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Vigis - Rugged Outdoors Waterproof + Shockproof Mobile Phone (Walkie Talkie + GPS + Compass)
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Vigis - Rugged Outdoors Waterproof + Shockproof Mobile Phone (Walkie Talkie + GPS + Compass)
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Products Desciption
All-Purpose Waterproof, Dustproof, and Shockproof Mobile Phone for use in any outdoor environment. Virtually indestructible and with tons of useful features (including a walkie talkie + built-in GPS + compass), the Vigis outdoors phone is here to stay.
This ultra-durable Vigis mobile phone features an internal hardened magnesium frame and 3.5mm rubberized casing that repels water, dust, blunt force, and so much more - providing the ultimate in real world durability. That means you can drop it, throw it, step it on it, submerge it in water, hit it with a baseball bat, run it over with a jeep, and it'll still come out in perfect shape. So the next time you need a rugged mobile handset on the construction site, while climbing Mount Kilimanjaro, or when swimming across the Gulf of Sidra, look to the Vigis phone.
This rugged mobile phone also provides a full set of outdoor tools and functions for any occasion:
Bright, built-in LED flashlight that turns on and off with the single press of a button
Wind up power charger for emergencies
Walkie talkie between other Vigis phone units, or other PTT intercom devices
Built-in compass, air pressure, and temperature sensor
GPS navigation and information, including latitude, longitude, altitude, sunrise and sunset time, and much more
This professional outdoor mobile phone is designed specifically for tough people who need a tougher phone. It's also perfect for the internet storefront re-seller who wants to offer his customers something new, unique and useful. This model is available to you at a low wholesale price from the leader in factory-direct electronics, Wholesale-Star.
At a Glance...
All-environment rugged mobile phone
Waterproof, dustproof, shockproof
Built-in GPS
Built-in flashlight
Compass, air pressure, and temperature sensor
Walkie talkie feature
The ultimate outdoors phone
Manufacturer Specifications
Main Function: All-purpose waterproof, dustproof, shockproof rough service GSM cellphone
Chipset: MTK6235
CPU: 208 MHz
GSM Compatibility: Quad Band 850MHz, 900MHz, 1800MHz, 1900MHz
Type: Non-touch
Size: 2 inch back lit LCD
Resolution: 240 x 320
Camera Resolution: 2MP
Internal: 9.7MB
External: 4 GB Micro SD card included (16 GB Max)
Type: Rechargeable 1400mAh Li-ion polymer
Battery Life (Talk time): Up to 11 hours
Battery Life (Standby time): Up to 240 hours
Waterproof/Dustproof: IP57 (submersible up to 1 meter under water)
Shockproof: Can resist drops from up to 2 meters on cement
Walkie Talkie Frequency: 400MHz all frequency intercom (3-5km of communication distance on open ground)
Dimensions: 120mm x 55mm x 24mm (L x W x H)
Languages: English, French, Spanish, Portuguese, Italian, German, Turkish, Russian
Package Contents
Vigis Rugged Outdoors Mobile Phone
2x Batteries
USB Cable
Walkie Talkie Antenna
User Manual
Power Adapter (100-240V 50Hz)
Rotary-turn Hand Charger
Car Charger
Ordering from Wholesale-Star provides you with the following benefits;
- Orders processed and shipped within 24-hours
- 12 month warranty
- In-house QC
- Member discounts
- Quantity order discounts
- Worldwide Shipping
Additional Information
Model: CVXM-M273
This product was added to our catalog on Monday 07 May, 2012.
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text: timber industry Expiration Of Canadian Lumber Agreement Could Bring Falling Timber Prices By Edward O'Brien • 15 hours ago PD Listen Listening... / 1:04 Expiration Of Canadian Lumber Agreement Could Bring Falling Timber Prices Montana's timber industry is watching to see if Canadian lumber will soon flood the market. That's because a 9 year-old U.S.-Canada Lumber trade Agreement expired today. Columbia Falls Company Works To Build A Future With Cross-Laminated Timber By Corin Cates-Carney • Apr 30, 2015 Corin Cates-Carney Listen Listening... / 3:53 Columbia Falls Company Works To Build A Future With Cross-Laminated Timber A young company in Columbia Falls is finding success in developing new construction material, and they've just received a federal grant to help push that success to the next stage. Sen. Tester: Lawsuit Claim An 'Error' By Eric Whitney • Feb 19, 2015 courtesy photo Yesterday, in a story about attempts to boost revenue for Montana counties that are mostly federal land, Montana Senator Jon Tester made the following statement: "Unfortunately, every logging sale in Montana right now is under litigation. Every one of them." Several listeners questioned that statement, so we asked Senator Tester to respond. His communications director Marnee Banks said he is unavailable this week. From real estate to biofuels – the timber industry is changing By Sally Mauk • Mar 13, 2014 Mike Covey went to work for the Plum Creek timber company right after getting his forestry degree from the University of Montana in 1980, and stayed with Plum Creek for 23 years. Covey is now chairman and CEO of the Spokane-based Potlatch Corporation, another big timber holder in the Pacific Northwest. Covey was in Missoula this week to lecture at his alma mater and he also took time to sit down in our studios with News Director Sally Mauk, to talk about the sweeping changes in the timber industry in the last few decades.

subset: commoncrawl


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Saffron Indian Bistro
7607 N. Oracle Rd., Ste. 101 Send to Phone
520-742-9100 | Make Restaurant Reservations | Order Now! | Menu
OpenBuffet, Lunch & Dinner daily
- Dress code: Casual
- Full bar
* Click here for rating key
Saffron Indian Bistro Restaurant Review: Saffron Indian Bistro is tucked away behind a flurry of department stores, banks and fast food joints, but it's where you'll find some of the city's best Indian fare. Begin with the vegetable or chicken samosas or the house Saffron shrimp. From there you can pick from a long list of entrées. Most of the dishes can be prepared with chicken, lamb or shrimp, including the vindaloo --- this is one hot and spicy plate, but you can request a milder version if you so wish. One of our favorites is the ajwain fish with its creamy yogurt based marinade and a light sear. We also suggest adding naan that comes as a simple side or in more complex versions; the crispy keema naan is topped with a deeply seasoned ground lamb and the paneer kulcha is stuffed with cheese that is made in-house. Cool your taste buds with traditional Indian ice cream, kulfi, available in mango or almond.
Check out the 2015 edition of GAYOT's Annual Restaurant Issue, which features the Top 40 Restaurants in the US and more.


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Climate change to destroy Great Barrier Reef irreversibly in just 16 years
The Great Barrier Reef will be irreversibly damaged by climate change in just 16 years, according to leading reef researcher.
The reef has lost about half its coral coverage since the mid-1980s, with increased carbon dioxide concentrations contributing about 10 percent alongside damage from other sources such as invasive species and farm nutrient run-off, Professor Ove Hoegh-Guldberg, a professor of marine science at the University of Queensland, said.
Climate change, though, is fast taking over as the main threat to the world's reefs as warmer waters increase the frequency of coral bleaching, while acidifying oceans weaken or erode coral structures, the Sydney Morning Herald reported.
The reef's plight will be a focus of this year's Earth Hour, expected to be observed in 152 nations around the world.
By 2030, on present projections for the growth of carbon dioxide emissions, conditions will be "getting close to what we understand to be some of the limits in terms of rapidly calcifying reefs", Professor Hoegh-Guldberg said.
By mid-century, the Great Barrier Reef may have shrunk to 10 per cent or less of its previous coverage if the present trajectory continues, he said.
A new report, Lights out for the reef, by University of Queensland scientist Selina Ward also highlights the potential ecological and economic damage to the reef from global warming.
Not only will shrinking coral reefs diminish the annual 6-billion-dollar reef tourism industry and the 63,000 jobs it supports, there will be other impacts, the report said.
(Posted on 07-03-2014)
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Luxurious Song Saa Private Island retreat
Song Saa Private Island resort in the Koh Rong Islands, Cambodia is an eco-luxe escape spread over a pair of pristine isles, with thatch and stone villas dotted among the jungle canopy or lolling above the sea. This glamorous hotel features 27 suites with harmony, sustainability and world-class luxury as the core principles that underpin the design of the villas. Natural materials create a sense of synergy with the sea, the rainforests and the local culture. Everywhere you look there are references to the colors and textures of Cambodia's traditional fishing villages with their pitched roofs and open plan living spaces.
Once inside your expansive thatched roof villa you will find recycled timber from disused fishing boats, furniture made from driftwood collected from local beaches and coves, earthy stone, polished marble walls and floors made from timber salvaged from old factories, warehouses and demolition yards around Cambodia and Thailand. But importantly, you will find every luxury waiting for you. Four-poster beds, Moroccan lanterns and carved statues add flair to the eco-chic space with over-sized baths and outdoor showers beside private decks and pools. Bespoke hand-crafted furniture made by local artisans. Each villa offers ocean views with their own private sea-view plunge pool.
The hotel also boasts a gym, spa and wellness sanctuaries positioned in the rainforest and along the shore, yoga and meditation center on the shoreline and beautiful gardens. The infinity-edge pool offers beautiful views, cleverly straddling the east and west sides of the island. The overwater, open-sided world-class restaurant and lounge are spectacularly positioned just off the island's shoreline. For a romantic dinner for two, opt for a private beach cabana. A short stroll on the boardwalk will leave you perfectly positioned to take in dramatic sunsets, seascapes and starry nights.
Rates for a double room starts at $1,351 per night, which includes include all meals, house wine, beer and spirits, soft drinks, watersports, boat transfers to and from Song Saa, 15-minute foot massage on arrival and guided tours, from here.
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Making a permanent impression since 1994
X Trials | Teen suicide | Teen pregnancy | School violence | Travel | Journals | Daily Sketch | Awards | Contact us
August 1, 2005
-- Review --
The Boss in Bridgeport
By Zach Brokenrope
I've been to a considerable number of
concerts during my life. Some, like Green Day, were energetic. Others, like
KISS, were pathetic. Some, like Good Charlotte, I'm embarrassed to say I
Only one concert though, truly affected me –
moved me, if you will.
I'll admit I used to be a Bad Springsteen
fan. You know the type, and they exist for all artists.
I was one of those fans who knew one or two
songs by the artist, presumably their most famous, and had decided that I was a
true fan. I'm ashamed to admit this now, but happy to say it's no longer the
On the last leg of his Devils and Dust tour, Bruce Springsteen stopped in
But nothing quite prepared me for the
experience of seeing Springsteen on stage.
For an hour before the concert I sat next to a
man from
I saw this man consume eight glasses of
alcohol and later dance in the aisle. Despite being crazy, he was right about
one thing. I would leave the concert feeling older.
From the first note played, I was entranced. The music was beautiful and deep, Springsteen's voice roughly poetic and gentle.
As the concert continued I would fall deeper in love with every song played, sometimes closing my eyes just to feel the sensation of the music overcome me.
The concert moved me; I'd never felt as emotional as I did then. That's how amazing the music was.
Springsteen orchestrated his concert with perfection, and left no doubt that he is, and always will be, The Boss.
Help The Tattoo thrive! Your donation can help us continue to provide the world's premier teen journalism.
|© 2005 by The Tattoo. All rights reserved.


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We can give thanks to God for the way in which he has grown CESA in Southern Africa. New generations don't always appreciate the desperate situation in which the denomination found itself in the 1960's and early 70's. The subsequent two decades saw remarkable growth in the number of CESA Churches, especially across KZN and the Western Cape.
All of this happened without any specific strategy or process. So why do we need one now?
A few reasons:
Planting and growth has slowed down: We're just not planting as many churches as we used to. According to some church growth models our "real" rate of growth as a denomination is negative.
There are many areas that we don't reach or have a very limited evangelical presence: We have little presence in many large, densely populated areas of our major urban centres.
Our country has changed and it's wise to plan a strategy in response: Just consider the radical change to urban living in South Africa over the past twenty years:
The end of apartheid has led to changing demographics in many communities and the emergence of new, racially mixed communities.
Dying or struggling CBD's (especially in Johannesburg and Durban) have led to new business areas springing up in suburban areas (e.g. Sandton, Umhlangha, Claremont) and a concentration of residential developments around those areas.
Population movement has lead to rapid growth in the size of our cities. Within our borders there has been significant movement out of the Eastern Cape into other urban centres. Immigration from other African states has also had a huge impact.
Infrastructure has therefore not been able to keep up and there has been a rapid growth in informal settlements. For example, Diepsloot in Johannesburg (population: 200 000 +) and Masiphumelele in Cape Town (population: 35 000 +) did not exist 25 years ago.
Concerns over rising crime rates have led to massive growth in the number of security complexes. These have transformed the make-up of many middle-upper class communities.
It is therefore no surprise that many of our churches find themselves operating in totally different contexts from twenty years ago. Even those who have been less directly affected may now find it very difficult to envision a plan to initiate church planting into their surrounding communities.
These challenges were confirmed by responses to the 2011 CESA National Church Planting Survey (NCPS). All the respondents expressed support for the notion of church planting. Most of them had identified vague opportunities for church planting in their community. And yet, for a host of reasons, there was very little certainty as to how it would be possible to make those new plants happen.
Most respondents called on the denomination to co-ordinate some kind of strategic thinking and planning on this issue. For this reason, the following motion was presented to Synod, 2011:
"This Synod recognizes that planting and developing new churches is an effective way to reach our nation with the Gospel and asks the Presiding Bishop respectfully to set up a working party to prepare for the next Synod a report on research into the practice and experience of church planting in South Africa and overseas and in the light of that research present a draft denominational strategy for evangelistic church planting. This report should particularly include examination of research into and recommendations for evangelistic church planting in different cultural groups, in South Africa.
The report would look to provide insight in the following areas (amongst others): Identification and training potential church planters; Targeting relatively unreached communities and people groups; Providing resources for church planting; Assessment of current denominational structures vis-à-vis church planting; Preparing existing churches for church planting."
Of course we acknowledge that all of this will take place under God and through the powerful work of his Holy Spirit. Indeed, we need to be clear, up front, about our understanding of human strategy in the context of God's plan for the world:
We trust that God is busy bringing about his purpose – "to bring all things in heaven and on earth under one head, even Christ" (Eph 1:10). This is his great strategy for the world and he achieves it through the work of his Holy Spirit as the gospel is communicated.
Amazingly though, he involves us in this plan. It's clear in Scripture (and throughout church history) that he will inspire different types of Christians to dedicate themselves to a myriad of different gospel ministries which will bring about this plan: evangelistic campaigns in sports stadia and tents; Christian crèches and Christian high schools; theological colleges and house churches; evangelistic short courses and one-to-one discipling programs; campus ministries and funeral services; Christian broadcasting and Christian blogging; the faithful building up of existing churches and the planting of new ones.
We believe that multiplying the number of CESA congregations in multiple communities across South Africa could play an especially important role in the furtherance of the gospel. Our chief aim is not to sustain or grow a denomination, per se, but to reach more people with the gospel. But we link this closely to the work of CESA because, by the grace of God, the doctrines and traditions of this denomination have been effective in advancing the cause of the gospel in South Africa, up to now.


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Sounds like its going to be a neat place!
Paulette's Original Donuts and Chicken
Paulette's Donuts & Chicken opened Monday - and thanks to the new donut trend sweeping the city, a successful debut at the Stop's night market, and the fact that it's owned by Devin Connell of Delica Kitchen - there was no shortage of customers. I was going to drop by after the lunch rush so I could loiter like usual to take pictures, but well, I got hungry.
Paulette's offers a lot in the way of food, but not space (takeaway only), so what little they have was jam packed with people by the time I got there at 11:30. It's darn cute though, with its mint green walls and uniformed staff, so nobody seemed to mind the line. Those in wait stayed occupied by deciding on chicken sauces or salts, and of course, the donuts of the day - one of each showcased behind glass, in Japanese food display fashion.
Just a couple of weeks ago, I took a trip to New York, and I fell in love with a donut (and then promptly cheated with one of its closest friends). It was a toasted coconut by Brooklyn operation Dough, so when I read that Paulette's had recently been there on a donut and fried chicken "research" trip, I got a little bit too excited. Apparently I'm not very monogamous when it comes to donuts.
Fried chicken on the other hand, has never won me over, but being open to new possibilities I, along with my friend, ordered a snack size portion ($8). Each came with two good sized pieces of chicken and a choice of dipping sauce or salt. We went with Graham's Burning Hot Sauce and Chili Maple Dip.
Now to be honest, we were looking at the chicken as a bit of a roadblock as it stood in the way of our donuts, and we had to finish our meal before our dessert...even if they were the nutritional equivalent of one another. We were blown away though. It was incredible. The tempura-like batter has to be among the lightest and crunchiest of its kind, and although my current cholesterol levels might prove otherwise, it wasn't greasy.
In direct contrast to the batter was the chicken, which was unbelievably moist and so tender that it fell away from the bone. Both sauces paired very nicely, but I favoured the Maple Chili as the hot sauce tasted more of Frank's than Graham's.
Seeing as we did such a good job of eating our meals (it turned out to be pretty easy after all), we moved on to the dessert portion. We ordered a D'oreo -one of their "fancy" full sized donuts ($2.75 each) - and a bag of Garam Masala Hot Donut Dots ($4.50), the indie version of TimBits.
The garam masala flavour on the dots was nice, but the dots themselves were a bit of a disappointment. They were somewhat dry and boring. Maybe if they were piping hot, and I had a cup of coffee for dipping, it would have been a different story.
The D'oreo however was something else. It had a dense cake texture, and the icing that surrounded it on all sides tasted exactly like the innards of its namesake cookie. My friend can be quoted as saying "This might be the most delicious donut ever".
And because I'm a good girlfriend, I bought two more donuts to take home in the name of sharing. And because I had to write this article, I took a bite of each before they made it there...in the name of research.
The Raspberry Royal, covered in fuchsia icing and sprinkled with graham crumbs, wasn't cloyingly sweet as I would have guessed. It was even a bit tart with a hit of raspberry flavour that started strong and then faded until the next bite.
The Root Beer Float might have been my favourite. Its flavour was muted in comparison to the others, but the root beer had a strong enough presence to make it an interesting eat, without making it taste like one of those Bottle Cap candies.
So we came for the donuts, but it was the chicken that stole the show. My American toasted coconut love affair may not have been swayed, but in terms of fried poultry, Paulette's has my heart. And in the new battle between donuts and cupcakes (I'm on Team Donut), Paulette's is a new stronghold - they sold out of full sized ones by 3pm. Good thing I went early.
52 Comments
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Sounds like its going to be a neat place!
Address or map of location would be nice though
You can fume about your readers "not getting it" but bottom line is, the current approach doesn't seem to work.
Seems like this little stretch of Queen is where I need to be.
But I do think the chicken seems over priced especially since you can't dine in. At Delica, the prices seem to keep going up and up... so is that what is in store for Paulette's as well? I hope not.
I haven't tried the chicken but the doughnuts are yummy. The dough has a distinct taste to it. I like that it's about the flavors and not gimmicky toppings on top the doughnut.
personally way too sweet though..... just glazing the top would be more than enough for me!
cinnamon was the one I preferred.
Maybe it was just a bad day, but I'm not remotelytempted to return. And "fancy".....whaaaa????
Its at Queen and Logan. How inconvenient is that?
You hop on the Queen St/King St street-car, maybe ride your BMX or your car and go east for maybe 10 minutes.
I will be back, but just for the doughnuts.
This place is not cheap - I think the above order totalled almost $30 - and for ironically presented trendy junk food it is not as filling as Burger Priest. For a once in a while treat it is worth a short trip. We'll be back and I wish them success, which they should get at the markups they must have.
(Also please help solve the mystery of where all the skinny hipsters in line are putting away this fatty food? Surely they can't fixie-bike it off??).
I was really looking forward to trying this place out but I am glad that I read before hand that the fried chicken "batter" was THICK as it was really different than any other fried chicken I had before. For $8 for two peices I will not be getting it again but at the same time I was glad that I tried it just to understand what people were talking about. The sauce I had with it (honey and some spices) was good.
I enjoyed the balsamic blueberry donut that I had but I can see what people are saying about them being too "cakey" because I had a bite of the strawberry jammie and it wasn't what I was expecting at all.
Wish them well.... but, if you are in the area to try the donuts I would go to Leslieville Pumps and grab a sandwich to fill you up, you will probably need it after the chicken.
Value: not great
Flavour: pretty good
Notes: food was not fresh. Donought holes were tough and chicken dried out—room temp. Chicken batter is as hard and brittle as rock candy.
Portions are carefully controled like airline food.
I wont be returning.
lol just ask around leslieville and people love this place. i think you are smoking to many cigarettes marty! how could each donut taste the same ;)
The fried chicken was hard and chewy. Seemed like it had been sitting under the lamp for awhile. The flavor was ordinary. The donut (oreo) was MEH. The dipping sauce (honey mustard) was probably the only thing that stood out for me.
The staff was a bit odd.
The biggest let down was how overly priced it was. $8.00 for 2 dried up pieces of chicken and dipping sauce??
I'll stick to KFC and Tim Horton's and spend a quarter of the cost.
As someone said, they took a good idea and blew it. :(
So true comment from above. I wish peeps couldnt annonymously post on here.
-the chicken was quite tasty and with the dip I have to say that I did enjoy it. HOWEVER, if I'm going to go for fried chicken, I would still prefer KFC if I'm going to indulge. Have not tried stockyards. I like fried chicken to be greasy and over the top. Thats why I eat fried chicken for god sakes.
the donuts and the mac were really just meh. maybe if the donut was fresher I would have liked it more... the mac was not cheesy enough - i make a way better mac and cheese at home.
will be back to try the other doughnuts they have on offer.
They only sell cake and no raised yeast donuts which is a letdown. Taking advantage of a rising trend and gouging people.$2.75 is way too expensive even though competition sells for more. All they are is white cake donuts with original glazes. Big deal. Most clever one was balsamic blueberry. But look at the work done on the competitors' products.. Works of art, toasted marshmallows,meringue,brown butter icing and twice the size.


text:
Abdominal aortic aneurysm (AAA) is a dilatation of the aorta affecting most frequently elderly men. Histologically AAAs are characterized by inflammation, vascular smooth muscle cell apoptosis, and extracellular matrix degradation. The mechanisms of AAA formation, progression, and rupture are currently poorly understood. A previous mRNA expression study revealed a large number of differentially expressed genes between AAA and non-aneurysmal control aortas. MicroRNAs (miRNAs), small non-coding RNAs that are post-transcriptional regulators of gene expression, could provide a mechanism for the differential expression of genes in AAA.
To determine differences in miRNA levels between AAA (n = 5) and control (n = 5) infrarenal aortic tissues, a microarray study was carried out. Results were adjusted using Benjamini-Hochberg correction (adjusted p < 0.05). Real-time quantitative RT-PCR (qRT-PCR) assays with an independent set of 36 AAA and seven control tissues were used for validation. Potential gene targets were retrieved from miRNA target prediction databases Pictar, TargetScan, and MiRTarget2. Networks from the target gene set were generated and examined using the network analysis programs, CytoScape® and Ingenuity Pathway Core Analysis®.
A microarray study identified eight miRNAs with significantly different expression levels between AAA and controls (adjusted p < 0.05). Real-time qRT-PCR assays validated the findings for five of the eight miRNAs. A total of 222 predicted miRNA target genes known to be differentially expressed in AAA based on a prior mRNA microarray study were identified. Bioinformatic analyses revealed that several target genes are involved in apoptosis and activation of T cells.
Our genome-wide approach revealed several differentially expressed miRNAs in human AAA tissue suggesting that miRNAs play a role in AAA pathogenesis.
Keywords:Apoptosis; Microarray analysis; Vascular biology; miRNA-mRNA analysis; Network analysis
Abdominal aortic aneurysm (AAA) is a dilatation of the aorta (>3 cm) that occurs below the renal arteries [1]. In the majority of cases AAA is asymptomatic until it reaches a size that requires surgical intervention due to increased risk of rupture, which is often fatal. The only option for patients diagnosed with AAA ≥55 mm is surgical repair of the aorta, but the risk of surgery must be weighed with the risk of rupture. For patients with smaller AAAs, there is currently no treatment. The most important known risk factors for AAA include smoking, male sex, family history, and advanced age [1,2]. Additionally, biomechanical analyses of AAA demonstrated that there are many factors contributing to aortic wall strength [3]. Previous studies have shown that AAA has a strong genetic component [4], but the biological mechanisms of AAA are not fully understood [2,5]. AAA is characterized by the apoptosis of smooth muscle cells, degradation of the extracellular matrix, a potent inflammatory response, and increased oxidative stress in the abdominal aortic wall [2,5-8]. Infiltration by inflammatory cells may act as mediators that lead to apoptosis of vascular smooth muscle cells [7]. A previous genome-wide mRNA expression study identified a large number of genes with differences in the levels of expression in AAA compared to abdominal aortic tissues from age-and sex-matched controls [9].
MicroRNAs (miRNAs) are a class of small non-coding RNAs, whose primary function is the post-transcriptional regulation of gene expression. miRNAs are incorporated into the RNA induced silencing complex (RISC) and preferentially bind to the 3' untranslated region (3'UTR) of target mRNA. RISC then inhibits gene expression by either mRNA degradation or by inhibiting translation [10]. miRNAs have been predicted to regulate thousands of target genes [11], which belong to many biological pathways including immune response and apoptosis [12]. Recent studies have demonstrated that miRNAs play roles in several cardiovascular diseases [13].
In the current study, we investigated the expression patterns of microRNAs in AAA as a potential mechanism for the differences in gene expression observed in our prior study [9]. A microarray-based genome-wide screening study was followed by assaying miRNAs individually with real-time quantitative RT-PCR (qRT-PCR). Bioinformatic analyses were carried out to predict gene targets of the miRNAs and analyze their potential roles in AAA.
Human aortic samples
Full thickness aortic wall tissue specimens were collected from patients undergoing AAA repair operations (n = 41) at the Geisinger Medical Center, Danville, Pennsylvania, USA, or at the Department of Visceral, Thoracic and Vascular Surgery, Technical University of Dresden, Dresden, Germany. Non-aneurysmal aortic samples (n = 12) were collected at autopsies or were obtained from the National Disease Research Interchange (NDRI, Philadelphia, PA; http://www.ndriresource.org webcite). Tissue samples for RNA isolation were stored in RNAlater (Ambion, Austin, TX) or snap-frozen. Table 1 summarizes the demographics of the different groups used in the microarray and qRT-PCR studies. All samples used in the study and information about the donors are listed in Additional file 1: Table S1. The investigation conformed to the principals outlined in the Declaration of Helsinki. AAA patients gave written informed consent for the use of their aortic tissue samples for research. The collection of the human tissues was approved by the Institutional Review Board of Geisinger Clinic, Danville, Pennsylvania, USA, and the Ethics Committee of the Medical Faculty at the Technical University of Dresden, Germany.
Additional file 1. Table S1. Samples used in microarray and real time qRT-PCR experiments.
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Table 1. Summary of experimental groups
RNA isolation
RNA was isolated with mirVana™ miRNA Isolation Kit (Ambion Applied Biosystems, Austin, TX). Quality of the RNA samples was assessed by 2100 Bioanalyzer (Agilent Technologies, Inc., Santa Clara, CA).
Microarray study
miRNA expression was compared in AAA (n = 5) and control (n = 5) samples using an Affymetrix GeneChip miRNA 1.0 Array (Santa Clara, CA). The microarray contained 847 miRNAs probes and 922 probes for other small non-coding RNAs. The expression values were computed using the R package Affycoretools version 1.24.0 (available at http://bioconductor.org/ webcite) Robust Multivariate Average [14]. miRNAs were identified by calculating the Empirical Bayes Statistics using the R package Limma [15]. Benjamini-Hochberg correction was applied to control the false discovery rate (FDR) [16].
Previously our laboratory generated global mRNA expression profiles for both aneurysmal and non-aneurysmal human infrarenal abdominal aorta [9]. The microarray data can be obtained at the Gene Expression Omnibus (GEO) database (Series# GSE7084; http://www.ncbi.nlm.nih.gov/geo/ webcite). We used this data set here for the target gene analysis (see below).
Real-time quantitative reverse transcriptase-polymerase chain reaction
Eight miRNAs (miR-133a, miR-133b, miR-146 a, miR-181a*, miR-204, miR-21, miR-30c-2*, miR-331-3p) which showed significant differences in their levels with an adjusted p < 0.05 in the microarray experiment were selected for qRT-PCR validation. TaqMan® MicroRNA Assays for these miRNAs and a small non-coding RNA U6 (Applied Biosystems, Carlsbad, CA) were run according to manufacturer's recommendation first on RNA from twelve AAA samples from patients undergoing elective repair of an aneurysm and seven control samples that were independent of the microarray study (Table 1 and Additional file 1: Table S1). Next, for the subset of miRNAs with expression medians and variance that warranted further investigation, we expanded the study with an additional thirteen AAA samples from patients undergoing elective repair and eleven AAA samples from patients with aneurysm rupture for a total of seven control, 25 elective repair AAA, and eleven ruptured AAA samples. The relative expression levels of the miRNAs were calculated using the ΔCT method with the expression of the small non-coding RNA U6 as an internal control. The p values were calculated using the Wilcoxon rank-sum test using the statistical program R version 2.13.1 (R Foundation for Statistical Computing, Vienna, Austria).
Bioinformatic Analyses
Targets were predicted for qRT-PCR validated miRNAs (miR-133a, miR-133b, miR-331-3p, and miR-204), which were all down regulated in AAA. miR-30c-2* was not included because it is a miRNA* strand; passenger (*) strands of miRNA are usually degraded upon uploading of the miRNA duplex into the RISC complex [17]. The miRNA target prediction databases TargetScan, MirTarget2, and Pictar were queried using the R package RmiR.hsa [18]. The predicted targets were then compared to a list of upregulated genes found in our previous study [9]. In addition, we queried targets of miR-331-3p from TargetScan's non-conserved target prediction dataset (http://www.targetscan.org/ webcite) and retrieved gene targets that were conserved across placental mammals.
To evaluate the strength of the binding of miRNAs to their targets, the minimum free energy for miRNA–mRNA hybridization was calculated using program RNAhybrid version 2.1. [19]. The median minimum free energy of hybridization was taken for genes with multiple transcripts. For this analysis the miRNA sequences of qRT-PCR validated miRNAs were retrieved from miRbase version 17 (http://www.mirbase.org webcite). The sequences of the target gene 3'UTR were retrieved from Ensemble Biomart (http://useast.ensembl.org/ webcite). CytoScape®, version 2.8.1 software available at http://www.cytoscape.org webcite[20] was used to generate a network showing the miRNA-mRNA connections and indicating the strength of the binding based on the minimum free energy values.
Functional classification of the target genes was carried out with Gene Ontology (GO) analysis using WebGestalt to create a hierarchy of the GO annotations of the predicted targets (http://bioinfo.vanderbilt.edu/webgestalt/ webcite). For this procedure, a list of the Entrez IDs for predicted targets that were known to be differentially expressed based on our previous study [9] was uploaded to the web application WebGestalt Gene Set Analysis Toolkit Version 2 [21]. Directed acyclic graphs (DAGs) were generated representing a hierarchical categorization of the significant GO annotations.
Potential target gene interactions were analyzed via networks generated using Ingenuity Pathway Analysis® (IPA) tool version 9.0, (Ingenuity Systems, http://www.ingenuity.com webcite). The four biologically active qRT-PCR-validated miRNAs with their targets were uploaded to IPA. Since IPA combines the targets of mature miRNAs with similar sequences (2–3 nucleotide difference) to miRNA families, experimentally validated targets of miR-133a/miR-133b, miR-211/204, and miR-331-3p were retrieved.
Results and Discussions
A microarray study was performed comparing miRNA expression levels in infrarenal aortic tissue samples between AAA (n = 5) and age- and sex-matched controls (n = 5) (Table 1). The empirical Bayes statistics revealed that out of the 847 miRNAs probes and 922 probes for other small non-coding RNAs, eight miRNAs and one snoRNA had significantly different expression (adjusted p < 0.05 after applying Benjamini Hochberg correction; Figure 1) [16]. The three upregulated miRNAs were miR-181a* (MIMAT0000270), miR-146a (MIMAT0000449), and miR-21 (MIMA0000076), while five miRNAs, miR-133b (MIMAT0000770), miR-133a (MIMA000427), miR-331-3p (MIMAT0000760), miR-30c-2* (MIMAT0004550), and miR-204 (MIMA0000265), were significantly down regulated (Figure 1). In addition, HBII-85-29, a small nucleolar RNA, C/D box 116–29, was found to be significantly down regulated (Figure 1). The full lists of the 139 miRNAs and 78 other small non-coding RNAs with expression differences with nominal p < 0.05 (no correction for multiple testing) are shown in Additional file 2: Table S2, and Additional file 3: Table S3, respectively.
Additional file 2. Table S2. List of the miRNAs which were found to have significantly different (nominal p < 0.05) expression in AAA (n = 5) compared to control tissue (n = 5).
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Additional file 3. Table S3. List of other small RNAs with significantly different (nominal p < 0.05) expression in AAA (n = 5) compared to controls (n = 5).
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Figure 1. Volcano plot demonstrating differences in expression levels of miRNAs between AAA and control abdominal aorta based on the microarray study. The log-fold change is plotted against the log odds of differential expression using the R package limma. The miRNAs with significant differences in expression levels between the AAA (n = 5) and control (n = 5) groups (p < 0.05) after Benjamini-Hochberg correction are indicated. Complete lists of nominally significant miRNAs and snoRNAs are shown in Additional file 2: Table S2 and Additional file 3: Table S3, respectively.
The expression levels of the eight miRNAs identified in the microarray study were initially validated using individual real-time qRT-PCR assays and a new set of twelve AAA and seven control aortic tissue samples (Table 1 and Additional file 1: Table S1). The five down regulated miRNAs showed significantly different expression in AAA tissue compared to the control infrarenal abdominal aorta samples, but the three up regulated miRNAs failed to replicate (Figure 2A). Since it is plausible to hypothesize that AAA initiation, growth and rupture have different molecular mechanisms, we compared the expression levels of the five qRT-PCR-validated miRNAs in ruptured (n = 11) and non-ruptured, electively repaired (n = 25) AAAs (Figure 2B). No significant differences were found between the AAA samples from patients undergoing elective repair operations (eAAA) and those with ruptured AAA (rAAA; Figure 2B). In the combined qRT-PCR analysis including all the 36 AAA tissue samples and seven controls, the differences in expression levels of the five miRNAs, miR-133b, miR-133a, miR-331-3p, miR-30c-2*, and miR-204, between AAA and control groups were highly significant (Figure 2).
Figure 2. Validation of microarray results by real-time qRT-PCR in an independent set of samples.A. Eight miRNAs identified as significantly different between AAA and controls in the microarray study were evaluated by qRT-PCR in an independent set of twelve AAA and seven control samples. B. Five down regulated miRNAs validated by qRT-PCR (from panel A), were analyzed using thirteen additional samples from elective AAA repairs (eAAA) and eleven samples from ruptured AAAs (rAAA). The expression levels for each miRNA were adjusted to the expression levels of U6. The p values were calculated using the Wilcoxon rank-sum test. Significance between each comparison is shown. NS, not significant; *, p < 0.05; **, p < 0.001; ***, p < 0.0001.
We searched the literature for information on miR-133b, miR-133a, miR-204, miR-331-3p, and miR-30c-2*, the five miRNAs with confirmed downregulated expression between AAA and control abdominal aorta. The functions of miR-133b, miR-133a, and miR-204 have been thoroughly examined in a cardiovascular context [22-28], but nothing was known about their role in AAA. A recent study on thoracic aortic dissections [29] found several miRNAs with nominally significant (p < 0.05) differences when compared to normal thoracic aorta (summarized in Additional file 2: Table S2). Of the validated miRNAs in the current study only miR-133a and miR-133b differed in expression also in thoracic aortic dissections compared to controls [29]. The differences in the results of these two studies reinforce the distinct nature of these two aortic diseases.
While the current study was under review miR-21 and miR-29b (MIMAT0000100) were identified as potential therapeutic targets in an animal model of aortic aneurysms [30,31]. In addition, miR-21 was shown to be upregulated in human AAA tissue using qRT-PCR [30]. Although miR-21 was upregulated in AAA in our microarray study (Figure 1), it was not validated by qRT-PCR (Figure 2A). The discordant results could be due to differences in ages of the control subjects in the two studies. We did not detect significant differential expression of miR-29b; however, miR-29b-2* was downregulated in our microarray study before FDR correction (Additional file 2: Table S2).
We characterized the putative functions of the miRNAs by identifying genes they are predicted to regulate. Predicted targets for miR-133a, miR-133b, miR-331-3p, and miR-204 were retrieved from the miRNA–mRNA target databases TargetScan, Pictar, and MirTarget2 with the R package RmiR.hsa [18]. There are no predicted target genes for miR-30c-2* in the TargetScan, Pictar, or MirTarget2 data sets [11,32,33]. The list of predicted targets was compared to a list of genes that were previously identified as having altered expression levels in AAA from our microarray-based mRNA expression study [9]. The four downregulated miRNAs miR-133a, miR-133b, miR-331-3p, and miR-204 had 1,836 potential target genes, 222 of which were significantly upregulated in our prior mRNA microarray study (Additional file 4: Table S4) [9], consistent with the proposed regulatory action of the miRNAs.
Additional file 4. Table S4. A list of predicted target genes for miR-133a/miR-133b, miR-204, and miR-331-3p that were also upregulated in our prior microarray study.
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We explored further the miRNA–mRNA interactions with the downloadable version of RNAhybrid program to compute the minimum free energy of the miRNA–mRNA binding [19]. The rationale for this analysis is that interactions with lower predicted minimum free energy are predicted to be more stable and more likely to occur. We ranked the miRNA–target gene interactions and generated a network using CytoScape® to visualize the predicted miRNA–mRNA interactions (Figure 3). There was a redundancy between the predicted targets of miR-133a and miR-133b due to the similarity in their sequences; however, the two base pair difference had an impact on the calculated minimum free energies, suggesting that they may have different affinities for individual target silencing [19]. In general miR-331-3p had the lowest calculated minimum free energy of hybridization to its predicted targets, which suggests it may have stronger binding affinity for its targets.
Figure 3. A network of miRNAs miR-133a, miR-133b, miR-331-3p, miR-204, and their target genes. miR-30c-2* was not included because it is a miRNA* strand that is usually degraded upon miRNA loading to the RISC complex [17]. Bioinformatic analysis predicted 222 genes (see Additional file 4: Table S4) with upregulated expression in AAA based on a prior microarray study [9] were targets of miR-133a, miR-133b, miR-331, or miR-204. The predicted minimum free energy of the miRNA and target mRNA hybridization from RNAhybrid is shown by the line and node color. Black lines indicate that the 3'UTR sequence was not available from Biomart, and the minimum free energy was not calculated. The figure was generated using CytoScape® [20].
Several genes were identified as potential targets of two or more of the miRNAs (Figure 3). Four genes (CSRNP1, SLC7AB, PLK3, and FURIN) were predicted targets of miR-133a/miR-133b and miR-331-3p. Two genes (APH1A and VHL) were predicted targets of miR-204 and miR-331-3p. Eight genes (DNM2, DNAJB1, TGFBR1, TGOLN2, BCL11A, EDEM1, SFXN2, YTHDF3) were predicted targets of miR-204 and miR-133a/miR-133b. Hypermethylated in cancer 2 (HIC2) was the only gene predicted to be targeted by all four miRNAs (Figure 3). Although the function of HIC2 has not been extensively studied, it is closely related to HIC1, which is an important tumor suppressor gene that deactivates repressors of P53 and E2F1 induced senescence [34].
We analyzed the GO terms to assign potential functions to the miRNA targets using the web application, WebGestalt [21]. The results with the most enriched biological processes and molecular functions are shown as a DAG in Figure 4. The most significant biological function was the "positive regulation of apoptosis" (Figure 4). It was interesting given the fact that smooth muscle cell apoptosis is a characteristic histological feature of aneurysmal aortic wall in humans. Previous cell culture studies, however, have shown a role for miRNAs in smooth muscle cell proliferation [27,35]. A possible explanation for the contradictory results could be that we are looking at late stages of the human aneurysmal disease requiring surgical intervention, while the previously published cell culture experiments on smooth muscle cells [25] may be more relevant to the initial stages of arterial wall injury. This conclusion is supported by other studies in which mice treated with antagomirs for miR-133a showed cardiomyocyte hypertrophy [25], but knockout mice lacking miR-133a displayed dilated cardiomyopathy with increased apoptosis [22,25]. Another possible explanation is that our results indicate high turnover of vascular smooth muscle cells.
Figure 4. Biological categories of miRNA target genes. A DAG of the GO categories of the set of 222 upregulated mRNAs was generated by the web application WebGestalt. Categories shown in red were significant (adjusted p < 0.001).
Several target genes with functions in apoptosis were of interest in AAA. Two tumor necrosis factor receptors, TNFRSF10B and TNFRSF8, were predicted targets of miR-133a/miR-133b and miR-204, respectively. TNFRSF10B, also known as death receptor 5, is involved in DR5/FADD/caspase-8 signaling and is an important component of the extrinsic apoptotic pathway [36]. TNFRSF8, also known as CD30, is involved in NFκB activation and is expressed by activated T and B cells [37]. Tumor protein p53-inducible nuclear protein 1 (TP53INP1) is a p53 target gene that responds to multiple types of cellular stress events, including oxidative stress, and promotes cell cycle arrest and apoptosis [38].
Another significant GO term among the target genes included "T cell activation" (Figure 4), which is highly relevant finding to AAA, since inflammation is a characteristic of AAA [5], and antigen-independent co-stimulation is a crucial step in T cell activation [39]. CD28, CD86, and ICOS, which are important co-stimulatory molecules, were predicted to be targets of miR-204, miR-133a/miR-133b, and miR-331-3p, respectively [40]. CD28 and ICOS are important receptors of co-stimulatory signals, which are triggered by ICOSL in human vascular endothelial cells [39]. CD86, which is expressed in antigen presenting cell types including dendritic cells, macrophages, and B cells [41], acts as a ligand to CD28. CD86 is not expressed in endothelial cells [40], but its levels are elevated in the plasma [42] of AAA patients. Furthermore, the mRNA levels of CD86, CD80, CTLA, and ICOS are elevated in the aortic wall of AAA patients [9].
"Response to organic substance" and "purinergic nucleotide receptor activity" were additional significant GO terms among the upregulated target genes (Figure 4). Approximately half of the genes annotated in "Response to organic substance" were also genes annotated as apoptotic genes. Four of the genes (DUSP4, AQP9, SOCS1, and PTPN2) are involved in injury response [43-46]. Genes which were annotated to play roles in responding to organic substance included the niacin receptors, GPR109A and GPR109B. Niacin has been studied for its potential use based on its anti-inflammatory and anti-atherosclerotic effects of raising HDL [47], although no benefit to patients with clinical disease has been shown to date [48].
Ingenuity Systems® Pathway Analysis tool was used to generate a network from 45 experimentally verified interactions of the four biologically active, validated, down regulated miRNAs (miR-133a, miR-133b, miR-331-3p, and miR-204) (Figure 5). We further explored the regulation of the targets by examining the interactions of the validated targets with the predicted miRNA targets (Figure 6), and found that 54 of the predicted miRNA targets interacted with the experimentally validated miRNA targets. The interaction networks (Figures 3, 5, and 6) demonstrate a complex role for miRNAs in AAA. Since miRNAs usually inhibit mRNA expression of their target genes [10], we expected that target mRNAs of the miRNAs down regulated in AAA would be upregulated; several gene targets exhibited expression levels consistent with this expectation (shown in red in Figure 5). For example, MMP9 was identified as a target of miR-204 [49]. This finding is highly relevant to AAA pathogenesis, since the decreased level of miR-204 could contribute to the increased mRNA and protein expression level of MMP9 seen in human AAA tissue (Figures 5 and 6), and thereby increase the degradation of the extracellular matrix in AAA [50].
Figure 5. A network of the interactions of the miRNA target genes. Ingenuity Pathway Analysis® tool was used to generate the network from experimentally observed miRNA–mRNA interactions of miR-133a/miR-133b, miR-204, and miR-331-3p. Molecules shown in red (increased expression) and green (decreased expression) were identified in our previous microarray study [9]. Solid lines represent direct interactions and dashed lines indirect interactions.
Figure 6. Expanded network of the validated miRNA–mRNA interactions. The network was generated using Ingenuity Pathway Analysis® tool. The validated network shown in Figure 5 was expanded to include experimentally validated interactions with our list of the 222 predicted miRNA targets (Additional file 4: Table S4). Green molecules are the four down regulated miRNAs (miR-133a/miR-133b, miR-204, and miR-331-3p), yellow molecules are experimentally verified target genes of the four miRNAs, and grey molecules are predicted targets of the four miRNAs. Solid lines represent direct connections and dashed lines represent indirect connections
There were also several genes known to be regulated by these miRNAs whose expression was decreased in AAA (shown in green in Figure 5) [9]. Most of these genes have proliferative and anti-apoptotic functions based on our literature search. For example, in cell culture experiments, miR-133a/miR-133b down regulation is associated with a switch in vascular smooth muscle cells to a proliferative phenotype [27]. miR-133a regulates the expression of a gene called nuclear factor of activated T cells, calcineurin-dependent-4 (NFATc4/NFAT3), which is a ubiquitously expressed member of the NFAT transcription factor family and is involved in cell proliferation. NFATC4 mediates the effect of miR-133a in increasing cell proliferation in cardiomyocyte hypertrophy in vivo[24], but its expression is decreased in AAA [9]. One potential explanation for the down regulation of NFATC4 is competition with other biological pathways. HOXA9 indirectly promotes NFATC4 expression [51,52]. The expression of the members of the HOXA family is decreased in AAA [53]. Also, in hypertrophy NFATC4 is regulated by calcium mediated response of angiotensin II, endothelin, and norepinephrine binding to their receptors [54], but in AAA the expression of these receptors is down regulated [9]. KLF15 is also a target of miR-133a/miR-133b [23], and its expression is reduced in both mouse aneurysm models and human AAA [9,55]. These findings suggest that multiple competing regulators are important in AAA, and the phenotype is a result of complex interactions between regulatory molecules with different functions.
Our study has several limitations. One limitation is the use of end-stage disease human tissue, since it is plausible to collect human aortic aneurysmal samples only from AAAs large enough to require surgical intervention or from ruptured aortas. Additionally, since the study is observational, it is not possible to differentiate between cause and consequence, which would require intervention in a model system. It is also possible that the differences in mRNA and miRNA expression are merely reflective of the changes in the aortic wall architecture in AAA. The histological characterization of the aortic wall in AAA to "inflammatory", "active" and "amorphous regions" has been proposed [56,57]; the regions may, however, overlap and do not necessarily show a clear progression of the disease. Based on histological and immunohistochemical analyses in our previous studies [58,59], the samples were from the so called "active region" of the AAAs.
Our genome-wide study followed by qRT-PCR validation identified five miRNAs with significantly downregulated expression in AAA aortic tissue from a control group of human infrarenal aortic tissues. Bioinformatic analysis indicated that miR-133a, miR-133b, miR-331-3p, and miR-204 target apoptotic genes, which may play a role in the loss of vascular smooth muscle cells in AAA. The miRNAs are also involved in the activation of the immune cells and the alteration of their response to chemical signaling. Taken together, the results provide strong evidence for an important regulatory function of miRNAs in vascular remodeling of the aorta.
AAA: Abdominal Aortic Aneurysm; DAG: Directed Acyclic Graph; FDR: False Discovery Rate; GEO: Gene Expression Omnibus; IPA®: Ingenuity Pathway Analysis®; miRNA: microRNA; NDRI: National Disease Research Interchange; RT-PCR: Reverse Transcriptase-PCR; RISC: RNA induced silencing complex; qRT-PCR: quantitative Reverse Transcriptase-PCR; snoRNA: small non-coding RNA; 3'UTR: 3' untranslated region.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
MCP designed experiments, analyzed data, carried out bioinformatic analyses, and drafted the manuscript. KD prepared RNA samples for microarray and qRT-PCR, and ran the qRT-PCR assays. GG, IH, JRE and DPF recruited patients, obtained tissue samples from cases and controls, verified clinical information and critically reviewed the manuscript. CMS carried out the microarray analyses. TCP and DJC contributed to the experimental design and data analysis, and critically reviewed the manuscript. JLG recruited patients, and obtained tissue samples. GT contributed to the experimental design, statistical analysis, computational aspects, as well as drafting and editing of the manuscript. HK contributed to the experimental design, data analysis, drafting and editing of the manuscript, and obtained funding for the study. All authors read and approved the final manuscript.
We acknowledge use of human aortic tissues provided by the National Disease Research Interchange (NDRI), with support from NIH grant 5 U42 RR006042-20. This work was supported by the National Heart, Lung, and Blood Institute (HL064310 to H.K.), NIH, and the American Heart Association Great Rivers Affiliate (to D. J. C.), as well as by Geisinger Clinic. IH was a recipient of Research Fellowships from Deutsche Forschungsgemeinschaft (Hi 1479/2-1) and from the Technical University of Dresden ("Frauenhabilitationsstipendium der Medizinischen Fakultät Dresden"), Germany, as well as a recipient of Aortenpreis 2011 der Deutschen Gesellschaft für Gefäβchirurgie und Gefäβmedizin.
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Liao M, Zou S, Weng J, Hou L, Yang L, Zhao Z, Bao J, Jing Z: A microRNA profile comparison between thoracic aortic dissection and normal thoracic aorta indicates the potential role of microRNAs in contributing to thoracic aortic dissection pathogenesis.
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Maegdefessel L, Azuma J, Toh R, Deng A, Merk DR, Raiesdana A, Leeper NJ, Raaz U, Schoelmerich AM, McConnell MV, et al.: MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion.
Maegdefessel L, Azuma J, Toh R, Merk DR, Deng A, Chin JT, Raaz U, Schoelmerich AM, Raiesdana A, Leeper NJ, et al.: Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development.
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Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M, et al.: Combinatorial microRNA target predictions.
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Wang X, El Naqa IM: Prediction of both conserved and nonconserved microRNA targets in animals.
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Van Rechem C, Boulay G, Pinte S, Stankovic-Valentin N, Guerardel C, Leprince D: Differential regulation of HIC1 target genes by CtBP and NuRD, via an acetylation/SUMOylation switch, in quiescent versus proliferating cells.
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Courboulin A, Paulin R, Giguere NJ, Saksouk N, Perreault T, Meloche J, Paquet ER, Biardel S, Provencher S, Cote J, et al.: Role for miR-204 in human pulmonary arterial hypertension.
J Exp Med 2011, 208:535-548. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Sun SY: Understanding the Role of the Death Receptor 5/FADD/caspase-8 Death Signaling in Cancer Metastasis.
Mol Cell Pharmacol 2011, 3:31-34. PubMed Abstract | PubMed Central Full Text
Aizawa S, Nakano H, Ishida T, Horie R, Nagai M, Ito K, Yagita H, Okumura K, Inoue J, Watanabe T: Tumor necrosis factor receptor-associated factor (TRAF) 5 and TRAF2 are involved in CD30-mediated NFkappaB activation.
J Biol Chem 1997, 272:2042-2045. PubMed Abstract | Publisher Full Text
Cano CE, Gommeaux J, Pietri S, Culcasi M, Garcia S, Seux M, Barelier S, Vasseur S, Spoto RP, Pebusque MJ, et al.: Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function.
Cancer Res 2009, 69:219-226. PubMed Abstract | Publisher Full Text
Pober JS, Tellides G: Participation of blood vessel cells in human adaptive immune responses.
Trends Immunol 2012, 33:49-57. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Krummel MF, Allison JP: Pillars article: CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. The journal of experimental medicine. 1995. 182: 459–465.
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Collins M, Ling V, Carreno BM: The B7 family of immune-regulatory ligands.
Genome Biol 2005, 6:223. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
Sakthivel P, Shively V, Kakoulidou M, Pearce W, Lefvert AK: The soluble forms of CD28, CD86 and CTLA-4 constitute possible immunological markers in patients with abdominal aortic aneurysm.
J Intern Med 2007, 261:399-407. PubMed Abstract | Publisher Full Text
Al-Mutairi MS, Cadalbert LC, McGachy HA, Shweash M, Schroeder J, Kurnik M, Sloss CM, Bryant CE, Alexander J, Plevin R: MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana.
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Colli ML, Moore F, Gurzov EN, Ortis F, Eizirik DL: MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta-cell responses to the viral by-product double-stranded RNA.
Hum Mol Genet 2010, 19:135-146. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Dimayuga PC, Li H, Chyu KY, Fredrikson GN, Nilsson J, Fishbein MC, Shah PK, Cercek B: T cell modulation of intimal thickening after vascular injury: the bimodal role of IFN-gamma in immune deficiency.
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Loitto VM, Forslund T, Sundqvist T, Magnusson KE, Gustafsson M: Neutrophil leukocyte motility requires directed water influx.
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Lee K, Ahn TH, Kang WC, Han SH, Choi IS, Shin EK: The effects of statin and niacin on plaque stability, plaque regression, inflammation and oxidative stress in patients with mild to moderate coronary artery stenosis.
Korean Circ J 2011, 41:641-648. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W: Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
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Ferrell CM, Dorsam ST, Ohta H, Humphries RK, Derynck MK, Haqq C, Largman C, Lawrence HJ: Activation of stem-cell specific genes by HOXA9 and HOXA10 homeodomain proteins in CD34+ human cord blood cells.
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Li C, Li J, Cai X, Sun H, Jiao J, Bai T, Zhou XW, Chen X, Gill DL, Tang XD: Protein kinase D3 is a pivotal activator of pathological cardiac hypertrophy by selectively increasing the expression of hypertrophic transcription factors.
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Lillvis JH, Erdman R, Schworer CM, Golden A, Derr K, Gatalica Z, Cox LA, Shen J, Vander Heide RS, Lenk GM, et al.: Regional expression of HOXA4 along the aorta and its potential role in human abdominal aortic aneurysms.
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Berridge MJ, Bootman MD, Roderick HL: Calcium signalling: dynamics, homeostasis and remodelling.
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Haldar SM, Lu Y, Jeyaraj D, Kawanami D, Cui Y, Eapen SJ, Hao C, Li Y, Doughman YQ, Watanabe M, et al.: Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation.
Curci JA, Liao S, Huffman MD, Shapiro SD, Thompson RW: Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms.
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Yoshimura K, Ikeda Y, Aoki H: Innocent bystander? Intraluminal thrombus in abdominal aortic aneurysm.
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Hinterseher I, Erdman R, Donoso LA, Vrabec TR, Schworer CM, Lillvis JH, Boddy AM, Derr K, Golden A, Bowen WD, et al.: Role of complement cascade in abdominal aortic aneurysms.
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Pre-publication history
The pre-publication history for this paper can be accessed here:


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Super StarDust Delta | Launch Trailer (HD)
Create black holes, launch swarm missiles and unleash shockwaves with all-new PlayStation Vita controls Read More
Create black holes, launch swarm missiles and unleash shockwaves with all-new PlayStation Vita controls Read More
What games should you get for PlayStation Vita when it officially launches this week? Read More
The twin-stick shooter returns on a whole new level for Sony's handheld Read More
Our Kingdoms of Amalur review, Darkness II review, Star Wars: The Old Republic review, and more Read More
Hope your shooting skills are up to snuff. Read More
The stuntman returns in a spirited new "director's cut". Read More
Like the Pixeljunk games and Super Stardust, this one is a must for your collection Read More
Earlier this month Sony announced a new promotion named PSN PLAY. In the announcement, they stated that PLAY would be an annual program aimed at prom Read More
I was annoyed by this whole PlayStation Network debacle. At first, I was perturbed because all I wanted to do was play The Fancy Pants Adventures. Bu Read More
How in the world do you top such an awesome feat? A few years ago, the development team at Housemarque created one of the PlayStation Network's bigge Read More
The Super Stardust HD team's next game, Dead Nation, is set to release on November 30. From Sony: You'll be surrounded by more onscreen zombies tha Read More
Are the latest indie releases worth your time? GameZone travels abroad to go deep undercover and find out so that you don't have to*.*No GameZone emp Read More
Ubisoft announced today the development of Outland, an action-adventure game for Xbox LIVE Arcade and Playstation Network. Developed by Housemarque, Read More
Tuesday evening. That means it's time for another PlayStation Store update. This week PlayStation Plus subscribers get a Red Faction Guerrilla trial, Read More
In a move which is sure to be fan-pleasing, Sony is reaching out to PSN users to ask what games, classics and trials they would like to see become available on PlayStation Plus. The company isn't promising that suggested titles will eventually make their way onto the service, but they are interested in giving users some more input into what offerings will be available. More info after the break. Read More
Sony is gearing up to turn the PS3 into not just a console for 3D games, but a total 3D entertainment set-top box, not forgetting to cover the little things. Within the next year Sony wants to give all current PS3 owners access to not just 3D games, but also 3D movies, photos, and even online videos, touting how thorough-yet-automatic the update will be. It's coming piecemeal though, starting with a measure for Soy to cover their collective legal behinds. Read More
Sony released the first trailer for Dead Nation, and to be honest, it looks awesome. Check it out after the break and learn why this game just may be worth picking up. Read More
In a very recent interview interview with CVG, Sony revealed that the majority of its future first-party titles will be in 3D, as the technology gains more ground with consumers. The PS3 will be getting a firmware update today that enables 3D stereoscopic gaming, for those lucky enough to own a 3D enabled TV of course. The four 3D titles playable as of today are WipEout HD, Super Stardust HD, PAIN, and the demo of MotorStorm Pacific Rift. But what's next for Sony? Hit the jump to find out. Read More
Apparently, Japan won't be the only ones jumping into the future tomorrow. It turns out that American PlayStation 3 owners will be able to play stereoscopic 3D as long as they downloaded the free firmware update that was released back in April. WipEout HD, Super Stardust HD, PAIN, and MotorStorm Pacific Rift (demo) will all be popping out into the Z axis come the morning. It seems like 3D gaming just snuck up us. But are gamers ready for it? Hit the break for more. Read More
Whether 3D ends up a fad or the future, it's hard to argue that it has become the biggest change in the film industry in many years. After the exploding popularity of Avatar, practically every single major film company under the sun has jumped onto the 3D bandwagon - with Sony, of course leading the way. If you were to visit Sony's booth at CES 2010 this past January, the message was clear. 3D is the future, and if they have their way, every movie you see, every show you watch, and every video game you play will have you looking at them through ridiculous-looking glasses. This week, Sony also announced a new firmware update to its line of Blu-ray players, bringing long-awaited 3D movie support to the format. That is, their line of Blu-ray players with the exception of the most popular: The PlayStation 3. Read More


text:
Internal commands are commands that are already loaded in the system.
They can be executed any time and are independent. On the other hand, external
commands are loaded when the user requests for them. Internal commands don't
require a separate process to execute them. External commands will have an
individual process. Internal commands are a part of the shell while external
commands require a Path. If the files for the command are not present in the
path, the external command won't execute.
The commands that are directly executed by the shell are known as internal
commands. No separate process is there to run these commands.
The commands that are executed by the kernel are knows as external commands.
Each command has its unique process id.
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Nslookup is used to find details related to a Domain name server. Details like
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Our in house paint specialists and artists produce only the highest quality work for your vehicle or bike. If you can think it, we can do it.
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Bangladeshi women form a human chain as they participate in a One... Fotografía de noticiasAdulto,Bangladesh,Cadena,Dhaka,Horizontal,Mujeres,One Billion Rising,Personas,Temas socialesPhotographer MUNIR UZ ZAMANCollection: AFP 2013 AFP Bangladeshi women form a human chain as they participate in a One Billion Rising rally in Dhaka on February 14, 2013. The one-day event called for one billion women around the world to walk away from their homes, businesses, and jobs, and join together to dance in a show of collective strength. The word 'billion' refers to the one billion women who are survivors of abuse. AFP PHOTO/ Munir uz ZAMAN (Photo credit should read MUNIR UZ ZAMAN/AFP/Getty Images)


text: Top 5 Craziest Women (page 5) January 9, 2012 3:28 PM View Comments Related Tags: Casey Anthony, Chris Brown, crazy women, Elin Nordegren, Ex Girlfriend, Katy Perry, Rihanna, Russel Brand, Tiger Woods #http://cbswvmv.files.wordpress.com/2012/01/72826357-285x385.jpg / gettyimages.com 1. Elin Nordegren - (Tiger Woods ex wife) she recently bought a $12,000,000 home and destroyed it!!! she didn't want the mansion she just wanted the property the house was on… What is wrong with this woman? why would you do this? just because you can? People this stupid shouldn't have this much money… That money could have gone to many other things if you were just going to waste it. starving kids in a 3rd world country or you could have saved the whales, but you Elin took that 12 million dollars and earned a spot on my craziest woman list, you even beat out Casey Anthony! PAGES: 1 2 3 4 5 View Comments


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|The Colbert Report
|Mon - Thurs 11:30pm / 10:30c
|Indecision 2012 - Rick Santorum's Energy War Alarm
Steven Colbert began Monday's broadcast by addressing the absence of his show in the finals days of last week. He addressed rumors found on the internet and other sources, including Joan Rivers joking about him having plastic surgery. He finally alluded to the true reason he was absent – he was visiting his mother, whose health seems to be improving as he referred to her as "tough as nails."
Colbert then talked about the Michigan Republican Primary campaign, in which Romney seems to be trailing Rick Santorum despite Michigan being Romney's home state, and being shaped like a mitt. Romney is suffering in the polls possibly due to his opposition to the auto-company bailouts that have been helping Michigan prosper. But Romney has an ace in the hole – Donald Trump. Trump has been speaking in favor of Romney. Romney lost three of the last handful of primaries to Santorum, and needs Michigan to give his campaign some life. Romney tried to garner support with a speech in which he said he loved Michigan, noting his love of cars, his appreciation for lakes, and the seemingly appropriate "tree-height" in the state.
Colbert proceeded to talk about Rick Santorum. He leads Romney in the national polls 10%. Santorum spoke out against Obama's attempts to revolutionize energy and radical environmentalists. He accused Obama of having a phony agenda. He also said that America is fighting a spiritual war, saying Satan is only attacking America. Colbert reported Santorum will declare war on Hell if elected.
Colbert's guest was Ann Patchet, who is working to save independent book stores. She is the co-owner of a bookstore in Nashville Tennessee. Colbert compared her to Meg Ryan in the movie You've Got Mail. They discussed the advantages of a small local bookstore as opposed to shopping online, including the ability to discuss books with intelligent people. He gave her the "Colbert Bump" and she offered to have him come to Nashville when his book comes out and have a book signing.


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DANBURY, Conn. Ludlow Harris scored the games first three goals and added an assist as the Watertown Privateers rolled past the Danbury Whalers, 5-1, on Saturday night in a Federal Hockey League game at Danbury Ice Arena.
Britt Ouellette assisted on each of Harriss tallies and then scored a goal for the Privateers (14-14), who won for the seventh time in their past eight games. Dane Erickson contributed three assists.
Matt Anthony made 37 saves for the win in the first of eight consecutive road games for Watertown.
After Harris scored two goals within the first 7 1/2 minutes of the game, he struck again three minutes, 51 seconds into the second period. Ouellette scored later in the period for a 4-0 lead.
Thousands of readers like you have made Northern New York Newspapers the number one ranked website* for local news and sports coverage in the north country.
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Ready to feel old? Tatyana Ali, who played Will Smith's teen cousin "Ashley Banks" on "Fresh Prince of Bel-Air," turns 33-years-old today!
Since the show went off the air in 1996, Ali worked on a music career and continued acting in shows like "Love That Girl" and "The Young and the Restless" -- which she got an NAACP Image Award for in 2011.
Check out the gallery above to see what Tatyana and the rest of the "Fresh Prince of Bel-Air" cast looks like today!
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The animals in Australia's Northern Territory tend to be bigger and stranger than wildlife elsewhere, so when reports emerged in June that thousands of feral cats, reportedly weighing up to 45 pounds, were roaming around and tearing apart anything smaller and less mean than them, it wasn't exactly a shock. But it is a problem—the cats are growing bigger and bigger and killing so many small critters, they're damaging the biodiversity of the ecosystem.
READ MORE: http://www.vice.com/read/how-do-you-kill-giant-cats-get-some-giant-dogs-000200-v20n8
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- Musician's Friend Best Selection, Price & Service. Guaranteed.
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at: 800-449-9128
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Compact 8-pad controller with built-in sound library.
The MPX8SD from Akai takes everything Akai is known for, and packs it into a compact 8-pad controller with a built-in library of popular sounds, samples, and bumps. The 8 velocity-sensitive pads give you plenty of room for expression, and creativity. USB MIDI and standard MIDI I/O gives you all the connection options you need to start making music. Drag and drop samples via the included sound editor program for Mac and PC, or load in sounds through the SD card slot from your SD cards. The MPX8SD has all of the beat-making possibilities of it's larger cousins, but in a size that can move as freely as you do.
The MPX8SD is great for both live and studio applications, order today.
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Comments about Akai Professional MPX8SD Sample Player:
This was my first sampler. Was looking for something to incorporate samples into my live set (I play guitar in a rock band) without having to drag around my laptop. This works great for that. The controls are pretty easy to use (though I can't imagine myself altering the sample parameters during a set) and the interface is pretty straightforward. The software does the job it needs to do, could be better but ah well. I wish it had mute groups. The loading of samples from the SD card is slow, and you have to load every time you switch kits. You can not play any samples while it is loading either, so if you're looking to do more than 8 samples in a song this might not be for you. Overall, I'm pretty happy with it and the price was definitely right.
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Comments about Akai Professional MPX8SD Sample Player:
Another Well made product from AKAI, Rock solid and stable! Built in sequencing would have earned it five stars! But still a great buy for the price...
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Patient Success Stories
Bone & Joint Program got him back in the game
Keith Forbes
As a competitive athlete, Malden native and former minor league pitcher Keith Forbes is no stranger to regular visits to the hospital. Still, it wasn't until he came to Hallmark Health's innovative Bone & Joint Program that he found out what clinical excellence was truly all about.
Keith made 74 appearances with the San Diego Padres farm system during the 2000 season, but was sidelined after he tore the labrum, a muscle in the shoulder, in his pitching arm. He had surgery and went through rehabilitation, but never fully recovered from the injury.
Keith returned to Massachusetts and started his own business, using his knowledge of pitching mechanics to help young pitchers stay healthy and avoid injury. He began throwing regularly again and soon the pain in his pitching arm returned, eventually becoming constant.
That all changed when Keith was referred to Abraham Shurland, MD, a highly skilled orthopedic surgeon with the Hallmark Health Bone & Joint Program. Dr. Shurland performed a second surgery on Keith's shoulder and now close to 10 years later he is growing his business and living his life pain free, even when throwing 90-mile an hour fastballs.
Looking back, Keith wishes Dr. Shurland could have performed the surgery after his initial injury, wondering if that would have given him more years as a player. Still, he is very appreciative of Dr. Shurland and Hallmark Health for helping him get back in the game.
"The difference between the two surgeries was night and day," said Forbes, 33, who now lives in Newton. "Thanks to Dr. Shurland and Hallmark Health I'm back to doing what I love to do and couldn't be happier."
The Hallmark Health Bone & Joint Program is modeled after the best bone and joint programs in the country and has been tailored to fit into a community hospital setting. The program is staffed with high-quality, board-certified orthopedic surgeons and specially trained nurses and therapists that are among the best in the region.
No longer do patients and their families need to navigate the traffic and parking issues of Boston in order to receive high quality bone and joint care, as the Hallmark Health Bone & Joint Program offer the same up-to-date techniques close to home.
For more information about the Hallmark Health Bone & Joint Program click here here or call 781-979-3705.
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Thursday, August 27 2015 12:41


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Fast Facts
- Population:
- 17,019,068
- Capital:
- Tallahassee; 155,171
- Area:
- 65,755 square miles (170,304 square kilometers)
- Per Capita Income:
- Date Statehood Achieved:
- March 3, 1845
This subtropical playground—long favored by retirees—is one of the fastest growing states. But nature suffers as life-giving wetlands are drained, overbuilding accelerates coastal erosion, and the drawing down of the water table causes saltwater intrusion and sinkholes. Miami, the bilingual gateway for Latin America, is more than half Hispanic—mostly Cuban. In central Florida, Sea World, Universal Studios, and Walt Disney World make big money. High-tech industry supplements tourism and agriculture, mainly citrus, tomatoes, landscaping plants, and sugarcane.
- Industry: Health services, business services, communications, banking, electronic equipment, insurance, tourism
- Agriculture: Citrus, vegetables, field crops, nursery stock, cattle, dairy products
—Text From National Geographic Atlas of the World, Eighth Edition
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The Community Of Easington Colliery On The Day Of Former Prime Minister Margaret Thatcher's Ceremonial Funeral In London
Former miner Les Ingram enjoys a pint in the Victory Pub on the 20th... News PhotoAnniversary,Coal Mine,Coal Miner,Easington,England,Enjoyment,Former,Funeral,Horizontal,Human Interest,Margaret Thatcher,Miner,Mining,Pint Glass,Politics,Roadblock,UKPhotographer Ian ForsythCollection: Getty Images News 2013 Getty ImagesEASINGTON, ENGLAND - APRIL 17: Former miner Les Ingram enjoys a pint in the Victory Pub on the 20th anniversary of the closure of the colliery in Easington on April 17, 2013 in Easington, England. Former miners and their families are today holding a commemoration party for the closure of the pit at Easington Colliery; coinciding with the ceremonial funeral for Baroness Thatcher, who took on the mining union during the miners' strike which ultimately led to the closure of the mines and the loss of jobs. Dignitaries from around the world today join Queen Elizabeth II and Prince Philip, Duke of Edinburgh as the United Kingdom pays tribute to former Prime Minster Baroness Thatcher during a Ceremonial funeral with military honours at St Paul's Cathedral. Lady Thatcher, who died last week, was the first British female Prime Minister and served from 1979 to 1990. (Photo by Ian Forsyth/Getty Images)


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Faculty of Human and Social Sciences
Faculty of Human and Social Sciences Exam Conflict
This form is for students who have a final exam conflict that is NOT for any of the following reasons: 2 exams at the same time, 3 exams in 24 hours, or campus conflict. If one of these 3 situations apply to you, click here, otherwise, the below form is completed by students experiencing an "extraordinary incident/circumstance."
updated April 17/15


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Pavement/Stephen Malkmus Tribute and Michael Heald Book Release: Point Juncture, WA; Velella Velella; the World Radiant; Fruit Bats; Muscle and Marrow; Your Rival; Awkward Energy; Purrbot; Time Waster; Adieu Caribou
7:30 pm., Thursday November 29 | Free.
115 NW 5th Ave.
115 NW 5th Ave.
[ON THE STEREO] I was a little surprised to learn some of the bands here weren't already Pavement cover bands—I'm looking at you, Your Rival, and Point Juncture, WA—but it'll be interesting to see if and how Velella Velella and Purrbot stretch their chops to fill Stephen Malkmus' shoes. The whole motivation for this event is a little confusing. Local publisher Michael Heald wrote a book of essays, titled Goodbye to the Nervous Apprehension, where he compares himself to Malkmus (among others) after moving to Portland and encountering the Pavement singer around town. He then rounded up local bands to fuse a reading with a geek-out tribute night. But, hey, I need no excuse to listen to Pavement.
Where: Backspace
Phone: 248-2900
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This is a group for discussing everything pertaining to website design & software development, SEO techniques, best practices & patterns, tips & tricks.
This group was created for information technology professionals to share their challenges, knowledge and/or experience!
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