text:
GOP Can't Afford to Write Off California
By Mark Z. Barabak
In 2000, Texas Gov. George W. Bush spent more than $20 million in California as part of a vigorous effort to carry the state in his first presidential bid. He lost to Vice President Al Gore by 1.3 million votes.
In 2004, seeking reelection, President Bush virtually ceded the state to Massachusetts Sen. John F. Kerry, spending minimal time and resources here. He lost California by 1.2 million votes.
Two approaches -- fight and flight -- produced the same result and showed just how inhospitable California has been to this president. His appearances in the state over the last two days have been limited to hand-picked audiences in the safe GOP harbors of Coronado in San Diego County and Rancho Cucamonga in San Bernardino County. Underscoring Bush's poor image, Republican Gov. Arnold Schwarzenegger was notably absent from the president's side, departing from the usual political protocol.
Still, party strategists and outside analysts say national Republicans would be foolhardy to write off California in presidential elections. The state is simply too big, too wealthy and too important to be continually ignored, they say.
Moreover, they suggest, the state is more competitive than Bush's travails indicate. The right Republican -- "a different kind of Republican," as several observers phrased it -- could put California back in play as early as 2008, with consequences well beyond the state's lengthy borders.
Bush has proved that Republicans can win the White House without California, but "it's a tough go, even with an incumbent president," said Rhodes Cook, a nonpartisan campaign analyst in Washington, D.C. "It seems to me if Republicans are really going to be a long-running majority party, California needs to be a part of that majority. Otherwise, they're going to be a tenuous and not very long-running majority."
Political fortunes can change quickly. California was a reliable Republican redoubt for more than a generation until then-Arkansas Gov. Bill Clinton won here in 1992. As president, he quickly turned the state into a Democratic stronghold.
Demographic changes were important to Clinton's success, as Latino clout grew and conservatives left Southern California for the low-tax bastions of Arizona, Nevada and other Rocky Mountain states. But Clinton also lavished plenty of attention on California, visiting often and establishing a special White House liaison whose sole responsibility was the care and feeding of the Golden State.
When Bush took office, "that warm spot" for California was "replaced by Texas," Leon Panetta, a longtime congressman from the Monterey area, said a few days into the new administration.
The reality hit soon enough, during the 2001 energy crisis, when Bush took a hands-off approach and the state sweltered through a summer of rolling blackouts and soaring electricity bills. In focus groups conducted for then-Gov. Gray Davis' reelection campaign, many voters assumed Bush's actions were payback for losing the state in 2000.
"California is like any other state," Panetta, White House chief of staff under Clinton, said Monday, expanding on his earlier comments. "If it feels like an administration is paying attention to its problems, then it will be friendly to that administration."
White House officials and Bush allies say the president has never spurned California.
Introducing Bush on Monday in Rancho Cucamonga, Rep. David Dreier (R-San Dimas) referred to the president's quick reaction to Hurricane Katrina, and said Bush has likewise been responsive to California catastrophes, such as mudslides and wildfires.
"He has always been there to support the needs of Californians," Dreier said.
But clearly the perception exists among many voters that the state is low on Bush's list of priorities. That poses a double challenge for Republicans looking ahead to 2008 -- reassuring Californians that the party cares about them and finding a candidate who can win over social conservatives while staying in sync with the state's live-and-let-live philosophy.
Party strategists offer up names of several Republicans who might be strong California prospects: former New York City Mayor Rudolph W. Giuliani, Massachusetts Gov. Mitt Romney and, especially, Sen. John McCain of Arizona. Each has broken at some point with Republican orthodoxy on abortion, gay rights, campaign finance or other issues, suggesting a maverick streak that could appeal to libertarian California voters.
But those very qualities also make it less likely that any of the three could survive party primaries in Iowa or South Carolina, for instance, where balloting is dominated by religious conservatives.
"That's a hurdle you need to clear to be the nominee, but in a sense that can make a candidate less electable in a state like California," said Thomas Schaller, a University of Maryland expert on the presidential nominating process.
For now, Bush remains the face of the Republican Party and, as his poll numbers continue to sag, he makes an increasingly welcome target for Democrats -- and a not entirely welcome presence for the state's Republican governor.
Schwarzenegger -- struggling to pass a handful of measures in the special election he called for Nov. 8 -- is burdened with his own plunge in approval ratings. A recent statewide survey by the Public Policy Institute of California showed 34% of Californians approving of his job performance, compared with 38% giving approval to Bush's.
To achieve his goals in the special election, Schwarzenegger needs the votes of Democrats and independents who make up the majority of the state's voters. He can ill afford to antagonize them by a close association with Bush, particularly since Democrats probably will try to tie him in voters' minds to the president.
"I think a major problem that Arnold faces this fall is that this special election is a great chance for Californians to vote against Bush," said Tony Quinn, a Sacramento analyst and co-editor of the Target Book, a nonpartisan guide to state politics. "The best way to turn out [Democratic voters] is to energize them by attacking Bush. It's going to be easy for the Democrats to say, 'Send Bush a message. Vote against Arnold.' "
Rob Stutzman, a spokesman for the governor, dismissed that analysis. "I think people tend to over-think these dynamics," he said. "Just like the recall election, this November's special [election] won't have anything to do with national politics. Voters will act upon what's best for California's future."
Times staff writer Peter Wallsten in Coronado contributed to this report.
Mark Z. Barabak
Mark Z. Barabak covers state and national politics for the Los Angeles Times, based in the San Francisco Bay Area.


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Ce se întâmplă doctore? este o revistă "glossy" pentru femei din România, deținută de trustul de presă Publimedia.
Revista a fost lansată în octombrie 2005 și se adresează femeilor cu vârste între 18-35 de ani din mediul urban.
Spre deosebire de celelalte publicații pentru femei din România, revista "Ce se întâmplă, doctore?" se axa pe viața sănătoasă.

Platforma www.csid.ro a fost lansată în 2007, fiind varianta on-line a brandului numărul 1 de lifestyle sănătos din România, "Ce se întâmplă, doctore?", dezvoltat inițial ca emisiune TV, apoi ca revistă print și ulterior, ca site on-line. Platforma conține mai multe secțiuni cu articole, informații și baze de date realizate în colaborare cu medici și clinici medicale.

Site-ul csid.ro are ca principale secțiuni sănătatea, frumusețea, dieta, sportul, creșterea și dezvoltarea copilului și psihologia. Site-ul conține și o secțiune importantă de materiale video, cu interviuri și informații din domeniul sănătății și stilului de viață sănătos.

De asemenea, platforma on-line "Ce se întâmplă, doctore?" conține și o secțiune dedicată evenimentelor organizate cu participarea specialiștilor și cititorilor. Redactorul-șef al platformei este Beatrice Osanu, iar astăzi, site-ul csid.ro face parte din Gândul Media Network.

În anul 2019, Ioan Radu Budeanu, fondatorul Ciao! și al Cancan, a cumpărat mărcile Gândul, Descoperă, CSID, Apropo TV și Go4IT, de la Adrian Sârbu, proprietarul Mediafax Group.

Premii și distincții
În 2014, revista "Ce se întâmplă, doctore?", a primit premiul "Cea mai bună revistă" din partea Radar de Media.

Note

Legături externe
www.csid.ro - Site web oficial

Reviste mondene din România
Mediafax Group
Fondări în 2005

redpajama_set_name: RedPajamaWikipedia


Happy new year, everyone! How was your holiday? Great? Good? Not so good? Terrible? Hello? Personally, we're already itching for another one. And not just some quick weekend getaway, but a full-blown vacation to a distant land. That's right, gents. Our new year's resolution is to turn around and act like we're still off the clock for another week or two. Should you feel the same way, here are some Amazon Finds to help make it happen.
There's so much to do in Japan that it's easy to get overwhelmed. Allow this trusty book from Lonely Planet to be your guide. In it you'll find tips, maps, insights, info, and so much more.
When travelling abroad, you need luggage you can trust. Meanwhile, Samsonite is among the most trusted names in travel gear. You do the math.
"I couldn't stand that screaming baby!" your girlfriend proclaims as you exit the plane together. "What screaming baby?" you casually reply. Your girlfriend arches her brow before remembering you rocked the Bose QuietComfort 35 Series II Wireless Headphones with active noise cancellation for the entire flight. It sounds like she could use a pair herself.
Should you roll onto the plane with the aforementioned Bose QuietComfort Headphones, you'll want to scoop up this audio adapter from uxcell as well. It's cheap and it works. What more do you need to know?
It's waterproof. It's wireless. It's portable. It's powerful. It's compatible with up to two smartphones or tablets at a time. It's the JBL Flip 4 and it's ready to rock. Whenever. Wherever.
Don't settle for any old passport holder when you can get this one from Herschel Supply Co. Equipped with multiple card slots, the holder combines waxed nubuck leather and striped fabric liner to premium perfection.
Designed for the modern traveller, this water-resistant backpack from Kopack features a hidden laptop compartment, a detachable USB cable, and a cosy back support system, among other things.
Even in the age of binge streaming and virtual reality, there's nothing quite like a good book. Speaking of good books, "Bridge of Clay" by Aussie author Markus Zusak (of "The Book Thief" fame) received all sorts of rave reviews.
The TRAVELPAL Universal Adapter is a pal, indeed. Compatible across 200 countries, the handy accessory can charge up to five devices at once. Don't go overseas without one.
Made of tough canvas and equipped with plenty of pocket room, this toiletry roll might very well be the last one you ever buy.
Why bring just one book on vacation when you can bring a whole library? In addition to its impressive storage capacity, the all-new Kindle Paperwhite is both waterproof and effortlessly portable.
Quick to dry and stretchy to boot, these swim trunks from Speedo's will have you cruising the beach in comfort and style.


Clear Read-Only is powerful tool for clearing Read-Only file attribute.
Complete File Recovery is a universal file recovery software.
Retrieve deleted files from hard drives, flash cards and other storage devices.
Handy data recovery tool to undelete and recover erased or unreadable files.
NoZip is a cross-platform file joiner and splitter with steganography capabilities.
HiFi MP3 Splitter Joiner builds mp3 cutter and mp3 joiner in one software.
PDF Prime can help you merge, split, lock, and unlock your PDF files with ease!


Posted on March 31, 2017 March 31, 2017 by Fausta Rodriguez WertzPosted in opinion/newsTagged DaTechGuy's Magnificent Seven, Fausta Rodriguez Wertz, russia.
Posted on March 31, 2017 March 30, 2017 by DatechguyPosted in cultureTagged culture wars, Mike Pence.
What are the Dems after?
For quite a while, the Democrats have repeatedly engaged in the following: Maoist-type censorship of speech and free expression through political correctness mores: What, exactly, does "political correctness" mean? In the 1980s and '90s, the term was a sarcastic reference to Maoist or Stalinist thought police, popularized largely by conservatives in order to deride the liberal-led … Continue reading What are the Dems after?
Posted on March 29, 2017 March 29, 2017 by DatechguyPosted in catholicTagged catholic, the priesthood.
It's the Supreme Court Stupid!
If you asked Republicans the most important reason they voted for Donald Trump, a significant number would answer the U.S. Supreme Court. The nomination of Neil Gorsuch is more important that Obamacare, the wall or anything else. It is conceivable that Trump may appoint at least two other justices during his tenure as Justices Ginsburg … Continue reading It's the Supreme Court Stupid!
Are Russian Hackers an Actual Threat to Democracy?
Are Russian hackers an actual threat to democracy? Or are US intelligence agencies with "deep state" factions opposed to the government the bigger threat? And what do the Vault 7 revelations along with others coming out since the change of administration tell us about the Democrats' constant finger pointing and fear mongering? When the Intelligence … Continue reading Are Russian Hackers an Actual Threat to Democracy?
Posted on March 28, 2017 March 28, 2017 by VariousPosted in UncategorizedTagged russia, sponsored guest posts, tech.
Missing the Ledes on the Montreal "Anti Semitic Imam" story Lede Two: Al_Nawawi's Hadith? never heard of It.
Col Klink: No it's not possible, General Mulendorf Gestapo Captain Borman: With his arm around your shoulders. Col Klink: Yes we were friends Gestapo Captain Borman: Close Friends, and very possibly associated in za plot to assassinate the Führer Col Klink: I hardly knew the man, went to school together ten years, saw each … Continue reading Missing the Ledes on the Montreal "Anti Semitic Imam" story Lede Two: Al_Nawawi's Hadith? never heard of It.
Defund Planned Parenthood immediately. No need to attach it to any other bills.
One of the strategies Speaker Paul Ryan used in attempting to sell the American Health Care Act was to include defunding Planned Parenthood as part of the deal. It was a good attempt to sugarcoat "Obamacarelite" with some conservative honey for positive press and leverage against right-wing opposition to the bill, but it obviously didn't … Continue reading Defund Planned Parenthood immediately. No need to attach it to any other bills.


Singapore's first commercial vertical farm was started by the entrepreneur Jack Ng. He says, "he can produce five times as many vegetables as regular farming looking up instead of out." Half a ton of his Sky Greens bok choy and Chinese cabbages, have already reached Singapore's grocery stores.
Vertical farming is a proposal to build high rise buildings within urban areas. It enables the growing of food crops to help avoid the food shortage which is expected in the near future. It is thought that by the year 2050 the world's population will have grown by a further 3 billion people. There will be more land needed than is available to grow the crops needed to feed everybody. We'll have to come up with ideas to consider how these extra crops can be grown. Vertical farming could provide year round food production and better crop production. It will require less land to produce more crop compared to traditional horizontal farming. Simply put, vertical farming is like a high rise greenhouse, which can also be called farm scrapers.
The process of vertical farming at Sky Greens: trays of Chinese vegetables are stacked inside an aluminum A-frame, and a belt rotates them so that the plants receive equal light, good air flow and irrigation. The whole system has a footprint of only about 60 square feet, or the size of an average bathroom.
The success of vertical farms really depends on the location and the light since the total food produced depends on the amount of light reaching plants.
Some benefits of vertical farming are more plants can squeeze into tight city spaces, and fresh produce can grow right next to grocery stores, potentially reducing transportation costs, carbon dioxide emissions and risk of getting spoiled. Also, most vertical farms are indoors, so plants are sheltered from shifting weather and damaging pests.
Two companies are already working on this approach. Gotham Greens is producing pesticide-free lettuce and basil for restaurants and retailers from rooftop greenhouses in Brooklyn, while Lufa Farms grows 23 veggie varieties in a 31,000 foot greenhouse atop a Montreal office building.
Commercial: Concerned with or engaged in commerce or money.
Vertical: Such that the top is directly above the bottom.
Entrepreneur: A person who organizes and operates a business or businesses.
Crops: A plant that is grown as food.
Production: The harvesting or refinement of something natural.
Irrigation: Supplying dry land with water by means of ditches.
Traditional: Existing in or as part of a tradition.
Horizontal: Parallel to the plane of the horizon.
Emission: To produce and discharge something.


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The EU Enlargement and Income Convergence: Central and Eastern European Countries vs. Western Balkan Countries
Author(s): Nenad Stanišić, Nikola Makojević, Tijana Tubić Ćurčić
Subject(s): Supranational / Global Economy, Economic policy, Economic development, EU-Accession / EU-DEvelopment
Published by: Uniwersytet Ekonomiczny w Krakowie
Keywords: income convergence; transition economies; European Union; unit root tests;
Summary/Abstract: Objective: This article analyses the stochastic convergence of income per capita between the Western Balkan (WB) and the Central and Eastern European (CEE) countries compared to developed EU countries (EU15). Research Design & Methods: Stochastic convergence implies that all shocks in country's income relative to the average income of the group are only temporary. In order to test stochastic convergence, the tests of the unit root were used. The Augmented Dickey-Fuller (ADF) test is supplemented with the Zivot-Andrews (ZA) unit root test, which allows for the structural breaks in time series of income per capita. Findings: Results confirm the existence of stochastic convergence of income per capita toward the EU15 average in the cases of the Czech Republic, Slovakia, Poland, Slovenia, Estonia, Latvia and Romania. Income convergence is not found in the case of the Western Balkan countries. Implications & Recommendations: While income convergence toward the EU15 average level was found in the case of 7 CEE countries, it was not found in the case of any WB country. This could be a proof of the importance of further support to reforms in the Western Balkan countries. Contribution & Value Added: The scientific contribution of the article is reflected in the fact that the existing literature dealing with income convergence of the Western Balkan countries toward the income of the EU15 countries is still very limited in number, as is the number of studies that compare convergence of income per capita toward the EU15 between the Western Balkan and CEE countries.
Journal: Entrepreneurial Business and Economics Review
Issue Year: 6/2018
Convergence between the business cycles of Central and Eastern European countries and the Euro area Convergence between the business cycles of Central and Eastern European countries and the Euro area 2013

redpajama_set_name: RedPajamaCommonCrawl


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Ricki Ellison New Director of Diversity, Equity and Inclusion for Wichita Regional Chamber
by September 21, 2021 August 31, 2022
Rikki Ellison
The Wichita Regional Chamber has named Ricki Ellison as its new director of Diversity, Equity and Inclusion (DEI). Currently the Clinical Educator and Academic Advisor for the Sport Management Department of the College of Applied Studies at Wichita State University, Ricki's first day at the Chamber will be October 1st.
Ellison got her start at Wichita State working in the Admissions Office where she was the Diversity (Multicultural) Recruitment Manager, managing from selection to training to deployment.
In this role, Ellison will serve as an ambassador and advocate for inclusive and equitable initiatives, as well as act as a strategic partner to Chamber leaders, DEI workgroups and key stakeholders and investors. She will also work to align DEI initiatives with business strategies focusing on the overall workforce, marketplace and community, and develop and deliver innovative inclusive programs that align with business objectives.
"In selecting the next DEI Director it was important that we found someone who was invested in our community and who understands the importance of the DEI space. It was also an opportunity for us to champion our words with action, by investing in our own and retaining our young professionals," said LaShonda Garnes, director of Inclusion, Equity and Diversity for Fidelity Bank and member of the interviewing team.
"I'm so excited that Ricki will be joining the Chamber in an area that I am personally so passionate about. I see commitment and opportunity to view ALL Chamber work through a diversity lens and Ricki's proven leadership abilities will be able to elevate that work in the DEI space making us even more valuable to our members," said Junetta Everett, interim director of Diversity, Equity and Inclusion for the Wichita Regional Chamber of Commerce and immediate past chair of the Chamber board.
Since working at Wichita State, Ellison has earned three promotions and progressive responsibilities. A bright, motivated and energetic personality allow her to follow her passion of diversity education. She believes that diversity, equity and inclusion are how we unleash the power and true potential of a business or organization. Ellison strives to help educate, prepare and connect those she surrounds for their successes.
Ellison currently serves on the WSU Alumni Association Board of Director, WSU College of Engineering Diversity Advisory Board, LGBTQ+ Task Force, WSU College of Applied Studies Diversity Committee, Steve Clark YMCA Board of Directors and is a WSU on-campus advisor for Kappa Alpha Psi Fraternity, Inc. and co-advisor for the Black Student Union.


text:
International flash fiction competition - Quantum Shorts - is back!
11 Dec 2019 Tara Roberson
Calling all writers! EQUS is delighted to announce a new call for entries to the Quantum Shorts flash fiction competition. We want stories of up to 1000 words long that take inspiration from the mind-blowing world of quantum physics. The Quantum Shorts competition is free to enter, offering prizes of up to US$1500.
As before, this year's writers will have a constraint to work with. Their stories must include the phrase "things used to be so simple". This phrase was taken from the winning story of the 2017 edition of the competition, "Acceptable Loss" by Przemysław Zańko.
The Quantum Shorts competition started in 2012, alternating between annual calls for flash fiction and short films. It is organised by the Centre for Quantum Technologies (CQT) at the National University of Singapore, and encourages writers to imagine how quantum physics might impact future lives – or to explore the hidden effects it might already be having on the world around us.
Artur Ekert, CQT Director and one of the judges, says, "In these days of quantum computers and quantum satellites, even the news can read like sci-fi. We invite writers to explore behind the headlines and tell stories with emotion and imagination."
Every year, Quantum Shorts is supported by a hard-working group of elite partners. Scientific American, the longest continuously published magazine in the U.S., and Nature, the international weekly journal of science, are media partners for the competition. The competition is also supported by its scientific partners, leading quantum research centres around the world. They are the Dodd-Walls Centre, the ARC Centre of Excellence for Engineered Quantum Systems, the Institute for Quantum Computing (IQC), the Institute for Quantum Information and Matter (IQIM), QuTech, and the UK National Quantum Technologies Programme.
From all the entries submitted, a panel of experts will shortlist 10 outstanding flash fictions before the competition's distinguished judges select the winner and runner-up for the top prizes. The People's Choice Prize from the shortlisted entries will be decided by public vote.
Submissions to Quantum Shorts can be entered via the website at http://shorts.quantumlah.org, which also features resources on quantum physics and a full set of rules and guidelines. The deadline for entries is 23:59 GMT, 29 February 2020.
Launching together with the new call for entries is an anthology of past winners and shortlisted entries from the flash fiction editions of the competition. The Quantum Shorts e-book presents stories ranging from bold imaginings of a quantum future to contemplations rooted in the everyday.
"We are very proud to launch this unique collection of extraordinary stories," says Michael Brooks, who is one of the book's editors. "Each of the authors offers a fresh and exciting take on our place in the quantum world."
The e-book is free to download on the Google Play Store, Apple Books, Kobo stores, farisbooks.com, and the Quantum Shorts website.
No storm in a teacup - it's a cyclone on a silicon chip
Quantum paradox experiment may lead to more accurate clocks and sensors
Scholarships announced for 2019 Science meets Parliament
National quantum-themed competition for game designers
Physicists find quantum states of time induced by gravity
Upcoming events and opportunities
Competition: Quantum Games – 2 Sep 2019 to 31 Mar 2020


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Field Marshal Montgomery Pipe Band
Premier HTS and Professional Series are great sounding drums that are easy to set well. We know Premier drums are the loudest and clearest on the field; some others can produce a good bright sound, but nowhere near the same clarity, volume or projection.
The Field Marshal Montgomery Pipe Band is one of the leading pipe bands in the world, and the most influential and successful pipe band from Northern Ireland ever. Led by Pipe Major Richard Parkes MBE, Pipe Sergeant Alastair Dunn and Drum Sergeant Keith Orr, the band has won every major championship title available, including ten coveted World Pipe Band Championships, three 'Grand Slams', 13 Champions of Champions titles, 21 All Ireland Championships and 60 RSPBA major championship titles.
Based in Lisburn, the band is representative of Northern Ireland with membership spanning all four corners of the country. In recent years, FMM has attracted members from as far afield as Australia, New Zealand, Canada, USA, Denmark, France, Scotland, England, and of course the north and south of Ireland. The band is exceptionally proud of both its Northern Irish and international status.
The Field Marshal Montgomery Pipe Band has become one of the most consistent and decorated competitive pipe bands in history. Though its philosophy has been competition based since its inception 70 years ago, the band also performs at concerts, festivals, radio and television appearances, and civil and social functions.
The band has produced four highly successful albums to date:Début, Live in Concert, Unplugged and RE:CHARGED.
For the Field Marshal Montgomery Pipe Band, the successes of today are a steady progression from humble roots. The band was founded in 1945 in the townland of Drumalig, a few miles from Carryduff on the outskirts of Belfast. A group of farmer's sons had decided to form a band as a leisure pursuit in the wake of World War II, and they proposed to call their formation after one of the great heroes of the war, Bernard Law Montgomery. The youths wrote Field Marshal Montgomery to ask for permission to use his name. Not only was permission granted, but their hero even sent a ten shilling note as a personal contribution to the band's funds.
In the years to follow, the band successfully worked its way through the lower grades, led by FMM's first pipe major Billy Maxwell. Billy was President of the band right up to his sad passing in 2013 and was a huge influence on the development of FMM into the competitive force it is today.
Billy was succeeded by Sandy Cuming, Ricky Newell, and eventually Richard Parkes, who took over with his brother Gordon as leading drummer in 1981. 45 years after its inception, the band won its first major championship in Grade 1 at the Cowal Championships in 1990.
The band's first World Championship win in 1992 catapulted Field Marshal Montgomery from the status of an up-and-coming local band in Northern Ireland to the pinnacle of the pipe band world. This first 'Worlds' win was followed by a second title in 1993, subsequently winning the elusive "Grand Slam" of all five major championship titles in a single season. This placed FMM as one of only a small number of bands who can claim such an achievement.
Gordon Parkes stepped down as leading drummer in 1998, and was succeeded by Andrew Scullion, and in 2003 by current Drum Sergeant Keith Orr.
Over the years 2000-2009, the Field Marshal Montgomery Pipe Band rose to become the most dominant pipe band of the decade, securing 28 major championship wins, including four more World Championships (and five runners-up awards).
This decade however was not all smooth sailing. In 2004, Pipe Major Richard Parkes suffered a stroke and the entire piping world waited to hear about the health of one of the most respected Pipe Majors in history. The band pulled together to support Richard, with Alastair Dunn stepping in to lead the band to victories at the Scottish and All Ireland Championships. In one of the pipe band world's fairy-tale stories, Richard recovered his health and was able to lead the band to win the last three championships of the season, including FMM's fourth World Championship title.
Already in the works but unbeknownst to Richard and the band, at the conclusion of 2004, Richard was awarded an MBE for his services to pipe band music in Northern Ireland: a great honour for the man who had changed the history of pipe bands in his country. The Field Marshal Montgomery Pipe Band has often been dubbed "The Richard Parkes Success Story," and the great respect for Richard from within his own band and from his competitors is as much a part of the band's hallmark as is its list of prizes.
In the years that followed, FMM continued its record of competition success, winning the Champions of Champions award for the most consistency in a pipe band season in both 2009 and 2010.
The band regained the Worlds in 2011 before securing the title once again in 2012, 2013 and 2014 – taking the band's record of World Championship victories to ten. During that period two further Grand Slams were also delivered, making FMM the only ever band to achieve such a feat more than once.
2013 was a special year with Keith Orr's Drum Corps winning the World Drum Corps title for the first time in the band's history and – courtesy of also winning the British and European titles – securing its second Champions of Champions Drum Corps award under Keith's leadership.
Field Marshal Montgomery Pipe Band is proud of its association with sponsors R. G. Hardie & Co Ltd and Premier Music International Ltd. Both provide the band with first-class products to showcase its talent, and their support is central to the band's ongoing success.
Over the past 70 years, the Field Marshal Montgomery Pipe Band has risen to the top of the pipe band world. We are extremely grateful for the support we receive wherever we play and remain as driven and motivated as ever for the future.
0800CHM-C (x14)
14'' x 12'' HTS 800
Tenor and Bass:
396512CHM (x2)
15'' x 12'' Professional Series Tenor Drum
396614CHM
28'' x 18'' Professional Series Bass Drum
Chrome Metallic (CHM)
www.fmmpb.com/
Our artists:
Austin Lane
Bailey Cassell
Bob Richards
Canterbury Caledonian Society Grade 1 Pipe Band
Cassell The Beatmaker
Chris Sharrock
Doane Perry
Dominic Boyce
Ezio Zaccagnini
Frank Benbini
Frederic Macarez
Gaetano Fasano
Ged Lynch
Haydn Evans
Jay Sharrock
Joe Emmett
John Keeble
John Watt
Josh McKenzie
Julien Brown
Luke Bullen
Luke Marc Hughes
Martin Esser
Mauricio Hidalgo
Michael Brush
Michael Schumm
Nathan Curran a.k.a. Tugg The Drummer
Ollie Howell
Olly Betts
Peel Regional Police Pipe Band
Police Scotland Fife Pipe Band
Sara Leigh Shaw
Scottish Power Pipe Band
Seb Sternberg
Shotts & Dykehead Caledonia Pipe Band
St. Laurence O'Toole Pipe Band
Stephan Schott
Stephen Creighton
Ulf Wadenbrandt
Vicky O'Neon
Zel Kaute


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Q: How to avoid repeating myself in Salt states? We have two different environments, dev and production, managed by a single Salt server.
Something like this:
base:
  'dev-*':
    - users-dev
  'prod-*':
    - users-prod

user-dev and users-prod states are pretty much the same, like this:
{% for user, data in pillar['users-dev'].items() %}
{{ user }}-user:
  user.present:
    < ...something... >
{{ user }}_ssh_auth:
  ssh_auth.present:
    < ...something... >
{% endfor %}

We did not want to duplicate the code so our initial idea was to do something like this:
{% users = pillar['users'].items() %}
include:
  - users-common

and then to refer to users in users-common, but this did not work because the proper Jinja syntax was set users = pillar['users'].items() and this was not intended to work across Salt states includes.
So, the question is how to do it properly?

A: All jinja is evaluated before any of the states (including the include statements) are evaluated.
However, I would think you would just be able to refer directly to pillar['users'].items() inside of users-common.  Is it not allowing you to access pillar from within that state?

redpajama_set_name: RedPajamaStackExchange


text:
Healthcare Industry News: beclomethasone
Critical Therapeutics' Zileuton Provides Additional Asthma Control When Combined with Inhaled Corticosteroids
Study Data Presented in Peer-Reviewed Journal Respiratory Medicine
LEXINGTON, Mass.--(HSMN NewsFeed)--Critical Therapeutics, Inc. (Nasdaq: CRTX ), a biopharmaceutical company focused on the development and commercialization of products for respiratory, inflammatory and critical care diseases, announced today the publication of a peer-reviewed article based on a study of zileuton, the Company's 5-lipoxygenase (5-LO) inhibitor. The study suggests that combining zileuton (400 or 600 mg QID) with a low-dose inhaled corticosteroid (ICS) improves pulmonary lung function and may be an effective therapeutic approach to achieving asthma control in patients with moderate to severe persistent disease.
The article, "Zileuton added to low-dose inhaled beclomethasone for treatment of moderate to severe persistent asthma", was published in the June issue of Respiratory Medicine. The lead author is Brian J. O'Connor, M.D. of King's College London School of Medicine.
Data presented in the article was based on a two-week, single-blind run-in period, followed by a 12-week randomized, active-controlled, multi-center study. A total of 320 patients qualified for the double-blind testing period and were randomized to three groups across 32 centers in Canada and Europe: zileuton 400 mg 4 times per day plus 400 mg beclomethasone dipropionate (BDP) twice daily (n=108); zileuton 600 mg 4 times per day plus 400 mg BDP twice daily (n=110); and placebo group plus 800 mg BDP twice daily (n=102).
The study was designed to assess the therapeutic effects of oral zileuton tablets combined with low-dose BDP, compared to doubling the dose of BDP, in improving lung function and reducing asthma symptoms. There were no clinically significant differences between treatment groups in the primary outcome of Forced Expiratory Volume in one second (FEV(1)), as all treatment groups improved. There were significant improvements in Peak Expiratory Flow (PEF) in the 400 and 600 mg zileuton groups, compared to baseline. The data suggests that the addition of zileuton to low-dose BDP may be an alternative to using higher doses of ICS in patients unable to achieve asthma control on a low-dose ICS therapy.
In this study, adverse events were similar across all groups. Five patients had alanine aminotransferase (ALT) values of greater than two times the upper limit of normal (greater than or equal to 2x ULN): four on zileuton and one on placebo. Of the four patients taking zileuton who had ALT values greater than or equal to 2x ULN, two had values that returned to normal while patients continued treatment and in the other two patients, resolution occurred within 20 days after discontinuation of the study drug.
About Zileuton / ZYFLO CR(TM)/ ZYFLO®
Zileuton inhibits 5-lipoxygenase (5-LO), an enzyme that catalyzes the formation of leukotrienes from arachidonic acid. 5-LO is the main enzyme responsible for the production of leukotrienes, a family of inflammatory mediators that can trigger asthma symptoms, including inflammation, swelling, bronchoconstriction and mucus secretion. ZYFLO CR(TM) (zileuton) extended-release tablets and ZYFLO® (zileuton tablets) have a unique mechanism of action that works early in the inflammatory cascade, thus blocking all types of leukotrienes. ZYFLO CR and ZYFLO are the only FDA-approved leukotriene synthesis inhibitors for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. ZYFLO CR and ZYFLO are not indicated for use in the reversal of bronchospasm in acute asthma attacks. Therapy with ZYFLO CR and ZYFLO can be continued during acute exacerbations of asthma. ZYFLO CR uses SkyePharma PLC's (LSE: SKP ) proprietary Geomatrix® drug delivery technology, which controls the amount and rate of drug released into the body.
The recommended dose of ZYFLO CR is two 600 mg extended-release tablets twice daily, within one hour after morning and evening meals, for a total daily dose of 2400 mg. The recommended dose of ZYFLO is one 600 mg immediate-release tablet four times a day for a total daily dose of 2400 mg.
ZYFLO CR and ZYFLO are contraindicated in patients with active liver disease or transaminase elevations greater than or equal to three times the upper limit of normal. A small percentage of patients treated with ZYFLO CR (2.5%) and ZYFLO (1.9%) in placebo-controlled trials showed an increased release of a liver enzyme known as ALT and bilirubin (an orange or yellowish pigment in bile). As a result, the level of liver enzymes in patients treated with ZYFLO CR and ZYFLO should be measured by a simple blood test. It is recommended that physicians perform this test before administering ZYFLO CR and ZYFLO and repeat the test on a regular basis while patients are on the medication. Patients taking ZYFLO CR or ZYFLO and theophylline should reduce the theophylline dose by 50%. Patients taking ZYFLO CR or ZYFLO and propranolol or warfarin should be monitored and doses adjusted as appropriate. Most common side effects associated with the use of ZYFLO CR and ZYFLO are sinusitis, nausea and pharyngolaryngeal pain and abdominal pain, upset stomach and nausea, respectively.
For full prescribing information for ZYFLO CR, please visit www.zyflocr.com or call the Company's toll free telephone number 1-866-835-8216 to request medical information.
For full prescribing information for ZYFLO, please visit www.zyflo.com or call the Company's toll free telephone number 1-866-835-8216 to request medical information.
About Critical Therapeutics
Critical Therapeutics, Inc. is developing and commercializing innovative products for respiratory, inflammatory and critical care diseases. The Company owns worldwide rights to two FDA-approved drugs for the prevention and chronic treatment of asthma in patients 12 years of age and older: twice-daily ZYFLO CR(TM) (zileuton) extended-release tablets and ZYFLO® (zileuton tablets). Critical Therapeutics is working to develop products for acute asthma attacks that lead patients to the emergency room and other urgent care settings. The Company also is developing therapies directed toward the body's inflammatory response. Critical Therapeutics is located in Lexington, Mass. For more information, please visit www.crtx.com.
Any statements in this press release about future expectations, plans and prospects for Critical Therapeutics, Inc., including, without limitation, statements regarding possible therapeutic benefits, market acceptance and future sales of ZYFLO CR; the anticipated success of the co-promotion arrangement with DEY; the progress, timing and success of the product launch for ZYFLO CR; prospects, plans and objectives of management; and all other statements that are not purely historical in nature, constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words "anticipate," "believe," "could," "estimate," "expect," "intend," "may," "plan," "project," "should," "will," "would" and similar expressions are intended to identify forward-looking statements. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including risks and uncertainties relating to: our ability to successfully market and sell ZYFLO CR, including the success of our co-promotion arrangement with DEY; our ability to develop and maintain the necessary sales, marketing, distribution and manufacturing capabilities to commercialize ZYFLO CR; patient, physician and third-party payor acceptance of ZYFLO CR as a safe and effective therapeutic product; adverse side effects experienced by patients taking ZYFLO CR; our heavy dependence on the commercial success of ZYFLO CR; our ability to maintain regulatory approvals to market and sell ZYFLO CR; our ability to successfully enter into additional strategic co-promotion, collaboration or licensing transactions on favorable terms, if at all; conducting clinical trials, including difficulties or delays in the completion of patient enrollment, data collection or data analysis; our ability to obtain the substantial additional funding required to conduct our research, development and commercialization activities; our dependence on our strategic collaboration with MedImmune, Inc.; and our ability to obtain, maintain and enforce patent and other intellectual property protection for ZYFLO, ZYFLO CR, our discoveries and our drug candidates. These and other risks are described in greater detail in the "Risk Factors" section of our most recent Quarterly Report on Form 10-Q and other filings that we make with the Securities and Exchange Commission. If one or more of these factors materialize, or if any underlying assumptions prove incorrect, our actual results, performance or achievements may vary materially from any future results, performance or achievements expressed or implied by these forward-looking statements.
In addition, the statements in this press release reflect our expectations and beliefs as of the date of this release. We anticipate that subsequent events and developments will cause our expectations and beliefs to change. However, while we may elect to update these forward-looking statements publicly at some point in the future, we specifically disclaim any obligation to do so, whether as a result of new information, future events or otherwise. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this release.
ZYFLO® is a registered trademark of Critical Therapeutics, Inc.
ZYFLO CR(TM) is a trademark of Critical Therapeutics, Inc.
Geomatrix® is a registered trademark of SkyePharma PLC
Source: Critical Therapeutics
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In a constantly evolving blend of comedy and drama, the Boston College theatre department's production of The Cherry Orchard depicted the imperfections and deliberations of the human condition with instinctual performances and inviting aesthetics.
Written by renowned Russian playwright Anton Chekhov, The Cherry Orchard captures the emotional and financial struggles of a Russian landowning family at the turn of the 20th century. While no two characters are quite alike in their dispositions or obstacles, all unite in their admiration of the natural wonder that is the cherry orchard, and all attempt to grasp onto their respective realities with a nod toward the future and possibility for improvement.
Before actors even graced the stage of Robsham Theater, a few pieces of rustic, period furniture populated a tile-painted floor, situating audience members in the Russian countryside of the early 1900s. Such bare serenity diminished, however, as the lights rose to reveal anxious anticipation for a train, creating an opening scene in which Yermolay Lopakhin (Michael Mazzone, MCAS '19), a clumsy, self-deprecating businessman, awaits the arrival of the train's passengers with Dunyasha (Isabel Litterst, MCAS '21), the flighty house maid. While a tinge of slapstick comedy with the tragically infatuated, flower-dropping Semyon Yepikhodov (Stephen McAlee, MCAS '18) elevates the already chaotic atmosphere, the mayhem culminates in the entrance of an ensemble adorned with travel garments and luggage.
The standout of this bustling crew is Lyubov Ranyevskaya (Samuela Nemathcoua, MCAS '18), the owner of the estate that hosted acres of cherry orchards. Returning to her beloved childhood home from a five-year hiatus in Paris, Lyubov voices a blissful satisfaction with this transition that counters the financial worries that her daughters, Anya (Ally Lardner, MCAS '21) and Varya (Noelle Scarlett, MCAS '18), and Yermolay acknowledge. Lyubov spends money frivolously, giving to her family or to perfect strangers what she does not have to give. She cares not about the implications of her spending or charity but thrives off of the help or joy she can bring those around her, a kindhearted inclination that might soon result in the loss of the estate.
Yermolay has a plan to ameliorate the gradual economic downfall of the family. He proposes that Lyubov cut down the cherry orchard and divide the land into plots for lease for the new generation of vacationers in need of tranquil getaway spots.
Hostility to the proposal arises in every inhabitant or visitor of the estate, establishing the defining tension of the play as well as a persistent symbol of sentimentality and unblemished beauty. Such symbolism heightens when the veil that initially hid the trees lifts to reveal a masterpiece of BC set design—massive wooden structures embellished with delicate white tufts. This new backdrop underpins the rest of the production, ceaselessly reminding audience members of the life-or-death fate of this natural phenomenon that will eventually resolve by the play's conclusion.
Amidst the conflict, the arrival of Petya Trofimov (Andrew Meck, MCAS '18) adds another layer of incongruence accompanied with a call to intellectual introspection. Petya is a student and former tutor of Lyubov's son who recently drowned in the river running through the cherry orchard. His discourse invites a nearly philosophical interruption into the jubilant or superficial conversations of the ensemble, and his entrance welcomes romantic feelings between him and Anya that leave the audience mystified about a possible future together.
Nuance and uninterrupted fluidity characterize the overall performances of each and every cast member in The Cherry Orchard. Nemathcoua energized every movement, line, and expression with elegant effervescence, serving the graceful innocence of Lyubov without judgment towards the tumultuous consequences of her actions. Lardner executed the youthful purity of Anya with a stunning vocal clarity and telling eyes, and Mazzone drove home Yermolay's thirst for self-actualization and improvement from his family's subjugation with his consistent physical quirks.
Exquisite costuming, replete with rich colors and textures, and a furry co-star acted as playful finishing touches to the comedy-turned-tragedy. Charlotta (Catherine Backer, MCAS '18), the bizarre governess, performs magic tricks as well as dog tricks, offering relief from the more serious convictions of the show.
In her director's note, Patricia Riggin explains the relatability of The Cherry Orchard, citing how the humanity of the characters in the face of unavoidable yet unchangeable adversity still exists within all people today. However, Chekhov's focus on the "foolishness of the world around him" punctured the seriousness of humanity's undoing. The attention paid to mastering comedic moments and their timing, lifting them from the sometimes despondent dialogue, affirms the success of Riggin's attempt to highlight the farce of The Cherry Orchard.
While bleak possibilities and conclusions loomed throughout the The Cherry Orchard, they did not characterize its entirety. Rather, emotionally sincere performances and well-executed comedic vignettes offered a whole perspective into the ebbs and flows of human emotion.


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FERNANDA RUIZ
Web & Digital Designer focused on mixing design with newer, experimental, web based technologies to build non-traditional user interfaces and interactive platforms for a diverse range of collaborators and clients.
Currently working as Senior Digital Designer at Future Corp, formerly Web & Digital Projects Leader at Monumento and Senior Web Designer at Face.
Most, if not all of these projects are work in progress and will always be. This portfolio is incomplete and will always be.
Instagram Are.na WORKING NOT WORKING LinkedIn Email
Mexico 68 Poster
Poster design created with code. The shapes that make up the 68 number change according to the volume levels of the original audio recording of the 1968 Tlatelolco massacre in Mexico City.
On October 2nd, 1968, the Mexican government opened fire and murdered hundreds of students who were protesting during the Olympics held in Mexico City. The event was silenced for decades, with the government claiming the students were the ones opening fire against the military. That was a lie. October 2, 1968 was one of many days the government has turned against its own people. The country can still relate.
This poster has been featured in Poster Womxn
Base code is p5js / p5js Sound


Here's something I discovered recently and would like to share with you. If you are using Skype for Business Online and want to control access to it using Conditional Access policy, you should be aware that under certain circumstances the control can be completely bypassed.
Conditional Access is not processed by legacy clients, i.e. those that do not support modern authentication. For example, the Skype for Business 2015 client (the one that ships with Office 2013, and without modern authentication enabled) cannot interpret the Conditional Access policy and as such will bypass the controls.
In this example, I have created a new Conditional Access policy specifically for Skype for Business Online.
I want all users to be included in the policy.
I only want the policy to apply to Skype for Business Online.
And finally, I only want access to be permitted from Hybrid Azure AD devices (i.e. those that are joined to on-premises AD and device registered in AAD).
I've left all of the other settings within the policy at their defaults. Once I've enabled and saved the policy the next thing to do is test whether it works as expected.
The first test is to determine whether the policy blocks access from the Skype for Business 2016 client (click-to-run version) running on a device that does not meet the Hybrid Azure AD condition. As expected, the access is denied along with a friendly and reasonably helpful error message (shown below).
The second test is run from a machine that also doesn't meet the Hybrid Azure AD condition, but this time the sign-in attempt is from the Skype for Business 2015 client. In this test, the user is able to sign-in without any problems.
The Skype for Business 2015 client is effectively able to completely bypass the Conditional Access control, thereby rendering it effectively useless. Your Skype for Business Online instance can be accessed from any device from anyone who has valid credentials. The question is then what you can do about it? There's currently no silver bullet to handle this scenario. Microsoft makes provision to block legacy client apps for SharePoint Online and, to an extent Exchange Online, but there is nothing obviously available for Skype for Business Online.
One workaround is to force MFA (at the Azure AD level) for the users that need to access Skype for Business. With MFA enabled the user sees the following (spectacularly unhelpful) error when trying to sign-in from the Skype for Business 2015 client.
I understand that Microsoft are (as of November 2017) looking a method – currently in private preview – to address issues with legacy clients and Conditional Access, not just for Skype for Business, but across the board. Watch this space.
Posted by admin on November 30, 2017 at 12:55 pm under Azure Active Directory, Conditional Acces, Skype for Business.
I recently had a challenge with a customer that had on-premises Skype for Business (SfB) and were looking to migrate to SfB Online. They did not want to federate the two infrastructures, but instead wanted to undertake a re-pointing of users at a given point in time by modifying the DNS records. When they introduced AAD Connect the default synchronisation included the SfB attributes, which is standard behaviour when AAD Connect detects that the schema extensions for SfB are present in on-premises AD. The presence of SfB-related user attribute values in the synchronisation flow caused SfB Online to detect all existing SfB on-premises users as hybrid. It meant my customer could not assign SfB Online access to synchronised users, which would have been a problem for testing the cut-over. The workaround for this was to modify the AAD Connect synchronisation rules to set the SfB attribute values to null. The steps implemented to achieve this are shown below.
1. Stop the AAD Connect sync scheduler.
2. Open the Synchronisation Rules Editor and create an editable copy of the 'In from AD – User Lync' inbound synchronisation rule.
3. Set the new rule to have a higher precedence (lower numeric value) than the original rule.
4. Leave the scoping filter as is, i.e. no change.
5. Leave the join rules as is, i.e. no change.
6. Edit the transformation for each of the shown values. Change the flow type to Expression and the source to Authoritative Null.
Note. This command requires the Skype for Business Online Windows Powershell Module, available here.
The output should show your synchronised users with an InterpretedUserType of 'NoService'. If any appear as 'HybridOnPrem' then the custom synchronisation rule has not taken effect.
The synchronised users should now be available to enable for Skype for Business Online.
Hopefully, this has been useful to you. Let me know if you have any corrections or suggestions for improvements by adding a comment.
Posted by admin on September 16, 2017 at 3:00 pm under Azure Active Directory, Skype for Business.


Rastro # 22/24 apt.15, 2nd floor e/ Belascoain & Campanario, Centro Habana.
Familiar modern house with 2 extended bedrooms with ensuite bathrooms, just a few minutes from Vedado and Old Havana. It has been suited to pass an enjoyable layover between family and friends.
Familiar modern house with 2 extended bedrooms with ensuite bathrooms, located in a centrical Havana city, just a few minutes from Vedado and Old Havana. Each bedroom has two double size bed with an special possibility to add other personal bed if it is necessary. Accomodation has been suited to pass an enjoyable layover between family and friends.
I would like to book on 'Casa Daniel, Havana' where rooms prices are Double 30 CUC x night / Full Apartment 55.00 CUC.


text:
Schumer 'f--ked it up' on Build Back Better negotiations, senior Dem aide says
Joe Manchin demands that only parents working and making less than $200,000 get the full child tax credit — otherwise he'll tank it
Manchin's 'no' stance on Build Back Better means the Dec. 15 child-tax-credit payment could be the last one families ever see.
Goldman cuts GDP forecast after Sen. Manchin says he won't support Biden's 'Build Back Better' plan
West Virginia Sen. Joe Manchin said on Sunday that he would not support the $1.75 trillion bill.
How to make sure you don't fall for a gift card scam this holiday season
The FBI and Better Business Bureau (BBB) are issuing warnings about gift card scams this holiday season.
Donating to an online fundraiser? Here's how to make sure you don't get scammed
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Help Me Hank: Beware of popular puppy scams
We're talking thousands of dollars. Thieves are preying on your emotions.
How the $1.75 trillion Build Back Better plan could impact Americans' taxes
From extra taxes on adjusted gross income to higher limits on SALT deductions, here's who would be affected by the proposed tax changes in the BBB plan.
Black America to receive billions from Biden's BBB plan — here are the hard numbers
The White House and members U.S. Congress have been dropping hints that they are nearing a deal on the Build […] The post Black America to receive billions from Biden's BBB plan — here are the hard numbers appeared first on TheGrio.
'Cramming' bills scam: What it is and what you can do to protect yourself
Automatically paying bills means that, chances are, you might never actually open them -- which means you may not even know what you're paying for.
Online scams on the rise as we head into Holiday shopping season
The holiday shopping season is already underway and that means scammers are also making their moves.
How to spot warning signs of identity theft
Reports of identity theft in the U.S. doubled last year, and the problem isn't going away anytime soon.
Wyandotte man loses $3,000 in credit union impersonating scam
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Experts warn of scammers on mobile payment apps
It's easier than ever to digitally send and receive money right from your smartphone -- the trouble is, scammers know this, too.
Ordering takeout online? Beware of fraudulent websites
Ordering takeout is easier these days than ever before -- but, of course, with the convenience comes the potential for scams.
Scammers target people trying to donate to Haiti, Afghanistan
Many people want to offer financial help to those in Haiti and Afghanistan and scammers are taking advantage of that.
Scammers use QR codes to trick consumers into opening malicious links
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Beware of scammers trying to take child tax credit payments
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Michigan residents collecting unemployment need to watch out for new scam
Michigan residents who are collecting unemployment need to watch out for a new scam.
Fake contractor scams on the rise
If you've tried to get a quote recently to have work done to your home, chances are you have discovered that contractors are busy and in high demand.
Why you should clear digital clutter to protect your identity
The increased threat of identity theft is why experts are urging people to clean up their devices to protect their personal information.
Red flags to look for amid tax scam season
According to the Better Business Bureau, tax scams are still a problem this year. If you haven't filed your taxes yet this season, don't put it off any longer! The IRS discovers cases of identity theft because personal information is stolen and a fake claim for a refund is filed. "The IRS is not going to contact you and give you those high pressure tactics," Blankenship said. "There are unfortunately people out there that they're banking on the fact that you're not going to look into them any further, especially if they look professional," Blankenship said.
Experts warn of scams involving prepaid gift cards
The caller said all he had to do was buy $480 in eBay gift cards. Prepaid gift cards are being requested in several different types of scams, including government employee impersonation scams, secret shopper scams and puppy scams. The Better Business Bureau scam tracker showed that Americans lost nearly $3 million involving payments with prepaid gift cards in 2020. "Whenever you purchase a prepaid gift card, unfortunately it's just like cash, you can't get that money back," Blankenship said. Click here for more information on prepaid gift card scams.
Scam Alert: 'Like Farming' on Facebook
You may have seen a Facebook post that claimed a free Jayco RV would be given away to someone who shares and comments on the post -- or you've seen posts similar to it. RELATED: Better Business Bureau warns consumers of 'going out of business' online shopping scamMelanie Duguesnel, with the Better Business Bureau, said that by liking the page, you're potentially giving your personal information away. The BBB is warning people that "Like Farming" scams are still going strong. The free RV scam is so popular that Jayco has a post pinned to the top of its Facebook page to let people know they aren't running a giveaway. READ: More scam coverageTo prevent from falling for these scams, use your good judgement and don't "Like" every post on your feed -- that's what scammers are hoping you'll do.
Work from home scams: How to spot a fake job posting
DETROIT – With so many people looking for work, scam artists are turning to posting fake job opportunities in hopes of taking advantage of people desperate for a job and money. The Better Business Bureau is urging residents to pay attention to job postings online. You can report a complaint to the Better Business Bureau here. Michigan's attorney general outlined four specific types of COVID-19 vaccine scams circulating in the state and explained how they're targeting residents. Gretchen Whitmer to warn Michiganders about scammers looking to capitalize on the COVID-19 vaccine excitement.
Scammers using excitement surrounding COVID-19 vaccine to target Michigan residents
The delivery of COVID-19 vaccines in the state of Michigan is exciting and promising news for millions, but it's also a call for scammers to try to capitalize on the moment. Scams involving the COVID-19 vaccine have the attention of Michigan Attorney General Dana Nessel. The first Pfizer COVID-19 vaccine doses are rolling out to Michigan hospitals and clinics this week, and scammers know that. That's now how distribution of the vaccine will work, medical officials said. Anyone who has questions about the vaccine or any suspicious contact about the distribution should contact a trusted medical professional.
Better Business Bureau warns of COVID-19 vaccine scams
The Better Business Bureau is sounding the alarm in hopes you won't be fooled. Read: How Henry Ford Hospital played key role in Moderna vaccine studyCon artist are offering up ways to get a vaccine by telling people they can take part in clinical trials. Watch out for red flags -- if you haven't inquired about a clinical trial and you get a message about one, delete it. Once a COVID-19 vaccine is approved, Henry Ford says it is prepared to receive and store the vaccine -- which requires storage at extremely low temperatures. Drug companies Pfizer and Moderna have both developed promising COVID-19 vaccines that are nearing approval in the U.S.
Better Business Bureau warns of texting scams offering money to participate in COVID study
Scam artists have found many ways during the coronavirus pandemic to try and con people out of their money or personal information. The Better Business Bureau is warning consumers about a new text message claiming to offer $1,200 for participation in a local COVID study. "We have heard from consumers that there's a text message going around that says if you participate in the study, you'll earn $1,200," said Melanie Duquesnel, president and CEO of eastern Michigan Better Business Bureau. The difficulty is that you cannot, through a text message, determine if they're a reputable company."Click here to view the Better Business Bureau Scam TrackerWhen it comes to phishing scams, beware any unsolicited communication. Never click on links or download anything from a text message or email.
How your Facebook 'likes' could make you a target for scams
Watch out for online shopping scams as holiday shopping season kicks into high gear
DETROIT – Holiday shopping season is kicking into high gear and because of the coronavirus (COVID-19) pandemic, more people will be shopping online. Melanie Duquesnel is the president of the Better Business Bureau serving Eastern Michigan. "If a deal appears to be too good to be true, it probably is," Duquesnel said. The scammers call and when you answer you get a recorded message claiming to be from Amazon stating there is a problem with your Amazon account. Scammers also send emails or texts, asking you to verify your personal information -- all so they can steal it.
Better Business Bureau wants you to be wary of scammers pretending to be with the government
DETROIT – The Better Business Bureau is issuing a warning about scam artists who are taking advantage of people by targeting their cellphones. Scammers are pretending to be from the government, a police agency, or even COVID-19 contact tracers. They're trying to get your information to sell, or your money. "They're trying to bait you into being fearful," Duquesnel said. Walk away."If you have given away any personal information, contact your bank or credit card company immediately.
Scammers pretending to be from Amazon have been spoofing the Better Business Bureau's phone number
DETROIT – Con artists are posing as Amazon employees, calling people, and claiming to need information about their account, according to the Better Business Bureau. The scammers have been spoofing the Better Business Bureau's number while making this scam calls. READ: Better Business Bureau warns consumers of 'going out of business' online shopping scamHow does the scam work? Amazon will never ask you to disclose sensitive personal information or offer you a refund you don't expect. Amazon will also never send you an unsolicited message that asks you to provide personal information.
Better Business Bureau warns consumers of 'going out of business' online shopping scam
DETROIT – The Better Business Bureau is warning consumers about an online shopping scam involving "going out of business" advertisements. Melanie Duquesnel, president of the Better Business Bureau serving Eastern Michigan, said the difficulty they're finding is that clients are not getting the product but yet they're getting charged for it. READ: Scammers use multiple methods to target victims -- Here's what to watch out for"Just because an advertisement is on Facebook doesn't mean that it's a 100% trustworthy business," Duquesnel said. With more people buying cars, RVs and boats online, the BBB says vehicle shipper and escrow scams are going up. How do you know that you're going to get your money back?" Duquesnel said.
Seal coating scammers targeting Metro Detroiters who are home due to coronavirus pandemic
Seal coating scams typically take place this time of year, but now thieves are going door-to-door and targeting people who are home because of the coronavirus (COVID-19) pandemic. Police and officials with the Better Business Bureau issued a warning about the scam in Metro Detroit. With more people staying at home during the pandemic, scammers are having more success going door-to-door, experts said. Melanie Duquesnel, of the BBB, is urging residents to be cautious if anyone shows up at the door and offers a great deal. You can watch the full Help Me Hank report in the video above.
Consumers warned about hoverboards website: What to know
The Better Business Bureau is getting a steady dose of complaints about hoverboards.com. Here's what you need to know to avoid getting scammed. More: Help Me Hank
Tracking new election scam targeting voters in key swing states, including Michigan
Help Me Hank is tracking a new election scam thats targeting voters in key swing states, including Michigan. Its a key state for both sides, but now a new election scam is targeting Michigan voters, including those in Metro Detroit. Melanie Duquesnel, of the Better Business Bureau, is tracking the robocall scam. Voters think theyre getting a recorded call from politicians asking for a donation. In reality, the calls have been edited using the candidates actual words and splicing them together to make people think theyre asking for credit card or personal information.
Stimulus uncertainty and the money conversations you should be having
DETROIT – Many people are hurting financially and with the debate raging over the next possible stimulus -- it's a good time for many people to look at their finances. READ: Money saving resources during coronavirus pandemicMany credit card companies are waiving late fees. Some debt consolation companies are offering assistance. The details hidden in the fine print could cost you big time in the future. READ: Financial expert helps you manage your money during the coronavirus (COVID-19) crisisWatch the video for the full report
Lured by low rates, companies issue high-grade debt at one of the fastest paces ever this week
Companies rushed to sell $69 billion in high-grade bonds this week, the second-highest weekly amount ever, according to BofA Securities. "I think this is going to be another year where issuance volumes are down," said Hans Mikkelsen, head of investment grade corporate strategy at BofA Securities. He said the rate on the ICE/Bank of America investment grade bond index is 2.87%, about the same it was at in early September. That represents the rate on corporate bonds at all investment grade rating levels that have an average 11 years before maturity. Mikkelsen expects this year's total issuance to trail last year's $1.205 trillion in investment grade debt.
Watch Local 4 News at 4 -- Aug. 2, 2019
DETROIT - Here's what is coming up on Local 4 News at 4:GM plantIt's the end of the line for the General Motors Warren Transmission plant. NYPD choke-holdThere's a new ruling in a controversial police case in New York City. BBB helping natureWe've been bringing you stories about people helping our birds, bees and butterflies. Delta sign languageDelta is expanding it's customer service for the hearing impaired. Copyright 2019 by WDIV ClickOnDetroit - All rights reserved.


Low pressure air curtains for commercial doors.
MINIBEL air curtain is recommended for openings up to 1.8 m in height. Also can be used as an electrical over door heater for higher entrances in order to provide a warm welcome.
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The transcription factor Helios has been reported to be a marker of regulatory T cells (Treg) of thymic origin, distinguishing them from Treg induced in the periphery (iTreg). In this study, we demonstrate Helios expression in Foxp3+ iTreg, both in vitro and in vivo. Following i.v. peptide injection, in vivo Helios expression in adoptively transferred TCR transgenic T cells was more rapid than Foxp3 induction but less stable at later time points without a second injection of peptide. Our in vitro data suggest that APC influence Helios expression in a manner distinct from stimuli required for Foxp3 induction. Thus, Helios expression in iTreg may reflect the context of stimulation during Foxp3 induction. In summary, the robust Helios expression we observe in iTreg precludes its use as a marker of thymic Treg.
Expression of the transcription factor Foxp3 is required for the development, maintenance, and suppressive function of regulatory T cells (Treg) (1, 2). Although most Treg begin expressing Foxp3 during thymic selection, a subset known as induced Treg (iTreg) leave the thymus as CD4+Foxp3− T cells and begin to express Foxp3 upon encounter of Ag in the periphery (3). Weak TCR stimulation often results in Foxp3 induction, although increased concentrations of TGF-β may allow for Foxp3 induction when Ag density or potency is otherwise too high (4). Although peripheral induction of Foxp3 has been demonstrated in a variety of experimental systems, the absence of a specific marker for iTreg has made it difficult to assess their role in homeostasis and importance during physiological immune responses. Recently, it has been suggested that expression of the transcription factor Helios differentiates thymic-derived Treg from those induced in the periphery (5). Helios is a member of the Ikaros family of transcription factors, whose five members contain conserved C-terminal zinc finger motifs, which allow homodimeric or heterodimeric interactions between family members (6, 7). Through such dimerization, Helios may alter the function of Ikaros (8–10), which has been reported to influence T helper differentiation (11–13). In the steady state, Helios expression is largely restricted to Foxp3+ Treg (5, 14–16).
Recent reports have demonstrated Helios upregulation in both CD4 and CD8 T cell subsets upon stimulation, independent of Foxp3 expression (17, 18), and have also shown expression of Helios in Treg induced in vitro (18, 19). These findings raise concerns regarding the use of Helios as a marker to distinguish thymic-derived Treg from iTreg. Using an Ag-specific system, we show expression of Helios in iTreg induced in vivo and characterize the kinetics of this expression. A single low dose of high-affinity peptide, previously described to induce Foxp3 expression in a population of adoptively transferred naive 5C.C7 TCR transgenic cells (20), triggers Helios expression in the resulting in vivo iTreg. Time-course experiments reveal that after TCR stimulation, Helios expression precedes Foxp3, but that the levels of Helios expression are less stable in the absence of continued exposure to Ag. Our in vitro data suggest that APC influence Helios expression independently of Foxp3 induction, potentially reconciling the differences between our in vivo system and those published previously (5). In summary, although iTreg induced under some conditions may lack Helios, it clearly can be expressed in Foxp3+ Treg induced in vivo, and this precludes its use as a marker of thymic Treg.
5C.C7 TCR transgenic RAG2−/− CD45.1 mice were used as donor mice in adoptive transfer experiments, as described previously (20). Male B10.A mice, purchased from Taconic, were used as adoptive transfer recipients at between 6 and 9 wk of age. All mice were maintained in microisolator cages and treated in accordance with the regulations of the National Institutes of Health and the American Association of Laboratory Animal Care. Experiments in this study were approved by the Memorial Sloan-Kettering Cancer Center Institutional Animal Care and Use Committee.
Moth cytochrome c (MCC 88-103) peptide was synthesized and HPLC purified (≥95%) by Biosynthesis (Lewisville, TX).
Cells were cultured in a 37°C humidified chamber with 5% CO2 in complete RPMI 1640 medium (supplemented with 10% FCS, 2 μM glutamine, 100 U/ml penicillin and streptomycin, and 2 μM 2-ME). Single-cell suspensions were prepared from lymph nodes (LN) harvested from 5C.C7 RAG2−/− mice (routinely >90% Vαll+Vβ3+ by flow cytometry) and stimulated in duplicate in 96-well round bottom plates. A total of 1 × 105 5C.C7 T cells were cultured with either plate-bound anti-CD3 (clone 500-A2), with or without anti-CD28 (clone 37.N), or with 4 × 105 irradiated T-depleted splenocytes and either anti-CD3 or MCC peptide. MCC and anti-CD3 were titrated in each experiment as the optimal doses for Foxp3 induction vary among experiments; the doses shown are 0.1 μg/ml for plate-bound anti-CD3, 0.02 μg/ml for anti-CD3 with APCs, and 1 nM MCC. In addition, in vitro assays included 100 U/ml recombinant human IL-2 (PeproTech) and 5 ng/ml TGF-β1 (PeproTech). Cells were cultured for 90–96 h before cells were stained for flow cytometry analysis.
Abs to surface markers were from BD Pharmingen, eBioscience, or BioLegend. Foxp3 (clone FJK-16s; eBioscience) and Helios (clone 22F6; BioLegend) were detected after fixation and permeabilization with eBioscience reagents. Flow cytometry was done on a BD LSRII. Data were analyzed using FlowJo version 8.8.6 and further processed using Prism 5.0 (GraphPad Software).
Between 5 × 105 and 1 × 106 5C.C7 RAG2−/− CD45.1 T cells were transferred into B10.A recipients by tail vein injection. Mice were subsequently injected i.v. with 0.2 μg MCC peptide diluted in PBS. In some experiments, a second injection of MCC peptide was administered 14 d after the initial stimulation, as indicated. To enrich for 5C.C7 T cells prior to flow cytometry analysis, CD4+ T cells were purified from LN suspensions by Dynal negative selection (Invitrogen).
A previous report demonstrated enrichment of Helios− Treg in the peripheral lymphoid organs, relative to the thymus (5). Consistent with this, we found that nearly all Foxp3+ Treg in the thymus of naive wild-type animals express high levels of Helios, whereas ∼70% of Treg found in the peripheral LN and mesenteric LN (MLN) are Helios positive (Fig. 1A, 1C). Of note, in the Helios+ Treg population, the peak of expression is broader and more variable in peripheral Tregs compared with Treg found in the thymus, resulting in lower Helios mean fluorescence intensity (Fig. 1B, 1D). Decreased Helios expression in Treg found in the periphery, compared with the thymus, is consistent with either the possibility that Foxp3+Helios− cells are iTreg (5) or with the recent suggestion that Helios is a marker of T cell activation (18), because the temporal proximity of TCR stimulation is likely to be more variable for Treg in the LN than for those recently selected in the thymus.
Treg expression of Helios is lower in the periphery than in the thymus. Endogenous Foxp3+ Treg in wild-type B10.A mice were assessed for Helios expression. A, Representative flow plots, gated on CD4+ T cells, show the frequency of cells expressing Foxp3 and Helios. B, Overlayed histograms show Helios expression in Foxp3+ CD4 T cells found in the thymus (thick solid line), LN (thin solid line), and MLN (dashed line). The shaded histogram represents the Foxp3− compartment. The frequency of Foxp3+ CD4 T cells expressing Helios (C) and the geometric mean fluorescence intensity (GMFI) of Helios in Helios+Foxp3+ population (D), as normalized to percent maximum, were pooled from three independent experiments.
There has been some controversy as to whether iTreg generated in vitro express Helios (5, 18, 19). The minimal requirements for in vitro Foxp3 induction are TCR stimulation and the cytokines IL-2 and TGF-β (4, 21–23). When TCR stimulation is in the form of plate-bound anti-CD3, Helios expression is minimal, despite robust Foxp3 induction (5, 18, 19). However, when Foxp3 is induced using peptide presented by APC, a sizable proportion of the in vitro iTreg are Helios positive (19). Using 5C.C7 TCR transgenic T cells, which recognize MCC peptide in the context of I-Ek (24), we assessed expression of Helios in a variety of culture conditions used to induced expression of Foxp3 in vitro and addressed whether the presence of APC or the type of TCR stimulation was the variable resulting in differential Helios expression in previous reports. We were surprised to find that both anti-CD3 and MCC were similar in their ability to induce Helios and Foxp3 expression when presented by APC (Fig. 2). Thus, the presence of APC enhances Helios expression in iTreg induced in vitro, regardless of the type of TCR stimulation. These data suggest the existence of an APC-specific signal that is important for expression of Helios but not required for Foxp3 induction.
APC-specific stimuli distinct from those required for Foxp3 induction enhance expression of Helios in vitro. 5C.C7 RAG2−/− TCR transgenic T cells were stimulated with the indicated combinations of anti-CD3, anti-CD28, MCC peptide, and APCs. After 4 d in culture, cells were stained for Foxp3 and Helios. Data are representative of at least three independent experiments.
Although Helios is upregulated in iTreg generated in vitro, previous work has demonstrated that iTreg induced in vivo with oral administration of Ag do not express Helios (5). It was unclear whether all in vivo iTreg lack Helios or whether expression could vary depending on the route of Ag administration. We have previously characterized in vivo Foxp3 induction in adoptively transferred 5C.C7 T cells (20). In this system, 5C.C7 Rag2−/−CD45.1+ T cells are transferred into wild-type B10.A recipients before subsequent i.v. injection of a single dose of MCC peptide. We found that low doses of MCC were most efficient at inducing Foxp3 (20), consistent with previous work demonstrating that weak stimulation favors this process in vivo (25). Thus, using an optimal low dose of MCC peptide (0.2 μg), we induced Foxp3 and assessed Helios expression in 5C.C7 found in the LN 15 d after peptide injection. Adoptively transferred 5C.C7 do not express Foxp3 in the absence of peptide (Fig. 3A), indicating that all Foxp3+ 5C.C7 observed upon in vivo stimulation are not of thymic origin. We found that nearly all Foxp3+ 5C.C7 expressed Helios, with a portion of the Foxp3− 5C.C7 T cells also expressing Helios after stimulation, although at somewhat lower levels (Fig. 3A). This is consistent with a recent report observing that Helios was expressed at lower levels in polyclonal CD4+Foxp3− cells, compared with Treg, and that Helios expression correlated with markers of Ag experience (18). Induced Foxp3+ 5C.C7 had a lower level of Helios than the endogenous LN Treg compartment (Fig. 3B), although the significance of this is unclear, because the function of Helios in Treg is unknown.
Foxp3+ 5C.C7 induced in vivo express Helios. Congenically marked 5C.C7 RAG2−/− T cells were adoptively transferred and subsequently stimulated with a single i.v. injection of MCC peptide. Fifteen days later, CD45.1+ LN cells were assessed for expression of Foxp3 and Helios. A, Representative flow plots show the frequency of Foxp3+ and Helios+ 5C.C7, with or without injection of MCC peptide. B, Histograms show Helios expression in induced Foxp3+ 5C.C7 T cells (dashed line), in endogenous Foxp3+ CD4 T cells (solid line), or in total 5C.C7 from naive mice (shaded histogram). Data are representative of at least three independent experiments.
To better characterize the in vivo expression of Helios and Foxp3 in iTreg, we stained 5C.C7 for the two transcription factors between 1 and 21 d after injection of peptide (Fig. 4). We found that i.v. injection of MCC resulted in Helios upregulation in 5C.C7 T cells as early as 1 d after stimulation, with roughly half expressing Helios by day 2 (Fig. 4A, 4B). This was in contrast to Foxp3 expression, which was not apparent until later time points and gradually increased over the 3 wk of the time course. Interestingly, between days 4 and 21, the loss of cells within the Helios+Foxp3− quadrant corresponds with the gain of Helios+Foxp3+ 5C.C7 (Fig. 4A). This may suggest that Helios expression precedes Foxp3 expression within the same population of cells or alternatively that there is selective loss of the Helios+Foxp3− population, which would be consistent with a general loss of the Foxp3− compartment, as we described previously (20).
Kinetic analysis of in vivo Helios expression in iTreg. Adoptively transferred 5C.C7 RAG2−/− T cells were analyzed for expression of Foxp3 and Helios at varying time points after i.v. injection of low-dose MCC peptide. A, Representative flow plots are shown for the indicated days after peptide injection. The percentage of 5C.C7 T cells expressing Foxp3 or Helios (B) and the geometric mean fluorescence intensity (GMFI) for Foxp3 or Helios in the induced Foxp3+ 5C.C7 (C) are shown throughout the time course. Error bars represent SEM with two mice per group. Data are representative of two independent experiments.
To assess the stability of Helios expression in iTreg induced in vivo, we analyzed the mean fluorescence intensity of Helios in Foxp3+ 5C.C7 over time. At all time points where a significant proportion of the adoptively transferred cells expressed Foxp3, this population contained higher levels of Helios than the Foxp3−Helios+ cells (Fig. 4A). However, despite increasing or stable levels of Foxp3 expression, between days 9 and 21, there was a decrease in the mean intensity of Helios expression in the Foxp3+ 5C.C7 (Fig. 4A, 4C). Our previous work suggested that a significant amount of i.v. injected peptide is cleared within 2 d (20). Thus, we expected that this apparent decrease in Helios protein levels at the latest time point likely resulted from lack of continued TCR ligation. This would be consistent with the correlation between Helios expression and markers of T cell activation and with decreased Helios expression in Treg cultured ex vivo in the absence of TCR stimulation (18). To test this, in some experiments, we administered a second injection of MCC peptide, given 2 wk after the initial in vivo stimulation. This second dose of peptide resulted in higher Helios expression at day 21 (Fig. 5A, 5B). These data suggest that Treg may require frequent TCR stimulation and/or Ag-specific interactions with APC to maintain Helios expression.
Continued Ag-dependent stimulation is required for maintenance of Helios expression in vivo. Adoptively transferred 5C.C7 T cells were stimulated in vivo with either a single injection of low-dose MCC peptide at day 0 or with day 0 stimulation and an additional injection of MCC 14 d later, as indicated. At day 21, 5C.C7 T cells were analyzed for expression of Foxp3 and Helios. A, The geometric mean fluorescence intensity (GMFI) of Helios in Foxp3+ 5C.C7 from one experiment is shown beside B, Representative histograms of Helios expression in induced Foxp3+ 5C.C7 T cells (dashed line), in endogenous Foxp3+ CD4 T cells (solid line), or in total 5C.C7 from nonstimulated mice (shaded histogram). Data are representative of two independent experiments.
In summary, we have demonstrated expression of Helios in Foxp3+ iTreg induced in vivo. Our in vitro data suggest that the presence of APC is important for Helios expression, whereas our in vivo time-course experiments suggest that levels of Helios expression in iTreg may be less stable than Foxp3, because Helios seems to require more frequent stimulation. Our data are not inconsistent with the possibility that iTreg induced under certain conditions lack Helios. However, we observe robust expression of Helios in iTreg, which should preclude its use as a marker for thymic Treg.
The absence of a marker to distinguish iTreg from thymic-derived Treg has made it difficult to assess the role of peripheral Foxp3 induction in maintenance of homeostasis and during physiological immune responses. Several lines of evidence suggested that the Ikaros transcription factor family member Helios may be such a marker, with its expression in being restricted to Treg of thymic origin (5). However, more recent work has demonstrated that Helios expression may in fact reflect recent T cell activation; in both Foxp3+ and Foxp3− T cells, Helios expression correlated with markers of Ag experience and proliferation (18). In this article, we report robust Helios expression in iTreg induced both in vitro and in vivo, definitively precluding its use to distinguish thymic Treg from those induced in the periphery.
Expression of Helios in iTreg induced in vitro has been reported to vary based on the method of activation (5, 18, 19). We found that TCR stimulation with either peptide or anti-CD3 could induce Helios-expressing iTreg so long as APC were present in the cultures. These data show that the requirements for upregulation of Foxp3 and Helios in vitro are distinct and suggest that one or more APC-derived stimuli are important for expression of Helios, independent of Foxp3 induction. Thus, expression of Helios in Treg could be influenced by the phenotype and function of the stimulating APC.
Upon assessing in vivo iTreg, we found that a single low dose of MCC peptide administered i.v. was sufficient to induce both Foxp3 and Helios expression in a population of adoptively transferred 5C.C7 T cells. Differences in APC phenotype and function, and the potential importance of these for the expression of Helios in iTreg, may reconcile our in vivo observations with the lack of Helios expression observed in iTreg induced by oral administration of Ag (5). The specialized APC known to induce Foxp3 in the intestine and MLN express unique surface and secreted proteins (26). Mucosal APC responding to oral Ag and the APC inducing Foxp3 following i.v. injection of peptide could differ in their ability to trigger Helios expression. This would be consistent with enhanced Helios expression in the presence of APC in vitro, independent of the minimal stimuli required for Foxp3 induction. Thus, our data are not inconsistent with the possibility that Helios−Foxp3+ iTreg exist in wild-type mice but also demonstrate that iTreg may express Helios.
A recent report demonstrated that Helios expression correlated with markers of activation, independent of Foxp3 induction (18). By using an Ag-specific stimulation, we were able to characterize the kinetics of Helios expression in vivo. Helios upregulation was very rapid and peaked at 9 d after peptide injection, at which point levels began to decrease in both the Foxp3+ and Foxp3− compartments (Fig. 4). Of note, Helios expression was higher in the Foxp3+ compartment at all time points, consistent with evidence that Foxp3 may play a role in Helios regulation (15, 16). A second dose of peptide resulted in increased levels of Helios at later time points, suggesting that frequent TCR stimulation may be important for maintenance of Helios expression (Fig. 5). The possibility that Treg in wild-type mice receive frequent stimulation is consistent with evidence for Treg expression of self-reactive TCR (27, 28). Thus, it is interesting to speculate that Treg with lower levels of Helios may have been stimulated less recently. This would be consistent with the highest levels of Helios expression in the thymus, where cells have just been selected, and with loss of Helios in thymic Treg cultured ex vivo without TCR stimulation (18). In this scenario, cells with decreased Helios expression could include iTreg whose Ag was only transiently encountered but could also include thymic Treg that have not recently been stimulated in the periphery.
In conclusion, the robust expression of Helios in iTreg induced in vivo should preclude its use as a marker of thymic Treg. However, the lack of Helios expression by some Treg in the periphery may still distinguish a subset of cells that differ in their stimulation history, either by temporal proximity or the type of APC. Thus, it remains of interest to better understand the regulation of Helios in vivo and to investigate phenotype and function of Helios-Treg.
We thank A. Trumble-Koncelik for technical assistance and T. Simpson for helpful discussion and critical reading of the manuscript.
R.A.G. was a predoctoral fellow of the Cancer Research Institute. J.P.A. is an investigator of the Howard Hughes Medical Institute.
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