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Synarc A/S Zweigniederlassung Hamburg
SYNARC is a leading provider of central radiology services for worldwide clinical trials conducted by the pharmaceutical and biotechnology industry.
SYNARC'S advanced capabilities enable pharmaceutical industry clients to accelerate clinical trials and decrease the time, uncertainty and cost of drug development. Our services integrate all aspects of the design and execution of imaging in clinical trails, including: clinical site selection and training, image quality control and analysis, efficacy and safety reporting and support of client submissions of data to global health regulatory authorities. Therapeutic areas range from osteoporosis and arthritis to Alzheimer's and cancer. SYNARC supports a wide variety of imaging techniques, from DXA and conventional X-ray to MRI, CT and Scintigraphy. Please visit our web site at www.synarc.com.
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Girls' Generation's Tiffany talks about achieving her dreams in comeback teaser clip for 'Holiday Night'
Girls' Generation released a teaser clip of Tiffany for the new album 'Holiday Night'.
Tiffany is the second member following YoonA to greet fans with the comeback teaser. In the video, Tiffany talks about how she dreamed of becoming an idol and the meaning of Girls' Generation. She also emphasizes that importance of never changing.
SEE ALSO: Lee Jung Hyun says she was aware of co-star Song Joong Ki's relationship prior to public announcement
Watch the new teaser clip and stay tuned for more on Girls' Generation's 10th-anniversary comeback!

subset: commoncrawl


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Add to basket BLOOD SUCKERS
A collection of Vampire films from the genre's beginning with 'Nosferatu' from 1922 through to those made in the sixties and seventies. Including Italian, Spanish, German and American films this collection looks at the vampire through the eyes of different countries and different time periods.
The Films:
Disc 1
1. Nosferatu (1922)
2. Vampyr (1932)
Disc 2
1. Atom Age Vampire (1960)
2. Count Dracula And His Vampire Bride (1973)
Disc 3
1. Fangs Of The Living Dead (1969)
2. Vampire Night Orgy (1973)
* All original artwork by noted underground Australian illustrator Graeme Dickenson.
Extra Features
- -
- Various
- Various


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A list of famous charity workers.
Mother Teresa – Mother Teresa founded the Missionaries of Charity and dedicated her life to serving the poor in India and around the world.
"Let us not be satisfied with just giving money. Money is not enough, money can be got, but they need your hearts to love them. So, spread your love everywhere you go. " – Mother Teresa
The Eva Peron foundation raised millions to fund orphanages, hospitals and schools. The Foundation aimed to 'to contribute or collaborate by any possible means to the creation of works tending to satisfy the basic needs for better life of the less privileged classes.'
Audrey Hepburn supported UNICEF from the 1950s. In the later part of her life, she retired from acting to devote more time to UNICEF projects in Africa and other countries.
"The 'Third World' is a term I don't like very much, because we're all one world. I want people to know that the largest part of humanity is suffering."– Audrey Hepburn.
Princess Diana was associated with many hundreds of charities. She paid particular attention to charities involved with AIDS, landmines, prisoners' families and palliative care.
"I knew what my job was, it was to go out and meet the people and love them" – Princess Diana.
Involved in various charities including DATA (Debt, AIDS, Trade, Africa) established in 2002 with Bobby Shriver. DATA aims to eradicate poverty and HIV/AIDS in Africa. Also involved in Drop the Debt campaign.
Bob Geldof was moved by African famine of 1984. He released hit single "Do They Know Its Christmas Time" and organised 'Live Aid'. Has been involved in various charities ever since.
Oprah has donated millions of her own fortune for charities such as Angel Network and a charity helping young girls gain an education in South Africa.
Has worked with the United Nations High Commissioner for Refugees (UNHCR). She also founded charities such as Maddox Jolie-Pitt Foundation community development and environmental conservation in Cambodia.
The Jane Goodall Foundation seeks to protect Chimpanzees and their environment.
The well known campaigner against apartheid has also sought to tackle issues such as AIDS in Africa.
Iconic nurse who helped to standardise and improve the quality of nursing in Nineteenth Century Britain.
Other Celebrities noted for their charity work.
- Scarlett Johansson
- Sir Richard Branson


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TEMECULA -- Jim Fritz doesn't give away bottles of his beer anymore.
He'll happily offer someone a glass, but it comes with a warning.
"If you like Budweiser, you won't like my beer," said the Wildomar resident, a member of the Temecula Valley Homebrewers Association.
Mike Billups, association president, has heard some horror stories.
One of the tales involves a homebrewer who selected two or three bottles of his best beer and gave them to a friend as a gift. The friend had assured the brewer that he liked beer, Billups explained.
When the brewer inquired later to find out how the recipient enjoyed the beer, he was told that the bottles -- including a "good India Pale Ale" -- had been poured down the drain.
Fritz and fellow association member Jim McMahon, both sitting nearby at a table in the corner of Temecula's Barley and Hops Olde World Tavern, nodded their heads in morose recognition.
"Everyone has the same stories," Billups said.
And it's the shared experience of those stories, the men said, that helped spur a group of local brewers to start the association, one of hundreds across the country, in the early 1990s.
A fellow homebrewer knows that it takes weeks to make a batch of beer. A brewer knows how different hops add different flavors or aroma depending on when the hops are added to a boiling kettle. If someone is tasting a porter, they know why it's a porter and how a porter differs from a lager.
Members aren't quick to grimace after tasting another member's creation. It's a patient and supportive group of people who know how tough homebrewing can be.
"Everyone makes the same mistakes," McMahon said.
Talking through those mistakes with fellow homebrewers helps the members get better at their craft-slash-hobby.
"We learn different tricks. We learn from others," he said.
Fritz, sitting behind empty glasses of Black Butte Porter from Oregon, said, "If it wasn't for the club, I'd have dropped out of brewing."
Since Fritz helped revive the group in 2006, membership in the association has grown to 35. About 20 brewers attend monthly meetings to swap recipes, discuss new brewing techniques and homebrewing gear and plan for upcoming brew fests, large gatherings of brewers.
Membership costs less than $40 per year, with the dues going to help defray the cost of reserving booth space and camping spots at the annual brew fests.
While he has sipped some bad homebrewed beers before -- ask him about a chipotle porter that was "vile" -- Billups said most of the people who snub home brews or give up on the hobby after a few funky batches just aren't accustomed to the taste.
They are used to beer that is one-dimensional or mass-produced, said Billups, a French Valley resident.
When a beer is mass-produced, even a craft or microbrew, the brewer strives to make sure that each bottle of beer tastes the same as every other bottle. If you're buying a six-pack of Firestone Double Barrel Ale, it's supposed to taste like the six-pack you bought last week.
With homebrewing, one batch, even if the same ingredients are used, rarely tastes the same as another batch. For brewers, that's part of the hobby's charm.
Fritz said he used to give away bottles of his beer when he started brewing about eight years ago but, after hearing too many complaints, he started making batches for himself. In his many years of brewing, he's only had to throw out one batch that was actually "bad."
"My wife doesn't even drink my beer. She might have a taste and, say, 'This is good,' but that's it," he said.
A common misconception among non-homebrewers is that most homebrewers want to start a moneymaking microbrewery, Billups said.
While it has happened -- the founder of Samuel Adams was a homebrewer -- it's more common for someone to start brewing because they love beer.
That was the hook for Fritz, who decided, on a whim, to buy a $100 starter kit and start making his own. After some missteps along the way, he has developed a signature beer. It's an Irish red he named "Wild Omar's Irish Red," a nod to the community of Wildomar, which will become a city this summer.
Billups' interest was stoked when he was a kid by a family friend. After years of thinking about it, his wife, a fellow beer fan, recommended grabbing a kit during a shopping trip and he hasn't stopped brewing since. The kits usually include some instruments, a kettle and some of the ingredients.
Novice brewers who want to upgrade can find plenty of gear on the Internet or brewing shops in the San Diego area, which, Billups said, is an underrated hotbed of home- and microbrewing.
While most of the members have a refrigerator they use to chill their beer and a kitchen counter's worth of equipment, there are some members who can fill at least half a garage with their gear.
McMahon, who makes a mean pale ale, took up the hobby after trying bread-making.
"I just use the yeast a different way," he said with a smile.
Contact Aaron Claverie at (951) 676-4315, Ext. 2624, or email@example.com .
- For more information on the association, e-mail Jim Fritz at email@example.com or visit thegroup's Web site:
Basic Homebrewing
Here is the basic process for homebrewing beer, as explained by members of the Temecula Homebrewers Association
Heat some water in a large multi-gallon kettle.
While the water is heating up, add some specialty grains. After about a half-hour, remove the grains.
Bring water to boil and add wort, a malted barley mixture that can be bought in syrup or powder form. (Ratcheting up the difficulty, some homebrewers make their own wort.)
As the water and wort mixture boils, add hops. Add three measured servings of hops at three separate times in the process to add bitterness, flavor and aroma.
Pull mixture from heat and chill immediately, the faster the better.
Once it is below 80 degrees, shake or stir the mixture to introduce oxygen.
Add yeast.
Put mixture into a carboy, which is a large water bottle.
Add yeast.
Cap with a special seal that allows carbon dioxide to escape.
During this part of the process the yeast will "eat" the sugars in the mixture, causing the mixture to chemically churn. (This is one of the coolest parts of homebrewing, association members said.)
Leave mixture in carboy for a week.
Transfer to another container a week later.
Pour into bottles and cap. Leave in bottles for two weeks.
Refrigerate and serve, avoiding sediment at bottom of bottles.


text: This thin volume defines four political outlooks: superpatriotism, political cynicism, anarchism, and critical citizenship. Emphasizing the reader's development of a personal outlook toward politics and public life, Nathanson (Northeastern U.) analyzes each position and the philosophers and activists who have supported these views. Annotation c. Book News, Inc., Portland, OR


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Thank you very much for the compliments.
I have an extensive amount of research collected in the Psychology field due to being a student of Psychology for many years.
I am trying to think of topics that I am interested in or that other people will be interested in. I don't have a lot of views yet, but I am hoping that will change as I start getting the hang of writing about things that people actually want to read!
I also read the forums and take advice where I can get from the successful people here. I think I'd be totally lost if it were not for them!
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Fortunately, we have a written transcript from CNN, so we can read exactly what Gingrich said about the issue (scroll down about 3/4th of the way to find it on the transcript), as well as the follow-up exchange with Michelle Bachmann, Mitt Romney, and Rick Perry:
BLITZER: Speaker Gingrich, let me let you broaden out this conversation. Back in the '80s -- and you remember this well. I was covering you then. Ronald Reagan and you -- you voted for legislation that had a pathway to citizenship for illegal immigrants, as you well remember. There were, what, maybe 12 million, 10 million -- 12 million illegal immigrants in the United States right now.
Some called it amnesty then; they still call it amnesty now. What would you do if you were President of the United States, with these millions of illegal immigrants, many of whom have been in this country for a long time?
GINGRICH: Let me start and just say I think that we ought to have an H-1 visa that goes with every graduate degree in math, science and engineering so that people stay here.
GINGRICH: You know, about five blocks down the street, you'll see a statue of Einstein. Einstein came here as an immigrant. So let's be clear how much the United States has drawn upon the world to be richer, better and more inclusive.
I did vote for the Simpson-Mazzoli Act. Ronald Reagan, in his diary, says he signed it -- and we were supposed to have 300,000 people get amnesty. There were 3 million. But he signed it because we were going to get two things in return. We were going to get control of the border and we were going to get a guest worker program with employer enforcement.
We got neither. So I think you've got to deal with this as a comprehensive approach that starts with controlling the border, as the governor said. I believe ultimately you have to find some system -- once you've put every piece in place, which includes the guest worker program, you need something like a World War II Selective Service Board that, frankly, reviews the people who are here.
If you're here -- if you've come here recently, you have no ties to this country, you ought to go home, period. If you've been here 25 years and you got three kids and two grandkids, you've been paying taxes and obeying the law, you belong to a local church, I don't think we're going to separate you from your family, uproot you forcefully and kick you out.
The Creeble Foundation is a very good red card program that says you get to be legal, but you don't get a pass to citizenship. And so there's a way to ultimately end up with a country where there's no more illegality, but you haven't automatically given amnesty to anyone.
Gingrich's immigration proposals are spelled out HERE, and to his credit, he at least supports making English the official language of the United States.
But the CNN transcript also shows that Michelle Bachmann immediately disagreed with Gingrich, characterizing the DREAM Act as offering amnesty to at least 11 million illegals and further condemning it for offering illegals taxpayer-subsidized benefits. Bachmann subsequently issued a detailed press release chronicling Gingrich's previous expressions of support for amnesty. Mitt Romney also disagreed with Gingrich, characterizing amnesty as a magnet. Romney explained that allowing amnesty for long-term illegals will merely encourage more people to come here illegally.
Although Gingrich has since fired back, claiming that Romney supported amnesty for illegals in 2007, ALIPAC, which has established itself as the most vocal of the immigration reform lobbies, immediately flagged Gingrich's comments and predicted that the Gingrich campaign will implode in the same fashion as the Perry campaign did immediately following Perry's expressed support for in-state tuition for illegal immigrants during a previous debate. CBS is not so pessimistic; while they agree that Gingrich's campaign could suffer, they believe it will take at least a week for the effects to become manifest. Furthermore, they believe that there are no other alternatives to Mitt Romney, once again minimizing or ignoring Ron Paul as so much of the big media have done.
Republican presidential candidates who promote amnesty for illegal immigrants will have a tough row to hoe, particularly in Utah, where the two leading Republican candidates for Utah's new Fourth Congressional District, Carl Wimmer and Stephen Sandstrom, are both outspoken opponents of amnesty.


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In another development, trainer Jerry Hollendorfer told Churchill officials that USS Tinosa would ship to Louisville Wednesday or Thursday. With $83,750 in graded stakes earnings, he would not draw into the 20-horse field unless others above him on the list dropped out.Also, the Nick Zito-trained Straight Gin and Crimson Hero are still under consideration for the Derby, but both rank outside the top 20 on the graded stakes earnings list.
In what trainer Paco Gonzalez said was a faster work than he preferred, Santa Anita Derby winner Came Home zipped six furlongs in 1:12 3/5 at Churchill Downs on Tuesday in preparation for the May 4 Kentucky Derby. Also working Tuesday were Derby contenders Medaglia d'Oro and Ocean Sound."He went a little faster than I wanted, but he handled the track very well," said Gonzalez, who noted that Came Home will work five-eighths of a mile before the Derby. Said jockey Chris McCarron: "Came Home is extremely businesslike and is not distracted by anything."McCarron was also aboard Ocean Sound, who worked seven furlongs in 1:28 1/5. The fractions were :50 3/5, 1:03, and 1:15 2/5, with a gallop out time of 1:43 1/5."He was very relaxed, more relaxed than I anticipated," McCarron said.Trainer Jim Cassidy said his goal with the workout was to get Ocean Sound to relax. "He will work fast if I want him to. I was trying to get a stamina work in him. He will blow out three-eighths of a mile in six or seven days." Cassidy said Alex Solis has been enlisted to ride Ocean Sound in the Derby.In the only other work Tuesday for a Derby horse, Medaglia d'Oro went five furlongs in 1:01 2/5 for trainer Bobby Frankel. He galloped out six furlongs in 1:16 3/5 after fractional splits of :12 1/5, :24, and :49."I didn't want him to do too much," Frankel said. "I just want to keep him happy."


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Dr. R.
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ExperienceI am a qualified energetic teacher and having More than 10 years teaching and private tutoring experience in different countries (Japan,Pakistan and Beijing China) of General chemistry students (A-level and IGSCE) and (A-level, AS, IB and IGCSE Chemistry students Chemistry ). In addition to this I have been mentoring and teaching undergraduate students for three years. I have been tutoring to student in Beijing since 2010 to date in Key Stage 2 Science, IGCSE/A-Level AS, IB and GCSE General Chemistry.
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Del B's My City Rocks' beat has made alot of Celebrites come out of their luxury to rep cities with different expressions!
New act by the name Dammy ISAAC takes the song to another level with his soulful expression. RnB and Pop feels on an Afro beat is not you come by always. I think this talent has come to stay! Produced by Del B, Mixed and mastered by Dharpsykord.
Listen and share your thoughts!


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Advanced Search
Age: 34
Occupation: Publicist, Kane & Associates
Resides: Hollywood
Claim to Fame: Handled Roseanne Barr and lived to tell about it
Favorite Music/Band: Dan Finnerty & The Dan Band
Favorite food(s): Goat cheese salads and In & Out burgers
Favorite Drink(s): Aside from a good glass of wine? Ivy Gimlet (from the infamous LA restaurant, The Ivy), Boddington's, Arnold Palmers
Favorite Book: My iBook (tangerine)
Favorite TV Show(s): Curb Your Enthusiasm, The Mole
Favorite Film(s): Waiting for Guffman, Get Shorty, and Kurt & Courtney
1) How often do you have a glass of wine?
Often... It's good for the blood
2) If you could only drink one wine (or type of wine) for the rest of your life, what would it be and why?
Any good full-bodied Chilean... We're talking about wine, right?
3) Why do you think people feel intimidated about wine?
The same reasons they're intimidated by me.
4) How long does an open bottle last in your house?
Not to get political, but I am the president and founder of the NO RECORKING CLUB!
5) What's the best/worst bottle of wine you've received as a gift?
My dad (Ronnie Kane), who created the "Mimosa," gave me a bottle of Mumms Champagne for my 21st. A true Mimosa is made with Mumm's Champagne (Mummosa). True story.
6) Ever drink wine right from the bottle? Through a straw? Outta someone's navel?
Does Boones Farm Strawberry Hill count?
7) What would be your dream meal?
I could say some fava beans and a nice Chianti, but it's a tired answer to a tired question.
8) Would you be turned off by a screw cap on an expensive bottle of wine?
Isn't that like saying, "But he's got a GREAT personality"?
9) Ever use wine to lure someone into bed? (Details, details!)
No, but maybe to get them out.
10) Favorite winery/wine producer? Why?
The first vineyard I ever visited was Francis Ford Coppola's, and you know what they say about your first.
11) What's the sexiest thing you've ever done with a bottle of champagne? (Graphic details, please!)
At a New Year's party, I took the cheapest bottle of champagne...shook it up...and aimed it at my ex's date. I don't know. Are black eyes sexy?
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Caffeine Molecule Infinity Scarf
Wear your favorite methylated xanthine*
- Printed with repeating caffeine molecule design
- 95% modal / 5% Lycra
- It's basically like being hugged around the neck by caffeine
Wear your favorite methylated xanthine*Scarf caffeine infinitely? Yes, please! We could totally scarf up some coffee and chocolate without end. Oh wait. "Scarf" the noun? Oh, yeah, well, considering this is a product at our warehouse, that probably DOES make more sense.
This Caffeine Molecule Infinity Scarf is a white scarf printed with a black repeating caffeine molecule design. While many infinity scarves are lightweight and see-thru, this one is a medium-weight modal fabric, which means it's stretchy and soft against the skin. So it's basically like being hugged around the neck by caffeine.
* Unless it's theobromine. Cause that's a good one, too.
Product Specifications
- Caffeine Molecule Infinity Scarf
- Printed with repeating caffeine molecule design
- Materials: 95% modal / 5% Lycra
- Care Instructions: Machine wash warm. Tumble dry low heat. (That's what it says, and we kind of like that verb for our clothes which frequently end up rumpled.)
- Imported
- Dimensions: 12" tall x 24" wide (48" doubled-over since it's a tube)
Wanna chat about it?
Have questions about Caffeine Molecule Infinity Scarf or your order? We monitor these comments daily, but it may be faster to email us directly or call us at 1-888-GEEKSTUFF.


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Low-grade systemic inflammation is a common manifestation of hypertension; however, the exact mechanisms that initiate this pathophysiological response, thereby contributing to further increases in blood pressure, are not well understood. Aberrant vascular inflammation and reactivity via activation of the innate immune system may be the first step in the pathogenesis of hypertension. One of the functions of the innate immune system is to recognize and respond to danger. Danger signals can arise from not only pathogenic stimuli but also endogenous molecules released following cell injury and/or death [damage-associated molecular patterns (DAMPs)]. In the short-term, activation of the innate immune system is beneficial in the vasculature by providing cytoprotective mechanisms and facilitating tissue repair following injury or infection. However, sustained or excessive immune system activation, such as in autoimmune diseases, may be deleterious and can lead to maladaptive, irreversible changes to vascular structure and function. An initial source of DAMPs that enter the circulation to activate the innate immune system could arise from modest elevations in peripheral vascular resistance. These stimuli could subsequently lead to ischemic- or pressure-induced events aggravating further cell injury and/or death, providing more DAMPs for innate immune system activation. This review will address and critically evaluate the current literature on the role of the innate immune system in hypertension pathogenesis. The role of Toll-like receptor activation on somatic cells of the vasculature in response to the release of DAMPs and the consequences of this activation on inflammation, vasoreactivity, and vascular remodeling will be specifically discussed.
- innate immunity
- vascular dysfunction
- vascular remodeling
this article is part of a collection on Pathophysiology of Hypertension. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.
Hypertension is a chronic condition characterized by elevated systemic blood pressure and is the most common and important risk factor preceding the development of other cardiovascular diseases (102, 121). Normal systemic blood pressure is defined as systolic blood pressure <120 mmHg and diastolic blood pressure <80 mmHg. Prehypertension and hypertension are systemic pressures equal to and above these values (25). Hypertension can be classified as either primary/essential, in which the disease is idiopathic, or secondary, in which the cause of the disease is known or "secondary" to another identifiable cause (e.g., renal disease), respectively. Despite the elusive nature of essential hypertension, it is known that its etiology is heterogeneous and multifactorial.
Although there is substantial debate regarding the relative contribution of kidneys, autonomic nervous system, and vasculature to the development and maintenance of hypertension, it has been established that the immune system and its aberrant activation also play a role. Low-grade systemic inflammation in these organs leads to the commencement or acceleration of pathological processes and worsening of cardiovascular risks (1, 46, 136). However, the initiation of this inflammatory response, thereby contributing to further increases in blood pressure, has not been elucidated (34).
Inflammation is one of the first responses of the immune system to danger. Clinically, inflammation can be described as dolor (pain), calor (heat), rubor (redness), tumor (swelling), or function laesa (loss of function) (122). More specifically, inflammation is the increased production of pro-inflammatory cytokines whose expression pattern guides the adaptive immune response (e.g., IL-6, TNF-α, and IFN-γ). Additionally, inflammation can be characterized as increased chemokines (chemotactic cytokines) that guide the migration of immune cells to target tissues [e.g., monocyte chemoattractant protein-1 (MCP-1)] and cell adhesion molecules that promote the binding, rolling, and infiltration of immune cells into the vascular wall and translocation to end organs (e.g., ICAM-1 and VCAM-1) (86).
The danger that stimulates inflammation can occur from not only pathogens [pathogen-associated molecular patterns (PAMPs)] but also host-derived endogenous molecules that arise due to cell death and/or injury [damage-associated molecule patterns (DAMPs)] (95, 96). This initial inflammatory response by the innate immune system subsequently signals for the adaptive immune system to elicit a more robust defense. The participation of the adaptive immune system and different lymphocyte populations in the development of hypertension has been supported for various animal models of hypertension, such as spontaneously hypertensive rats (SHRs), DOCA-salt induced hypertension, and ANG II-induced hypertension (8, 47, 64, 89, 93). However, the role of the innate immune response to DAMPs, and its subsequent effects on the activation of the adaptive immune system in the context of the pathogenesis of hypertension, is currently unknown.
Many DAMPs are present in hypertension due to chronic cell injury and death, contributing to persistent inflammation (16). Recognition of these host-derived molecules by innate immune receptors such as Toll-like receptors (TLRs), and subsequent TLR activation, may be an important link between hypertension and activation of the adaptive immune system. Accordingly, the focus of the following review will be on the emerging role of TLRs in the etiology of vascular dysfunction, vascular remodeling, and hypertension. The current literature on TLRs in cardiovascular disease will be summarized and gaps in our current knowledge regarding the potential role of TLRs in hypertension will be identified.
Vascular Dysfunction and Vascular Remodeling: Physiological Adaptations With Pathophysiological Consequences
Vascular remodeling of both conduit and resistance vessels is a hallmark of hypertension that generally precedes disease development and exacerbates the disease phenotype (37, 109, 129). Although initial remodeling of the vascular wall occurs as an adaptation to normalize exacerbated shear stress, chronic shear stress results in maladaptive changes in vessel structure (43). Pressure-dependent remodeling of large artery composition is characterized by vessel stiffening (decreased compliance and elasticity) and outward hypertrophic remodeling (105, 125, 126), whereas small artery pressure-dependent remodeling is defined as either inward eutrophic remodeling or inward hypertrophic remodeling, depending on whether the media cross-sectional area is enlarged (51, 110, 130).
Compliant conduit vessels, such as the aorta, provide important buffering actions for each ventricular contraction that ameliorates pulse pressure. Augmented pulsatile hemodynamics that occur with stiffening contribute to increased cardiac afterload, decreased diastolic blood flow to tissues, and further detrimental vascular remodeling of resistance vessels and organ damage (20, 104). Remodeling of resistance vessels can lead to decreased tissue perfusion and organ damage (129).
Vascular dysfunction is another deleterious characteristic of hypertension and prehypertension (31, 136). Vascular dysfunction has multiple characteristics including increased contractility and/or decreased relaxation (via modified production and responsiveness to vasoconstrictors and vasodilators), increased expression of pro-inflammatory and/or decreased anti-inflammatory cytokines, cell death (apoptosis, necrosis, aberrant autophagy), adhesion of immune cells to the endothelium (and subsequent infiltration into the vascular wall), increased production of reactive oxygen species (ROS), and vascular smooth muscle cell (VSMC) hypertrophy, proliferation, and migration (136). Many of these manifestations of vascular dysfunction occur in parallel, and elucidation of the initial insult on the vasculature is usually difficult and multifactorial in nature.
Vascular remodeling is the summation of dysfunctional vasomotor events that ultimately reorganize the structural composition of the vessel. In other words, vascular remodeling is thought to be initiated in vessels with chronic dysfunction, either as exacerbated vasoconstriction and/or attenuated vasorelaxation (75). There is evidence that such abnormal vasoreactivity works in conjunction with renal dysfunction and sympathetic overactivity to drive the vascular remodeling process (31). A role for augmented vasoconstrictors and/or attenuated vasodilators in the genesis and maintenance of vascular remodeling is supported by the fact that many of these vasoactive agents [e.g., ANG II, endothelin-1 (ET-1), vasopressin, prostaglandins, and nitric oxide (NO)] are pleiotropic in their effects. As a result, these vasoactive factors can also contribute to vascular remodeling through other mechanisms including VSMC proliferation, inflammation, apoptosis, and fibrosis (55).
Vascular remodeling and the progression of hypertension subsequently becomes the result of a positive feedback loop of augmented shear stress-induced changes via exacerbated vasoconstriction and attenuated vasorelaxation. Under these conditions, the maintenance of tissue perfusion through chronically constricted vessels results in increased force to the vessel wall. This force subsequently leads to remodeling of the vessels as a mechanism of normalizing this high shear stress. Eventually, a new steady state of tissue blood flow is sustained at elevated pressures by structural remodeling, rather than vasoreactivity mechanisms. Temporally, altered vascular structure in response to vascular dysfunction has been shown to occur rapidly in resistance arteries. However, these hemodynamic changes only reach pathophysiological significance ∼2 to 3 days after initiation of increased pressure, and need at least a week to be fully completed (87, 92).
A novel and potentially significant focus of research recently has been the observation that TLRs are able to modulate vascular function (15, 19, 82), and genomic analysis has revealed that different vascular beds exhibit distinctive TLR profiles (120). Specifically, TLR2 and TLR4 were ubiquitously present within the vasculature, whereas TLR7 and TLR9 were sparse, and TLR1, TLR3, TLR5, TLR6, and TLR8 were expressed in selective patterns. However, to the best of our knowledge, there are only two investigations illustrating a role of TLRs mediating vascular dysfunction and low-grade inflammation, subsequently contributing to hypertension (15, 82), as well as one investigation on a potential involvement of TLRs (via MyD88 adaptor protein) in vascular remodeling (142). Therefore, TLRs could be significant contributors to the etiology of vascular dysfunction, and consequently, vascular remodeling and hypertension.
The Innate Immune System: The First Line of Defense Against Danger
The innate immune system is the early warning system of the body that rapidly detects danger and damage. This consequently allows time for the adaptive immune system to mount an antigen-specific response. The pattern of inflammatory cytokine response after activation of the innate immune receptors diverts the adaptive immune system toward either the cell-mediated T helper 1 (TH1) response or the humoral/antibody T helper 2 (TH2) response.
Components of the innate immune system include antimicrobial chemicals on epithelial surfaces (skin and mucosa), phagocytes (macrophages and neutrophils), natural killer cells, and polymorphonuclear leukocytes, which include neutrophils, eosinophils, basophils, and mast cells. Additionally, the complement system is known to be an essential component of the innate immune system for the destruction of pathogens and clearing of cellular debris. Finally, TLRs and NOD-like receptors (nucleotide-binding oligomerization domain receptors) are sentinel pattern recognition receptors of the innate immune system that help initiate the inflammatory response. Although short-term inflammation is necessary for tissue defense, chronic and/or excessive activation of the innate immune system results in deleterious maladaptations (e.g., autoimmune diseases), and the salutary effects of this evolutionarily conserved system are negated (Fig. 1).
Currently, there is limited knowledge of the role of the innate immune system in the pathogenesis of hypertension and how the inflammation associated with this condition is initiated. As a result, various components of the innate immune system, including TLRs, are becoming a significant research focus in the field of hypertension (15, 49).
The Adaptive Immune System In Hypertension
Upon initiation of the innate immune response by pattern recognition receptors, antigen-presenting cells migrate to lymph nodes and present antigenic molecules to cells of the adaptive immune system. The adaptive immune response is then initiated by the recognition of antigens by T and B lymphocytes. Proliferation and differentiation of naive lymphocytes into effector cells is necessary for elimination of the antigen and production of memory cells, which protect the host upon subsequent encounters with the antigen (3).
T and B lymphocytes are the two major cell types of the adaptive immune system. The participation of T lymphocytes in the pathogenesis of experimental hypertension was demonstrated by Guzik et al. (47). This investigation found that mice lacking T lymphocytes are resistant to the development of both ANG II and DOCA-salt-induced hypertension. Adoptive transfer of T lymphocytes, but not B lymphocytes, restored hypertension in these animals (47). In corroboration of these findings, mice with severe combined immunodeficiency and lacking both T and B lymphocytes have a blunted blood pressure response and reduced sodium retention during ANG II-induced hypertension (29). However, it has also been demonstrated that T lymphocyte activation occurs due to a blood pressure elevation, since anti-hypertensive drug hydralazine was able to prevent activation of T lymphocytes in an ANG II model of hypertension (93). Therefore, if aberrant inflammation is involved in the initiation of hypertension, in contrast with its progression, elucidation of this mechanism has not been demonstrated.
Given that T lymphocytes play a critical role in hypertension, the subset of T lymphocytes that contributes to this disease has been a growing area of investigation. T-helper cells have been cited as a possibility since these cells differentiate into distinct subsets generally classified as either the cell-mediated "TH1" response or the humoral/antibody "TH2" response. These T-helper subsets perform different functions and elicit unique patterns of cytokine secretion (107). As such, imbalances between these subsets are implicated in a variety of autoimmune (74) and cardiovascular pathologies (98, 132). T-helper 17 cells are a subset of T-helper cells that produce the pro-inflammatory cytokine IL-17. The profound effects of IL-17 on the etiology of hypertension were demonstrated by Madhur et al. (89). It was revealed that ANG II increased IL-17 production from T lymphocytes and that ANG II-induced elevations in blood pressure were not sustained in IL-17−/− mice. Moreover, IL-17−/− mice showed improved vascular reactivity, decreased superoxide anion production, and less T-lymphocyte infiltration into the vascular wall (89).
Another type of T lymphocyte revealed to play a role in hypertension is T-regulatory cells (Treg). Tregs suppress innate and adaptive immune responses, as opposed to exacerbating them. In fact, adoptive transfer of Tregs prevented ANG II-induced blood pressure elevation, vascular stiffness, vascular inflammation and oxidative stress, endothelial dysfunction, and immune cell infiltration (11). The vasculoprotective effects of Tregs have also been observed in aldosterone-induced vascular dysfunction and hypertension (64).
Although the importance of the adaptive immune system in hypertension is not in question, how exactly the adaptive immune response is first activated is not well understood. TLRs are known to be expressed on immune cells such as T and B lymphocytes (54, 62) and antigen-presenting cells. Furthermore, TLRs are expressed by somatic cells of the vasculature [e.g., VSMCs and endothelial cells (ECs)]. Therefore, TLRs may be molecular links between DAMPs, chronic vascular inflammation, and hypertension (Fig. 2).
TLRs and DAMPs: A New Source of Danger
Researchers studying the development of the fruit fly Drosophila melanogaster first discovered the Toll receptor when they found that a mutation in the Toll gene resulted in abnormal development (6). The mutated flies were termed Toll (German for "wow") after embryos carrying the mutation were remarkably dissimilar to wild-type flies. A more closely related human homologue to Drosophila Toll was subsequently identified (101), and the human Toll was then renamed TLR4 because it was "Toll-like."
At least 13 TLRs have been reported in mammals (1–10 in humans and 11–13 in mice) (91). TLRs that primarily recognize bacterial and fungal components are localized on the cell surface (TLR1, TLR2, TLR4, TLR5, and TLR6), whereas TLRs that primarily recognize viral or microbial nucleic acids are localized to intracellular membranes such as endosomes or phagosomes (TLR3, TLR7, TLR8, and TLR9) (52). Recently, human TLR10 has been discovered (26); however, its function and specific ligand have yet to be determined. Moreover, the TLR11 gene is known to be encoded in humans; however, it contains at least one stop codon, and the protein is not expressed (156).
TLRs are responsible for recognizing and initiating an inflammatory response to dangerous molecules (95, 96). As such, potential PAMPs and DAMPs are varied and numerous and can include pathogen-derived cell wall components (e.g., LPS), DNA, and metabolic byproducts. Endogenous (host-derived) molecules that arise from injured and dying cells and activate TLRs include extracellular matrix components (e.g., hyaluronan), plasma membrane, nuclear, and cytosolic proteins (e.g., high-mobility group box protein 1), and elements of damaged/fragmented organelles [e.g., mitochondrial DNA (mtDNA)]. Table 1 provides several examples of DAMPs specific to hypertension and their corresponding TLRs [updated from reference (16)]. This list is by no means exhaustive, since numerous other yet unknown molecules may fulfill our inclusion criteria of being TLR ligands that are elevated in hypertension.
Another possibility for aberrant TLR activation, inflammation, and the development of cardiovascular pathologies (5) could be genetic abnormalities of innate immune system components (39, 112) and endogenous molecules (thus converting them to DAMPs). These anomalies may include an irregular expression of various TLR, polymorphisms and mutations, the aberrant gene expression of various cytokines, and distribution of immune cell populations. Also, TLR-induced epigenetic and chromatin modifications may be important (38). As such, these genetic components of TLRs and DAMPs may also contribute to the pro-inflammatory state seen in hypertension.
TLR Signaling: Interactions With Known Vascular Signaling
In addition to being expressed in immune cells, TLRs are expressed in other tissues, such as those of the cardiovascular system (40, 91). Expression of TLRs in the cardiovascular system, as well as immune cells, is consistent with the theory that tissues tailor their own immune responses (97). TLRs are type I transmembrane proteins that possess an amino-terminal leucine-rich repeat domain for ligand binding, a single transmembrane domain, and a carboxyl-terminal intracellular signaling domain that is similar to IL-1. This common intracellular signaling motif is termed the "Toll-IL-1 receptor" (TIR) homology domain.
A number of different signaling pathways are activated by TLRs, and some of these are unique to particular TLRs. This differential signaling is dependent on which adaptor molecules are present to associate with the respective TLR. These adaptors, all of which contain TIR domains, include myeloid differentiation primary response protein (MyD88), TIR domain-containing adaptor protein (TIRAP), TIR-domain-containing adaptor inducing interferon-β (TRIF), and TRIF-related adaptor molecule (TRAM) (Fig. 3). TLR signaling has been extensively reviewed previously [(40) and (91)] and will not be extensively discussed here. These signaling events result in the upregulation of pro-inflammatory mediators (cytokines, chemokines, and adhesion molecules) either through a MyD88-dependent pathway (TLR1, TLR2, TLR4, TLR5, TLR6, TLR7, TLR8, and TLR9) or a MyD88-independent(/TRIF-dependent) pathway (TLR3 and TLR4). The MyD88-dependent pathway involves induction of the NF-κB gene, stimulation of the transcription factor activator protein 1 (AP-1) by MAPKs, or activation of interferon regulatory factor (IRF)7. The MyD88-independent pathway involves IRF3 activation, as well as NF-κB signaling (4, 65). The unique signaling cascades for each TLR allow for the induction of specific responses. This specificity may be attributed to the type of cell where the TLR is expressed (32) and/or the defense needed for that particular tissue (97). The ability of TLRs to discriminate particular stimuli expanded the defensive repertoire of the innate immune system.
As stated above, NF-κB activation is downstream of MyD88-dependent signaling. The NF-κB family is composed of homo- and heterodimers of Rel proteins [NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel (Rel)]. The NF-κB (p50/p65) transcription factor is a ubiquitous, constitutive, and inducible heterodimer with domains for dimerization and DNA binding, a nuclear translocation signal, and a binding site for the inhibitor of κB (IκB) (17, 23). Along with regulating pro-inflammatory cytokines, NF-κB activation mediates the expression of inducible NO synthase (iNOS), cyclooxygenase 2, growth factors, inhibitors of apoptosis, and effector enzymes in response to ligation of TLRs and other receptors involved in immunity, including T lymphocyte receptors and B lymphocyte receptors (17).
Synthesis of NF-κB is not de novo; therefore, its transcriptional activity is silenced by interactions with inhibitory IκB proteins present in the cytoplasm. Downstream of specific TLR signaling, the inhibitor IKK complex phosphorylates IκB, which leads to its ubiquitylation and subsequent degradation by the proteasome. As a result, the inhibitory influence on NF-κB is alleviated and NF-κB is then able to translocate from the cytoplasm into the nucleus to regulate gene expression (17, 23) (Fig. 3).
In VSMCs and ECs, ANG II activates NF-κB (99, 140, 148), and sustained inhibition of NF-κB with pyrrolidine dithiocarbamate prevents inflammation and hypertension (108, 123). Because NF-κB has been established in the development of inflammation and hypertension, investigation of the pro-inflammatory process upstream of NF-κB activation is warranted; thus TLRs represent an ideal candidate.
Another mechanism of MyD88-dependent signaling is MAPK activation of AP-1 transcription factor. Mitogen-activated protein kinases are serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli. Mitogen-activated protein kinase expression and signaling is initiated through a MAPK module, which functions to prolong transient cell signals into sustained ones that can be relayed downstream to the nucleus to alter the pattern of gene expression. This module contains at least three protein kinases in series that culminate in the activation of a multifunctional MAPK (Fig. 3). Once activated, the MAPK relays the signal downstream by phosphorylating various proteins within the cell, including gene regulatory proteins and other protein kinases. Mitogen-activated protein kinases are major components of pathways controlling embryogenesis, cell differentiation, cell proliferation, and cell death (119). After TLR activation, MAPK signaling leads to translocation of AP-1 transcription factor to the nucleus and upregulation of the expression of pro-inflammatory mediators (66) (Fig. 3).
Prominent MAPKs include ERK1 and ERK2, JNK/SAPK, and p38 MAPK pathways. The ERK1/2 phosphorylation cascade involves MEK1/2 (MAP/ERK kinase), whereas the signaling processes leading to JNK/SAPK and p38 MAPK activation involve MEK4/7 and MEK3/6, respectively (119). Further upstream signaling of MAPKs, within the MAPK module, is recognized to be primarily dependent on the nonreceptor tyrosine kinase c-Src (56, 88, 147). However, c-Src-independent regulators of MEK, such as the Ras-Raf pathway, have also been reported (72, 155).
In VSMCs and ECs, MAPKs are involved in a multitude of physiological and pathophysiological actions (e.g., contraction, migration, adhesion, collagen deposition, growth, differentiation, and survival) (68, 119, 136). Inhibition of ERK1/2 abolishes sustained contraction and normalizes the ANG II effects on mesenteric VSMCs from SHRs (145), and rapid tyrosine phosphorylation of ERKs occurs in human VSMCs treated with ANG II (146). The hypertension-associated effects of ERK are not limited to ANG II-dependent hypertension. Basal aortic tone of DOCA-salt hypertensive rats was significantly attenuated by ERK inhibition (67), and DOCA treatment resulted in augmented aortic contractile responses mediated by increased phosphorylation of ERK1/2 and decreased expression of mitogen-activated protein kinase phosphatase 1 (42).
In addition to ERK, JNK/SAPK and p38 MAPKs also contribute to vascular dysfunction and the hypertensive phenotype. The role of p38 is unequivocal, with its inhibition improving indexes of inflammation, oxidative stress, endothelial function, vascular reactivity, cardiac hypertrophy, renal function, and blood pressure, as well as morbidity/mortality (10, 13, 80, 111, 115). In addition, inhibition of JNK/SAPK signaling attenuates contractile responses in isolated aortic segments (79, 113, 158), suggesting a role of JNK/SAPK in vasoconstriction mechanisms. These findings collectively indicate a role of MAPKs in the etiology of vascular dysfunction and hypertension. Therefore, novel upstream mediators of MAPK signaling, such as TLRs, should be investigated.
The final MyD88-dependent signaling transcription factor is IRF7. IRF7 activation is specific to TLR9 (65), and it requires phosphorylation and dimerization to trigger its translocation to the nucleus and induce type I IFNs and IFN-inducible genes (Fig. 3). Currently, knowledge of the contribution of IRF7 on vascular function and hypertension is not known. However, in one investigation that used human ECs infected with bacteria Chlamydophila pneumonia, IRF7-dependent signaling was activated, as well as IRF3-dependent and mitochondrial antiviral signaling. This signaling induced type I IFN expression that successfully inhibited bacterial growth. We subsequently hypothesized that type I IFNs, produced via IRF signaling, may contribute to the control of infectious-vascular lesions in atherosclerosis (18).
MyD88-independent signaling is associated only with TLR3 and TLR4 and results in the induction of type I IFNs and IFN-inducible genes (4, 65). Because this signaling involves the recruitment of the adaptor proteins TRIF and TRAM instead of MyD88, it is also known as TRIF-dependent signaling. MyD88-independent signaling results in the phosphorylation and dimerization of IRF3, as well as activation of NF-κB signaling (Fig. 3).
Research into the contribution of MyD88-independent signaling to vascular dysfunction and hypertension is limited. However, it has been demonstrated in VSMCs that C-reactive protein stimulates IL-6 production and inhibits peroxisome proliferator-activated receptor-γ expression via TLR4-MyD88-independent signaling (84). Additionally, using an in vivo model of hindlimb ischemia-reperfusion, TLR4 on myocytes mediated pro-inflammatory responses through MyD88, whereas regenerative processes occurred through TLR4 and TRIF (124). Although, these investigations observed a roll of TLR-MyD88-independent signaling in vascular dysfunction, more are still required to establish its roll in hypertension pathogenesis.
TLRs in Cardiovascular Disease Etiology
Unlike other TLRs, which are functionally active as homomers, TLR2 has developed the unique ability to signal via heterodimers with TLR1 or TLR6. In fact, signaling does not appear to occur downstream of TLR2 homodimers (116). TLR2 is required for functional recognition of gram-positive, gram-negative, fungi, viral, and mycoplasma lipoproteins, and peptidoglycan, and heterodimerization of TLR2 with TLR1 and TLR6 allows it to attain specificity for a diverse range of ligands (141). In addition to microbial factors, TLR2 can bind pathophysiologically modified HDL (135), as well as endogenous heat shock proteins (e.g., heat shock proteins 60 and 70) (7, 33).
Illustrating its potential for cardiovascular disease pathogenesis, TLR2 activation induces a dedifferentiated migratory and proliferative phenotype in VSMCs (33, 78). In ECs, "abnormal" HDL from patients with chronic kidney disease acted upon TLR2 (via a TLR1- or TLR6-coreceptor-independent pathway) and reduced NO bioavailability, leading to impaired endothelial repair and enhancing endothelial pro-inflammatory activation (135). These data in cells provide evidence as to why TLR2 activation has been associated with the development of atherosclerosis (30). Nonetheless, the contribution of TLR2 to vascular dysfunction in hypertension remains to be clarified.
TLR3 recognizes double-stranded RNA, and TLR7 and TLR8 recognize single-stranded RNA released from viruses (or retroviruses) or necrotic cells. TLR3 has been shown to have a protective effect on the vascular wall after mechanical and hypercholesterolemia-induced arterial injury (27). This protective effect may stem from the ability of TLR3 to induce the expression of cytoprotective and anti-inflammatory glycoprotein clusterin/apolipoprotein J to counteract the progression of atherosclerosis (9). On the other hand, maternal hypertension (from here on referred to as preeclampsia) was developed in rodents treated with agonists of TLR3, -7, and -7/8 (combined) (21, 22, 144). In pulmonary artery VSMCs, TLR3 induction was found to release IL-8, IFN-γ-induced protein 10 (also known as CXCL10), and ET-1 (41). Yang et al. (153) identified that TLR3 activation induced the expression of chemokine MCP-1 and pro-inflammatory cytokine IL-6 in human coronary VSMCs. Finally, activation of TLR7/8 with its agonist (Clo97) exacerbated the pro-inflammatory effects exerted by ANG II and nicotine in SHR splenocytes (49). These effects were replicated in vivo and may have important implications for ANG II and nicotinic modulation of the autonomic nervous system and sympathetic drive in hypertension (1, 93). Accordingly, these data illustrate that TLR3, -7, and -8, and their endogenous ligand (RNA), could contribute to the development of hypertension and other hypertensive disorders (e.g., preeclampsia).
TLR4 has been well characterized in various cardiovascular diseases (40), and it has been observed to induce a pro-inflammatory and proliferative phenotype to endogenous molecules in VSMCs (33, 131, 152). Endogenous agonists of TLR4 include vasoactive molecules heat shock protein 60 and ANG II (36).
TLR4 was the first TLR to be implicated in the etiology of vascular dysfunction and hypertension (15). Specifically, Bomfim et al. (15) showed that TLR4 is elevated in SHRs and that treatment with anti-TLR4 antibody attenuated aortic contractility, serum IL-6 levels, and mean arterial pressure. This ability of TLR4 to mediate heightened aortic contractility in SHRs opposes the findings that TLR4 activation with gram-negative (Escherichia coli) bacteria causes vascular dysfunction via attenuation of murine aortic contractility through the induction of iNOS (19). However, it should be noted that the goal of Cartwright et al. (19) was to emulate septic shock. More recently, it was reported that TLR4 mutation protected obese, type II diabetic mice against endothelial dysfunction in conduit and resistance vessels, hyperglycemia, and hypertension via downregulation of NAD(P)H oxidase isoforms 1 and 4 and cyclooxygenase 1 activity (82).
In support of these vascular-specific data, impaired functioning of other cell types that play a role in the pathogenesis of hypertension has been attributed to TLR 4. For example, TLR4 expression was elevated in cardiomyocytes of SHRs compared with Wistar-Kyoto (WKY) controls, NOS inhibition upregulated the expression of TLR4, and high-doses of angiotensin-converting enzyme inhibitor (ACEi) ameliorated the expression of TLR4 (35). In human aortic VSMCs, induction of TLR4 expression by LPS increased iNOS expression and NO production. Furthermore, LPS upregulated the expression of IL-8, vascular endothelial growth factor (VEGF), ICAM-1, and VCAM-1 (53).
Despite the fact that TLR4 polymorphisms have not been shown to be a significant predictor of coronary heart disease in healthy men (106), the abovementioned investigations illustrate a significant contribution of TLR4 to the development of cardiovascular pathologies, including hypertension. As a result, the contribution of other TLRs in hypertension and cardiovascular disease development should be investigated, as well as progressing TLR4-targeted therapy.
TLR5 functions similarly to TLR2 in that it recognizes flagella (2, 133). Specifically, TLR5 recognizes flagellin, a principal component of flagella from both gram-positive and gram-negative bacteria (50). Although an endogenous molecule or DAMP specific for TLR5 has not been reported, TLR5 deficiency leads to altered gut microbiota and metabolic syndrome (150), which can encompass hypertension.
Unmethylated CpG dinucleotides activate TLR9. Although these unmethylated CpG motifs are most common of microbial DNA, unmethylated CpG motifs can also be found in mtDNA, which can be released during cell injury and/or death. Circulating mtDNA released due to trauma is then able to act on TLR9 and induce an inflammatogenic response (157). This ability occurs due to the evolutionarily conserved similarities between mitochondria and saprophytic bacteria, which at one point during evolution entered the eukaryotic cell and became an intracellular organelle (127). It has been demonstrated that pressure-overload released mtDNA that escapes autophagic degradation, leads to TLR9-mediated inflammatory responses in cardiomyocytes, inducing myocarditis and dilated cardiomyopathy (114). Additionally, activation of TLR9 with its synthetic agonist (ODN 2395) exacerbated the pro-inflammatory effects exerted by ANG II and nicotine in SHR splenocytes (49). Nonetheless, the role of TLR9 on vascular function, vascular remodeling, and hypertension remains to be elucidated, and this hypothesis will be proposed later in this review.
Interestingly, it has been shown the TLR adapter molecule MyD88 is necessary for vascular remodeling of carotid arteries. Specifically, inward remodeling was associated with MyD88-dependent and superoxide anion initiated cytokine and chemokine generation, as well as macrophage infiltration and activation in the vascular wall. (142). However, an association between MyD88 and a specific TLR was not deduced, since MyD88 is downstream of various TLRs (Fig. 3).
An endogenous peptide that is dysregulated during the development and establishment of hypertension is ANG II. Along with its profound effects on vasoconstriction, aldosterone and antidiuretic hormone (ADH) secretion, sympathetic activation, and fluid and ion reabsorption, ANG II is also able to influence various TLRs and their signaling. For example, ANG II upregulated TLR4 protein and mRNA expression, as well as TLR4-induced myeloperoxidase secretion in murine macrophage (RAW264.7) cells (60). Activation of TLRs7/8 and TLR9 exacerbated the IL-6 secretion to ANG II in SHR splenocytes, but not WKY, and this pro-inflammatory cytokine production in SHRs following ANG II and TLR7/8 agonist administration was further replicated in vivo (49). Inhibition of ANG II by antagonism of the ANG II type 1 receptor with olmesartan was able to reduce the TLR2/TLR4-mediated inflammatory action in ApoE−/− mice, subsequently improving indexes of vascular disease (e.g., inhibition of intimal neovascularization and matrix metalloproteinase activation), decreasing atherosclerotic plaque growth, and increasing plaque instability (24). Finally, given that TLRs are expressed by T lymphocytes (62) and T lymphocytes mediate ANG II-induced hypertension (47), it is conceivable that ANG II alters TLR expression on T lymphocytes and contributes to the aberrant inflammation seen in hypertension. Overall, these findings illustrate a novel effect of ANG II on various TLRs. Therefore, further exploration of the effects of ANG II on TLRs is justified, as well as investigation into the TLR interactions with other DAMPs that are upregulated due to the pathogenesis of hypertension.
TLR9 and Mitochondrial DNA: Novel Contributors to Hypertension?
As mentioned earlier, TLR9 has affinity for unmethylated CpG dinucleotides common of bacteria and viruses but not for methylated CpG dinucleotides common of vertebrate DNA. This ability of the immune system to discriminate the methylation pattern of DNA is important for preventing TLR9-dependent autoimmunity (12, 137). However, unmethylated CpG dinucleotides are also found in mtDNA, as mitochondria evolved from saprophytic bacteria to become intracellular organelles (127). Recently, the inflammatogenic properties of mtDNA, as a result of TLR9 activation, have been demonstrated (114, 157). Although the existence of TLR-independent pathways activated by nucleic acids have been previously described (151), emerging data suggest that activation of TLR9 by mtDNA could be a novel mechanism of vascular dysfunction, vascular remodeling, and hypertension. In support of this hypothesis, previous investigations have shown that cell-free CpG DNA is increased in patients with essential hypertension (149) and preeclampsia (28).
TLR9 is expressed in various immune cells such as B lymphocytes, monocytes, macrophages, and plasmacytoid dendritic cells (52), as well as vascular tissues (44). In immune cells, immature TLR9 is localized to the endoplasmic reticulum, and upon CpG internalization via class III phosphatidylinositol 3-kinase-dependent mechanism (71), translocates to endosomal vacuoles (76). Activation of TLR9 by CpG motifs involves an intracytoplasmic signaling cascade that proceeds through MyD88, IL-1-receptor-activated kinase (IRAK), and TNF receptor -associated factor 6 (TRAF6) cascade. This signaling leads to the activation of both MAPKs and IKK complexes and culminates in the upregulation of pro-inflammatory transcription factors, including NF-κB, AP-1 via MAPKs, and IRF7, stimulating the production of a TH1 response (71). Given that NF-κB and MAPKs are also involved in the pathogenesis of vascular dysfunction and hypertension, it is conceivable that TLR9 may play a role in augmented expression of pro-inflammatory cytokines, chemokines, and adhesion molecules seen in association with vascular remodeling. We have recently found that TLR9 is expressed in both conduit (aortic) and resistance (mesenteric) VSMCs, and activation of TLR9 with its synthetic ligand, ODN 2395, results in augmented contractile responses in isolated conduit (100) and resistance (45) arteries.
TLR-mediated generation of pro-inflammatory cytokines, chemokines, and adhesion molecules have been extensively investigated in immune cells (157), and recently our laboratory (15, 44), and others (19, 82), have extended some of these findings into the vasculature. Plausibly, vascular remodeling and hypertension may be promoted via mtDNA activation of TLR9 in VSMCs, ECs, and immune cells (e.g., monocytes and macrophages) in concert. For example, TLR9 activation and the presence of mitochondrial DAMPs increase endothelial permeability (57, 139). We propose it would only take a minor insult to cause cellular injury and initiate the deleterious cascade of mtDNA release and TLR9 activation (e.g., prehypertensive stimuli such as ANG II, high salt, or chronic stress). This release of mtDNA and other DAMPs could lead to further pressure- and ischemia-induced cell injury and death as vascular remodeling ensues and blood pressure rises.
In summary, although TLR9 promotor polymorphisms have not been shown to play a role in atherogenesis (48), the inflammatogenic properties of circulating mtDNA could be the missing link between TLR9 activation, vascular dysfunction, vascular remodeling, hypertension, and further cardiovascular pathologies (Fig. 4).
Clinical Implications
It is well known that resistance arteries are the major contributors to total peripheral resistance and thus blood pressure regulation, due to large composite cross-sectional area and sympathetic innervation. As such, deleterious alterations to their structure can promote the development and progression of hypertension (129). Moreover, stiffening of conduit vessels influences blood pressure regulation through propagation of blood flow to the downstream arterial tree (e.g., turbulent or laminar blood flow and subsequent vascular adaptations to shear stress). In fact, aortic stiffening is a precursor to the development of hypertension (63), is associated with inflammation in patients with untreated essential hypertension (90), and is a strong independent predictor of cardiovascular morbidity in hypertension (77). Therefore, investigations of the molecular mechanisms that contribute to global vascular remodeling throughout the arterial tree should be conducted.
Although the etiology of essential hypertension is heterogeneous and has not been fully elucidated, immune system activation and chronic inflammation have been recently acknowledged as a significant contributor to the hypertensive process (1, 34, 46, 55, 118, 136). The interaction between DAMPs and TLRs on vascular tissues may be the starting point for the development of vascular dysfunction and remodeling, the adaptive immune system response, and the genesis and establishment of hypertension (Fig. 2).
The discovery of TLRs has guided the field of immunology to an era of accelerated advancement and has created exciting therapeutic and experimental possibilities for targeting infections and noninfectious inflammatory diseases (14). The involvement of TLRs in the pathogenesis of hypertension, as described in the current review, extends these therapeutic possibilities above and beyond the current challenges in immunology. TLRs may be the missing link between host-derived "dangerous" molecules (DAMPs such as mtDNA), low-grade inflammation, vascular remodeling, and hypertension. Moreover, activation of TLRs may be a necessary precursor of adaptive immune system involvement in the development of hypertension. The etiology of essential hypertension is multifactorial, and a plethora of endogenous molecules have been previously linked to the development this disease (Table 1), further increasing the complexity its pathophysiology. Paradoxically, TLR signaling presents a low complexity system (i.e., 10 TLRs in humans, 4 adaptor molecules, and 2 downstream inflammatory transcription factors are required for most invading and host-derived molecule recognition) (14). The low complexity of TLR signaling and the existence of specific inhibitors and antagonists for components of the TLR signaling may lead to exciting and novel therapeutic interventions for hypertension and other hypertensive disorders.
This study was supported in part by the American Heart Association (No. 13PRE14080019), the National Institutes of Health (R01 HL-071138 and R01 DK-083685), the Society for Women's Health Research, the Preeclampsia Foundation (Vision Grant), the CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil, and the Naito Foundation, Japan.
No conflicts of interest, financial or otherwise, are declared by the author(s).
Author contributions: C.G.M. and S.G. prepared figures; C.G.M. drafted manuscript; C.G.M., S.G., C.F.W., K.M.S., T.M., and R.C.W. edited and revised manuscript; C.G.M., S.G., C.F.W., K.M.S., T.M., and R.C.W. approved final version of manuscript.
- Copyright © 2014 the American Physiological Society
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Opinion > InterBay
Is it commercial lending's time in the sun?6 months ago
The past few months have been particularly buoyant for the commercial mortgage market as hurdles els...
AIB provides funding for acquisition of 190 homes
AIB Corporate Banking has formed a partnership with Túath Housing Association to fund the acquisition of up to 190 social homes across every county and district in Ireland.
Virgin Money set to enter SME banking market
Virgin Money Holdings UK has announced plans to enter the UK SME banking market in January 2018.
British Business Bank welcomes extra £2.5bn government funding
The British Business Bank has welcomed the extra £2.5bn of government funding, announced in the Autumn Budget.
£11m UTB facility saves developer from considerable funding costs
United Trust Bank's (UTB) structured finance team has provided an £11m facility to save a property development company from paying considerable funding costs.
Behind the scenes at Metro Bank's new London store opening
Metro Bank opened its 52nd store in Liverpool Street, London, last Thursday (16th November), with the lord mayor of the City of London Alderman Charles Bowman cutting the ribbon.
Do people underestimate the scale of UK SMEs?
Only 2% of British people realise that SMEs make up 99% of total UK businesses, new research has revealed.
We need to aim higher than 'a nation of shopkeepers'
I read an interesting newspaper article the other day with the headline: "UK bank scandals are making entrepreneurs reluctant borrowers".
What are the key changes from the Autumn Budget 2017?
In the first Autumn Budget, the chancellor of the exchequer Philip Hammond has set out the government's plan for the UK economy.
CYBG reports 6% lending growth
CYBG PLC has reported total lending growth of 6% during the year ending 30th September 2017.
Do enough businesses realise the benefits of asset finance?
Only one in 10 business owners (11%) describe the strength of their companies' working capital facilities as "very strong", even though their businesses are performing well, a report has revealed.
Banks join forces to finance Berlin's Sony Center
Landesbank Baden-Württemberg (LBBW), pbb Deutsche Pfandbriefbank AG and ING Wholesale Banking have provided €625m to finance the Sony Center in Berlin.
Shawbrook Bank revamps website
Shawbrook Bank has announced the launch of its new-look website.
Al Rayan reduces rental rates across discounted variable HPP range
Al Rayan Bank has reduced rental rates across its entire range of discounted variable home purchase plans (HPPs) by 0.25%.
Over 16,000 businesses sign up to Revolut
Digital banking app Revolut has revealed that over 16,000 businesses have signed up to its business account during the past three months.
Coutts launches offset mortgage
Private bank Coutts has launched a new offset mortgage product.
EIB commits €85m to fund Limerick commercial development
The European Investment Bank (EIB) has committed €85m to Limerick City and County Council to fund a commercial development in the city centre.


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Stock Graphic >> Texture - Leather Library 100 Textures INTRO 195036 by Ornaments of Grace @ CreativeMarket
File Size: 17.41 MB; DPI: 400 DPI.
INTRO! $25 until March 15 / Regular $35
If you liked The Full-Grain Leather Collection and Leather Love, you'll love this. Leather Library represents the rest of my best leather textures. Made from high-quality scans of leather goods and samples from our extensive leather collection (alright, so we're into leather around here) this comprehensive collection features a variety of leathers including full-grain, top-grain, bonded, genuine, and faux leathers. I hope these textures will come in handy for your next project!
Software Requirements: PNGs work in Photoshop, Photoshop Elements, etc; PSDs work with Adobe Photoshop (CS4+) only.
NOTE: This is an enormous collection! Due to the total size of the files in this bundle (over 2 GB!) you'll receive a "Download Links" PDF with links and instructions to download the files.
Features of this collection.
Check out a preview/dimensions of the textures in this PDF: bit.ly/OGleatherlibraryPRV
- 100 textures: 99 PNG, 1 PSD with 7 color adjustment layers
- Textures include a variety of leathers including full-grain, top-grain, faux, bonded, suede, and pigskin
- Colors: browns, tans, black, gray, and multicolor
- Bonus! Row of high-quality, authentic stitches also included as a PSD ( Requires Adobe Photoshop CS4+ )
About the displays.
- The 20 textures on the display is a small sampling of the 100 textures that come in this collection.
- Fonts used are Brandon Printed and Thankful Modern Filigree (http://crtv.mk/cxgo)
- Leather tooling and stamping effects used are from The Leathercrafter - Smart PSD (http://crtv.mk/sxpX)
- Ornaments used are from Thankful Extras (http://crtv.mk/gyYw)
Keywords: leather, masculine, rugged, vintage, texture, grunge, distressed, western, textile, background, scrapbooking, stitching, faux, suede, pigskin.


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Scientific Expertise Search
The Scientific Expertise directory is a way for members to connect with other members or the general public. You'll find members with self-selected areas of expertise who can discuss specific topics/areas of research. Note that if you are not a member, you will only be shown those members who are willing to have their expertise listed in the public directory.
Please enter your search information below and click Search.
The Scientific Expertise directory has been compiled solely on the self-evaluation of each member as to their areas of expertise. SSSA as a result does not accept any responsibility for the accuracy of information or expertise asserted, nor do we in any way represent or warrant that the individuals contained in this directory are in a position that they can or will be able to provide such expertise or service to others.


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Deb Haus formed The Consulting Haus— An Independent Resource for Major Goals—in 2006 after leaving Sony Music Nashville as VP of Creative Services, Marketing and Artist Development. Haus' 20-year major label stint began in her home town of Austin, Texas shortly after earning a degree in Film at the University of Texas. During her two decades with Sony she worked on campaigns for Award winning artists such as Dixie Chicks, Miranda Lambert, Gretchen Wilson, Montgomery Gentry and many more.
"My transition from the label was smooth," Haus recalls. "I took a three month break and then began doing what I love to do, but on my own terms." The Consulting Haus has offices and clients in both Austin and Nashville and specializes in Brand Imaging, Creative Direction, Video Production, Music Marketing and Artist Development. Recent clients include Rebel Engine Ent., Red Light Management, HitShop Records, Tenacity Records, Emblem Music Group, 16 Minutes Ent. and I.R.S. Nashville.
Haus believes "Teamwork is essential," and brings that focus to her work. Those professionals that have worked with her are also apt to praise her project management skills and ability to keep a team focused on its goals. Having worked with her recently, this writer can testify she is self-assured, but calm and easy going.
During our interview Haus discussed important steps in the artist development process, pitfalls to avoid, pathways to success and her latest analysis of the "it" factor. She also noted how the opportunity landscape for new artists is evolving… Read On
NEKST: What's the process of starting with a new artist?
Deb Haus: It's so important to get to know the person. I'm going to be responsible for matching that artist's personality with a creative team that can make them feel comfortable, keep them who they are and not try to change them. That includes photographers, directors, stylists, hair and makeup and more. Every artist is completely different, but they all have the exact same goal—a successful long term music career. As the artist development process kicks in—we begin by establishing a core fan base and being honest about the artist's identity. I tell artists, "Don't try to be something you're not." The scariest new artist to work with is the one that doesn't know who they are and seems way too open to being molded. That's a big red flag.
NEKST: What are some of the pitfalls you help new artists avoid?
DebHaus: Often artists come to town and begin spending lots of money and rushing into things before they have a timeline and a plan. Equally 101 is, "Do you really love being around people and the idea of having fans?" Many new artists say, "Yes I love my fans," and in the beginning they believe it. But if, as time goes on and success kicks in, you start to see them retreat from those meet and greets then that is not going to point them toward a long term successful career in country music.
NEKST: Can you spot the artists with that special personality?
Deb Haus: I'm not always right, but I do have an instinctual grasp based upon doing this for 20 years. Usually a client is coming to me that already has a manager or a label. If I get the vibe that an artist is playing the "role" of country artist or if I don't see that drive I'll find a polite way to discuss it with the manager or person backing them and help them dig a little deeper. I used to subscribe to the "it factor" theory—something you're born with and everyone can immediately tell if you have it. But I've actually changed my way of thinking. I've seen people who weren't that shining star walking into a room in the beginning, but with time, success and added confidence they evolve and can actually become an "it factor" person. And sadly, I've also seen people lose that "it factor" over time—perhaps due to failures, discouragement or even because they self-destruct emotionally, physically or spiritually.
NEKST: What are your favorite artist development tools?
Deb Haus: Any tool whether written or visual that helps people get to know a person is valuable. When an artist sits in front of their computer and says to their fans, "Look what just happened to me," or "Here's how I feel this week," or "Here's a little bit of a song I just wrote, tell me what you think," that interaction is one of the best ways to connect. We hear the word "authenticity" everywhere and it's so true. If an artist isn't being authentic the fans will see through it. It goes back to asking do you really want to interact with your fans? Because the most important tool in an artist tool box is that genuine love of people. There's also artists who are savvy in the marketing and self promotion department and, for example, are great at remembering names. However, there's the skill of remembering a face and name, but there is also the intent behind it. If you genuinely want to know who everyone is and how they fit into this giant industry puzzle then you are leagues ahead in the artist development process because you are authentic and genuine. So part of what I do is teach them about the industry and explain what everybody does. If they take the extra step to be genuinely interested, it benefits them greatly. Another artist development tool is listening. A lot of artists (and execs) feel so compelled to say whatever it is they need to say that they don't stop and listen.
NEKST: You also offer project management, why?
Deb Haus: The project manager is the nucleus, the center of a whole group of talented people each focusing on their own role. Somebody has to share those elements and keep everyone on the same page. Communicating the collective goals generates consistency in branding, imaging and timing. Seeing action steps, production schedules and timelines all credited to those involved helps everyone feel engaged, empowered and important. And that's important.
NEKST: Besides online, what's the biggest artist development change in Nashville?
Deb Haus: It's no longer only a few companies deciding who the new artists will be. There's a giant buffet of available talent in Nashville. An artist with a true gift has a better shot of being heard and partnered up with the right people than ever before. Consultants like me are blessed to work with a variety of people. I'm currently on six projects each with different teams. One of those is well known Nashville painter, Shelia B. I'm finding the only difference between marketing a painter and a musician, artist development-wise is I'm going to a gallery instead of a concert.
NEKST: How do artist images grow?
Deb Haus: When deciding how to launch an artist visually my advice is always don't get above your raising. You want to be extra cool, but the fans have to give you the permission to do that. Miranda Lambert's a good example. I worked on her first two albums with the Sony team. Look at that brilliant video she made this year and compare it with her early work. That great, hip Pistol Annie vibe wouldn't have worked in her very first video. But now her fans have allowed her to get there. And Miranda's done an amazing job because she is authentic and totally herself.


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23 Oct 2015
Transport technology making progress
Since the first variable message sign for the project was put in place earlier this year, the project team has been making progress with the installation of intelligent transport system technology.
A further 10 variable message signs out of a total of 16 signs have been put in place to date. These signs feature increased functionality and will display two colour text and four colour pictures as required.
When in use, road users will be provided real time traffic information such as expected travel times, congestion information and details of any incidents that have taken place on the network.
Alongside variable message sign installation, the project team has been making headway with the installation of cameras and fibre optic cables with configuration and testing work taking place on an ongoing basis.
There will be a staged approach to the launch of the intelligent transport system technology on the project as the work draws closer to completion.


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Don Sayers
Niwot, CO
Commissioned Work
If you would like to commission Don to draw/paint figurative, architectural, floral, equestrian, brochure or book illustrations, or other artwork, please contact him directly at the contact information above.
Don's work is currently on display at Osmosis Gallery in Niwot Colorado. If you are interested in viewing an original painting or giclée print listed as available on this website please contact Don or visit Osmosis Gallery.
Don's studio will be open to the public as part of the Longmont Studio Tour September 27 and 28, 2014. Studio visits can be scheduled at other times by contacting Don.


text: Establishment of Wi-Fi Display session between source and sink device in wireless Android screencastingYacob W. Sitorus, Gabriel Frans, Prasetiyo, Trio Adiono, Amy H. Salman, Nur Ahmadi2015 International Symposium on Intelligent…2015Wireless technology has been rapidly developing. Wi-Fi Alliance several years ago presented Wi-Fi Direct, a new feature that makes it possible to connect devices using ad-hoc network. Since then this technology has been developed and now comes Wi-Fi Display (WFD). This technology is utilized to implement the system of wireless Android screencasting. This… (More)


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How to book a Hotel in Gustavsberg: Travelbru.com
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The Manager of the Sultan Abubakar III International Airport, Sokoto, Alhaji Abubakar Lawal, said yesterday that more than 14,346 intending pilgrims had been airlifted to Saudi Arabia for this year's hajj.
Lawal told the News Agency of Nigeria (NAN) in Sokoto that the operation was carried out in 28 flights. He said that 4,927 of the intending pilgrims were from Sokoto State, 4,239 from Zamfara State and 5,180 from Kebbi State.
Abubakar expressed optimism that additional 3,500 intending pilgrims from the three states in the zone would be transported before the close of the exercise.
A total of 17,846 intending pilgrims are expected to be transported through the airport. He commended the management of Kabo Air and Max Air Airlines for ensuring a hitch-free exercise.
Source: Naija.ng