text:
As Greeks voted overwhelmingly to reject Europe's latest bailout offer with severe austerity as a condition, the country's atheist Prime Minister Alexis Tsipras called it a "victory of democracy." The Eurogroup chief, on the other hand, expressed concern, saying the result is "very regrettable for the future of Greece."
The final result for Sunday's referendum shows that 61.31 percent voted "no" and 38.69 percent voted "yes," local newspapers reported.
This sets Greece on an uncertain path, as the nation could now be headed for a worse economic disaster and even loss of its place in the euro. more >>
This Friday the Labor Department will release the Jobs Report for May. The monthly Jobs Report is based on data from a survey of 60,000 households and from a separate survey of business establishments. The Bureau of Labor Statistics uses the data to estimate the unemployment rate and the number of jobs added to the economy in the just ended month. They also revise the estimates made for the prior two months to take into account more complete information.
Last month's report for April was an estimated gain of 233,000 jobs, but March was only 85,000 additional jobs. It takes over 150,000 additional jobs per month to absorb the growth in the labor force as young workers enter the work force and older workers retire. We can hope that the progress seen in April will continue in May and beyond.
When the jobs report is released on Friday morning, there will be instant analysis on Wall Street and again on the Sunday talk shows. Pundits will discuss the political and economic implications of whatever the outcome turns out to be. As a student of the economy, this is all interesting to me. But sometimes we need to step back from the instant moment to gain perspective. The graph below illustrates my point. more >>
This was the horrible week in which millions of Americans paid their taxes to the ever increasing and intrusive federal government. This year, the tax burden has grown with Tax Freedom Day appearing on April 24, meaning that Americans will spend approximately one third of the year working for government before they can provide for their families.
Taxes are certainly oppressive in this country. Compared to last year, tax revenue increased 4.3% to $1.478 trillion in the first 6½ months of the 2015 fiscal year. Even worse, the insatiable federal government continues to spend money with reckless abandon. Through April 1 of this year, the budget deficit was an astounding $439 billion, a significant increase from 2014.
Not only are taxes and deficits increasing, but the actual size of the federal tax code is exploding. When the income tax was created in 1913, the tax code was only 400 pages. It increased to 26,000 pages by 1984 and has tripled in size in the last 30 years. Since the implementation of Obamacare in 2010, the federal tax code has increased another 3,300 pages, resulting in more rules and regulations for Americans to decipher. Today, the federal tax code is over 74,000 pages of bureaucratic nonsense, making it impossible for the average American to complete their own tax return. It is no surprise that 94% of Americans need professional assistance in finishing their tax return. more >>
It is tax week 2015. If you completed your tax return on time and wrote that check you'd much rather leave in your account, why not pour yourself a cup of coffee (or maybe a bottle of antacid relief) and plop yourself down in your favorite easy chair and sit a spell. You deserve it. While relaxing, why not take a minute to entertain yourself and learn how your hard-earned money was spent.
Now-retired Sen. Tom Coburn's (R-Okla.) "Wastebook 2014" reports the government spent $856,000 to teach mountain lions how to run on a treadmill, $171,000 to teach monkeys how to gamble and $387,000 to give rabbits massages. It spent $331,000 to see if spouses are more likely to stab "significant other" voodoo dolls when hungry, $15,000 to attract Colorado young people to the symphony by funding the creation of "Classically Cannabis: The High Note Series." While we're on that high note, the IRS paid $4.2 billion in tax refunds to identity thieves and the Defense Department paid $1 billion to destroy $16 billion in unneeded military-grade ammunition.
"Waste Watch," a publication released by Rep. Steve Russell (R-Okla.) discovered things like $456,669 million was spent on a firing range in Afghanistan that "melted" away after it rained. Another expenditure you probably missed in 2014, was a $100 million "bailout" the State Department discretely transferred to the Afghanistan government without much explanation. An example of how cracked the system is, in 2013, the State Department paid $207,297 to Humpty Dumpty Institute to fly young Iraqi filmmakers to Los Angeles to show them how filmmaking is done, resulting in the production of an anti-American film. more >>
In 2008, many conservatives opposed the bank bailout. Why send $700 billion of hardworking Americans' taxpayer dollars to banks that had failed? Some of us argued it was unfair. Some of us argued it was unnecessary. But among the strongest arguments we made was the moral-hazard argument. Bailing out reckless behavior today will only encourage reckless behavior in the future.
I continue to believe we were right to worry about the bad lesson the bank bailout would teach financial institutions. But in hindsight, we should have also focused on what it would teach others. All across the United States, in high school study halls and college dorm rooms, more than a few young Americans were watching Congress, the President, and Wall Street.
Any parent with children knows that when they are watching what you do, they are learning from what you do. If you swear, they will learn to swear. If you cut corners, they will learn to cut corners. The young learn the habits of the old – for better or worse. more >>
There's an old saying that all politics is local. If that is the case, it should follow that local politicians should be among the best informed, armed with iron-clad facts as they weigh in on issues that affect not only their areas, but the nation as a whole. The U.S. Conference of Mayors, however, has generated some confusion recently by throwing their support behind the embattled Export-Import Bank of the United States – apparently on the strength of some questionable data.
The group has supported the bank in the past and passed a resolution in favor of renewing Ex-Im's charter last June as the debate over the it's reauthorization raged in Congress. At that point, politicians from both parties along with a number of groups and individuals outside government were questioning the necessity of this eighty-year-old institution to the American people.
The bank is supposed to provide funding to facilitate deals between U.S. and foreign companies so that American products can be exported overseas. In practice, this has often translated into a government institution picking winners and losers. Ten large corporations, for instance, end up receiving more than half of Ex-Im's total funding. One of these, Boeing, received more than $8 billion by itself. more >>


text:
Occupy Wall Street Protesters Attempted To Occupy The NYSE On Wednesday Night
The Wall Street protesters on Wednesday October 6th night tried to occupy Wall Street in front of the Stock Exchange. Cops fought to barricade them on Broadway. They were not able to enter. See photos below.
Photos of Occupy Wall Street on Wednesday night in front of the NYSE > »
Comments on this post are now closed.

subset: commoncrawl


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PATERSON - A frustrated Paterson resident decided to fill in a pothole on his street that was proving costly to nearby residents.
William Villalona, a resident on East 21st Avenue, says a pothole on the block had already cost him two tires. He was set to take a picture of the hole when he noticed one of his neighbors attempting to fix it with supplies from a hardware store.
"Maybe when [the city] sees it, they'll realize the situation we live in and they'll fix it," said Frami Holguyn.
Holguyn told News 12 that he was tired of waiting for the city to fill the gap. He said it took him 45 minutes and $30 worth of supplies to fill the hole with cement.
Paterson Mayor Jeffery Jones says the city has more potholes than it can count. He blames the harsh winter for busting the budget and public works employees he describes as "derelict in doing their tasks."
Jones says the city will have to borrow $250,000 to hire contractors to handle the pothole problem. He says the city lacks the manpower and equipment to get the job done.


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Robert Shingledecker has announced the release of Tiny Core Linux 3.7, a minimalist, but extensible desktop distribution in 10 megabytes: "Team Tiny Core is pleased to announce the release of Tiny Core Linux 3.7. Final change log: new multicore.iso both Tiny Core and Micro Core installation and network tools edition; new added kernel module for NTFS to base, allows read access to NTFS partition; new GUI loadpack to load, when required, Starter Pack after boot; updated rebuildfstab now supports NTFS-3G for NTFS-3G extension, allows read-write access; updated cpanel to reflect changes in the base; updated tc-functions to better handle TCVD virtual disk; updated network GUI to record udhcpc PID for services support when DHCP is requested...."
Here is the release announcement with a changelog.
Download: tinycore_3.7.iso (10.3MB, MD5). The "mulitcore" CD image with a graphical system installer is available from here: multicore_3.7.iso (45.5MB, MD5).
• 2011-05-01: Distribution Release: Tiny Core Linux 3.6
• 2011-02-14: Distribution Release: Tiny Core Linux 3.5
• 2010-12-19: Distribution Release: Tiny Core Linux 3.4
• 2010-11-23: Distribution Release: Tiny Core Linux 3.3
• 2010-10-15: Distribution Release: Tiny Core Linux 3.2
Install Tiny Core Linux.
1. Obtaining cfdisk and GRUB via Appbrowser
default 0
timeout 10
title tinycore
kernel /boot/bzImage quiet
initrd /boot/tinycore.gz
For every letter after that, add one.
'b' is '1', 'c' is '2', 'd' is '3', etc.
Subtract 1 from y to get n.
'1' becomes '0', '2' becomes '1', '3' becomes '2', etc.
and that the use of hda for hdX means (hdM) is (hd0)
root (hd0,0)
setup (hd0)
eject /dev/hdc


text:
Luxury: exceptional accommodations, superior service and a full range of amenities
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Standard: pleasant accommodations, good service with many amenities available
Modest: comfortable accommodations with some services and amenities
Basic: simple accommodations with few services and amenities
Hotel rating to be determined
Check-in Policy:
Hotel requires a credit/debit card authorization or cash deposit upon check-in for incidentals; this will place a hold on your funds.
Convention Policy:
Individuals attending a convention cannot book this property for their stay. If found attending a convention, guests may be subject to higher room rates upon arrival.
Hotel Spring Break Policy:
This hotel cannot guarantee a spring-break-free environment.
General Information:
Room taxes are included in vacation price.
Minimum night stay restrictions may apply.
Reservation changes may not be permitted unless authorized by the hotel.
Obstructed View
Rooms offer 1 queen and 1 double bed or 1 king bed and a sofa sleeper.
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Luau and show
Moana Athletic Club exercise room (open 24 hours), weight training, fitness classes.
200 Nohea Kai Drive
Lahaina, Maui, HI 96761
TripAdvisor Traveler Rating
Please wait…
©1999 - 2016 Trisept Solutions


text:
Reviewed By jeffrey f (FOLSOM, CA) Reviewed for a 2015 Ford F-150 —10/12/2016 8:44 AM
The liner is thicker than some of its competitors. The fit is superb. The only situation I had was on one radius it look like there was a cut from a saw that was approximately 1/8 of an inch deep. Other than that the product was flawless and fit perfectly


text:
States, districts, charter networks and schools across the country have shared a common goal: putting an effective teacher in every classroom. However, the journey to reach that end result is not an easy one.
Instructional frameworks are the centerpiece of successful teacher effectiveness initiatives and are a vital component of a comprehensive teacher evaluation system. Frameworks define the actions effective teachers take to engage their students, ultimately resulting in higher achievement.
Insight partners with schools, districts and states to build customized frameworks or implement the Insight Core Framework — one of the only instructional frameworks specifically aligned to College- and Career-Ready Standards.
The Insight Core Framework consists of five core practices and indicators that describe what teachers can do help students master the CCRS and develop the skills and habits of mind needed to succeed in college and careers.
Insight has extensive experience in building customized instructional frameworks for schools, districts, and states that reflect the unique priorities, visions and contexts.
After conducting a thorough review of widely used instructional frameworks, relevant research and performance data, we partner with the school, district or state to establish a design team to develop the customized framework and rubric.
To learn more about Insight can support your organization, let's set up a time to talk.


text:
The man who's body was found in a burned home in Miller County on April 8 died while trying to burglarize it, according to Miller County Sheriff Bill Abbott.
Investigators determined during the burglary on Eldon Road, 23-year-old Brent Comer set the house on fire to cover up the burglary and got caught inside. A gas can was found in the house near a stove.
The Missouri medical examiner said Comer died from smoke inhalation.
The owner of the home, Treba Taylor Crismon, who lives down the road, said the home was vacant and in-between renters.
Miller County Sheriff Bill Abbott said through their investigation, it was determined Comer acted alone.


text:
Get Real
Release Date: April 30th, 1999
R|1 hr. 48 min.
Plot Summary
Steven (Ben Silverstone) spends his school days longing for all-star athlete John (Brad Gorton). But John has a gorgeous girlfriend, and Steven is still in the closet about being gay. The only one who knows the teenager's secret is his friend Linda (Charlotte Brittain). After a curious run-in with John in a public restroom, Steven starts to wonder if the jock is straight after all. When they start a romance, it threatens to expose the truth about both of them.
Cast: Ben Silverstone, Brad Gorton, Charlotte Brittain, Stacy A. Hart, Kate McEnery, Tim Harris, James D. White, Patrick Nielsen
Director: Simon Shore
Genres: Comedy drama
Distributor: Paramount Pictures


text:
Nancy Walker
- Birthday
- May 10, 1922
The daughter of vaudevillians, 4'11" entertainer Nancy Walker had wanted to establish herself as a serious singer. But when Nancy auditioned for Broadway impresario George Abbott, he burst out laughing at her reading of the line "Is this where the aliens go to register?" and immediately cast her as the hoydenish Blind Date in his 1941 musical production… More Bio:
The daughter of vaudevillians, 4'11" entertainer Nancy Walker had wanted to establish herself as a serious singer. But when Nancy auditioned for Broadway impresario George Abbott, he burst out laughing at her reading of the line "Is this where the aliens go to register?" and immediately cast her as the hoydenish Blind Date in his 1941 musical production Best Foot Forward. She went on to make her Hollywood debut in the film version of this production, then returned to Broadway, where she skyrocketed to stardom in such productions as On the Town (1944) and Look, Ma, I'm Dancin' (1948). She continued headlining on Broadway throughout the 1950s, occasionally showing up on television variety series, most memorably as the teen-aged president of the Milton Berle fan club. Despite her enormous success as a comedienne, Walker was the archetypal "laughing on the outside, crying on the inside" type in private life, undergoing several years of therapy to purge herself of her insecurities. When theatrical opportunities began drying up in the late 1960s, Nancy relied more and more on television for a living. She was featured as Rosie the waitress in a series of paper-towel commercials ("It's the quicker picker upper"), co-starred as Mildred the maid on MacMillan and Wife (1971-75), and, most memorably, was cast as Ida Morgenstern, the Jewish mama to end all Jewish mamas, on The Mary Tyler Moore Show (1970-77) and Rhoda (1974-78). Though nominated for five Emmies, she never won the coveted statuette, a fact that seemed to bother her husband David Craig (a vocal coach whom she'd met when she lost her voice during Look Ma, I'm Dancing) more than Walker. Banking on her renewed celebrity, she attempted several TV starring vehicles of her own, but none lasted beyond the first season. She had better luck as a stage director, helming such theatrical productions of UTBU and A Pushcart Affair. In 1980, Walker made her film directorial debut with the Village People starrer Can't Stop the Music, produced by her then-manager Alan Carr. Nancy Walker's final regular TV-series stint was on the 1990 Fox Network weekly True Colors; two years later she died of lung cancer at the age of 71.
That's Entertainment! III (1994)
- Actor
- 100%
Can't Stop the Music (1980)
- Director
- 8%
Human Feelings (1978)
- Actor
Won Ton Ton, the Dog Who Saved Hollywood (1976)
- Mrs. Fromberg
Murder by Death (1976)
- Yetta the Maid
- 65%
- See all 14 films
Nancy Walker Videos
Born Today
- Simon Le Bon (58 years old)
- Troy Gentile (23 years old)
- Manami Konishi (38 years old)
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- Paul Fox (91 years old)
- Marla Maples (53 years old)
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text:
Vtech® V.Reader Interactive E-Reading System in English
This product is currently not available.
Item #: 16039120310
Online Availability: Out of stock
In-store availability - show
About this product
About this product
Product features
Product features
Plays fully animated stories with story narration, character voices, vivid graphics and exciting music and sounds
- Touch the screen to read the story, and play interactive reading games.
- Durable, kid-tough design
- Includes USB port for downloading of additional content and SD memory card slot for memory expansion
- Plastic & PCB board
- Includes 3 types of activities: Watch the Story, Reading Games and Story Dictionary
- 1.10" l x 6.60" w x 8.20" h
- Ages 3+ yrs
- Requries 4 alkaline AA batteries, not included. AC adaptor compatible
- USB cable and SD card sold separately
You may also like
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Specifications & warranty
Specifications & warranty
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Product depth (in.)
Product height (in.)
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Product width (in.)
Ratings & reviews
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Questions & answers


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text:
Nintendo is More Valuable Than Sony Because You're All Pokémon Go Freaks
Let that sink in for a second.
Let that sink in for a second.
Out of the box thinking but we're not convinced.
One to snap up, or overdeveloped idea?
AR, a Pensieve for muggles and actual improved vision.
What's 55 million minus 36 million?
Essentially, it'll allow developers to create more advanced versions of the games they are working on, without spoiling the fun of existing PS4 owners.
Still no word on when 4K will actually be switched on though.
3.50 update does more than advertised.
Can it really compete with Oculus Rift and HTC Vive? Having just tried it, I can safely say: Hell yes.
Your machine needs to be running Windows 8.1 or higher, or OS 10.10 or higher.
Now that Marvel and Sony have joined forces to make the next Spider-Man movie, expectations for the film among fans are impossibly high. This possible title for the film should temper those expectations a bit.
Shut up and give me LittleBigPlanet or Jak and Daxter on my iPhone ASAP.
4K PS4 gaming for the players.
Want to see what the future looks like?
Standalone PSP portal closes on March 31st.
With variable pressure sensitivity for accurate Street Fighter VI punches.


text:
Bells are attached to fabric strips and then mounted to a wooden handle.
Bells are attached to fabric strips and then mounted to a wooden handle.
Reviewed by 1 customer
Comments about Trophy 25 Sleigh Bells on Handle:
Nicely shaped grip, turned on a well finished piece of hard-wood, with nylon strapping stapled to the core, and 25 steel bells rivetted to the strapping. I wouldn't throw it in a sound effects box with lots of heavy stuff on top, the bells might get loose after a while. Otherwise, seems durable. A good value. TIP: for clean articulation, turn the individual bells so the slots are all aligned vertically and the balls rest in the 'corner' of each bell. Quieter in preparation too.
Our product catalog varies by country due to manufacturer restrictions. If you change the Ship-To country, some or all of the items in your cart may not ship to the new destination.


text:
realmagick.com The shrine of knowledge.
Actuarial Notation
A selection of articles related to actuarial notation.
Original articles from our library related to the Actuarial Notation. See Table of Contents for further available material (downloadable resources) on Actuarial Notation.
- The Legend of Stonehenge
- Stonehenge has fascinated thousands of people throughout the ages, even today people are still wondering about the origins of the mysterious Stonehenge. Today's scientists and historians are still unable to come to a solid theory of when, why, by whom, and...
Earth Mysteries >> Mystic Places
- Feasts of the Times
- "There are rituals of the elements and feasts of the times." - AL II,36 The Tropical Zodiac, while not shifting with the precession of the Earth like the Sidereal Zodiac, has the charming...
Magick >> Thelema
Actuarial Notation is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Actuarial Notation books and related discussion.
Suggested News Resources
- Opinion versus practice regarding the use of rehabilitation services in home
- Resources for home care rehabilitation are limited, and many home care clients who could benefit do not receive rehabilitation therapy. The interRAI Contact Assessment (CA) is a new screening instrument comprised of a subset of interRAI Home Care (HC) ...
- Health Care Law Update for November 2' 2015
- This increase was initiated after it was determined there would be no cost-of-living adjustment in Social Security payments, meaning some beneficiaries would see an increase in order to maintain the actuarial balance of the Medicare program. Roughly 70 ...
- Does Your Defined Benefit Plan Need to be Amended Before Year-End?
- A hybrid plan must include special rules for determining interest credits and actuarial adjustments after a plan termination. Actuarial Increases after Normal Retirement Age.
Great care has been taken to prepare the information on this page. Elements of the content come from factual and lexical knowledge databases, realmagick.com library and third-party sources. We appreciate your suggestions and comments on further improvements of the site.
Actuarial Notation Topics
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text:
Feb. 2, 2009
PITTSBURGH (AP) -- Sam Young had 23 points and DeJuan Blair 18 and No. 6 Pittsburgh beat Robert Morris 92-72 on Monday night.
Levance Fields added 12 points and 13 assists and Jermaine Dixon 15 points for the Panthers (20-2), who were playing their first game while not ranked in the top five since Nov. 22.
Pitt has won four of five since losing for the first time this season and falling from the No. 1 ranking it held for two weeks.
Jeremy Chappell had 19 points and added a team-high eight assists for the Colonials (15-8), who had a nine-game winning streak snapped.
Young is Pitt's leading scorer at 18.1 points per game. But he had cooled recently, having scored at least that many only three times in his previous 11 games--including a season-low five against Notre Dame on Saturday. Monday, he shot 8-for-11 from the field and 7-for-8 from the free throw line.
Robert Morris, which has lost all 27 all-time meetings with Pittsburgh, was within 24-22 midway through the first half but the Panthers went on a 29-11 run before the break to take over the game. Pitt scored a season-high 53 first-half points and has scored 185 points the past two games.
The Colonials led with 13 minutes to play in the two team's most recent meeting Nov. 29, 2006, but the Panthers won that one going away, too.
Rob Robinson had 15 points and Francisco Bateko 13 for Robert Morris, which shot 57 percent from the field but committed 19 turnovers and had only two offensive rebounds.
Pitt is 66-0 against teams from the Northeast Conference. Robert Morris, a school located in suburban Pittsburgh which is coached by former Panthers assistant Mike Rice, is in first place in that league.
The Panthers completed their non-conference season 13-0, marking the third time in the program's history they went undefeated outside of conference--all in the past six seasons.
Pitt Picked 12th in ACC Preseason Poll
Panthers Conclude Open Scrimmage
Pitt Announces Basketball Theme Days & Ticket Offers
Young Named to Karl Malone Award Watch List
Pitt Basketball Weekend Set For Oct. 22-23


text:
Pam shares a story about attending a GWAR show, since lead singer and found Dave Brockie has died. Then, Shaun the Intern challenges AJ to a few round of iPod-o-rama. Former Producer Ed is now a father, and called in to share the good news, and News 8 SportzEdge reporters John Pierson and Erika Wachter play an impromptu round of shock collar trivia. DO NOT MISS: Pam's story about pooping on roller blades.
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text:
how to start a skateboard deck company - download fast -=COqG=-
how to start a skateboard deck company.zip - download 2015
Name: how to start a skateboard deck company.zip
Release: 2015
Type: WinZip
Total Downloads: 14196
License model: Shareware
Language: English
Last updated on: 01/28/2015 16:07:40
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Follow up on "As We Grow Up" exhibition!
Ha Noi - Until April 2014 the Vietnamese Museum of Ethnology (VNE) hosts the exhibition "As We Grow Up".
Follow all the activities and stories about this exciting adventure which took place from November 2013 to the end of April 2014!
» Read the story about the launch of the exhibition
» Read Who has visited the exhibition so far?
» Read about January's interactive session "Windows of Love Offline'"
» Discover the photo diary of January's "Windows of Love Offline"
» Read about February's interactive session "Windows of Love Offline"
» Discover the photo diary of February's "Windows of Love Offline"
» Read about the exhibition's celebration of International Women's Day 2014
» Read about the final youth dialogue about school-related violence
» Discover the photo diary from the exhibition's final interactive dialogue
The exhibition was a joint effort between the Ministry of Education and Training (MOET), the Ho Chi Minh Communist Youth Union (HCYU), the Vietnamese Museum of Ethnology (VME) and the One UN in Viet Nam (with UNESCO as the lead agency in collaboration with UNFPA, UNAIDS, UN Women, UNODC and UNICEF).
For more information, please contact:
Vu Nguyet Minh (Ms)
National HIV and Education Programme Officer
UNESCO Ha Noi Office
23, Cao Ba Quat Street
Tel.: +84 (4) 37 47 02 75
Mob: +84 (9) 04 88 22 18
<- Back to: UNESCO Office in Ha Noi


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I consider both PFE and MRK to be fully valued. They both sell for 12 to 13 times consensus 2014 earnings with expected earnings growth rates no more than mid single-digits at least through 2015 and with dividend yields in the mid 3's.
Here are earnings expectations for both companies:
2012: $2.19 for PFE, $3.82 for MRK (actual)
2013: $2.21 for PFE, $3.51 for MRK (consensus)
2014: $2.35 for PFE, $3.79 for MRK (consensus)
2015: $2.43 for PFE, $4.02 for MRK (consensus)
2016: $2.57 for PFE, $4.61 for MRK (consensus)
There's little to excite about PFE's earnings growth prospects all the way through 2016. For MRK, there's hope in the form of 2016 earnings but hefty expirations are taking a big bite out of 2013 earnings and the fact is that earnings for 2014 will be no more than what they earned in 2012.
But just because there is little to get excited about with respect to the company's STOCK, there are nice prospects for those who consider deep out-of-tyhe-money naked puts such as the March 23-strikes.
These newly-introduced puts are currently trading at $58 per contract bid, $63 asked. Cash margin requirements at TD Ameritrade (andONLY art Ameritrade) arwe $293 per contract and up-front premiums after commissions for those selling at the bid price are $57.40. The nominal return for those holding the 9.8 months to March expiration is 19.6% which is 24$ annualized or a full 2% per month.
In order for a buy-and-hold Pfizer investor to earn 19.6%, the stock would have to be at least a $34 number factoring in the three dividend payments. Looking at those earnings prospects, what are the realistic chances of the stock getting much over $34 by then? On the iother side of the coin, there is the very real chance of the stock falling somewhat. Even at say $26, this wouldn't exactly be the buy of the century.
Now if the stock does fall to $26 at March expiration, buy-and-hold investors would be staring at an overall 7% LOSS (10% loss on the stock less 3% dividend
Thanks for the reply to my post. What is your opinion on the biotech companies such as Celgene and Biogen? Is it true that the biotech companies are less vulnerable to generic competition than the pharmaceutical companies such as Pfizer and Merck because it is much more difficult to copy a biotech drug receipe than it is to make a generic version of a successful pharmaceutical drug such as Lipitor or Singulaire?
Practically all of the drugmakers have had great runs the last six months and most are either fairly valued or overvalued. One that has not moved is TEVA which I consider the one that is safest and most undervalued at just seven times the 2014 consensus. There isn't a lot of growth there but it does pay a 3%-plus dividend similar to PFE and MRK.
CELG has had a fine run-up but valuations still aren't bad relative to growth prospects. Other than TEVA, it's the only one that I would consider buying now. BIIB is a similar 20% annual earnings grower but it's selling at 30 times earnings and the consensus one-year target price is 5% LESS than the current market quote. As a value investor, it's not my kind of stock.
Yes - biologics are tougher to replicate but biosimilars as they are called are making good inroads in Europe and it's just a matter of time before they are more prevalent here.
BIDU remains my favorite stock. Its growth rate is at least as great as CELG but it sells for only a multiple under 16 relative to 2014 expectations. It has always been known as the "Google of China" but now it has become both the Google AND the Netflix of China. I am already up by 27% in just two months on my 300K options investment.
On the other hand, a naked put investor selling the March 23's wouldn't be fazed at all by a stock price drop to $26. He would STILL earn that 19.6% for 9.8 months even while buy-and-hold investors wereLOSING money. So not only are the returns with naked puts superior unless that stock really takes off (unlikely for PFE with such tepid prospects) but there is considerable downside safety as well.
You say you don't know much about options or can't get the all-important NAKED put authorization at Ameritrade? Well, I consider myself to be an excellent teacher and moreover, all members of my investing group WILL receive naked put authorization and they will all receive 21% commission discounts as well.
The commission savings alone often are as much as or more than the 1% fee that I charge (a whopping $50 for a 5K account for instance). For those that think that my returns are too good to be true, let me assure you that they ARE true.
As for those who remember that I lost 92% of my original money during the 2008/2009 crash, let me say that DEEP-out-of-the-money naked puts were NOT available during the crash. Had such options been trading, my percentage losses would have been much smaller.
If you or anyone else here is interested in finding out more about my one-of-a-kind program that offers outsized returns with less risk than buying and holding the stock, I can be reached at (213) 222-5547. What do you have to lose by calling?


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For many, the holiday season is a time filled with joy. From gatherings of friends and family to participation in religious and civic activities, the months of November and December provide much to do.
But the holidays can also be an unfortunate time—a time when ne'er-do-wells are all too intent on dashing holiday spirits.
The anticipation has been building over the past weeks as fishermen await the arrival of the giant bluefin tuna to our waters. Since 2005, these powerful and highly valuable fish have provided sport and much needed supplemental income to local fishermen. As this is still a new fishery to our area, every year the big question is, "I wonder if they'll show."
As a working journalist, I have met a lot of different folks over the years. Interviews are one of the facets of writing I dearly love. It's fun to meet new people, to ask questions, to find out what makes them tick.
Last week, I met a real raconteur, a guy who has a great life story and a gift of gab to go with it.
Charlie Megaswing has been teaching the game of golf at the State Line Driving Range for more than 10 years. The facility is on the southbound lane of U.S. 17, right on the border of North and South Carolina.
After being rained out Friday and Saturday, Beach Assembly of God presented Bethlehem Live for the first time on Sunday, Dec. 6.
About 500 people attended Sunday night despite the cold. The church had more than 2,500 people make reservations to attend one of six performances.
Performances are set for Friday, Dec. 11, Saturday, Dec. 12 and Sunday, Dec. 13.
To make reservations, or for more information, call the church at 579-9701.
A Columbus County grand jury has found probable cause that R.C. Soles Jr., the state's longest-serving legislator, assaulted a man during the August shooting at Sole's Tabor City home.
On Thursday, 12 grand jurors found sufficient evidence that Soles, a state senator and Tabor City attorney whose district includes Brunswick County, assaulted Kyle Blackburn during an altercation at his home on Aug. 23.
While the grand jury found probable cause, no charges have been filed.
On the outside, it's the Brunswick Family Assistance Christmas headquarters on Main Street. Inside, it's a Santa's workshop of sorts, with an army of volunteers packing, wrapping and organizing presents to fulfill local children's Christmas wish lists.
Shallotte police officers are investigating a robbery with a dangerous weapon, kidnapping and assault by pointing a gun at Hardee's on Main Street on Saturday night.
Officers reported two suspects entered the store and rushed an employee into the office where the manager was. The suspects held employees against their will and stole $2,700 from the restaurant.
CAROLINA SHORES—Mayor Stephen Selby said this week he doesn't plan to further pursue a breach of his e-mail account at town hall.
A few weeks ago, it was discovered Selby had not received e-mail sent to him at town hall for about a month because it had been "compromised."
Speaking at a town board of commissioners' workshop Dec. 7, Selby said he did not receive e-mails sent to his town hall address from Oct. 19 through Nov. 23.
All of his e-mail had been forwarded to a now defunct address, to "Mica Richards" at yahoo.com.
Property owners in the Midway Road area, one of two areas the town of St. James has approved for involuntary annexation, recently filed suit against the town seeking to declare the annexation ordinance "null and void."
The suit claims the annexation plan does not meet the requirements of state statutes regarding annexation and criticizes methods the town used to select the property.
Shallotte police officers have charged a Hardee's employee in connection with a robbery at the restaurant on Main Street on Saturday night. Two other suspects remain at large.
Jessica Danielle Cortes, 17, of 4731 Babson Road, Ash, has been charged with aiding and abetting an armed robbery and conspiracy to commit armed robbery.
Arrests of the two suspected robbers are pending, police said Tuesday.
Copyright © 2016
The Brunswick Beacon is your source for local news, sports, events and information in Brunswick County, North Carolina and surrounding areas.


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How M&A is powering growth in the 'Internet of Things' -- Facebook launches new features to threaten eBay, Amazon -- and more from TheStreet and its affiliates.
After 31 years, MetLife is leaving Snoopy and the Peanuts Gang behind.
Doug Kass shares his thoughts on life insurance and how Fastenal is dropping like a stone.
Doug Kass shares his thoughts on how friends don't let friends do Deutsche Bank and how Berkshire Hathaway is no longer your father's Berkshire Hathaway.


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Rodizio Grill opening in former Sabor space
Different restaurant, but same concept: A Rodizio Grill will open in the former Sabor Brazilian Churrascaria space downtown on Dec. 6, the first Wisconsin restaurant for the Utah-based chain.
The franchisee opening the Milwaukee restaurant is Oshkosh-based Supple Restaurant Group. »Read Full Blog Post(2)
MSO, Swingle Singers enchant with rare 'Sinfonia'
One of the great joys of having a high-quality symphony orchestra in town is the opportunity to experience an enormous variety of music - live.
Friday's Milwaukee Symphony Orchestra concert presented a rare opportunity to hear Luciano Berio's "Sinfonia" for eight voices and orchestra. »Read Full Article(2)


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Though psychology as a distinct discipline is typically considered to date back to 1879 when Wilhelm Wundt established the first psychology laboratory, its subject matter goes much further back. Our understanding of how people think and behave shapes how we deal with problems in how people think and behave, and a good example of this is the millennia-old practice of trepanation (or trephination) – making holes in the skull to alleviate psychological symptoms. In my psychology lectures on this for first-years, I show some skulls that have been holed, some square and raggedly saw-toothed at the edges, some rounder and smoother. Importantly, the smooth-edged holes indicate the patients must have lived long enough for the bone to at least
start to heal.
Around 800 trepanned skulls have been dug up, and from all over the globe. From these, it appears survival rates were around 90%, indicating the practitioners responsible were pretty good at what they did. A variety of techniques were practised, but the most common involved gradually scraping away at the skull until the dura mater, the membrane that encloses the brain and spine, was exposed. Why would anyone do such a thing? Well, if you believe that the symptoms we identify with depression, anxiety or schizophrenia are caused by evil spirits taking up residence in our noggin, then doesn't it also make sense to let them out? At least that's the story I tell, and it's a common one in introductory psychology textbooks. In truth, it seems we can't be sure that trepanation was always conducted for this reason. Hippocrates, the "father" of medicine, wrote of trepanation as a procedure for dealing with various types of head trauma – that head injuries caused a build-up of blood that could go bad and should therefore be released.
Paul Broca, famous in neurological circles for identifying in the mid-1800s a key area of the brain associated with speech production, is also credited with playing a part in the "discovery" of trepanation in historic skulls. He speculated initially that the procedure might have served some ritual purpose (bits of skull have been attributed powerful totemic significance), and later speculated the procedure might have been used to treat epilepsy. Hippocrates aside, there are few records to explain the rationale for trepanation among many of the "non literate" and now "dead" cultures that practised it. But these people were uncivilised, right? Surely, these days we need a hole in the head like, well, we need a hole in the head. Not so fast.
First, to characterise this historical practice as irrational is unfair because (where we know the reasoning) it was entirely consistent with the theories of mind and behaviour dominant at the time. Second, trepanation-like surgery is currently used (for example, after head trauma) to relieve swelling that could lead to more serious consequences. Third, you don't have to do much googling to find people advocating for elective (and freely available) trepanation on the grounds that it is a path to enlightenment and general psychological good health. The International Trepanation Advocacy Group has argued for some time that trepanation has benefits and has even collaborated on research projects testing the underlying theory that trepanation can improve psychological performance by increasing cerebral blood flow. As of 2010, this research has shown that blood flow can indeed increase following trepanation. But call me a sceptic – this doesn't automatically mean the procedure will be beneficial.


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User:Jeff Silvers
From Wikipedia, the free encyclopedia
My name is Jeff Silvers. I've been contributing to Wikipedia since early May 2005 (though didn't actually create an account until September 2005).
I'm sure I'll add more to this page eventually, but in the meantime, allow me to shamelessly plug my web site, jeffsilvers.com!


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When Brett Netson pulled into Old Town Portland for the first time back in the early '90s, to play Satyricon with his psychedelic punk band, Caustic Resin, he felt like a kid in a candy store—the sketchiest, most run-down candy store in the Northwest.
"Oh my God, it was beautiful," says Netson, now a member of Built to Spill. "It was everything I ever wanted: drugs, prostitution, espresso drinks and art." Coming from Boise, where cheap thrills were limited to pulling a steelhead out of the town's eponymous river, the urban rot was exotic, even intoxicating. He'd been to Seattle, but found it too high-minded. Salt Lake City was, well, Salt Lake City. This place, though? It was the sleazebag paradise of his punk-rock dreams. "Back then, Portland was dangerous,â he says. âBoiseâs not dangerous.â
These days, of course, "dangerous" isn't the first word often associated with Portland. But then, Boise has changed, too. It's not exactly the new capital of sex, drugs or even espresso, but its arts scene has developed to the point that it can now support a huge, multi-day music festival. This week, 360 bands—including 48 from Portland—will descend on the City of Trees for Treefort, a sort of slimmed-down South By Southwest, with shows spread across multiple venues in downtown Boise. Now in its third year, the festival is headlined by national and international acts, including Run the Jewels, RJD2 and the Joy Formidable, and also features a film and tech component, but its true function is as a showcase for the emerging Pacific Northwest music scene. And by hosting, Boise is sending a message: We're not just about the Potato Bowl anymore.
âThereâs a sense in Boise of forward momentum,â says Treefort founder Eric Gilbert, frontman of indie-pop group Finn Riggins. Moving back to Boise from Hailey, Idaho, in 2009, Gilbert found a city resembling the Portland of 10 years ago, with a music culture expanding just below the rest of the country's radar. He started Treefort as a means of galvanizing that growth. But he says the goal isn't necessarily to make Boise the next Portland. "A lot of us like it for its quaintness," he says.
In the days before the Internet, though, that "quaintness" is what drove a lot of bands out of town. Historically, Boise has acted as a developmental league for artists who'd go on to greater success elsewhere. Seminal Nuggets-era garage-rockers Paul Revere and the Raiders formed in Boise but didn't notch their biggest hits until after moving to Portland in the early 1960s. Tad Doyle was the city's answer to Greg Sage in the '80s, leading the DIY punk scene before departing for Seattle, starting the band Tad, signing to Sub Pop and getting credited as a grunge pioneer. Until Doug Martsch founded indie-rock guitar heroes Built to Spill in 1992, the closest thing Boise could claim as a homegrown success story was Providence, a '70s soft-rock group whose lone album went gold in the U.K.
"Portland was in the shadow of Seattle, and we felt we were in shadow of both," says Todd Dunnigan, a fixture of the Boise music scene for 30 years.
That inferiority complex still existed when Gilbert came back to town five years ago. "The general populace was not listening to a lot of local bands," he says. That changed in 2011, with the launch of Radio Boise, the city's first free-form community radio station. Treefort followed the next year, capitalizing on a mindset shifting toward supporting local music rather than regarding it with cynicism.
"It's changed drastically in the last few years, like big-time," says Ryan Peck of Boise synth-pop duo Edmond Dantes, one of the 150 Boise bands playing Treefort this year. "Maybe Boise is still an awkward teenager and not an eloquent adult like Brooklyn, but man, so much has changed."
"Boise hasn't seen its golden age," Gilbert adds, "but it feels like it's in reach."
Other residents, though, think it's still got a long way to go. Netson, who'll play Treefort with Built to Spill and a reunited Caustic Resin, acknowledges the strides his hometown has made. But for a guy who grew up pining for the grittiness of Old Portland, the city is still too polite for its own good.
"Everyone's still in the romance period, but for me personally, I'm looking forward to the time it gets more real," Netson says. "Hopefully it keeps going to the point where people get a little less nice.â
SEE IT: Treefort Music Fest is Wednesday-Sunday, March 19-23, in downtown Boise. See treefortmusicfest.com for a complete lineup.


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Published on January 10, 2016
UPEI Panthers goaltender Marie-Soleil Deschenes grabs the puck on a shot by Maddy Koughan of the Mount Allison Mounties during Atlantic University Sport action Saturday at MacLauchlan Arena. Koughan is a first-year Mountie from Mermaid.
Published on December 30, 2010
UPEI Panthers
Kara Anthony scored the game-winning goal Saturday as the Mount Allison Mounties defeated the UPEI Panthers 4-1 in Atlantic University Sport women's hockey action.
Jennifer Dillon, Heather Richards on the power and Samantha Bujold into an empty net also scored in the win at MacLauchlan Arena.
Emma Weatherbie scored on the power play for the Panthers with assists to Kiana Strand and Emma Martin.
Keri Martin made 24 saves for the win while Marie-Soleil Deschenes stopped 31 shots in the loss.
Mount Allison held period leads of 1-0 and 2-1. Both teams were 1-for-4 on the power play.
The Mounties improved to 6-7-0 and gain two points on UPEI (2-9-3).


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Hotel Manofa
A budget hotel in the center of Amsterdam, Hotel Manofa is situated at the Damrak, one of the main streets of Amsterdam, and enables easy walking access to most attractions, shopping areas, bars, and restaurants. Kalverstraat, the main shopping street, is close by, only 2 minutes by foot. Straight across the street there are many touring boats so you can go for a tour of the famous canals.
Hotel Manofa has a 24-hour reception and offers complimentary wireless Internet access. Parking is available nearby at additional cost.
Hotel Manofa
Hotel Info: 1-877-214-4288from $43
- Single Room
- Twin Room
- Basic Twin Room, Shared Bathroom
- Triple Room
- Quadruple Room
- Family Room
- Basic Single Room, Shared Bathroom
Also popular with travelers from the USA
At a glance
Key facts
Hotel size
- This hotel has 47 rooms
- This hotel is arranged over 4 floors
- Check-in time 2 PM-midnight
- Check-out time is 11 AM
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
- Minimum check-in age is 18
Travelling with others
- Pets not allowed
- Free WiFi in public areas
In the hotel
- Free breakfast
- 24-hour front desk
- Multilingual staff
- Number of buildings/towers - 1
- Safe-deposit box at front desk
In the room
- Iron/ironing board (on request)
- Hair dryer (on request)
- Daily housekeeping
Hotel Manofa's small print
Also known as
- Hotel Manofa
- Hotel Manofa Amsterdam
- Manofa
- Manofa Amsterdam
- Manofa Hotel
- Manofa Hotel Amsterdam
Noise-free guestrooms cannot be guaranteed.
This property does not have elevators.
Special cancellation policies or charges may apply for group reservations (more than 8 rooms for the same property / stay dates).
Mandatory fees
You'll be asked to pay the following charges at check in or check out:
- A 5 percent city/local tax will be charged
Optional extras
Parking is available nearby and costs EUR 20 per 24 hours
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.


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Most Cited BBA Gene Regulatory Mechanisms Articles
The most cited articles published since 2011, extracted from Scopus.
Role of miRNAs and siRNAs in biotic and abiotic stress responses of plantsBasel Khraiwesh | Jian Kang Zhu | Jianhua Zhu
Volume 1819, Issue 2, February 2012, Pages 137-148
Small, non-coding RNAs are a distinct class of regulatory RNAs in plants and animals that control a variety of biological processes. In plants, several classes of small RNAs with specific sizes and dedicated functions have evolved through a series of pathways. The major classes of small RNAs include microRNAs (miRNAs) and small interfering RNAs (siRNAs), which differ in their biogenesis. miRNAs control the expression of cognate target genes by binding to reverse complementary sequences, resulting in cleavage or translational inhibition of the target RNAs. siRNAs have a similar structure, function, and biogenesis as miRNAs but are derived from long double-stranded RNAs and can often direct DNA methylation at target sequences. Besides their roles in growth and development and maintenance of genome integrity, small RNAs are also important components in plant stress responses. One way in which plants respond to environmental stress is by modifying their gene expression through the activity of small RNAs. Thus, understanding how small RNAs regulate gene expression will enable researchers to explore the role of small RNAs in biotic and abiotic stress responses. This review focuses on the regulatory roles of plant small RNAs in the adaptive response to stresses. This article is part of a Special Issue entitled: Plant gene regulation in response to abiotic stress. © 2011 Elsevier B.V.
AP2/ERF family transcription factors in plant abiotic stress responsesJunya Mizoi | Kazuo Shinozaki | Kazuko Yamaguchi-Shinozaki
Volume 1819, Issue 2, February 2012, Pages 86-96
In terrestrial environments, temperature and water conditions are highly variable, and extreme temperatures and water conditions affect the survival, growth and reproduction of plants. To protect cells and sustain growth under such conditions of abiotic stress, plants respond to unfavourable changes in their environments in developmental, physiological and biochemical ways. These responses require expression of stress-responsive genes, which are regulated by a network of transcription factors. The AP2/ERF family is a large family of plant-specific transcription factors that share a well-conserved DNA-binding domain. This transcription factor family includes DRE-binding proteins (DREBs), which activate the expression of abiotic stress-responsive genes via specific binding to the dehydration-responsive element/C-repeat (DRE/CRT) cis-acting element in their promoters. In this review, we discuss the functions of the AP2/ERF-type transcription factors in plant abiotic stress responses, with special emphasis on the regulations and functions of two major types of DREBs, DREB1/CBF and DREB2. In addition, we summarise the involvement of other AP2/ERF-type transcription factors in abiotic stress responses, which has recently become clear. This article is part of a Special Issue entitled: Plant gene regulation in response to abiotic stress. © 2011 Elsevier B.V.
NAC transcription factors in plant abiotic stress responsesKazuo Nakashima | Hironori Takasaki | Junya Mizoi | Kazuo Shinozaki | Kazuko Yamaguchi-Shinozaki
Volume 1819, Issue 2, February 2012, Pages 97-103
Abiotic stresses such as drought and high salinity adversely affect the growth and productivity of plants, including crops. The development of stress-tolerant crops will be greatly advantageous for modern agriculture in areas that are prone to such stresses. In recent years, several advances have been made towards identifying potential stress related genes which are capable of increasing the tolerance of plants to abiotic stress. NAC proteins are plant-specific transcription factors and more than 100 NAC genes have been identified in Arabidopsis and rice to date. Phylogenetic analyses indicate that the six major groups were already established at least in an ancient moss lineage. NAC transcription factors have a variety of important functions not only in plant development but also in abiotic stress responses. Stress-inducible NAC genes have been shown to be involved in abiotic stress tolerance. Transgenic Arabidopsis and rice plants overexpressing stress-responsive NAC (SNAC) genes have exhibited improved drought tolerance. These studies indicate that SNAC factors have important roles for the control of abiotic stress tolerance and that their overexpression can improve stress tolerance via biotechnological approaches. Although these transcription factors can bind to the same core NAC recognition sequence, recent studies have demonstrated that the effects of NAC factors for growth are different. Moreover, the NAC proteins are capable of functioning as homo- or hetero-dimer forms. Thus, SNAC factors can be useful for improving stress tolerance in transgenic plants, although the mechanism for mediating the stress tolerance of these homologous factors is complex in plants. Recent studies also suggest that crosstalk may exist between stress responses and plant growth. This article is part of a Special Issue entitled: Plant gene regulation in response to abiotic stress. © 2011 Elsevier B.V.
The role of WRKY transcription factors in plant abiotic stressesLigang Chen | Yu Song | Shujia Li | Liping Zhang | Changsong Zou | Diqiu Yu
Volume 1819, Issue 2, February 2012, Pages 120-128
The WRKY gene family has been suggested to play important roles in the regulation of transcriptional reprogramming associated with plant stress responses. Modification of the expression patterns of WRKY genes and/or changes in their activity contribute to the elaboration of various signaling pathways and regulatory networks. Furthermore, a single WRKY gene often responds to several stress factors, and then their proteins may participate in the regulation of several seemingly disparate processes as negative or positive regulators. WRKY proteins also function via protein-protein interaction and autoregulation or cross-regulation is extensively recorded among WRKY genes, which help us understand the complex mechanisms of signaling and transcriptional reprogramming controlled by WRKY proteins. Here, we review recent progress made in starting to reveal the role of WRKY transcription factors in plant abiotic stresses. This article is part of a Special Issue entitled: Plant gene regulation in response to abiotic stress. © 2011 Elsevier B.V.
Pol II waiting in the starting gates: Regulating the transition from transcription initiation into productive elongationSergei Nechaev | Karen Adelman
Volume 1809, Issue 1, January 2011, Pages 34-45
Proper regulation of gene expression is essential for the differentiation, development and survival of all cells and organisms. Recent work demonstrates that transcription of many genes, including key developmental and stimulus-responsive genes, is regulated after the initiation step, by pausing of RNA polymerase II during elongation through the promoter-proximal region. Thus, there is great interest in better understanding the events that follow transcription initiation and the ways in which the efficiency of early elongation can be modulated to impact expression of these highly regulated genes. Here we describe our current understanding of the steps involved in the transition from an unstable initially transcribing complex into a highly stable and processive elongation complex. We also discuss the interplay between factors that affect early transcript elongation and the potential physiological consequences for genes that are regulated through transcriptional pausing. © 2010.
The plant heat stress transcription factor (Hsf) family: Structure, function and evolutionKlaus Dieter Scharf | Thomas Berberich | Ingo Ebersberger | Lutz Nover
Volume 1819, Issue 2, February 2012, Pages 104-119
Ten years after the first overview of a complete plant Hsf family was presented for Arabidopsis thaliana by Nover et al. [1], we compiled data for 252 Hsfs from nine plant species (five eudicots and four monocots) with complete or almost complete genome sequences. The new data set provides interesting insights into phylogenetic relationships within the Hsf family in plants and allows the refinement of their classification into distinct groups. Numerous publications over the last decade document the diversification and functional interaction of Hsfs as well as their integration into the complex stress signaling and response networks of plants. This article is part of a Special Issue entitled: Plant gene regulation in response to abiotic stress. © 2011 Elsevier B.V.
Nonsense-mediated mRNA decay - Mechanisms of substrate mRNA recognition and degradation in mammalian cellsChristoph Schweingruber | Simone C. Rufener | David Zünd | Akio Yamashita | Oliver Mühlemann
Volume 1829, Issues 6-7, June 2013, Pages 612-623
The nonsense-mediated mRNA decay (NMD) pathway is well known as a translation-coupled quality control system that recognizes and degrades aberrant mRNAs with truncated open reading frames (ORF) due to the presence of a premature termination codon (PTC). However, a more general role of NMD in posttranscriptional regulation of gene expression is indicated by transcriptome-wide mRNA profilings that identified a plethora of physiological mRNAs as NMD targets. In this review, we focus on mechanistic aspects of target mRNA identification and degradation in mammalian cells, based on the available biochemical and genetic data, and point out knowledge gaps. Translation termination in a messenger ribonucleoprotein particle (mRNP) environment lacking necessary factors for proper translation termination emerges as a key determinant for subjecting an mRNA to NMD, and we therefore review recent structural and mechanistic insight into translation termination. In addition, the central role of UPF1, its crucial phosphorylation/dephosphorylation cycle and dynamic interactions with other NMD factors are discussed. Moreover, we address the role of exon junction complexes (EJCs) in NMD and summarize the functions of SMG5, SMG6 and SMG7 in promoting mRNA decay through different routes. This article is part of a Special Issue entitled: RNA Decay mechanisms. © 2013 Elsevier B.V.
FOXM1: From cancer initiation to progression and treatmentChuay Yeng Koo | Kyle W. Muir | Eric W F Lam
Volume 1819, Issue 1, January 2012, Pages 28-37
The Forkhead box protein M1 (FOXM1) transcription factor is a regulator of myriad biological processes, including cell proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis and apoptosis. Elevated FOXM1 expression is found in cancers of the liver, prostate, brain, breast, lung, colon, pancreas, skin, cervix, ovary, mouth, blood and nervous system, suggesting it has an integral role in tumorigenesis. Recent research findings also place FOXM1 at the centre of cancer progression and drug sensitivity. In this review the involvement of FOXM1 in various aspects of cancer, in particular its role and regulation within the context of cancer initiation, progression, and cancer drug response, will be summarised and discussed. © 2011 Elsevier B.V.
Transgenerational epigenetic inheritance in plantsMarie Theres Hauser | Werner Aufsatz | Claudia Jonak | Christian Luschnig
Volume 1809, Issue 8, August 2011, Pages 459-468
Interest in transgenerational epigenetic inheritance has intensified with the boosting of knowledge on epigenetic mechanisms regulating gene expression during development and in response to internal and external signals such as biotic and abiotic stresses. Starting with an historical background of scantily documented anecdotes and their consequences, we recapitulate the information gathered during the last 60. years on naturally occurring and induced epialleles and paramutations in plants. We present the major players of epigenetic regulation and their importance in controlling stress responses. The effect of diverse stressors on the epigenetic status and its transgenerational inheritance is summarized from a mechanistic viewpoint. The consequences of transgenerational epigenetic inheritance are presented, focusing on the knowledge about its stability, and in relation to genetically fixed mutations, recombination, and genomic rearrangement. We conclude with an outlook on the importance of transgenerational inheritance for adaptation to changing environments and for practical applications. This article is part of a Special Issue entitled "Epigenetic control of cellular and developmental processes in plants". © 2011 Elsevier B.V.
Interpreting the language of histone and DNA modificationsScott B. Rothbart | Brian D. Strahl
Volume 1839, Issue 8, January 2014, Pages 627-643
A major mechanism regulating the accessibility and function of eukaryotic genomes are the covalent modifications to DNA and histone proteins that dependably package our genetic information inside the nucleus of every cell. Formally postulated over a decade ago, it is becoming increasingly clear that post-translational modifications (PTMs) on histones act singly and in combination to form a language or 'code' that is read by specialized proteins to facilitate downstream functions in chromatin. Underappreciated at the time was the level of complexity harbored both within histone PTMs and their combinations, as well as within the proteins that read and interpret the language. In addition to histone PTMs, newly-identified DNA modifications that can recruit specific effector proteins have raised further awareness that histone PTMs operate within a broader language of epigenetic modifications to orchestrate the dynamic functions associated with chromatin. Here, we highlight key recent advances in our understanding of the epigenetic language encompassing histone and DNA modifications and foreshadow challenges that lie ahead as we continue our quest to decipher the fundamental mechanisms of chromatin regulation. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function. © 2014 Elsevier B.V.
Tristetraprolin (TTP): Interactions with mRNA and proteins, and current thoughts on mechanisms of actionSeth A. Brooks | Perry J. Blackshear
Volume 1829, Issues 6-7, June 2013, Pages 666-679
Changes in mRNA stability and translation are critical control points in the regulation of gene expression, particularly genes encoding growth factors, inflammatory mediators, and proto-oncogenes. Adenosine and uridine (AU)-rich elements (ARE), often located in the 3' untranslated regions (3'UTR) of mRNAs, are known to target transcripts for rapid decay. They are also involved in the regulation of mRNA stability and translation in response to extracellular cues. This review focuses on one of the best characterized ARE binding proteins, tristetraprolin (TTP), the founding member of a small family of CCCH tandem zinc finger proteins. In this survey, we have reviewed the current status of TTP interactions with mRNA and proteins, and discussed current thinking about TTP's mechanism of action to promote mRNA decay. We also review the proposed regulation of TTP's functions by phosphorylation. Finally, we have discussed emerging evidence for TTP operating as a translational regulator. This article is part of a Special Issue entitled: RNA Decay mechanisms. © 2013.
Mitochondrial transcription factor A regulates mitochondrial transcription initiation, DNA packaging, and genome copy numberChristopher T. Campbell | Jill E. Kolesar | Brett A. Kaufman
Volume 1819, Issues 9-10, September 2012, Pages 921-929
Mitochondrial transcription factor A (mtTFA, mtTF1, TFAM) is an essential protein that binds mitochondrial DNA (mtDNA) with and without sequence specificity to regulate both mitochondrial transcription initiation and mtDNA copy number. The abundance of mtDNA generally reflects TFAM protein levels; however, the precise mechanism(s) by which this occurs remains a matter of debate. Data suggest that the usage of mitochondrial promoters is regulated by TFAM dosage, allowing TFAM to affect both gene expression and RNA priming for first strand mtDNA replication. Additionally, TFAM has a non-specific DNA binding activity that is both cooperative and high affinity. TFAM can compact plasmid DNA in vitro, suggesting a structural role for the non-specific DNA binding activity in genome packaging. This review summarizes TFAM-mtDNA interactions and describes an emerging view of TFAM as a multipurpose coordinator of mtDNA transactions, with direct consequences for the maintenance of gene expression and genome copy number. This article is part of a Special Issue entitled: Mitochondrial Gene Expression. © 2012 Elsevier B.V.
Dynamic phosphorylation patterns of RNA polymerase II CTD during transcriptionMartin Heidemann | Corinna Hintermair | Kirsten Voß | Dirk Eick
Volume 1829, Issue 1, January 2013, Pages 55-62
The eukaryotic RNA polymerase II (RNAPII) catalyzes the transcription of all protein encoding genes and is also responsible for the generation of small regulatory RNAs. RNAPII has evolved a unique domain composed of heptapeptide repeats with the consensus sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 at the C-terminus (CTD) of its largest subunit (Rpb1). Dynamic phosphorylation patterns of serine residues in CTD during gene transcription coordinate the recruitment of factors to the elongating RNAPII and to the nascent transcript. Recent studies identified threonine 4 and tyrosine 1 as new CTD modifications and thereby expanded the "CTD code". In this review, we focus on CTD phosphorylation and its function in the RNAPII transcription cycle. We also discuss in detail the limitations of the phosphospecific CTD antibodies, which are used in all studies. This article is part of a Special Issue entitled: RNA Polymerase II Transcript Elongation. © 2012 Elsevier B.V.
LncRNA: A link between RNA and cancerGuodong Yang | Xiaozhao Lu | Lijun Yuan
Volume 1839, Issue 11, November 2014, Pages 1097-1109
© 2014 Published by Elsevier B.V.Unraveling the gene expression networks governing cancer initiation and development is essential while remains largely uncompleted. With the innovations in RNA-seq technologies and computational biology, long noncoding RNAs (lncRNAs) are being identified and characterized at a rapid pace. Recent findings reveal that lncRNAs are implicated in serial steps of cancer development. These lncRNAs interact with DNA, RNA, protein molecules and/or their combinations, acting as an essential regulator in chromatin organization, and transcriptional and post-transcriptional regulation. Their misexpression confers the cancer cell capacities for tumor initiation, growth, and metastasis. The review here will emphasize their aberrant expression and function in cancer, and the roles in cancer diagnosis and therapy will be also discussed.
Regulation of cellular miRNA expression by human papillomavirusesZhi Ming Zheng | Xiaohong Wang
Volume 1809, Issues 11-12, November 2011, Pages 668-677
High-risk HPV infection leads to aberrant expression of cellular oncogenic and tumor suppressive miRNAs. A large number of these miRNA genes are downstream targets of the transcription factors c-Myc, p53, and E2F and their expression can therefore be modulated by oncogenic HPV E6 and E7. Cervical cancer represents a unique tumor model for understanding how viral E6 and E7 oncoproteins deregulate the expression of the miR-15/16 cluster, miR-17-92 family, miR-21, miR-23b, miR-34a, and miR-106b/93/25 cluster via the E6-p53 and E7-pRb pathways. Moreover, miRNAs may influence the expression of papillomavirus genes in a differentiation-dependent manner by targeting viral RNA transcripts. Cellular miRNAs affecting HPV DNA replication are of great interest and will be a future focus. We are entering an era focusing on miRNA and noncoding RNA, and the studies on HPV and host miRNA interactions will continue shedding more light on our understanding of the HPV life cycle and the mechanistic underpinnings of HPV-induced oncogenesis. This article is part of a Special Issue entitled: "MicroRNAs in viral gene regulation". © 2011.
Histone modifications in transcriptional activation during plant developmentAlexandre Berr | Sarfraz Shafiq | Wen Hui Shen
Volume 1809, Issue 10, October 2011, Pages 567-576
In eukaryotic cell nuclei, chromatin states dictated by different combinations of post-translational modifications of histones, such as acetylation, methylation and monoubiquitination of lysine residues, are part of the multitude of epigenomes involved in the fine-tuning of all genetic functions and in particular transcription. During the past decade, an increasing number of 'writers', 'readers' and 'erasers' of histone modifications have been identified. Characterization of these factors in Arabidopsis has unraveled their pivotal roles in the regulation of essential processes, such as floral transition, cell differentiation, gametogenesis, and plant response/adaptation to environmental stresses. In this review we focus on histone modification marks associated with transcriptional activation to highlight current knowledge on Arabidopsis 'writers', 'readers' and 'erasers' of histone modifications and to discuss recent findings on molecular mechanisms of integration of histone modifications with the RNA polymerase II transcriptional machinery during transcription of the flowering repressor gene FLC. © 2011 Elsevier B.V.
Ubiquitin-Proteasome System and mitochondria - ReciprocityNurit Livnat-Levanon | Michael H. Glickman
Volume 1809, Issue 2, February 2011, Pages 80-87
Recently, sporadic links have been published between mitochondria - membrane-confined organelles - and the cytosolic ubiquitin-proteasome system (UPS) for removal of cellular proteins. For example, Fzo1, a mitochondrial outer membrane mitofusin was shown to be ubiquitinated by a ubiquitin ligase, Cdc53MDM30, and degraded by the proteasome. Two additional ubiquitin ligases, MITOL/MARCH-V and MULAN, as well as a deubiquitinating enzyme, Ubp16/USP30, are embedded in mitochondrial outer membranes and participate in mitochondrial dynamics. Defects in mitochondrial morphology or respiration capacity are also reported for mutations in other UPS components such as the Ub ligases Parkin and Rsp5 as well as in proteasome subunits. These examples are likely to reflect a pervasive involvement of UPS in recycling of mitochondria-associated proteins. The flux of imported proteins and the proximity to oxidative phosphorylation results in abundant damaged or misfolded proteins that generate the need for a responsive quality control system. Within the mitochondrial matrix there is a self-contained ATP-dependent system for protein turnover. However at the outer membrane, the UPS may play a corresponding role in recycling either membrane-embedded or imported proteins. In a parallel process, ubiquitination also partakes in selection of damaged mitochondria to the lysozome/vacuole via autophagy. In the reverse direction, components of the UPS are sensitive to cellular REDOX potential, and as such are affected by reactive oxygen species (ROS) generated as a byproduct of mitochondrial respiration. This review will try to address the regulation of mitochondrial morphology and metabolic function by UPS, as well as the reciprocal relationship between aberrant ROS produced by mitochondria and ubiquitination or proteasome activity. © 2010 Elsevier B.V.
RNA decay machines: The exosomeAleksander Chlebowski | Michał Lubas | Torben Heick Jensen | Andrzej Dziembowski
Volume 1829, Issues 6-7, June 2013, Pages 552-560
The multisubunit RNA exosome complex is a major ribonuclease of eukaryotic cells that participates in the processing, quality control and degradation of virtually all classes of RNA in Eukaryota. All this is achieved by about a dozen proteins with only three ribonuclease activities between them. At first glance, the versatility of the pathways involving the exosome and the sheer multitude of its substrates are astounding. However, after fifteen years of research we have some understanding of how exosome activity is controlled and applied inside the cell. The catalytic properties of the eukaryotic exosome are fairly well described and attention is now drawn to how the interplay between these activities impacts cell physiology. Also, it has become evident that exosome function relies on many auxiliary factors, which are intensely studied themselves. In this way, the focus of exosome research is slowly leaving the test tube and moving back into the cell.The exosome also has an interesting evolutionary history, which is evident within the eukaryotic lineage but only fully appreciated when considering similar protein complexes found in Bacteria and Archaea. Thus, while we keep this review focused on the most comprehensively described yeast and human exosomes, we shall point out similarities or dissimilarities to prokaryotic complexes and proteins where appropriate.The article is divided into three parts. In Part One we describe how the exosome is built and how it manifests in cells of different organisms. In Part Two we detail the enzymatic properties of the exosome, especially recent data obtained for holocomplexes. Finally, Part Three presents an overview of the RNA metabolism pathways that involve the exosome. This article is part of a Special Issue entitled: RNA Decay mechanisms. © 2013 Elsevier B.V.
DNA methylation in higher plants: Past, present and futureBoris F. Vanyushin | Vasili V. Ashapkin
Volume 1809, Issue 8, August 2011, Pages 360-368
A relatively high degree of nuclear DNA (nDNA) methylation is a specific feature of plant genomes. Targets for cytosine DNA methylation in plant genomes are CG, CHG and CHH (H is A, T, C) sequences. More than 30% total m5C in plant DNA is located in non-CG sites. DNA methylation in plants is species-, tissue-, organelle- and age-specific; it is involved in the control of all genetic functions including transcription, replication, DNA repair, gene transposition and cell differentiation. DNA methylation is engaged in gene silencing and parental imprinting, it controls expression of transgenes and foreign DNA in cell. Plants have much more complicated and sophisticated system of the multicomponent genome methylations compared to animals; DNA methylation in plant mitochondria is performed in other fashion as compared to that in nuclei. The nDNA methylation is carried out by cytosine DNA methyltransferases of, at least, three families. In contrast to animals the plants with the major maintenance methyltransferase MET1 (similar to animal Dnmt1) inactivated do survive. One and the same plant gene may be methylated at both adenine and cytosine residues; specific plant adenine DNA methyltransferase was described. Thus, two different systems of the genome modification based on methylation of cytosines and adenines seem to coexist in higher plants. This article is part of a Special Issue entitled: Epigenetic control of cellular and developmental processes in plants. © 2011 Elsevier B.V.
Transcription-associated histone modifications and cryptic transcriptionMichaela Smolle | Jerry L. Workman
Volume 1829, Issue 1, January 2013, Pages 84-97
Eukaryotic genomes are packaged into chromatin, a highly organized structure consisting of DNA and histone proteins. All nuclear processes take place in the context of chromatin. Modifications of either DNA or histone proteins have fundamental effects on chromatin structure and function, and thus influence processes such as transcription, replication or recombination. In this review we highlight histone modifications specifically associated with gene transcription by RNA polymerase II and summarize their genomic distributions. Finally, we discuss how (mis-)regulation of these histone modifications perturbs chromatin organization over coding regions and results in the appearance of aberrant, intragenic transcription. This article is part of a Special Issue entitled: RNA polymerase II Transcript Elongation. © 2012 Elsevier B.V.
Chromatin dynamics during spermiogenesisChristina Rathke | Willy M. Baarends | Stephan Awe | Renate Renkawitz-Pohl
Volume 1839, Issue 3, March 2014, Pages 155-168
The function of sperm is to safely transport the haploid paternal genome to the egg containing the maternal genome. The subsequent fertilization leads to transmission of a new unique diploid genome to the next generation. Before the sperm can set out on its adventurous journey, remarkable arrangements need to be made during the post-meiotic stages of spermatogenesis. Haploid spermatids undergo extensive morphological changes, including a striking reorganization and compaction of their chromatin. Thereby, the nucleosomal, histone-based structure is nearly completely substituted by a protamine-based structure. This replacement is likely facilitated by incorporation of histone variants, post-translational histone modifications, chromatin-remodeling complexes, as well as transient DNA strand breaks. The consequences of mutations have revealed that a protamine-based chromatin is essential for fertility in mice but not in Drosophila. Nevertheless, loss of protamines in Drosophila increases the sensitivity to X-rays and thus supports the hypothesis that protamines are necessary to protect the paternal genome. Pharmaceutical approaches have provided the first mechanistic insights and have shown that hyperacetylation of histones just before their displacement is vital for progress in chromatin reorganization but is clearly not the sole inducer. In this review, we highlight the current knowledge on post-meiotic chromatin reorganization and reveal for the first time intriguing parallels in this process in Drosophila and mammals. We conclude with a model that illustrates the possible mechanisms that lead from a histone-based chromatin to a mainly protamine-based structure during spermatid differentiation. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development. © 2013 The Authors.
XRN 5'→3' exoribonucleases: Structure, mechanisms and functionsVinay K. Nagarajan | Christopher I. Jones | Sarah F. Newbury | Pamela J. Green
Volume 1829, Issues 6-7, June 2013, Pages 590-603
The XRN family of 5'. →. 3' exoribonucleases is critical for ensuring the fidelity of cellular RNA turnover in eukaryotes. Highly conserved across species, the family is typically represented by one cytoplasmic enzyme (XRN1/PACMAN or XRN4) and one or more nuclear enzymes (XRN2/RAT1 and XRN3). Cytoplasmic and/or nuclear XRNs have proven to be essential in all organisms tested, and deficiencies can have severe developmental phenotypes, demonstrating that XRNs are indispensable in fungi, plants and animals. XRNs degrade diverse RNA substrates during general RNA decay and function in specialized processes integral to RNA metabolism, such as nonsense-mediated decay (NMD), gene silencing, rRNA maturation, and transcription termination. Here, we review current knowledge of XRNs, highlighting recent work of high impact and future potential. One example is the breakthrough in our understanding of how XRN1 processively degrades 5' monophosphorylated RNA, revealed by its crystal structure and mutational analysis. The expanding knowledge of XRN substrates and interacting partners is outlined and the functions of XRNs are interpreted at the organismal level using available mutant phenotypes. Finally, three case studies are discussed in more detail to underscore a few of the most exciting areas of research on XRN function: XRN4 involvement in small RNA-associated processes in plants, the roles of XRN1/PACMAN in Drosophila development, and the function of human XRN2 in nuclear transcriptional quality control. This article is part of a Special Issue entitled: RNA Decay mechanisms. © 2013.
Mitochondrial DNA nucleoid structureDaniel F. Bogenhagen
Volume 1819, Issues 9-10, September 2012, Pages 914-920
Eukaryotic cells are characterized by their content of intracellular membrane-bound organelles, including mitochondria as well as nuclei. These two DNA-containing compartments employ two distinct strategies for storage and readout of genetic information. The diploid nuclei of human cells contain about 6. billion base pairs encoding about 25,000 protein-encoding genes, averaging 120. kB/gene, packaged in chromatin arranged as a regular nucleosomal array. In contrast, human cells contain hundreds to thousands of copies of a ca.16. kB mtDNA genome tightly packed with 13 protein-coding genes along with rRNA and tRNA genes required for their expression. The mtDNAs are dispersed throughout the mitochondrial network as histone-free nucleoids containing single copies or small clusters of genomes. This review will summarize recent advances in understanding the microscopic structure and molecular composition of mtDNA nucleoids in higher eukaryotes. This article is part of a Special Issue entitled: Mitochondrial Gene Expression. © 2011 Elsevier B.V.
Viral miRNAs exploiting the endosomal-exosomal pathway for intercellular cross-talk and immune evasionD. Michiel Pegtel | Martijn D B van de Garde | Jaap M. Middeldorp
Volume 1809, Issues 11-12, November 2011, Pages 715-721
The class of persistent gamma-herpesviruses has developed a variety of strategies that exploit host-cell regulatory pathways to ensure a long-lasting, well-balanced infection of their host. However when these pathways are deregulated, an otherwise harmless infection can lead to disease including cancer. We recently demonstrated that the human herpes virus 4 (HHV4) also known as Epstein-Barr virus (EBV), encodes for small regulatory non-coding microRNAs (miRNAs) that can be transferred from an infected cell to uninfected neighboring cells. Upon arrival these miRNAs are functional in the recipient cell, in that they are able to down regulate specific target genes. These secreted miRNAs are transported to recipient cells via small nano-sized vesicles (known as exosomes) that are of endosomal origin, formed as intraluminal vesicles (ILV) inside multivesicular bodies (MVB). One question that needs to be addressed is how viral miRNAs are sorted into these exosomes. Mature miRNAs, including those of viral origin, are loaded into RNA-induced silencing complexes (RISC) for gene silencing via blocking mRNA translation and/or initiating mRNA decay. Recent insights indicate that cytoplasmic RNA granules rich in RISC complexes are closely associated with endosomes. In fact, selective components of RISC, including GW182 and Argonaut proteins, miRNAs and mRNAs are present in exosomes. Thus miRNA function, mRNA stability and exosome-mediated intercellular communication converge at the level of endosomes. Since endosomes can be considered as key intracellular cross-roads that regulate communication of cells with their exterior, including neighboring cells, it is perhaps not surprising that viruses have found means to exploit this pathway to their benefit. Little is known however, how and if (micro) RNA species are specifically sorted into ILVs and what (micro)RNA-binding proteins are involved. Here we discuss recent developments relating to intracellular trafficking and function of miRNA-containing protein complexes that EBV may exploit for promoting or restricting miRNAs sorting into exosomes for intercellular regulatory functions. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation. © 2011 Elsevier B.V.
Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancerMarta Kulis | Ana C. Queirós | Renée Beekman | José I. Martín-Subero
Volume 1829, Issue 11, November 2013, Pages 1161-1174
Ever since the discovery of DNA methylation at cytosine residues, the role of this so called fifth base has been extensively studied and debated. Until recently, the majority of DNA methylation studies focused on the analysis of CpG islands associated to promoter regions. However, with the upcoming possibilities to study DNA methylation in a genome-wide context, this epigenetic mark can now be studied in an unbiased manner. As a result, recent studies have shown that not only promoters but also intragenic and intergenic regions are widely modulated during physiological processes and disease. In particular, it is becoming increasingly clear that DNA methylation in the gene body is not just a passive witness of gene transcription but it seems to be actively involved in multiple gene regulation processes. In this review we discuss the potential role of intragenic DNA methylation in alternative promoter usage, regulation of short and long non-coding RNAs, alternative RNA processing, as well as enhancer activity. Furthermore, we summarize how the intragenic DNA methylome is modified both during normal cell differentiation and neoplastic transformation. © 2013 Elsevier B.V.