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Two Trains Running
March 30 — April 29, 2018
by August Wilson
Directed by Juliette Carrillo
Co-Production with Seattle Repertory Theatre
Fichandler Stage
It's 1969 and the Civil Rights Movement is sending tremors through Pittsburgh's Hill District. At the center of the community is Memphis Lee's diner, slated to be demolished – a casualty of the city's renovation project. Confronted with a rapidly changing world, Memphis and his regular customers struggle to maintain their solidarity and sense of pride. From Pulitzer Prize-winning playwright August Wilson comes this masterpiece about everyday lives in the shadow of great events, and of unsung citizens who are anything but ordinary. "Mr. Wilson's most adventurous and honest attempt to reveal the intimate heart of history." (New York Times)
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AUGUST WILSON (Playwright)'s plays include Gem of the Ocean, Joe Turner's Come and Gone, Ma Rainey's Black Bottom, The Piano Lesson (Pulitzer Prize winner), Seven Guitars, Fences (Pulitzer Prize winner, Tony Award winner), Two Trains Running, Jitney (Oliver Award winner), King Hedley II and Radio Golf. In 2003, he made his stage debut in his one-man show, How I Learned What I Learned. He received an Emmy Award nomination for his screenplay for The Piano Lesson. Other works include The Janitor, Recycle, The Coldest Day of the Year, Malcolm X, The Homecoming and the musical satire Black Bart and the Sacred Hills. Other awards include eight New York Drama Critics Circle Awards, Rockefeller and Guggenheim Fellowships in Playwriting, a Whiting Writers Award, 2003 Heinz Award, 1999 National Humanities Medal and induction into the Theater Hall of Fame.
JULIETTE CARRILLO (Director) is a graduate of the Yale School of Drama and has directed critically-acclaimed premieres and revival productions in theaters across the country including Oregon Shakespeare Festival, Mark Taper Forum, South Coast Repertory, Yale Repertory, Denver Center and Seattle Repertory. As a member of the Cornerstone Theater ensemble, she has developed work for and with various communities such as the Los Angeles River community, the addiction and recovery community, the Hindu community and seniors and their caregivers. She was an artistic associate and Director of the Hispanic Playwright's Project at South Coast Repertory for seven years, developing work with writers such as Nilo Cruz, Octavio Solis, José Rivera and Karen Zacarías. She is on faculty at University of California, Irvine. www.juliettecarrillo.com
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Manic Productions Presents:
Joe Fletcher & the Wrong Reasons, Toy Soldiers
Goodnight Blue Moon
Cafe Nine
250 State Street
New Haven, CT, 06511
This event is 21 and over
Joe Fletcher & the Wrong Reasons (Providence, RI) draw musically from the sounds of classic country, folk, and rock n' roll, while the highly literate lyrical content takes the listener down roads never before travelled. Fletcher's story-driven tales of life's losing end are balanced by those that search for redemption in a mixed-up world that blends the 19th century seamlessly with the present day. Their sophomore effort *White Lighter* has propelled them to great critical acclaim and an invitation to the 2012 Newport Folk Festival.
Toy Soldiers love a good song and dance. The lively & hard-working Philadelphia 5-piece have spent the past five years playing hundreds of shows, bringing their soulful brand of rock n' roll music to dive bars, festival stages and theaters all over the USA. And with the impending release of their second full-length, The Maybe Boys (produced by Bill Moriarty [Dr. Dog, Man Man]), they have no intention of slowing their roll. Named one of the "Top Bands to Watch in 2013" by USA Today, Toy Soldiers will continue to spread the music and inevitable good times well into 2013 and beyond.
Blending rich vocal harmonies with lush orchestrations, Goodnight Blue Moon has created a sound that is steeped in tradition, yet entirely current. Founded in New Haven, CT by husband and wife duo, Erik Elligers and Nancy Matlack, and longtime friend, Mathew Crowley, the band now includes of some of the most talented musicians in the state, adding strings and horns to a familiar folk outfit. GNBM is known for their energetic, honest, and dynamic live performances, offering a refreshing take on traditional Americana roots music.
Awarded Best Roots Act in the 2016 New England Music Awards, and Best Folk/Traditional Act in the 2013 Connecticut Music Awards, Goodnight Blue Moon has cemented their place as one of New England's premier groups. They have shared the stage with folk heavyweights Hurray for the Riff Raff, Spirit Family Reunion, Joe Fletcher and the Wrong Reasons, and Mother Falcon among others, in addition to creating a diverse and devoted following of their own. Goodnight Blue Moon has been regularly featured on Connecticut Public Radio's Where We Live and NEXT with John Dankosky. Their festival credits include CT Folk Festival, LAUNCH Music Festival, MUSIKFEST, Podunk Bluegrass Festival, I AM Festival and Block Island Music Festival. Goodnight Blue Moon is currently working on their third studio album, a follow up to their critically acclaimed 2014 release, A Girl I Never Met.
$10.00 - $12.00
Tickets Available at the Door
Upcoming Events
Cafe Nine
Sun, January 21
John McMillan
Sun, January 21
Elison Jackson, Cape Coma, Shakeout
Mon, January 22
Snake Oil
Tue, January 23
Aisha Burns
Wed, January 24
ditch boys, Righteous Continental, Bad Sun

subset: commoncrawl


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Dr. Steven Katz combines the best elements of modern dentistry with the warmth, concern, and personal touch that were the hallmarks of dentistry in the "old days." He cares about each of his patients, not simply in terms of their oral health, but in every regard. He truly wants his patients to feel their best, both physically and emotionally, and understands how fundamental having a beautiful smile is to that.
Dr. Katz established his dental practice in 1984, with a clear goal to provide the residents of Long Island with cosmetic and general dentistry of an exceptional standard. His ambition was to give each of his patients better care than they had ever before received, and for nearly three decades, he has been doing precisely that.
Reflective of his achievements in the field of dentistry, Dr. Katz has been awarded Mastership by the Academy of General Dentistry, the highest designation that a general dentist can receive from the esteemed organization. He is one of the few Masters in the state of New York.
Dr. Katz further distinguishes himself by being one of the rare dentists who, in addition to providing general and sedation dentistry of the highest quality, is also a gifted and experienced cosmetic dentist. He performs a full range of surgical procedures, including the placement of dental implants, which allows him to accept cases that other dentists might have to refer out. To ensure that each of his patients is able to receive the care they need, comfortably and without anxiety, Dr. Katz offers sedation dentistry to augment his warm, compassionate manner and gentle touch.
In preparation for his dental career, Dr. Katz earned degrees from Columbia University and the Washington University School of Dental Medicine. He underwent advanced training in oral surgery and served as Chief Resident in Dentistry at North Shore University Hospital, where he continues to function as an Attending Dentist and Instructor. He routinely lectures to his fellow dentists on a variety of topics, passing on the knowledge, insight, and unique perspectives on dentistry that he has developed throughout his career. He has also served as team dentist for the New York Jets professional football team.
When he is not serving his patients, Dr. Katz enjoys spending time with his wife, Regina, to whom he has been happily married since 1979. The couple has three beautiful daughters. In his spare time, he participates in numerous sports and is highly involved in the community of Roslyn Heights, where he makes his home.
It is rare to encounter a dentist who provides the breadth of services that Dr. Katz provides. Are you looking for a dentist who caters to the most discriminating needs of adult patients, but who also loves working with children? A dentist who understands the vital role that oral health plays in whole body health? A dentist who truly listens to his patients, who takes a conservative approach to dental care but is also willing to innovate to find the best possible solutions for his patients?
If you answered yes to any of these questions, then you have found your dentist in Dr. Steven Katz.
Dr. Katz is eager to introduce you to a dental experience unlike any you've ever had. Please contact Smiles on Broadway today, and discover for yourself just how comfortable, relaxing, and effective a trip to the dentist can be.
Active Membership Affiliations
- American Dental Association
- Academy of General Dentistry
- Academy of Cosmetic Dentistry
- Academy of Hospital Dentists
- Academy of Sports Dentistry
- Crown Council
- Dental Organization for Conscious Sedation


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Agave nectarAgave nectar is a sweetener commercially produced from several species of agave, including Agave tequilana and Agave salmiana. Agave syrup is sweeter than honey and tends to be less viscous. Most agave syrup comes from Mexico and South Africa.
Nutrition Facts
Agave nectar
Amount Per 100 grams
Calories 310
% Daily Value*Total Fat 0.5 g 0%
Cholesterol 0 mg 0%
Sodium 4 mg 0%
Potassium 4 mg 0%
Total Carbohydrate 76 g 25%
Dietary fiber 0.2 g 0%
Sugar 68 g
Protein 0.1 g 0%
Calcium 0% Iron 0%
Vitamin B-12 0% Magnesium 0%
*Per cent Daily Values are based on a 2,000 calorie diet. Your daily values may be higher or lower depending on your calorie needs.


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|Subject: Tanzania
OUCH Gretchen! I'll bet you're right. Our guide was not local. He and his
family were born and raised in Africa and finally settled in Atlanta, USA.
Very active in conservation worldwide and the most knowledgeable about Africa
I've ever met or read. He took excellent care of us, was known by everyone
and chose the specific drivers he wanted to be with us for the entire trip.
There were only five of us, plus the drivers of course, in two vehicles so
was a truly amazing experience. We met each evening for drinks before dinner
(usually in our room or tent) and questioned him on anything and everything -
politics, local economy, tribal beliefs, agriculture, education, antiquities
and on and on. His absolute passion is and always will be Africa and I've
never been on a so enlightened journey before. We feel very fortunate as we
did see some people jammed into vehicles with weary looks on their faces and
obviously not at ALL enlightened. Ours was not the run of the mill safari
I've since learned. On the trip over he met us in Arusha as he was ending a
safari there, but flew with us on the way back as he was ready to go home to
Atlanta for a while. So we felt well cared for indeed
You could have reported your incident to the Tanzanian government tourist office and they would have taken action in what was obviously a scam, albeit a pathetic one. Although how you would know to do that I don't know. Picked that up from our guide. The government is very anxious for tourists to be happy. A member of our group said her credit cards had been stolen and the manager of the Serena Lodge we were in met with Richard (our guide) then promptly fired the young woman despite her protests of innocence. None of us believed she did anything and it was quite sad. Those jobs are very rare and very coveted. Once fired the woman would not be hired by any reputable tent camp or lodge and as you saw it's not a great country to get a good job in. Richard told us Americans are especially bad about reporting thefts only to discover they had misplaced an item. However the employee was by then fired and even when the complaining parties tried to get the person rehired it was to no avail and the decision is always absolute. So these things CAN go both ways. Most of the staff we encountered were Maasai and supporting families. Being accused of theft also brought down the wrath of their own people as the Lodge would never hire a family member of the accused person. I only speak of the Lodges and camps we stayed at. Richard warned us about Arusha though he didn't have to. Cities in third world countries do not a safe place make. Happy travels, Lyn Dallas


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Vitamin D – For Successful Dieting?Written by Wellness Club on March 25, 2014 – 12:32 pm -
By Nurse Mark
Vitamin D, once thought to have little more importance than for the prevention of rickets, is proving to be more valuable and even vital to our overall health and well-being with each passing day.
We have long maintained here at The Wellness Club that Vitamin D is far more than just a "vitamin" – it is actually a mis-named hormone with a wide-ranging variety of effects in our bodies.
Now it turns out that low Vitamin D levels are strongly associated with overweight and obesity, and that improving Vitamin D deficiency improves dieting success.
Dr. Shalamar Sibley, a researcher in the University of Minnesota Medical School conducted a clinical study that looked at the relationship between Vitamin D levels and obesity and the success of weight loss efforts and said:
"What is suggested here is that if you start out with an inadequate vitamin D level, it's possible that this might inhibit or impede your ability to lose weight on a reduced caloric diet,"
The researchers found that pre-dieting Vitamin D levels predicted weight loss success and that for every increase of 1 ng/mL in level of 25-hydroxycholecalciferol (the precursor form of Vitamin D) dieters lost almost a half pound more over the course of their diet. Further, for each 1-ng/mL increase in the active or "hormonal" form of Vitamin D (1,25-dihydroxycholecalciferol), dieters shed nearly a quarter pound more.
The researchers also found that higher baseline vitamin D levels gave greater losses of abdominal fat.
"Our results suggest the possibility that the addition of vitamin D to a reduced-calorie diet will lead to better weight loss," Dr. Sibley said.
So, what's our take-home message from this?
Vitamin D deficiency is common in the US population. Overall, 41.6 % of Americans are Vitamin D deficient, and that number skyrockets to 82.1% of African Americans and 69.2% of Hispanics.
Obesity has become an epidemic in America – more than one in every 3 Americans are obese, and again Blacks and Hispanics are disproportionately affected.
Vitamin D testing is available and is relatively inexpensive for the valuable information that it provides. Please learn more about a simple at-home Vitamin D test here.
Vitamin D supplementation is cheap – mere pennies per day – and can be started while awaiting the results of your Vitamin D levels test. Learn more about inexpensive and effective optimal-dose Vitamin D supplements here.
Can we promise you that taking Vitamin D will help you lose weight?
Don't be silly – of course we can't promise that! You can only lose weight if you consume less energy (calories) than you need, forcing your body to turn to it's "money in the bank" (fat stores) for energy.
But it is very clear from this research that Vitamin D deficiency plays a greater role in obesity that we ever suspected, and it is also quite clear that improving levels of Vitamin D leads to greater fat loss over the course of a weight-loss diet.
Finally, there is every other reason to ensure that your Vitamin D levels are plentiful – since Vitamin D deficiency is linked to many other health conditions, including high blood pressure, cardiovascular problems, kidney disease, and a higher risk of cancer including breast and prostate cancers.
Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts. Published: February 05, 2013DOI: 10.1371/journal.pmed.1001383
Vitamin D and weight loss, University of Minnesota, December 18, 2009
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We are considering layind down laminate in our lower level walk-out. The installer has said we should lay down 4 mil poly before laying down the underlayment which would be "quietwalk" sold by ******* which already has a vapor barrier....but he says it is not good enough and he would lay down the poly mil first. will this in anyway not alloy the quiet walk to do its job of dispersing moisture etc. Is this a good idea? Could the poly mil get all stinky or moldy from lying against concrete for many many yrs? Thanks
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Domestic manufacturing declines in January 2017
Manufacturing outside of free zone industries declined significantly in January 2017. The Monthly Manufacturing Activity Index (IMAM) showed that manufacturing had declined to 40.2 points as compared to manufacturing levels in December 2016 that had registered 50.2 points.
The Dominican Republic Association of Industries (AIRD) called the decline alarming. AIRD, which calculates the IMAM index, noted the downward trend is similar to that which occurred from December 2015 to January 2016 when manufacturing also declined, from 54.0 to 38.2.
Source: DR1, Elcaribe
Mar 2, 2017
Category: DR News |


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Philip Rogers, ""Tory Brontëë: Shirley and the ''man''"" (pp.141––175)
Charlotte Brontëë's politics in Shirley (1849) conform to the Tory principles implicit in the Duke of Wellington's responses to Chartist unrest and parliamentary reform. Brontëë's representation of Robert Moore's defense of his mill against Luddite rioters directly reflects Wellington's hostility to mob violence and also his strategy, as Commander-in-Chief, for suppressing the Chartist demonstration of 10 April 1848. The novel's defensive eulogizing of Wellington derides the liberal Manchester politics of Richard Cobden and the Peace Society as unmanly and unpatriotic. The Duke also serves subtextually as the model for changes that Robert and Louis Moore must undergo to make them suitable matches for Caroline and Shirley. Wellington consequently presides over the joint resolutions of the novel's domestic and political narratives. In this essay I challenge the view of Brontëë's politics presented by Elizabeth Gaskell, subsequent biographers, and manycritics——who, understandably wishing to view Brontëë's proto-feminism as evidence of political liberalism, have blunted the anti-democratic edge of her conservatism.
- ©© 2003 by The Regents of the University of California/Society. All rights reserved.


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As a definitive missive of social protest, the opening track presents the only vocals on the record: a cry for justice ("America, do you think about the lives that you have stolen?") followed by a statement of return ("America, we're gonna put you on the homeward bound train"). Cooper-Moore sings and plays the diddley bow (a rumbling bass instrument with a percussive attack) while Assif Tsahar adds intermittent cries on tenor saxophone. The loping shuffle has a catchy groove which works as a complement for Tsahar's shrill blowing, together laying out the emotional themes to which the duo will refer through the course of America.
Tsahar, whose reeds are familiar in out jazz circles for their energy and timbral range, takes multiple opportunities here to amble along the relative straight and narrow. The aptly titled "Back Porch Chill" offers a relaxed country blues, as does "Beyond The Years"; the two pieces identically entitled "Lament For Trees" unfold as sparse, open ballads with gentle overtones of swing. None of these tunes would work without Cooper-Moore's thoroughly grounded, organic playing on banjo, piano, mouth bow, and diddley-bow. Cooper-Moore has never been one for the spotlight and his obvious humility serves this project well.
But lest you get too comfortable, America shoots some fiery sparks as well. "12th Avenue Messengers" juxtaposes Tsahar's overblown, emotional horn alongside punchy drums and cymbal. It's a pointed and binding reminder of the record's message. "Wounded Knee" opens up in a similarly edgy, forward vein. Cooper-Moore, for all of his work on the folksy instruments, is in his true element on the piano, which he hammers mercilessly in swirls around Tsahar. Following an extended open stretch, both players close out the record with another emphatic blast.
For its open candor and unforced message, America is a near masterpiece. It's most certainly not for the faint of heart, despite a generally friendly feel, but that's all part of the message. This is unequivocally one of the finest records to emerge this year. (Even though friendly critics everywhere have assembled their lists before they even had a chance to hear the disc. Their loss, not yours, at least in this case.)
Track Listing: America; Back Porch Chill; Tuscarora's Cry; 12th Avenue Messengers; Lament For Trees; The Tortoise & The Buzzard; No Cracklin No Bread; Lament For Trees; Beyond The Years; Wounded Knee.
Personnel: Cooper-Moore: piano, diddley-bo, banjo, mouth bow, drum-skins & cymbal; Assif Tsahar: tenor sax, bass clarinet, classical guitar.
Title: America | Year Released: 2003 | Record Label: Hopscotch Records


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This is a very nice 3 star hotel so if you go don't expect 5 stars. The hotel properly and the beach are beautiful but the hotel has been neglected for a long time and they are just starting to pick up so there are very few people still at the resort. Mostly older couples in their 50 and 60. But it looks like they are having a good time. They go there for peace and quite and its exactly what you get.
There is so little people that you know them all and they know you. If this is what you like go for it, its a perfect place for that. Have in mind that there are no shops on site (but the town is very short taxi or bus ride away). There is no entertainment of any sort, and there is nothing to eat between meals. Food is fine, not the best, not too many choices. Really good fish everyday.
Staff is very friendly, rooms are large and clean.
We went there to see the island so we didn't spent much time at the hotel as there is not much to do but to enjoy the beach (which is amazing)and the sun. If that's all you need then it is a place for you.
- Reservation Options:
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- Also Known As:
- Grand Royal Antiguan Beach Hotel St. John`s
- Grand Royal Antiguan Beach Resort Antigua/Saint John Parish


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Last Updated: 1/19/2018 1:27 PM
Description for 208 SW 4TH Avenue Decatur, AL 35601
Level lot in SW Decatur. Great for building. Convenient to downtown Decatur. Priced below 2015 Tax appraisal.
Sold Price:
Sold Date:02/08/2017
Morgan County
Level lot in SW Decatur. Great for building. Convenient to downtown Decatur. Priced below 2015 Tax appraisal.
Listing Information
Public Water Service
Public Sewer
School Information
Room Information
Exterior / Lot Features
City Road, Level
Driving Directions
from the Beltline go east on Moulton street turn right on 4Th Ave. lot on the left. From 6Th Ave. or Hwy 31 from river bridge turn right on Moulton St cross railroad track left on 4TH ave. Lot on the left.
Financial Considerations
Listing Price History
Decatur Real Estate
Decatur is located in Alabama. Decatur, Alabama 35601 has a population of 55,437.
The median household income in Decatur, Alabama 35601 is $42,867. The median household income for the surrounding county is $45,341 compared to the national median of $53,482. The median age of people living in Decatur 35601 is 38.4 years.
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Do you know a special woman who loves reading? This list of 20 Mothers Day gift ideas for book lovers is going to be your shopping guide and secret weapon. From pillow covers, mugs, and more, you can't go wrong saving money with this list.
Do you know a special woman who loves reading? I'm not talking about the 1 or 2 books a month kind of gal (although she might enjoy some of the things on this list too.)
I'm referring to the woman who "sleeps-with-a-book-under-her-pillow" and puts Princess Belle to shame kind of a reading fan.
If this is you or someone else you know, then you won't want to miss this list of Mothers Day gifts for book lovers. There is definitely something for everyone.
Because let's be honest, there is something special about your favorite book. You might love one of the characters, relate to an event, or feel like you were meant for that particular time.
And it doesn't matter how many times you read the same book because it's like you're visiting with old friends again.
This post contains affiliate links at no cost to you. Thank you for your support of the Home Faith Family community. If you have any questions, please send me an email or read my disclosure policy here.
And let's not get started on the fun that comes when you meet someone who enjoys the same books as you. There is so much excitement and so much to talk about.
Now, if you're not a book fan and you're looking through this list trying to figure out what to do, let me put you at ease. The things on this list are really reasonably priced (I have 3 kids under 4, finances and keeping things cheap are a must in my house).
The first thing I would suggest is to find out the favorite book of the person you're giving the gift to. If you have no idea, then that's okay, take a look through this fantastic list and have fun shopping for one of your favorite gals (or yourself).
20 Mothers Day Gifts for Book Lovers
1. If the woman you're buying the gift for is sentimental (and if the relationship is appropriate) I HIGHLY recommend doing the following. Purchase a pack of library cards and write the words, "I've been checking you out" on them. Insert this cute card into the front of a new book you'll be giving her.
Magnetic bookmarks are AMAZING. And there are so many you can choose from that the possibilities are endless. Allow me to show you (this is where knowing your person's "favorites" comes in handy).
2. Floral i-clip magnetic page markers (set of 8)
3. Flip flop i-clips magnetic page markers (set of 6)
4. Scriptures and words of inspiration (Christian based – set of 6)
5. Music fans i-clips magnetic page markers (set of 8)
6. London or Victorian England fan magnetic bookmarks
7. Harry Potter magnetic page clips (2 packs)
8. Star Wars Saga magnetic page clips
9. "Always" Harry Potter throw pillow cover (this cover is so romantic and adorable. If your sweetheart is a Harry Potter fan you won't go wrong with this one).
10. "Happiness Can Be Found" Harry Potter pillow case.
For the book lover who also loves their hot drinks, then you'll definitely want to check out these HOT mugs.
11. "My Weekend is all Booked" mug.
12. "A Day Without Reading" mug.
13. "All I Care About + 3 People" mug.
14. "Hot Girls Read" mug.
15. "I Am Silently Correcting Your Grammar" mug.
If you're looking for some adorable and really reasonably priced bookends that will make your special lady smile, you'll definitely want to check these out.
16. Elephant nonskid cute pair bookends.
17. Fasmov Ferris Wheel Art nonskid bookends.
18. Adorable Owls nonskid bookends.
19. Eiffel Tower nonskid bookends.
20. Blue English telephone booth nonskid bookends.
I hope you enjoyed looking through this list. There are some really fun finds (who knew, right?!) I would love to know what you're currently reading or what your favorite book is. You can leave a comment down below. I'm excited to read your responses.


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Our friends over in America are voting today for their next President of the United States, and apparently they are curious about who Taylor Swift is voting for!
According to recent 'Google Trends' data, the No. 1 question people have googled in the last few hours is: "Who is on my ballot?" And also "Who is Taylor Swift voting for?"
Well, I don't think we'll ever know the answer to that one, Taylor has not made one single public comment about this Presidential election and has not thrown her support behind either candidate, though many other celebrities have. We DO know that she voted, though, earlier today she sent a tweet urging people to vote.
Today is the day. Go out and VOTE pic.twitter.com/NdJ0OeiuUH
— Taylor Swift (@taylorswift13) November 8, 2016
Hmm..who do you think she voted for?
Tune into our sister station AM 900 CHML for live election updates! @AM900CHML on Twitter!


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You can download full version of this game, install it to your Windows/PC and play Tales of Lagoona: Orphans of the Ocean any time you want.
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Golden Trails 2: The Lost Legacy
Love Chronicles: The Sword and The Rose
Mystery of the Missing Brigantine
Nightmare Realm Collector's Edition
Sandra Fleming Chronicles: The Crystal Skulls
Sphera: The Inner Journey
Tales of Lagoona 2: Peril at Poseidon Park
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I Feel Really Lost Sometimes
Personal Stories, Advice, and Support 82 People
Over the past few years I've really gotten intolearning aobut a variety of different things like nutrition, the state of the environment, (gah I'm blanking on more specifics atm somehow!) and many other things. I'm really focused on trying to stay positive and see the good in every situation, remember that material things...
bluemoon2121 22-25, F 1 Response 0 May 1, 2014
"No punishment anyone might inflict on us couldpossibly be worse than the punishment we inflict on ourselves by conspiring in our own diminishment." - Parker Palmer
bluemoon2121 22-25, F 1 May 11, 2015
Had a great day. With great people.Still am. I'm a little bit drunk though, and can't stop thinking about my dad. Less than a week will be 3 years since he passed away.. And I'm a mess. So hard to have fun when all I want to do is cry. I just miss him so much. We weren't that close- we only lived with him since...
bluemoon2121 22-25, F 2 Apr 19, 2015


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No-churn ice cream
Prep: 5 mins Plus freezing
Condensed milk is a magic ingredient when making no-churn ice cream - the end result will be creamy, smooth and not at all icy
Nutrition and extra info
- Freezable
Nutrition: per serving
- kcal456
- fat43g
- saturates24g
- carbs15g
- sugars15g
- fibre0g
- protein3g
- salt0.13g
Save to My Good Food
- ½ a 397g can sweetened condensed milk
- 600ml pot double cream
- 1 tsp vanilla extract
Put the condensed milk, cream and vanilla into a large bowl. Beat with an electric whisk until thick and quite stiff, a bit like clotted cream. Scrape into a freezer container or a large loaf tin, cover with cling film and freeze until solid.
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Comments, questions and tips
14th Nov, 2017
I have tried this recipe and find it to be excellent. Those who complain that it is to 'fatty' should perhaps try a lighter alternative to double cream - I use whipping cream, and those who complain that it is too sweet should perhaps use less condensed milk and add in a fruit puree or a fairly bitter honey. My one wish would be for some addition that would help to achieve a softer freeze and wonder if perhaps the addition of one teaspoon of glycerine (as is common to keep Royal Icing from setting like a rock) would work?
27th Sep, 2016
I found it was like eating sugar although I didn't have an electric whisk at the time of making it, even if I did I don't think it would have made a difference to the sweetness. I did mix it all in well. I will try again with a electric whisk but I'm very tempted to stay with The Food Network for my recipes after this


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Canada: The Arsenal of Democracy. How the War Changed our International Identity . Democracy. Def'n : the political orientation of those who favor government by the people or by their elected representatives
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How the War Changed our International Identity
What does democracy mean to you, knowing so many Canadian soldiers gave their lives for the preservation of this process?
Value of Canada's gross domestic product (total value of all goods and services produced)
World War II is often called the good war?
It was a good war. I'm not talking about a good war from the standpoint of a high moral purpose. If going out and killing millions of Germans to get Hitler off his pedestal is a high moral purpose, then I'm all for it.
But it was a good war for Canada too, because it made us a great nation. I mean it showed what we could do. We just weren't a bunch of wheat farmers and Nova Scotia fishermen and lumberman in BC. We were a nation. A big and tough and strong nation.
Totalitarianism U-Boats
Mussolini Convoys
Hitler Italian Campaign
NAZI Operation Overlord/ D Day
Anti-Semitism V-E Day
Blitzkrieg Pearl Harbour
Luftwaffe POW
Battle of Britain V-J Day
Dieppe RCAF Women's Division
Enemy Aliens Internment Camps
Holocaust Final Solution
Auschwitz Tehran
Yalta Potsdam


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DT301S and DT311H are two Windows 10 hybrids
DT Research DT301S and DT311H specifications are now available. These two tablets are hybrid windows 10 tablets that come with detachable keyboard. These are super strong tablets that can withstand falls, harsh conditions, dust and water. DT301S specs include 10.1 inch touch screen packing full HD resolution and powered by sixth generation Intel Core i5


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The Naismith Memorial Basketball Hall of Fame is an American history museum and hall of fame, located at 1000 Hall of Fame Avenue in Springfield, Massachusetts. It serves as the sport's most complete library, in addition to promoting and preserving the history of basketball. Dedicated to Canadian physician and inventor of the sport James Naismith, it was opened and inducted its first class in 1959. As of the induction of the Class of 2016 on September 9, 2016, the Hall has formally inducted 354 individuals.
Shaquille Rashaun O'Neal (born March 6, 1972), nicknamed Shaq, is a retired American professional basketball player and former rapper who is currently an analyst on the television program Inside the NBA. Listed at 7 ft 1 in (2.16 m) tall and weighing 325 pounds (147 kg), he was one of the heaviest players ever to play in the NBA. O'Neal played for six teams throughout his 19-year NBA career.
Following his career at Louisiana State University, O'Neal was drafted by the Orlando Magic with the first overall pick in the 1992 NBA draft. He quickly became one of the best centers in the league, winning Rookie of the Year in 1992–93 and later leading his team to the 1995 NBA Finals. After four years with the Magic, O'Neal signed as a free agent with the Los Angeles Lakers. They won three consecutive championships in 2000, 2001, and 2002. Amid tension between O'Neal and Kobe Bryant, O'Neal was traded to the Miami Heat in 2004, and his fourth NBA championship followed in 2006. Midway through the 2007–2008 season he was traded to the Phoenix Suns. After a season-and-a-half with the Suns, O'Neal was traded to the Cleveland Cavaliers in the 2009–10 season. O'Neal played for the Boston Celtics in the 2010–11 season before retiring.
O'Neal's individual accolades include the 1999–2000 MVP award, the 1992–93 NBA Rookie of the Year award, 15 All-Star game selections, three All-Star Game MVP awards, three Finals MVP awards, two scoring titles, 14 All-NBA team selections, and three NBA All-Defensive Team selections. He is one of only three players to win NBA MVP, All-Star game MVP and Finals MVP awards in the same year (2000); the other players are Willis Reed in 1970 and Michael Jordan in 1996 and 1998. He ranks 7th all-time in points scored, 5th in field goals, 13th in rebounds, and 7th in blocks. Largely due to his ability to dunk the basketball, O'Neal also ranks 3rd all-time in field goal percentage (58.2%). O'Neal was elected into the Naismith Memorial Basketball Hall of Fame in 2016.
In addition to his basketball career, O'Neal has released four rap albums, with his first, Shaq Diesel, going platinum. He has appeared in numerous films and has starred in his own reality shows, Shaq's Big Challenge and Shaq Vs.. He currently hosts The Big Podcast with Shaq.
2016 Shaquille O'Neal Hall of Fame Ring
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Council of Architecture (COA) has postponed the registration date for NATA 2017 to January 4 now. According to COA officials, the registration or applications for NATA 2017 will now begin from January 4, 2017 onwards, whereas earlier registration of NATA 2017 was supposed to commence from December 24, 2016. The council has released a revised brochure for NATA 2017, wherein it has also extended dates related to some other events of the entrance test for admissions to B.Arch programme. As per the new dates, aspiring candidates can now fill up the application form of NATA 2017 till February 2, 2017 (11.59 pm). Candidates can upload the images till February 3, while the fee payment for the entrance exam can be done till February 4.
The exam conducting authority has also extended the date for printing the confirmation page and correction window. According to the revised dates, the applicants can now print their confirmation page till February 28, 2017 (11:59 pm), while the correction window (based on Council feedback and self-induced errors) along with uploading correct testimonials ca be done from February 20, 2017 (10:30 am) to February 24, 2017 (11:59 pm).
However, the dates related to the entrance exam, admit card and result availability have not been revised. Apart from the dates, COA has also made some changes in the application procedure. Also, clarification on NATA score validity has been released.
To go through the latest changes in application form, Click Here
Click Here to know about the score validity of NATA.
National Aptitude Test in Architect (NATA) 2017 will be conducted by the Council of Architecture (COA) on April 16, 2017. As per COA officials, for admission year 2017-18, NATA will be a single-day test. Unlike previous years, NATA 2017 will be conducted in offline (Pen & Paper) mode. Till 2016, NATA would be conducted in multiple-window in two phases from April to August. However, it will be just a single-day test for admission year 2017-18. NATA 2017 will be conducted for admissions to 5-year B. Arch programmes across its participating institutes.
Stay tuned to engineering.careers360.com for more news and updates on NATA 2017.


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Global support For Palestine UN bid - 150 countries to vote YES
In a few hours the UN body of nations will vote on the Palestine bid. 150 nations out of 193 will be voting YES. Show your support and solidarity and vote as a global concerned citizen and click:
More than 1.7 million signatures have been collected so far. Let's help Avaaz reach 2 million in the next few hours.
Supporters are now helping to
Campaign closed
The Knesset approved the first reading of the infamous Prawer Plan - a blueprint for removing 40,000 Bedouin people from their ancestral homeland. This massive violation of human rights just got a big step closer to reality. But it's not too late to stop it: if we act now, we can make a difference. We can't wait for one person to do everything for us. If each one of us take one small act (take a…
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Some Asia-based equity investors are sitting on the sidelines this week, or switching to emerging market bond investments, as political turmoil in the West spooks the buyside. Investors are switching allocation to cash bonds, as some EM debt--such as Brazilian government bonds-- provides solid yields, while investments in ...
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Each week I like to say thank you to those that linked up the previous week.
Over on Autism Mummy, little D helped to make Mrs E's Bran loaf, I really have to give this a try, what a great way of getting some extra fibre in your diet.
On Fun For Families even the lego helped out in the kitchen and they made some Awesome Almond Cookies.
Our regular little chef, The Beautiful Miss T from The Beesley Buzz (just take a look at the first photo, adorable) made some tasty looking Panko Chicken Nuggets.
Thank you for linking up everyone, I hope some more decide to join us this week, it's so inspirational sharing our recipes and enjoying the help (and I use that word lightly, lol) from our kids in the kitchen.
Toasted Sandwiches.
You can find out more about Kids in the Kitchen by clicking here.


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Just as Mark Zuckerberg says in his company's IPO Roadshow video: I grew up with the internet. I remember in college when I first got access to Facebook. We were friending everyone, and you began to say, "Facebook me" at parties whenever you met someone new. The concept of "friend" changed overnight…you counted everyone.
Over the past few years, the world in regards to Facebook has changed. We began to see a shift away from the sense of ownership belonging to those of us with profiles back to the business itself. Facebook is a marketing engine and it has to make money. We, as the users, are the product.
As Facebook goes IPO, we may see yet another shift. People who do not consider themselves business people may begin to talk about the business of Facebook. People may stop to learn about roadshows or IPOs, about market caps and shareholders. People might begin to really think about how Facebook monetizes "friendship," and how a personal profile changes how other businesses interact with them.
You don't have to have an MBA to be savvy about business. This is a good time to stop and think about how something you may use every day changes the face of Wall Street. Social media has brought the business world right to your doorstep, and you have an opportunity to consciously consider what that means to you.
Launch Facebook IPO Roadshow Video.


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Hoppertunity Seeks San Antonio Repeat
Karl Watson, Mike Pegram, and Paul Weitman's Hoppertunity will look for his second straight score in the $300,000 San Antonio Stakes (G2) Feb. 4 at Santa Anita Park.
Karl Watson, Mike Pegram, and Paul Weitman's Hoppertunity will look for his second straight score in the $300,000 San Antonio Stakes (G2) Feb. 4 at Santa Anita Park.
Without a clear favorite among the five entered in the $150,000 Robert B. Lewis Stakes (G3), trainer Doug O'Neill, who has three of the five, is hopeful any or all of his horses will seize an opportunity to move forward.
Gov. Andrew Cuomo quietly squashed a NYRA restructuring bill with a "pocket veto."
After three straight dominating wins, including an 11 1/4-length score in the Jerome Stakes (G3) Jan. 2 at Aqueduct Racetrack, 3-year-old El Areeb is back at Aqueduct for a crack at the $250,000 Withers Stakes (G3) Feb. 4.
Pegasus World Cup Invitational, Houston Ladies Classic, Hurricane Bertie, John B. Connally Turf Cup, La Prevoyante Handicap, W.L. McKnight Handicap, and more.
After an in-depth review of its racing medication rules relative to the Association of Racing Commissioners International's recommendations, a Kentucky council is recommending penalty classification changes for a pair of medications.
Atlanta Falcons' starting tight end Jacob Tamme is having a ball as a partner, along with fellow NFL star Wes Welker, in the Hat Creek Racing partnership run by Gatewood Bell.
John Oxley's reigning juvenile male champion Classic Empire makes his anticipated seasonal bow in the $350,000 Lambholm South Holy Bull Stakes (G2) against eight rivals at Gulfstream Park.
With positive returns in handle, attendance, television ratings, and the on-track experience, the Pegasus World Cup (G1) figures to remain in South Florida at The Stronach Group's Gulfstream Park.
Three Rules, the top Florida-bred juvenile last year and winner of five races at Gulfstream, will make his 2016 debut Feb. 4 in the seven-furlong Swale Stakes (G2).
Crestwood Farm's grade I-winning miler Jack Milton got his first foal Jan. 30, when a colt bred by David Lavoie was born on a farm near Ocala, Fla.
With her five-furlong move over the turf at Palm Meadows Training Center Feb. 1, Tepin again succeeded in sparking renewed hope that Plan 'A' can come off as scheduled.
The European Pattern Committee implemented a five-year ban on downgrading any group race of 13 furlongs or more.
Lauded as a "game changer" by organizers from Racing NSW and the Australian Turf Club, the 1,200-meter (six-furlong) race offers the same shareholder buy-in concept pioneered by The Stronach Group, which organized the Pegasus.
Steve Barham (Oregon), Bennett Liebman (New York), and Allan Monat (Illinois) will comprise the independent panel the Association of Racing Commissioners International has formed to certify compliance with key integrity standards each year.
The Barking Shark, a West Coast fan favorite who finished second in seven stakes, two grade 1s, died earlier this year of colic at the Glen Ellen Vocational Academy in California. The gelding by Naevus was 24.
Inaugural Pegasus World Cup generated sufficient buzz
With short yearlings a hot commodity at winter mixed sales, the stallion with the most foals of 2016 entered at the Feb. 6-7 Fasig-Tipton Kentucky auction is San Pablo, a son of Jump Start who who or placed in 16 of 19 career starts.
Recent EHV-1 (Equine herpesvirus 1) outbreaks have again focused attention on this nasty disease.


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Fighting erupted between two groups after Imam of Hari mosque in Batla House stopped a few youths from preaching that Imam Mehdi has arrived after Zohar prayer, according to eyewitnesses.When the Imam told them to sit down and not to spread rumours in the mosque and misguide others, the youths got agitated and argued with the Imam, said residents. "Following which fighting erupted as others also turned up. The misguided youths started pelting stones. A few people got hurt. They were chased and beaten up. Later on they were taken to the trauma centre. But they filed a complaint against the Imam," residents were heard talking among them outside the police station where hundreds gathered seeking arrest of the youths.
As words spread in the locality with announcement being made from mosque urging people to turn up at Jamia Nagar police station, many people turned up and demonstrated peacefully. Former Okhla Congress MLA Asif Md Khan also turned up at the station and said: "As Ramzan is coming it is important that peace is maintained in the locality. A group is trying to spread Mehdism in the locality hurting people's sentiments. The SHO has assured us that the youth will be arrested soon," Khan told the media assembled at the police station.
Another resident pointed out that the wayward youths have got some supporters in the locality too and they are fast spreading their wings by misguiding youths and we will never tolerate this.
AAP youth leader Zia Chaudhary also arrived on the spot.


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Longman Writer, The: Rhetoric, Reader, Research Guide, and Handbook
- Edition: 7th
- Format: Paperback
- Copyright: 01/01/2009
- Publisher: Longman
- Newer Edition
Note: Not guaranteed to come with supplemental materials (access cards, study guides, lab manuals, CDs, etc.)
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"Clear, step-by-step writing instruction, ample annotated student essays, and extensive practice opportunities for writing have made "The Longman Writer" one of the most successful methods-of-development guides for college writing. " Created by the authors of the best-selling "Longman Reader," the text draws on decades of teaching experience to integrate the best of the "product" and "process" approaches to writing. Its particular strengths include an emphasis on the reading-writing connection, a focus on invention and revision, attention to the fact that patterns blend in actual writing, and an abundance of class-tested activities and assignments-more than 350 in all.


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the Bad Plus, "Anthem of the Earnest" from Suspicious Activity (2005). Jazz' power trio in full stride.
Joe Henderson, "Pedro's Time" from Our Thing (Blue Note, 1964). Classic mid-60s BN date with Kenny Dorham on trumpet and Andrew Hill, piano in addition to the leader on tenor sax.
Dave Holland, "The Watcher" from Prism (2013). Pete's nominee for favorite record (of ones I heard) from '13, featuring the great bassist and a band including Kevin Eubanks (former Tonight Show band leader and brother of Robin, trombone player and Dave Holland Quintet member for years). Early 70s style fusion with thundering drums, distorted keyboards, and roaring guitar.
Django Reinhard, "The Blue Drag". The Basque guitarist recorded in the 30s.
Pat Martino, "East!" — extended (12 min.) jam on title track of a 1968 album for the guitarist who established a fine career in the 60s and 70s, suffered brain surgery and resultant amnesia in 1980, and re-learned guitar listening to his old records.
Stephon Harris / David Sanchez / Christian Scott, "Black Action Figure" from Ninty (2011). Best song on a great album made by young American musicians (vibes, sax, trumpet respectively) traveling 90 miles south to record with Cuban rhythm section.
Roland Kirk, "Volunteered Slavery" from the 1969 Atlantic album of the same name. Multiple horns played simultaneously, odd but cool lyrics, and an extended quote from "Hey Jude".
Steve Coleman and Five Elements, "Lymph Swag (Dance of the Leukocytes)" from Functional Arryhthms (2013). Odd album concept of tunes named for body functions. But cool music.
Larry Coryell and Eleventh House (1974). Channeling Mahavishnu Orchestra on "Low-lee-tah". Randy Brecker on trumpet giving the group a unique fusion sound.
Double Image, "Rodney's Dream of Fantasy and Self-Fulfillment" (1977). Distinctive sound with double vibes.


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Operational Report Board of Directors Meeting July 28, 2007 Garden Grove, California. Neal J. Couture, CPCM Executive Director. Year in Review: 2006-2007 Financial. Increased total revenue by 9% from 2005-2006, from $5.033 million to $5.494 million.
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Neal J. Couture, CPCM
Executive Director
Comparable flight availability and prices.
Comparable hotel facilities.
Foreign travel requirements for most attendees, may require special employer approvals.
85% attendees are members, but we have only 43 members in Canada.
Weather concerns for April.
Does not serve current strategic objectives.Action Item: World Congress in Canada


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We have ability to supply all kind of agricultural products specially:
Australian Trading Pty Ltd has positioned itself as a supplier of the high standard Agricultural products. We focus on consistently supplying speciality markets with competitive price. We aim to supply our customers with a closer link to their quality and end requirements, all over the world especially in Middle East and Asia.
Australian Trading Pty Ltd supplies Agricultural products from Australia, South America, Europe and Asia.
Australian Trading Pty Ltd as an entity has been approved as a counterparty of some Australian leading grain suppliers by DFAT (The Department of Foreign Affairs and Trade ) which is charged with advancing the interests of Australia and its citizens internationally, furthermore has been approved as a creditor of some Australian leading grain suppliers and as a local company has established strong connection with Australian main elevators which allow us to offer Australian grains (specially wheat) with competitive prices. Our abilities in Australia has made us difference among competitors in Middle East to supply agricultural products and we can offer better quality with competitive price to our buyers.
South America:
Australian Trading Pty Ltd has a local representative in Brazil allows us to buy agricultural products from local suppliers which supply for major international grain companies .
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Europe, Kazakhstan & India:
Based on our well established network with local suppliers and elevators in Europe, Kazakhstan and India, we have the opportunity to provide agricultural products with high quality and reasonable price for our clients.


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Dead Voices On Air
Some days are good and some days are really good… and some days your tape recorder doesn't work and you're left with nothing but the hastily written notes that were meant to make it easier to find the interesting passages from the interview. Guess what sort of day I had…
On the other hand there are pacifying weapons that can be used to combat stress. Albums that can draw you away from all those concerns and guide you to a worry-free environment where pressing matters are intangible and you're able to do attend to some much needed emotional healing.
It's hard to put into words the contributions that Mark Spybey has made to the experimental music scene. As a member of the legendary ensemble :Zoviet France he was involved in making some of the most fiercely original ambient music to flow from speakers. As well, :Zoviet France is credited with being one of the genre's few acts that were more than capable of proving their mettle on stage.
When the group separated a few years back Spybey ultimately settled in Vancouver, Canada more for the scenery than out of nostalgia for the city's famed experimental scene. Having recently experienced Vancouver for the first time it's not hard to understand… Still, local musicians have been included in Spybey's Dead Voices On Air project. The new album (Piss Frond) features members of 54.40 and Copyright, while previous releases have featured cEVIN Key from Download (a project that Spybey also worked on for a time). This isn't to imply that collaborations with artists in other locales don't occur, as the Fire In Bronx Zoo (with Not Breathing's Dave Wright) can attest to. It's just that they're done differently, often using a series of tape trades where contributions are mailed in.
Back to Piss Frond, though. The 2-disc set represents two differing styles. The first disc contains the collaborations mentioned above, while the second is solo work. The former is a somber and contemplative work full of striking sounds and lyrics that bring pause from the listener. The track Sulphur in particular generates an odd mood and is very effecting emotionally. The latter is instrumental and one of the best ambient discs I've heard in a very long time. Rich and textured soundscapes that can function as background music or as a hypnotic listening experience. More information, sound clips and liner notes can be found at http://www.dvoa.com/pissfrond/.
Spybey's current work is preparing for an upcoming tour, which will feature himself, and James Plotkin (Old) supporting former Can members Damo Suzuki and Michael Karoli. As a veteran live performer Spybey goes out of his way to put a show together. When asked about the performance Spybey is quick to point out differences between the improvisational nature of ::Zoviet France and his current performing style, which has a firmer base in established material, while still leaving more than enough room to change things up from night to night. The end product is much more consistent and makes for a more reliable performance, often despite the unpredictability of live situations.
When asked about the sort of instruments that are used on stage I'm somewhat surprised to hear that a lot of them are geared towards children. Although after some explaining, it all becomes clear. Ease of play and ruggedness are factors (i.e.: an 8 year old can be harder on a piece of equipment than a baggage handler), as well as an awareness of what works on stage. Spybey believes that a physical stage show is a necessity, that sitting behind a rack of synthesizers just isn't going to be as captivating as something kinetic.
On a more philosophical note he likes the idea that other musicians may be shocked or even intimidated to see what his sounds are made with. It's all part of his concept to develop abstraction… things that sound complex turn out to be made with simple devices. This strategy also proves another point that he feels strongly about: music isn't exclusive, it belongs to everyone… and in the case of Dead Voices On Air, it's something that we should all keep within reaching distance.
See http://www.dvoa.com for discography and further information.


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- 2012 CLH Rankings
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Tag Archives: Kentucky Wildcats
DeMarcus Cousins dominates UK vs UNC Alumni Game
DeMarcus Cousins is coming off of a dominating season that saw him make the NBA All-Star Team for the first time and appears to have been putting in some work during the off season. While the enigmatic post has all … Continue reading
Posted in Articles, College Tagged Big Blue Nation, DeMarcus Cousins, Kentucky, Kentucky Wildcats, UK vs UNC Alumni Game Leave a comment
2015 Kentucky Recruiting Class Video
John Calipari has been the talk of the town this past week with his huge win over Kansas. His "platoon" system has caught the attention of fans and players alike, proving that the truly can play a rotation of ten … Continue reading
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The Harrison twins are ready to lead #1 Kentucky
Expectations were high coming into their freshman year at Kentucky. In fact, they were nearly impossible to live up to for the Harrison twins. However, they got things going and by the end of the year, they had let UK … Continue reading
Tyler Ulis yanks defender at UK Blue/White scrimmage
For what Tyler Ulis lacks in the size department, he definitely makes up with his game. Constantly proving doubters wrong since the first time that we saw him in middle school, Ulis looks like he's going to do that yet … Continue reading
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2014 Kentucky Big Blue Madness Top Plays
Though Kentucky's 2014 Big Blue Madness merely consisted of two nine minute halves and a little three on three, there was no shortage of excitement for the 24,000 plus in attendance. The nation's #1 team has at least six potential … Continue reading
Drake introduces Coach Calipari at 2014 Kentucky Big Blue Madness
Kentucky's Big Blue Madness doesn't have all of the skits and dancing that many others do, but UK keeps it relatively simple. As opposed to waiting two hours to get to the men's hoops, the Wildcats kept it short and … Continue reading
Karl Towns shows takes athleticism to new level at 2014 Nike Hoop Summit
Karl Towns has always been known as a special prospect, but he took things to another level at the 2014 Nike Hoop Summit. Never considered a bad athlete, Towns exhibited much more explosively and was vastly improved running the floor … Continue reading
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Tyler Ulis is Kentucky's next floor general
Tyler Ulis has long been one of the more productive point guards in the class, but the major questions that centered around him revolved almost exclusively to his height. Dating back to his days in Lima, Ohio when he ran … Continue reading
Tyler Ulis captivates crowd at McCracken County Festival of Hoops
Tyler Ulis has been a fan favorite dating back to his middle school days with Mike Duncan's Ohio Basketball Club and with his continued improvement, has become one of the finest lead guards in the nation. At a mere 5'9, … Continue reading
Willie Cauley-Stein is putting NBA potential on full display
Willie Cauley-Stein has long been known as a player with all of the tools, but his level of production didn't always mirror that throughout his high school career. Now a sophomore at Kentucky, Cauley-Stein is putting it all together and … Continue reading
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Guild Member Profile
Keith Thomas
Technical writer for trade and popular press, including The Brewer International, Zymurgy, international publications, CAMRA publications and local newspapers. Specialisms include brewing technology, yeast and brewery microbiology, beer purity, flavour analysis and history of brewing technology. Co-ordinator of training courses in brewing, dispense and flavour analysis. Winner of the Travel Bursary in the Guild's Beer Writer of the Year Awards 2001. Faculty of Applied Sciences, University of Sunderland, Chester Road, Sunderland, SR1 3SD. 0191 515 2530 (w) 0191 549 9450 [email protected] Website: www.brewlab.co.uk


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Remember when the Internet was something you tapped into from home, and your car was something that got you from here to there? Now, of course, we hope can update a Facebook page or check a portfolio while cruising the interstate.
The market for Web-enabled electronics in cars is expected to skyrocket, and by 2017 more than 86 percent of the vehicles on the road will be connected, every new car sold in the U.S. will be connected.
It's a sign of the times we live in where personal wireless connectivity is kind of a part of life, We just want to be able to get such data out of the cloud wherever we are and whenever we want it. Though I have owned a Tesla for over an year now – it still intrigues me in many ways. Every time a a new software update is beamed down to the car – the anxiety to know about the new features take over. It's like owning a new gadget every few months. Many people have asked me if I like the car – my answer – "it is now part of my everyday life, it will be very hard to go to another car unless they can make it so connected and convenient."
And for the skeptics – Yes it is a 100% electric car and it goes 250 miles on a charge. It takes only 2 hours to charge it back up using a home charger!!!
Sharing photos of my own car here….!


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Learn how to update old furniture, take part in Upholstery Lessons > Please base article around this
Got a saggy old chair that's seen better days? Feel attached to the furniture, been through a lot together, finding it hard to throw the chair away? The good news is, you don't have to, simply give the chair a new lease of life and take a few Upholstery Lessons that'll teach you how to renovate old furniture items rather than having to throw them away.
Secure a spot in Upholstery Classes and take part in highly entertaining Upholstery Lessons that teach you how to breathe life into antiquated furniture. They're fun and informal and you'll leave the Upholstery Lessons with a wide range of new skills.
It's such a shame to throw away old furniture that could have many years of life left in it so why not learn how to makeover chairs, stools or sofas on workshop-based Upholstery Lessons?
When do Upholstery Lessons take place?
The highly informative Upholstery Classes are run throughout the year and you can choose half day, full day or evening classes that run over the course of six weeks. The beauty of Upholstery Lessons is they are taken at your pace and you'll learn how to upholster old furniture to a professional standard.
During the Upholstery Lessons pupils are taught a wide range of techniques including webbing, springing, stuffing and stitching, re-covering and deep buttoning as well. Go into the Upholstery Lessons as a novice and you'll leave with newfound knowledge taking furniture back home with you that's been totally renovated.
What do you need to take to the Upholstery Classes?
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Julia Roger - About Author:
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text: So the game MineCraft (am I allowed to name games like this? If not I'll edit it) isn't installing properly on my Knoppix and wanted to know if anybody else had any idea why? I think it works fine on Ubuntu, and I'm going to try installing it on a virtual Ubuntu computer to check. Anybody know anything, or a possible fix? :confused:


text:
The mechanisms underlying the modulation of both the malaria-specific immune response and the course of clinical malaria in the context of concomitant helminth infection are poorly understood. We used multiparameter flow cytometry to characterize the quality and the magnitude of malaria-specific T cell responses in filaria-infected and -uninfected individuals with concomitant asymptomatic Plasmodium falciparum malaria in Mali. In comparison with filarial-uninfected subjects, filarial infection was associated with higher ex vivo frequencies of CD4+ cells producing IL-4, IL-10, and IL-17A (p = 0.01, p = 0.001, and p = 0.03, respectively). In response to malaria Ag stimulation, however, filarial infection was associated with lower frequencies of CD4+ T cells producing IFN-γ, TNF-α, and IL-17A (p < 0.001, p = 0.04, and p = 0.04, respectively) and with higher frequencies of CD4+IL10+T cells (p = 0.0005). Importantly, filarial infection was associated with markedly lower frequencies of malaria Ag-specific Th1 (p < 0.0001), Th17 (p = 0.012), and "TNF-α" (p = 0.0008) cells, and a complete absence of malaria-specific multifunctional Th1 cells. Filarial infection was also associated with a marked increase in the frequency of malaria-specific adaptive regulatory T/Tr1 cells (p = 0.024), and the addition of neutralizing anti–IL-10 Ab augmented the amount of Th1-associated cytokine produced per cell. Thus, among malaria-infected individuals, concomitant filarial infection diminishes dramatically the frequencies of malaria-specific Th1 and Th17 T cells, and alters the quality and magnitude of malaria-specific T cell responses.
Despite their complexity, parasitic helminths are the most prevalent pathogens in resource-poor countries, especially in sub-Saharan Africa where soil- and vector-transmitted helminths affect ∼500 million people (1). Although helminths often cause chronic infections that rarely result in mortality, they do induce a regulatory environment that can influence the efficacy of vaccines and can modulate the host immune response to other pathogens (2). Although early or acute infection with tissue-invasive helminth parasites, such as schistosomes or filariae, are associated with proinflammatory innate responses and with a nonpolarized or mixed type 1/type 2 adaptive responses, as these infections become patent (when egg laying occurs or microfilariae appear), type 1 responses are markedly downregulated, and there is an expansion of those cells mediating type 2 responses (3, 4). With more longstanding infection, the dominant parasite-specific immune response is one characterized by the induction of regulatory networks mediated in large part by IL-10–producing adaptive regulatory T cells (aTregs)/Tr1 cells and natural regulatory T cells (nTregs) (5, 6). These regulatory networks induced during chronic helminth infection (particularly schistosome and filarial infections) have been implicated in both the modulation of parasite-specific immune responses and responses to nonparasite Ag, the latter through bystander effects (so-called spillover suppression) (7). Not only does the helminth-induced attenuation of the immune response extend to nonparasite soluble Ag, but also to responses to orally and parenterally administered vaccines (8–10), other infectious diseases (e.g., Helicobacter pylori, Mycobacterium tuberculosis, Plasmodium falciparum, and HIV) (11–14), and aeroallergens (15).
Of the diseases whose immune responses are modulated by the presence of concomitant helminth infection, malaria holds primacy as the infection affects >2 billion people worldwide resulting in >500 million clinical cases that lead to death in 1–2 million people annually (16, 17). Ninety percent of the clinical episodes and deaths occur in sub-Saharan Africa (16, 17). Sub-Saharan Africa bears not only the heaviest burden of malaria, but the region also has the greatest prevalence of the neglected tropical diseases, particularly soil- and vector-transmitted helminths (1). As in most tropical regions of the world, malaria and helminth infections in Africa often occur in the same host (18) with the outcome and/or control of one infection being influenced by opposing responses induced by the other (2, 19, 20). Despite the conflicting data with respect to clinical outcomes of malaria in helminth/malaria coinfection (13), it is clear that helminth infections [particularly those that are tissue invasive (e.g., filariae)] induce regulatory immune responses that modulate responses to a variety of pathogens, including malaria (21–23). Indeed, in a recent study in a malaria/filaria coendemic area of Mali, we showed that chronic filarial infection was associated with an IL-10–dependent diminution of malaria-specific production of IL-12p70, IFN-γ, and IP-10 (22), cytokines known to play an important role in mediating immunity to malaria (20, 24–28).
The advent of multiparameter flow cytometry and the development of polychromatic Abs for intracellular staining has led not only to the characterization of multifunctional Th cells and their association with disease outcomes, but also to the elucidation of the correlates of protection for diseases involving cellular immune responses (29, 30). Thus, in this study, we sought to use multiparameter flow cytometry to characterize the malaria-specific T cell compartments (effector and regulatory T cells [Tregs]) and to determine definitively the source(s) of IL-10 in the context of malaria/filaria coinfection. In so doing, we found that the presence of a patent filarial infection modulates the magnitude and quality of effector T cell responses to malaria Ag stimulation and does so through the expansion of both nTregs and aTregs. Moreover, we found that CD4+CD25−/low FOXP3− T cells were the major source of IL-10 that, in turn, was primarily responsible for the modulation of effector T cell responses.
Materials and Methods
Study population
The study was carried out in Tienéguébougou and Bougoudiana, two villages situated ∼105 km northeast of Bamako, Mali, in a malaria-endemic area with seasonal transmission. The study (NCT00471666) was approved by the National Institute of Allergy and Infectious Diseases Institutional Review Board and the Ethical Committee of the University of Mali, and informed consent was obtained from all participants in the local language.
Detection of filarial infection
Before the start of the study, screening of adults in the villages showed the prevalence of circulating Wuchereria bancrofti filarial antigenemia (TropBio, Townsville, Australia) (31) to be 53% in Tienéguébougou and 36% in Bougoudiana. The prevalence rate of Mansonella perstans microfilariae by calibrated thick smear examination was 62% in Tienéguébougou and 63% in Bougoudiana. At the time of the study, stool examinations revealed only Hymenolepis nana in four individuals and Enterobius vermicularis in one individual. No other helminth eggs or larvae were detected, likely reflecting the administration of single-dose mebendazole and praziquantel 6 wk before the study given to treat potential confounding schistosome and intestinal helminth infections.
The filaria-positive group (Fil+) was defined as positive for circulating filarial Ag and/or having either W. bancrofti or M. perstans microfilariae on examination of nighttime blood smears. The filaria-negative group (Fil−) had neither circulating Ag for W. bancrofti nor microfilariae of either W. bancrofti or M. perstans.
Detection of asymptomatic malaria
Malaria parasites were detected by microscopy using routine Giemsa-stained thick and thin blood smears. Slides were read in two different laboratories at the Malaria Research and Training Center Bamako by two well-trained biologists. Discordant results were reconciled by a third expert microscopist. In addition to parasitemia, the level of circulating P. falciparum histidine-rich protein 2 (PfHRP2) was determined using a commercially available PfHRP2 ELISA kit (Standard Diagnostics, Kyonggi-do, Korea) using a modified protocol as previously described (32). Recombinant PfHRP2 used to set a standard curve was a gift from Dr. D. Sullivan (Johns Hopkins Malaria Institute, Baltimore, MD). Asymptomatic malaria was defined as positive for either P. falciparum trophozoites by microscopy or positive for PfHRP2 ELISA and no symptoms. For this study, 28 volunteers between 11 and 18 y of age with asymptomatic malaria (13 Fil− and 15 Fil+) were enrolled before the start of the malaria transmission season.
Whole-blood culture.
Heparinized blood was collected from study subjects in the villages and transported at ambient temperature to the laboratory in Bamako for processing. Whole blood (1 ml) was used for leukocyte counts and differentials using an automated cell counter (Beckman-Coulter). The remaining blood samples were diluted 1:1 in RPMI 1640 supplemented with penicillin/streptomycin (100 U/100 μg/ml), lP. falciparum schizont lysate (PfSL) was prepared as described previously (22) and used at 104 infected RBCs/ml final concentration. One milliliter of diluted blood samples was left unstimulated, with the rest being stimulated PfSL or purified protein derivative ([PPD] Statens Serum Institut, Copenhagen, Denmark) or Staphylococcus aureus enterotoxin B ([SEB] Toxin Technologies, Sarasota, FL) for 24 h in a CO2 incubator at 37°C with 5% CO2
Flow cytometry.
For flow cytometry, cells were prepared and analyzed exactly as described previously (5). In brief, cells from stimulated whole blood fixed after lysing the RBCs were stored at −80°C in PBS-10% DMSO and transported to the United States in liquid nitrogen. After thawing the cells, they were washed in PBS, permeabilized, and blocked as described previously. The cells were then stained with the Ab panels for effector and regulatory cells (Supplemental Table I). Samples were acquired on a BD LSRII (BD Pharmingen) and analyzed using FlowJo (Tree Star, Ashland, OR). Fluorescence minus one staining was used to set up gates for positive events (Supplemental Fig. 1).
Statistical analyses.
Both medians and geometric means (GMs) were used as a measure of central tendency. The Mann–Whitney U and Wilcoxon signed rank tests were used for paired and unpaired analyses, respectively; the Spearman rank test was used for correlations; and p values were corrected for multiple comparisons using the Holm's correction. All analyses were performed using Prism V5.0 (GraphPad Software, San Diego, CA).
Study population
Patients used for this study were a subset of a cohort of Fil+ and Fil− subjects followed for a clinical trial in malaria/filaria coendemic region. The study was carried out in two Malian villages where malaria (P. falciparum) and filarial infections are coendemic. Two filarial parasites species are present in these villages, W. bancrofti and M. perstans. Malaria in these regions is caused mainly by P. falciparum. Twenty-eight individuals all with asymptomatic P. falciparum malaria were enrolled in the study before the malaria transmission season. As shown in Table I, 13 individuals were Fil− and 15 individuals were Fil+. At the time of the study, all individuals had asymptomatic malaria as determined by the presence of P. falciparum trophozoites on thick blood smear or PfHRP2 Ag ELISA. There were no differences between the groups in terms of demographics or measured hematologic parameters. As shown in Table I, there were no differences in the concentration of PfHRP2, the number of trophozoites, the hemoglobin levels, or the total number of WBCs between the two groups.
Filarial infection is associated with lower frequencies of PPD- and malaria-specific proinflammatory cytokine-producing CD4+ cells
As shown in Fig. 1, coinfected subjects spontaneously had higher frequencies of CD4+ T cells producing IL-17A, IL-10, and IL-4 in concert with what we have previously reported (5). The net frequencies of PPD and malaria Ag-specific cytokine-producing CD4+ cells (after subtraction of the frequencies of spontaneous production) were determined and compared between the Fil− and Fil+ groups (Fig. 1). The frequencies of malaria Ag-driven CD4+ cells producing IFN-γ (median [range]: 0.48 [0.31–0.56] versus 0.13 [0.00–0.16]; p < 0.0001), IL-17A (0.43 [0.12–0.86] versus 0.23 [0.02–0.88]; p = 0.04), and TNF-α (0.53 [0.27–1.36] versus 0.28 [0.14–1.30]; p = 0.04) were significantly higher in the Fil−/Mal+ group compared with the Fil+/Mal+ group. In contrast, the frequency of malaria Ag-driven CD4+ cells producing IL-10 (0.47 [0.08–1.58] versus 0.18 [0.1–0.32]; p = 0.0005) was significantly higher in the Fil+/Mal+ group compared with the Fil−/Mal− group (Fig. 1). There were no differences in the frequencies of cytokine-producing CD4+ cells between the two groups in response to PPD or SEB stimulation.
The absolute numbers of cytokine-producing CD4+ T cells were also calculated and compared between the two groups (Supplemental Table II). The absolute numbers of CD4+ cells producing IFN-γ (median [range]: 1767.0 [322.0–5023] versus 481.4 [0.0–631.49]; p = 0.0013) and TNF-α (2064.0 [234.5–7458.0] versus 1055 [48.26–4072.8]; p = 0.03) in response to PfSL stimulation were significantly higher in Fil− compared with Fil+ and reflected the difference seen using relative frequencies. Not surprisingly, the absolute number of IL-10–producing CD4+ T cells (884.3 [92.38–2929.0] versus 2261.0 [37.12–11239.0]; p = 0.04) was significantly higher in the Fil+ compared with Fil− group (Supplemental Table II). There were no differences in the absolute numbers of cytokine-producing CD4+ cells between the two groups in response to SEB stimulation (Supplemental Table II).
Frequency of Ag-specific multiple cytokine-producing CD4+ T cells
In the context of coinfection with two parasites that tend to polarize the immune response toward different effector CD4+ Th subsets, we used multiparameter flow cytometry to characterize the Th subsets induced by malaria Ag, PPD, or SEB stimulation in Fil+/Mal+ and Fil−/Mal+ individuals. The frequencies of malaria-specific CD4+ cells producing only IFN-γ, IL-17A, or TNF-α were significantly higher in the Fil−/Mal+ compared with the Fil+/Mal+ group (p < 0.0001, p = 0.0024, and p = 0.04, respectively; Fig. 2A). In contrast, the frequency of CD4+ cells producing IL-10 alone (p = 0.028) was significantly higher in the Fil+/Mal+ compared with the Fil−/Mal+ group. In addition, the frequencies of CD4+ cells coexpressing IFN-γ/TNF-α, IL-17A/TNF-α, 17A/IL-10, IL-10/TNF-α, or 17A/IL-10/TNF-α were significantly higher in the Fil−/Mal+ group compared with the Fil+/Mal+ group (p = 0.006, p = 0.011, p = 0.015, p = 0.006, and p = 0.018; Fig. 2A). However, the frequencies of CD4+ cells producing IL-4/IL-10 were significantly higher in Fil+/Mal+ compared with Fil−/Mal+ groups (p = 0.04). These differences were specific to malaria Ag because only the frequencies of CD4+ cytokine-producing cells in response to PPD (Fig. 2B) or SEB (Fig. 2C) were not different (with the exception of CD4+ IFN-γ+ cell in response to PPD; p = 0.026) between the two groups.
Multifunctional T cells in response to Ag stimulation
The ability to measure the simultaneous expression of multiple cytokines allowed us to categorize the cytokine-producing CD4+ T cells into functional subsets (Th1, Th2, Th17, "TNF-α," and aTreg/Tr1; Supplemental Table II). Because both Th1 and Th17 cells produce TNF-α and IL-10, CD4 T cells producing TNF-α either alone or together with IL-10 were arbitrarily classified as "TNF-α." As shown in Fig. 3, in response to malaria Ag stimulation, the frequencies of malaria-specific Th1, "TNF-α," and Th17 cells were significantly higher in the Fil−/Mal+ compared with the Fil+/Mal+ groups (median [range]: 0.39 [0.26–0.53] versus 0.09 [0.05–0.12], p < 0.0001; 0.25 [0.05–0.77] versus 0.17 [0.00–0.21], p = 0.0008; and 0.38 [0.17–0.71] versus 0.017 [0.07–0.17], p = 0.012, respectively). In contrast, the frequency of aTreg/Tr1 cells was significantly higher in the Fil+/Mal+ compared with the Fil−/Mal+ group (0.08 [0.01–0.57] versus 0.03 [0.00–0.19]; p = 0.024), with no differences seen in the frequencies of malaria-specific Th2 cells between the groups (Fig. 3A). In response to PPD, only the frequency of Th1 CD4+ T cells was significantly higher in the Fil−/Mal+ compared with the Fil+/Mal+ groups (0.23 [0.05–0.41] versus 0.11 [0.01–0.24]; p = 0.002; Fig. 3B). In response to SEB, the frequencies of all of these subsets were comparable between the two groups except for that of Th2 cells, which were higher in the Fil+/Mal+ compared with the Fil−/Mal+ groups (0.89 [0.13–4.00] versus 0.48 [0.01–1.71]; p = 0.03; Fig. 3C).
The use of polychromatic Abs in intracellular cytokine staining has led to the characterization of multifunctional Th cells and their association with disease outcomes (29, 30, 33). Thus, we calculated the percentage of patients in whom multifunctional T cells could be induced by malaria Ag, PPD, or SEB stimulation in the Fil− and Fil+ groups. As shown in Fig. 3D, the presence of filarial infection was associated with the complete absence of multifunctional Th1 cells (Th1 triple producers, p = 0.003) and a lower percentage (compared with Fil−) of patients with multifunctional and single Th17 cells (p = 0.016 and p = 0.007, respectively; data not shown) in response to malaria Ag stimulation. In contrast, there were no differences in the proportion of patients who produced multifunctional Th cells in response to PPD and SEB between the two groups (Fig. 3E, 3D, respectively).
Effect of anti–IL-10 blockade on the frequency of malaria Ag-induced cytokine-producing cells
Several studies have shown that blocking IL-10 can reverse the modulated Th1-type cytokine secretion by cells from Fil+ subjects (22, 34). Thus, we examined the effect of neutralizing anti–IL-10 Ab on Ag-specific cytokine production based on the integrated GM fluorescence intensity (GMFI), a parameter that encompasses cell number (frequency of cytokine-producing cells) and the quantity of the cytokine produced (GMFI). When the integrated GMFI of each cytokine produced in the presence or absence (isotype control) of neutralizing IL-10 Ab in malaria Ag-stimulated whole blood from Fil+/Mal+ and Fil−/Mal+ patients was calculated, we found that, in response to malaria Ag stimulation, the production of IFN-γ (GM [range]: 1296 [847.8–2978] versus 524.7 [47.1–1868]; p = 0.03) was significantly increased in the presence of neutralizing anti–IL-10 Ab (Fig. 4A). However, the addition of neutralizing anti–IL-10 to PPD-stimulated cultures did not increase cytokine production in CD4+ T cells (Fig. 4B).
Frequency of nTreg and the sources of IL-10 in response to malaria Ag stimulation
The frequency of nTreg induced by PfSL was next examined and shown to be significantly increased in the Fil+/Mal+ group compared with the Fil−/Mal+ group (median [range]: 0.26 [0.0–1.28] versus 0.04 [0.0–0.61]; p = 0.009; Fig. 5A).
Because IL-10 has long been implicated in immune modulation in both malaria and human lymphatic filariasis (35, 36), we sought to identify more definitively the sources of T cell-derived IL-10 in the context of coinfection. To this end, we compared the amount of IL-10 produced by effector cells (CD4+CD25−/lowFOXP3−) and Tregs (CD4+CD25highFOXP3+) within the same subject between Fil− and Fil+ groups in response to malaria Ag stimulation (Fig. 5B). Within a given individual, the amount of malaria-specific IL-10 produced by effector cells (CD4+CD25−/low) was significantly higher than that of IL-10 produced by nTregs (CD4+CD25+/high) in either the Fil− and Fil+ groups (p = 0.0012 and p = 0.0002, respectively). Aggregated group data showed the amount of IL-10 produced by CD4+ effector cells was significantly greater in the Fil+/Mal+ compared with the Fil−/Mal+ groups (p = 0.0002).
Because IL-10 has been shown to be produced by all CD4+ helper and regulatory subsets, we next examined the contribution of each of the major CD4+ cell subset to the CD4-derived IL-10 pool induced by malaria Ag. As shown in Fig. 5C, irrespective of filarial status, the aTreg/Tr1 cells provided the overwhelmingly largest contribution to IL-10 pool. The contribution of other IL-10–producing CD4+ subsets differed to a small degree as well between the two groups. Thus, in the context of coinfection, aTreg/Tr1 cells are the predominant producer of IL-10, with nTreg contributing little to the IL-10 pool in Fil+ subjects.
Tissue-invasive helminth parasites (such as schistosomes or the filariae) cause chronic infections that induce an immune response dominated by modulating cytokines (such as IL-10 and TGF-β) (35) and regulatory cell populations (36, 37). This immunomodulating environment not only regulates the immune response to specific parasite Ags but also to nonparasite Ags through bystander or "spillover" suppression (7). Although the mechanisms underlying this suppression are still not completely understood, it is thought that IL-10 plays the major role (22, 34). The IL-10–dominated environment induced by chronic helminth infection has been shown previously to modulate the responses to vaccination (8, 9, 12), allergen skin tests (15), and nonhelminth pathogens, including H. pylori (11), M. tuberculosis (38, 39), P. falciparum (21, 22, 40), and HIV (14).
Although helminth infections modulate the responses to many pathogens, their effect on the immune responses to pathogens that induce type 1 immune responses such as malaria and tuberculosis may have the greatest impact because the regions with the greatest prevalence of helminth infections are also where malaria and tuberculosis are most deadly (17, 41). Interestingly, protection to disease associated with these pathogens is mediated in large part by type 1 (Th1)-associated cytokines (IFN-γ, IL-2, and TNF-α) (42–44).
In helminth/malaria coendemic areas, infection with either schistosomiasis or the filarial parasite, W. bancrofti, has been shown to downregulate the production of malaria-specific IFN-γ in vitro, most likely through the actions of IL-10 (22). These data do not preclude the involvement of other regulatory mechanisms induced by helminth parasites, however. In fact, in a recent study in Indonesia, depletion of CD4+CD25+ Tregs was shown to reverse a downregulated malaria- and bacillus Calmette-Guérin–specific T cell proliferative response, as well as IFN-γ production (23).
IFN-γ and other Th1-associated cytokines play a pivotal role in immunity to malaria (26, 45). Although many cell types can produce IFN-γ, CD4+ Th1 cells are considered the major source of this cytokine in malaria (46, 47) though the presence of concomitant systemic helminth infection has been shown to impair the production of IFN-γ (23, 34).
Using multicolor flow cytometry, we were able to define broadly the different subsets of Th cells in helminth-infected and -uninfected subjects with concomitant asymptomatic malaria infection and, in so doing, found that filarial infections were associated with lower frequencies of malaria-specific Th1, Th17, and "TNF-α" CD4+ subsets. This suggests that the presence of a patent filarial infection prevents expansion of these important effector T cell subsets. Although the role of Th17 cells in malaria remains to be delineated, Th17 cells and their associated cytokines have been implicated in mediating some of the pathologic consequences in autoimmune diseases (48) and schistosomiasis-associated liver pathology (49). Furthermore, in a filarial/M. tuberculosis coinfection study in India, filarial infection was associated with reduced production of M. tuberculosis-specific Th1- and Th17-associated cytokines (IFN-γ, IL-12, IL-17, and IL-23) (38).
The "TNF-α" subset, defined as malaria Ag-driven CD4+ T cells producing TNF-α either alone or concurrently with IL-10, was also significantly diminished in filarial-infected individuals. The low production of TNF-α in Fil+ individuals may have direct consequences on the severity of and/or protection against malaria. Although exuberant production of TNF-α and other proinflammatory cytokines, such as IL-6 and IL-1b, have been associated with severe malaria, high plasma levels of TNF-α have also been associated with rapid malaria parasite clearance and cure (50, 51). Although TNF-α is produced by almost all cell types, CD4+ T cells have been shown to be an important source of this cytokine during malaria (52).
Furthermore, despite the paucity of flow cytometry-based studies in malaria, previous studies using four-color flow cytometry have found that the frequency of CD8+ and CD4+ T cells expressing either IFN-γ or IL-2 alone or coexpressing IL-2 and IFN-γ increased with age (53), and that the frequency of CD3+ cells producing and TNF-α or IFN-γ alone or in combination were associated with resistance to P. falciparum reinfection and protection against severe disease (54, 55).
A major finding in this study was the association of filarial infection with the absence of malaria-specific multifunctional Th1 cells and a lower proportion of malaria-specific Th17 single-, double-, and triple-cytokine–producing cells. Although the functional significance of these multifunctional CD4+ T cells in malaria remains to be elucidated among malaria-endemic populations, their importance in vaccine models in humans and animals has been elucidated. In fact, in a vaccine study with malaria-naive volunteers, Roestenberg and colleagues (56) showed that immunized volunteers were protected against peripheral blood parasitemia and induced polyfunctional memory Th1 cells. In animal models, vaccination of mice with an adenoviral vector coding for a liver stage Ag induced malaria-specific polyfunctional CD8+ cells and protection in a model of malaria (53, 57). Moreover, vaccination of either nonhuman primates or C57BL/6 mice with P. falciparum circumsporozoite protein with polyinosinic:polycytidylic acid (as an adjuvant) induced malaria-specific Abs and multifunctional CD4 T cells in both animal models (58). In fact, multifunctional CD4 T cells have been shown to be correlated with successful vaccination (33, 59, 60) and protection in disease involving cellular immune responses in HIV, hepatitis C virus, and tuberculosis (61–63). Because natural immunity to malaria is complex and involves both cell-mediated and Ab responses, the ability to detect multifunctional T cells during malaria is of utmost importance in assessing the quality of T cell response induced by natural infection and ultimately to measure the outcome of vaccine regimens (64).
In this study, we also found that filarial infection was associated with higher frequencies of nTreg and aTreg/Tr1 cells, the latter being the major source of IL-10. We have previously reported that filarial infection was associated with increased in vitro secretion of IL-10 that was responsible for the downregulation of malaria-specific proinflammatory cytokines (22). These data have parallels in a murine model of malaria in which IL-10 (capable of modulating malaria-specific proinflammatory responses) were produced by CD4+ FOXP3−CD25− cells (65). In this study, we investigated the impact of filarial infection on the malaria-specific T cell response in young infants with relatively shorter experience with chronic filarial infection compared with adults, or with no pathology. Although the immune interaction between filarial infection and malaria-specific immune response may be different in adults with patent filarial infection or with pathology, we recently showed that chronic filarial infection even in infants was associated with increased frequencies of nTregs and aTregs/Tr1 cells (5).
Our data demonstrate that in filarial/malaria coinfection, the presence of filarial infection clearly modulates both the magnitude and the quality of T cell responses to malaria Ag. This quantitative deficiency in malaria-specific Th1, Th17, and TNF-α CD4+ cells and the complete absence of multifunctional Th1 cells associated with filarial infection suggest that concomitant filarial infection may lead to a profound inability to mount a response important for providing protection from severe malaria and for dampening the success of malaria vaccination programs in filaria-endemic regions of the world, including sub-Saharan Africa.
The authors have no financial conflicts of interest.
This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- aTreg
- adaptive regulatory T cell
- Fil−
- filarial-negative (uninfected)
- Fil+
- filaria-positive (infected)
- geometric mean
- geometric mean fluorescence intensity
- nTreg
- natural regulatory T cell
- PfHRP2
- Plasmodium falciparum histidine-rich protein 2
- PfSL
- P. falciparum schizont lysate
- purified protein derivative
- Staphylococcus aureus enterotoxin B
- Treg
- regulatory T cell.
- Received November 16, 2010.
- Accepted February 11, 2011.