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Worth the risk
Older workers who find themselves out of work - whether it's voluntarily or involuntarily - around the age of 50 don't have to re-enter the job market looking for the same career. I
Perfect blend
Perfect blend
Messed up
Messed up
Older workers can add plenty to today's companies
Many employers are finding that hiring older workers provides them with a number of benefits, both financially and in terms of productivity.
Let's buck the DOT steamroller
As a Juneau resident who likes to stay informed of local issues, I am usually hard-pressed to find the time to get personally involved.
Empire needs to upgrade vocabulary
I am writing this as a private citizen, not as a member of any committee. As I was raising my children into their adulthood, there was at least one word that I preferred they not use.
Saying it's so doesn't make it true
J. Marc Mulkey's letter of July 13, "Setting The Record Clear on Bush," repeats the same tired old doggerel we've been treated to ever since Bush took office. But saying it is so still does not make it so.
Pipeline royalties should go to insurance
The Alaska gas pipeline project royalties should be used to grant state medical insurance for those who do not qualify for Medicaid or do not have any insurance at all.
Why no mention of voting record?
With a vote as important to the community as this vote by the Juneau Planning Commission (regarding the state's proposed road out of Juneau), I am curious why there was no mention of which members voted yes and which members voted no.
Homeless people aren't always drunks
Susan Lebeau's letter of July 14 made some valid points but I must take exception to her using the term "homeless" in reference to obvious drunks.
Candidate with most votes doesn't always win
I read with interest Mr. Gregory Acres' tutorial on voting 101, "How the political process works," on June 28. In his tutorial, Mr. Acres states that the person "who wins the election" is the person the most individuals cast their vote for.
Where the tales are above average
A Juneau appearance that might have been billed as a night of music and mirth from the star of "A Prairie Home Companion" inspired even more alliteration from one fan Sunday.
Photo: Orca out of water
Members of the U.S. Coast Guard and professional salvaging companies gather around a private boat named Orca, whose homeport is Portland, Ore., that ran aground Sunday morning in heavy fog near the Douglas Bridge.
Police & Fire
Reports from Juneau police, fire officials and state troopers.
Concert features unusual handbell choir
Masters of metal: The 15-member Bells Of The Sound ensemble will perform in Juneau on Thursday. photo courtesy of Bells Of The Sound
Photo: Setting sail
Sailboats line up at the start of the Admiralty Cove Rendezvous in Gastineau Channel on Saturday.
Police & Fire
Reports from Juneau police, fire officials and state troopers.
Around Town
Around Town is a listing of local nonprofit events.
Around Town
Around Town is a listing of local nonprofit events.
Patricia Joan (Gray) Rowland Vadman
Former Juneau resident Patricia Joan (Gray) Rowland Vadman, 67, died July 7, 2006, at her home in Yuma, Ariz., following a lengthy respiratory illness.
My Turn: Remember our citizen-soldiers
Every summer we celebrate our independence by saluting the flag, parading in our communities and grilling food with friends and loved ones. Alaskans have another reason to celebrate - and to truly remember the sacrifice of freedom.
Devils in the details regarding Measure 2
Measure 2 on the Aug. 22 primary election ballot assesses a $50 head tax on each Alaska cruise ship passenger, with the money going to the state and the ports welcoming the travelers. Sounds great, except there are devils in the details.
Road is a local issue too
When a Juneau Planning Commission member this week questioned state road planners' attention to the city's opinion of the proposed Juneau access highway, the Department of Transportation and Public Facilities had a disturbing retort.
Alaska Editorial: Language should not be a barrier to voting
Spanish isn't the only foreign language spoken by immigrants and newly naturalized citizens in the United States. Tagalog has long been a language of Filipino immigrants.
Petroglyphs provide reminder of ancestral lands
Before Berners Bay became a Mecca for wildlife viewing and gold mining, it was a home for many of Juneau's original Native settlers.
OUTSIDERS: Nicola Zantello and Gutchquena
Gutchquena and Zantello, both self-employed, like doing "anything on the water - boating, kayaking, canoeing, scuba diving, seal hunting."
Kennel manager leads dog trips through Denali
Karen Fortier may be a slender, petite brunette but to the 30 working dogs at the Denali National Park kennels, she's a giant.
Mount Roberts displays floral curiosities
A roughly two-mile climb through spruce-hemlock forest or a five-minute "flight" over it in the tram brings you near the tree line on the Mount Roberts Trail.
Out & About
Today: Juneau Gold Miners' Posse Cowboy Action Shoot, 9 a.m., Hank Harmon Rifle Range.
JRC-The Alaska Club Governor's Cup results
Sports in Juneau
Sports in Juneau is a service provided by the Juneau Empire to provide information on upcoming sports and outdoors events in Juneau.
Sports in Juneau
Sports in Juneau is a service provided by the Juneau Empire to provide information on upcoming sports and outdoors events in Juneau.
Miller captures Governor's Cup
n describing the 5-kilometer course for the 29th Annual JRC/The Alaska Club Governor's Cup race Saturday, winner Shawn Miller said it was a flat course with some deceptive hills along the way.
More Alaska teens are opting for GEDs
An alternative to a high school graduation diploma, the General Education Development credential, increasingly is being obtained by Alaska teenagers.
Sockeyes returning slowly to Kenai
A weak return of sockeye salmon to the Kenai River has many who look to the fish for their livelihood issuing a collective groan this year.
Legislators taking on gaming issue
Legislators entered a second special session in 2006 last week with a new word stuck in their heads: gaming.
Anchorage police arrest murder suspect
Anchorage police have arrested a man suspected of throwing a bottle that shattered and killed a Fort Richardson soldier seven years ago.
TransCanada offers gas pipeline proposal
TransCanada Corp., the Canadian company that applied in 2004 to build a natural gas pipeline to transport North Slope gas, has written the governor a letter.
Fort Knox Mine seeking permission to heap leach gold
A Fairbanks gold mine will seek permission to use heap leaching to extract gold from ore.
Native tribal leaders worry about road access to cultural landmarks
Rosa Miller, tribal leader of Juneau's Auk Kwaan, faces an uphill battle in keeping development far away from her tribe's culturally significant spots in Berners Bay.
State's first facility for veterans becomes reality
The transformation from Pioneers' Home to Alaska Veterans Home officially finished July 9 in Palmer, as Gov. Frank Murkowski formally dedicated the facility.
Haines seeking a voice on road
The Haines Borough is feeling stranded along the side of the road when it comes to the building of the Juneau access highway, officials said.
A fair-weather friend on Denali
apanese mountaineer Yoshitomi Okura climbs North America's highest mountain each year and installs a new weather station to defend the honor of three friends - blown off Mount McKinley during a winter climb.
Bear charges jogger twice on city trail
Warren Hancock thought he was going for a pleasant morning jog before work, but it turned into a frightening experience when a brown bear charged him twice as he ran along a trail in east Anchorage.
Alaska Digest
The state has approved $50,000 to rescue orphan moose calves but a rescue group will not see the money until it comes up with a solid plan for spending it, according to Fish and Game Commissioner McKie Campbell.
This Day in History
In Alaska, the Nation, and the World
This Day in History
In Alaska, the nation and the world
Ridicule hits Stevens after 'tubes' speech
Sen. Ted Stevens, R-Alaska, is enduring no end of ridicule in the blogosphere for his recent explanation, in a Commerce Committee debate, of how the Internet works.
© 2017. All Rights Reserved. | Contact Us


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by Christopher Freeburn | February 20, 2013 12:29 pm
[1]Viacom's (NASDAQ:VIAB[2]) cable channels MTV and BET did not have their accounts hacked this week[3].
On Tuesday, the Twitter accounts for both channels suddenly switched logos, making it seem as if hackers had gained access to the accounts. Followers of MTV's Twitter accounts saw BET's logo and profile, while BET Twitter followers saw MTV's logo, the Los Angeles Times noted.
MTV and BET appear to have been trying to boost their own number of Twitter followers with the fake hacking stunt. After about an hour, the two channels issued tweets unmasking the stunt and applauding each other.
On Monday, Burger King's (NYSE:BKW[4]) Twitter account was commandeered by hackers, who posted obscene tweets, prompting an apology from the burger chain[5]. The incident may have embarrassed Burger King, but it also saw 30,000 new users start following its Twitter account as news of the hacking spread. The sudden gain in Twitter followers prompted an MTV executive to suggest, via Twitter, that Burger King should have kept the account running all day to gain even more followers.
Also on Tuesday, real hackers siezed control of Jeep's Twitter account[6], posting fake tweets that the Chrysler brand was being sold to General Motors (NYSE:GM[7]).
Shares of Viacom fell more than 1% in Wednesday midday trading.
Source URL: https://investorplace.com/2013/02/why-mtv-bet-faked-their-own-twitter-hacking/
Short URL: http://invstplc.com/1nvUPU9
Copyright ©2017 InvestorPlace Media, LLC. All rights reserved. 700 Indian Springs Drive, Lancaster, PA 17601.

subset: commoncrawl


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Each year more than 220 Graduate Center Ph.D. students receive funding through the Doctoral Student Research Grant (DSRG) program. Read more
Graduate Center Distinguished Professor David Waldstreicher (History) was interviewed for a recent New York Times article covering the comments made by White House Chief of Staff John F. Kelly about the Civil War. Read more
The National Cancer Institute funds a student's study of the role of e-communications in surviving breast cancer. Read more
Miles Corak will join the economics department and the Stone Center on Socio-Economic Inequality. Read more
The $10,000 prize from the American Physical Society recognizes and encourages outstanding achievement in biological physics research. Read more
The Graduate Center (GC) of the City University of New York (CUNY) has entered into a joint endeavor with Princeton University to explore the interface between biology and physics through the establishment of the Center for the Physics of Biological Function. Read more
"It is a recognition that the story of great doctors is not the whole story of medicine,' said Distinguished Professor Gerald Markowitz (GC, John Jay/History). Read more
Elizabeth Wollman
A Critical Companion to the American Stage Musical
(Bloomsbury/Methuen, 2017)
Read more
David H. Richter
Reading the Eighteenth-Century Novel
(Wiley, 2017)
Read more
Martin D. Ruck, Michele Peterson-Badali, Michael Freeman, editors
Handbook of Children's Rights: Global and Multidisciplinary Perspectives
(Routledge, 2017)
Read more


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Originally Posted by Gorath
Okay, then it's understandable you couldn't include it. But maybe you should have simply asked in our forum. It's no secret Limbic is the developer, although Ubi follows their usual tight regime to brand everything as Ubi. Somebody would have told you.
And of course we need to know who does all the good things (-> developer) and who is responsible if the game sucks (-> publisher).
There's a big Limbic logo at the bottom of the OpenDev page, btw.


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Whoa, what a journey! Just wanted to share with everyone my personal X-Men comic reading adventure. I wanted to get into comics over a year ago and I started searching of a way to do that here on Comic Vine. I found out about DCs New 52 and picked up some issues and really enjoyed the potential entertainment I could get out of it. But I wanted to try something Marvel, and I wanted to go for X-Men. Of course, I was completely lost on where to start so I thought to check Kijiji (a Canadian specific Craigslist) on what I can get from issue one.
X-Men (1991) was there from issue 1 to 200 at a great price of $150 (USD and Canadian dollars are about the same for anyone wondering). That is of course until I was rushed by the seller who had the issues unorganized and in person admitting there are some missing. I still bought them thinking there couldn't be that many missing of the 200 issues on September 26, 2011. I was bummed after a careful organizing that I had only 136 unique issues and some doubles. There were plenty of holes in the collection and I was still determined to fill all the gaps. Only after a couple of days I found another 26-230ish set at $150 (though I was able to bring that down to $100). This guy was really nice and legit. Full, organized set and he really rose my ambitions on getting the entire volume. I held 223 unique issues and had doubles on 124. Was able to sell them at a comic shop for practically nothing ($31) and by November 5, 2011 I had 250 unique issues at a total cost of $241.60. This can go on for a lot longer but I'll summarize. I kept informing myself and wanted more X-Men titles, got Astonishing X-Men, Age of Apocalypse Omnibus, X-23 (vol3), House of M 1-8 issues, Messiah Complex/War/Second Coming Hardcovers, Avengers vs. X-Men hardcover and all missing gaps of issues from a variety of sources. They were found in used book stores, regular book stores, comic stores, local conventions, Kijiji and Ebay. I would say the total costs for everything I have would probably amount around $600-$700.
It's all worth it though. After I got settled into my new home, around November I began reading. Today I have read everything in this read order list I made for myself:
X-men 1-39
Age of Apocalypse
X-Men 42-113
New X-Men 114-156
Astonishing X-Men 1-6, X-Men 157-164
Astonishing X-Men 7-12, X-Men 165-174
House of M 1-8, X-Men 175-176
X-Men 177-181
Astonishing X-Men 13-18, X-Men 182-193
Astonishing X-Men 19-24 + Giant Size, X-Men 194-204
Messiah Complex
Astonishing X-Men 25-30, X-Men Legacy 208-218
Messiah War
Astonishing X-Men 31-35, X-Men Legacy 219-234
X-23 (v2) 1
Second Coming
Astonishing X-Men 36-47, X-Men Legacy 238-265
Avengers vs. X-Men
Astonishing X-Men 48-55, X-Men Legacy 266-275
Astonishing X-Men 56, All-New X-Men 1-2, X-Men Legacy (v2) 1-2
I wonder when I became such a fan? There were definitely some dry spots, but it was nothing compared to all the great 21 years worth of content I got to read in just about 1 year.
As for the present and future I will continue to get Astonishing X-Men, All-New X-Men, X-Men Legacy (v2) and MAYBE Uncanny X-Men (MarvelNow). I'm not wealthy or anything so the Uncanny X-Men is still up in the air.
If I had to mention the peak of enjoyment, it would have been during New X-Men, followed closely by Age of Apocalypse, Joss Whedon's Astonishing, House of M, Messiah trilogy. Just finishing All-New X-Men I get a glimpse of the X-Men from before my 21 years of content so I really feel like I have accomplished a lot and wanted to share that with you all.


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R Merryn G.wrote a question about The North Face Velocitee Singlet - Women's on July 2, 2013
What is the garment length?
What is the garment length?
What is the garment length?
0 Answers
The Danbee skirt is the only ISIS skirt I've tried, so I can't comment on consistency of sizing. I'm wearing the size four. For reference, I'm 5'2", about 120# and somewhere between apple and pear shaped. The skirt fits a little loose in the waist, which is my preference. This is perfect summer-wear: lightweight, non-wrinkly, has functional flat-laying pockets and is very comfortable. My first skirt was the Jet color. After wearing it once, I got online to find it in more colors. This time I went with the Mulberry, which is pretty true to the online color (mine is maybe a bit darker). I'm even considering getting another in Jet just so I always have one...
0 Comments


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|100 m²
|Property type
|Minimum Stay
|7 nights
The villa is classified Kaz Ti punch 'Catering 5 star and Labelled Clévacances (key 4) ...
... Let yourself to a dream holiday in the 'Kaz Ti punch' (with a private jacuzzi)!
Enjoy beautiful villa 5 * luxury, brand new, with swimming pool (villa Sky kaz) or jacuzzi (villas and Kaz Kaz Tibou Ti punch), sun terrace, garden and air conditioning. Relaxation and enjoyment are guaranteed!
Chic, comfortable, spacious and impeccably maintained ... you will feel so good!
The villa has an excellent level of comfort and modern amenities of a high quality (all private) pool or hot tub (in the villa) for relaxing, sunbathing terrace and sun loungers ideal for the relaxation and sunbathing, hammock invites you to relax, barbecue for convivial evenings, bedding very comfortable, quiet air conditioners and mosquito nets for peaceful nights, washing machine / dryer for travel lighter, satellite TV, stereo , DVD library, bliblitohèque and little games, Internet and phone must stay connected ...
The furniture is as comfortable as design. The decor is elegant, decorated with personal touches that make the difference: fresh flowers, trinkets of Caribbean artists ... You truly enjoy a thought management in detail, both functional and elegant.
We will offer you of course a warm welcome and cared for. During your stay we will be at your disposal, as discreet as available. People with disabilities are welcome.
Ideally located in Petit-Bourg in the center of the island, your villa you will radiate rapidly across Guadeloupe.
Nestled in a quiet, safe and green, with a beautiful view of the forest and surrounding countryside. Very close to remarkable sites (Cascade with Crayfish, Valombreuse Garden, Carbet Falls, driveway Dumanoir, Road Crossing ...) but also of Pointe-à-Pitre (15 mins), airport (20 min) and ZI Jarry (10 min).
The villa has air-conditioned rooms and room (s) modern shower (s), two lounges, a dining terrace and a fully equipped and functional kitchen.
For your comfort, the following consumables are available: salt, pepper, sugar, paper towels, sponges, cleaning products and paper tissues.
The quality of our service (villa, furnishings and home) is unanimously recognized, enjoy also: book early 'Heaven Kaz' (6 people) 'Kaz Tibou (4 people)' Kaz Ti punch (4 people ) or 'tightly bonded Kaz' (8 people)!
Our rates are also exceptional ...
Soon, Isabelle and Sylvain
Come stay in Petit-Bourg, green city and regional capital of hiking. Petit-Bourg is the ideal place to discover the Guadeloupe, as the center of the island.
Within a radius of 20km you can discover the Garden Valombreuse, Moreau falls, the Lézarde Jumping, Arm Break Fort, Cascade with Crayfish, Soursop rivers, David Bras, etc., the road of Udders The National Park and its many traces, the Garden of water, Montebello, rum falls of Carbet, Grand Etang, Laura Flessel room, driveway Dumanoir the sailing of Viard (sea kayaking, hobie cat , windsurfing, kite surfing ...)
Nearby cities: Petit-Bourg (5 min), Guava (10 mins), Capesterre-Belle-Eau (15 mins), Baie-Mahault (10 mins), Jarry industrial area (10 mins), Pointe-à-Pitre (15 mins), Les Abymes (15 mins), Gosier (20 mins), St. Anne (35 min).
Tarif toutes charges comprises (eau, électricité, climatisation, télévision satellite, Internet), 1er PDJ offert et linge de table, de lit et de toilette fourni à l'arrivée (sauf draps de plage et de piscine).
Ménage en fin de séjour (optionnel) : 100 euros.
Renouvellement des draps en cours de séjour (optionnel) : 30 euros.
Arrivée possible n'importe quel jour de la semaine.
Accueil le premier jour à partir de 16h30. Départ le dernier jour à 11h au plus tard.


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Legal Question in Real Estate Law in North Carolina
Hi, my wife and I made an agreement (home purchase agreement) to buy her sister's house once we could obtain a loan in our name as we did not have any credit built up. We went to our credit union and they ordered an appraisal on the home and it came back $5,000 less than what she is asking for the home so the credit union will not give us a loan unless we pay the difference. The house appraisal also stated that the home is only considered a 1 bedroom and we were told that it was a 2 bedroom. These major issues have caused my wife and i to decide not to buy the home. Her sister is now threatening to take us to court if we don't buy it. We have already given her 10% down and told her just to keep that money. Can she actually take us to court? We are located in North Carolina. Thanks
2 Answers from Attorneys
I would recommend consulting with a real estate attorney in your area. In order to begin to answer the question, an attorney would need to review the contract signed between you. Also it may be that you are entitled to your earnest money back.
Mr. Rosner is 100% correct, it depends completely on the purchase contract. Hopefully, the comtract was made contingent on you getting a loan. If this is the case, then not only can you get out of it, you should get the 10% back. Have a real estate attorney review the agreement.


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Denzel Washington stars in the revival of August Wilson's powerful drama.
Stephen McKinley Henderson has appeared in eight of August Wilson's 10 plays—including his warm and winning turn as Denzel Washington's best friend in Fences.
The Broadway revival of August Wilson's Fences opens at the Cort Theatre, starring Denzel Washington and Viola Davis.
Photographer: Bruce Glikas,
© Broadway.com


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Cardiovascular diseases, including hypertension and heart failure, are associated with activation of the renin-angiotensin system (RAS) and increased circulating and tissue levels of ANG II, a primary effector peptide of the RAS. Through its actions on various cell types and organ systems, ANG II contributes to the pathogenesis of cardiovascular diseases by inducing cardiac and vascular hypertrophy, vasoconstriction, sodium and water reabsorption in kidneys, sympathoexcitation, and activation of the immune system. Cardiovascular research over the past 15–20 years has clearly implicated an important role for elevated levels of reactive oxygen species (ROS) in mediating these pathophysiological actions of ANG II. As such, the use of antioxidants, to reduce the elevated levels of ROS, as potential therapies for various ANG II-associated cardiovascular diseases has been intensely investigated. Although some antioxidant-based therapies have shown therapeutic impact in animal models of cardiovascular disease and in human patients, others have failed. In this review, we discuss the benefits and limitations of recent strategies, including gene therapy, dietary sources, low-molecular-weight free radical scavengers, polyethylene glycol conjugation, and nanomedicine-based technologies, which are designed to deliver antioxidants for the improved treatment of cardiovascular diseases. Although much work has been completed, additional research focusing on developing specific antioxidant molecules or proteins and identifying the ideal in vivo delivery system for such antioxidants is necessary before the use of antioxidant-based therapies for cardiovascular diseases become a clinical reality.
- antioxidants
- free radical scavengers
- oxidative stress
- cardiovascular disease
- angiotensin
- therapy
cardiovascular diseases rank high among the most common and devastating disorders in adults. The World Health Organization reports that cardiovascular diseases are the number-one cause of death globally, claiming 17.1 million lives per year. According to the American Heart Association and the Centers for Disease Control and Prevention (CDC), ∼67 million adults in the United States have high blood pressure, that is, one in every three American adults. As reported by the National Heart, Lung, and Blood Institute, heart failure affects about 5.7 million people in the United States and is the cause of nearly 300,000 deaths per year. Cardiovascular diseases, like hypertension and heart failure, are commonly associated with increases in circulating and tissue levels of ANG II, which contributes to the cardiac and vascular hypertrophy, inflammation, sympathoexcitation, and oxidative stress observed in these diseases (36, 43, 46, 111). Although numerous therapies have been developed and are used clinically, many have undesirable side effects and are not 100% effective in all patients (40, 80, 104). Recent research efforts using various animal models of cardiovascular disorders, as well as clinical trials, have focused on antioxidant-based therapeutics to alleviate the oxidative stress involved in these diseases. Strategies to deliver antioxidants include gene therapy, dietary sources, low-molecular-weight free radical scavengers, polyethylene glycol (PEG) conjugation, and nanomedicine-based technologies (Table 1). The use of these antioxidant-based therapeutic strategies and their limitations in cardiovascular diseases are discussed in this review.
Renin-Angiotensin System, Reactive Oxygen Species, and Cardiovascular Disease
The renin-angiotensin system (RAS) plays an important role in regulating body fluid and cardiovascular homeostasis, and dysregulation of the RAS is associated with the pathogenesis of cardiovascular disease. The RAS and one of its primary effector peptides, ANG II, is known to exist not only in systemic circulation, but also locally within numerous organs, including the brain (4, 89), heart (4), vasculature (4), adipose tissue (35), gonads (132), pancreas (124), placenta (95), and kidney (4, 65). ANG II binds to its specific G protein-coupled receptors, ANG II type 1 receptor (AT1R) and ANG II type II receptor (AT2R), to induce its (patho)physiological actions. These actions, primarily carried out by AT1R activation, include increased sympathetic output, vasoconstriction, vasopressin and aldosterone release, cellular growth and migration, and sodium and water reabsorption in kidneys. More recently, AT1R signaling has also been shown to cause upregulation of the immune system, particularly T-cell activation, which participates in the development and maintenance of hypertension (79). The AT1R has a wide tissue distribution with high expression in the vasculature, kidney, cardiovascular control brain regions, adrenal gland, and heart. In general, AT2R-mediated actions are thought to oppose those of AT1R.
Production of reactive oxygen species (ROS), such as superoxide (O2˙−) and hydrogen peroxide (H2O2), and modulation of redox-sensitive signaling pathways are involved in the intracellular signaling pathway(s) of ANG II. It is well documented that increased ROS and the resulting oxidative stress in ANG II-associated cardiovascular diseases result from the activation of NADPH oxidases (112, 131), mitochondrial dysfunction (5, 18, 32, 154), and inflammation (38, 47, 78, 79, 122), as well as the reduction of endogenous antioxidant enzymes (17, 42). Nitric oxide synthase (NOS) is another source of O2˙− under conditions where its substrate arginine or cofactor tetrahydrobiopterin are limited, a phenomenon termed NOS uncoupling, which commonly occurs in ANG II-related pathological conditions, such as hypertension, atherosclerosis, and diabetes (87). Regardless of source, O2˙− is removed in the cell by SOD enzymes yielding H2O2 and oxygen, while various other antioxidant enzymes, such as catalase and glutathione peroxidases, work to scavenge H2O2.
The major ROS targets or downstream effectors in the ANG II signaling cascade include transcription factors, ion channels, matrix metalloproteinases (MMPs), kinases, and phosphatases. Redox-sensitive transcription factors, such as NF-κB and activator protein-1, can perpetuate the proinflammatory environment associated with ANG II-related cardiovascular diseases by inducing the expression of proinflammatory cytokines (44, 55, 71). ANG II-mediated increase in ROS, particularly O2˙−, has been shown to modulate ion channel activity, including potassium and calcium channels, which, in turn, regulate neuronal firing and vascular contraction (135, 154, 162). Two potential redox-sensitive targets that may mediate these ion channel activity changes are PKC and CaMKII, which are known to contribute to ANG II-induced modulation of neuronal potassium and calcium currents (135–137). ANG II-induced ROS also have a stimulatory effect on MMPs that regulate the extracellular matrix and vascular remodeling (68). Furthermore, ANG II-induced ROS can affect cell growth and apoptosis through its interactions with MAPK proteins, tyrosine kinases, and tyrosine phosphatases (121, 142). Collectively, these different ROS-sensitive effectors in various cell types work in concert to mediate systemic cardiovascular dysfunction.
Under normal conditions, the rate of ROS generation is balanced by the rate of elimination through endogenous and dietary antioxidants such as SOD, catalase, thioredoxin, glutathione, and vitamins. However, with dysregulation of ANG II signaling, this balance is tilted in favor of elevated ROS, which contributes to cardiovascular dysfunction leading to diseases, including hypertension, heart failure, atherosclerosis, stroke, ischemia-reperfusion (I/R) injury, and diabetes (17, 42, 94, 151, 158). In many cardiovascular diseases, ANG II and ROS induce vascular damage by promoting endothelial dysfunction, structural remodeling, and vascular inflammation (140–142).
Current pharmacological therapies for ANG II-associated cardiovascular diseases include angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), β-blockers, calcium channel blockers, renin inhibitors, statins, and diuretics. ACEi decrease the formation of ANG II, whereas ARBs prevent ANG II from binding to the AT1R. Although they are among the most commonly prescribed drugs for cardiovascular diseases, ACEi and ARBs can induce potential side effects, such as cough, hyperkalemia, and angioedema, and some patients fail to respond favorably to these treatments (52, 100, 110). In fact, according to the CDC, 23.9% of hypertensive patients in the United States (∼16 million people) have uncontrolled hypertension despite being on currently available prescription medications. β-blockers that reduce heart rate (HR) and blood pressure by blocking the effects of norepinephrine and epinephrine are another common therapy for cardiovascular disorders; however, their benefits are often constrained by poor outcomes in human patients due to an exaggerated decrease in HR (29).
To improve upon the current cardiovascular therapies, recent focus has been placed on using antioxidants and free radical scavenging molecules to target the ROS associated with ANG II-related cardiovascular diseases. Antioxidant therapies may have an advantage over current therapies, such as ACEi and ARBs, because of their ability to scavenge ROS generated not only by ANG II, but also by the proinflammatory cytokines that coincide with cardiovascular disease. As discussed below, scavenging ROS in numerous animal models has shown promise as a therapeutic strategy to prevent the development and exacerbation of ANG II-based cardiovascular diseases, but certain challenges must be overcome before antioxidant therapies become a clinical reality.
Gene Therapy and Viral Overexpression of Antioxidant Enzymes
The overall goal of gene therapy is to treat diseases by introducing new genes into a given population of somatic cells for the purpose of changing their cellular function. Typically, a segment of DNA is introduced into cells using a delivery system such as a viral vector. A wide variety of viral and nonviral delivery systems have been developed for the alteration of gene expression in experimental systems, each approach having strengths and weaknesses. Generally, nonviral gene delivery has lower toxicity and immunogenicity, unlimited transgene insertion size, and the ability to transfect both dividing and nondividing cells. However, low transfection efficiencies and lysosomal degradation of nonviral vectors equate to poor nuclear uptake and transgene expression. In contrast, viral vectors efficiently enter the nucleus leading to robust transgene expression; however, they can induce host immune responses and toxicity. Examples of viral delivery systems include recombinant adenovirus, adeno-associated virus, and retrovirus.
Numerous experimental models using adenoviral-mediated overexpression of endogenous antioxidant enzymes clearly indicate the therapeutic potential of such antioxidants. Adenovirally mediated overexpression of SOD (AdSOD) and catalase in the heart provides protection to the myocardium following I/R injury (69, 70, 149). Similarly, intravenous administration of adenovirus encoding CuZnSOD in rats minimizes I/R-induced acute renal failure (155). AdSOD injected directly into key cardiovascular control nuclei of the brain reduces levels of O2˙− specifically in these regions and subsequently decreases blood pressure in hypertensive animal models (17, 160, 161). In a rabbit heart failure model, AdSOD delivery to the carotid body normalizes chemoreflex sensitivity and favorably reduces sympathoexcitation in response to hypoxia (30, 31). Studies have also shown that AdSOD delivery to the brain in heart failure models improves cardiac function and prolongs survival (42, 73, 74). Although adenoviral vectors are excellent experimental tools in cardiovascular disease models, limitations hinder their potential clinical use. For example, adenoviruses may elicit immune responses, limiting their duration of expression in cardiovascular tissues to days or weeks (23, 27). Furthermore, viral vectors tend to accumulate in the liver following systemic administration (i.e., intravenous injection); thus, limiting their uptake and therapeutic potential in cardiovascular tissues (2, 23, 27).
Dietary Sources of Antioxidants
Several clinical studies have reported a correlation between consumption of fruits and vegetables rich in natural antioxidants and decreased risk of cardiovascular disease (123). One such natural antioxidant is water-soluble ascorbic acid (also known as vitamin C) that is present in numerous fruits and vegetables. Ascorbic acid is critical in the prevention of atherosclerotic plaque (83, 130) due to its ability to prevent lipid hydroperoxide formation in plasma lipoproteins, such as low-density lipoprotein (LDL), by reducing α-tocopherol radicals formed upon reaction with lipid peroxyl radicals. Supplemental ascorbic acid, typically administered at supraphysiological concentrations, has been widely studied as an antioxidant in a variety of pathological conditions linked to elevated oxidative stress. In animal models of myocardial infarction, orally administered or locally delivered ascorbic acid reduced the area of infarction and extent of myocardial damage (15, 84). Ascorbic acid has been shown to lower blood pressure in hypertensive (33, 39) and diabetic patients (90). When administered to individuals with chronic lower extremity vasoconstriction, two independent studies have shown marked improvements in lower extremity blood flow of postmenopausal women (88) and healthy older men (53) to levels comparable to younger control individuals. Furthermore, ascorbic acid has been shown to exert protective effects in a rat model of renal I/R injury (63). In contrast, several other studies did not report beneficial effects of ascorbic acid for stroke (64) or endothelial dysfunction (34, 147).
Tocopherol (vitamin E) is a fat-soluble radical-chain breaker found in vegetable oils, nuts, seeds, and leafy green vegetables. Because of its hydrophobic nature, tocopherol operates in a lipid environment providing antioxidant protection in membranes and lipoprotein domains. Data from several cardiovascular studies suggest that tocopherol reduces the risk of cardiovascular diseases, such as coronary heart disease (118, 133, 134). In several animal models and patients with heart failure or myocardial infarction, tocopherol stores are diminished and tocopherol supplementation improves cardiac performance, decreases infarct size, and delays progression to heart failure (28, 49, 102, 107). Tocopherol has also been shown to improve endothelial function and reduce blood pressure (13, 14). Despite its observed benefits in cardiovascular diseases, there have been several unsuccessful clinical trials with tocopherol treatment (56, 75, 144, 157). One limitation with tocopherol as an antioxidant-based therapeutic strategy is that low doses are ineffective but high doses are harmful (123). Another potential problem with tocopherol is that it concentrates in lipoproteins and thus does not interact with cytoplasmic ROS. As discussed above, ANG II and cytokines increase levels of intracellular ROS, which, in turn, mediate signaling pathways in various cell types, leading to cardiovascular dysfunction. To address the affinity for lipophilic environments, a water-soluble analog of tocopherol, trolox, was formulated. In a canine model of myocardial infarction, trolox protected myocyte cell cultures from free radical damage induced by hypoxanthine and xanthine oxidase and reduced myocardial damage (84). In addition, trolox prevented renal failure and improved the glomerular filtration rate following renal I/R injury in rats (148).
Dietary flavenoids, such as resveratrol, naringenin, quercetin, and catechins, are polyphenolic compounds with antioxidant properties that may also work to prevent and/or treat cardiovascular disease. These dietary antioxidants are found in tea, coffee, soy, fruit, vegetables, olive oil, cocoa, cinnamon, oregano, and red wine. Resveratrol was reported to have protective effects in diabetic nephropathy (60), coronary heart disease (150), myocardial infarction (20), hypertension (11), I/R injury (106), and stroke (120). Quercetin is another polyphenol with identified protective effects in a wide range of cardiovascular diseases, including atherosclerosis (61), myocardial infarction (109), cardiac hypertrophy (77), and hypertension (41). In addition to their antioxidant properties, polyphenols have been reported to have antiviral, antiallergic, antiplatelet, anti-inflammatory, and antitumor activities (24, 146). Given the abundance of studies that illustrate the beneficial effects of polyphenols in oxidative stress-related diseases, they appear to be a promising therapeutic strategy; however, more studies must be conducted to decipher the mechanisms and specific site of action and possible harmful effects before validating them as a clinically relevant therapeutic strategy for cardiovascular disorders.
Polyunsaturated hydrocarbon carotenoids are a group of phytochemicals that give many fruits and vegetables their characteristic pigment. They are recognized as critical players in the prevention of human diseases and maintenance of good health. Carotenes (vitamin A) and lycopene are types of carotenoids present in fruits, vegetables, liver, and eggs. Natural carotenes and lycopenes are free radical scavengers in lipophilic environments, such as membranes and lipoproteins (101, 113). Adequate consumption of carotenoids helps prevent cardiovascular diseases, such as atherosclerosis, ventricular remodeling following myocardial infarction, diabetes, and stroke (85, 113, 116). Lycopene supplementation has been shown to be beneficial for I/R injury (6, 48), atherosclerosis (115), long-term diabetic complications (93), and controlling cholesterol and blood pressure (117). β-carotene was reported to protect renal tissues against I/R-induced oxidative damage (50, 51). In spontaneously hypertensive rats, astaxanthin (a water-dispersible synthetic carotenoid)-enriched diet for 8 wk decreased oxidative stress, lowered systolic blood pressure, attenuated left ventricular hypertrophy, and improved endothelial function (86). In renal and hepatic I/R models, astaxanthin treatment reduced I/R injury (25). No adverse effects have been reported for astaxanthin, and it can be administered either orally or intravenously (37). In contrast to these carotenoid studies, many other carotenoid treatment trials have failed to demonstrate cardiovascular benefits and may even show deleterious effects (1, 3, 12, 56). Similar to tocopherol, carotenoids preferentially accumulate in lipophilic membranes; thus, it is tempting to speculate that these dietary antioxidants do not reliably provide protection in cardiovascular diseases because the ROS driving a particular pathology is likely produced in the cytoplasm and is able to exert its detrimental effects even when tocopherol and carotenoid levels are elevated.
Low-Molecular-Weight Free Radical Scavengers
Other antioxidants commonly used in experimental models of cardiovascular diseases are low-molecular-weight free radical scavengers. These are synthetic chemical compounds that often mimic naturally occurring antioxidants. In cardiovascular studies, the most commonly used compound from this group is the cell-permeable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol). Nitroxides like tempol are classified as nonmetal catalytic antioxidants that undergo one- or two-electron reduction reactions, yielding hydroxylamines or oxammonium cations, respectively, which themselves are interconvertible. Although tempol is often called an SOD mimetic because of its ability to catalytically scavenge O2˙−, this nomenclature is misleading because tempol also facilitates H2O2 metabolism through its catalase-like action (99). Nevertheless, several studies have reported that tempol decreases blood pressure in various hypertensive animal models, including high-fat diet-induced hypertension, spontaneously hypertensive rats, salt-induced hypertension, and ANG II-infused rats (9, 21, 76, 126). One major advantage of tempol for clinical application is that it can be administered orally. In fact, in ANG II-infused rats, orally administered tempol attenuated the ANG II-induced hypertension and improved vascular function (145). In rats with myocardial infarction caused by left descending coronary artery ligation, orally administered tempol initiated 4 h after infarction and continued for 6 wk prevented increases in left ventricular end-diastolic pressure, volume, and decreases in ejection fraction. Furthermore, orally administered tempol normalized the increased renal sympathetic nerve activity, plasma norepinephrine levels, and AT1R expression, while favorably attenuating the cardiac sympathetic afferent reflex in these myocardially infarcted rats (127). In a rabbit model of chronic heart failure, tempol reversed the ANG II-mediated NADPH oxidase-driven O2˙− signaling associated with enhanced carotid body chemoreceptor sensitivity to hypoxia (72). In two-kidney, one-clip Goldblatt hypertensive (2K-1C) rats, administration of tempol reduced the mean arterial blood pressure, prevented vascular dysfunction, and improved renal blood perfusion and oxygenation to a greater extent than administration of the ARB candesartan (22, 103). In a rat model of renal I/R injury, tempol treatment was also reported to reduce oxidative stress and cell death in kidneys (19).
Porphyrins, a second class of low-molecular-weight antioxidants, are metal-based catalytic antioxidants that can perform both one- and two-electron transfers and are often referred to as SOD and catalase mimetics. Metalloporphyrins have been shown to possess at least four distinct antioxidant properties, which include scavenging O2˙−, H2O2, peroxynitrite (ONOO−), and lipid radicals. Most metalloporphyrins contain either an iron or manganese moiety that is coordinated by four nitrogen axial ligands. Porphyrins have been successful in preventing the deleterious effects of cardiomyopathy, stroke, diabetes, I/R injury, and other oxidative stress conditions (7, 26). In addition, mangenese(III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP) prevented mitochondrial dysfunction and apoptosis in a rat model of I/R injury (96). A major drawback of porphyrins is that they exert toxicity at high doses (7).
Polyethylene Glycol-Conjugated Antioxidant Enzymes
PEG is an FDA-approved compound, composed of repeating ethylene glycol units, which is commonly used in industrial manufacturing and drug modifications. PEG has several favorable chemical properties that make it useful in various biological, chemical, and pharmaceutical applications. PEGylation delays protein clearance from the body by kidney excretion, phagocytosis by the reticulo-endothelial system, and proteolytic degradation. Furthermore, PEG is nontoxic and nonimmunogenic (143). The structure of PEG is highly flexible, which allows for protein conjugation without steric hindrance or loss of protein function. In addition, PEG is hydrophilic, which allows for increased solubility and decreased aggregation. Given the short half-life of many antioxidant proteins in circulation (98, 105), PEGylation has been shown to improve the circulation time of such proteins, including CuZnSOD (16, 57, 159). PEGylated CuZnSOD (PEG-SOD) has been shown to protect the heart from I/R-induced arrhythmias and reduce the myocardium infarct size following ischemic injury (143). In addition, numerous studies have used direct injection of PEG-SOD into the brain to increase SOD activity and inhibit the pathophysiological actions of ANG II-induced O2˙− (16, 57, 159). Although these direct brain injection studies support the concept that O2˙− contributes to brain angiotensinergic signaling, the clinical impact of PEG-SOD as it relates to neurocardiovascular diseases is quite limited as PEGylation decreases the permeability of proteins across the blood-brain barrier (143, 156), and peripheral administration of PEG-SOD does not significantly increase brain CuZnSOD activity (156). In addition to limited permeability across the blood-brain barrier, the ability of PEGylation to deliver proteins across the plasma membrane of neurons remains unclear. However, PEGylation may enhance delivery of antioxidant proteins to other cell types, such as endothelial cells (10, 81).
Nanoformulated Antioxidant Enzymes
Nanotechnology and nanomedicine-based therapeutics have become hot topics in scientific research. Nanotechnology is the science of changing the intrinsic and extrinsic properties of substances (i.e., shape, charge, hydrophobicity) that are present in both atomic and subatomic sizes for biomedical and engineering applications. The field of nanomedicine uses nanotechnology to address the pharmacodynamic and pharmacokinetic obstacles of pharmacological agents and to improve drug delivery by precise drug release into specified targets. Nanomaterials can be formulated to entrap, encapsulate, or bind agents, such as DNA, proteins, peptides, and low-molecular-weight compounds. As suggested by their name, one of the major advantages of nanomaterials is their size, which is typically in the 1–100-nm range. Because of their small size, nanocarriers can penetrate many physiological barriers, such as plasma membranes. Bound nanomaterials also improve the solubility, stability, and absorption of pharmacological agents. In addition, nanoformulations protect their cargo from clearance by the reticulo-endothelial system, renal system, and proteolytic degradation. Classes of nanomaterials include liposomes, nanoparticles, polymeric micelles, block ionomer complexes, nanogels, quantum dots, dendrimers, nanotubes, and nanofibers. Among these nanocarriers, liposomes and polymer-based nanomaterials are the most widely used systems in drug delivery because these compounds are generally biodegradable, do not accumulate in the body, and have low toxicity and immunogenicity (82).
Several antioxidant nanoformulations have been constructed and investigated for therapeutic impact in cardiovascular diseases, including I/R injury and stroke (58). For example, CuZnSOD protein encapsulated in biodegradable poly(d,l-lactide coglycolide), or PLGA nanoparticles (PLGA-SOD), has shown potential as a therapeutic agent for I/R injury. In a rat focal cerebral I/R injury model, PLGA-SOD administered at the time of reperfusion through intracarotid injection significantly reduced the infarct volume, maintained blood-brain barrier integrity, prevented edema, decreased levels of ROS, and protected neurons from apoptosis (114). Furthermore, the protection from I/R injury afforded by PLGA-SOD increased survival and improved the neurological function of rats exposed to the cerebral ischemia (114). Other nanoformulated antioxidants studied in models of I/R injury are peroxalate nanoparticles, which instantaneously and specifically decompose H2O2, the most abundant ROS generated during I/R injury (66, 67). However, clinical application of peroxalate nanoparticles is hindered by their instability in vivo (66, 67). More recent peroxalate nanoparticle formulations that were generated with p-hydroxybenzyl alcohol (HBA) incorporated into the hydrophobic polymer are more stable in vivo and retain high specificity for scavenging H2O2 (59). Polyoxalate is a commonly used scaffold for the polymeric HBA because of its ease of synthesis, biocompatibility, and complete biodegradation. These HBA-modified peroxalate nanoparticles have strong antioxidant and anti-inflammatory functions (59), and thus, they may have therapeutic potential in various cardiovascular diseases associated with oxidative stress and inflammation.
There have also been studies delivering antioxidants to the heart using nanotechnology for treatment of myocardial oxidative stress and dysfunction. In a monocyte chemoattractant protein-1 transgenic murine model of cardiomyopathy, cerium oxide (CeO2) nanoparticles administered intravenously twice a week for 2 wk markedly inhibited progression of left ventricular dysfunction and remodeling. Furthermore, CeO2 nanoparticle treatment decreased myocardial inflammation, oxidative stress, and endoplasmic reticulum stress (97). In other studies, poly(cyclohexane-1,4-diyl acetone dimethylene ketal) polymer was used to deliver CuZnSOD to the heart. These CuZnSOD polyketal particle-encapsulated microparticles (PKSOD) injected into the perimeter of the cyanotic ischemic zone scavenged excess O2˙−, prevented myocyte apoptosis, and improved cardiac function in a rat model of myocardial I/R injury (125). Although these PKSOD microparticles were not in the nanometer-size range, they could potentially be reformulated to afford the benefits of nanomedicine, including a more clinically relevant and noninvasive route of administration than direct myocardial injection. Another study using polyketal polymers for sustained release of drugs with self-assembling nanofibers reported that these multifunctional scaffolds could be used to deliver antioxidants to rat models of myocardial infarction (139).
Another focus of nanomedicine research is the delivery of antioxidants to the central nervous system for the treatment of ANG II-dependent neurocardiovascular diseases associated with oxidative stress, including hypertension and heart failure. Our laboratory is currently investigating the therapeutic potential of a polyethyleneimine-polyethylene gycol, PEI-PEG, polymer that electrostatically binds to CuZnSOD (so-called CuZnSOD nanozyme) to deliver CuZnSOD protein to the brain for treatment of neurogenic hypertension. We recently reported that CuZnSOD nanozyme delivers functional CuZnSOD protein to neurons resulting in an attenuation of ANG II-mediated O2˙− production and potassium channel inhibition without inducing significant cytotoxicity (119). In the same study, we also reported that a single intracarotid injection of CuZnSOD nanozyme inhibits the central ANG II-induced pressor response for up to 3 days (119). More recently, various polymers have been developed to increase the bioavailability of CuZnSOD nanozyme and extend the therapeutic impact beyond 3 days. Specifically, our second-generation nanozymes are composed of a highly positively charged polymer, poly-l-lysine (PLL). PLL is covalently bound to PEG to form a cationic block copolymer that is capable of electrostatically binding to negatively charged carboxyl groups on CuZnSOD protein. The second-generation nanozyme is synthesized, such that the complex retains a collective neutral charge at physiological pH. Furthermore, second-generation nanozymes are synthesized with increased levels of stability due to cross-link bonds between the PLL polymer chains (Fig. 1). Klyachko et al. (62) identified an advantage for cross-linking polymers when delivering nanoformulated complexes in vivo. Data from this study showed that mice that were given cross-linked nanozyme had significantly higher levels of CuZnSOD in the brain and blood 1 h following intravenous injection compared with non-cross-linked complexes. Thus, there has been a movement in the nanomedicine industry to synthesize cross-linked polymers to enhance protein delivery to the brain and increase circulation time of polymers in the blood. Importantly, cross-linking our second-generation nanozyme does not alter CuZnSOD activity, and complexes with either reducible or nonreducible cross-linked bonds are able to scavenge O2˙− to the same extent as non-cross-linked CuZnSOD nanozymes and free CuZnSOD protein (Fig. 2).
In addition to our nanozyme formulations, CuZnSOD protein conjugated to poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer (Pluronic-SOD) has also been shown to scavenge intracellular O2˙−. Pluronic-SOD delivers active CuZnSOD protein to neurons and inhibits ANG II-induced intraneuronal signaling (153). Notably, it has been demonstrated that pluronic-modified proteins are able to cross the blood-brain barrier and may subsequently become a primary therapeutic candidate for cardiovascular diseases associated with elevated O2˙− levels in the brain (8, 54, 108, 152).
While our group has focused on the delivery of nanoformulated antioxidants to the brain, others have targeted the vascular endothelium for treatment of the vascular oxidative stress and inflammation implicated in the pathogenesis of many cardiovascular diseases. Polystyrene or PGLA polymer nanocarriers have been used to deliver SOD and catalase to the vascular endothelium (91). To improve vascular specificity, SOD and catalase were conjugated to antibodies directed against constitutively expressed endothelial antigens, such as intercellular adhesion molecule-1 (ICAM-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1), so that these enzymes would bind to the endothelium following intravascular administration. In addition to augmenting antioxidant defenses, Muzykantov and colleagues propose that this immune-targeting strategy may have the added benefit of reducing inflammation and leukocyte-mediated vascular damage by blocking ICAM-1 and PECAM-1 uptake (92, 129, 138). PECAM-targeted SOD nanocarriers were successful in reducing vascular inflammation (128), while both the immunity-targeted SOD and catalase nanocarriers prevented ROS-induced vascular hyperpermeability (45). The advantageous properties substantiate the therapeutic potential of immune-targeting strategies for tissue edema. Although nanotechnology is a seemingly promising field, it is still a relatively new and developing area of study, especially in the field of cardiovascular research and requires further investigation and several improvements. Nanomaterials not only act on cells to produce biologically favorable effects but may also generate adverse effects. The risks and benefits of exposure to nanomaterials, routes of entry, molecular mechanisms of action, and potential cytotoxicity need to be further studied and better understood, especially with regard to clinically relevant treatments of cardiovascular diseases.
Perspectives and Significance
Cardiovascular diseases, particularly involving enhanced ANG II signaling, are associated with oxidative stress, resulting from overproduction of ROS and reduced levels of antioxidant activity. Several studies have investigated the ability of various antioxidants to treat and lower the risk of cardiovascular diseases. Gene therapy, dietary antioxidants, low-molecular-weight free radical scavengers, PEGylation of antioxidant proteins, and nanoformulated antioxidant delivery systems have all been examined for the treatment of ANG II-associated cardiovascular diseases (Fig. 3). Although many studies have shown significant therapeutic potential for antioxidant formulations, others have failed to reveal any beneficial effects. Lack of interaction between the therapeutic antioxidant and specific ROS driving the pathological condition may account for the inability of some antioxidant strategies to improve cardiovascular function. Specifically targeting tissues, cells, and subcellular locations where the oxidative stress occurs will likely improve the efficacy of these antioxidant treatments. Another possible reason for the ineffectiveness of antioxidant therapy could be that the antioxidants are administered too late for successful intervention when extensive pathology is present, whereas successful trials involve antioxidants administered early in the disease progression or as a preventative therapy. Alternatively, antioxidant interventions may fail due to incorrect dosing or inappropriate biomarkers of oxidative damage. Given the recent finding that ANG II signaling activates the immune system, which further fuels the oxidant fire, it is reasonable to continue promoting investigation of antioxidant-based therapeutic strategies for cardiovascular diseases.
The authors' original research incorporated into this review was supported by grants from the National Institutes of Health (R01 HL-103942, P20 GM103480, and P20 RR-017675 to M. C. Zimmerman; and F31 NS-073398 to E. G. Rosenbaugh). We acknowledge the assistance of the Nanomaterials Core facility of the Center for Biomedical Research Excellence (CoBRE) Nebraska Center for Nanomedicine supported by the Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103480.
No conflicts of interest, financial or otherwise, are declared by the authors.
Author contributions: E.G.R., K.K.S., and M.C.Z. conception and design of research; E.G.R., K.K.S., and M.C.Z. interpreted results of experiments; E.G.R., K.K.S., and M.C.Z. prepared figures; E.G.R. drafted manuscript; E.G.R., K.K.S., and M.C.Z. edited and revised manuscript; E.G.R., K.K.S., and M.C.Z. approved final version of manuscript; K.K.S. performed experiments; K.K.S. analyzed data; D.S.M. synthesized and characterized the CuZnSOD nanozymes used in Figure 2.
We acknowledge assistance from Dr. Alexander Kabanov in the synthesis of the CuZnSOD nanozymes that were used in Figure 2. The synthesis and characterization of these nanozymes were originally described in Manickam DS, et al. J Control Release 162: 636–645, 2012.
- Copyright © 2013 the American Physiological Society
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text:
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For Non-Profit Organizations (free of charge or fee for service)
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There's only one word that can describe the Serra Little League 10-year-old all-stars: Champions. The squad downed all comers in the District 44 All-Star Tournament, ending with a perfect record of 5-0.
Serra finished the tournament with a 5-2 win over Los Altos, and it was one of the closest battles of the tournament.
Los Altos got on the board eaerly, scoring a run in the top of the first inning.
Many 10-year-olds could have gotten down after allowing a run in the first, but not Serra. The 'stars picked up their bats and rallied for three runs to grab the lead.
Malcolm Hsu, who was pitching for Serra, blasted a one-out single to center, Blake Rogers knocked a single and Gilbert Murillo smacked a hit to left that drove in both runners. Murillo moved to second on a Ryan Lee base hit and then scored when Matt Merino reached on a fielder's choice.
In the bottom of the second Rogers crushed a ball off the wall for a two-run homer.
Los Altos scored in the fifth, and threatened again in the sixth with runners on first and second. Murillo broke the Los Altos spirits, though, when the batter knocked a line drive to center and he snagged the ball off one hop and fired it to third to force the advancing runner. Serra was able to finish the win without any more damage.
Hsu went four innings to the get mound win and Naoto Kataoka picked up the with a scoreless sixth inning. Hsu also led the club at the plate, going 3 for 3 and scoring twice.
After winning the District 44 tournament, Serra advanced to the Section 5 tournament held in Aptos. The winner of that tournament goes on to the Little League Northern California Championships.
Serra announced its presence in the district tourney with authority, crushing Sunnyvale Southern 11-1 in the opening game of the tournament. Devin James blasted an inside the park homer.
The second game in pool play really sealed the fact that Serra had what it took to go the distance. Serra trailed Santa Clara Homestead 9-1, but rallied for 11 unanswered runs. Lee went 3 for 3, blasting two doubles and driving in five runs.
Serra kept its offensive onslaught working in the third game of the tournament when it rolled over Moreland 12-2. Rogers smacked two doubles and drove in four runs. He also scored three times in the win.
After going 3-0 in pool play, Serra faced Westside in the semifinals and downed Westside 4-3 in a tight pitcher's duel. Justin Walker tossed 3 1/3 innings, allowing only one run, for his second win in the tournament.
Ryan Ohara and Roy Chang knocked the ball all over the yard and led a rally in the third inning that accounted for three of the four runs for Serra.
Hsu finished the District 44 tournament hitting .533, while Rogers and Lee crushed three doubles apiece. Rogers and Walker finished with two wins each on the mound and Kataoka had two saves.
The complete roster for the Serra 10-year-old all-star team includes Kataoka, James, Jacob Tang, Ohara, Matt Merino, Walker, Josh Willis, Roy Chang, Lee, Murillo, Hsu and Rogers.


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Thanks. There shouldn't also be tropical birds in the sky and a traditional band from Pernambuco state/Brazil. Militão dos Santos is a deaf painter who was born poor and make his art by himself. Fishing is a way to survive in Brazil Northest.
A lovely puzzle but surely there should not be fish on the table.


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Australia Says ASEAN Nations Keen on New Climate Pact
MELBOURNE Southeast Asian countries have expressed interest in joining a new U.S.-led partnership to cut greenhouse gas emissions by developing technology and economic incentives, Australian Foreign Minister Alexander Downer said.
The Asia Pacific Partnership on Clean Development and Climate between Australia, the United States, China, Japan, South Korea and India was unveiled at an Association of South East Asian Nations (ASEAN) forum in Laos last week.
"The ASEAN governments were asking me whether it would be possible for them to join this partnership in time," Downer said on Australian television on Sunday.
"And I made it clear that once we've worked out how we want it all to come together, we, in principle, would be very happy to see ASEAN countries become involved because their economies are growing and they're significant emitters as well," he said.
Unlike the Kyoto climate agreement, which requires cuts in greenhouse emissions by 5.2 percent below 1990 levels by 2008-12, the Asia-Pacific partnership has no time frames or targets.
"We hope that we'll start to get results under our partnership fairly quickly," Downer said.
"That's going to require collaborative research. It's also going to mean we'll have to investigate price signals coming from energy."
Downer said the work would probably be paid for jointly by governments and the private sector.
The six founding partners of the new pact account for 45 percent of the world's population, 48 percent of the world's greenhouse gas emissions and 48 percent of the world's energy consumption.
The United States and Australia are the only developed nations outside Kyoto. Both say Kyoto, agreed to in 1997, is flawed because it omits developing states.
The United Nations' Intergovernmental Panel on Climate Change (IPCC) has said world temperatures are likely to rise between 1.4 and 5.8 degree Celsius (2.5-10.4 degree Fahrenheit) by 2100, linked to the build-up of greenhouse gases from human activities.
Source: Reuters


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text: Kuwait hungry for Australian food products RSS Feeds 02 Mar 2016 Recent high-profile events in Kuwait showcasing Australian food have highlighted the growing opportunities for Australian producers and suppliers. In February, Kuwait's largest independent retailer and supplier of fresh food The Sultan Center (TSC) held an Australian Food Festival to promote more than 1,000 Australian products at key TSC stores. Australian brands included in the showcase included Australia's Own, Carman's and Bundaberg. Makram Malaeb, Commercial Director of TSC, said that Australia is now the third largest source of imported products for the supermarket chain. In a TSC media release, Malaeb said: 'Given Australia's natural resources, it's no surprise that it produces some of the world's best quality agricultural, dairy and meat products.' TSC's Australian range includes Wagyu beef, veal, organic lamb and beef, fruits and vegetables, bakery items, dairy products, frozen foods, dry foods, beverages, confectionery and more. 'The Sultan Center is looking to grow the number of Australian products in its stores, especially fresh produce, organic goods and gluten-free products, opening up opportunities for Australian food producers in these categories,' said Jack Hajjar, Trade Commissioner, Austrade Kuwait. Australian meat was the centre of attention at another event in Kuwait. Australian Meat & Livestock Australia (MLA) hosted an evening reception with celebrity chef Tarek Ibrahim, its brand ambassador for the MENA region. Ibrahim prepared dishes featuring Australian beef and lamb for more than 60 representatives from the Kuwaiti hospitality and food service industry and government. 'There is strong demand for Australian meat in Kuwait and the Middle East due to its high quality,' said Hajjar. 'Australia's halal licensing and regulation system is also well regarded in the region.' Australian food companies and organisations also had a large presence at Gulfood, one of the world's largest food and beverage trade events, held in Dubai in late February. The Australian Food Pavilion hosted government organisations from New South Wales, Queensland, South Australia, Victoria and Western Australia. Around 150 companies including Fletchers, Murray Goulburn, Wellard and Warrnambool Cheese and Butter also attended the event, as well as industry groups such as Meat & Livestock Australia and Food Innovation Australia. The Austrade showcase at Gulfood hosted 200 importers, suppliers and distributors. Austrade also introduced Australian attendees to potential clients and partners, and participated in food security seminars and networking events showcasing Australian products. 'Australian businesses should take advantage of Australia's reputation as a clean, fresh and reliable supplier of food to enter or expand into Kuwait and other Middle Eastern markets,' said Hajjar. 'There is genuine interest in and respect for our products among consumers, retailers and distributors in the region.' Read more about doing business in Kuwait or call Austrade on 13 28 78 or email firstname.lastname@example.com.


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Brandeis Study Abroad Account
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Want to learn more about studying abroad with a major in Psychology? Contact a Study Abroad Ambassador for more information.
Study Abroad
The Department of Psychology offers students the opportunity to establish a strong scientific and research foundation in psychology, which prepares them to be thoughtful and discerning problem solvers. The program examines the most up-to-date and comprehensive psychological research and theory and provides opportunities for direct involvement in its application to clinical, mental-health, business, educational, and other settings.
Psychology students are encouraged to take advantage of study abroad opportunities. Why not complete your psychology coursework while also acquiring relevant professional skills such as proficiency in a foreign language and cross-cultural awareness?
1. Can I receive Psychology credit for courses taken overseas?
Yes, as long as your chosen courses are comparable to Psychology courses offered at Brandeis and are approved by the department.
2. Is it possible to take "core" courses abroad?
We encourage students to take their core courses at Brandeis. In particular, for those contemplating study abroad, it is strongly recommended that they take their core courses before going abroad. In the special case of someone who begins the major late, permission is sometimes given to take one (but only one) of the core courses abroad.
3. How can I be sure if a class I take abroad will count towards my Psychology major at Brandeis?
Before going abroad, you can find out whether a specific course will or will not count as a Psychology requirement by speaking with and submitting a syllabus for the relevant course(s) to the Study Abroad Liaison in Psychology.
Sample of Approved Programs with Psychology Coursework
- CIEE/ University of Cape Town (UCT)
Cape Town, South Africa
- DIS/ Psychology
Copenhagen, Denmark
- IFSA-Butler/ Mendoza Universities Program
Buenos Aires, Argentina
Visit the Brandeis Approved Programs List to review a comprehensive list of programs that offer Psychology coursework.
Psychology Study Abroad Liaison
To assist students with their academic choices abroad and to help answer any questions about receiving major credit while abroad, each academic department and program has assigned a faculty member to serve as the study abroad liaison. Psychology majors who plan to study abroad should speak with the study abroad liaison before they go abroad, and again once they have returned from study abroad.
The liaison for Psychology is Prof. Joseph Cunningham.
Receiving Credit in Psychology
Students wishing to receive Psychology credit for work done off campus during the academic year should discuss their desired coursework with their study abroad liaison for Psychology. After returning from abroad, and after the course credits have been posted to your SAGE account, complete the electronic Petition to Request Substitution for a Requirement form.
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Visit the Study Abroad Financial Information page to read more about funding your study abroad experience.


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Use iOS folders to have a minimalist and icon-free iPad homescreen
If you're a fan of minimalist desktops and you have an iPad, you'll like this trick. Drag your favorite homescreen apps into a folder, rename it something useful, throw that folder into the iPad's Dock, and enjoy your homescreen free of any icons.
This tip would work the same on an iPhone or iPod touch too. You can also do this on your Mac by hiding all desktop icons and then keeping an apps and ~/Desktop folder in your Dock.
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Last year, wide receiver Demarre Kitt (Tyrone, Ga./Sandy Creek) emerged as one of the top young playmakers in Georgia, making 42 catches for 651 yards and 10 touchdowns. The 6-foot-1, 185-pound junior has continued where he left off, making nine catches for 244 yards and two touchdowns in two games this season. Nevertheless, the University of Georgia commitment expected more from his performance against Newnan last Friday.
"I had four catches but I dropped the first pass thrown to me," Kitt said. "I played OK but I did not really play my real game today."
Last month, Kitt attended a game played nearby in Atlanta between two out-of-state programs.
"I went to the Auburn vs. Clemson game at the Georgia Dome and that was probably the loudest game I have ever been to," Kitt said. "I sat in the front row and it was pretty hype. But I sat on the Auburn side, so everyone wanted me to cheer for Auburn. I was just neutral."
One of those programs is making a push for Kitt to reconsider his commitment to the Bulldogs, which he made back in April.
"Clemson is recruiting me really hard and I really get that offense," Kitt said.
Last weekend, Kitt made a trip to Clemson to see the Tigers take on Ball State. After his return, he updated where things stood with his recruitment.
"Nothing has changed," Kitt said. "Georgia has been messaging me and sending me letters since Sept. 1, so they are still on me and it looks like they still want me. They have been on me as much as other programs since I committed. It feels like home at Georgia and their pro-style offense is similar to what we do here at Sandy Creek, so I could learn plays easily there too."
An advantage Kitt has over most wideouts is the chance to go up against an ESPN 150 cornerback every day. Kitt says he does considerably well against the fellow Georgia commitment.
"I win probably 90 percent of my battles against Shaq Wiggins (Tyrone, Ga./Sandy Creek) in practice," Kitt said.
But Kitt said Georgia fans need not worry about the ability of Wiggins at the next level.
"I am just that good," Kitt said.


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(Reuters) – Phase I study results suggest that Pfizer Inc's lung cancer drug crizotinib (Xalkori) may be a highly effective treatment for children with a rare but aggressive type of lymphoma and other cancers, according to data from an early stage study released on Wednesday.
Crizotinib is approved to treat non-small cell lung cancer in patients with a specific mutation in the anaplastic lymphoma kinase (ALK) gene. But some patients with other types of cancer have also been found to have abnormal ALK.
The study included 70 children whose various cancers had progressed despite standard therapies. Determining the safety of crizotinib in children was the primary goal of the phase I study that tested the drug at several doses.
The trial, however, was not restricted to patients with known ALK abnormalities and was open to those with certain cancers that had relapsed or did not respond to other treatments, researchers said. Going forward, further studies will include only children with the ALK mutations, researchers say.
Of the 57 children in the study who could be fully evaluated for drug toxicity, toxic side effects were deemed to be minimal, even though many of the crizotinib doses tested were relatively high, according to a statement issued by the study team.
"The drug was exceedingly well-tolerated. Most toxicities were extremely low grade and did not impact quality of life," Dr. Yael Mosse, the study's lead researcher from the Children's Hospital of Philadelphia, told reporters on a conference call.
The studied doses ranged from 100 mg to 365 mg, taken twice a day for 28-day cycles. Based on the study findings, researchers determined that the recommended dose for children in future studies will be 280 mg, roughly twice the adult-recommended dose.
The data will be presented at next month's ASCO meeting in Chicago, but were released on Wednesday along with summaries of hundreds of other studies that will be featured at the year's most important cancer meeting.
Eight children in the study were suffering from anaplastic large cell lymphoma (ALCL), and seven of the eight had a complete response to the drug, with follow-up of up to 18 months.
The study also tested crizotinib in 27 children with neuroblastoma and in seven children with inflammatory myofibroblastic tumors (IMT).
Two of the neuroblastoma patients had a complete remission and eight had stable disease. The most demonstrable response in neuroblastoma was seen at the higher doses, researchers said. "These responders have remained on therapy for between 9 months to more than two years without progression – a notable finding given that most heavily pre-treated neuroblastoma patients on a Phase I trial experience cancer progression in 1 to 2 months," the research team said in a statement.
The majority of the seven IMT patients experienced substantial benefit, ranging from tumor shrinkage to complete tumor regression, researchers found. These responses have lasted up to two years so far. No other available anticancer therapies are effective in this disease, according to the investigators.
Dr. Michael Link, president of the American Society of Clinical Oncology (ASCO) and a pediatric oncologist, characterized the response rates as "pretty phenomenal." He was not involved in the research.
"The durability of the response is pretty amazing," he said.
"In ALCL this is dramatic activity. In neuroblastoma there's still a lot of work to be done to identify the patients likely to benefit," Dr. Mosse said.
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At Eden Park
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At Eden Park
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With a stay at At Eden Park in Auckland (Mount Eden), you'll be minutes from Eden Park and close to Mt. Eden. This aparthotel is close to Sky Tower and University of Auckland.
Make yourself at home in one of the 10 air-conditioned rooms featuring refrigerators and microwaves. Wired and wireless Internet access is complimentary, while 32-inch LCD televisions with cable programming provide entertainment. Private bathrooms with showers feature complimentary toiletries and hair dryers. Conveniences include desks and minibars, as well as phones with free local calls.
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Make use of convenient amenities such as complimentary wireless Internet access, a television in the lobby, and tour/ticket assistance.
Business, Other Amenities
Featured amenities include complimentary newspapers in the lobby, dry cleaning/laundry services, and luggage storage. Free self parking is available onsite.
Hotel Facilities
- Parking (limited spaces)
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- Total number of rooms - 10
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Room Facilities
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Know Before You Go
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Event Details
Car-Free Diet at Pentagon Centre
Friday, October 24, 2014
The Car-Free Diet gang will be at Pentagon Centre to answer all your questions about taking transit, walking or biking. You could even win a prize by playing our Transit Trivia game.
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Click here for car-free options from Car-Free Near Me.


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Bad news for Marc Jacobs fans. After reports surfaced in fashion circles on Friday, the American designer has confirmed his diffusion line Marc by Marc Jacobs will be discontinued.
The offshoot brand, loved for offering Jacobs' signature quirky styles at more affordable prices, will be folded into the main collection as part of the designer's expansion plan. So, the lower price points aren't disappearing entirely.
"In a sense, we're starting at the beginning," Jacobs explained to WWD.
"The intention now is no different than when Robert [Duffy] and I started Marc by Marc Jacobs or Marc-no-Jacobs" (the nickname he used to give his label).
"We believed that fashion could exist at lots of different prices. It could be flip-flops for $30, a well-priced T-shirt; there could be an honesty and integrity in different types of clothes. It wasn't supposed to be a second line or the poor-relative-of."
Jacobs added, "I think as myself as a fashion customer, and I know on a daily basis I will wear everything from American Apparel to Adidas to Marc Jacobs to Prada. I love that mix of things, that high and low, that rich and poor, all of those contrasts, the everyday and the extraordinary."
This news follows the announcement that Marc Jacobs will go public later this year.
As for MBMJ duo Katie Hillier and Luella Bartley? Vogue reports creative director Hillier will stay on at the company, while it's unknown whether womenswear designer Bartley will take up another position.
Love this brand? Here's a reminder of the S/S 15 collection:


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SPANISH FORK — Kali Thomson wanted to make the most of her final season of high school softball.
"My goal at the beginning of the year was just to prove myself," the senior said after she led top-ranked Manti over defending 2A state champion San Juan 10-1."I really wanted to be the best I could. So I ended up working out more. I trained every day, I still work out. It was a lot of hard work by myself."
It's paid off as Thomson has led the Templars to a 25-1 season and a berth into the state champion game Saturday afternoon. The biggest difference is in her confidence. "I'm no longer worried about getting strikes or balls," she said. "I'm focused on ball movement. Even when teams are hitting me, I don't worry about it because I know I can control it."
That was certainly the case Friday night as the Templars continued their domination of the 2A state softball tournament with a victory over San Juan. The Templars have scored 53 runs and given up only three runs to opponents.
"I didn't realize it was that much," said Manti head coach Susan Hatch. That's because the team focuses only on the most immediate task. "You've just got to focus on each game, on each inning," she said. "We also talked about staying consistent throughout the game — offensively and defensively."
The Templars had 16 hits to the Broncos' five hits. Not only did they put the ball in play, but they ran the bases aggressively, taking risks that often paid big rewards. The Broncos' only run came when Kellie Palmer hit a home run in the sixth inning, while the Tempars scored in every inning except the sixth.
Mikaela Cox hit two triples and went 3-for-5, while Lizzy Palmer hit a double in the win. The Broncos struggled at the plate, but they also made some costly fielding errors. Hatch said she told her players to relax and have fun. "They play better when they're relaxed," she said. "In fact, they seemed more calm today than yesterday."
Before the game that decided which team entered the 2A title game unbeaten, the Templars were signing and joking as they waited to warm up. "We're not looking ahead," said Thomson. "We're looking at the now."Comment on this story
Thomson said the team feels comfortable and confident in themselves and each other. "We have strong team unity," she said. "We're not afraid to sing out loud. We know we play better when we're having fun."
South Summit defeated Emery 8-2 to earn a shot at San Juan in Saturday morning's elimination bracket semifinal. The winner of that game will face Manti for the championship at 12:15 at the Spanish Fork Softball Complex. Manti defeated Enterprise 15-0 in Friday's first round, while San Juan beat Gunnison 16-4.
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I'm best man for my brother and taking him to Hamburg for his stag do in December. Does anyone in the collective know of any choice drinking establishments in order to send him off in good style? Stylish places with a view/good beer/proper German style beers?
Cheers in advance
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Hamburg- anyone know the good drinking spots?
I'm best man for my brother and taking him to Hamburg for his stag do in December. Does anyone in the collective know of any choice drinking establishments in order to send him off in good style? Stylish places with a view/good beer/proper German style beers?
Nobody goes to Hamburg for a stag do for "Stylish places with a view/good beer/proper German style beers" it's all about the Reeperbahn, so stop pretending otherwise.
I highly recommend this place: http://www.groeninger-hamburg.de/
Get the keg of beer with the Brewers Feast. We went there for a stag do and had an awesome time.
Otherwise you can't go far wrong in St Pauli.
I should add, don't go anywhere near a place called Eros. There be dragons.
Ideal! We are there for two days, probably take in a football game as well as hamburg are playing at home . But the main reason is for drinking quality beers in a pleasant town...oh and gluvine and sausage in the Christmas markets too
You might want to book a table if there's a lot of you.
Reeperbahn is awesome as is whole of St. Pauli area. If the Dom is in town you can kill an hour or 2 there as well. Be careful at the footy though as FC Hamburg have some shall we say rather extreme fans. Would have been better if St. Pauli were at home.
Dare I ask about euros?
What's the Dom?
If week go to the footsie would it be an idea to all have hamburg scarves on?
Cheers for the tip about booking
The Dom is a large travelling funfair but as it's german has huge beer kellers on it. Another good one is the fish market which has a huge beer keller which is open all night until the trawlers come into port. You will be fine at the footy just keep your eyes open.
I went to hamburg on a stag do 2 years ago, awful place, dirty and very seedy. Cancel it and go somewhere else would be my recommendation. There is however a 'british' pub on the little square, you'll find it don't worry. It shows UK footy, very funny coz when I went with a load of wednesday fans the only match on was a blades one and they all sat watching it, they they starting singing 'I'd rather be a (person from pakistan) than a blade,' nice group.
We took in a HSV match while we were there and it was fine. We were sat up in the gods. Think the ultras go behind the goals. All good though.
Hamburg is an awesome place. The Reeperbahn is obviously really very sleezy, but rather amusing for a quick visit on the way to St Pauli.
+1 jekkyl
Stag do in Hamburg last year-reeperbahn is awful, tacky, full of tourists, the beer is a ripoff and the strip clubs are full of horrid ugly strippers who want a 150 euro for a 10 minute dance.
I went 5 years ago, not on a stag do, and found the student area great though, and the city is nice if a little bleak and cold.
One final point, if it's strippers and sleaze you actually want then avoid Hamburg and go to far cheaper, less developed countries (the usual suspects) but if you really do want a classy night out there are lots better cities in Germany.
Berlin? Munich?
Amsterdam ! Prague !
I know Amsterdam's a cliche and everyone's been there but it is really nice and can provide all the stag do needs. I had my stag do in Prague, had a great time. We did a days shooting experience + you have access to all the strip bars and underground bars. Also went to a Jazz bar for the last evening, there was a jazz quintet on, utterly awesome.
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