save $1 per ticket. Get tickets >>
We do our best to provide the most relevant and timely information to our readers, but please confirm dates, times, and availability before attending an event. Events are posted on IWK from information found on, but not limited to, attraction sites, government city sites; as well as submissions from individual attractions, press releases and PR firms. All events are subject to change without notice and Indy with Kids cannot be held responsible.


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Hi,i am 24 years old i have a big scar on the right side of the face,after a fire accident i have it,can you help me with a surgery or something to remove it,thank you.
A burn injury is different from a linear scar. If it is just a linear scar then the scar is removed and a camouflaging technique like a geometric broken line or w-plasty would be used to make the straight line harder to see. if the scar is contracted and misaligned, a z-plasty can be used. dermabrasion could follow that to help with further camouflage.
if there is a larger area of your face burned and the skin does not look good, you would have most likely to rotate tissue from an adjacent area into the scarred area to remove it. ideally, you would not use a skin graft because it typically does not have as good color and texture match as tissue that is just adjacent to the burn. fortunately, the cheek typically has abundant tissue near it for rotation if the burn is not large. at 24 years of age, your skin may be a bit tighter though than say someone 70 years of age.
in summary, you really need to contact a facial plastic surgeon (you can find one near you in the locate a surgeon section of this Web site). i hope you find a solution to your problem.


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The 2014 inductees into the Baseball Hall of Fame will be announced next Wednesday. As of today, 101 sportswriters (of the 600-something eligible) have publicly shared their votes. Projecting from those ballots, four players will make it to Cooperstown, and a fifth will fall just short.
Baseball Think Factory has been constantly updating its HOF Ballot Collecting Gizmo, which tallies every ballot made public. It has its flaws, but these large-sample-size polls are never too far off: last year's edition nailed every player's vote to within 10 percent, and correctly predicted that no one would be elected. Here's this year's count as of today.
100 - Maddux
97.0 - Glavine
90.0 - F. Thomas
80.2 - Biggio
72.3 - Piazza
65.3 - Bagwell
62.4 - Jack Morris
56.4 - Raines
44.6 - Bonds
43.6 - Clemens
38.6 - Schilling
34.7 - Mussina
23.8 - Trammell
19.8 - L. Smith
19.8 - E. Martinez
15.8 - McGriff
12.9 - Kent
11.9 - L. Walker
10.9 - McGwire
8.9 - S. Sosa
7.9 - R. Palmeiro
5.0 - Mattingly
It's very important to remember that the 101 ballots counted are self-selected. Usually, that indicates a writer more engaged on the internet, still actively working—maybe younger than the average BBWAA member. That's a generalization, but comparing past Gizmo exit polls with the actual results have shown a pattern: "Old-school" players like Jack Morris received more actual votes than predicted, because those voting for them weren't publicly revealing their ballots, while PED-linked players like Barry Bonds received fewer votes than predicted, for the opposite reason—those voting for them were more likely to share their ballots ahead of time.
That would seem to hurt Mike Piazza's chances of making a late push, and indicate that Jack Morris's actual vote total will be closer to the 75-percent cutoff than predicted.
With all the caveats, the above poll would be a fascinating result. It would indicate significant growth in support for Piazza, Bonds, and Clemens from last year, with more modest gains for Tim Raines and Jeff Bagwell.
And could Greg Maddux be the first unanimous Hall of Famer? He's perfect through 101 ballots. At the very least, any morons not voting for him have enough sense not to announce it before the fact.
The 2014 HOF Ballot Collecting Gizmo! [Baseball Think Factory]


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Whether its air raid, bear raid, or power, putting a label on the offensive identity of the Pac-12 Conference doesn't come easily. But there's one guarantee: It's effective.
The Pac-12 had some of the most explosive offenses in the nation last season compared to the other BCS conferences. With 10 of 12 teams returning their starting quarterbacks this year, offenses in the West should flourish even more. But the style in which each Pac-12 team finds success on the scoreboard is varied, adding to a dynamic, but diverse, set of offenses in the conference.
"This league is a little unusual because there are so many different styles of play in this league," Cal coach Sonny Dykes said Wednesday at Pac-12 media day, "and there is a lot of teams that are really committed to doing something a certain way and they're very good at it."
Oregon is known for a spread offense geared toward its running attack, while Washington State spreads the field to go to the air. Somewhere in the middle, Arizona works to balance its offense, while Stanford hasn't bought in to the trendy up-tempo scheme and sticks to a power running game.
On average, Pac-12 teams score 33.2 points and rack up 445.2 yards per game.
With skill position players that Arizona coach Rich Rodriguez called "second to none," offenses in the Pac-12 are multi-headed monsters. Rodriguez emphasized that with more seven-on-seven passing leagues popping up all over the West Coast, especially in California where the weather permits outdoor football all year, athletes at the skill positions are more ready out of high school than ever.
Oregon on top
Oregon is the favorite to take home the Pac-12 title this season, as the media voted for the Ducks over UCLA in the conference championship game. This is the fourth time in five years that Oregon was picked to win the title.
Both the Ducks and the Bruins had 37 first-place votes in their respective divisions, while Oregon had 24 votes to UCLA's 13 in the championship game. Stanford and USC each got one vote in the championship game.
After winning the conference championship for two straight years, Stanford finished second in the North Division in the media poll with two first-place votes. USC and Arizona State both had one first-place vote in the South Division. Arizona, Utah and Colorado rounded out the south, while Washington, Oregon State, Washington State and Cal finished the north's rankings.
DirecTV standstill
The news on the Pac-12's grudge match with DirecTV is that there is no news. Pac-12 Commissioner Larry Scott did not mention the standoff during his 30-minute podium session, and did not take questions at the time. But he said afterward that it's "unlikely" that the two sides will reach a deal and there has been little progress in negotiations.


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Phil Jackson and the New York Knicks are working on an agreement that will give the former coaching great control of the team's front office, according to an ESPN report.
The announcement might not come until next week, according to ESPN's Chris Broussard, citing a league source.
Some believe Jackson, who won six NBA titles with the Bulls and five with the Lakers, is using the Knicks as leverage for a similar job — particularly with the Lakers, where fiancee Jeanie Buss is chief of business operations.
Jackson owns homes in Playa del Rey and Montana. He played for the Knicks from 1967-78 and was a key reserve on the 1973 NBA championship team.
Broussard reports Jackson will reportedly take over the Knicks' basketball operations department from president and general manager Steve Mills, who is expected to remain with the organization.


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Admit it, you've been lusting after the 15-inch MacBook Pro with Retina display since it was announced earlier in the year, but were worried that the screen was just too big.
Worry no longer, as Apple has launched a 13-inch version of the MacBook Pro with a refined chassis and the new screen technology that gives you that crisp experience, albeit in a smaller casing.
This time around the device ditches the optical drive, loses some weight, gains some ports and basically becomes a miniature version of the 15-inch model. That's no bad thing.
Our time with the new model was crowded and brief, but we can vouch that the device's screen is as good as billed. It's pin sharp, and if graphics and text matter to you, it will make your current MacBook Pro look fuzzy - even though you never thought it was until now.
The lack of optical drive will annoy some, but it's not the end of the world - really, when was the last time you used a DVD or CD with your computer - and the addition of two Thunderbolt ports is welcomed - especially if you are video editing off Thunderbolt drives.
There are concerns though, such as there being no dedicated graphics card as with the 15-inch model, which is a shame. But you'll keep reminding yourself that the screen really does look lovely.
From our brief time with the laptop in San Jose this looks like a real cracker that will deliver an impressive package for those looking for something a little more powerful than the MacBook Air without having to opt for the 15-inch monster.
Of course the launch of the 13-inch model also leaves us asking when the MacBook Air will get the Retina display. Apple, consider our request put in.


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|Search Results (2 videos found)
|America's Millenium on the Mall - Blues: Past and Future - B.B. King, Q & A
In the eleventh segment B.B. King answers questions from the audience.
Genre: Educational
Keywords: John Hope Franklin; birthday; Yale University; Church of God in Christ; faith; "devil's music";aunt; mother; British musicians; Eric Clapton; Rolling Stones; The Who; Beatles; historical icon; Gatemouth Moore; Roy Brown; Stevie Ray Vaughan; favorite guitar players; George Benson; Lonnie Johnson; Louis Jordan; Bobby Hackett; Johnny Hodges; link; Mahalia Jackson; Louis Armstrong; advice; future of blues; mainstream of music; radio; Sonny Bono; copyright;
Duration: 00:16:27
Popularity (downloads): 438
|NASASciFiles - The Case of the Galactic Vacation
NASA Sci Files video containing the following eleven segments. NASA Sci Files segment exploring the Arecibo Observatory, what it does, and where it is located. NASA Sci Files segment...
Genre: Educational
Keywords: NASA Sci Files; Arecibo Observatory; Telescope; Radio Telescope; Radio Waves; Signals; Universe; Pulsar; Quasar; Reflector; Receiver; Electrical Signal; Control Room; Scientists; Equator; Wavelength; Optical; Atmosphere; Solar System; Galaxy; Extraterrestrial Intelligence; Artificial Signal; Forces of Motion; Free Fall; Weightlessness; Inertia; Acceleration; Parabola; Accelerometer; Space Travel; Roller Coaster; Navigation and Vehicle Health Monitoring System; Modified Bathrooms; Gravity; Zero Gravity; Exercise Equipment; Kitchen; Starship 2040; Orbit; International Space Station; Living Environment; Earth; Commander; Mars; Tourist Attraction; Canyon; Crater; Solar System; Planet; Water; Liquid; Frozen; Seasons; Axis; Polar Ice Caps; Atmosphere; Gas; Carbon Dioxide; Oxygen; Nitrogen; Hydrogen; Temperature; Space Suit; Common Denomenator; Meteors; Astroids; Water; Earth; Moon; Moon Phases; Illuminations; Revolve; New Moon; Full Moon; First Quarter; Third Quarter; Sun; Lunar Phases; Axis; Apollo; Tides; Beach; Gravitational Pull; Oceans; Century; Space; Distances; Parallax; Experiment; Student Activity; Optics; Protractor; Vertex; Angle; Data; Propulsion System; Space Radiation; Bone Mass; Chemical Rockets; Spaceship; Gases; Plasma; Magnetic Field; Exhaust; Energy; Heat; Electricity; Nuclear Power; Fusion; Thermonuclear Reaction; Technology; Arecibo Telescope; Solar System; Extra-solar Planets; Stars; Planets; Lightyears; Reflecting Telescope; Light; Dim; Betelgeuse; Giant Star; Life; Colors; Red; Blue; Temperature; Yellow; Dwarf Star; Sun; Habitable Zone; Ultraviolet Radiation; Puerto Rico; Galaxy; Orion Nebula; Hydrogen Gas; Whirlpool Galaxy; Extreme Environment; Boiling Temperature; Air Pressure; Celcius; Oxygen; Gravitational Force; Jupiter; Kilometers; Inner Planets; Mercury; Venus; Lava Flows; Helium; Saturn; Uranus; Neptune; Pluto; Astronomer; Proxima Centauri;
Duration: 00:56:29
Popularity (downloads): 1602


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International Community Policing Series: Preview of IACP 2012
When police chiefs, international community policing leaders, and technology all come together, you get innovative solutions that make the world a safe place. With that said, I'm really excited that in a very short time period, I'll be headed to San Diego for IACP 2012, which is the 119th Annual International Association of Chiefs of Police Conference and Law Enforcement Education and Technology Exposition. This event runs from September 29 to October 3 and will showcase technology and bring together global leadership in community policing from around the world to share information and experiences and to work together to find solutions to issues they are facing as a community.
Check out the IACP video below featuring Police Chief William Lansdowne of the San Diego Police Department.
Among other things, the IACP 2012 event includes more than 200 educational sessions, an exhibit hall, and various networking opportunities. You can see a listing of all the events by checking out the IACP Schedule at a Glance.
The event is also where the winners of the 2012 IACP Community Policing Awards sponsored by Cisco are recognized. These awards pay special tribute to departments worldwide that have collaborated with their communities to bring about change, address crime and terrorism, and make their communities and nations a safer place to live, work, and play.
According to Chief Todd A. Miller, Chairperson of the IACP Community Policing Committee, "The philosophy of community policing is more relevant and needed more today than ever before. With resources limited by current economic conditions, the force multiplication agencies receive by implementing the community policing philosophy and partnering with citizens is the most effective means of making our communities safer. That is why we undertake this tremendous effort each year to recognize the best of the best."
Click on the image to the left to see previous winners of the IACP Community Policing Awards.
IACP 2012 promises to be a great event, and I can't even begin to describe how honored I feel to be able to see this year's winners of the IACP Community Policing Awards being recognized for such amazing accomplishments that make our world a safer place. And we'll be bringing you coverage from the event so stay tuned to the Cisco Government blog site, as well as to our Global Government Twitter and Facebook sites, not only for more on this year's winners of the IACP Community Policing Awards, but also for more on technology and community policing, stories, and pictures.
And for those of you attending, hope to see you there!
In an effort to keep conversations fresh, Cisco Blogs closes comments after 60 days. Please visit the Cisco Blogs hub page for the latest content.


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Natives Rifle Club OPM will be held once again immediately preceding the NRAA Queens, 16-17/06/2018. Two days of shooting covering all ranges shot over the Presidents and Queens series with generous prizes for all grades and divisions. Pre-entry available, or otherwise roll-up on the day(s). As always, we will be using the HEXTA electronic targets with ample support available for newcomers to the system.
We would love to see you all there and appreciate your support!
Natives Rifle Club OPM 2018
Results, photos of recent events, plan future events, let people know where you'll be competing.
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An apple a day keeps the doctor away. There's no better way to enjoy a fresh, juicy apple than one of our hand-dipped, wonderfully decorated fall treat. Candied apples make the perfect autumn gift no matter what occasion you're celebrating.
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I've been nagged to write something here, so apologies in advance for my vague and meandering note, wherever it might take me. And apologies for breaking with tradition by failing to write this in the third person, at least until such a time as I'm nagged again!
I'm Christine, or at least I am now, both in terms of my real name and my username: it's just the feminised version of my birth name, but I'm a lot happier with it; and it's the latest in a series of usernames including Vometia (as I'm known most places) and cbh (my initials) because I seem to be fundamentally incapable of deciding what to call myself!
Me, yesterday
At the time of writing, I'm 45 years old, and transitioned when I was 43. In my case, "transition" was a rather gradual process, but December 2011 is when I formally changed my name, so that seems as good a date as any if I have to choose one. That followed two or three years of prevarication which in turn followed a long period of living in denial and making myself thoroughly miserable. I'm still pre-op, something which gives me endless opportunities to gripe and complain, which are my main pastimes.
My other main pastime is video-games, which is relevant inasmuch as I eventually realised that the character I was role-playing was actually me: it was an escape from "real life role-playing" where I'd adopted a male persona to try to fit in and meet everyone else's expectations, which eventually struck me as being a rather silly situation to find myself in so the real me finally made an appearance.
And prior to all that, I started to realise that something was amiss back in 1980ish, just prior to hitting puberty. During early childhood, the differences between boys and girls were rather lost on me and I'd assumed they were largely arbitrary designations: until I was about 10 or 11, I was happy enough being whatever I was. Then things started to change: I found myself wanting to do things that the girls were doing: not in any obvious "I want to be a girl!" sort of a way, at least not then: it was a lot more insidious, an interest in the way they dressed, their shoes, their jewellery and so on. And then puberty was a thoroughly miserable time of my life, when I remember being yelled at about not wanting to grow up. Damn right, I certainly didn't want to grow into a man, the idea horrified and upset me. Eventually I resigned myself to the awfulness of it and turned into a rather withdrawn misery. Anyone reading and struggling with their own decision, please take the hint to not do that!
Here's a before-and-after picture. I may look happier in the first picture, but believe me, I wasn't. And I was just too lazy to attempt to smile in the second!
So what else is there? Well other than the malarky surrounding my transition, I was born in Jarrow at the tail end of the '60s, a town which a friend referred to as "The Jewel of the North". I suspect there's a possibility he wasn't being entirely serious. I moved down south, went to college, and worked as a computer programmer, sysadmin, web developer and stuff like that until, well, I couldn't do it any more. Hopefully I'll get back to it once I'm done.
I live in Oxford with my long-term and long-suffering girlfriend. We have no children, and currently, no cats. She's been incredibly supportive, and the vast majority of my friends have been accepting of the "new" me.
I also play bass quite badly and take poorly-composed photographs.
I prefer to identify as female, lesbian and a generally grumpy old bag.
Some (but not all) of the support team here.
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Re: Christine
Time for a new photo. This was the old one. "So I don't look more gormless", was the rationale. I can't say it's necessarily been any improvement.
I still need to re-write this so it it's in the third person as is The Correct Way Of Doing Things(tm).
I still need to re-write this so it it's in the third person as is The Correct Way Of Doing Things(tm).
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School Funding Comparisons by the NYC Independent Budget Office (IBO) (2010-11)
How do the funding levels compare, and the funding streams interact, for New York City charter and district schools? The City's Independent Budget Office (IBO) has issued three analyses on this topic, to which the Charter Center has responded with increasing, detailed criticism. The NYC Department of Education has also raised strong objections.


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Social Studies 2011
Reflections in a social eye….Once again perusing the photo ops and ink generated by all the events over the past year brought about marvelous mems and smiles for this social columnist. So many of these memorable events were for charitable causes and came about due to the undying efforts of so many to strengthen our community. After reviewing and reminiscing the extensive list of events, here is the top 20 stellar soirees of 2011:
1. Baptist Hospitals of Southeast Texas Cirque De Le Soiree.
2. Symphony League of Beaumont Crystal Ball Gala
3. Mr. Habitat 2011 Fundraiser
4. 2011 Heart Ball: "I Left My Heart in San Francisco – A Golden Gate Affair"
5. Red Cross 23rd annual Hurricane Party
6. Chamber of Commerce Spice of The Season Celebrity Waiter Dinner
7. Golden Triangle Go Red for Women Luncheon
8. Lamar University 2011 Le Grand Bal "Rhapsody in LU"
9. Beaumont Main Street RECREATE
10. Art Museum of Southeast Texas ARTOPIA Gala
11. Kelly High School Tailgate Fundraiser
12. Chef's Delight Dinner
13. Catholic Charities Harvest of Hope Gala
14. Girls' Haven Gala
15. Ubi Caritas third annual Date Auction
16. G.O.L. Julie Richardson Procter Ribbon Run
17. Junior League Main Street Market Luncheon
18. TAN's Paint the Town Red Soiree
19. Santa's Elves third annual fundraiser
20. Zummo's Holiday Party
Tata, 2011 … hello New Year 2012!


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State: NY
Zip: 11590
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Thursday, June 21
Good morning, TexMessengers! ObamaCare has survived — at least until Monday.
If Twitter gives us the first reaction to breaking news from our Texas delegation (in 140 characters or less), Facebook gives elected officials a chance for "in-depth" analysis (more than 140 characters).
After yesterday's House committee vote to find Attorney General Eric Holder in contempt of Congress, many Texas politicians took to their Facebook pages to explain their (critical) views. Republicans, at least.
Congressman Pete Olson
"Mr. Holder gives us no choice. If contempt proceedings move forward, I will support them so we learn the truth."
Congressman Kevin Brady
"If you have nothing to hide, why is AG Holder so determined to keep the truth about Operation Fast and Furious from coming out?"
Senator John Cornyn
"Cornyn on WH assertion of exec privilege: "The AG and now the President have refused to turn over documents to investigators and failed to hold anyone accountable for his department's mishandling of Fast and Furious"
Congressman Blake Farenthold
"'The American people do not tolerate being lied to…' http://youtu.be/kYXgnyTJicM"
Presidential Campaign:
Every morning, we share some headlines from the 2012 presidential campaigns.
★Ron Paul: Romney 'doesn't have the control of the hearts and the minds of the people'
Reader Comment of the Day
In response to our article "Jerry Patterson condemns 'misuse' of tax dollars for endangered species lawsuits" reader "namsmog" wrote in the comments forum:
"Time to make Patterson an endangered political species!"
Texas Watch
TxPotomac lets you know what stories to look out for later this week.
★ Thursday, June 21. House Homeland Security — Subcommittee on Oversight, Investigations and Management. Panel Discussion: U.S.-Caribbean Border Issues. Cannon building, 9 a.m.
★ Thursday, June 21. Inter-American Dialogue. Panel Discussion: police force overhaul in Mexico. 1211 Connecticut Avenue, 9 a.m.
Tomorrow and beyond:
★ Tuesday, June 26. Utah primary


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New Volvo A25G and A30G Articulated Haulers Reinvent a Classic
Articulated haulers from Volvo Construction Equipment have often been copied — but never beaten. And with the new G-Series, the Volvo proven concept is even better, with new features for optimized productivity. Since their debut in 1966, Volvo articulated haulers have stood as the construction equipment industry's gold standard — and the leader in off-road […]Read more